Intestinal barrier disruption with Plasmodium falciparum infection in pregnancy and risk of preterm birth: a cohort study.

BACKGROUND: Malaria in early pregnancy is a risk factor for preterm birth and is associated with sustained inflammation and dysregulated angiogenesis across gestation. This study investigated whether malaria is associated with increased gut leak and whether this contributes to systemic inflammation, altered angiogenesis, and preterm birth. METHODS: We quantified plasma concentrations of gut leak markers, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) from 1339 HIV-negative pregnant Malawians at <24 weeks gestational age. We assessed the relationship of sCD14 and LBP concentrations with markers of inflammation, angiogenesis, and L-arginine bioavailability and compared them between participants with and without malaria, and with and without preterm birth. FINDINGS: Plasma concentrations of sCD14 and LBP were significantly higher in participants with malaria and were associated with parasite burden (p <0.0001, both analyses and analytes). The odds ratio for preterm birth associated with one log sCD14 was 2.67 (1.33 to 5.35, p = 0.006) and 1.63 (1.07-2.47, p = 0.023) for LBP. Both gut leak analytes were positively associated with increases in proinflammatory cytokines CRP, sTNFR2, IL18-BP, CHI3L1 and Angptl3 (p <0.05, all analytes) and sCD14 was significantly associated with angiogenic proteins Angpt-2, sENG and the sFLT:PlGF ratio (p <0.05, all analytes). sCD14 was negatively associated with L-arginine bioavailability (p <0.001). INTERPRETATION: Malaria in early pregnancy is associated with intestinal barrier dysfunction, which is linked to an increased risk of preterm birth. FUNDING: Open Philanthropy, Canadian Institutes of Health Research, Canada Research Chair program, European and Developing Countries Clinical Trials Partnership, Bill & Melinda Gates Foundation.

Soluble Urokinase-Type Plasminogen Activator Receptor as a Prognostic Marker of Ugandan Children at Risk of Severe and Fatal Malaria.

BACKGROUND: Current malaria diagnostic tests do not reliably identify children at risk of severe and fatal infection. Host immune and endothelial activation contribute to malaria pathogenesis. Soluble urokinase-type plasminogen activator receptor (suPAR) is a marker of these pathways. We hypothesized that measuring suPAR at presentation could risk-stratify children with malaria. METHODS: Plasma suPAR levels were determined in consecutive febrile children with malaria at presentation to hospital in Jinja, Uganda. We evaluated the accuracy of suPAR in predicting in-hospital mortality, and whether suPAR could improve a validated clinical scoring system (Lambaréné Organ Dysfunction Score [LODS]). RESULTS: Of the 1226 children with malaria, 39 (3.2%) died. suPAR concentrations at presentation were significantly higher in children who went on to die than in those who survived (P < .0001). suPAR levels were associated with disease severity (LODS: 0 vs 1, P = .001; 1 vs 2, P < .001; 2 vs 3, 0 vs 2, 1 vs 3, and 0 vs 3, P < .0001). suPAR concentrations were excellent predictors of in-hospital mortality (area under the receiver operating characteristic curve [AUROC], 0.92 [95% confidence interval {CI}, .91-.94]). The prognostic accuracy of LODS (AUROC, 0.93 [95% CI, .91-.94]) was improved when suPAR was added (AUROC, 0.97 [95% CI, .96-.98]; P < .0001). CONCLUSIONS: Measuring suPAR at presentation can identify children at risk of severe and fatal malaria. Adding suPAR to clinical scores could improve the recognition and triage of children at risk of death. suPAR can be detected with a point-of-care test and can now be evaluated in prospective trials.

Intestinal Injury in Ugandan Children Hospitalized With Malaria.

BACKGROUND: Severe malaria is associated with multiple organ dysfunction syndrome (MODS), which may involve the gastrointestinal tract. METHODS: In a prospective cohort study in Uganda, we measured markers of intestinal injury (intestinal fatty-acid binding protein [I-FABP] and zonula occludens-1 [ZO-1]) and microbial translocation (lipopolysaccharide binding protein [LBP] and soluble complement of differentiation 14 [sCD14]) among children admitted with malaria. We examined their association with biomarkers of inflammation, endothelial activation, clinical signs of hypoperfusion, organ injury, and mortality. RESULTS: We enrolled 523 children (median age 1.5 years, 46% female, 7.5% mortality). Intestinal FABP was above the normal range (≥400 pg/mL) in 415 of 523 patients (79%). Intestinal FABP correlated with ZO-1 (ρ = 0.11, P = .014), sCD14 (ρ = 0.12, P = .0046) as well as markers of inflammation and endothelial activation. Higher I-FABP levels were associated with lower systolic blood pressure (ρ = -0.14, P = .0015), delayed capillary refill time (ρ = 0.17, P = .00011), higher lactate level (ρ = 0.40, P < .0001), increasing stage of acute kidney injury (ρ = 0.20, P = .0034), and coma (P < .0001). Admission I-FABP levels ≥5.6 ng/mL were associated with a 7.4-fold higher relative risk of in-hospital death (95% confidence interval, 1.4-11, P = .0016). CONCLUSIONS: Intestinal injury occurs commonly in children hospitalized with malaria and is associated with microbial translocation, systemic inflammation, tissue hypoperfusion, MODS, and fatal outcome.

