KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors.

Acquired chromosomal instability and copy number alterations are hallmarks of cancer. Enzymes capable of promoting site-specific copy number changes have yet to be identified. Here, we demonstrate that H3K9/36me3 lysine demethylase KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1γ overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Our results demonstrate that overexpression of a chromatin modifier results in site-specific copy gains. This begins to establish how copy number changes could originate during tumorigenesis and demonstrates that transient overexpression of specific chromatin modulators could promote these events.

Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high-altitude exposure.

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.

Impact of disability-based discrimination in healthcare on parents of children with medical complexity.

AIM: To qualitatively assess the impact of disability-based discrimination in healthcare on the parents of children with medical complexity (CMC). METHOD: In this qualitative study, we conducted in-depth, semi-structured interviews with the parents of CMC. Data collection and analysis occurred iteratively; constant comparison methods were used to identify themes describing the impact of disability-based discrimination in pediatric healthcare on the parents of CMC. RESULTS: Thirty participants from 15 US states were interviewed. Four themes were developed regarding the impact of disability-based discrimination in healthcare on parents. The themes were: (1) discrimination leads to a loss of trust in healthcare providers; (2) discrimination increases the burden of caregiving; (3) discrimination impacts parental well-being; and (4) racism and poverty-based discrimination amplifies disability-based discrimination. INTERPRETATION: The experience of discrimination toward their child results in loss of trust and therapeutic relationship between provider and parent, causes increased burden to the family, and contributes to decreased parental well-being. These experiences are magnified in minoritized families and in families perceived to have a lower socioeconomic status based on insurance type.

Effectiveness of atropine in managing sialorrhea: A systematic review and meta-analysis.

OBJECTIVES: To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling. MATERIALS AND METHODS: We included randomized controlled studies, quasi-randomized trials, case reports, clinical trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale. RESULTS: A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes. CONCLUSION: Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.

Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity.

Bivalent proteolysis-targeting chimeras (PROTACs) drive protein degradation by simultaneously binding a target protein and an E3 ligase and forming a productive ternary complex. We hypothesized that increasing binding valency within a PROTAC could enhance degradation. Here, we designed trivalent PROTACs consisting of a bivalent bromo and extra terminal (BET) inhibitor and an E3 ligand tethered via a branched linker. We identified von Hippel-Lindau (VHL)-based SIM1 as a low picomolar BET degrader with preference for bromodomain containing 2 (BRD2). Compared to bivalent PROTACs, SIM1 showed more sustained and higher degradation efficacy, which led to more potent anticancer activity. Mechanistically, SIM1 simultaneously engages with high avidity both BET bromodomains in a cis intramolecular fashion and forms a 1:1:1 ternary complex with VHL, exhibiting positive cooperativity and high cellular stability with prolonged residence time. Collectively, our data along with favorable in vivo pharmacokinetics demonstrate that augmenting the binding valency of proximity-induced modalities can be an enabling strategy for advancing functional outcomes.

Circulating and skeletal muscle microRNA profiles are more sensitive to sustained aerobic exercise than energy balance in males.

MicroRNAs (miRNAs) regulate molecular processes governing muscle metabolism. Physical activity and energy balance influence both muscle anabolism and substrate metabolism, but whether circulating and skeletal muscle miRNAs mediate those effects remains unknown. This study assessed the impact of sustained physical activity with participants in energy balance (BAL) or deficit (DEF) on circulating and skeletal muscle miRNAs. Using a randomized cross-over design, 10 recreational active healthy males (mean ± SD, 22 ± 5 years, 87 ± 11 kg) completed 72 h of high aerobic exercise-induced energy expenditures in BAL (689 ± 852 kcal/day) or DEF (-2047 ± 920 kcal/day). Blood and muscle samples were collected under rested/fasted conditions before (PRE) and immediately after 120 min load carriage exercise bout at the end (POST) of the 72 h. Trials were separated by 7 days. Circulating and skeletal muscle miRNAs were measured using microarray RT-qPCR. Independent of energy status, 36 circulating miRNAs decreased (P < 0.05), while 10 miRNAs increased and three miRNAs decreased in skeletal muscle (P < 0.05) at POST compared to PRE. Of these, miR-122-5p, miR-221-3p, miR-222-3p and miR-24-3p decreased in circulation and increased in skeletal muscle. Two circulating (miR-145-5p and miR-193a-5p) and four skeletal muscle (miR-21-5p, miR-372-3p, miR-34a-5p and miR-9-5p) miRNAs had time-by-treatment effects (P < 0.05). These data suggest that changes in miRNA profiles are more sensitive to increased physical activity compared to energy status, and that changes in circulating miRNAs in response to high levels of daily aerobic exercise are not reflective of changes in skeletal muscle miRNAs. KEY POINTS: Circulating and skeletal muscle miRNA profiles are more sensitive to high levels of aerobic exercise-induced energy expenditure compared to energy status. Changes in circulating miRNA in response to high levels of daily sustained aerobic exercise are not reflective of changes in skeletal muscle miRNA.

