Calcineurin inhibitor effects on kidney electrolyte handling and blood pressure: tacrolimus versus voclosporin.

BACKGROUND AND HYPOTHESIS: Calcineurin inhibitors affect kidney electrolyte handling and blood pressure through an effect on the distal tubule. The second generation calcineurin inhibitor voclosporin causes hypomagnesemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. METHODS: Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric blood pressure recordings, and analysis of mRNA and protein levels of distal tubular transporters at day 28. RESULTS: Compared to vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at mRNA and/or protein level, including the sodium-chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium-calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium-chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased blood pressure, whereas voclosporin caused a gradual but persistent increase in blood pressure which was further characterized by high renin, normal aldosterone, and low endothelin-1. CONCLUSIONS: In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two calcineurin inhibitors.

Complexity leadership in action: a team science case study.

Introduction: This team science case study explores one cross-disciplinary science institute's change process for redesigning a weekly research coordination meeting. The narrative arc follows four stages of the adaptive process in complex adaptive systems: disequilibrium, amplification, emergence, and new order. Methods: This case study takes an interpretative, participatory approach, where the objective is to understand the phenomena within the social context and deepen understanding of how the process unfolds over time and in context. Multiple data sources were collected and analyzed. Results: A new adaptive order for the weekly research coordination meeting was established. The mechanism for the success of the change initiative was best explained by complexity leadership theory. Discussion: Implications for team science practice include generating momentum for change, re-examining power dynamics, defining critical teaming professional roles, building multiple pathways towards team capacity development, and holding adaptive spaces. Promising areas for further exploration are also presented.

Feasibility of an adaptive riding pilot study and acceptability to dementia care partners: "Your spirits are lifted".

OBJECTIVES: We sought to assess the feasibility and acceptability of an adaptive riding program with dyads (persons living with dementia, family care partners) and a gardening comparison condition. DESIGN: This is a two-arm (adaptive riding and adaptive gardening), mixed methods, convergent, feasibility study that occurred February 2019-June 2019. INTERVENTIONS: Upon enrollment, dyads (n=9) self-selected into either community-based adaptive riding (n=5) or adaptive gardening (n=4), two complementary interventions in Northern Colorado. Interventions occurred for hour-long, weekly sessions for eight weeks. OUTCOME MEASURES: Feasibility was measured with recruitment (actual/planned, response rate, participants enrolled/month) retention, adherence to study procedures (attendance, retention, fidelity), and data collection processes (planned versus collected); and analyzed with descriptive statistics. Acceptability of adaptive riding was measured with pre/post care partner interviews and analyzed using thematic analysis. Afterwards, findings were converged. RESULTS: We recruited n=10/24 dyads (6 dyads per month), with the highest response rates for referrals and in-person events, n=9 dyads enrolled. We adhered to study procedures with attendance (6/8 gardening, 8/8 riding), retention (100%), fidelity (100%) and data collected (98%). Care partners (n=5) found the adaptive riding intervention acceptable with two themes Overall hopes: "Joy in the present moment" and "Experience as a Whole: "Your spirits are lifted," affirming quantitative attendance and retention data. CONCLUSION: Findings underscore the feasibility and acceptability of including care partners of persons living with dementia in complementary interventions involving horsemanship activities. Feasibility data can guide study designs and implementation processes for other nature-based complementary interventions for this population.

The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.

Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI's in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.

Relationships between social climate and indoor environmental quality and frequently reported health symptoms among teachers and staff in a suburban school district.

Public school teachers represent one of the largest occupational groups in the United States and are vulnerable to job stress and burnout. School social and physical environments may be adversely impacting the health of teachers and other staff, though few studies have explored these relationships. We partnered with a suburban school district in Colorado to assess the association between school environmental quality, social climate, and staff member health. We modeled the number of self-reported frequent health symptoms (experienced at least once a week) using generalized linear models. School-level predictors of interest included: overall social climate scores (unitless), building operations report card (ORC) scores (unitless), and indoor air quality (IAQ) scores (unitless). In total, we had data from 134 staff members from 11 schools in the district. A majority (62%) of our participants were teachers, who reported a greater number of frequent (i.e., at least once a week) health symptoms (mean = 3.2 symptoms experienced at least once per week) compared to staff in other roles (mean = 2.3 symptoms per week). We found that a one standard-deviation (10.5) increase in the overall social climate score was associated with a 0.77-fold (95% CI: 0.60-0.99) change in the number of frequent health symptoms reported. However, this association was attenuated among teachers compared to other staff members. Our results suggested effect modification by social climate on the relationship between IAQ and health, albeit with some uncertainty. For participants with a school climate score below the mean, a one standard-deviation (10.5) increase in IAQ score was associated with a 0.49-fold (95% CI: 0.35-0.70) change in the number of frequently reported symptoms. Overall, our study suggests school climate may be associated with self-reported health symptoms, but that the benefits of improved school climates may not be as strong for teachers compared to other staff. Future work should assess perceived climate at the individual level to assess how staff roles impact how school environments are associated with health outcomes.

