Citations

Background: Investigations of the relationship between vancomycin trough concentrations and area under the concentration time curve (AUC) are growing, but still limited. The authors sought to determine vancomycin exposure among hospitalized adults with presumed or confirmed invasive staphylococcal infections using 2-level pharmacokinetic monitoring to inform changes to an institutional vancomycin dosing protocol. Methods: This was a retrospective observational study performed in 2 acute care hospitals. Adults prescribed vancomycin (therapeutic trough 15–20 mg/L) for a presumed or documented invasive staphylococcal infection were evaluated. Two steady-state serum vancomycin levels were used to determine each patient's 24-hour AUC to minimum inhibitory concentration ratio (AUC/MIC) using a non-Bayesian, equation-based approach. Patient demographics and crude clinical outcomes were also collected. Results: Thirty-four patients were included in the study, with 2 patients having vancomycin levels drawn twice (36 sets of levels). Most patients were located in an intensive care unit (91.2%), and 85.3% of patients were prescribed vancomycin for bacteremia, pneumonia, or endocarditis. The mean ± SD vancomycin Cmin was 16.6 ± 6.1 mg/L, and the mean AUC/MIC was 588 ± 156 mg/L × hour. The rate of 24-hour vancomycin AUC/MIC target attainment was 91.2% (n = 31/34). Of the patients with a Cmin > 9 mg/L, 100% (n = 33) achieved AUC/MIC values >400 mg/L × hour and 93.9% were >500 mg/L × hour. There was a strong correlation between vancomycin Cmin and AUC24 hr (R2 = 0.731; P < 0.001). Conclusions: Targeting a vancomycin trough between 15 and 20 mg/L frequently resulted in an AUC/MIC greater than that thought to be necessary for efficacy optimization. Considering these findings alongside the practical challenges associated with wide-scale implementation of AUC monitoring, reducing the target trough as a means to prevent vancomycin overexposure warrants clinical consideration and further evaluation.

Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1–4 as most to least likely to respond based on the algorithmic assessment of individual patient’s genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.

OBJECTIVEThe authors sought to investigate the incidence and predictors of venous thromboembolic events (VTEs) after craniotomy for tumor resection, which are not well established, and the efficacy of and risks associated with VTE chemoprophylaxis, which remains controversial.METHODSThe authors investigated the incidence of VTEs in a consecutive series of patients presenting to the authors’ institution for resection of an intracranial lesion between 2012 and 2017. Information on patient and tumor characteristics was collected and independent predictors of VTEs were determined using stepwise multivariate logistic regression analysis. Review of the literature was performed by searching MEDLINE using the keywords “venous thromboembolism,” “deep venous thrombosis,” “pulmonary embolism,” “craniotomy,” and “brain neoplasms.”RESULTSThere were 1622 patients included for analysis. A small majority of patients were female (52.6%) and the mean age of the cohort was 52.9 years (SD 15.8 years). A majority of intracranial lesions were intraaxial (59.3%). The incidence of VTEs was 3.0% and the rates of deep venous thromboses and pulmonary emboli were 2.3% and 0.9%, respectively. On multivariate analysis, increasing patient age (unit OR 1.02, 95% CI 1.00–1.05; p = 0.018), history of VTE (OR 7.26, 95% CI 3.24–16.27; p < 0.001), presence of motor deficit (OR 2.64, 95% CI 1.43–4.88; p = 0.002), postoperative intracranial hemorrhage (OR 4.35, 95% CI 1.51–12.55; p < 0.001), and prolonged intubation or reintubation (OR 3.27, 95% CI 1.28–8.32; p < 0.001) were independently associated with increased odds of a VTE. There were 192 patients who received VTE chemoprophylaxis (11.8%); the mean postoperative day of chemoprophylaxis initiation was 4.6 (SD 3.8). The incidence of VTEs was higher in patients receiving chemoprophylaxis than in patients not receiving chemoprophylaxis (8.3% vs 2.2%; p < 0.001). There were 30 instances of clinically significant postoperative hemorrhage (1.9%), with only 1 hemorrhage occurring after initiation of VTE chemoprophylaxis (0.1%).CONCLUSIONSThe study results show the incidence and predictors of VTEs after craniotomy for tumor resection in this patient population. The incidence of VTE within this cohort appears low and comparable to that observed in other institutional series, despite the lack of routine prophylactic anticoagulation in the postoperative setting.

