Urine biomarkers individually and as a consensus model show high sensitivity and specificity for detecting UTIs.

BACKGROUND: Current diagnoses of urinary tract infection (UTI) by standard urine culture (SUC) has significant limitations in sensitivity, especially for fastidious organisms, and the ability to identify organisms in polymicrobial infections. The significant rate of both SUC "negative" or "mixed flora/contamination" results in UTI cases and the high prevalence of asymptomatic bacteriuria indicate the need for an accurate diagnostic test to help identify true UTI cases. This study aimed to determine if infection-associated urinary biomarkers can differentiate definitive UTI cases from non-UTI controls. METHODS: Midstream clean-catch voided urine samples were collected from asymptomatic volunteers and symptomatic subjects ≥ 60 years old diagnosed with a UTI in a urology specialty setting. Microbial identification and density were assessed using a multiplex PCR/pooled antibiotic susceptibility test (M-PCR/P-AST) and SUC. Three biomarkers [neutrophil gelatinase-associated lipocalin (NGAL), and Interleukins 8 and 1ß (IL-8, and IL-1ß)] were also measured via enzyme-linked immunosorbent assay (ELISA). Definitive UTI cases were defined as symptomatic subjects with a UTI diagnosis and positive microorganism detection by SUC and M-PCR, while definitive non-UTI cases were defined as asymptomatic volunteers. RESULTS: We observed a strong positive correlation (R2 > 0.90; p < 0.0001) between microbial density and the biomarkers NGAL, IL-8, and IL-1ß for symptomatic subjects. Biomarker consensus criteria of two or more positive biomarkers had sensitivity 84.0%, specificity 91.2%, positive predictive value 93.7%, negative predictive value 78.8%, accuracy 86.9%, positive likelihood ratio of 9.58, and negative likelihood ratio of 0.17 in differentiating definitive UTI from non-UTI cases, regardless of non-zero microbial density. NGAL, IL-8, and IL-1ß showed a significant elevation in symptomatic cases with positive microbe identification compared to asymptomatic cases with or without microbe identification. Biomarker consensus exhibited high accuracy in distinguishing UTI from non-UTI cases. CONCLUSION: We demonstrated that positive infection-associated urinary biomarkers NGAL, IL-8, and IL-1ß, in symptomatic subjects with positive SUC and/or M-PCR results was associated with definitive UTI cases. A consensus criterion with ≥ 2 of the biomarkers meeting the positivity thresholds showed a good balance of sensitivity (84.0%), specificity (91.2%), and accuracy (86.9%). Therefore, this biomarker consensus is an excellent supportive diagnostic tool for resolving the presence of active UTI, particularly if SUC and M-PCR results disagree.

Rapid growth of a large penile median raphe cyst.

A 57-year-old male presented to the emergency department due to sudden growth of a penile mass. On physical exam, the mass was located on the ventral surface of the penis at the level of the corona and measured 7cm × 4cm x 3.5cm. Ultrasound suggested that it was cystic in nature. The mass was surgically removed, and final pathology revealed a median raphe cyst.

Trimodality therapy for esophageal cancer: The role of surgical and radiation treatment parameters in the development of anastomotic complications.

BACKGROUND: Here, we investigated the relationship between clinical parameters, including the site of surgical anastomosis and radiation dose to the anastomotic region, and anastomotic complications in esophageal cancer patients treated with trimodality therapy. METHODS: Between 2007 and 2016, esophageal cancer patients treated with trimodality therapy at a tertiary academic cancer center were identified. Patient, treatment, and outcome parameters were collected. Radiation dose to the gastric regions were extracted. Anastomotic complication was defined as leak and/or stricture. We used Fisher's exact and Wilcoxon rank-sum tests to compare the association between clinical parameters and anastomotic complications. RESULTS: Of 89 patients identified, the median age was 63 years, 82% (n = 73) were male, and 82% had distal (n = 47) or gastroesophageal junction (n = 26) tumors. Median follow-up was 25.8 months. Esophagectomies were performed with cervical (65%, n = 58) or thoracic anastomoses (35%, n = 31). Anastomotic complications developed in 60% (n = 53). Cervical anastomosis was associated with anastomotic complications (83%, n = 44/53, p < 0.01). Radiation to any gastric substructure was not associated with anastomotic complications (p > 0.05). In the subset of patients with distal/gastroesophageal junction tumors undergoing esophagectomy with cervical anastomosis where radiation was delivered to the future neoesophagus, 80% (n = 35/44) developed anastomotic complications. In this high-risk subgroup, radiation was not associated with anastomotic complications (p > 0.05). CONCLUSIONS: Our analysis did not demonstrate an association between radiation dose to gastric substructures and anastomotic complications. However, it showed an association between esophagectomy with cervical anastomosis and anastomotic complications. Patients with distal/gastroesophageal junction tumors who undergo esophagectomy with cervical anastomosis have higher rates of anastomotic complications unrelated to radiation to gastric substructures.

