Associations Between End-Tidal Carbon Dioxide During Pediatric Cardiopulmonary Resuscitation, Cardiopulmonary Resuscitation Quality, and Survival.

BACKGROUND: Supported by laboratory and clinical investigations of adult cardiopulmonary arrest, resuscitation guidelines recommend monitoring end-tidal carbon dioxide (ETCO2) as an indicator of cardiopulmonary resuscitation (CPR) quality, but they note that "specific values to guide therapy have not been established in children." METHODS: This prospective observational cohort study was a National Heart, Lung, and Blood Institute-funded ancillary study of children in the ICU-RESUS trial (Intensive Care Unit-Resuscitation Project; NCT02837497). Hospitalized children (≤18 years of age and ≥37 weeks postgestational age) who received chest compressions of any duration for cardiopulmonary arrest, had an endotracheal or tracheostomy tube at the start of CPR, and evaluable intra-arrest ETCO2 data were included. The primary exposure was event-level average ETCO2 during the first 10 minutes of CPR (dichotomized as ≥20 mm Hg versus <20 mm Hg on the basis of adult literature). The primary outcome was survival to hospital discharge. Secondary outcomes were sustained return of spontaneous circulation, survival to discharge with favorable neurological outcome, and new morbidity among survivors. Poisson regression measured associations between ETCO2 and outcomes as well as the association between ETCO2 and other CPR characteristics: (1) invasively measured systolic and diastolic blood pressures, and (2) CPR quality and chest compression mechanics metrics (ie, time to CPR start; chest compression rate, depth, and fraction; ventilation rate). RESULTS: Among 234 included patients, 133 (57%) had an event-level average ETCO2 ≥20 mm Hg. After controlling for a priori covariates, average ETCO2 ≥20 mm Hg was associated with a higher incidence of survival to hospital discharge (86/133 [65%] versus 48/101 [48%]; adjusted relative risk, 1.33 [95% CI, 1.04-1.69]; P=0.023) and return of spontaneous circulation (95/133 [71%] versus 59/101 [58%]; adjusted relative risk, 1.22 [95% CI, 1.00-1.49]; P=0.046) compared with lower values. ETCO2 ≥20 mm Hg was not associated with survival with favorable neurological outcome or new morbidity among survivors. Average 2 ≥20 mm Hg was associated with higher systolic and diastolic blood pressures during CPR, lower CPR ventilation rates, and briefer pre-CPR arrest durations compared with lower values. Chest compression rate, depth, and fraction did not differ between ETCO2 groups. CONCLUSIONS: In this multicenter study of children with in-hospital cardiopulmonary arrest, ETCO2 ≥20 mm Hg was associated with better outcomes and higher intra-arrest blood pressures, but not with chest compression quality metrics.

In-band pumped Kerr-lens mode-locked Tm,Ho-codoped calcium aluminate laser.

We report on a Kerr-lens mode-locked Tm,Ho-codoped calcium aluminate laser with in-band pumping of the Tm ions by a spatially single-mode 1678 nm Raman fiber laser. The structurally disordered CaGdAlO4 host crystal is also codoped also with the passive Lu ion for additional inhomogeneous line broadening. The Tm,Ho,Lu:CaGdAlO4 laser generates soliton pulses as short as 79 fs at a central wavelength of 2073.6 nm via soft-aperture Kerr-lens mode-locking. The corresponding average output power amounts to 91 mW at a pulse repetition rate of ∼86 MHz. The average output power can be scaled to 842 mW at the expense of slightly longer pulses of 155 fs at 2045.9 nm, which corresponds to a peak power of ∼58 kW. To the best of our knowledge, this represents the first demonstration of an in-band pumped Kerr-lens mode-locked Tm,Ho solid-state laser at ∼2 µm.

Symptoms and steroid dose adjustments following the Covid-19 vaccine in patients with adrenal insufficiency.

