The social life of natural experiments in epidemiology and public health.

Over the twentieth century, the concept of the natural experiment has become increasingly prominent across a variety of disciplines, albeit most consequentially in epidemiology and public health. Drawing on an analysis of the scientific and medical literature, we explore the social life of the natural experiment, tracing its changing use, meaning and uptake to better understand the work done by the concept. We demonstrate how the natural experiment became central to the identity of post-war epidemiology as the discipline professionalised, turned its attention to the prevention of chronic disease and took centre stage in the field of public health. We then turn to its growing significance amid the rise of evidence-based medicine, and the new meanings natural experiments came to take on in the context of concerns about policy and evidence. Finally, we turn to the newest iteration of the natural experiment in the COVID-19 era, which saw an explosion of studies drawing on the term, albeit in ways that reveal more about the underlying politics of health than the method itself. Throughout, we illustrate that the concept of the natural experiment has always been fundamentally social and political and tied to disciplinary claims-making about evidence and what should count as such.

Scholarly Publishing, Boundary Processes, and the Problem of Fake Peer Reviews.

Over the past decade, the phenomenon of "fake" peer reviews has caused growing consternation among scholarly publishers. Yet despite the significant behind-the-scenes impact that anxieties about fakery have had on peer review processes within scholarly journals, the phenomenon itself has been subject to little scholarly analysis. Rather than treating fake reviews as a straightforward descriptive category, in this article, we explore how the discourse on fake reviews emerged and why, and what it tells us about its seeming antithesis, "genuine" peer review. Our primary source of data are two influential adjudicators of scholarly publishing integrity that have been critical to the emergence of the concept of the fake review: Retraction Watch and the Committee on Publication Ethics. Via an analysis of their respective blog posts, Forum cases, presentations, and best practice guidance, we build a genealogy of the fake review discourse and highlight the variety of players involved in staking out the fake. We conclude that constant work is required to maintain clear lines of separation between genuine and fake reviews and highlight how the concept has served to reassert the boundaries between science and society in a context where they have increasingly been questioned.

Association of strength, power, and function with muscle thickness, echo intensity, and lean tissue in older males.

Dual-energy X-ray absorptiometry (DXA) appendicular lean tissue is used to screen older adults for sarcopenia. However, emerging data indicates that ageing-related muscle atrophy largely occurs within specific muscles, which may be masked using appendicular lean tissue. Comparisons between appendicular lean tissue and site-specific measures of muscle in relation to strength and physical function are needed to advance our understanding of these features in the context of poor muscle function in aged adults. Our primary objective was to compare correlations between lean tissue and site-specific muscle characteristics in relation to strength and physical function in older males. Older males (≥65 years) were evaluated for muscle strength, physical function (6-minute walk and 30-second sit-to-stand), and muscle size (appendicular and site-specific) and composition (echo intensity) using DXA and ultrasound. Of the 32 older males (75.4 ± 7.9 years), 12 had low appendicular lean tissue. All DXA and ultrasound muscle characteristics were associated (r = 0.39 to 0.83, p < 0.05) with torque or power producing capabilities. Except for the knee flexors, no differences in correlation coefficients were observed between muscle thickness or regional lean tissue in relation to muscle strength. Neither DXA nor ultrasound muscle characteristics were associated with physical function. In older males, ultrasound-based muscle thickness and DXA lean tissue provided similar associations with strength. Novelty: Lean tissue and muscle thickness provide similar associations with strength. Muscle thickness can distinguish low and normal appendicular lean tissue in older adults.

Altered features of body composition in older adults with type 2 diabetes and prediabetes compared with matched controls.

