Screening for SARS-CoV-2 Infection Within a Psychiatric Hospital and Considerations for Limiting Transmission Within Residential Psychiatric Facilities - Wyoming, 2020.

In the United States, approximately 180,000 patients receive mental health services each day at approximately 4,000 inpatient and residential psychiatric facilities (1). SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), can spread rapidly within congregate residential settings (2-4), including psychiatric facilities. On April 13, 2020, two patients were transferred to Wyoming's state psychiatric hospital from a private psychiatric hospital that had confirmed COVID-19 cases among its residents and staff members (5). Although both patients were asymptomatic at the time of transfer and one had a negative test result for SARS-CoV-2 at the originating facility, they were both isolated and received testing upon arrival at the state facility. On April 16, 2020, the test results indicated that both patients had SARS-CoV-2 infection. In response, the state hospital implemented expanded COVID-19 infection prevention and control (IPC) procedures (e.g., enhanced screening, testing, and management of new patient admissions) and adapted some standard IPC measures to facilitate implementation within the psychiatric patient population (e.g., use of modified face coverings). To assess the likely effectiveness of these procedures and determine SARS-CoV-2 infection prevalence among patients and health care personnel (HCP) (6) at the state hospital, a point prevalence survey was conducted. On May 1, 2020, 18 days after the patients' arrival, 46 (61%) of 76 patients and 171 (61%) of 282 HCP had nasopharyngeal swabs collected and tested for SARS-CoV-2 RNA by reverse transcription-polymerase chain reaction. All patients and HCP who received testing had negative test results, suggesting that the hospital's expanded IPC strategies might have been effective in preventing the introduction and spread of SARS-CoV-2 infection within the facility. In congregate residential settings, prompt identification of COVID-19 cases and application of strong IPC procedures are critical to ensuring the protection of other patients and staff members. Although standard guidance exists for other congregate facilities (7) and for HCP in general (8), modifications and nonstandard solutions might be needed to account for the specific needs of psychiatric facilities, their patients, and staff members.

Urinary biomarker incorporation into the renal angina index early in intensive care unit admission optimizes acute kidney injury prediction in critically ill children: a prospective cohort study.

BACKGROUND: The inconsistent ability of novel biomarkers to predict acute kidney injury (AKI) across heterogeneous patients and illnesses limits integration into routine practice. We previously retrospectively validated the ability of the renal angina index (RAI) to risk-stratify patients and provide context for confirmatory serum biomarker testing for the prediction of severe AKI. METHODS: We conducted this first prospective study of renal angina to determine whether the RAI on the day of admission (Day0) risk-stratified critically ill children for 'persistent, severe AKI' on Day 3 (Day3-AKI: KDIGO Stage 2-3) and whether incorporation of urinary biomarkers in the RAI model optimized AKI prediction. RESULTS: A total of 184 consecutive patients (52.7% male) were included. Day0 renal angina was present (RAI ≥8) in 60 (32.6%) patients and was associated with longer duration of mechanical ventilation (P = 0.04), higher number of organ failure days (P = 0.003) and increased mortality (P < 0.001) than in patients with absence of renal angina. Day3-AKI was present in 15/156 (9.6%) patients; 12/15 (80%) fulfilled Day0 renal angina. Incorporation of urinary biomarkers into the RAI model increased the specificity and positive likelihood, and demonstrated net reclassification improvement (P < 0.001) for the prediction of Day3-AKI. Inclusion of urinary neutrophil gelatinase-associated lipocalin increased the area under the curve receiver-operating characteristic of RAI for Day3-AKI from 0.80 [95% confidence interval (CI): 0.58, 1.00] to 0.97 (95% CI: 0.93, 1.00). CONCLUSIONS: We have now prospectively validated the RAI as a functional risk stratification methodology in a heterogeneous group of critically ill patients, providing context to direct measurement of novel urinary biomarkers and improving the prediction of severe persistent AKI.

Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in critically ill children (AWARE): study protocol for a prospective observational study.