Carbohydrate intake in recovery from aerobic exercise differentiates skeletal muscle microRNA expression.

Posttranscriptional regulation by microRNA (miRNA) facilitates exercise and diet-induced skeletal muscle adaptations. However, the impact of diet on miRNA expression during postexercise recovery remains unclear. The objective of this study was to examine the effects of consuming carbohydrate or a nutrient-free control on skeletal muscle miRNA expression during 3 h of recovery from aerobic exercise. Using a randomized, crossover design, seven men (means ± SD, age: 21 ± 3 yr; body mass: 83 ± 13 kg; V̇o2peak: 43 ± 2 mL/kg/min) completed two-cycle ergometry glycogen depletion trials followed by 3 h of recovery while consuming either carbohydrate (CHO: 1 g/kg/h) or control (CON: nutrient free). Muscle biopsy samples were obtained under resting fasted conditions at baseline and at the end of the 3-h recovery (REC) period. miRNA expression was determined using unbiased RT-qPCR microarray analysis. Trials were separated by 7 days. Twenty-five miRNAs were different (P < 0.05) between CHO and CON at REC, with Let7i-5p and miR-195-5p being the most predictive of treatment. In vitro overexpression of Let7i-5p and miR-195-p5 in C2C12 skeletal muscle cells decreased (P < 0.05) the expression of protein breakdown (Foxo1, Trim63, Casp3, and Atf4) genes, ubiquitylation, and protease enzyme activity compared with control. Energy sensing (Prkaa1 and Prkab1) and glycolysis (Gsy1 and Gsk3b) genes were lower (P < 0.05) with Let7i-5p overexpression compared with miR-195-5p and control. Fat metabolism (Cpt1a, Scd1, and Hadha) genes were lower (P < 0.05) in miR-195-5p than in control. These data indicate that consuming CHO after aerobic exercise alters miRNA profiles compared with CON, and these differences may govern mechanisms facilitating muscle recovery.NEW & NOTEWORTHY Results provide novel insight into effects of carbohydrate intake on the expression of skeletal muscle microRNA during early recovery from aerobic exercise and reveal that Let7i-5p and miR-195-5p are important regulators of skeletal muscle protein breakdown to aid in facilitating muscle recovery.

Mild to Moderate Food Deprivation Increases Hepcidin and Results in Hypoferremia and Tissue Iron Sequestration in Mice.

BACKGROUND: Short-term starvation and severe food deprivation (FD) reduce dietary iron absorption and restricts iron to tissues, thereby limiting the amount of iron available for erythropoiesis. These effects may be mediated by increases in the iron regulatory hormone hepcidin; however, whether mild to moderate FD has similar effects on hepcidin and iron homeostasis is not known. OBJECTIVES: To determine the effects of varying magnitudes and durations of FD on hepcidin and indicators of iron status in male and female mice. METHODS: Male and female C57BL/6J mice (14 wk old; n = 170) were randomly assigned to consume AIN-93M diets ad libitum (AL) or varying magnitudes of FD (10%, 20%, 40%, 60%, 80%, or 100%). FD was based on the average amount of food consumed by the AL males or females, and food was split into morning and evening meals. Mice were euthanized at 48 h and 1, 2, and 3 wk, and hepcidin and indicators of iron status were measured. Data were analyzed by Pearson correlation and one-way ANOVA. RESULTS: Liver hepcidin mRNA was positively correlated with the magnitude of FD at all time points (P < 0.05). At 3 wk, liver hepcidin mRNA increased 3-fold with 10% and 20% FD compared with AL and was positively associated with serum hepcidin (R = 0.627, P < 0.0001). Serum iron was reduced by ∼65% (P ≤ 0.01), and liver nonheme iron concentrations were ∼75% greater (P ≤ 0.01) with 10% and 20% FD for 3 wk compared with AL. Liver hepcidin mRNA at 3 wk was positively correlated with liver Bmp6 (R = 0.765, P < 0.0001) and liver gluconeogenic enzymes (R = >0.667, P < 0.05) but not markers of inflammation (P > 0.05). CONCLUSIONS: FD increases hepcidin in male and female mice and results in hypoferremia and tissue iron sequestration. These findings suggest that increased hepcidin with FD may contribute to the disturbances in iron homeostasis with undernutrition.

