ABSTRACT Clonal hematopoiesis (CH) increases the risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1β alters population dynamics of hematopoietic cells upon Tet2 deletion ( Tet2 -KO) is not well understood. We demonstrated IL1β expands Tet2 -KO monocytes/macrophages, and long-term hematopoietic stem cells. IL1β promoted myeloid bias over other lineages of Tet2 -KO HSPCs coinciding with the failure to demethylate lineage-associated enhancer and transcription factor binding sites. IL1β enhanced the self-renewal ability of Tet2 -KO HSPCs by upregulating genes associated with self-renewal and by resisting the demethylation of binding sites of transcription factors promoting terminal differentiation. The IL1β-mediated premalignant phenotype is suppressed by the IL1β antagonist or deletion of the IL1 receptor-1, in vivo in aged mice. Our results demonstrate that targeting IL1 signaling could be an efficient early intervention strategy in preleukemic disorders. STATEMENT OF SIGNIFICANCE IL1β promoted myeloid expansion and self-renewal capacity of TET2-null pre-leukemic cells. Lineage bias occurred early within progenitors towards pro-inflammatory macrophages. Genes specific to aging and with roles in promoting self-renewal capacity, and myeloid bias were upregulated. Hypermethylation occurred within lymphoid and erythroid lineage-specific regulatory elements. Targeting IL1R1 reduced aberrant myeloid bias and premalignant phenotype.

PURPOSE: No single measure to detect real time hydration status is without limits; however, the validity of using urine specific gravity (USG) has received considerable scrutiny recently. Data used to draw these conclusions potentially suffers from multiple flaws (e.g. samples collected immediately after exercise or when significant sweat loss has not been incurred) in regards to practical application for runners. This study examined the efficacy of USG to detect inadequate beverage fluid consumption between training bouts in a twice-per-day training scenario. METHODS: Data was pooled from multiple studies resulting in 143 total samples. USG of male and female runners was measured 10-14 hours after runs of 60-90 min in temperate to hot environments. Two meals and snacks were provided during the recovery period of each study. Multiple type of beverages were consumed, and all beverage fluid consumption was measured with some samples being taken before and after the second meal. Pearson r was examined for percent of sweat loss that was replaced with fluid from beverages and USG. Inadequate fluid intake detection was deemed to have taken place when <100% of sweat losses were replaced and USG was ≥1.020. Analysis were repeated after removing 80 samples in which participants did not begin their run euhydrated (USG <1.020) and/or lost <3% body mass in sweat. RESULTS: When all samples were included, moderate correlation between fluid replacement percentage and USG (r = -0.50; p < 0.001) was found. Total false diagnosis was detected in 22.4% (n = 32) of samples with 22% of runners replacing <100% of sweat losses exhibiting a USG < 1.020. After removing samples correlation strength increased (r = -0.69). Total false diagnosis was reduced to 12.7% (n = 8), and most importantly error for runners replacing <100% of sweat losses exhibiting a USG < 1.020 was decreased to 15%. CONCLUSIONS: Pre-run spot USG assessment can be used as a practical field assessment to determine if intentional increased recovery fluid intake is warranted when training twice per day, particularly if the first running bout is undertaken in a euhydrated state (USG < 1.020) and significant sweat losses are incurred (3% body mass).