Effect of phenylephrine on cerebral oxygen saturation and cardiac output in adults when used to treat intraoperative hypotension: a systematic review.

OBJECTIVE: The objective of this review was to examine the effect of phenylephrine on cerebral oxygen saturation, cardiac output, and middle cerebral artery blood flow velocity when used to treat intraoperative hypotension. INTRODUCTION: While the etiology of postoperative cognitive dysfunction in adults following surgery is likely multifactorial, intraoperative cerebral hypoperfusion is a commonly proposed mechanism. Research evidence and expert opinion are emerging that suggest phenylephrine adversely affects cerebral oxygen saturation and may also adversely affect cerebral perfusion via a reduction in cardiac output or cerebral vascular vasoconstriction. The administration of phenylephrine to treat intraoperative hypotension is common anesthesia practice, despite a lack of evidence to show it improves cerebral perfusion. Therefore, a systematic review of the effect of phenylephrine on cerebral hemodynamics has significant implications for anesthesia practice and future research. INCLUSION CRITERIA: Studies of adults 18 years and over undergoing elective, non-neurosurgical procedures involving anesthesia were included. In these studies, participants received phenylephrine to treat intraoperative hypotension. The effect of phenylephrine on cerebral oxygen saturation, cardiac output, or middle cerebral artery blood flow velocity was measured. METHODS: Key information sources searched included MEDLINE (Ovid), Embase, CINAHL (EBSCO), and Google Scholar. The scope of the search was limited to English-language studies published from 1999 through 2017. The recommended JBI approach to critical appraisal, study selection, data extraction, and data synthesis were used. RESULTS: This systematic review found that phenylephrine consistently decreased cerebral oxygen saturation values despite simultaneously increasing mean arterial pressure to normal range. Results also found that ephedrine and dopamine were superior to phenylephrine in maintaining or increasing values. Phenylephrine was found to be similar to vasopressin in the extent to which both decreased cerebral oxygen saturation values. Results also showed that phenylephrine resulted in statistically significant declines in cardiac output, or failed to improve abnormally low preintervention values. The effect of phenylephrine on middle cerebral artery blood flow velocity was only measured in one study and showed that phenylephrine increased flow velocity by about 20%. Statistical pooling of the study results was not possible due to the gross variation in how the intervention was administered and how effect was measured. CONCLUSIONS: This review found that phenylephrine administration resulted in declines in cerebral oxygen saturation and cardiac output. However, the research studies were ineffective in informing phenylephrine's mechanism of action or its impact on postoperative cognitive function. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO (CRD42018100740).

Exploring the Relationship of Radiation Dose Exposed to the Length of Esophagus and Weight Loss in Patients with Lung Cancer.