BACKGROUND: Ageing is accompanied by muscle loss and fat gain, which may elevate the risk of type 2 diabetes (T2D). However, there is a paucity of data on the distribution of regional lean and fat tissue in older adults with T2D or prediabetes compared with healthy controls. The objective of this study was to compare regional body composition [by dual-energy x-ray absorptiometry (DXA)], muscle and subcutaneous adipose tissue (SAT) thicknesses (by ultrasound), and ultrasound-based muscle texture features in older adults with T2D or prediabetes compared with normoglycaemic controls. METHODS: Eighteen adults > 60 years with T2D or prediabetes (T2D group) were individually matched to normoglycaemic participants [healthy matched (HM) group] for age (±5 years), sex, and body fat (±2.5%). In a single study visit, all participants received a whole-body DXA scan and ultrasound assessment of the abdomen and anterior thigh. At these two landmarks, we used ultrasound to measure muscle and SAT thickness, as well as texture features of the rectus femoris and rectus abdominis. We also conducted an exploratory subanalysis on a subset of participants (n = 14/18 in the T2D group and n = 10/18 in the HM group) who underwent additional assessments including strength testing of the knee extensors (using a Biodex dynamometer), and a fasting blood sample for the measurement of circulating markers of glucose metabolism [glucose, insulin, c-peptide, and the homoeostatic model assessment of insulin resistance (HOMA-IR)]. RESULTS: The T2D group was 72 ± 8 years old (mean ± SD), predominantly male (n = 15/18; 83%), and overweight (BMI: 27.8 ± 4.2 kg/m2 , 33.2 ± 5.3% body fat). DXA-derived upper arm lean mass was 0.4 kg greater (P = 0.034), and leg fat mass was 1.4 kg lower (P = 0.048), in the T2D vs. HM group. Ultrasound-based texture features were distinct between the groups [rectus abdominis blob size: 0.07 ± 0.06 vs. 0.30 ± 0.43 cm2 , P = 0.045; rectus femoris local binary pattern (LBP) entropy: 4.65 ± 0.05 vs. 4.59 ± 0.08 A.U., P = 0.007]. When all participants who underwent additional assessments were pooled (n = 24), we observed that certain ultrasound-based muscle texture features correlated significantly with muscle strength (rectus abdominis histogram skew vs. power during an isokinetic contraction at 60°/s: r = 0.601, P = 0.003) and insulin resistance (rectus femoris LBP entropy vs. HOMA-IR: r = 0.419, P = 0.042). CONCLUSIONS: Our findings suggest a novel body composition phenotype specific to older adults with T2D or prediabetes. We are also the first to report that ultrasound-based texture features correspond with functional outcomes. Future larger scale studies are needed to uncover the mechanisms underpinning these regional body composition differences.

Body size normalization of ultrasound measured anterior upper leg muscle thickness in younger and older males and females.

BACKGROUND: Ultrasound measurements of the anterior upper leg muscle thickness are often used to quantify muscle mass; however, the ideal normalization approach is unclear. Our primary objective was to examine how the anterior upper leg muscle thickness scales with indices of body size in younger and older adults. Our secondary objectives were to examine how normalization with body size alters the identification of low muscle thickness and associations with strength and physical function. METHODS: Younger (<45 years) males (n = 38) and females (n = 24) and older (≥60 years) males (n = 53) and females (n = 24) were evaluated for anthropometrics and anterior upper leg muscle thickness. Allometric models were used to examine how body size metrics scale with anterior upper leg muscle thickness. A subset of older males was evaluated for strength and function. RESULTS: Weight and BMI scaled with anterior upper leg muscle thickness with coefficients less than 1 (0.58 to 0.82, r2 = 0.15 to 0.31, p < 0.05) for both younger and older males and females. Compared to absolute anterior upper leg thickness, normalized indices identified a greater proportion of older adults with low muscle thickness (p < 0.05). Absolute muscle thickness provided stronger associations with strength compared to weight normalized indices. CONCLUSIONS: Scaling exponents less than 1 for weight and BMI for the anterior upper leg muscle thickness indicate that allometric normalization is the ideal approach to develop body size independent metrics. However, allometric normalization of muscle thickness increases the proportion of older adults classified as low muscle mass but decreased the associations with strength.

Epidemic confusions: On irony and decolonisation in global health.

The movement to decolonise global health is gathering pace. In its concern with the fundamental, distal causes of inequality and its call for social justice, the decolonisation movement forces us to question how global health works, for whom, where it is located, its funding practices, power asymmetries, cultures of collaboration and publication. This paper uses a new book by Harvard-based physician-anthropologist Eugene T. Richardson, Epidemic Illusions, as a point of departure for a broader analysis of the nature of global health knowledge, science, authorship, research and practice. Written in a 'carnivalesque' style, the book proceeds through a series of 'ironic (re)descriptions' to argue that global public health is an 'apparatus of coloniality'. In so doing, the book is generative of four ironic turns that we explore through the themes of guilt, humility, privilege and ambiguity. In locating these ironic turns within the broader landscape of global health, we reflect on whether the means of such a book achieve the ends of decolonisation.

Influence of Subcutaneous Adipose Tissue and Skeletal Muscle Thickness on Rectus Femoris Echo Intensity in Younger and Older Males and Females.

