The influence of dietary carbohydrate and fat on kidney calcification and the urinary excretion of N-acetyl-beta-glucosaminidase (EC 3.2.1.30).

1. Male Sprague-Dawley rats were fed on diets containing either sucrose or starch as the carbohydrate component. In one experiment, the diets also contained 200 g either butter or polyunsaturated margarine/kg; in a second experiment, the diets contained less fat in the form of 20 g maize oil/kg. 2. Over a period of 11 months assays were made in the urine of several ions and of the activity of the enzyme N-acetyl-β-glucosaminidase (β-2-acetamido-2-deoxy-β-D glucoside acetamidodeoxygluco-hydrolase; EC 3.2.1.30); at 13 months, examination was made of some of the abdominal viscera, especially of the kidneys. 3. In rats fed on the higher amount of fat, dietary sucrose produced a higher activity of the enzyme than did dietary starch, and a greater excretion of inorganic phosphate. 4. With both the higher and lower amounts of dietary fat, sucrose led to an increase in the weight of the liver and of the kidneys, and an increase in the concentration of calcium and of phosphate in kidney tissue. With the higher amount of fat, sucrose also produced an increase in the concentration of magnesium in the kidney. There was no difference in the concentration of any of the ions assayed in the plasma or, apart from inorganic phosphate, in the urine. 5. The kidneys of the sucrose-fed rats showed nephrocalcinosis, mostly in the cortico-medullary region, and basophilic deposits in the tubules. Attention is drawn to this unusual occurrence of nephrocalcinosis in male rats

Comparison of the EPIC Physical Activity Questionnaire with combined heart rate and movement sensing in a nationally representative sample of older British adults

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Identifying Improved Sites for Heterologous Gene Integration Using ATAC-seq

Constructing efficient cellular factories often requires integration of heterologous pathways for synthesis of novel compounds and improved cellular productivity. Few genomic sites are routinely used, however, for efficient integration and expression of heterologous genes, especially in nonmodel hosts. Here, a data-guided framework for informing suitable integration sites for heterologous genes based on ATAC-seq was developed in the nonmodel yeast Komagataella phaffii. Single-copy GFP constructs were integrated using CRISPR/Cas9 into 38 intergenic regions (IGRs) to evaluate the effects of IGR size, intensity of ATAC-seq peaks, and orientation and expression of adjacent genes. Only the intensity of accessibility peaks was observed to have a significant effect, with higher expression observed from IGRs with low- to moderate-intensity peaks than from high-intensity peaks. This effect diminished for tandem, multicopy integrations, suggesting that the additional copies of exogenous sequence buffered the transcriptional unit of the transgene against effects from endogenous sequence context. The approach developed from these results should provide a basis for nominating suitable IGRs in other eukaryotic hosts from an annotated genome and ATAC-seq data

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS

Multifaceted intervention to reduce haemodialysis catheter related bloodstream infections: REDUCCTION stepped wedge, cluster randomised trial.

OBJECTIVE: To identify whether multifaceted interventions, or care bundles, reduce catheter related bloodstream infections (CRBSIs) from central venous catheters used for haemodialysis. DESIGN: Stepped wedge, cluster randomised design. SETTING: 37 renal services across Australia. PARTICIPANTS: All adults (age ≥18 years) under the care of a renal service who required insertion of a new haemodialysis catheter. INTERVENTIONS: After a baseline observational phase, a service-wide, multifaceted intervention bundle that included elements of catheter care (insertion, maintenance, and removal) was implemented at one of three randomly assigned time points (12 at the first time point, 12 at the second, and 13 at the third) between 20 December 2016 and 31 March 2020. MAIN OUTCOMES MEASURE: The primary endpoint was the rate of CRBSI in the baseline phase compared with intervention phase at the renal service level using the intention-to-treat principle. RESULTS: 1.14 million haemodialysis catheter days of use were monitored across 6364 patients. Patient characteristics were similar across baseline and intervention phases. 315 CRBSIs occurred (158 in the baseline phase and 157 in the intervention phase), with a rate of 0.21 per 1000 days of catheter use in the baseline phase and 0.29 per 1000 days in the intervention phase, giving an incidence rate ratio of 1.37 (95% confidence interval 0.85 to 2.21; P=0.20). This translates to one in 10 patients who undergo dialysis for a year with a catheter experiencing an episode of CRBSI. CONCLUSIONS: Among patients who require a haemodialysis catheter, the implementation of a multifaceted intervention did not reduce the rate of CRBSI. Multifaceted interventions to prevent CRBSI might not be effective in clinical practice settings. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12616000830493

Trends in healthcare utilization among older Americans with colorectal cancer: A retrospective database analysis

<p>Abstract</p> <p>Background</p> <p>Analyses of utilization trends (cost drivers) allow us to understand changes in colorectal cancer (CRC) costs over time, better predict future costs, identify changes in the use of specific types of care (eg, hospice), and provide inputs for cost-effectiveness models. This retrospective cohort study evaluated healthcare resource use among US Medicare beneficiaries diagnosed with CRC between 1992 and 2002.</p> <p>Methods</p> <p>Cohorts included patients aged 66+ newly diagnosed with adenocarcinoma of the colon (n = 52,371) or rectum (n = 18,619) between 1992 and 2002 and matched patients from the general Medicare population, followed until death or December 31, 2005. Demographic and clinical characteristics were evaluated by cancer subsite. Resource use, including the percentage that used each type of resource, number of hospitalizations, and number of hospital and skilled nursing facility days, was evaluated by stage and subsite. The number of office, outpatient, and inpatient visits per person-year was calculated for each cohort, and was described by year of service, subsite, and treatment phase. Hospice use rates in the last year of life were calculated by year of service, stage, and subsite for CRC patients who died of CRC.</p> <p>Results</p> <p>CRC patients (mean age: 77.3 years; 44.9% male) used more resources than controls in every category (<it>P </it>< .001), with the largest differences seen in hospital days and home health use. Most resource use (except hospice) remained relatively steady over time. The initial phase was the most resource intense in terms of office and outpatient visits. Hospice use among patients who died of CRC increased from 20.0% in 1992 to 70.5% in 2004, and age-related differences appear to have evened out in later years.</p> <p>Conclusion</p> <p>Use of hospice care among CRC decedents increased substantially over the study period, while other resource use remained generally steady. Our findings may be useful for understanding CRC cost drivers, tracking trends, and forecasting resource needs for CRC patients in the future.</p

Detection of weak gravitational lensing distortions of distant galaxies by cosmic dark matter at large scales

Most of the matter in the universe is not luminous and can be observed directly only through its gravitational effect. An emerging technique called weak gravitational lensing uses background galaxies to reveal the foreground dark matter distribution on large scales. Light from very distant galaxies travels to us through many intervening overdensities which gravitationally distort their apparent shapes. The observed ellipticity pattern of these distant galaxies thus encodes information about the large-scale structure of the universe, but attempts to measure this effect have been inconclusive due to systematic errors. We report the first detection of this ``cosmic shear'' using 145,000 background galaxies to reveal the dark matter distribution on angular scales up to half a degree in three separate lines of sight. The observed angular dependence of this effect is consistent with that predicted by two leading cosmological models, providing new and independent support for these models.Comment: 18 pages, 5 figures: To appear in Nature. (This replacement fixes tex errors and typos.

Future changes in tropical cyclone activity in the North Indian Ocean projected by high-resolution MRI-AGCMs

Open Access at publisher's web site: http://www.springerlink.com/content/b682734237171631

Group interventions to improve health outcomes : a framework for their design and delivery

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