Predicting mortality from acetaminophen poisoning shortly after hospital presentation.

AIMS: Early identification of patients likely to die after acetaminophen (APAP) poisoning remains challenging. We sought to compare the sensitivity and time to fulfilment (latency) of established prognostic criteria. METHODS: Three physician toxicologists independently classified every in-hospital death associated with APAP overdose from eight large Canadian cities over three decades using the Relative Contribution to Fatality scale from the American Association of Poison Control Centres. The sensitivity and latency were calculated for each of the following criteria: King's College Hospital (KCH), Model for End Stage Liver Disease (MELD) ≥33, lactate ≥3.5 mmol/L, phosphate ≥1.2 mmol/L 48+ hours post-ingestion, as well as combinations thereof. RESULTS: A total of 162 in-hospital deaths were classified with respect to APAP as follows: 26 Undoubtedly, 40 Probably, 27 Contributory, 14 Probably not, 25 Clearly not, and 30 Unknown. Cases from the first three classes (combined into n = 93 "APAP deaths") typically presented with supratherapeutic APAP concentrations, hepatotoxicity, acidaemia, coagulopathy and/or encephalopathy, and began antidotal treatment a median of 12 hours (IQR 3.4-30 h) from the end of ingestion. Among all patients deemed "APAP deaths", meeting either KCH or lactate criteria demonstrated the highest sensitivity (94%; 95% CI 86-98%), and the shortest latency from hospital arrival to criterion fulfilment (median 4.2 h; IQR 1.0-16 h). In comparison, the MELD criterion demonstrated a substantially lower sensitivity (55%; 43-66%) and longer latency (52 h; 4.4-∞ h, where "∞" denotes death prior to criterion becoming positive). CONCLUSIONS: Meeting either KCH or serum lactate criteria identifies most patients who die from acetaminophen poisoning at or shortly after hospital presentation.

Severe energy deficit at high altitude inhibits skeletal muscle mTORC1-mediated anabolic signaling without increased ubiquitin proteasome activity.

Muscle loss at high altitude (HA) is attributable to energy deficit and a potential dysregulation of anabolic signaling. Exercise and protein ingestion can attenuate the effects of energy deficit on muscle at sea level (SL). Whether these effects are observed when energy deficit occurs at HA is unknown. To address this, muscle obtained from lowlanders ( n = 8 males) at SL, acute HA (3 h, 4300 m), and chronic HA (21 d, -1766 kcal/d energy balance) before [baseline (Base)] and after 80 min of aerobic exercise followed by a 2-mile time trial [postexercise (Post)] and 3 h into recovery (Rec) after ingesting whey protein (25 g) were analyzed using standard molecular techniques. At SL, Post, and REC, p-mechanistic target of rapamycin (mTOR)Ser2448, p-p70 ribosomal protein S6 kinase (p70S6K)Ser424/421, and p-ribosomal protein S6 (rpS6)Ser235/236 were similar and higher ( P < 0.05) than Base. At acute HA, Post p-mTORSer2448 and Post and REC p-p70S6KSer424/421 were not different from Base and lower than SL ( P < 0.05). At chronic HA, Post and Rec p-mTORSer2448 and p-p70S6KSer424/421 were not different from Base and lower than SL, and, independent of time, p-rpS6Ser235/236 was lower than SL ( P < 0.05). Post proteasome activity was lower ( P < 0.05) than Base and Rec, independent of phase. Our findings suggest that HA exposure induces muscle anabolic resistance that is exacerbated by energy deficit during acclimatization, with no change in proteolysis.-Margolis, L. M., Carbone, J. W., Berryman, C. E., Carrigan, C. T., Murphy, N. E., Ferrando, A. A., Young, A. J., Pasiakos, S. M. Severe energy deficit at high altitude inhibits skeletal muscle mTORC1-mediated anabolic signaling without increased ubiquitin proteasome activity.

