Somatic PIK3R1 variation as a cause of vascular malformations and overgrowth

PURPOSE: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1. METHODS: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity. RESULTS: The phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone. CONCLUSION: Somatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway

Comparison of a nurse initiated insulin infusion protocol for intensive insulin therapy between adult surgical trauma, medical and coronary care intensive care patients

<p>Abstract</p> <p>Background</p> <p>Sustained hyperglycemia is a known risk factor for adverse outcomes in critically ill patients. The specific aim was to determine if a nurse initiated insulin infusion protocol (IIP) was effective in maintaining blood glucose values (BG) within a target goal of 100–150 mg/dL across different intensive care units (ICUs) and to describe glycemic control during the 48 hours after protocol discontinuation.</p> <p>Methods</p> <p>A descriptive, retrospective review of 366 patients having 28,192 blood glucose values in three intensive care units, Surgical Trauma Intensive Care Unit (STICU), Medical (MICU) and Coronary Care Unit (CCU) in a quaternary care hospital was conducted. Patients were > 15 years of age, admitted to STICU (n = 162), MICU (n = 110) or CCU (n = 94) over 8 months; October 2003-June 2004 and who had an initial blood glucose level > 150 mg/dL. We summarized the effectiveness and safety of a nurse initiated IIP, and compared these endpoints among STICU, MICU and CCU patients.</p> <p>Results</p> <p>The median blood glucose values (mg/dL) at initiation of insulin infusion protocol were lower in STICU (188; IQR, 162–217) than in MICU, (201; IQR, 170–268) and CCU (227; IQR, 178–313); <it>p </it>< 0.0001. Mean time to achieving a target glucose level (100–150 mg/dL) was similar between the three units: 4.6 hours in STICU, 4.7 hours in MICU and 4.9 hours in CCU (<it>p </it>= 0.27). Hypoglycemia (BG < 60 mg/dL) occurred in 7% of STICU, 5% of MICU, and 5% of CCU patients (<it>p </it>= 0.85). Protocol violations were uncommon in all three ICUs. Mean blood glucose 48 hours following IIP discontinuation was significantly different for each population: 142 mg/dL in STICU, 167 mg/dL in MICU, and 160 mg/dL in CCU (<it>p </it>< 0.0001).</p> <p>Conclusion</p> <p>The safety and effectiveness of nurse initiated IIP was similar across different ICUs in our hospital. Marked variability in glucose control after the protocol discontinuation suggests the need for further research regarding glucose control in patients transitioning out of the ICU.</p

Parameterizing and Validating Existing Algorithms for Identifying Out-of-Bed Time Using Hip-Worn Accelerometer Data from Older Women

Objective: To parameterize and validate two existing algorithms for identifying out-of-bed time using 24-hour hip-worn accelerometer data from older women. Approach: Overall, 628 women (80±6 years old) wore ActiGraph GT3X+ accelerometers 24 hours/day for up to 7 days and concurrently completed sleep-logs. Trained staff used a validated visual analysis protocol to measure in-bed periods on accelerometer tracings (criterion). The Tracy and McVeigh algorithms were adapted for optimal use in older adults. A training set of 314 women was used to choose two key thresholds by maximizing the sum of sensitivity and specificity for each algorithm and data (vertical axis, VA, and vector magnitude, VM) combination. Data from the remaining 314 women were then used to test agreement in waking wear time (i.e., out-of-bed time while wearing the accelerometer) by computing sensitivity, specificity, and kappa comparing the algorithm output with the criterion. Waking wear time-adjusted means of sedentary time, light-intensity physical activity (light PA) and moderate-to-vigorous-intensity physical activity (MVPA) were then estimated and compared. Main results: Waking wear time agreement with the criterion was high for Tracy_VA, Tracy_VM, McVeigh_VA, and highest for McVeigh_VM. Compared to the criterion, McVeigh_VM had mean sensitivity=0.92, specificity=0.87, kappa=0.80, and overall mean difference (±SD) of -0.04±2.5 hours/day. Minutes of sedentary time, light PA, and MVPA adjusted for waking wear time using the criterion measure and McVeigh_VM were not statistically different (p \u3e0.43 | all). Significance: The McVeigh algorithm with optimal parameters using VM performed best compared to criterion sleep-log assisted visual analysis and is suitable for automated identification of waking wear time in older women when visual analysis is not feasible

Association of Light Physical Activity Measured by Accelerometry and Incidence of Coronary Heart Disease and Cardiovascular Disease in Older Women