BACKGROUND: A proportion of patients with adrenal insufficiency (AI) require increases in their maintenance glucocorticoids following the Covid-19 vaccine as a result of vaccine-related symptoms or development of incipient or frank adrenal crisis. In a large cohort of AI patients, we aim to characterise symptoms, changes in glucocorticoid dosage, occurrence of adrenal crises and whether there are differences between the mRNA and adenovirus vector vaccines. PATIENTS AND METHODS: Patients with AI of any aetiology were invited to complete a short, structured questionnaire of their experience of the Covid-19 vaccination. RESULTS: 279 of the 290 patients enrolled to this study fully completed the questionnaires. 176, 100 and 3 received the Astra Zeneca (AZ), Pfizer-BioNTech (PB) and Moderna (MD) as initial vaccine respectively; and for the second vaccine, 170, 99 and 10 received AZ, PB and MD respectively. Moderate to severe symptoms occurred in 44.8 and 39.7% after the first and second vaccines respectively, were of early onset (6.0 h, IQR 2-12 &. 6.0 h, IQR 2-24 h) and short duration (24 h, IQR 12-72 h & 26 h, IQR 12-72 h). 34.4 and 29.7% increased their maintenance glucocorticoid dose. DISCUSSION: The Covid-19 vaccines appear well-tolerated in patients with AI, with similar frequency of symptoms to that reported in the background population. The AZ vaccine leads to slightly greater post-vaccination symptom burden and need to increase glucocorticoid dosage, but this does not translate to greater adverse outcomes.

Energy scaling of a narrowband, periodically poled LiNbO3, nanosecond, nonresonant optical parametric oscillator.

We demonstrate that 3-mm-thick, periodically poled L i N b O 3 enables energy scaling of a nonresonant optical parametric oscillator operated in the narrowband mode with a volume Bragg grating at the signal wavelength. Utilizing the full available pump power at 1064 nm, we obtained maximum average powers of 2.25 and 2.08 W for the signal (1.922 µm) and idler (2.383 µm) pulses at 10 kHz, at a total conversion efficiency of 32.8%, which represents a fourfold increase in terms of peak powers over our previous work. The signal and idler spectral linewidths were ∼1n m, with pulse lengths of ∼6n s and an idler beam propagation factor of ∼5.

ChAdOx1 SARS-CoV-2 vaccination: A putative precipitant of adrenal crises.

BACKGROUND: Patients with adrenal insufficiency (AI) have excess mortality, in part due to the occurrence of life-threatening adrenal crises. Infective processes, including that of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are recognised as the major precipitant of adrenal crises. Adverse reactions to the ChAdOx1 SARS-CoV-2 vaccine occur in a significant proportion of individuals, however, are mild-moderate in the majority of cases. DESIGN: Case series. PATIENTS & RESULTS: We describe five cases where more severe adverse reactions to the ChAdOx1 SARS-CoV-2 vaccine led to actual or incipient adrenal crises requiring parenteral hydrocortisone within 24 h of receiving the first ChAdOx1 SARS-CoV-2 vaccination. CONCLUSION: In individuals with adrenal insufficiency, adverse reactions to the initial dose of the ChAdOx1 SARS-CoV-2 vaccination can precipitate adrenal crises. We recommend that patients with AI should immediately increase their maintenance glucocorticoid dosage 2-3 fold on experiencing any symptoms in the initial 24 h following vaccination.

Mid-infrared difference-frequency generation directly pumped by a fiber four-wave mixing source.

We demonstrate a new, to the best of our knowledge, method of generating mid-infrared pulses by difference frequency mixing the Stokes pulse generated by four-wave mixing in a photonic crystal fiber with the remaining pump pulse. The Stokes pulses generated by four-wave mixing are inherently overlapped temporally and spatially with the pump pulse at the output of the fiber. Focusing this output into a nonlinear crystal phase matched for difference frequency generation between the pump and Stokes pulses results in a simple method of generating mid-infrared pulses. With a pump source at 1.064 µm, and a photonic crystal fiber engineered to generate Stokes pulses at approximately 1.65 µm, we generate 160 mW of mid-infrared light at approximately 3 µm through difference frequency generation.

Outcomes of 756 patients with differentiated thyroid cancer and excellent response to treatment: An evidence-based paradigm for long-term surveillance strategies.