A Systematic Review of Behavioral and Environmental Interventions for Procedural Pain Management in Preterm Infants.

PROBLEM: Current research suggests behavioral and environmental interventions to prevent neonatal pain prior to an invasive procedure are rarely administered and seldom documented. The aim of this study was to systematically review findings from published randomized controlled trials that tested the effects of behavioral and environmental procedural pain management interventions on behavioral pain response in preterm infants. ELIGIBILITY CRITERIA: Randomized controlled trials examining the effects of behavioral and environmental pain management interventions on behavioral pain response in preterm infants were identified. Articles accepted for inclusion met the following criteria: English language, original, peer refereed, randomized controlled clinical trials published within the past 5 years, study sample: preterm infants, setting: neonatal intensive care units, study intervention behavioral and environmental, outcome pain measurement score from valid and reliable pain scale. SAMPLE: Fourteen randomized controlled trials from a literature search of PubMed and Medline databases were included in this review. RESULTS: Across all age groups, facilitated tucking, oral sucrose, and kangaroo care decreased behavioral and physiologic pain response alone and in combination with other behavioral and environmental interventions. CONCLUSION: Among preterm infants, facilitated tucking, oral sucrose, and kangaroo care significantly mitigates biobehavioral pain response associated with acutely painful procedures. IMPLICATIONS: Evidence suggests that behavioral and environmental interventions can decrease biobehavioral pain response associated with acutely painful procedures in preterm infants. This review highlights the need for rigorous studies to help healthcare providers to build a tailored pain treatment plan for preterm infants.

Using a retention in care protocol to promote positive health and systems related outcomes.

People living with HIV can experience the full benefits of retention when they are continuously engaged in care. Continuous engagement in care promotes improved adherence to ART and positive health outcomes. An infectious disease clinic has implemented a protocol to primarily improve patient retention. The retrospective, facility-based, costing study took place in an infectious disease clinic in Washington DC. Retention was defined in two ways and over a 12-month period. Micro-costing direct measurement methods were used to collect unit costs in time series. Return on investment accounted for the cost of treatment based on CD4 strata. ROI was expressed in 2016USD. The difference in CD4 and viral load levels between the two periods of analysis were determined for active patients, infected with HIV. The year before the intervention was compared to the year of the intervention. Total treatment expenditure decreased from $2,435,653.00 to $2,283,296.23, resulting in a $152,356.77 gain from investment for the healthcare system over a 12-month investment period. The viral load suppression rate increased from 81 to 95 (p = 0.04) over the investment period. The number of patients in need of HIV related opportunistic infection prophylaxis decreased from 21 to 13 (p = 0.06). Improved immunologic, virologic and healthcare expenditure outcomes can be linked to the quality of retention practice.

TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS.

TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation.

Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiological stress.

The magnitude, temporal dynamics, and physiological effects of intestinal microbiome responses to physiological stress are poorly characterized. This study used a systems biology approach and a multiple-stressor military training environment to determine the effects of physiological stress on intestinal microbiota composition and metabolic activity, as well as intestinal permeability (IP). Soldiers (n = 73) were provided three rations per day with or without protein- or carbohydrate-based supplements during a 4-day cross-country ski-march (STRESS). IP was measured before and during STRESS. Blood and stool samples were collected before and after STRESS to measure inflammation, stool microbiota, and stool and plasma global metabolite profiles. IP increased 62 ± 57% (mean ± SD, P < 0.001) during STRESS independent of diet group and was associated with increased inflammation. Intestinal microbiota responses were characterized by increased α-diversity and changes in the relative abundance of >50% of identified genera, including increased abundance of less dominant taxa at the expense of more dominant taxa such as Bacteroides Changes in intestinal microbiota composition were linked to 23% of metabolites that were significantly altered in stool after STRESS. Together, pre-STRESS Actinobacteria relative abundance and changes in serum IL-6 and stool cysteine concentrations accounted for 84% of the variability in the change in IP. Findings demonstrate that a multiple-stressor military training environment induced increases in IP that were associated with alterations in markers of inflammation and with intestinal microbiota composition and metabolism. Associations between IP, the pre-STRESS microbiota, and microbiota metabolites suggest that targeting the intestinal microbiota could provide novel strategies for preserving IP during physiological stress.NEW & NOTEWORTHY Military training, a unique model for studying temporal dynamics of intestinal barrier and intestinal microbiota responses to stress, resulted in increased intestinal permeability concomitant with changes in intestinal microbiota composition and metabolism. Prestress intestinal microbiota composition and changes in fecal concentrations of metabolites linked to the microbiota were associated with increased intestinal permeability. Findings suggest that targeting the intestinal microbiota could provide novel strategies for mitigating increases in intestinal permeability during stress.