Surviving and Thriving: Qualitative Results from a Multi-Year, Multidimensional Intervention to Promote Well-Being among Caregivers of Adults with Dementia.

(1) Introduction: Caring for an adult with dementia is both challenging and rewarding. Research indicates that community-based, social support, and/or arts engagement interventions can play a key role in ameliorating the negative outcomes associated with caregiving while enhancing its more positive attributes. This study explores the psychosocial outcomes experienced by dementia caregivers who participated in a multi-year, multidimensional intervention aimed at promoting caregiver and care recipient well-being. This intervention included bringing caregivers and people with Alzheimer's disease or related dementias (ADRD) to local symphony performances, hosting a social reception prior to the performance, and assessing the outcomes of participation for both caregiver and the care recipient. (2) Materials, Methods, and Analysis: Qualitative data from participant phone interviews (n = 55) as well as focus groups are analyzed using thematic analysis from a phenomenological perspective. (3) Results: Across three years of participation, caregivers reported three main program benefits: relationship building (both with other participants as well as within the broader community); restored humanity (experiencing a greater sense of personal dignity and momentary return to normalcy), and positivity (experiencing positive emotions during the program). (4) Discussion: These findings point to the value of creating caregiver programming that brings together multiple dimensions of successful interventions in order to enhance caregiver experiences and positive intervention outcomes.

Tiny Bodies, Big Needs: Prospective Biobanking of Neonatal Clinical Remnant Samples.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.

A comparison of quality of life indicators during two complementary interventions: adaptive gardening and adaptive riding for people with dementia.

OBJECTIVES: We sought to provide a fine-grain description and comparison of how people living with dementia responded to adaptive gardening and adaptive riding through durations of their observed participation and emotional well-being, two dimensions of quality of life. DESIGN: A descriptive case study design enabled in-depth description and comparison of participation and emotional well-being, two quality of life indicators, observed during four videotaped sessions of adaptive gardening and adaptive riding. INTERVENTIONS: Eight people living with dementia self-selected into one of two complementary interventions, community-based adaptive gardening (n = 4) or adaptive riding (n = 4), in Northern Colorado. Both occurred for hour-long, weekly sessions for eight-weeks. OUTCOME MEASURE: Durations of observed quality of life indicators of participation and apparent affect were documented using a modified version of the Activity-in-Context-in-Time on 31 hours of videotaped data. Durations for each quality of life indicator were averaged per participant and aggregated by group for comparison using a Wilcoxon Mann-Whitney U test RESULTS: Both interventions supported emotional well-being and participation. Longer durations of active participation were observed during adaptive riding with significantly higher durations of complex active participation (U = 16, p= 0.029). CONCLUSION: Both interventions supported quality of life and merit continued development. Adaptive riding appeared to support longer durations of active participation with more complex forms when compared to adaptive gardening. Findings can inform healthcare providers' recommendations for adaptive gardening and adaptive riding for people with dementia. More research is needed with a larger sample size to further examine similarities and differences.

Obesity as a Risk Factor for Radiographic Contrast-Induced Nephropathy.

Contrast-induced nephropathy (CIN) is common. Risk factors include preexisting renal impairment, diabetes, elderly age, and dehydration. In a single-centre prospective study, we investigated which factors are implicated for CIN in patients with peripheral arterial disease due for angiography. Serum creatinine was measured before, 1, 2, and 7 days post-angiography. We also considered the chronic kidney disease stage of the patients at admission and 48 hours post-contrast. All patients received 500 mL normal saline pre- and post-angiography and a low-osmolality contrast medium. 6 of 94 patients developed CIN: 1 required dialysis and 1 died partly due to renal failure. Only 2 factors were associated with CIN: body mass index (BMI; P = .019) and kidney function (P = .001); 4 of 6 patients with CIN were obese (BMI ≥30) and only 2 were nonobese (P = .0092). Diabetes, contrast volume, and age were not significant risk factors. Our results confirm renal impairment raises the risk of CIN. To our knowledge, we report for the first time that obesity may be a risk factor for CIN. Pending confirmatory studies and given the rising prevalence of obesity, this finding could help identify at-risk patients and hence reduce the burden of CIN.

