Improving clinical prediction rules in acute kidney injury with the use of biomarkers of cell cycle arrest: a pilot study.

INTRODUCTION: Early recognition of patients developing acute kidney injury (AKI) is of considerable interest, we report the first use of a combination of a clinical prediction rule with a biomarker in emergent adult medical patients to improve AKI recognition. METHODS: Single-centre prospective pilot study of medical admissions without AKI identified as high risk by a clinical prediction rule. Urine samples were obtained and tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) - biomarkers associated with cell cycle arrest, were measured. OUTCOME: Creatinine-based KDIGO hospital-acquired AKI (HA-AKI). RESULTS: Of 69 patients recruited, HA-AKI developed in 13% (n = 9), in whom biomarker values were higher (median 0.43 (interquartile range (IQR) 0.21-1.25) vs. 0.07 (0.03-0.16) in cases without (p = 0.008). Peak rise in creatinine was higher in biomarker positive cases (median 30 µmol/L (7-72) vs. 1 µmol/L (0-16), p = 0.002). AUROC was 0.78 (95% CI 0.57-0.98). At the suggested cut-off (0.3) sensitivity for predicting AKI was 78% (95% CI 40-97%), specificity 89% (78-95%), positive predictive value 50% (31-69%) and negative predictive value 96% (89-99%). DISCUSSION: Addition of a urinary biomarker allows exclusion of a significant number of patients identified to be at higher risk of AKI by a clinical prediction rule.

Association between collapse and serum creatinine and electrolyte concentrations in marathon runners: a 9-year retrospective study.

OBJECTIVE: Abnormal biochemical measurements have previously been described in runners following marathons. The incidence of plasma sodium levels outside the normal range has been reported as 31%, and the incidence of raised creatinine at 30%. This study describes the changes seen in electrolytes and creatinine in collapsed (2010-2019 events) and noncollapsed (during the 2019 event) runners during a UK marathon. METHODS: Point-of-care sodium, potassium, urea and creatinine estimates were obtained from any collapsed runner treated by the medical team during the Brighton Marathons, as part of their clinical care, and laboratory measurements from control subjects. RESULTS: Results from 224 collapsed runners were available. Serum creatinine was greater than the normal range in 68.9%. About 6% of sodium results were below, and 3% above the normal range, with the lowest 132 mmol/l. Seventeen percent of potassium readings were above the normal range; the maximum result was 8.4 mmol/l, but 97% were below 6.0 mmol/l. In the control group, mean creatinine was significantly raised in both the collapse and control groups, with 55.4% meeting the criteria for acute kidney injury, but had resolved to baseline after 24 h. Sodium concentration but not the potassium was significantly raised after the race compared with baseline, but only 15% were outside the normal range. CONCLUSION: In this study, incidence of a raised creatinine was higher than previously reported. However, the significance of such a rise remains unclear with a similar rise seen in collapsed and noncollapsed runners, and resolution noted within 24 h. Abnormal sodium concentrations were observed infrequently, and severely abnormal results were not seen, potentially reflecting current advice to drink enough fluid to quench thirst.

A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator.

Selective progesterone receptor modulators (SPRMs) have been suggested as therapeutic agents for treatment of gynecological disorders. One such SPRM, asoprisnil, was recently in clinical trials for treatment of uterine fibroids and endometriosis. We present the crystal structures of progesterone receptor (PR) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor (NCoR) and SMRT. This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors. These structures show PR in a different conformation than PR complexed with progesterone (P4). We profiled asoprisnil in PR-dependent assays to understand further the PR-mediated mechanism of action. We confirmed previous findings that asoprisnil demonstrated antagonism, but not agonism, in a PR-B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay. Asoprisnil, but not RU486, weakly recruited the coactivators SRC-1 and AIB1. However, asoprisnil strongly recruited the corepressor NCoR in a manner similar to RU486. Unlike RU486, NCoR binding to asoprisnil-bound PR could be displaced with equal affinity by NCoR or TIF2 peptides. We further showed that it weakly activated T47D cell gene expression of Sgk-1 and PPL and antagonized P4-induced expression of both genes. In rat leiomyoma ELT3 cells, asoprisnil demonstrated partial P4-like inhibition of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In the rat uterotrophic assay, asoprisnil demonstrated no P4-like ability to oppose estrogen. Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to RU486 or P4, and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus.