OBJECTIVES: Ultrasound measurements of muscle echo intensity are commonly used surrogates of muscle composition (eg, intramuscular adipose tissue). However, given that soundwaves are increasingly attenuated with tissue depth, the interpretation of echo intensity may be confounded by adipose and skeletal muscle thickness. Our objectives are to compare the associations between adipose or muscle tissue thickness and rectus femoris echo intensity in younger and older males and females. METHODS: Participants included in this analysis were derived from 3 previously published cohorts of younger (<45 years) and older (≥60 years) males and females. Ultrasound images of the rectus femoris were evaluated for muscle thickness, echo intensity, and subcutaneous adipose tissue thickness. RESULTS: Older adults (n: 49 males, 19 females) had a higher body mass index (P = .001) compared with younger adults (n: 37 males, 49 females). Muscle thickness was negatively associated with echo intensity in older males (r = -0.59) and females (r = -0.53), whereas no associations were observed in younger males (r = 0.00) or females (r = -0.11). Subcutaneous adipose tissue thickness displayed no associations with echo intensity in any group. CONCLUSIONS: Despite the known influence of subcutaneous adipose tissue thickness on beam attenuation, we observed no association with muscle echo intensity, indicating that adipose tissue correction may be required to better understand muscle echo intensity across differences in adiposity. The negative associations between muscle thickness and echo intensity in older, but not younger adults, suggests these associations may be related to the co-occurrence of skeletal muscle atrophy and intramuscular adipose tissue infiltration with advancing age.

Low-frequency exercise training improves cardiovascular fitness and strength during treatment for breast cancer: a single-arm intervention study.

Aerobic and resistance exercise during and after cancer treatment are important for health-related outcomes, however treatment-specific barriers may inhibit adherence. We explored the effect of lower-frequency exercise training on fitness, body composition, and metabolic markers (i.e. glucose and lipids) in a group of recently diagnosed breast cancer patients. Fifty-two females ≥ 18 years with stage I-IIIB breast cancer were instructed to attend 2 cardiovascular and strength training sessions/week over 12 weeks, but program length was expanded as needed to accommodate missed sessions. Pre- and post-intervention, we measured: (1) cardiovascular fitness, (2) isometric strength, (3) body composition (dual-energy X-ray absorptiometry), and (4) fasting glucose, insulin, c-peptide, and lipids. Pre-intervention, participants were 53 ± 10 years old (mean ± SD) and overweight (BMI: 27.5 ± 5.4 kg m-2, 40.1 ± 6.5% body fat). Forty participants completed the program over a median 20 weeks (range: 13-32 weeks, median frequency: 1.2 sessions/week), over which predicted VO2peak improved by 7% (2.2[0.1-4.4] mL/kg/min) (delta[95% CI]), and strength increased by 7-9% (right arm: 2.3[0.1-4.5] N m; right leg: 7.9[2.1-13.7] N m; left leg: 7.8[1.9-13.7] N m). Body composition and metabolic markers were unchanged. An exercise frequency of 1.2 sessions/week stimulated significant improvements in fitness, and may represent a practical target for patients during active treatment.

Associations between skeletal muscle echo intensity and thickness in relation to glucose homeostasis in healthy and glucose impaired older males.

BACKGROUND: Aging-related changes in muscle composition and mass may predispose older adults to developing insulin resistance. Ultrasound echo intensity and thickness are surrogates of muscle composition and mass, however, their associations with glucose homeostasis are not well established. We examined how muscle echo intensity and thickness correlate with markers of glucose homeostasis in older (≥65 years) males with normal (n = 22) or impaired (n = 10) glucose control. METHODS: Echo intensity was measured for the biceps brachii, rectus abdominis, and rectus femoris. Muscle thickness was evaluated for the biceps brachii + brachioradialis, rectus abdominis, and rectus femoris + vastus intermedius. Glucose homeostasis was evaluated using a 2-h oral glucose tolerance test. RESULTS: In older males with normal glucose homeostasis, higher echo intensity of the rectus abdominis and rectus femoris was moderately (r = 0.36 to 0.59) associated with 2-h glucose. On the contrary, higher muscle echo intensity of the rectus abdominis, biceps brachii, and rectus femoris was moderately-to-strongly (r = -0.36 to -0.79) associated with indices of better glucose homeostasis in the impaired group. Rectus abdominis muscle thickness was moderately associated (r = 0.36) with better glucose tolerance in the normal glucose homeostasis; however, in the glucose impaired group, muscle thickness was associated with (r = 0.37 to 0.73) with poorer glucose homeostasis. CONCLUSIONS: Muscle echo intensity displays divergent associations with glucose homeostasis in older males with normal compared to impaired glucose control. Larger muscle thickness was associated with poorer glucose homeostasis in the glucose impaired group, but rectus abdominis muscle thickness was correlated with better homeostasis in healthy older males.

