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This study sought to characterize the bacterial and fungal microbiota changes associated with Clostridium difficile infection (CDI) among inpatients with diarrhea, in order to further explain the pathogenesis of this infection as well as to potentially guide new CDI therapies. Twenty-four inpatients with diarrhea were enrolled, 12 of whom had CDI. Each patient underwent stool testing for CDI prior to being treated with difficiledirected antibiotics, when appropriate. Clinical data was obtained from the medical record, while each stool sample underwent 16S rRNA and ITS sequencing for bacterial and fungal elements. An analysis of microbial community structures distinct to the CDI population was also performed. The results demonstrated no difference between the CDI and non-CDI cohorts with respect to any previously reported CDI risk factors. Butyrogenic bacteria were enriched in both CDI and non-CDI patients. A previously unreported finding of increased numbers of Akkermansia muciniphila in CDI patients was observed, an organism which degrades mucin and which therefore may provide a selective advantage toward CDI. Fungal elements of the genus Penicillium were predominant in CDI; these organisms produce antibacterial chemicals which may resist recovery of healthy microbiota. The most frequent CDI microbial community networks involved Peptostreptococcaceae and Enterococcus, with decreased population density of Bacteroides. These results suggest that the development of CDI is associated with microbiota changes which are consistently associated with CDI in human subjects. These gut taxa contribute to the intestinal dysbiosis associated with C. difficile infection. [ABSTRACT FROM AUTHOR]

Background: Current Clostridium difficile infection (CDI) antibiotic regimens have become increasingly ineffective at achieving cure and preventing recurrence. A recently developed alternative to conventional antibiotics are phage tail-like particles (PTLPs), which are proteins that are morphologically similar to bacteriophages and are produced by C difficile. This study examines the in vitro killing spectrum of a previously unreported PTLP isolated from a clinical isolate of C difficile. Methods: Using patient-derived samples from an institutional review board-approved C difficile tissue bank, a ribotype 078 C difficile isolate was anaerobically incubated on blood agar plates that were preswabbed with norfloxacin to induce the production of PTLPs. Concentrated PTLP populations were confirmed using transmission electron microscopy. Using a standard lawn spot approach, bactericidal activity was assessed as indicated by a clearing within the bacterial lawn. The PTLP genomic cluster was also fully sequenced and open reading frames were annotated according to predicted function. Results: PTLPs were assessed using 64 patient-derived C difficile isolates of varying ribotypes. PTLPs demonstrated complete bactericidal activity in 21 of 25 ribotype 027 isolates with partial activity in 2 of the 25. Complete bactericidal activity was not demonstrated against any other ribotype or non-difficile bacteria, suggesting a species and ribotype specificity. Functional genes, which may be necessary for killing, were identified within the PTLP genetic locus. Conclusion: PTLPs demonstrate capability in eradicating C difficile in vitro, and with further development, may represent an organism-specific, microbiome-sparing therapy for CDI. [ABSTRACT FROM AUTHOR]