OBJECTIVEGastrostomy tube placement can temporarily seed the peritoneal cavity with bacteria and thus theoretically increases the risk of shunt infection when the two procedures are performed contemporaneously. The authors hypothesized that gastrostomy tube placement would not increase the risk of ventriculoperitoneal shunt infection. The object of this study was to test this hypothesis by utilizing a large patient cohort combined from multiple institutions.METHODSA retrospective study of all adult patients admitted to five institutions with a diagnosis of aneurysmal subarachnoid hemorrhage between January 2005 and January 2015 was performed. The primary outcome of interest was ventriculoperitoneal shunt infection. Variables, including gastrostomy tube placement, were tested for their association with this outcome. Standard statistical methods were utilized.RESULTSThe overall cohort consisted of 432 patients, 47% of whom had undergone placement of a gastrostomy tube. The overall shunt infection rate was 9%. The only variable that predicted shunt infection was gastrostomy tube placement (p = 0.03, OR 2.09, 95% CI 1.07–4.08), which remained significant in the multivariate analysis (p = 0.04, OR 2.03, 95% CI 1.04–3.97). The greatest proportion of shunts that became infected had been placed more than 2 weeks (25%) and 1–2 weeks (18%) prior to gastrostomy tube placement, but the temporal relationship between shunt and gastrostomy was not a significant predictor of shunt infection.CONCLUSIONSGastrostomy tube placement significantly increases the risk of ventriculoperitoneal shunt infection.

AbstractFibrosing mediastinitis is a rare, often debilitating and potentially lethal disease characterized by an exuberant fibroinflammatory response within the mediastinum. Patients typically present with insidious symptoms related to compression of adjacent structures including the esophagus, heart, airways, and cardiac vessels. Fibrosing mediastinitis is most often triggered by Histoplasmosis infection; however, antifungal and anti‐inflammatory therapies are largely ineffective. While structural interventions aimed at alleviating obstruction can provide significant palliation, surgical interventions are challenging with high mortality and clinical experience with percutaneous interventions is limited. Here, we will review the presentation, natural history, and treatment of fibrosing mediastinitis, placing particular emphasis on catheter‐based therapies.

Objective: Review the use of upper-extremity orthoses and casts after injuries to the wrist and hand in the pediatric, adolescent, and young adult population. The common injuries reviewed include pediatric distal radius fractures, scaphoid fractures, metacarpal fractures, mallet fingers, volar plate injuries of the proximal interphalangeal (PIP) joint, and ulnar collateral ligament (UCL) tears of the thumb metacarpophalangeal (MCP) joint. Data Sources: We conducted a literature review from 1985 to 2016 of upper-extremity orthotic interventions. Non–English language citations and animal studies were excluded. Citations from retrieved studies were used to identify other relevant publications. This review included cases of common injuries to the upper extremity, which required orthotic intervention. Main Results: Immobilization recommendations for nonsurgical pediatric distal radius fractures, nonsurgical metacarpal fractures, mallet fingers, and UCL tears of the thumb MCP include a removable orthosis. Nondisplaced scaphoid fracture orthosis recommendations include initial immobilization in a nonremovable short-arm thumb spica cast. Volar plate injuries of the PIP joint require buddy straps for healing. Conclusions: The literature demonstrates the effectiveness of removable orthoses in healing, patient satisfaction, and time to return to activity after many common upper-extremity injuries. Removable orthoses should be considered an equal or superior treatment method to cast immobilization, immobilization of additional joints, or longer periods of immobilization.

