Obstructing Ureteral Calculi and Presumed Infection: Impact of Antimicrobial Duration and Time From Decompression to Stone Treatment in Developing Urosepsis.

OBJECTIVE: To determine whether the duration of antibiotic treatment and timing between urgent renal decompression and stone intervention impacts the risk of developing urosepsis following definitive stone treatment. MATERIALS & METHODS: A retrospective review of patients who were diagnosed with obstructive urolithiasis and underwent urgent decompression with a ureteral double J stent or percutaneous nephrostomy at our institution between 2012 and 2018 was performed. We narrowed our analysis to the subset of patients who had suspected infection and received definitive stone treatment at our institution. Demographic, infection and antimicrobial data, and initial admission to stone treatment characteristics were collected. Factors associated with developing urosepsis were analyzed. RESULTS: We identified 872 patients who were treated with urgent renal decompression, of which 215 were analyzed that had suspected infection and also received definitive stone removal at our institution. Thirty-three had fevers, 64.2% had a positive urine culture, and 45.6% had urosepsis at the initial presentation. The median antibiotics duration post decompression was 13 days (IQR 8-18). The median duration from decompression to stone treatment was 17 days (IQR 12-27). Of all, 4.6% of the patients developed urosepsis post ureteroscopy and 5% post percutaneous nephrolithotomy. No factors were associated with developing urosepsis post stone treatment on logistic regression analyses. CONCLUSION: In patients requiring urgent decompression for obstructing urolithiasis and suspected infection, the time between decompression and stone treatment and the length of antibiotic exposure did not impact rates of postoperative urosepsis. This highlights the importance of maintaining high clinical suspicion for prolonged use of antibiotics, to prevent overtreatment and possible exacerbation of antibiotic resistance.

Does tamsulosin decrease postoperative urinary retention in spine surgery? A double-blind, randomized controlled trial.

OBJECTIVE: The authors' objective was to determine whether preoperative administration of tamsulosin decreases postoperative urinary retention after spine surgery. METHODS: In this randomized, double-blind, placebo-controlled clinical trial performed at a single institution between 2016 and 2019, eligible males aged 50 to 85 years were administered tamsulosin or placebo for 5 days prior to elective spine surgery. Patients were excluded if they were taking alpha adrenergic blocking drugs; were allergic to tamsulosin, lactose, or sulfa drugs; had a preexisting indwelling urinary catheter, orthostatic hypotension, history of urological surgery, or renal failure; or were scheduled for cataract surgery within 2 weeks. Screening identified 1051 eligible patients (140 declined participation, 150 did not meet the inclusion criteria, and 151 did not enroll for other reasons). A total of 610 patients were randomly assigned to receive 0.4 mg oral tamsulosin or an identical placebo capsule for 5 days preoperatively and 2 days postoperatively. RESULTS: A total of 497 patients were included in the final statistical analysis. The overall rate of postoperative urinary retention was 9.7%, and tamsulosin had no observed effect on reducing the rate of postoperative urinary retention as compared with placebo (9.4% vs 9.9%, p = 0.96). There were no significant differences in the reported adverse events between groups. Multivariate logistic regression was performed to model the effects of patient, surgical, and anesthetic factors on postoperative urinary retention, and the study drug remained an insignificant factor. CONCLUSIONS: This study did not detect an effect of perioperative tamsulosin on reducing the rate of postoperative urinary retention in male patients aged 50 to 85 years who underwent elective spine surgery. This study does not support the routine use of tamsulosin to reduce postoperative urinary retention in patients without a previous prescription. It is unknown if subpopulations exist for which prophylactic tamsulosin may reduce postoperative urinary retention.

Depression and Impulsivity Self-Assessment Tools to Identify Dopamine Agonist Side Effects in Patients With Pituitary Adenomas.