BACKGROUND: Acute kidney injury (AKI) is associated with poor outcome in critically ill children. While data extracted from retrospective study of pediatric populations demonstrate a high incidence of AKI, the literature lacks focused and comprehensive multicenter studies describing AKI risk factors, epidemiology, and outcome. Additionally, very few pediatric studies have examined novel urinary biomarkers outside of the cardiopulmonary bypass population. METHODS/DESIGN: This is a prospective observational study. We anticipate collecting data on over 5000 critically ill children admitted to 31 pediatric intensive care units (PICUs) across the world during the calendar year of 2014. Data will be collected for seven days on all children older than 90 days and younger than 25 years without baseline stage 5 chronic kidney disease, chronic renal replacement therapy, and outside of 90 days of a kidney transplant or from surgical correction of congenital heart disease. Data to be collected includes demographic information, admission diagnoses and co-morbidities, and details on fluid and vasoactive resuscitation used. The renal angina index will be calculated integrating risk factors and early changes in serum creatinine and fluid overload. On days 2-7, all hemodynamic and pertinent laboratory values will be captured focusing on AKI pertinent values. Daily calculated values will include % fluid overload, fluid corrected creatinine, and KDIGO AKI stage. Urine will be captured twice daily for biomarker analysis on Days 0-3 of admission. Biomarkers to be measured include neutrophil gelatinase lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (l-FABP), and interleukin-18 (IL-18). The primary outcome to be quantified is incidence rate of severe AKI on Day 3 (Day 3-AKI). Prediction of Day 3-AKI by the RAI and after incorporation of biomarkers with RAI will be analyzed. DISCUSSION: The Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology (AWARE) study, creates the first prospective international pediatric all cause AKI data warehouse and biologic sample repository, providing a broad and invaluable resource for critical care nephrologists seeking to study risk factors, prediction, identification, and treatment options for a disease syndrome with high associated morbidity affecting a significant proportion of hospitalized children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01987921.

Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in Critically Ill Children (AWARE): A Prospective Study to Improve Diagnostic Precision.

BACKGROUND: Acute kidney injury (AKI) is associated with poor outcomes in critically ill children. Recent international consensus panels recommend standardized classification systems to improve the precision of AKI diagnosis, but there is a paucity of data to enable this refinement, particularly in pediatric critical care. METHODS/DESIGN: This is a prospective observational study. We anticipate collecting data from more than 5500 critically ill children admitted to 32 pediatric intensive care units (PICUs) across the world, during the calendar year of 2014. Data will be collected continuously for three months at each center on all children older than 90 days and younger than 25 years admitted to the ICU. Demographic, resuscitative, and daily physiological and lab data will be captured at individual centers using MediData Rave™, a commercial system designed to manage and report clinical research data. Kidney specific measured variables include changes in serum creatinine and urine output, cumulative fluid overload (%), serum creatinine corrected for fluid balance, and KDIGO AKI stage. Urinary AKI biomarkers to be measured include: urinary neutrophil gelatinase lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (l-FABP), and interleukin-18 (IL-18). Biomarker combinations will be created from different pairs and triplets of urinary biomarkers. The primary analysis will compare the discrimination of these panels versus changes in creatinine for prediction of severe AKI by Day 7 of ICU admission. Secondary analysis will investigate the prediction of biomarkers for injury 'time based phenotypes': duration (>2 days), severity (KDIGO stage, use of renal replacement therapy), reversibility (time to return of serum creatinine to baseline), association with fluid overload > 10%, and disease association (sepsis, hypovolemia, hypoxemia, or nephrotoxic). DISCUSSION: The Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology (AWARE) study will be the largest ever prospective study of any disease process in pediatric critical care. Data from AWARE will enable refinement of AKI classification. AWARE creates the largest ever all-cause pediatric AKI data warehouse and biologic sample repository, providing a broad and invaluable resource for critical care nephrologists seeking to study risk factors, prediction, identification, and treatment options for a disease syndrome with high associated morbidity affecting a significant proportion of hospitalized children. Improving the precision of AKI diagnosis using biomarker combinations provides a foundation for targeted, personalized therapy for different injury phenotypes. TRIAL REGISTRATION NUMBER: NCT01987921.