PURPOSE: We investigate whether esophageal dose-length parameters (Ldose) can robustly predict significant weight loss-≥5% weight loss during radiation therapy (RT) compared with the weight before RT-in patients with lung cancer treated with definitive intent. METHODS AND MATERIALS: Patients with lung cancer treated with conventionally fractionated RT between 2010 and 2018 were retrospectively identified. LFdose and LPdose, the length of full- and partial-circumferential esophagus receiving greater than a threshold dose in Gy, respectively, were created. Multivariate logistic regression examined the associations between individual Ldose and weight loss after adjusting for clinical parameters and correcting for multiple comparisons. Ridge logistic regression examined the relative importance of Ldose compared with dose-volume (Vdose), mean dose (Dmean), and clinical parameters in determining weight loss. Univariate logistic regression examined the unadjusted probability of weight loss for important Ldose parameters. RESULTS: Among the 214 patients identified, median age was 66.9 years (range, 31.5-88.9 years), 50.5% (n = 108) were male, 68.2% (n = 146) had stage III lung cancer, median RT dose was 63 Gy (range, 60-66 Gy), and 88.3% (n = 189) received concurrent chemotherapy. Esophagus lengths receiving high full-circumferential (LF50-LF60) and high partial-circumferential doses (LP60) were associated with significant weight loss (P ≤ .05). LF65 and LP65 reached near significance (P = .06 and .053, respectively). LF65 > LF60 > LP65 were the most important dose parameters in determining weight loss compared with other Ldose, Vdose, and Dmean parameters. CONCLUSIONS: Esophageal Ldose parameters are an efficient way of interpreting complex dose parameters in relation to weight loss toxicity among patients with lung cancer receiving definitive RT.

Effectiveness of deep general anesthesia compared to the standard depth of general anesthesia for acute postoperative pain and patient safety: a systematic review protocol.

OBJECTIVE: The objective of this systematic review is to synthesize the best available evidence related to the effectiveness of deep general anesthesia on acute postoperative pain and patient safety in adult patients. INTRODUCTION: Acute postoperative pain is a common physiological side effect of surgery that should be alleviated as soon as possible to reduce suffering and other detrimental effects. Given the adverse effects related to the use of opioids for pain management, and in the current opioid epidemic, evidence-based clinical practice recommendations are needed to reduce the use of opioids in the treatment of acute postoperative pain. INCLUSION CRITERIA: This review will include studies of adult patients that incorporate the intervention of deep general anesthesia (bispectral index values of 45 or less), compared to the provision of a standard depth of general anesthesia (bispectral index values 45-60). Included studies will report acute postoperative pain (within the first 48 hours after surgery) as a primary outcome variable. Secondary outcomes of interest include opioid consumption and any reported adverse outcomes. METHODS: A three-step search strategy will be used to locate studies published in English from 1992 (advent of electroencephalography index monitoring technology) in Ovid MEDLINE, Embase and CINAHL databases. Two independent reviewers will assess retrieved studies against inclusion criteria, complete critical appraisal for methodological quality and extract data using a standardized tool. Data will be synthesized using statistical meta-analysis, where possible.

Applying Non-Homogeneous Dose Optimization to Improve Conventionally Fractionated Radiation Plan Quality in Patients with Non-Small Cell Lung Cancer.

PURPOSE: Nonhomogeneous dose optimization (NHDO) is exploited in stereotactic body radiation therapy (SBRT) to increase dose delivery to the tumor and allow rapid dose falloff to surrounding normal tissues. We investigate changes in plan quality when NHDO is applied to inverse-planned conventionally fractionated radiation therapy (CF-RT) plans in patients with non-small cell lung cancer. METHODS AND MATERIALS: Patients with near-central non-small cell lung cancer treated with CF-RT in 2018 at a single institution were identified. CF-RT plans were replanned using NHDO techniques, including normalizing to a lower isodose line, while maintaining clinically acceptable normal tissue constraints and target coverage. Tumor control probabilities were calculated. We compared delivered CF-RT plans using homogenous dose optimization (HDO) versus NHDO using Wilcoxon signed-rank tests. Median values are reported. RESULTS: Thirteen patients were replanned with NHDO techniques. Planning target volume coverage by the prescription dose was similar (NHDO = 96% vs HDO = 97%, P = .3). All normal-tissue dose constraints were met. NHDO plans were prescribed to a lower-prescription isodose line compared with HDO plans (85% vs 97%, P = .001). NHDO increased mean dose to the planning target volume (73 Gy vs 67 Gy), dose heterogeneity, and dose falloff gradient (P < .03). NHDO decreased mean dose to surrounding lungs, esophagus, and heart (relative reduction of 6%, 14%, and 15%, respectively; P < .05). Other normal tissue objectives improved with NHDO, including total lung V40 and V60, heart V30, and maximum esophageal dose (P < .05). Tumor control probabilities doubled from 31.6% to 65.4% with NHDO (P = .001). CONCLUSIONS: In select patients, NHDO principles used in SBRT optimization can be applied to CF-RT. NHDO results in increased tumor dose, reduction in select organ-at-risk dose objectives, and better maintenance of target coverage and normal-tissue constraints compared with HDO. Our data demonstrate that principles of NHDO used in SBRT can also improve plan quality in CF-RT.