Background: Dopamine agonists (DA) are the first line therapy for prolactinoma and symptomatic hyperprolactinemia; use as an adjuvant treatment for acromegaly and Cushing's disease is rare. Some patients develop de novo psychiatric symptoms or have exacerbation of pre-existing conditions during DA therapy. A practical, clinically sensitive depression and impulse control disorders (ICD; particularly hypersexuality and gambling disorders) detection tool is important for identifying at risk patients. The Barratt Impulsivity Scale (BIS-11) and the 9-item Patient Health Questionnaire (PHQ-9) are sensitive in identifying impulsivity and depression. Objective: Detail use of the BIS-11 and PHQ-9 as screening tools for depression and ICD in patients with pituitary disease at a high-volume academic pituitary center. Methods: DA-treated and naïve patients with pituitary disease were included. Patients with a known history of depression or psychiatric disorder were excluded. PHQ-9 standardized interpretation criteria were utilized to classify depression severity. For BIS-11, threshold was established based on previous studies. Statistical analysis was with SPSS version 25. Results: Seventy-six DA-treated and 27 naïve patients were included. Moderate and moderately severe depression were more prevalent in DA-treated patients; severe depression only found in DA-treated patients. A normal BIS-11 score was noted in 76.69%; higher scores (not significant) were noted in DA-treated patients. There was a positive correlation between higher BIS-11 and PHQ-9 scores; higher in DA-treated patients (r = 0.52, p < 0.001) than DA-naïve patients. Patients with BIS-11 scores ≥60 were younger and received lower cumulative DA doses compared to patients with BIS scores <60. There was no association between male sex and BIS-11 ≥60 and male sex did not increase the odds of increased scores (OR = 0.66, CI95% 0.25-1.76, p = 0.41). No significant difference was found for macroadenoma, prolactin levels, testosterone levels, hypogonadism, testosterone replacement in men, and increased impulsivity or depression scores. Conclusion: Use of PHQ-9 and BIS-11 is practical for routine screening of depression and ICD during outpatient pituitary clinic visits for patients with pituitary disease both naïve to treatment and during DA therapy. We recommend close follow-up after initiation of DA therapy for younger patients, regardless of dose.

Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation.

Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.

A Study on Pharmacokinetics of Bosentan with Systems Modeling, Part 1: Translating Systemic Plasma Concentration to Liver Exposure in Healthy Subjects.

Understanding liver exposure of hepatic transporter substrates in clinical studies is often critical, as it typically governs pharmacodynamics, drug-drug interactions, and toxicity for certain drugs. However, this is a challenging task since there is currently no easy method to directly measure drug concentration in the human liver. Using bosentan as an example, we demonstrate a new approach to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically based pharmacokinetic modeling. The prediction was verified to be both accurate and precise using sensitivity analysis. For bosentan, the predicted pseudo steady-state unbound liver-to-unbound systemic plasma concentration ratio was 34.9 (95% confidence interval: 4.2, 50). Drug-drug interaction (i.e., CYP3A and CYP2B6 induction) and inhibition of hepatic transporters (i.e., bile salt export pump, multidrug resistance-associated proteins, and sodium-taurocholate cotransporting polypeptide) were predicted based on the estimated unbound liver tissue or plasma concentrations. With further validation and refinement, we conclude that this approach may serve to predict human liver exposure and complement other methods involving tissue biopsy and imaging.

In vitro studies with two human organic anion transporters: OAT2 and OAT7.

1. Penciclovir, ganciclovir, creatinine, para-aminohippuric acid (PAH), ketoprofen, estrone 3-O-sulfate (E3S), dehydroepiandrosterone 3-O-sulfate (DHEAS) and cyclic guanosine monophosphate (cGMP) were screened as substrates of human liver organic anion transporters OAT2 and OAT7. 2. For OAT7, high uptake ratios (versus mock transfected HEK293 cells) of 29.6 and 15.3 were obtained with E3S and DHEAS. Less robust uptake ratios (≤3.6) were evident with the other substrates. OAT2 (transcript variant 1, OAT2-tv1) presented high uptake ratios of 30, 13, ∼35, ∼25, 8.5 and 9 with cGMP, PAH, penciclovir, ganciclovir, creatinine and E3S, respectively. No uptake was observed with DHEAS. 3. Although not a substrate of either transporter, ketoprofen did inhibit transfected OAT2-tv1 (IC50 of 17, 22, 23, 24, 35 and 586 µM; creatinine, ganciclovir, penciclovir, cGMP, E3S and prostaglandin F2α, respectively) and penciclovir uptake (IC50 = 27 µM; >90% inhibition) by plated human hepatocytes (PHH). 4. It is concluded that penciclovir and ketoprofen may serve as useful tools for the assessment of OAT2 activity in PHH. However, measurement of OAT7 activity therein will prove more challenging, as high uptake rates are evident with E3S and DHEAS only and both sulfoconjugates are known to be substrates of organic anion transporting polypeptides.

