Citations

Background Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder affecting populations living in conditions of poor sanitation and hygiene. The study tested intestinal barrier function in infants with EED. Methods We prospectively studied an advanced high-performance liquid chromatography mass spectrometry assay of urine collected after oral intake of the monosaccharide, L-rhamnose and the disaccharide, lactulose, in 112 children from three continents. Findings Compared to the US cohort (n=27), the cohorts of children from Peru (n=19) and Zambia (n=85) were older with evidence of growth impairment. The median (range) of age (months) was 8.0 (2.0 to 13.0), 27.0 (15.0 to 29.0) and 21.0 (12.0 to 36.0), respectively. The median (range) of height for age Z score was −0.1 (−1.8 to 2.4), −1.8 (−3.3 to −0.2) and −2.3 (−8.5 to 1.2), respectively. Among children with valid sugar data (n=22 USA, n=19 Peru, n=73 Zambia), there were no significant differences in the median rhamnose urine concentrations between the three groups. The median (range) lactulose concentration (µg/mL) was 6.78 (0.29 to 31.90), 47.60 (4.23 to 379.00) and 75.40 (0.67 to 873.00) in the US, Peruvian and Zambian cohorts, respectively (p<0.001). The lactulose/rhamnose ratio (LRR) was higher in cohorts from Peru (0.75, 0.15, 5.02) and Zambia (2.26, 0.08, 14.48) compared to the US (0.14, 0.06, 1.00) cohort (p<0.001). In a multivariate effect modification model, higher weight-for-age z scores were associated with lower post-dose lactulose when rhamnose excretion was constant (p=0.003). Conclusions This non-invasive two saccharide permeability protocol measures changes in intestinal permeability in children with EED and permits the identification of individuals for interventional trials.

Significance Ubiquitin-specific protease 6 (USP6) is a deubiquitylase that is overexpressed by chromosome translocation in two human neoplasms, aneurysmal bone cyst and nodular fasciitis. The relevant substrates of this ubiquitin-specific protease are not clear. Here, we identify the Wnt receptor Frizzled (Fzd) as a key target of the USP6 oncogene. Increased expression of USP6 increases the membrane abundance of Fzd, and hence increases cellular sensitivity to Wnts. USP6 opposes the activity of the ubiquitin ligase and tumor suppressor ring finger protein 43 (RNF43). This study identifies a new mechanism for pathological Wnt pathway activation in human disease and suggests a new approach to regulate Wnt activity therapeutically.

A 39-year-old male, who recently underwent a composite valve graft of the aortic root and ascending aorta for bicuspid aortic valve and aortic root aneurysm, was hospitalized for severe sepsis, rhabdomyolysis (creatine kinase 29000 U/L), and severe liver dysfunction (AST > 7000 U/L, ALT 4228 U/L, and INR > 10). Cardiac magnetic resonance imaging (MRI) findings were consistent with sternal osteomyelitis with a 1.5 cm abscess at the inferior sternotomy margin, which was contiguous with pericardial thickening. Aspiration and culture of this abscess did not yield any organisms, so he was treated with vancomycin and cefepime empirically for 4 weeks. Because this patient was improving clinically on antibiotics and did not show external signs of wound infection, there was no compelling indication for sternectomy. This patient’s unusual presentation with osteomyelitis and rhabdomyolysis has never been reported and is crucial for clinicians to recognize in order to prevent delays in diagnosis.

AbstractBackgroundPressure drift (PD), resulting from differences between room and body temperature, reduces the accuracy of pressure measurements with the Manoscan high resolution manometry (HRM) system. Our aims were to assess PD during anorectal HRM.MethodsDefined as the residual pressure measured immediately after the catheter was removed, PD was calculated for each sensor and averaged across all 12 sensors in 454 anorectal consecutive studies recorded with 3 HRM catheters. The relationship between PD and study duration, number of prior uses of a catheter, and peak and average pressure exposure during a study were evaluated. The correction of PD with a software algorithm (thermal compensation) was evaluated in 76 studies where the most distal sensor was outside the body.Key ResultsThe PD varied among sensors and across catheters. The average PD (7.3 ± 0.2 mmHg) was significantly greater for newer catheters, during longer studies, or when sensors were exposed to higher pressures. Together, these factors explained 81% of the variance in overall PD. After thermal compensation, the uncorrected median PD for the most distal sensor was 2.5–5 mmHg over the study duration. Correcting this changed the interpretation (e.g., as abnormal instead of normal) of at least 1 anorectal parameter in eight of 76 studies.Conclusions & InferencesDuring anorectal HRM, PD declines with catheter use and is greater for newer catheters, when sensors are exposed to higher pressures, and for studies of longer duration. While PD is partially corrected with thermal compensation algorithms, the impact on interpretation is modest.

Abstract To move beyond a select few genes/drugs, the successful adoption of pharmacogenomics into routine clinical care requires a curated and machine-readable database of pharmacogenomic knowledge suitable for use in an electronic health record (EHR) with clinical decision support (CDS). Recognizing that EHR vendors do not yet provide a standard set of CDS functions for pharmacogenetics, the Clinical Pharmacogenetics Implementation Consortium (CPIC) Informatics Working Group is developing and systematically incorporating a set of EHR-agnostic implementation resources into all CPIC guidelines. These resources illustrate how to integrate pharmacogenomic test results in clinical information systems with CDS to facilitate the use of patient genomic data at the point of care. Based on our collective experience creating existing CPIC resources and implementing pharmacogenomics at our practice sites, we outline principles to define the key features of future knowledge bases and discuss the importance of these knowledge resources for pharmacogenomics and ultimately precision medicine.

Hypophosphatemia has been described in patients undergoing right hepatectomy for liver cancer and in living donors for liver transplantation who also received total parenteral nutrition. At the study centre, significant hypophosphatemia (0.36 mmol/L or less) requiring intravenous replacement was seen in two of the first nine living donors for adult-to-adult liver transplantation. To determine the frequency of hypophosphatemia in living donors, the authors obtained phosphate levels on stored serum samples from postoperative days 0, 1, 3 and 7 in all nine patients, none of whom were on total parenteral nutrition. Within the first week, hypophosphatemia developed in 55.6% of patients and phosphate levels returned to normal by day 7 in all nine patients. One patient had normal phosphate levels during the first week, but had profound hypophosphatemia (0.32 mmol/L) on day 14 when he presented with a Staphylococcus aureus infection of a bile collection and significant hypoxemia. The extent of hepatectomy and the rate of liver regeneration, estimated by baseline and postoperative day 7 volumetric computed tomography scans, did not correlate with the development of hypophosphatemia. In conclusion, hypophosphatemia is common in living donors undergoing right hepatectomy and may be associated with complications. All living donors should be monitored for the development of hypophosphatemia during the first two postoperative weeks.