An electronic survey was sent to 1,026 rehabilitation sciences faculty members at higher education institutions around the nation to determine the relative importance faculty in the rehabilitation sciences placed on technical literacy skills in higher education. The survey contained a list of 55 technology and distance education skills in six broad areas: electronic searches and resources, computer productivity tools, Web-based instruction, teleconferencing, using technology to deliver instruction, and virtual mentoring. For each skill, respondents indicated the level of importance they attached to each skill as it relates to successful performance as a faculty member in the rehabilitation professions by selecting a number between 1 and 5, with 1 indicating that the skill is not at all important and 5 indicating that the skill is extremely important. The return rate of the survey was 17.6%. Although there was considerable variability for rated importance of skills within categories, results indicated that skills related to computer productivity and electronic searches were judged as most important to faculty success. Those skills related to newer technologies and skills related to troubleshooting were rated as least important. Discussion of these findings and implications for future research and doctoral instruction are presented. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC) are a significant cause of childhood diarrhea in low-resource settings. ETEC are defined by the production of heat-stable enterotoxin (ST) and/or heat-labile enterotoxin (LT), which alter intracellular cyclic nucleotide signaling and cause the secretion of water and electrolytes into the intestinal lumen. ETEC take cues from chemicals (e.g., glycans, bile salts, and solutes) that may be liberated following enterotoxin activity to recognize entrance into the host. ETEC then alter the expression of surface adhesins called colonization factors (CFs) to attach to the intestinal epithelium, proliferate, and cause disease. Here, we used an in vivo model of oral ST intoxication to determine its impact on luminal ion concentrations via ICP-MS. We also used functional assays, including Western blots, qPCR, and toxin activity assays, to assess the impact of luminal ion flux on CF and toxin expression. Finally, we assessed ETEC strains with CFs CFA/I or CS6 in a streptomycin mouse model of ETEC colonization. ST causes rapid and significant increases in luminal chloride but significant decreases in luminal magnesium and iron. We confirmed that increased sodium chloride suppresses CFA/I production in ETEC H10407 but does not affect CS6 production in ETEC 214-4. CFA/I production in ETEC H10407 is increased when magnesium becomes limiting, although it does not affect CS6 production in ETEC 214-4. Iron restriction via deferoxamine induces CFA/I expression in ETEC H10407 but not CS6 expression in ETEC 214-4. We demonstrate that ST production is suppressed via iron restriction in H10407, 214-4, and over 50 other ETEC clinical isolates. Lastly, we demonstrate that the iron restriction of mice using oral deferoxamine pre-treatment extends the duration of ETEC H10407 (CFA/I + ) fecal shedding while accelerating ETEC 214-4 (CS6 + ) fecal shedding. Combined, these data suggest that enterotoxins modulate luminal ion flux to influence ETEC virulence including toxin and CF production.

Enterotoxigenic Escherichia coli (ETEC) remain a major cause of diarrheal mortality and morbidity in children in low-resource settings. Few studies have explored the consequences of simultaneous intoxication with heat-stable enterotoxin (ST) and heat-labile enterotoxin (LT) despite the increased prevalence of wild ETEC isolates expressing both toxins. We therefore used a combination of tissue culture and murine models to explore the impact of simultaneous ST + LT intoxication on epithelial and myeloid cells. We report that LT induces sustained production of interleukin 33 (IL-33) and interleukin 1 receptor antagonist (IL-1Ra) in T84 intestinal epithelial cells via cAMP production and protein kinase A activation. We demonstrate that combined ST + LT intoxication hastens epithelial transcriptional responses induced more slowly by LT alone. ST- and LT-mediated luminal fluid accumulation in vivo correlates with significant increases in IL-33 and IL-1Ra in small intestinal mucosal scrapings. Additionally, IL-33 receptor (IL-33R)-deficient mice are significantly less susceptible to ST-mediated secretion than wildtype mice. In the immune compartment, IL-33 is sensed by myeloid cells, and LT suppresses IL-33-induced tumor necrosis factor α (TNF-α) secretion from macrophages and bone marrow-derived dendritic cells (BMDCs) but amplifies IL-33-mediated induction of IL-6 from BMDCs. In conclusion, our studies suggest that enterotoxin-induced IL-33 and IL-1Ra modulate intestinal inflammation and IL-1 receptor signaling in the intestinal mucosa in response to ETEC enterotoxins.

Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries. Previous studies identified heat-stable enterotoxin (ST)-producing ETEC as a prevalent diarrheal pathogen in children younger than 5 years. While many studies have evaluated the interaction of ETEC heat-labile enterotoxin (LT) with host epithelium and immunity, few investigations have attempted similar studies with ST. To further understand ST pathogenesis, we examined the impact of ST on cGMP localization, epithelial cell cytokine production, and antibody development following immunization. In addition to robust intracellular cGMP in T84 cells in the presence of phosphodiesterase inhibitors (PDEis) that prevent the breakdown of cyclic nucleotides, we found that prolonged ST intoxication induced extracellular cGMP accumulation in the presence or absence of PDEis. Further, ST intoxication induced luminal cGMP in vivo in mice, suggesting that secreted cGMP may have other cellular functions. Using transcriptome sequencing (RNA-seq) and quantitative PCR (qPCR), we demonstrated that ST intoxication, or treatment with the clinically used ST mimic linaclotide, altered inflammatory cytokine gene expression, including the interleukin 1 (IL-1) family member IL-33, which could also be induced by cell-permeative 8-Br-cGMP. Finally, when present during immunization, ST suppressed induction of antibodies to specific antigens. In conclusion, our studies indicate that ST modulates epithelial cell physiology and the interplay between the epithelial and immune compartments., (Copyright © 2021 Motyka et al.)