Older males exhibit reduced anterior upper leg and anterior abdominal muscle thickness compared to younger males when matched for relative appendicular lean tissue.

Background Ageing-related muscle atrophy does not occur uniformly across the body; rather, atrophy occurs to a greater extent in specific muscle groups compared to others. However, site-specific comparisons of muscle mass between older and younger adults typically do not account for relative muscle mass (i.e., matched for age- and sex-specific percentiles), which may confound site-specific differences. Furthermore, the uniformity of ageing-related differences in muscle composition (e.g., intramuscular adipose tissue) across the body are not well characterized. Purpose To examine site-specific muscle mass and composition differences between younger and older males matched for relative muscle mass. Methods Younger (18-44 years old, n = 19) and older (≥65 years old, n = 19) males were matched for relative appendicular lean tissue index (NHANES age- and sex-specific Z-scores) measured using dual-energy x-ray absorptiometry. Site-specific differences in skeletal muscle size (thickness) and composition (echo-intensity) were evaluated using ultrasound for 8 distinct landmarks across the body. Results Relative appendicular lean tissue mass was well matched between younger and older males (Z-score difference: -0.02, p = 0.927). Compared with younger males, older males had smaller muscle thickness for the anterior upper leg (difference: -1.08 cm, p < 0.001) and anterior abdomen (difference: -0.53 cm, p < 0.001). However, older adults displayed higher echo intensity across all muscles (p < 0.05), except for the posterior upper arm (p = 0.377), in comparison to the younger males. Conclusions When matched for relative appendicular lean tissue, muscle thickness differences between younger and older males are not-uniform across the body, whereas echo intensity was more uniformly higher in the older males.

Correction: A whey protein-based multi-ingredient nutritional supplement stimulates gains in lean body mass and strength in healthy older men: A randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0181387.].

Corrigendum: A Multi-Ingredient Nutritional Supplement in Combination With Resistance Exercise and High-Intensity Interval Training Improves Cognitive Function and Increases N-3 Index in Healthy Older Men: A Randomized Controlled Trial.

[This corrects the article DOI: 10.3389/fnagi.2019.00107.].

Corrigendum: Integrated Myofibrillar Protein Synthesis in Recovery From Unaccustomed and Accustomed Resistance Exercise With and Without Multi-ingredient Supplementation in Overweight Older Men.

[This corrects the article DOI: 10.3389/fnut.2019.00040.].

Myokines and adipokines in sarcopenia: understanding cross-talk between skeletal muscle and adipose tissue and the role of exercise.

Detrimental age-associated changes in skeletal muscle and adipose tissue increase the risk of sarcopenia. Age-related changes in myokines, such as myostatin and irisin, as well as adipokines, such as leptin and adiponectin, contribute to cross-talk between muscle and adipose tissue. These age-related changes in myokines and adipokines have important implications for sarcopenia, however, recent literature highlights discrepancies in these relationships. Exercise may alter serum profiles and muscle receptor expression of these factors, but future work is needed to determine whether these changes in myokines and adipokines relate to improvements in muscle mass and function. Here, we describe myokine-mediated and adipokine-mediated interactions between muscle and adipose tissue, and discuss the fundamental importance of these cytokines to understanding the development of sarcopenia.

Age-related changes to the satellite cell niche are associated with reduced activation following exercise.

Skeletal muscle satellite cell (SC) function and responsiveness is regulated, in part, through interactions within the niche, in which they reside. Evidence suggests that structural changes occur in the SC niche as a function of aging. In the present study, we investigated the impact of aging on SC niche properties. Muscle biopsies were obtained from the vastus lateralis of healthy young (YM; 21 ± 1 yr; n = 10) and older men (OM; 68 ± 1 yr; n = 16) at rest. A separate group of OM performed a single bout of resistance exercise and additional muscle biopsies were taken 24 and 48 hours post-exercise; this was performed before and following 12 wks of combined exercise training (OM-Ex; 73 ± 1; n = 24). Muscle SC niche measurements were assessed using high resolution immunofluorescent confocal microscopy. Type II SC niche laminin thickness was greater in OM (1.86 ± 0.06 µm) as compared to YM (1.55 ± 0.09 µm, P < .05). The percentage of type II-associated SC that were completely surrounded by laminin was greater in OM (13.6%±4.2%) as compared to YM (3.5%±1.5%; P < .05). In non-surrounded SC, the proportion of active MyoD+ /Pax7+ SC were higher compared to surrounded SC (P < .05) following a single bout of exercise. This "incarceration" of the SC niche by laminin appears with aging and may inhibit SC activation in response to exercise.

Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.

JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.

Ultrasound image resolution influences analysis of skeletal muscle composition.

INTRODUCTION: Analysis of muscle composition using ultrasound requires standardization of several equipment settings (i.e. gain). However, the influence of image resolution, which is altered by imaging depth, on measures of muscle composition is unknown. METHODS: We analysed rectus femoris muscle composition using ultrasound images captured from 32 males and females (aged 28 ± 5 years) at depths of 9.0, 7.3, 5.9 and 4.7 cm. The transducer's orientation was fixed using a clamp during image acquisition to minimize movement. Across each image resolution, a region of interest encompassing the same anatomical area within the muscle was used for muscle composition analysis. Muscle composition was analysed using a combination of first-, second- and higher-order texture features. Muscle composition agreement across image resolutions was evaluated using a one-way ANOVA and intraclass correlation coefficients (ICC). RESULTS: Most muscle composition features displayed differences due to image resolution (p < .05). ICCs demonstrated poor-to-good agreement across different image resolutions. In general, higher resolution images (i.e. shallower imaging depth) demonstrated better agreement (ICC > 0.90) compared to lower resolution images. CONCLUSIONS: Ultrasound image resolution influences muscle composition analysis. Image resolution should be fixed within and between individuals when evaluating muscle composition using ultrasound.

Signs, things and packaging: Recovering the material agency of the cigarette packet.

In recent years, cigarette packets have become the site of considerable legislative attention, via initiatives to remove industry branding from tobacco products. These efforts are based on the premise that branded cigarette packaging acts as a 'silent salesman' for smoking. According to this perspective, the cigarette packet has a particular sort of agency, but one rooted in its communicative powers rather than its material qualities. In this article, I reconsider this view, based on an analysis of archives in the Truth Tobacco Industry Documents Library produced by a search of the term 'packet design', and scholarship on containerization. Taking up the idea of containers as undertheorized forms of materiality, I argue that the cigarette packet is best conceptualized as a technology with powerful, albeit largely invisible, physical consequences on the circulation of cigarettes and the practice of smoking itself.

Bioelectrical Impedance Analysis Overestimates Fat-Free Mass in Breast Cancer Patients Undergoing Treatment.

BACKGROUND: Bioelectrical impedance analysis (BIA) is commonly used to assess fat-free mass (FFM) and fat mass (FM) in breast cancer patients. However, because of the prevalence of overweight, obesity and variable hydration status in these patients, assumptions for existing prediction equations developed in healthy adults may be violated, resulting in inaccurate body composition assessment. METHODS: We measured whole-body FFM using single-frequency BIA (50 kHz) and dual-energy x-ray absorptiometry (DXA) in 48 patients undergoing treatment for breast cancer. We applied raw BIA data to 18 previously published FFM prediction equations (FFMBIA ) and compared these estimates to DXA (FFMDXA ; reference method). RESULTS: On average, patients were 52 ± 10 (mean ± SD) years of age and overweight (body mass index: 27.5 ± 5.5 kg/m2 ; body fat by DXA: 40.1% ± 6.6%). Relative to DXA, BIA overestimated FFM by 4.1 ± 3.4 kg (FFMDXA : 42.0 ± 5.9 kg; FFMBIA : 46.1 ± 3.4 kg). Individual equation-generated predictions of FFMBIA ranged from 39.6 ± 6.7 to 52.2 ± 5.6 kg, with 16 equations overestimating and 2 equations underestimating FFMBIA compared with FFMDXA . Based on equivalence testing, no equation-generated estimates were equivalent to DXA. CONCLUSION: Compared with DXA, BIA overestimated FFM in breast cancer patients during treatment. Although several equations performed better than others, none produced values that aligned closely with DXA. Caution should be used when interpreting BIA measurements in this clinical population, and future studies should develop prediction equations specific to breast cancer patients.