BACKGROUND: The 2014 British Thyroid Association thyroid cancer guidelines recommend lifelong follow-up of all thyroid cancer patients. This is probably unnecessary, particularly for differentiated thyroid cancer (DTC) patients with an excellent response to treatment and places significant demand on health service resources. DESIGN: Single centre retrospective cohort analysis of patients diagnosed and treated at the Leeds Cancer Centre between 2001 and 2014. PATIENTS: A total of 756 patients were dynamically risk-stratified (DRS) as having 'excellent response to treatment' after total thyroidectomy and radioiodineremnant ablation (RRA) for DTC. RESULTS: Median follow-up was 11.2 (range: 6.5-18.5) years. Radiological recurrence occurred in 15/756 (2.0%) patients and was always preceded by a raised thyroglobulin or thyroglobulin antibody level. The vast majority of tumour recurrences (13/15, 85%) were identifiable within 5 years of diagnostic surgery. Patients classified as having high-risk disease as per American Thyroid Association (ATA) guidelines had an almost threefold higher recurrence rate (2/34 [5.9%] vs. 13/722 [1.8%]) than those with ATA low-risk or intermediate-risk disease. Tumour histology subtype was a significant contributing factor, with Hürthle cell cancer having a worse prognosis than papillary thyroid cancer (PTC) (5/68 [7.4%] vs. 9/582 [1.5%]; relative risk: 4.76 [95% confidence interval: 1.64-13.8]). CONCLUSIONS: The recurrence rate of DRS patients with excellent response to treatment is low. It is reasonable to consider discharge of ATA low-risk or intermediate-risk patients with PTC who remain disease-free after 5 years of secondary care follow-up. Lifelong follow-up, however, currently remains the standard for subgroups at greater risk.

The severity of obstructive sleep apnoea does not influence ambient IGF-I levels.

OBJECTIVE: Obstructive sleep apnoea (OSA) is reported to have effects on a number of hormone systems including the hypothalamo-pituitary axis. We aimed to determine the impact of OSA severity on insulin-like growth factor-I (IGF-I) levels. DESIGN AND METHODS: This is a prospective cohort study performed between November 2014 and May 2017. IGF-I was measured on serum samples, and data were collected on demographics, BMI and parameters of OSA. RESULTS: 611 participants were recruited (202 female, 53.5 ± 12.5 years; mean BMI 36.2 ± 8.0 kg/m2 ). 26.2% had mild OSA; 27.3%, moderate OSA; and 44.5%, severe OSA. 15.2% of IGF-I values were below the age-related reference range. Increasing BMI correlated with greater AHI (r = .28, p < .001), ODI (r = .30, p < .001), severity of OSA (r = .17, p < .001), duration with oxygen saturation (SaO2 ) <90% (r = .29, p = .001) and reduced median SaO2 levels (r = .19, p < .001). IGF-I levels correlated negatively with age (r = -.13, p = .001), BMI (r = -.16, p < .001), diabetes (r = -.108, p = .009), AHI (r = -0.10, p = .043) and severity of OSA (r = -.10, p = .013). No association of IGF-I was observed with ODI, median SaO2 levels or duration of SaO2  < 90%. Regression analyses were used to examine determinants of IGF-I, all of which contained the independent variables of age, gender and BMI. All models showed IGF-I to be predicted by age and BMI (p < .05); however, none of the parameters of OSA were significant within these models. CONCLUSION: Insulin-like growth factor-I levels in OSA are dependent on age and BMI; however, no additional effect of any OSA parameter was observed, supporting the hypothesis that OSA effects on IGF-I are indirect through concomitant body composition and metabolic parameters.

Safety and effectiveness of replacement with biosimilar growth hormone in adults with growth hormone deficiency: results from an international, post-marketing surveillance study (PATRO Adults).