Patients with unresectable hepatic metastases, from uveal or ocular melanoma, are challenging to treat with an overall poor prognosis. Although over the past decade significant advances in systemic therapies have been made, metastatic disease to the liver, especially from uveal melanoma, continues to be a poor prognosis. Percutaneous hepatic perfusion (PHP) is a safe, viable treatment option for these patients. PHP utilizes high dose chemotherapy delivered directly to the liver while minimizing systemic exposure and can be repeated up to 6 times. Isolation of the hepatic vasculature with a double-balloon catheter allows for high concentration cytotoxic therapy to be administered with minimal systemic adverse effects. A detailed description of the multidisciplinary treatment protocol used at an institution with over 12 years of experience is discussed and recommendations are given. A dedicated team of a surgical or medical oncology, interventional radiology, anesthesiology and a perfusionist allows PHP to be repeatedly performed as a safe treatment strategy for unresectable hepatic metastases.

There has been no prior application of matched metagenomics and metatranscriptomics in Clostridioides difficile infection (CDI) evaluating the role of fungi in CDI or identifying community functions that contribute to the development of this disease. We collected diarrheal stools from 49 inpatients (18 of whom tested positive for CDI) under stringent inclusion criteria. We utilized a tiered sequencing approach to identify enriched bacterial and fungal taxa, using 16S and internal transcribed spacer (ITS) rRNA gene amplicon sequencing, with matched metagenomics and metatranscriptomics performed on a subset of the population. Distinct bacterial and fungal compositions distinguished CDI-positive and -negative patients, with the greatest differentiation between the cohorts observed based on bacterial metatranscriptomics. Bipartite network analyses demonstrated that Aspergillus and Penicillium taxa shared a strong positive relationship in CDI patients and together formed negative cooccurring relationships with several bacterial taxa, including the Oscillospira , Comamonadaceae , Microbacteriaceae , and Cytophagaceae Metatranscriptomics revealed enriched pathways in CDI patients associated with biofilm production primarily driven by Escherichia coli and Pseudomonas , quorum-sensing proteins, and two-component systems related to functions such as osmotic regulation, linoleic acid metabolism, and flagellar assembly. Differential expression of functional pathways unveiled a mechanism by which the causal dysbiosis of CDI may self-perpetuate, potentially contributing to treatment failures. We propose that CDI has a distinct fungus-associated bacteriome, and this first description of metatranscriptomics in human subjects with CDI demonstrates that inflammation, osmotic changes, and biofilm production are key elements of CDI pathophysiology. IMPORTANCE Our data suggest a potential role for fungi in the most common nosocomial bacterial infection in the United States, introducing the concept of a transkingdom interaction between bacteria and fungi in this disease. We also provide the first direct measure of microbial community function in Clostridioides difficile infection using patient-derived tissue samples, revealing antibiotic-independent mechanisms by which C. difficile infection may resist a return to a healthy gut microbiome., (Copyright © 2019 Stewart et al.)