A Unique Presentation of an Ectopic Pregnancy After Appendectomy.

Ectopic pregnancies account for the majority of deaths in early pregnancy. A 27-year-old woman with unexplained infertility and a history of an appendectomy was referred to the reproductive endocrinology clinic. She was initially diagnosed with a pregnancy of unknown location and was later found to have an ectopic pregnancy. Final pathology found a surgical staple likely present from a previous appendectomy within the fallopian tube proximal to the ectopic site. The surgical staple is postulated to have entered the tube through ciliary action and caused the ectopic pregnancy. This rare case highlights physicians' need to carefully monitor and remove visible loose staples after using automated stapling devices.

Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets.

The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin. Voclosporin (VCS), a next-generation calcineurin inhibitor, is reported to cause fewer incidences of NODAT but the reason is unclear. While calcineurin signaling plays important roles in pancreatic ß-cell survival, proliferation, and function, its effects on human ß-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied 2 clinically relevant doses of TAC (10 ng/mL, 30 ng/mL) and VCS (20 ng/mL, 60 ng/mL), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad, and milder, effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery.

Diabetes, Fetal Demise, and Shoulder Dystocia: The Importance of Glucose Screening to Prevent Catastrophic Obstetric Outcomes.

Diabetes is associated with increased risk of stillbirth and shoulder dystocia. Compared with uncomplicated pregnancies, diabetic patients have a 4-6x risk of stillbirth and 2-3x risk of shoulder dystocia. A 34 yo G2P0010 presented with a 40+3 wga IUFD with nonstandard antenatal glucose screening. Admission labs included a hemoglobin A1c of 6.6. She had a vaginal delivery complicated by a 30-minute shoulder dystocia that was not relieved by McRoberts, suprapubic pressure, Rubin II, Wood's Screw, or posterior arm delivery. Nitroglycerine was administered, after which Wood's Screw was successful resulting in delivery of an infant weighing 4190 grams (85th percentile for gestational age). A 31 yo G1 presented with a 37+1 wga IUFD. Her 28 wga three-hour GTT was notable for an elevated value at one hour (216 mg/dL). Admission labs included a hemoglobin A1c of 6.6. She had a vaginal delivery complicated by a 30-minute shoulder dystocia that was relieved via posterior axillary sling after failure of McRoberts, suprapubic pressure, Rubin II, Wood's Screw, and Gaskin's, resulting in the delivery of an infant weighing 3590 g (92nd percentile for gestational age). We present two cases of severe shoulder dystocia in patients who both presented with term IUFD and diabetic-range hemoglobin A1c. There is minimal literature on diabetic patients with pregnancies affected by both stillbirth and shoulder dystocia. These cases underscore the importance of glucose screening and control to prevent catastrophic obstetric outcomes.

Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells.

PURPOSE: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies. EXPERIMENTAL DESIGN: In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models. RESULTS: Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition. CONCLUSIONS: Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.

B Sharp-The cognitive effects of a pilot community music program for people with dementia-related disorders.

INTRODUCTION: Dementia has been described as the greatest global challenge for healthcare in the 21st century. Pharmaceutical interventions have dominated dementia treatment despite limited efficacy. There is increasing interest in alternatives to delay the progression of cognitive decline, such as community-based programs, promoting social and stimulating experiences. This article discusses a pilot music-based community program (B Sharp) for persons with dementia-related disorders. METHOD: In the pilot study, we assessed 23 persons with dementia-related disorders who, with their caregivers, attended the symphony season and accompanying social hours over a 10-month period. Participants completed a baseline and follow-up brief neuropsychological test to assess cognitive changes. RESULTS: Significant improvements were observed between the pre- and post-B Sharp program assessments (P < .010). DISCUSSION: Results support the feasibility of the B Sharp program as a community-based program to target cognitive decline. Additional research is needed to understand the mechanisms involved in the improvements observed in this program.

Implementation of a Digitally Enabled Care Pathway (Part 2): Qualitative Analysis of Experiences of Health Care Professionals.