IMPORTANCE To our knowledge, no studies have examined light physical activity (PA) measured by accelerometry and heart disease in older women. OBJECTIVE To investigate whether higher levels of light PA were associated with reduced risks of coronary heart disease (CHD) or cardiovascular disease (CVD) in older women. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of older women from baseline (March 2012 to April 2014) through February 28, 2017, for up to 4.91 years. The setting was community-dwelling participants from the Women's Health Initiative. Participants were ambulatory women with no history of myocardial infarction or stroke. EXPOSURES Data from accelerometers worn for a requested 7 days were used to measure light PA. MAIN OUTCOMES AND MEASURES Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs for physician-adjudicated CHD and CVD events across light PA quartiles adjusting for possible confounders. Light PA was also analyzed as a continuous variable with and without adjustment for moderate to vigorous PA (MVPA). RESULTS Among 5861 women (mean [SD] age, 78.5 [6.7] years), 143 CHD events and 570 CVD events were observed. The HRs for CHD in the highest vs lowest quartiles of light PA were 0.42 (95% CI, 0.25-0.70; P for trend <. 001) adjusted for age and race/ethnicity and 0.58 (95% CI, 0.34-0.99; P for trend = .004) after additional adjustment for education, current smoking, alcohol consumption, physical functioning, comorbidity, and self-rated health. Corresponding HRs for CVD in the highest vs lowest quartiles of light PA were 0.63 (95% CI, 0.49-0.81; P for trend <. 001) and 0.78 (95% CI, 0.60-1.00; P for trend = .004). The HRs for a 1-hour/day increment in light PA after additional adjustment for MVPA were 0.86 (95% CI, 0.73-1.00; P for trend = .05) for CHD and 0.92 (95% CI, 0.85-0.99; P for trend = .03) for CVD. CONCLUSIONS AND RELEVANCE The present findings support the conclusion that all movement counts for the prevention of CHD and CVD in older women. Large, pragmatic randomized trials are needed to test whether increasing light PA among older women reduces cardiovascular risk.National Heart, Lung, and Blood Institute (NHLBI) [R01 HL105065]; NHLBI [T32HL079891-11]; National Institutes of Health; US Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Exercise and pregnancy in recreational and elite athletes: 2016/17 evidence summary from the IOC Expert Group Meeting, Lausanne. Part 3 - Exercise in the postpartum period

This is Part 3 in the series of reviews from the IOC expert committee on exercise and pregnancy in recreational and elite athletes. Part 1 focused on the effects of training during pregnancy and on the management of common pregnancy-related complaints experienced by athletes1; Part 2 addressed maternal and fetal perinatal outcomes.2 In this part, we review the implications of pregnancy and childbirth on return to exercise and on common illnesses and complaints in the postpartum period. The postpartum period can be divided into hospital-based (during hospital stay), immediate postpartum (hospital discharge to 6 weeks postpartum) and later postpartum (6 weeks to 1 year, corresponding sometimes to cessation of breast feeding).3 In the literature, the postpartum period is usually defined as the first 6 weeks after pregnancy, during which time women have not typically been encouraged to exercise, except for strength training of the pelvic floor muscles. However, 6 weeks is an arbitrary time point and, anecdotally, many elite athletes report starting exercise inside that period. For the purpose of the present review, we consider the postpartum period to be up to 12 months following birth

The Organization of Agricultural Research in Western Developed Countries

This paper reviews agricultural research structural and organization changes in western developed countries, examines new financing prospects for agricultural research, and provides some tentative conclusions about which organizations are best positioned to provide services for the 21st century. Giventhat these countries faces many similar economic, political, scientific, andagroclimatic factors and fiscal issues, we canexpect a similar set of similar new developments thathave potentially important and widespread long-run implications. After three common developments are outlined, principles ofimpure public good financing are applied leading to the following agricultural science policy recommendations (i) new political jurisdictions should be formed to finance research, e.g., new alliances across countries and subregions within large countries, (ii) intellecmal property rights should be strengthened to increase the total amount and share oftotal (public and private) agricultural research that is privately financed and conducted, i.e., the private sector should find it profitable to undertake a large share ofapplied research but not be expected to finance public sector agriculmral research, (iii) the public sector should redirect its research efforts increasingly to areas that are socially worthwhile but not privately undertaken, e.g.,in the basic and pretechnology areas, on envkonmental, resources, food safety and human nutrition, and policy. Finally, large countries that have developed asystem ofshared public and private financmg and performance and decentralized public support ofagricultural research seem best position for meeting the needs ofthe 21st centur

Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data

We report a quasi-differential upper limit on the extremely-high-energy (EHE) neutrino flux above $5\times 10^{6}$ GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above $10^{6}$ GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between $5 \times 10^{6}$ and $5 \times 10^{10}$ GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\ {\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}$at$10^9\ {\rm GeV}$. A significant part of the parameter-space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review

The prevalence and correlates of physical inactivity among adults in Ho Chi Minh City