Objective To present 6‐month safety and effectiveness data from a multicentre prospective study of aquablation in men with lower urinary tract symptoms (LUTS) attributable to benign prostatic hyperplasia ( BPH ) with prostate volumes between 80 and 150 mL. Methods Between September and December 2017, 101 men with LUTS attributable to BPH were prospectively enrolled at 16 centres in Canada and the USA. Results The mean prostate volume was 107 mL. The mean length of hospital stay after the aquablation procedure was 1.6 days (range: same day to 6 days). The primary safety endpoint (Clavien–Dindo grade 2 or higher or any grade 1 event resulting in persistent disability) at 3 months occurred in 45.5% of men, which met the study design goal of < 65% ( P < 0.001). At 6 months, 22% of the patients had experienced a Clavien–Dindo grade 2, 14% a grade 3 and 5% a grade 4 adverse event. Bleeding complications requiring intervention and/or transfusion were recorded in eight patients prior to discharge and in six patients after discharge. The mean International Prostate Symptom Score improved from 23.2 ± 6.3 at baseline to 6.7 ± 5.1 at 3 months, meeting the study's primary efficacy endpoint goal ( P < 0.001). The maximum urinary flow rate increased from 8.7 to 18.8 mL/s ( P < 0.001) and post‐void residual urine volume decreased from 131 at baseline to 47 at 6 months ( P < 0.0001). At 6 months, prostate‐specific antigen concentration reduced from 7.1 ± 5.9 ng/mL at baseline to 4.0 ± 3.9 ng/mL, a 44% reduction. Conclusions Aquablation is safe and effective in treating men with larger prostates (80–150 mL), without significant increase in procedure or resection time.

Abstract The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states contributes to their metastatic potential. Therefore, driving tumor cells into a stable mesenchymal state, as opposed to complete tumor cell eradication, presents an opportunity to pharmacologically limit disease progression by promoting an asymptomatic state of dormancy. Here, we compare a reversible model of epithelial–mesenchymal transition (EMT) induced by TGFβ to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor lapatinib. Only cells capable of returning to an epithelial phenotype resulted in skeletal metastasis. Gene expression analyses of the two mesenchymal states indicated similar transition expression profiles. A potently downregulated gene in both datasets was spleen tyrosine kinase (SYK). In contrast to this similar diminution in mRNA, kinome analyses using a peptide array and DNA-conjugated peptide substrates showed a robust increase in SYK activity upon TGFβ-induced EMT only. SYK was present in cytoplasmic RNA processing depots known as P-bodies formed during the onset of EMT, and SYK activity was required for autophagy-mediated clearance of P-bodies during mesenchymal–epithelial transition (MET). Genetic knockout of autophagy-related 7 (ATG7) or pharmacologic inhibition of SYK activity with fostamatinib, a clinically approved inhibitor of SYK, prevented P-body clearance and MET, inhibiting metastatic tumor outgrowth. Overall, this study suggests assessment of SYK activity as a biomarker for metastatic disease and the use of fostamatinib as a means to stabilize the latency of disseminated tumor cells. Significance: These findings present inhibition of spleen tyrosine kinase as a therapeutic option to limit breast cancer metastasis by promoting systemic tumor dormancy. See related commentary by Farrington and Narla, p. 1756

AbstractPurposeThe increased prevalence of home enteral nutrition (HEN), reemergence of blenderized tube feeding (BTF), and conversion of enteral connectors to the ISO 80369‐3 standard are creating a significant need to better understand the practices of the HEN population. A cross‐sectional survey of current HEN consumers was conducted to evaluate the demographics of HEN consumers, including formulas and feeding tubes being used.MethodsIn order to disseminate the survey to a wide range of HEN consumers, we partnered with private infusion companies (Coram and Pediatric Home Services) along with the Oley and Tube Feeding Awareness Foundations. A validated survey focusing on patient demographics, tube types, formula used, and tube clogging complications was placed online from September 1, 2016, to October 15, 2016.ResultsDuring the study period, 1519 surveys were completed, with 1062 respondents in the pediatric group (<18 years old) and 457 in the adult group (≥18 years old). The most popular formulas were standard polymeric and specialized formulas in both the pediatric and adult groups. However, a significant number in the pediatric (31.2%) and adult (18.6%) groups used BTF either alone or in combination with other formulas. Clogging was also quite prevalent and correlated with tube size.ConclusionsThe present study highlights the significant diversity of the HEN practice in terms of types and sizes of tubes as well as formulas used, including confirmation of the widespread use of BTF. These data are key to ensure HEN providers are able to appropriately support and educate their patients.