Pediatric moped-related injuries in the United States from 2002 to 2014: Age-related comparisons of mechanisms and outcomes.

Mopeds are a popular means of transportation, especially in urban areas. However, few studies have investigated moped-related injuries in the United States. This study's goal was to compare the crash mechanisms and injuries suffered in moped-related crashes involving youth versus adults, as well as between younger and older children. INTRODUCTION: Mopeds are a popular means of transportation, especially in urban areas. However, few studies have investigated moped-related injuries in the United States. This study's goal was to compare the crash mechanisms and injuries suffered in moped-related crashes involving youth versus adults, as well as between younger and older children. METHODS: Descriptive and comparative analyses were performed using National Electronic Injury Surveillance System (NEISS) data and additional variables coded from injury narratives. Multivariate regression analyses were used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for categorical outcomes, controlling for significant covariates. RESULTS: From 2003 to 2014, there were 779 youth (17 years or younger) and 2,453 adult moped-related emergency department visits in the database. The number of youth injured remained relatively constant over time, while the number of adult victims doubled. Relative to 14- to 17-year olds, victims younger than 14 years were more commonly female (p = 0.037) and non-Caucasian (p = 0.008). Victims 14 to 17 years of age had a higher proportion of brain injuries (p = 0.012) and were more commonly in motor vehicle collisions (p = 0.02), as compared to younger victims. Relative to adults, youth crashes occurred more commonly in the summer (p < 0.0001), and off the street/road (p < 0.0001). Logistic regression analysis showed crashes on streets/roads were two and a half times more likely to involve victims who were 14 to 17 years of age as compared to those younger (aOR, 2.55; CI, 1.64-3.97). Additionally, male youths were twice as likely as females to have a motor vehicle collision (aOR, 1.97; CI, 1.19-3.24), and pediatric crashes were approximately twice as likely to result in extremity injuries as compared to adult crashes (aOR, 1.95; CI, 1.19-3.20). CONCLUSION: Differences in crash mechanism and injuries sustained between two youth age groups and between youths and adults indicate the importance of targeted injury prevention efforts. This would include improved operator training and standardized, evidence-based, well-enforced safety legislation. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Postoperative antibacterial prophylaxis for the prevention of infectious complications associated with tube thoracostomy in patients undergoing elective general thoracic surgery: a double-blind, placebo-controlled, randomized trial.

OBJECTIVE: To determine whether extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery with tube thoracostomy reduces the risk of infectious complications compared with preoperative prophylaxis only. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Brigham and Women's Hospital, an 800-bed tertiary care teaching hospital in Boston, Massachusetts. PARTICIPANTS: A total of 251 adult patients undergoing elective thoracic surgery requiring tube thoracostomy between April 2008 and April 2011. INTERVENTIONS: Patients received preoperative antibacterial prophylaxis with cefazolin sodium (or other drug if the patient was allergic to cefazolin). Postoperatively, patients were randomly assigned (at a 1:1 ratio) using a computer-generated randomization sequence to receive extended antibacterial prophylaxis (n = 125) or placebo (n = 126) for 48 hours or until all thoracostomy tubes were removed, whichever came first. MAIN OUTCOME MEASURES: The combined occurrence of surgical site infection, empyema, pneumonia, and Clostridium difficile colitis by postoperative day 28. RESULTS: A total of 245 patients were included in the modified intention-to-treat analysis (121 in the intervention group and 124 in the placebo group). Thirteen patients (10.7%) in the intervention group and 8 patients (6.5%) in the placebo group had a primary end point (risk difference, -4.3% [95% CI, -11.3% to 2.7%]; P = .26). Six patients (5.0%) in the intervention group and 5 patients (4.0%) in the placebo group developed surgical site infections (risk difference, -0.93% [95% CI, -6.1% to 4.3%]; P = .77). Seven patients (5.8%) in the intervention group and 3 patients (2.4%) in the placebo group developed pneumonia (risk difference, -3.4% [95% CI, -8.3% to 1.6%]; P = .21). One patient in the intervention group developed empyema. No patients experienced C difficile colitis. CONCLUSIONS: Extended postoperative antibacterial prophylaxis for patients undergoing elective thoracic surgery requiring tube thoracostomy did not reduce the number of infectious complications compared with preoperative prophylaxis only. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00818766.