Background: Newborn screening (NBS) for hemoglobinopathies is important for the early detection and effective management of affected children. Objectives: To determine the frequency of occurrence, types of, and factors associated with abnormal haemoglobins in newborns at Muhimbili National Hospital (MNH), Dar es Salaam. Methods: A hospital-based, descriptive cross-sectional design was used to recruit newborns at Muhimbili National Hospital in 2009. Blood specimens were analyzed by High Performance Liquid Chromatography and alkaline Hb electrophoresis to determine the type and proportion of hemoglobin variants. Complete blood counts including red cell indices were done by automated hematology analyzer. Results: Out of 2,053 samples analyzed, the prevalence of hemoglobinopathies was 18.2% (n=374). The percentages of children with defined hemoglobinopathies included 12.6% (n=258) with sickle cell trait (Hb FAS); 0.9% (n=19) as sickle cell carrier or Hb S Beta + -thalassemia (Hb FSA); 0.54% (n=11) had SCA or Hb S Beta 0 -thalassemia (Hb FS); one Hb FA-D variant and 5.3% (n=109) with possibly α -thalassemia (Hb Bart’s). The frequency of occurrence of abnormal haemoglobins were highest among participants whose parental origin were Costal Regions, 35.6% (n=133) and Lake Zone, 10.2% (n=38). Participants from the Northern Region of Tanzania had the lowest frequency of occurrence, 6.7% (n=25) (X 2 = 37.7, p < 0.01). Having abnormal haemoglobins increased the likelihood of newborns being born at low gestational age (23.8%) by 1.5 fold as compared to newborns (16.3%) born without abnormal haemoglobins (X 2 =11.7, p=0.001). Conclusions: The frequency of occurrence of abnormal hemoglobin is high and fulfills the World Health Organization (WHO) criteria of a disorder of public health significance. Therefore, newborn screening programme is highly recommended in Tanzania. The ethnic origin of the parents and the gestational age were significantly associated with occurrence of abnormal haemoglobins. Keywords: Newborn screening, neonates , abnormal haemoglobins (Hemoglobinopathies), frequency of occurrence, High Performance Liquid Chromatography

Runners typically only replace a small percentage of sweat losses incurred during runs even if fluid are readily available. This paradigm createsadditional importance on adequately rehydrating between exercise bouts. PURPOSE: This study examined the effect of environmental conditions on voluntary fluid intake during and after runs of the same intensity. METHODS: Male runners (n = 12) completed two, 1-h treadmill runs at 65% VO2 max in a temperate (18 °C WBGT) and hot environment (26 °C WBGT). Runners were provided access to 750 mL of chilled water during each run and with a variety of beverages for the following 24-h. Body mass, fluid intake, urine specific gravity (USG), and urine output were measured at ~12 and 24-h post-run. RESULTS: Runners lost 1.355 ± 0.263 and 1.943 ± 0.485 L of sweat following runs in temperate and hot environments, respectively. Fluid intake during and at 1-h post-run was greater following runs in the heat, but did not differ at 12-h (2.202 ± 0.600 vs 2.265 ± 0.673 L) or 24-h (3.602 ± 0.807 vs 3.742 ± 1.205 L). There were no differences (p > 0.05) in body mass at 12 (temperate = 77.9 ± 6.8; hot = 77.6 ± 6.7 kg) or 24 h (temperate = 78.2 ± 6.6; hot = 78.0 ± 6.7 kg). Runners replaced a lower percentage of sweat losses and displayed higher USG (p < 0.001) for hot (119 ± 34%; 1.027 ± 0.004) versus temperate (166 ± 51%; 1.018 ± 0.004) at 12-h while exhibiting repeatable rehydration efforts (ICC = 0.80). Ten runners replaced <140% of sweat losses (3 replaced < 90%) and all 10 exhibited USG levels > 1.025 at 12-h. CONCLUSIONS: Voluntary fluid intake met the demands for most runners under temperate conditions. However, runners did not modify fluid replacement despite greater sweat losses following a run in the heat. This thirst threshold could potentially reduce subsequent run performance if training bouts are separated by ≤ 12 h. USG values exceeding 1.025 were able to identify runners that failed to replace fluids adequately. Spot USG assessment could be beneficial in detecting chronic hypohydraters.