suPAR to Risk-Stratify Patients With Malaria.

Severe malaria (SM) is a leading cause of global morbidity and mortality, particularly in children in sub-Saharan Africa. However, existing malaria diagnostic tests do not reliably identify children at risk of severe and fatal outcomes. Dysregulated host immune and endothelial activation contributes to the pathogenesis of SM. Current research suggests that measuring markers of these pathways at presentation may have clinical utility as prognostic indicators of disease progression and risk of death. In this review, we focus on the available evidence implicating soluble urokinase-type plasminogen activator receptor (suPAR) as a novel and early predictor of severe and fatal malaria and discuss its potential utility for malaria triage and management.

Implementing and evaluating the efficacy of an acute care urology model of care in a large community hospital.

INTRODUCTION: We implemented an acute care urology (ACU) model at a large Canadian community hospital to determine the impacts on safe and timely care of patients with renal colic. The model includes a dedicated ACU surgeon, a clinic for emergency department (ED) referrals, and additional daytime operating room (OR) blocks for urgent cases. METHODS: We conducted a chart review of 579 patients presenting to the ED with renal colic. Data was collected before (pre-intervention, September to November 2015) and after (post-intervention, September to November 2016) implementation of the ACU model. Secondary methods of evaluation included surveying patients and 20 ED physicians to capture subjective feedback. RESULTS: Of the 579 patients presenting with renal colic,194 were diagnosed with an obstructing kidney stone and were referred to urology for outpatient care. The ED-to-clinic time was significantly lower for those in the ACU model (p<0.001). Furthermore, the ACU clinic resulted in significantly more patients being referred for outpatient care (p=0.0004). There was also higher likelihood that patients would successfully obtain an appointment post-referral (p=0.0242). The number of after-hours and weekend surgeries decreased significantly after dedicated ACU daytime OR blocks were added in September 2015 (p<0.0001). All surveyed patients rated the care as either "excellent" or "very good," and all physicians believed the ACU model has improved patient care. CONCLUSIONS: The ACU model has shown benefit in ensuring timely followup for ED patients, reducing use of after-hour OR time, and improving patient and physician satisfaction.

Transperineal Prostate Biopsies Using Local Anesthesia: Experience with 1,287 Patients. Prostate Cancer Detection Rate, Complications and Patient Tolerability.

PURPOSE: We report our experience with transperineal prostate biopsy as well as the cancer diagnosis rate, complications and patient tolerability in 1,287 consecutive patients at risk for prostate cancer. MATERIALS AND METHODS: Beginning in October 2016 transperineal prostate biopsy was performed using local anesthesia in all patients undergoing prostate biopsy. Data on prebiopsy characteristics and results, including the cancer detection rate, complications and patient tolerability scores, were collected retrospectively from patient records. RESULTS: The cancer detection rate of transperineal prostate biopsy was 49.8% (641 of 1,287 patients). Clinically significant prostate cancer was detected in 385 patients and 62 (9.7%) had exclusively anterior zone pathology findings. Urinary retention developed in 20 patients (1.6%) following transperineal prostate biopsy, requiring temporary catheterization. In 4 patients (0.3%) lower urinary tract symptoms were suggestive of infection but only 1 had a positive urine culture. The only hospital admission was for a patient with persistent hypotension after biopsy. Patients tolerated transperineal prostate biopsy reasonably well and generally reported only mild levels of discomfort on a pain visual analogue scale. Infiltration of the anesthesia was rated more painful than the biopsy. CONCLUSIONS: Transperineal prostate biopsy with the patient under local anesthesia is a feasible alternative to transrectal biopsy in the detection of prostate cancer. Transperineal prostate biopsy has an acceptable cancer detection rate with additional detection of anterior zone cancers. It is a safer alternative in patients due to the low risk of complications, in particular urosepsis, and it is well tolerated. Transperineal prostate biopsy using local anesthesia could be considered a standard modality for the initial diagnosis of prostate cancer.