PURPOSE: To evaluate safety and effectiveness of biosimilar recombinant human growth hormone (rhGH; Omnitrope®) in adults with growth hormone deficiency (GHD), using data from the PATRO Adults study. METHODS: PATRO Adults was a post-marketing surveillance study conducted in hospitals and specialized endocrinology units across Europe. The primary objective was to assess the safety of rhGH in adults treated in routine clinical practice. All adverse events (AEs) were monitored and recorded for the complete duration of Omnitrope® treatment. Effectiveness was evaluated as a secondary objective. RESULTS: As of January 2020, 1447 patients (50.9% male) had been enrolled from 82 centers in 9 European countries. Most patients had adult-onset GHD (n = 1179; 81.5%); 721 (49.8%) were rhGH-naïve at study entry. Overall, 1056 patients (73.0%) reported adverse events (AEs; n = 5397 events); the majority were mild-to-moderate in intensity. Treatment-related AEs were reported in 117 patients (8.1%; n = 189 events); the most commonly reported (MedDRA preferred terms) were arthralgia (n = 19), myalgia (n = 16), headache (n = 14), and edema peripheral (n = 10). In total, 495 patients (34.2%) had serious AEs (SAEs; n = 1131 events); these were considered treatment-related in 28 patients (1.9%; n = 35 events). Mean (standard deviation) IGF-I SDS increased from - 2.34 (1.47) at baseline to - 0.23 (1.65) at 12 months, and remained relatively stable thereafter (up to 3 years). Body mass index remained stable between baseline and 3 years. CONCLUSION: Data from PATRO Adults indicate biosimilar rhGH (Omnitrope®) is not associated with any unexpected safety signals, and is effective in adults with GHD treated in real-world clinical practice.

Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.

BACKGROUND: Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. METHODS AND FINDINGS: We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders. CONCLUSIONS: Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings. TRIAL REGISTRATION: ISRCTN89971375.

Differences between predicted outer membrane proteins of genotype 1 and 2 Mannheimia haemolytica.

BACKGROUND: Mannheimia haemolytica strains isolated from North American cattle have been classified into two genotypes (1 and 2). Although members of both genotypes have been isolated from the upper and lower respiratory tracts of cattle with or without bovine respiratory disease (BRD), genotype 2 strains are much more frequently isolated from diseased lungs than genotype 1 strains. The mechanisms behind the increased association of genotype 2 M. haemolytica with BRD are not fully understood. To address that, and to search for interventions against genotype 2 M. haemolytica, complete, closed chromosome assemblies for 35 genotype 1 and 34 genotype 2 strains were generated and compared. Searches were conducted for the pan genome, core genes shared between the genotypes, and for genes specific to either genotype. Additionally, genes encoding outer membrane proteins (OMPs) specific to genotype 2 M. haemolytica were identified, and the diversity of their protein isoforms was characterized with predominantly unassembled, short-read genomic sequences for up to 1075 additional strains. RESULTS: The pan genome of the 69 sequenced M. haemolytica strains consisted of 3111 genes, of which 1880 comprised a shared core between the genotypes. A core of 112 and 179 genes or gene variants were specific to genotype 1 and 2, respectively. Seven genes encoding predicted OMPs; a peptidase S6, a ligand-gated channel, an autotransporter outer membrane beta-barrel domain-containing protein (AOMB-BD-CP), a porin, and three different trimeric autotransporter adhesins were specific to genotype 2 as their genotype 1 homologs were either pseudogenes, or not detected. The AOMB-BD-CP gene, however, appeared to be truncated across all examined genotype 2 strains and to likely encode dysfunctional protein. Homologous gene sequences from additional M. haemolytica strains confirmed the specificity of the remaining six genotype 2 OMP genes and revealed they encoded low isoform diversity at the population level. CONCLUSION: Genotype 2 M. haemolytica possess genes encoding conserved OMPs not found intact in more commensally prone genotype 1 strains. Some of the genotype 2 specific genes identified in this study are likely to have important biological roles in the pathogenicity of genotype 2 M. haemolytica, which is the primary bacterial cause of BRD.

Performance of the unilateral AV/IVC index in primary hyperaldosteronism subtype prediction: A validation study in a single tertiary centre.