Importance: Recent evidence from an animal model suggests that peripheral loss of eosinophils in Clostridium difficile infection (CDI) is associated with severe disease. The ability to identify high-risk patients with CDI as early as the time of admission could improve outcomes by guiding management decisions., Objective: To construct a model using clinical indices readily available at the time of hospital admission, including peripheral eosinophil counts, to predict inpatient mortality in patients with CDI., Design, Setting, and Participants: In a cohort study, a total of 2065 patients admitted for CDI through the emergency department of 2 tertiary referral centers from January 1, 2005, to December 31, 2015, formed a training and a validation cohort. The sample was stratified by admission eosinophil count (0.0 cells/μL or >0.0 cells/μL), and multivariable logistic regression was used to construct a predictive model for inpatient mortality as well as other disease-related outcomes., Main Outcomes and Measures: Inpatient mortality was the primary outcome. Secondary outcomes included the need for a monitored care setting, need for vasopressors, and rates of inpatient colectomy., Results: Of the 2065 patients in the study, 1092 (52.9%) were women and patients had a mean (SD) age of 63.4 (18.4) years. Those with an undetectable eosinophil count at admission had increased in-hospital mortality in both the training (odds ratio [OR], 2.01; 95% CI, 1.08-3.73; P = .03) and validation (OR, 2.26; 95% CI, 1.33-3.83; P = .002) cohorts in both univariable and multivariable analysis. Undetectable eosinophil counts were also associated with indicators of severe sepsis, such as admission to monitored care settings (OR, 1.40; 95% CI, 1.06-1.86), the need for vasopressors (OR, 2.08; 95% CI, 1.32-3.28), and emergency total colectomy (OR, 2.56; 95% CI, 1.12-5.87). Other significant predictors of mortality at admission included increasing comorbidity burden (for each 1-unit increase: OR, 1.13; 95% CI, 1.05-1.22) and lower systolic blood pressures (for each 1-mm Hg increase: OR, 0.99; 95% CI, 0.98-1.00). In a subgroup analysis of patients presenting without initial tachycardia or hypotension, only patients with undetectable admission eosinophil counts, but not those with an elevated white blood cell count, had significantly increased odds of inpatient mortality (OR, 5.76; 95% CI, 1.99-16.64)., Conclusions and Relevance: This study describes a simple, widely available, inexpensive model predicting CDI severity and mortality to identify at-risk patients at the time of admission.

Background: Despite data suggesting safety and efficacy in ulcerative colitis patients treated with inpatient infliximab, prior studies did not focus on patients with extensive colitis, the group at highest risk for requiring surgery., Methods: This was a single center, retrospective study (2008-2015) of consecutive patients who required admission because of severe extensive ulcerative colitis defined by preoperative symptoms and computed tomography scans and postoperative histology. Patients admitted for high-dose steroids were compared with steroid refractory inpatients provided with one or two infusions of infliximab. The primary study outcome was colectomy rates; secondary outcomes included mean length of stay and 60-d complication rates., Results: A total of 174 patients required admission with steroids for extensive ulcerative colitis. Of these, 19 (10%) also received infliximab. Among the subjects treated with infliximab, 15 (78%) required total colectomy during that admission versus 81 (52%) who received steroids alone (P = 0.03). Postoperative readmission rates, surgical-site infections, return to the operating room, and all-complication rates were similar between the cohorts (P > 0.05)., Conclusions: For steroid refractory extensive ulcerative colitis, inpatient infliximab did not lower colectomy rates or increase postoperative complications compared with patients treated with steroids alone., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Palliative care is associated with decreased cost and improved quality of life, although its use in stage IV rectal cancer is understudied., Materials and Methods: Stage IV rectal cancer patients (2004-2011) who did not undergo surgery with curative intent were identified within the National Cancer Database. Patients receiving palliative therapy were stratified by the type of intervention, as were patients undergoing chemotherapy that was not designated as palliative. Logistic regression was used to identify factors associated with the receipt of palliative therapy., Results: A total of 11,245 patients were analyzed, of which 2314 (20.6%) received palliative therapy. Use of palliative therapy as a category of treatments did not change significantly from 2004-2012 (19.4%-23.0%; P = 0.14), but the use of palliative chemotherapy nearly doubled (4.7%-8.7%; P < 0.001). Factors associated with the use of palliative therapy included age >60 y and increasing chronic comorbidities; these subgroups also had lower odds of receiving chemotherapy that was not designated as palliative. Differences in gender and race were not associated with variations in the receipt of palliative therapy., Conclusions: For stage IV rectal cancers managed without curative intent, use of palliative therapies remains consistently low, with a preference for sicker patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diverticular disease is commonly associated with the older population in the United States. As individual's age, diverticulae, or herniation of the mucosa through the colonic wall, develop. In 10-25% of individuals, the diverticulae become inflamed, resulting in diverticulitis. The gut ecosystem relies on the interaction of bacteria and fungi to maintain homeostasis. Although bacterial dysbiosis has been implicated in the pathogenesis of diverticulitis, associations between the microbial ecosystem and diverticulitis remain largely unstudied. This study investigated how the cooperative network of bacteria and fungi differ between a diseased area of the sigmoid colon chronically affected by diverticulitis and adjacent non-affected tissue. To identify mucosa-associated microbes, bacterial 16S rRNA and fungal ITS sequencing were performed on chronically diseased sigmoid colon tissue (DT) and adjacent tissue (AT) from the same colonic segment. We found that Pseudomonas and Basidiomycota OTUs were associated with AT while Microbacteriaceae and Ascomycota were enriched in DT. Bipartite co-occurrence networks were constructed for each tissue type. The DT and AT networks were distinct for each tissue type, with no microbial relationships maintained after intersection merge of the groups. Our findings indicate that the microbial ecosystem distinguishes chronically diseased tissue from adjacent tissue.