Preoperative contralateral lung radiation dose is associated with postoperative pulmonary toxicity in patients with locally advanced non-small cell lung cancer treated with trimodality therapy.

PURPOSE: In patients with non-small cell lung cancer (NSCLC) who undergo trimodality therapy (chemoradiation followed by surgical resection), it is unknown whether limiting preoperative radiation dose to the uninvolved lung reduces postsurgical morbidity. This study evaluated whether radiation fall-off dose parameters to the contralateral lung that is unaffected by NSCLC are associated with postoperative complications in NSCLC patients treated with trimodality therapy. METHODS AND MATERIALS: We retrospectively reviewed NSCLC patients who underwent trimodality therapy between March 2008 and October 2016, with available restored digital radiation plans. Fischer's exact test was used to assess associations between patient and treatment characteristics and the development of treatment-related toxicity. Spearman rank correlation was used to measure the strength of association between dosimetric parameters. RESULTS: Forty-six patients were identified who received trimodality therapy with intensity modulated radiation (median, 59.4 Gy; range, 45-70) and concurrent platinum doublet chemotherapy, followed by surgical resection. The median age was 64.9 years (range, 45.6-81.6). The median follow-up time was 1.9 years (range, 0.3-8.4). Twenty-four (52.2%) patients developed any-grade pulmonary toxicity and 14 (30.4%) patients developed grade 2+ pulmonary toxicity. There was an increased incidence of any-grade pulmonary toxicity in patients with contralateral lung volume receiving at least 20 Gy (V20) ≥7% compared with <7% (90%, n = 9 vs 41.7%, n = 15; P = .01). Similarly, contralateral lung V10 ≥20% was associated with an increased rate of any-grade pulmonary toxicity compared with V10 <20% (80%, n = 12 vs 38.7%, n = 12; P = .01). Pneumonectomy/bilobectomy was associated with grade 2+ pulmonary toxicity (P = .04). CONCLUSIONS: Patients who received a higher radiation fall-off dose volume parameter (V20 ≥7% and V10 ≥20%) to the contralateral uninvolved lung had a higher incidence of any-grade postoperative pulmonary toxicity. Limiting radiation fall-off dose to the uninvolved lung may be an important modifiable radiation parameter in limiting postoperative toxicity in trimodality patients.

Cutaneous polyarteritis nodosa localized to a region of lymphedema secondary to Streptococcus viridans cellulitis and multiple surgeries.

Cutaneous polyarteritis nodosa (CPAN) is a chronic, indolent, single organ arteritis that generally presents with lower extremity nodules and/or livedo racemosa, accompanied by malaise and arthralgias. CPAN is often triggered by infection, commonly Group A streptococcal species, and is considered an autoimmune reaction. Scarring from surgery and obliterative lymphangiitis from bacterial cellulitis are the causes of lymphedema. Lymphedematous skin is predisposed to autoimmune disorders. Herein we report a 53-year-old woman who developed CPAN restricted to a localized area of the right upper arm-shoulder that had undergone multiple surgeries, complicated by episodes of Streptococcus viridans cellulitis. Clinically, a 15 cm diameter plaque exhibited violaceous, reticulate margins, subtle papules and nodules and central livedo racemosa. Biopsy showed numerous foci of arteritis in active, subacute and reparative stages. In addition, a broad zone of fibrosis replaced the deep dermis-subcutis zone and harbored numerous dilated lymphatic vessels scar lymphedema. Treatment consisted of high potency topical corticosteroids under occlusion; remission after 3 months therapy and follow-up. CPAN primarily affects the lower legs, a region of frequently affected by phlebolymphedema. This report of CPAN localized to an area of scar lymphedema underscores the importance of lymphatic function in the pathogenesis of CPAN.