Delayed presentation of perisplenic abscess following arterial embolization.

INTRODUCTION: Splenic abscess formation is a rare but significant complication that may occur after non-operative management (NOM) of a blunt splenic injury (BSI). we describe an unusual case of perisplenic abscess formation nearly 4 months after splenic artery angioembolization for a grade III splenic laceration. PRESENTATION OF CASE: A 52-year-old male was transferred to the Emergency Department (ED) of our institution after falling off his bicycle. He was hemodynamically stable but complained of left upper quadrant pain. Computed tomography (CT) was notable for a Grade III splenic laceration. The patient underwent a successful splenic artery embolization on hospital day 1. He had an uneventful post-embolization course and was discharged 3 days later, afebrile, with a stable hematocrit. Four months after his initial presentation, the patient presented to the ED with fever, malaise, and left upper quadrant abdominal pain. A CT scan revealed a multiloculated perisplenic abscess. He underwent a splenectomy and drainage of peri-splenic abscess, received a course of antibiotics, and had an uneventful recovery. DISCUSSION: NOM including splenic angioembolization (SAE) is the standard of care for blunt splenic trauma in hemodynamically stable patients. Known complications from SAE include bleeding, missed injuries to the diaphragm and pancreas, and splenic abscess. This report documents a delayed perisplenic abscess following NOM of blunt splenic trauma, a rare but potential complication of SAE. CONCLUSION: Formation of a perisplenic abscess may occur several months after NOM of a blunt splenic injury. Prompt surgical management and antibiotic therapy are critical to avoid life-threatening complications.

Manual in-line stabilization increases pressures applied by the laryngoscope blade during direct laryngoscopy and orotracheal intubation.

BACKGROUND: Manual in-line stabilization (MILS) is recommended during direct laryngoscopy and intubation in patients with known or suspected cervical spine instability. Because MILS impairs glottic visualization, the authors hypothesized that anesthesiologists would apply greater pressure during intubations with MILS than without. METHODS: Nine anesthetized and pharmacologically paralyzed patients underwent two sequential laryngoscopies and intubations, one with MILS and one without, in random order. A transducer array along a Macintosh 3 laryngoscope blade continuously measured applied pressures, and glottic view was characterized. RESULTS: With MILS, glottic visualization was worse in six patients, and intubation failure occurred in two of these six patients. Maximum laryngoscope pressure at best glottic view was greater with MILS than without (717 +/- 339 mmHg vs. 363 +/- 121 mmHg, respectively; n = 8; P = 0.023). Other measures of pressure application also indicated comparable increases with MILS. CONCLUSION: Pressures applied to airway tissues by the laryngoscope blade are secondarily transmitted to the cervical spine and result in cranio-cervical motion. In the presence of cervical instability, impaired glottic visualization and secondary increases in pressure application with MILS have the potential to increase pathologic cranio-cervical motion.

Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease.

Bactericidal/permeability-increasing (BPI) protein has been shown to play an important role in innate immunity to gram-negative bacteria, by direct microbicidal as well as endotoxin-neutralizing action. Here we examined potential interactions between a recombinant 21-kDa bioactive fragment of BPI, rBPI21, and the gram-positive pathogen Streptococcus pneumoniae. rBPI21 bound to pneumococci and pneumolysin (Ply) in a direct and specific fashion. We observed an enhanced inflammatory response in mouse macrophages when rBPI21 was combined with killed pneumococci or supernatant from overnight growth of pneumococci. In addition, rBPI21 augmented the proapoptotic activity of Ply+ (but not Ply-) pneumococci in TLR4-defective murine macrophages (known to be defective also in their apoptotic response to pneumolysin) in a tumor necrosis factor alpha-dependent manner. rBPI21 also enhanced the association of pneumococci with murine macrophages. In a model of invasive pneumococcal disease in TLR4-defective mice, the intranasal administration of rBPI21 following intranasal inoculation of Ply+ pneumococci both enhanced upper respiratory tract cell apoptosis and prolonged survival. We have thus discovered a novel interaction between pneumococcus and rBPI21, a potent antimicrobial peptide previously considered to target only gram-negative bacteria.