Scimitar syndrome is a rare association of congenital cardiopulmonary anomalies characterized by partial anomalous pulmonary venous return, in which an abnormal right pulmonary vein drains into the inferior vena cava. This case exemplifies the role of transesophageal echocardiography in perioperative management and surgical decision-making.

Background: The optimal treatment for an intra-abdominal abscess/infection secondary to perforating ileocolic Crohn's disease (PCD) is unclear., Methods: Forty-seven consecutive PCD patients treated via an institutional protocol of ileocolectomy after a 7-day period of percutaneous abscess drainage were retrospectively compared with 160 consecutive patients who underwent an elective ileocolectomy for Crohn's disease (ECD) between 1992 and 2014. Outcomes were compared using univariate analysis and propensity score matching., Results: Univariate analysis demonstrated significant differences in ileostomy rates (PCD: 48.9% vs ECD: 18.8%; P = .001), 30-day readmissions (PCD: 38.3% vs ECD: 18.8%; P = .01), and overall 30-day postoperative complications (PCD: 29.8% vs ECD: 15%; P = .03). After matching, a statistically significant difference was retained in ileostomy rates (P = .02) and 30-day readmissions (P = .01)., Conclusions: Early operative intervention after percutaneous drainage in perforating CD may be associated with a high incidence of diversions and readmissions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Patients admitted with Clostridium difficile infection are managed in a variety of settings. If their care is inadequate, these patients can rapidly deteriorate., Objective: The purpose of this study was to evaluate whether mortality for patients admitted with C difficile differed between medical and general/colorectal surgery services., Design: This was a retrospective cohort study with multivariable logistic regression used to evaluate the effect of admitting service on in-hospital mortality rates, with propensity score matching used to validate this relationship., Settings: The study was conducted at a single, tertiary care center., Patients: Inpatients with a positive C difficile stool test within 24 hours of admission to medical or surgical services were identified (2005-2015) using institutional electronic data sources., Main Outcome Measure: We measured inpatient mortality rate., Results: Of 1175 patients, 985 (83%) were admitted to medical services, whereas 190 (17%) were admitted by surgeons. Medical patients were older (63.9 vs 58.9 years; p = 0.001) and had a mean of 0.6 additional comorbidities (p < 0.001); cohorts were similar regarding vasopressors, peak white blood cell counts, and rate of intensive care unit admissions. Mortality was lower among surgery patients (2.6% vs 6.8%; p = 0.028), and logistic regression demonstrated lower odds of mortality for this group OR = 0.18 (95% CI, 0.05-0.58)). After propensity score matching for age, comorbidities, and severity of disease, this difference was confirmed (2.6% vs. 9.5%). A higher incidence of total colectomy for surgery patients (14.2% vs 0.4%) was a causal factor in their longer lengths of stay and higher total hospital costs. The time between orders for stool testing and metronidazole therapy was shorter in the surgery group (1.8 vs 3.8 hours; p = 0.002), although this trend was not observed with vancomycin therapy., Limitations: This was a retrospective study from a single institution, thereby limiting generalizability, with a lack of information regarding premorbid creatinine levels, ileus, or megacolon., Conclusions: In-hospital mortality rates for patients admitted with C difficile were lower on surgery services, perhaps in part related to higher colectomy rates.