Effects of deployment on diet quality and nutritional status markers of elite U.S. Army special operations forces soldiers.

BACKGROUND: Special Operations Forces (SOF) Soldiers deploy frequently and require high levels of physical and cognitive performance. Nutritional status is linked to cognitive and physical performance. Studies evaluating dietary intake and nutritional status in deployed environments are lacking. Therefore, this study assessed the effects of combat deployment on diet quality and serum concentrations of nutritional status markers, including iron, vitamin D, parathyroid hormone (PTH), glucose, and lipids, among elite United States (U.S.) Army SOF Soldiers. METHODS: Changes from baseline to post-deployment were determined with a repeated measure within-subjects design for Healthy Eating Index-2010 (HEI-2010) scores, intake of foods, food groups, key nutrients, and serum nutritional status markers. Dietary intake was assessed with a Block Food Frequency Questionnaire. The association between post-deployment serum 25-hydroxy vitamin D (25-OH vitamin D) and PTH was determined. Analyses of serum markers were completed on 50 participants and analyses of dietary intake were completed on 33 participants. RESULTS: In response to deployment, HEI-2010 scores decreased for total HEI-2010 (70.3 ± 9.1 vs. 62.9 ± 11.1), total fruit (4.4 ± 1.1 vs. 3.7 ± 1.5), whole fruit (4.6 ± 1.0 vs. 4.2 ± 1.4), dairy (6.2 ± 2.7 vs. 4.8 ± 2.4), and empty calories (14.3 ± 3.2 vs. 11.1 ± 4.5) (P ≤ 0.05). Average daily intakes of foods and food groups that decreased included total dairy (P < 0.01), milk (P < 0.01), and non-juice fruit (P = 0.03). Dietary intake of calcium (P = 0.05) and vitamin D (P = 0.03) decreased. PTH increased from baseline (3.4 ± 1.6 vs. 3.8 ± 1.4 pmol/L, P = 0.04), while there was no change in 25-OH vitamin D. Ferritin decreased (385 ± 173 vs. 354 ± 161 pmol/L, P = 0.03) and soluble transferrin receptor increased (16.3 ± 3.7 vs. 17.1 ± 3.5 nmol/L, P = 0.01). There were no changes in glucose or lipids. Post-deployment, serum 25-OH vitamin D was inversely associated with PTH (r = -0.43, P < 0.01). CONCLUSIONS: HEI-2010 scores and dietary intake of milk, calcium, and vitamin D decreased following deployment. Serum PTH increased and iron stores were degraded. No Soldiers were iron deficient. Personnel that deploy frequently should maintain a high diet quality in the U.S. and while deployed by avoiding empty calories and consuming fruits, vegetables, and adequate sources of calcium, vitamin D, and iron. Improving availability and quality of perishable food during deployment may improve diet quality.

Nonemergency PCI at hospitals with or without on-site cardiac surgery.

BACKGROUND: Emergency surgery has become a rare event after percutaneous coronary intervention (PCI). Whether having cardiac-surgery services available on-site is essential for ensuring the best possible outcomes during and after PCI remains uncertain. METHODS: We enrolled patients with indications for nonemergency PCI who presented at hospitals in Massachusetts without on-site cardiac surgery and randomly assigned these patients, in a 3:1 ratio, to undergo PCI at that hospital or at a partner hospital that had cardiac surgery services available. A total of 10 hospitals without on-site cardiac surgery and 7 with on-site cardiac surgery participated. The coprimary end points were the rates of major adverse cardiac events--a composite of death, myocardial infarction, repeat revascularization, or stroke--at 30 days (safety end point) and at 12 months (effectiveness end point). The primary end points were analyzed according to the intention-to-treat principle and were tested with the use of multiplicative noninferiority margins of 1.5 (for safety) and 1.3 (for effectiveness). RESULTS: A total of 3691 patients were randomly assigned to undergo PCI at a hospital without on-site cardiac surgery (2774 patients) or at a hospital with on-site cardiac surgery (917 patients). The rates of major adverse cardiac events were 9.5% in hospitals without on-site cardiac surgery and 9.4% in hospitals with on-site cardiac surgery at 30 days (relative risk, 1.00; 95% one-sided upper confidence limit, 1.22; P<0.001 for noninferiority) and 17.3% and 17.8%, respectively, at 12 months (relative risk, 0.98; 95% one-sided upper confidence limit, 1.13; P<0.001 for noninferiority). The rates of death, myocardial infarction, repeat revascularization, and stroke (the components of the primary end point) did not differ significantly between the groups at either time point. CONCLUSIONS: Nonemergency PCI procedures performed at hospitals in Massachusetts without on-site surgical services were noninferior to procedures performed at hospitals with on-site surgical services with respect to the 30-day and 1-year rates of clinical events. (Funded by the participating hospitals without on-site cardiac surgery; MASS COM ClinicalTrials.gov number, NCT01116882.).