BACKGROUND: Failure of cannulation of the right adrenal vein is frequent during AVS for investigation of primary aldosteronism (PA). The aldosterone:cortisol ratio of either adrenal vein compared with the inferior vena cava (AV/IVC index) has been proposed to differentiate between unilateral and bilateral disease, and aid in lateralization of unilateral disease. METHODS: Sixty-two patients with unilateral or bilateral PA identified by either successful bilateral (45 patients) or unilateral (17 patients) adrenal vein cannulation, and with biochemical remission following surgery were enrolled into the analysis. The diagnostic performances of the previously identified AV/IVC index cut-offs of ≥5.5 to predict ipsilateral disease and ≤0.5 to predict contralateral disease were validated using data from the entire cohort. RESULTS: Fifty-three patients had unilateral PA and 9 patients bilateral PA. The area under ROC curve (AUROC) of the AV/IVC cut-off ≤0.5 for identifying unilateral aldosterone secretion from the contralateral adrenal was 0.95 (95% CI; 0.88-0.99), whereas the AUROC of the AV/IVC cut-off ≥5.5 for identifying unilateral aldosterone secretion from ipsilateral adrenal was 0.96 (95% CI; 0.92-0.99). The AV/IVC index cut-off value of 0.5 had 93% sensitivity and 91% specificity, and the AV/IVC index cut-off value of 5.5 had 21% sensitivity and 100% specificity. The optimal AV/IVC cut-offs to achieve 100% specificity for our cohort were >2.4 and <0.1 to predict ipsilateral and contralateral disease. CONCLUSION: Our data confirm that the AV/IVC index is a potential tool for subtype classification and lateralization in patients with PA in the setting of failed bilateral, but successful unilateral, adrenal vein cannulation during AVS.

Construction of a predictive scoring system as a guide to screening and confirmation of the diagnosis of primary aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. In Southern Thailand, the aldosterone-renin ratio (ARR) is only available within a small number of tertiary centres, necessitating need for a simple clinical assessment to determine the requirement for ARR. OBJECTIVE: This study aimed to identify predictive factors for the diagnosis of PA and generate a predictive scoring system (PSS) for use in screening and diagnosis of PA. PATIENTS AND METHODS: A total of 420 patients aged >15 years with paired plasma aldosterone concentration and plasma renin activity values allowing calculation of ARR were identified from the electronic hospital database between 2011 and 2016. RESULTS: The overall prevalence of PA was 16.7% (range; adrenal incidentaloma 5.6% to hypokalaemia 30%). Predictive factors for diagnosis of PA were as follows: age <60 years, BMI < 25 kg/m2 , presence of diabetes, ≥3 antihypertensive agents, serum sodium ≥ 141 mmol/L and serum potassium < 3.5 mmol/L. A predictive scoring system (PSS) (range -2 to 13) was generated by the coefficients of the variables with ROC curve AUC 0.87 [95% CI: 0.83-0.91]. Using the PSS, a total score <4 provided a robust negative predictive value (sensitivity, 0.97; specificity, 0.48; NPV, 0.99; PPV, 0.27) for PA. In patients at high risk of PA (PAC > 15 ng/dL and PRA < 1.0 ng/mL/hr), a PSS score > 9 had specificity and PPV of 100%, essentially confirming PA in these individuals. CONCLUSION: The proposed PSS for PA will enable more focused and cost-effective use of ARR screening and confirmatory testing. In our cohort, 40% and 42% of patients would not require ARR screening or confirmatory tests, respectively.

Dietary Calcium and Phosphorus Amounts Affect Development and Tissue-Specific Stem Cell Characteristics in Neonatal Pigs.