Due to the inherent limitations of conventional antibiotics for the treatment of C. difficile infection (CDI), there is a growing interest in the development of alternative treatment strategies. Both bacteriophages and R-type bacteriocins, also known as phage tail-like particles (PTLPs), show promise as potential antibacterial alternatives for treating CDI. Similar to bacteriophages, but lacking a viral capsid and genome, PTLPs remain capable of killing target bacteria. Here we describe our experience in the induction and purification of C. difficile PTLPs. These methods have been optimized to allow production of concentrated, non-contractile, and non-aggregated samples for both sensitivity testing and structural electron microscopy studies.

Background: Compared with standard laparoscopy, single-site laparoscopic colorectal surgery may potentially offer advantages by creating fewer surgical incisions and providing a multifunctional trocar. Previous comparisons, however, have been limited by small sample sizes and selection bias., Objective: The purpose of this study was to compare 60-day outcomes between standard laparoscopic and single-site laparoscopic colorectal surgery patients undergoing elective and urgent surgeries., Design: This was an unselected, retrospective cohort study comparing patients who underwent elective and unplanned standard laparoscopic or single-site laparoscopic colorectal resections for benign and malignant disease between 2008 and 2014. Outcomes were compared using univariate analyses., Settings: This study was conducted at a single institution., Patients: A total of 626 consecutive patients undergoing laparoscopic colorectal surgery were included., Main Outcome Measures: Morbidity and mortality rates within 60 postoperative days were measured., Results: A total of 318 (51%) and 308 patients (49%) underwent standard laparoscopic and single-site laparoscopic procedures. No significant differences were noted in mean operative time (standard laparoscopy, 182.1 ± 81.3 vs single-site laparoscopy, 177.0 ± 86.5; p = 0.30) or postoperative length of stay (standard laparoscopy, 4.8 ± 3.4 vs single-site laparoscopy, 5.5 ± 6.9; p = 0.14). Conversions to laparotomy and 60-day readmissions were also similar for both cohorts across all of the procedures performed. A significant difference was identified in the number of patients who developed postoperative complications (standard laparoscopy, 19.2% vs single-site laparoscopy, 10.7%; p = 0.004), especially with respect to surgical-site infections (standard laparoscopy, 11.3% vs single-site laparoscopy, 5.8%; p = 0.02)., Limitations: This was a retrospective, single institution study., Conclusions: Single-site laparoscopic colorectal surgery demonstrates similar results to standard laparoscopic colorectal surgery with regard to operative time, length of stay, and readmissions. Single-site laparoscopic colorectal surgery may provide advantages in limiting the development of certain complications, such as superficial surgical-site infections.

Study Objective: To determine whether an automated intermittent bolus technique provides enhanced analgesia compared with a continuous infusion for femoral nerve block., Design: Prospective, single-blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT01226927)., Setting: Perioperative areas and orthopedic surgical ward of a university hospital., Patients: 45 ASA physical status 1, 2, and 3 patients undergoing unilateral primary total knee arthroplasty., Interventions: All patients received single-injection sciatic and femoral nerve blocks plus femoral nerve catheter placement for postoperative analgesia. Patients were randomly assigned to an automated intermittent bolus (5 mL every 30 min with 0.1 mL/hr basal rate) or a continuous infusion (10.1 mL/hr) delivery method of 0.2% ropivacaine., Measurements: Consumption of intravenous patient-controlled analgesia (IV-PCA) and visual analog scale (VAS) pain scores were assessed postoperatively at set intervals until the morning of postoperative day (POD) 2., Main Results: The mean (SEM) cumulative IV-PCA dose (mg of hydromorphone) for the 36-hour postoperative interval measured was 12.9 ± 2.32 in the continuous infusion rate group (n = 20) and 7.8 ± 1.02 in the intermittent bolus group [n = 21, t(39) = 2.04, P = 0.048; a 39 ± 14% difference in total usage]. Pain scores were statistically significantly lower in the intermittent bolus group in the afternoon of POD 1 (t(39) = 2.47, P = 0.018), but were otherwise similar., Conclusions: An automated intermittent bolus infusion technique for femoral nerve catheters is associated with clinically and statistically significantly less IV-PCA use (ie, an opioid-sparing effect) than a continuous infusion technique., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Contrast-induced nephropathy (CIN) refers to a decline in renal function following exposure to iodinated contrast media (CM). The present study was initiated to explore the role of known human risk factors (spontaneous hypertension, diabetes, protein-losing nephropathy) on CIN development in rodent models and to determine the effect of CM administration on kidney injury biomarkers in the face of preexisting kidney injury. Spontaneously hypertensive rats (hypertension), streptozotocin-treated Sprague Dawley rats (diabetes), and Dahl salt-sensitive rats (protein-losing nephropathy) were given single intravenous injections of the nonionic, low osmolar contrast medium, iohexol. Blood urea nitrogen (BUN), serum creatinine (sCr), and urinary biomarkers; albumin, lipocalin 2 (Lcn-2), osteopontin (Opn), kidney injury molecule 1 (Kim-1), renal papillary antigen 1 (Rpa-1), α-glutathione S-transferase (α-Gst), µ-glutathione S-transferase (µ-Gst), and beta-2 microglobulin (β2m) were measured in disease models and appropriate controls to determine the response of these biomarkers to CM administration. Each disease model produced elevated biomarkers of kidney injury without CM. Preexisting histopathology was exacerbated by CM but little or no significant increases in biomarkers were observed. When 1.5-fold or greater sCr increases from pre-CM were used to define true positives, receiver-operating characteristic curve analysis of biomarker performance showed sCr was the best predictor of CIN across disease models. β2m, Lcn-2, and BUN were the best predictors of histopathology defined kidney injury.