Agonist-antagonist paired set (APS) training refers to resistance training that focuses on grouping exercises targeting the agonist and antagonist muscle groups in an alternating manner. PURPOSE: The current study compared set and total volumes between traditional (TRA) and APS resistance training during a flat bench press. METHODS: Nineteen male participants (age = 22.47 ± 1.80 years; height = 176.95 ± 6.53 cm; weight = 93.14 ± 28.08 kg) completed three resistance training sessions. One repetition maximum (RM) bench press and 20 RM seated cable rows were measured during the first session. Trial two and three were the experimental sessions consisting of TRA or APS protocols conducted in a randomized, counterbalanced design. During the trials, three sets of bench press to volitional failure (80% 1RM) were completed with 3-minute rest intervals between each set. During APS protocol, the rest period included 10 repetitions of seated cable rows (20RM load). RESULTS: The mean 1RM bench press, 80% 1RM bench press, and 20RM cable rows was 124.2 ± 23.5 kg, 99.8 ± 19.3 kg, and 51.0 ± 7.24 kg, respectively. A two-factor repeated measures analysis of variance revealed significant decreases in volume for both TRA (set 1: 1632.7 ± 386.4 kg; set 2: 1190.0 ± 209.2 kg; set 3: 930.1 ± 172.4 kg) and APS (set 1: 1579.1 ± 332.8 kg; set 2: 1172.0 ±269.6 kg; set 3: 909.1 ± 232.4 kg) as the sets progressed through the exercise session (p < .001). These decreases were similar between both methods (p = .471). There was not a significant interaction of volume between the APS and TRA groups (p = .772). CONCLUSION: The results indicate that there were no differences in volume between TRA and APS resistance session. The APS training appears to be a time efficient alternative to TRA resistance training.

OBJECTIVE:Glycemic variability may contribute to adverse medical outcomes of type 2 diabetes, but prior therapies have had limited success in controlling glycemic fluctuations, and the hypothesis has not been adequately tested.RESEARCH DESIGN AND METHODS:People with insulin-requiring type 2 diabetes and high cardiovascular risk were enrolled during a run-in period on basal-bolus insulin (BBI), and 102 were randomized to continued BBI or to basal insulin with a prandial GLP-1 receptor agonist (GLIPULIN) group, each seeking to maintain HbA(1c) levels between 6.7% and 7.3% (50-56 mmol/mol) for 6 months. The primary outcome measure was glycemic variability assessed by continuous glucose monitoring; other measures were HbA(1c), weight, circulating markers of inflammation and cardiovascular risk, albuminuria, and electrocardiographic patterns assessed by Holter monitoring.RESULTS:At randomization, the mean age of the population was 62 years, median duration of diabetes 15 years, mean BMI 34 kg/m(2), and mean HbA(1c) 7.9% (63 mmol/mol). Thirty-three percent had a prior cardiovascular event, 18% had microalbuminuria, and 3% had macroalbuminuria. At baseline, the continuous glucose monitoring coefficient of variation for glucose levels was similar in both groups.CONCLUSIONS:FLAT-SUGAR is a proof-of-concept study testing whether, in a population of individuals with type 2 diabetes and high cardiovascular risk, the GLIPULIN regimen can limit glycemic variability more effectively than BBI, reduce levels of cardiovascular risk markers, and favorably alter albuminuria and electrocardiographic patterns. We successfully randomized a population that has sufficient power to answer the primary question, address several secondary ones, and complete the protocol as designed.

Current American College of Sports Medicine (ACSM) guidelines recommend replacing 150% of sweat losses between training bouts separated by ≤12 hours, but little evidence exists concerning the implications of this strategy for runners. Participants (n = 13) in this study replaced 75% (1637 ± 372 mL) or 150% (3099 ± 850 mL) of sweat losses following an outdoor evening run (∼75 minutes; Wet-bulb-globe temperature (WBGT) = ∼27°C) and consumed a standardised evening meal and breakfast before completing an outdoor (WBGT = ∼23°C) 10-km time-trial the following morning. Urine was collected between runs and urine specific gravity (USG) was assessed pre-run. Significant differences were found in pre-run body mass (75% = 69.6 ± 9.2; 150% = 70.1 ± 9.3 kg; P = 0.02) and USG (75% = 1.026 ± 0.005; 150% = 1.014 ± 0.007; P < 0.001). Heart rate during 10-km run (168 ± 14 versus 168 ± 12 beats min(-1)) and post-run intestinal temperature (39.08 ± 0.52 versus 39.00 ± 0.70 °C) did not differ for 75% and 150%, respectively, despite an ∼3% performance improvement (75% = 47.28 ± 6.64; 150% = 45.93 ± 6.04 minutes; P = 0.001) due to a faster pace in the second half of the run with 150% replacement. Session rate of perceived exertion (RPE) was lower (P = 0.02) during 150% (7.5 ± 1.3) versus 75% (8.4 ± 0.9). Reluctant drinkers potentially hinder training quality between evening and morning runs in the heat, but copious urine production and difficulty in consuming recommended fluid volumes suggest fluid replacement <150% may be more ideal.