BACKGROUND: One reason for the introduction of digital technologies into health care has been to try to improve safety and patient outcomes by providing real-time access to patient data and enhancing communication among health care professionals. However, the adoption of such technologies into clinical pathways has been less examined, and the impacts on users and the broader health system are poorly understood. We sought to address this by studying the impacts of introducing a digitally enabled care pathway for patients with acute kidney injury (AKI) at a tertiary referral hospital in the United Kingdom. A dedicated clinical response team-comprising existing nephrology and patient-at-risk and resuscitation teams-received AKI alerts in real time via Streams, a mobile app. Here, we present a qualitative evaluation of the experiences of users and other health care professionals whose work was affected by the implementation of the care pathway. OBJECTIVE: The aim of this study was to qualitatively evaluate the impact of mobile results viewing and automated alerting as part of a digitally enabled care pathway on the working practices of users and their interprofessional relationships. METHODS: A total of 19 semistructured interviews were conducted with members of the AKI response team and clinicians with whom they interacted across the hospital. Interviews were analyzed using inductive and deductive thematic analysis. RESULTS: The digitally enabled care pathway improved access to patient information and expedited early specialist care. Opportunities were identified for more constructive planning of end-of-life care due to the earlier detection and alerting of deterioration. However, the shift toward early detection also highlighted resource constraints and some clinical uncertainty about the value of intervening at this stage. The real-time availability of information altered communication flows within and between clinical teams and across professional groups. CONCLUSIONS: Digital technologies allow early detection of adverse events and of patients at risk of deterioration, with the potential to improve outcomes. They may also increase the efficiency of health care professionals' working practices. However, when planning and implementing digital information innovations in health care, the following factors should also be considered: the provision of clinical training to effectively manage early detection, resources to cope with additional workload, support to manage perceived information overload, and the optimization of algorithms to minimize unnecessary alerts.

Implementation of a Digitally Enabled Care Pathway (Part 1): Impact on Clinical Outcomes and Associated Health Care Costs.

BACKGROUND: The development of acute kidney injury (AKI) in hospitalized patients is associated with adverse outcomes and increased health care costs. Simple automated e-alerts indicating its presence do not appear to improve outcomes, perhaps because of a lack of explicitly defined integration with a clinical response. OBJECTIVE: We sought to test this hypothesis by evaluating the impact of a digitally enabled intervention on clinical outcomes and health care costs associated with AKI in hospitalized patients. METHODS: We developed a care pathway comprising automated AKI detection, mobile clinician notification, in-app triage, and a protocolized specialist clinical response. We evaluated its impact by comparing data from pre- and postimplementation phases (May 2016 to January 2017 and May to September 2017, respectively) at the intervention site and another site not receiving the intervention. Clinical outcomes were analyzed using segmented regression analysis. The primary outcome was recovery of renal function to ≤120% of baseline by hospital discharge. Secondary clinical outcomes were mortality within 30 days of alert, progression of AKI stage, transfer to renal/intensive care units, hospital re-admission within 30 days of discharge, dependence on renal replacement therapy 30 days after discharge, and hospital-wide cardiac arrest rate. Time taken for specialist review of AKI alerts was measured. Impact on health care costs as defined by Patient-Level Information and Costing System data was evaluated using difference-in-differences (DID) analysis. RESULTS: The median time to AKI alert review by a specialist was 14.0 min (interquartile range 1.0-60.0 min). There was no impact on the primary outcome (estimated odds ratio [OR] 1.00, 95% CI 0.58-1.71; P=.99). Although the hospital-wide cardiac arrest rate fell significantly at the intervention site (OR 0.55, 95% CI 0.38-0.76; P<.001), DID analysis with the comparator site was not significant (OR 1.13, 95% CI 0.63-1.99; P=.69). There was no impact on other secondary clinical outcomes. Mean health care costs per patient were reduced by £2123 (95% CI -£4024 to -£222; P=.03), not including costs of providing the technology. CONCLUSIONS: The digitally enabled clinical intervention to detect and treat AKI in hospitalized patients reduced health care costs and possibly reduced cardiac arrest rates. Its impact on other clinical outcomes and identification of the active components of the pathway requires clarification through evaluation across multiple sites.

Evaluation of a digitally-enabled care pathway for acute kidney injury management in hospital emergency admissions.

We developed a digitally enabled care pathway for acute kidney injury (AKI) management incorporating a mobile detection application, specialist clinical response team and care protocol. Clinical outcome data were collected from adults with AKI on emergency admission before (May 2016 to January 2017) and after (May to September 2017) deployment at the intervention site and another not receiving the intervention. Changes in primary outcome (serum creatinine recovery to ≤120% baseline at hospital discharge) and secondary outcomes (30-day survival, renal replacement therapy, renal or intensive care unit (ICU) admission, worsening AKI stage and length of stay) were measured using interrupted time-series regression. Processes of care data (time to AKI recognition, time to treatment) were extracted from casenotes, and compared over two 9-month periods before and after implementation (January to September 2016 and 2017, respectively) using pre-post analysis. There was no step change in renal recovery or any of the secondary outcomes. Trends for creatinine recovery rates (estimated odds ratio (OR) = 1.04, 95% confidence interval (95% CI): 1.00-1.08, p = 0.038) and renal or ICU admission (OR = 0.95, 95% CI: 0.90-1.00, p = 0.044) improved significantly at the intervention site. However, difference-in-difference analyses between sites for creatinine recovery (estimated OR = 0.95, 95% CI: 0.90-1.00, p = 0.053) and renal or ICU admission (OR = 1.06, 95% CI: 0.98-1.16, p = 0.140) were not significant. Among process measures, time to AKI recognition and treatment of nephrotoxicity improved significantly (p < 0.001 and 0.047 respectively).