Amid the global economic crisis, the President's Emergency Plan for AIDS Relief (PEPFAR) and other organizations have been pressed to do more with constrained resources to meet unmet needs in the worldwide HIV/AIDS pandemic. PEPFAR has approached this challenge through the development of an Impact and Efficiency Acceleration Plan, which includes improving the collection and use of economic and financial data, increasing the efficiency of HIV/AIDS program implementation, and collaborating with governments and multilateral organizations to maximize the impact of the resources provided by the United States. For example, by linking financial data with program outputs, PEPFAR was able to help its implementing partners in Mozambique reduce mean unit expenditures for people receiving antiretroviral treatment by 45 percent, from $265 to $145 per person, between 2009 and 2011. This article describes the plan's elements, provides examples of progress and challenges to its implementation, and assesses the prospects for further improvements in efficiency and impact.

We designed a study to provide reversibility and comparative injury data for several candidate urinary biomarkers of kidney injury in the United States Food and Drug Administration biomarker qualification process. The nephrotoxin gentamicin was given to rats once on each of three days and the animals were killed during dosing or over the following 42 days. Between days one and three, all biomarkers except albumin were elevated, peaked at day 7, and returned to control levels by day 10 (μ- and α-glutathione S-transferases, and renal papillary antigen-1) or day 15 (kidney injury molecule-1, lipocalin-2, osteopontin, and clusterin). All biomarkers performed better during injury than during recovery except osteopontin, which performed equally well in both time periods. During the evolution of injury, kidney injury molecule-1, renal papillary antigen-1, and clusterin best mirrored the histopathologic lesions. During injury resolution, kidney injury molecule-1, osteopontin, and blood urea nitrogen best reflected recovery. Based on histopathology, necrosis, or apoptosis scoring, kidney injury molecule-1 was the best biomarker of overall renal injury. Evaluation by regeneration score showed that renal papillary antigen-1 best reflected tubular and/or collecting duct regeneration, especially during recovery. Thus, these biomarkers performed with different effectiveness when evaluated by individual pathological processes such as necrosis, apoptosis, and regeneration.

Background: Rho1 is a small GTPase of the Ras superfamily that serves as the central component in a highly conserved signaling pathway that regulates tissue morphogenesis during development in all animals. Since there is tremendous diversity in the upstream signals that can activate Rho1 as well as the effector molecules that carry out its functions, it is important to define relevant Rho1-interacting genes for each morphogenetic event regulated by this signaling pathway. Previous work from our lab and others has shown that Rho signaling is necessary for the morphogenesis of leg imaginal discs during metamorphosis in Drosophila, although a comprehensive identification of Rho1-interacting genes has not been attempted for this process., Methodology/principal Findings: We characterized an amorphic allele of Rho1 that displays a poorly penetrant dominant malformed leg phenotype and is capable of being strongly enhanced by Rho1-interacting heterozygous mutations. We then used this allele in a second-site noncomplementation screen with the Exelixis collection of molecularly defined deficiencies to identify Rho1-interacting genes necessary for leg morphogenesis. In a primary screen of 461 deficiencies collectively uncovering approximately 50% of the Drosophila genome, we identified twelve intervals harboring Rho1-interacting genes. Through secondary screening we identified six Rho1-interacting genes including three that were previously identified (RhoGEF2, broad, and stubbloid), thereby validating the screen. In addition, we identified Cdc42, Rheb and Sc2 as novel Rho1-interacting genes involved in adult leg development., Conclusions/significance: This screen identified well-known and novel Rho1-interacting genes necessary for leg morphogenesis, thereby increasing our knowledge of this important signaling pathway. We additionally found that Rheb may have a unique function in leg morphogenesis that is independent of its regulation of Tor.