This study examined 24-h post-run hydration status and sweat loss estimation accuracy in college age runners (men=12, women=8) after completing a 1-h self-paced outdoor run (wet bulb globe temperature=19.9±3.0 °C). Sweat losses (1353±422 mL; 1.9%±0.5% of body mass) were significantly greater (p<0.001) than perceived losses (686±586 mL). Cumulative fluid consumption equaled 3876±1133 mL (218±178 mL during) with 37% of fluid ingested lost through urine voids (1450±678 mL). Fluid balance based on intake and urine production equaled +554±669 mL at 12 h and +1186±735 mL at 24 h. Most runners reported euhydrated (pre-run urine specific gravity (USG)=1.018±0.008) with no changes (p=0.33) at hours 12 or 24 when both genders were included. However, USG was higher (p=0.004) at 12 h post-run for men (1.025±0.0070 vs. 1.014±0.007), who consumed 171%±40% of sweat losses at 12 h vs. 268%±88% for women. Most runners do not need intervention concerning between bout hydration needs in temperate environments. However, repeated USG measurements were able to identify runners who greatly under or over consumed fluid during recovery. Practitioners can use multiple USG assessments as cheap method to detect runners who need to modify their hydration strategies and should promote assessment of sweat losses by change in body mass, as runners had poor perception of sweat losses.

Kinetic geochemical testwork is routinely used to assist with the acid and metalliferous drainage (AMD) assessment component of environmental and social impact studies during the pre-feasibility and feasibility stages of mine project development. Such studies are generally completed to fulfil regulatory requirements, but kinetic testwork data can also be relevant to mine planning, operations and the development of closure strategies. The three main types of kinetic geochemical test procedures are column or test pile leach, humidity cell and oxygen consumption. The primary aim of these tests is to quantify acidity generation rates, estimate the likely lag time prior to the onset of acid drainage and to provide an indication of the likely quality of leachate from mine materials. In essence, these tests routinely identify the need for AMD / NMD management and provide focus on problematic materials and potential soluble pollutants. The three common procedures offer different capabilities for assessing the geochemical behaviour of mine materials and the strengths and limitations of each approach is discussed. Recent advances in kinetic test procedures have extended their capabilities beyond routine assessment of material behaviour under wetting and drying scenarios, to the evaluation of closure scenarios of increasing complexity. Kinetic procedures now permit accurate determination of acidity generation rates from waste rock, wallrock in pits, underground voids, tailings, ore and concentrate as a function of particle size distribution, sulfide type, sulfide concentration, moisture content (analogue for oxygen diffusion), humidity, temperature, oxygen concentration and pore moisture pH. With independent control over these test variables, mine plans, closure strategies, remediation options and water treatment requirements can be more accurately designed and evaluated. Kinetic test procedures make it possible to quantify the likely performance of management strategies such as: oxygen limiting cover systems; waste rock encapsulation, waste rock blending or waste rock-tailings co-disposal; optimising waste rock compaction and moisture contents to limit acidity generation; limiting moisture contents in waste rock in arid settings; paste tailings, paste rock or tailings-cement mixtures; alkalinity producing covers to decrease the pyrite oxidation rate in mine wastes; variable depth water covers over tailings; and inert atmospheres in mine voids. The procedures can also assist with pit lake water quality modelling and dewatering water quality predictions. As their predictive capability improves, kinetic geochemical test procedures are becoming increasingly relevant to mine planning, operational activities, closure planning and site rehabilitation.