24-Hour vs. Spot Urinary Sodium and Potassium Measurements in Adult Hypertensive Patients: A Cohort Validation Study.

BACKGROUND: Sodium intake is correlated with the development of hypertension. Guyton's principals suggest that the 24-hour urinary sodium excretion reflects sodium ingestion over the same period. 24-hour urine collections are arduous to collect, so many centers use spot urinary measurements instead. We compared spot to matched 24-hour urinary electrolyte measurements. METHODS: We examined 419 hypertensive patients from the UCL Complex Hypertension Clinic. 77 had matched and complete 24-hour and spot urinary and serum biochemistry to examine.We compared the spot and 24-hour urinary; sodium concentration, Na/Cr ratio, FENa, Kawasaki and Tanaka estimated sodium excretion as well as the potassium concentration, K/Cr ratio, Kawasaki and Tanaka potassium excretion. RESULTS: Our cohort was 58% male and the median age was 41 years. The 24-hour and spot Na concentrations correlated moderately (r = 0.4633, P < 0.0001). The 24-hour and spot Na/creatinine ratios correlated weakly (r = 0.2625, P = 0.0194). The 24-hour and spot FENa results showed a weak negative correlation (r = -0.222, P = ns). The 24-hour sodium excretion and the Kawasaki-derived spot urine sodium excretion correlated moderately (r = 0.3118, P = 0.0052). All Bland-Altman analyses showed poor agreement.The 24-hour and spot potassium concentrations correlated very poorly (r = 0.1158, P = ns). The 24-hour and spot urinary K/creatinine ratios correlated weakly (r = 0.47, P ≤ 0.0001). 24-hour and Kawasaki and Tanaka estimated potassium excretions correlated much better (r = 0.58, P < 0.0001). CONCLUSIONS: Spot urinary measurements of sodium give a very poor understanding of the natriuresis occurring over the same 24-hour period. The Kawasaki and Tanaka estimations of the 24-hour sodium excretion showed a much lower correlation than previously reported.

AQX-1125, small molecule SHIP1 activator inhibits bleomycin-induced pulmonary fibrosis.

BACKGROUND AND PURPOSE: The phosphatase SHIP1 negatively regulates the PI3K pathway, and its predominant expression within cells of the haematopoietic compartment makes SHIP1 activation a novel strategy to limit inflammatory signalling generated through PI3K. AQX-1125 is the only clinical-stage, orally administered, SHIP1 activator. Here, we demonstrate the prophylactic and therapeutic effects of AQX-1125, in a mouse model of bleomycin-induced lung fibrosis. EXPERIMENTAL APPROACH: For prophylactic evaluation, AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or dexamethasone (1 mg·kg-1 ·d-1 , i.p.) were given to CD-1 mice starting 3 days before intratracheal administration of bleomycin (0.1 IU per mouse) and continued daily for 7 or 21 days. Therapeutic potentials of AQX-1125 (3, 10 or 30 mg·kg-1 ·d-1 , p.o.) or pirfenidone (90 mg·kg-1 ·d-1 , p.o.) were assessed by initiating treatment 13 days after bleomycin instillation and continuing until day 28. KEY RESULTS: Given prophylactically, AQX-1125 (10 and 30 mg·kg-1 ) reduced histopathological changes in lungs, 7 and 21 days following bleomycin-induced injury. At the same doses, AQX-1125 reduced the number of total leukocytes, neutrophil activity, TGF-ß immunoreactivity and soluble collagen in lungs. Administered therapeutically, AQX-1125 (10 and 30 mg·kg-1 ) improved lung histopathology, cellular infiltration and reduced lung collagen content. At 30 mg·kg-1 , the effects of AQX-1125 were similar to those of pirfenidone (90 mg·kg-1 ) with corresponding improvements in disease severity. CONCLUSIONS AND IMPLICATIONS: AQX-1125 prevented bleomycin-induced lung injury during the inflammatory and fibrotic phases. AQX-1125, given therapeutically, modified disease progression and improved survival, as effectively as pirfenidone.