Purpose: To examine the effect of a systematic vocabulary instructional technique in African American 2nd-grade children with below average vocabulary skills. An additional goal was to examine the role of book type in the retention of novel vocabulary words., Method: Using an adapted alternating treatments design, storybooks were used as a source for contextualizing vocabulary words in the context of robust vocabulary training. Five children's productive definitions were used to assess developing word knowledge using a 4-stage continuum ranging from no knowledge to full concept knowledge., Results: Superior word learning for instruction words in comparison with control words replicated across children provided evidence of behavior change that was attributable to robust vocabulary instruction. Gains in word learning were maintained 2 weeks following conclusion of the study. Use of storybooks that displayed sociocultural images and experiences that were similar to versus different from their own did not have a reliable effect on word learning among these African American children., Conclusions: The findings demonstrate the potential impact of robust vocabulary instruction for facilitating vocabulary development in children with below average vocabulary skills. Analysis of the results indicates that the use of the African American book was not a potent influence in facilitating retention of words.

Background and Objective: HIV chemoprophylaxis may be a future prevention strategy to help control the global epidemic of HIV/AIDS. Safety and efficacy trials of two agents are currently underway. We assess the expected number of HIV cases prevented and cost-effectiveness of a hypothetical HIV chemoprophylaxis program among men who have sex with men in a large US city., Design and Methods: We developed a stochastic compartmental mathematical model using HIV/AIDS surveillance data to simulate the HIV epidemic and the impact of a 5-year chemoprophylaxis program under varying assumptions for epidemiological, behavioral, programmatic and cost parameters. We estimated program effectiveness and costs from the perspective of the US healthcare system compared with current HIV prevention practices. The main outcome measures were number of HIV infections prevented and incremental cost per quality-adjusted life-years saved., Results: A chemoprophylaxis program targeting 25% of high-risk men who have sex with men in New York City could prevent 780 (4%) to 4510 (23%) of the 19 510 HIV infections predicted to occur among all men who have sex with men in New York City in 5 years. More than half of prevented infections would be among those not taking chemoprophylaxis but who benefit from reduced HIV prevalence in the community. Under base-case assumptions, incremental cost was US$ 31 970 per quality-adjusted life-years saved. The program was cost-effective under most variations in efficacy, mechanism of protection and adherence., Conclusion: HIV chemoprophylaxis among high-risk men who have sex with men in a major US city could prevent a significant number of HIV infections and be cost-effective.

Purpose: This study examined the extent to which using non-evocative, explicit referencing of print concepts during shared storybook reading in the context of language therapy facilitated print concept knowledge in children with language impairment., Method: Five children, ages 4 to 5 years, were provided scripted input on 20 print concepts during shared storybook reading that was incorporated into individualized 30-min language intervention sessions that were conducted in the children's classroom twice weekly. The children were not required to make any response to the input on print concepts, and the input was secondary to instruction in the language targets during the 10-min shared storybook reading activity., Results: Using a single-subject, multiple probe design across subjects, results indicated that children's knowledge of print concepts improved markedly when the procedure was incorporated into shared storybook reading and that they continued to learn and maintain knowledge of print concepts with repeated input., Clinical Implications: These findings suggest that children with language impairment may benefit from simple non-evocative, explicit referencing strategies that can be easily incorporated into the context of storybook reading during language therapy, thus providing speech-language pathologists with an additional tool for facilitating children's literacy skills.