Process characterization of powder blending by near-infrared spectroscopy: blend end-points and beyond.

The purpose of this paper is to utilize near-infrared (NIR) spectroscopy to characterize powder blending in-line. A multivariate model-based approach was used to determine end-point and variability at the end-point of blending processes. Two monitoring positions for NIR spectrometers were evaluated; one was located on the top of the Bin-blender and the other was on the rotation axis. A ternary powder mixture including acetaminophen (APAP, fine and coarse powder), lactose (LAC) and microcrystalline cellulose (MCC, Avicel 101 and 200) was used as a test system. A Plackett-Burman design of experiments (DOE) for different blending parameters and compositions was utilized to compare the robustness of end-point determination between the multivariate model-based algorithm and reference algorithms. The end-point determination algorithm, including root mean square from nominal value (RMSNV) and two-tailed Student's t-test, was developed based on PLS predicted concentrations of all three constituents. Mean and standard deviation of RMSNV after end-point were used to characterize blending variability at the end-point. The blending end-point and variability of two sensors were also compared. The multivariate model-based algorithm proved to be more robust on end-point determination compared to the reference algorithms. Blending behavior at the two sensor locations demonstrated a significant difference in terms of end-point and blending variability, indicating the advantage to employ process monitoring via NIR spectroscopy on more than one location on the Bin-blender.

A COMBINED TREATMENT APPROACH EMPHASIZING IMPAIRMENT-BASED MANUAL THERAPY AND EXERCISE FOR HIP-RELATED COMPENSATORY INJURY IN ELITE ATHLETES: A CASE SERIES.

BACKGROUND/PURPOSE: Athletes experiencing hip, groin, and low back pain often exhibit similar clinical characteristics. Individuals with hip, groin and low back pain may have the presence of multiple concurrent pathoanatomical diagnoses. Regardless, similar regional characteristics and dysfunction may contribute to the patient's chief complaint, potentially creating a sub-group of individuals that may be defined by lumbopelvic and hip mobility limitations, motor control impairments, and other shared clinical findings. The purpose of this case series is to describe the conservative management of elite athletes, within the identified aforementioned sub-group, that emphasized regional manual therapy interventions, and therapeutic exercise designed to improve lumbopelvic and hip mobility, stability and motor control. CASE DESCRIPTIONS: Five elite athletes were clinically diagnosed by a physical therapist with primary pathologies including adductor-related groin pain (ARGP), femoral acetabular impingement (FAI) with acetabular labral lesion and acute, mechanical low back pain (LBP). Similar subjective, objective findings and overall clinical profiles were identified among all subjects. Common findings aside from the chief complaint included, but were not limited to, decreased hip range of motion (ROM), impaired lumbopelvic motor control and strength, lumbar hypomobility in at least one segment, and a positive hip flexion-adduction-internal rotation (FADIR) special test. A three-phase impairment-based physical therapy program was implemented to resolve the primary complaints and return the subjects to their desired level of function. Acute phase rehabilitation consisted of manual therapy and fundamental motor control exercises. Progression to the sub-acute and terminal phases was based on improved subjective pain reports and progress with functional impairments. As the subjects progress through the rehabilitation phases, the delivery of physical therapy interventions were defined by decreased manual therapies and an increased emphasis and priority on graded exercise. OUTCOMES: Significant reductions in reported pain (>2 points Numeric Pain Rating Scale), improved reported function via functional outcome measures (Hip and Groin Outcome Score), and continued participation in sport occurred in all five cases without the need for surgical intervention. DISCUSSION: The athletes described in this case series make up a common clinical sub-group defined by hip and lumbopelvic mobility restrictions, lumbopelvic and lower extremity motor control impairments and potentially other shared clinical findings. Despite differences in pathoanatomic findings, similar objective findings were identified and similar treatment plans were applied, potentially affecting the movement system as a whole. Subjects were conservatively managed allowing continued participation in sport within their competitive seasons. CONCLUSION: Comprehensive conservative treatment of the athletes with shared impairments, as described in this case series, may be of clinical importance when managing athletes with hip, groin, and low back pain. LEVEL OF EVIDENCE: Therapy, Level 4, Case Series.