Accuracy and reproducibility of bending stiffness measurements by mechanical response tissue analysis in artificial human ulnas.

Osteoporosis is characterized by reduced bone strength, but no FDA-approved medical device measures bone strength. Bone strength is strongly associated with bone stiffness, but no FDA-approved medical device measures bone stiffness either. Mechanical Response Tissue Analysis (MRTA) is a non-significant risk, non-invasive, radiation-free, vibration analysis technique for making immediate, direct functional measurements of the bending stiffness of long bones in humans in vivo. MRTA has been used for research purposes for more than 20 years, but little has been published about its accuracy. To begin to investigate its accuracy, we compared MRTA measurements of bending stiffness in 39 artificial human ulna bones to measurements made by Quasistatic Mechanical Testing (QMT). In the process, we also quantified the reproducibility (i.e., precision and repeatability) of both methods. MRTA precision (1.0±1.0%) and repeatability (3.1 ± 3.1%) were not as high as those of QMT (0.2 ± 0.2% and 1.3+1.7%, respectively; both p<10(-4)). The relationship between MRTA and QMT measurements of ulna bending stiffness was indistinguishable from the identity line (p=0.44) and paired measurements by the two methods agreed within a 95% confidence interval of ± 5%. If such accuracy can be achieved on real human ulnas in situ, and if the ulna is representative of the appendicular skeleton, MRTA may prove clinically useful.

Activating mutations of Tn3 resolvase marking interfaces important in recombination catalysis and its regulation.

Catalysis of DNA recombination by Tn3 resolvase is conditional on prior formation of a synapse, comprising 12 resolvase subunits and two recombination sites (res). Each res binds a resolvase dimer at site I, where strand exchange takes place, and additional dimers at two adjacent 'accessory' binding sites II and III. 'Hyperactive' resolvase mutants, that catalyse strand exchange at site I without accessory sites, were selected in E. coli. Some single mutants can resolve a res x site I plasmid (that is, with one res and one site I), but two or more activating mutations are necessary for efficient resolution of a site I x site I plasmid. Site I x site I resolution by hyperactive mutants can be further stimulated by mutations at the crystallographic 2-3' interface that abolish activity of wild-type resolvase. Activating mutations may allow regulatory mechanisms of the wild-type system to be bypassed, by stabilizing or destabilizing interfaces within and between subunits in the synapse. The positions and characteristics of the mutations support a mechanism for strand exchange by serine recombinases in which the DNA is on the outside of a recombinase tetramer, and the tertiary/quaternary structure of the tetramer is reconfigured.

Agonist-induced capping of adhesion proteins and microparticle shedding in cultures of human renal microvascular endothelial cells.

Capping and release of membranous, small (< 1.5 microm) endothelial microparticles were quantified by immunofluorescence microscopy and flow cytometry after treatment of cultures of human renal microvascular endothelial cells with agonists tumor necrosis factor-alpha (TNF-alpha) or mitomycin C. For constitutive marker CD31, both agonist-treated attached, monolayer, and detached, free endothelial cells formed caps and released microparticles. TNF-alpha and mitomycin C induced dissimilar appearing CD31-containing caps after 3 h, followed by endothelial microparticle release after 6 h. The degree of capping correlated with increasing counts of released microparticles. For lymphokine-inducible CD54, TNF-alpha also induced CD54-containing caps and microparticle release, but mitomycin C failed to induce the expression of either entity. Neither capping nor microparticle release caused by TNF-alpha was part of an apoptotic pathway that involved caspase 3. Mitomycin C treatment of endothelial cells caused capping and microparticle release with a time course similar to TNF-alpha induction for 15 to 24 h, but assays for caspase 3 were positive, confirming the apoptotic action of mitomycin C. Membrane capping and microparticle release from endothelial cells are a convenient experimental model for studying protein movement, release of microparticles, and their possible biological significance.