The development and implementation of an interdisciplinary on-line academic course using a life course perspective.

The University of Wisconsin-Madison Pediatric Pulmonary Center (UW PPC) provides interdisciplinary leadership training for graduate students and postgraduate professionals. The training includes a three-credit on-line course entitled Interdisciplinary Care of Children with Special Health Care Needs. This paper describes the course, the content and organization of which was guided by the life course perspective (LCP). The UW PPC team used the LCP to guide course organization, content development, and evaluation approaches. UW PPC trainees took responsibility for content areas, performed literature reviews and reviews of resources, and suggested student activities. Course content was focused on the child with special health care needs (CSHCN) embedded in contextual environments of family, community, culture, and larger social and public policy arenas. The content included three case-study videos that followed a child with cystic fibrosis from birth to age 18. Key concepts of the LCP were woven in throughout the videos and other course materials. Emphasis was on representing development of the individual during critical/sensitive periods and on social determinants of health. At semester's end, qualitative and quantitative student evaluation results were very positive for all areas of the course. The final course paper, organized similarly to course modules, synthesized all aspects of the course. A successful paper included LCP concepts woven throughout to show integration of course content. The LCP provided a useful framework for course organization and content, and served as a lens through which students came to understand the care needs of CSHCN and their families. A course such as this can serve the important goal of educating future maternal child health professionals in using the LCP to understand how multiple determinants of health interact across the life span to produce health outcomes in this population.

Strengthening families program (10-14): effects on the family environment.

This study examined whether parent-youth dyads participating in the Strengthening Families Program 10-14 (SFP 10-14) would demonstrate greater postprogram family cohesion, communication, involvement, and supervision and if youth would report less alcohol, tobacco, and other drugs involvement in contrast to a comparison group. From 16 randomly selected schools, we recruited 167 parent-youth dyads: 86 from intervention and 81 from comparison schools. The intention-to-treat analysis found one significant change in family environment. Considering dose, it was found that among dyads receiving a full dose, all the outcomes were in the expected direction and effect sizes were moderate. Among dyads receiving a partial dose, 10 of 18 outcomes were in the direction opposite that expected. Youth participation in alcohol, tobacco, and other drugs was very low and did not differ postprogram. Although the expected outcomes were not realized, findings descriptive of dosage effects make a valuable contribution to the field. Study of factors that distinguish intervention completers from noncompleters is recommended.

Electron paramagnetic resonance studies of functionally active, nitroxide spin-labeled peptide analogues of the C-terminus of a G-protein alpha subunit.

The C-terminal tail of the transducin alpha subunit, Gtalpha(340-350), is known to bind and stabilize the active conformation of rhodopsin upon photoactivation (R*). Five spin-labeled analogues of Gtalpha(340-350) demonstrated native-like activity in their ability to bind and stabilize R*. The spin-label 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC) was employed at interior sites within the peptide, whereas a Proxyl (3-carboxyl-2,2,5,5-tetramethyl-pyrrolidinyloxy) spin-label was employed at the amino terminus of the peptide. Upon binding to R*, the electron paramagnetic resonance spectrum of TOAC(343)-Gtalpha(340-350) revealed greater immobilization of the nitroxide when compared to that of the N-terminally modified Proxyl-Gtalpha(340-350) analogue. A doubly labeled Proxyl/TOAC(348)-Gtalpha(340-350) was examined by DEER spectrocopy to determine the distribution of distances between the two nitroxides in the peptides when in solution and when bound to R*. TOAC and Proxyl spin-labels in this GPCR-G-protein alpha-peptide system provide unique biophysical probes that can be used to explore the structure and conformational changes at the rhodopsin-G-protein interface.

Crystal structures and proposed structural/functional classification of three protozoan proteins from the isochorismatase superfamily.