<p>Abstract</p> <p>Background</p> <p>Socioeconomic changes have led to profound changes in individuals' lifestyles, including the adoption of unhealthy food consumption patterns, prevalent tobacco use, alcohol abuse and physical inactivity, especially in large cities like Ho Chi Minh City (HCMC). The Stepwise Approach to Surveillance of Non-communicable Disease Risk Factors survey was conducted to identify physical activity patterns and factors associated with 'insufficient' levels of physical activity for health in adults in HCMC.</p> <p>Methods</p> <p>A cross-sectional survey was conducted in 2005 among 1906 adults aged 25–64 years using a probability proportional to size cluster sampling method to estimate the prevalence of non-communicable disease risk factors including physical inactivity. Data on socioeconomic status, health behaviours, and time spent in physical activity during work, commuting and leisure time were collected. Physical activity was measured using the validated Global Physical Activity Questionnaire (GPAQ). Responders were classified as 'sufficiently active' or 'insufficiently active' using the GPAQ protocol. Correlates of insufficient physical activity were identified using multivariable logistic regression.</p> <p>Results</p> <p>A high proportion of adults were physically inactive, with only 56.2% (95% CI = 52.1–60.4) aged 25–64 years in HCMC achieving the minimum recommendation of 'doing 30 minutes moderate-intensity physical activity for at least 5 days per week'. The main contributors to total physical activity among adults were from working and active commuting. Leisure-time physical activity represented a very small proportion (9.4%) of individuals' total activity level. Some differences in the pattern of physical activity between men and women were noted, with insufficient activity levels decreasing with age among women, but not among men. Physical inactivity was positively associated with high income (OR = 1.77, 95% CI = 1.05–2.97) and high household wealth index (OR = 1.86, 95% CI = 1.29–2.66) amongst men.</p> <p>Conclusion</p> <p>Public health policies and programs to preserve active commuting in HCMC and to promote time spent in recreational physical activity in both genders and across all age groups, but especially among young adults, will be critical in any comprehensive national plan to tackle inactivity. Clear and consistent national recommendations about how much physical activity Vietnamese people need for preventing and managing non-communicable diseases should also be part of this population-wide promotional effort.</p

Comparison of Questionnaire and Device Measures of Physical Activity and Sedentary Behavior in a Multi-Ethnic Cohort of Older Women

Background: Limited data are available regarding the correlation between questionnaire and device-measured physical activity (PA) and sedentary behavior (SB) in older women. Methods:We evaluated these correlations in 5,992 women, aged 63 and older, who completed the Women’s Health Initiative (WHI) and Community Healthy Activities Model Program for Seniors (CHAMPS) PA questionnaires and the CARDIA SB questionnaire prior to wearing a hip-worn accelerometer for 7 consecutive days. Accelerometer-measured total, light, and moderate-to-vigorous PA (MVPA), and total SB time were defined according to cutpoints established in a calibration study. Spearman coefficients were used to evaluate correlations between questionnaire and device-measures. Results: Mean time spent in PA and SB was lower for questionnaire than accelerometer measures, with variation in means according to age, race/ethnicity, bodymass index, and functional status. Overall, correlations between questionnaires and accelerometer measures were moderate for total PA, MVPA, and SB (r ≈ 0.20–0.40). Light intensity PA correlated weakly for WHI (r ≈ 0.01–0.06) and was variable for CHAMPS (r ≈ 0.07–0.22). Conclusion: Questionnaire and accelerometer estimates of total PA, MVPA, and SB have at best moderate correlations in older women and should not be assumed to be measuring the same behaviors or quantity of behavior. Light intensity PA is poorly measured by questionnaire. Because light intensity activities account for the largest proportion of daily activity time in older adults, and likely contribute to its health benefits, further research should investigate how to improve measurement of light intensity PA by questionnaires

Home-based exercise rehabilitation in addition to specialist heart failure nurse care: design, rationale and recruitment to the Birmingham Rehabilitation Uptake Maximisation study for patients with congestive heart failure (BRUM-CHF): a randomised controlled trial

BACKGROUND: Exercise has been shown to be beneficial for selected patients with heart failure, but questions remain over its effectiveness, cost-effectiveness and uptake in a real world setting. This paper describes the design, rationale and recruitment for a randomised controlled trial that will explore the effectiveness and uptake of a predominantly home-based exercise rehabilitation programme, as well as its cost-effectiveness and patient acceptability. METHODS/DESIGN: Randomised controlled trial comparing specialist heart failure nurse care plus a nurse-led predominantly home-based exercise intervention against specialist heart failure nurse care alone in a multiethnic city population, served by two NHS Trusts and one primary care setting, in the United Kingdom. 169 English speaking patients with stable heart failure, defined as systolic impairment (ejection fraction ≤ 40%). with one or more hospital admissions with clinical heart failure or New York Heart Association (NYHA) II/III within previous 24-months were recruited. Main outcome measures at 1 year: Minnesota Living with Heart Failure Questionnaire, incremental shuttle walk test, death or admission with heart failure or myocardial infarction, health care utilisation and costs. Interviews with purposive samples of patients to gain qualitative information about acceptability and adherence to exercise, views about their treatment, self-management of their heart failure and reasons why some patients declined to participate. The records of 1639 patients managed by specialist heart failure services were screened, of which 997 (61%) were ineligible, due to ejection fraction>40%, current NYHA IV, no admission or NYHA II or more within the previous 2 years, or serious co-morbidities preventing physical activity. 642 patients were contacted: 289 (45%) declined to participate, 183 (39%) had an exclusion criterion and 169 (26%) agreed to randomisation. DISCUSSION: Due to safety considerations for home-exercise less than half of patients treated by specialist heart failure services were eligible for the study. Many patients had co-morbidities preventing exercise and others had concerns about undertaking an exercise programme