Practice Trends in the Use of Extracorporeal Treatments for Poisoning in Four Countries.

Extracorporeal treatments (ECTRs) such as hemodialysis (HD), enhance the elimination of a small number of toxins. Changes in overdose trends, prescribing practices, antidotes, and dialysis techniques may alter the indications and rates of ECTR use over time. This study analyzed trends in ECTR for poisonings in four countries. A retrospective study of national poison center databases from the United States, Denmark, United Kingdom, and five regional databases within Canada was performed. All cases of patients receiving an ECTR were included. ECTR cases were totalled annually and reported as annual rates per 100,000 exposures with stratification per types of ECTR and toxins. The data collection varied by countries. United States, 1985-2014; United Kingdom, 2011-2013; Denmark, 2005-2014, and regions of Canada as follows: Alberta, 1991-2015; Saskatchewan, 2001-2015; Nova Scotia-PEI, 2006-2015; Quebec, 2008-2014; Ontario-Manitoba, 2009-2015; British Columbia, 2012-2015. During the study period, the total number of ECTRs and rates per 100,000 exposures, respectively, were: United States, 40,258 and 65.7; United Kingdom, 343 and 232.6; Denmark, 616 and 305.5; Canada, 2709 and 177.5; case rates increased over time for the United States, Denmark, and Canada, but decreased in the United Kingdom. Across the United States and Denmark, HD was the preferred modality used. Toxins for which ECTR was most often used were: United States, ethylene glycol; Canada, methanol; United Kingdom, ethylene glycol; Denmark, salicylates. A high number of ECTRs were performed for atypical toxins such as acetaminophen and benzodiazepines. These data demonstrate a growing use of HD for poisoning with significant regional variations in the overall rates and indications.

Dietary protein level and source differentially affect bone metabolism, strength, and intestinal calcium transporter expression during ad libitum and food-restricted conditions in male rats.

High-protein (HP) diets may attenuate bone loss during energy restriction. The objective of the current study was to determine whether HP diets suppress bone turnover and improve bone quality in male rats during food restriction and whether dietary protein source affects this relation. Eighty 12-wk-old male Sprague Dawley rats were randomly assigned to consume 1 of 4 study diets under ad libitum (AL) control or restricted conditions [40% food restriction (FR)]: 1) 10% [normal-protein (NP)] milk protein; 2) 32% (HP) milk protein; 3) 10% (NP) soy protein; or 4) 32% (HP) soy protein. After 16 wk, markers of bone turnover, volumetric bone mineral density (vBMD), microarchitecture, strength, and expression of duodenal calcium channels were assessed. FR increased bone turnover and resulted in lower femoral trabecular bone volume (P < 0.05), higher cortical bone surface (P < 0.001), and reduced femur length (P < 0.01), bending moment (P < 0.05), and moment of inertia (P = 0.001) compared with AL. HP intake reduced bone turnover and tended to suppress parathyroid hormone (PTH) (P = 0.06) and increase trabecular vBMD (P < 0.05) compared with NP but did not affect bone strength. Compared with milk, soy suppressed PTH (P < 0.05) and increased cortical vBMD (P < 0.05) and calcium content of the femur (P < 0.01) but did not affect strength variables. During AL conditions, transient receptor potential cation channel, subfamily V, member 6 was higher for soy than milk (P < 0.05) and HP compared with NP (P < 0.05). These data demonstrate that both HP and soy diets suppress PTH, and HP attenuates bone turnover and increases vBMD regardless of FR, although these differences do not affect bone strength. The effects of HP and soy may be due in part to enhanced intestinal calcium transporter expression.