We have determined the crystal structures of three homologous proteins from the pathogenic protozoans Leishmania donovani, Leishmania major, and Trypanosoma cruzi. We propose that these proteins represent a new subfamily within the isochorismatase superfamily (CDD classification cd004310). Their overall fold and key active site residues are structurally homologous both to the biochemically well-characterized N-carbamoylsarcosine-amidohydrolase, a cysteine hydrolase, and to the phenazine biosynthesis protein PHZD (isochorismase), an aspartyl hydrolase. All three proteins are annotated as mitochondrial-associated ribonuclease Mar1, based on a previous characterization of the homologous protein from L. tarentolae. This would constitute a new enzymatic activity for this structural superfamily, but this is not strongly supported by the observed structures. In these protozoan proteins, the extended active site is formed by inter-subunit association within a tetramer, which implies a distinct evolutionary history and substrate specificity from the previously characterized members of the isochorismatase superfamily. The characterization of the active site is supported crystallographically by the presence of an unidentified ligand bound at the active site cysteine of the T. cruzi structure.

Motion of carboxyl terminus of Galpha is restricted upon G protein activation. A solution NMR study using semisynthetic Galpha subunits.

The carboxyl terminus of the G protein alpha subunit plays a key role in interactions with G protein-coupled receptors. Previous studies that have incorporated covalently attached probes have demonstrated that the carboxyl terminus undergoes conformational changes upon G protein activation. To examine the conformational changes that occur at the carboxyl terminus of Galpha subunits upon G protein activation in a more native system, we generated a semisynthetic Galpha subunit, site-specifically labeled in its carboxyl terminus with 13C amino acids. Using expressed protein ligation, 9-mer peptides were ligated to recombinant Galpha(i1) subunits lacking the corresponding carboxyl-terminal residues. In a receptor-G protein reconstitution assay, the truncated Galpha(i1) subunit could not be activated by receptor; whereas the semisynthetic protein demonstrated functionality that was comparable with recombinant Galpha(i1). To study the conformation of the carboxyl terminus of the semisynthetic G protein, we applied high resolution solution NMR to Galpha subunits containing 13C labels at the corresponding sites in Galpha(i1): Leu-348 (uniform), Gly-352 (alpha carbon), and Phe-354 (ring). In the GDP-bound state, the spectra of the ligated carboxyl terminus appeared similar to the spectra obtained for 13C-labeled free peptide. Upon titration with increasing concentrations of AlF4-, the 13C resonances demonstrated a marked loss of signal intensity in the semisynthetic Galpha subunit but not in free peptide subjected to the same conditions. Because AlF4- complexes with GDP to stabilize an activated state of the Galpha subunit, these results suggest that the Galpha carboxyl terminus is highly mobile in its GDP-bound state but adopts an ordered conformation upon activation by AlF4-.

Enhancing survey data collection among youth and adults: use of handheld and laptop computers.

Tobacco use, alcohol and other drug use, early sexual behavior, dietary practices, physical inactivity, and activities that contribute to unintentional and intentional injuries are a significant threat to the health of young people. These behaviors have immediate and long-term consequences and contribute to diminished health, educational, and social outcomes. Research suggests that health risk behaviors exhibited during adolescence and adulthood have their origins earlier in childhood and preventive interventions are less successful after the risk behaviors have begun. Therefore, efforts to prevent health risk behaviors are best initiated in late childhood or early adolescence. However, to document the efficacy of these efforts, reliable, valid, and parent/child-friendly systems of data collection are required. Computerized data collection for research has been found to improve privacy, confidentiality, and portability over the paper-and-pencil method, which, in turn, enhances the reliability of sensitive data such as alcohol use or sexual activity. We developed programming tools for the personal computer and a handheld personal data assistant to offer a comprehensive set of user interface design elements, relational databases, and ample programming languages so that adults could answer 261 items and youth 346 items. The purpose of the article was to describe an innovative handheld computer-assisted survey interview method of collecting sensitive data with children aged 9 to 11. The method was developed as part of a large multisite, national study to prevent substance use.