BACKGROUND: Dietary calcium and phosphorus are required for bone and muscle development. Deficiencies of these macrominerals reduce bone mineral and muscle accretion potentially via alterations of mesenchymal stem cell (MSC) and satellite cell (SC) activities. OBJECTIVES: With increasing interest in the role of early-life events on lifetime health outcomes, we aimed to elucidate the impact of dietary calcium and phosphorus, from deficiency through excess, on MSC and SC characteristics during neonatal development. METHODS: Neonatal pigs [30 females, 1-d-old, 1.46 ± 0.04 kg body weight (BW)] were fed milk replacers for 16 d that were isonitrogenous and isocaloric with a consistent ratio of calcium to phosphorus, but either 25% deficient (calcium: 0.78%; phosphorus: 0.60%; CaPD), adequate (calcium: 1.08%; phosphorus: 0.84%; CaPA), or 25% in excess (calcium: 1.38%; phosphorus: 1.08%; CaPE) of calcium and phosphorus requirements based on sow-milk composition and extrapolation from NRC requirements for older pigs. BW and feed intake were recorded daily. Blood was collected for serum phosphorus, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23) determination. Humeri were collected for MSC isolation and radii/ulnae bone were collected for analysis. Longissimus dorsi muscle was collected for SC isolation and analysis. RESULTS: There was 4.6% increase in bone ash percentage in CaPE- versus CaPD-fed pigs (P < 0.05). In vivo proliferation indicated a 41.3% increase in MSCs in CaPA compared with CaPD and a 19% increase in SCs in CaPA compared with both CaPE and CaPD. MSCs from CaPD had 2- to 5-fold greater expression of peroxisome proliferator-activated receptor γ (PPARγ), fatty acid-binding protein 4 (FABP4), and lipoprotein lipase (LPL) but lower osteocalcin (BGLAP) and fibronectin (FN1) expression than CaPA (P < 0.05). SCs from CaPD-fed pigs had 19% lower in vivo proliferation than in CaPA-fed pigs. CONCLUSIONS: These findings demonstrated that feeding a diet marginally deficient in calcium and phosphorus to neonatal pigs had a great impact on bone development, MSC, and SC characteristics. These dietary deficiencies may program future bone health and muscle development by altering MSC and SC activities.

Fruits, vegetables, and health: A comprehensive narrative, umbrella review of the science and recommendations for enhanced public policy to improve intake.

Fruit and vegetables (F&V) have been a cornerstone of healthy dietary recommendations; the 2015-2020 U.S. Dietary Guidelines for Americans recommend that F&V constitute one-half of the plate at each meal. F&V include a diverse collection of plant foods that vary in their energy, nutrient, and dietary bioactive contents. F&V have potential health-promoting effects beyond providing basic nutrition needs in humans, including their role in reducing inflammation and their potential preventive effects on various chronic disease states leading to decreases in years lost due to premature mortality and years lived with disability/morbidity. Current global intakes of F&V are well below recommendations. Given the importance of F&V for health, public policies that promote dietary interventions to help increase F&V intake are warranted. This externally commissioned expert comprehensive narrative, umbrella review summarizes up-to-date clinical and observational evidence on current intakes of F&V, discusses the available evidence on the potential health benefits of F&V, and offers implementation strategies to help ensure that public health messaging is reflective of current science. This review demonstrates that F&V provide benefits beyond helping to achieve basic nutrient requirements in humans. The scientific evidence for providing public health recommendations to increase F&V consumption for prevention of disease is strong. Current evidence suggests that F&V have the strongest effects in relation to prevention of CVDs, noting a nonlinear threshold effect of 800 g per day (i.e., about 5 servings a day). A growing body of clinical evidence (mostly small RCTs) demonstrates effects of specific F&V on certain chronic disease states; however, more research on the role of individual F&V for specific disease prevention strategies is still needed in many areas. Data from the systematic reviews and mostly observational studies cited in this report also support intake of certain types of F&V, particularly cruciferous vegetables, dark-green leafy vegetables, citrus fruits, and dark-colored berries, which have superior effects on biomarkers, surrogate endpoints, and outcomes of chronic disease.

100% Fruit Juice in Child and Adolescent Dietary Patterns.

Objective: Nutritional advice based on strengthening the dietary pattern offers a very different perspective from the reductionist practice of reporting risks or benefits for individual foods.Methods: A healthful dietary pattern can be composed of innumerable different combinations of foods and beverages that collectively and synergistically protect health. Although pure juices lack fiber, juicing retains the majority of health-promoting nutrients and phytochemicals of the whole fruit. Bioactive components of 100% fruit juice have demonstrated positive clinical effects on oxidative markers, inflammation, endothelial reactivity, lipid profiles, hypertension, and platelet aggregation. Fruit juice consumers have higher scores for diet quality. They consume more whole fruit, less added sugar, and greater amounts of vitamin C, magnesium, potassium, and fiber-containing foods than non-consumers.Results: Concerns that 100% fruit juice may be associated with childhood weight gain or metabolic consequences have not been supported by recent systematic reviews and meta-analyses. Juice consumption may be particularly important for the diet quality of lower-socioeconomic-status populations. Over the past 3 decades, as fruit juice intake has fallen substantially, the vacuum has not been filled by a comparable increase in servings of whole fruit, keeping Americans from meeting daily fruit recommendations.Conclusions: Counseling about individual foods without considering their impact on overall diet quality may harm the dietary pattern without discernible health benefits.

DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease.

The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rearrangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could act as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.

FUT2 Genetic Variants and Reported Respiratory and Gastrointestinal Illnesses During Infancy.

BACKGROUND: Fucosyltransferase 2 (FUT2) controls the production of digestive and respiratory epithelia of histo-blood group antigens involved in the attachment of pathogens. The aim of our study was to relate FUT2 variants to reported gastrointestinal and respiratory illnesses in infancy. METHODS: In the Southampton Women's Survey, FUT2 genetic variants (single-nucleotide polymorphisms [SNPs] rs601338 and rs602662) were genotyped in 1831 infants and related to infant illnesses, after adjustment for sex, breastfeeding duration, and potential confounders. RESULTS: For FUT2 SNP rs601338, the risk ratios for ≥1 bout of diarrhea during ages 6-12 months and ages 12-24 months per additional risk (G) allele were 1.23 (95% confidence interval [CI], 1.08-1.4; P = .002) and 1.41 (95% CI, 1.24-1.61; P = 1.7 × 10-7), respectively; the risk ratio for ≥1 diagnosis of a lower respiratory illness (ie, pneumonia or bronchiolitis) during ages 12-24 months per additional G allele was 2.66 (95% CI, 1.64-4.3; P = .00007). Similar associations were found between rs602662 and gastrointestinal and respiratory illnesses, owing to the high linkage disequilibrium with rs601338 (R2 = 0.92). Longer breastfeeding duration predicted a lower risk of diarrhea, independent of infant FUT2 genotype. CONCLUSIONS: We confirmed that FUT2 G alleles are associated with a higher risk of infant gastrointestinal illnesses and identified novel associations with respiratory illnesses. FUT2 locus variants need consideration in future studies of gastrointestinal and respiratory illnesses among infants.

Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood.

BACKGROUND: The early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course. METHODS: DNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women's Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue. RESULTS: Lower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6-7 years (p = 0.0001) and % fat mass at 6-7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6-7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults. CONCLUSIONS: These data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.

Hypothalamic-pituitary axis irradiation dose thresholds for the development of hypopituitarism in adult-onset gliomas.

BACKGROUND: Childhood brain tumour survivors who receive cranial radiotherapy undergo regular surveillance for the development ofhypothalamic-pituitary (HP) axis dysfunction. Much less attention has been given to radiation-induced hypopituitarism in patients with malignant brain tumours of adult onset. DESIGN: Retrospective cohort study. PATIENTS/MEASUREMENTS: We assessed the effects of cranial radiotherapy (cXRT) on pituitary function in 58 adults (32 male) with gliomas distant to the HP axis. The XRT dose exposure at the HP axis was correlated with individual axis dysfunction to establish dose thresholds. RESULTS: Mean age at cXRT was 41.2 ± 10.9 years and duration of endocrine follow-up 8.2 ± 5.2 years. Mean XRT dose to the HP axis was 35.9 ± 15.5 Gy. Overall prevalence of radiation-induced hypopituitarism was 84.5%. GH, LH/FSH, ACTH and TSH deficiency were present in 82.8%, 20.7%, 19% and 6.9% of patients, respectively. Hyperprolactinaemia was noted in 10.3% (n = 6) and was persistent in one case. GH deficiency and "any degree of hypopituitarism" positively correlated with the radiotherapy dose to the hypothalamic-pituitary axis. HP axis XRT dose thresholds for the development of GHD, LH/FSH, ACTH and TSH deficiency were established at 10, 30, 32 and 40.8 Gy, respectively. A gradual increase in the prevalence of all anterior pituitary hormone deficits was observed throughout the follow-up period. CONCLUSIONS: Hypopituitarism post-cXRT in adults with gliomas is a frequent, progressive and dose-dependent phenomenon. Dose thresholds suggest long-term endocrine surveillance is important where the HP axis XRT dose is higher than 30 Gy. Identification of deficits to allow early and appropriate hormone replacement therapy is important to improve well-being in these individuals with limited prognosis.