Understanding patient preference for physician attire: a cross-sectional observational study of 10 academic medical centres in the USA.
Several large studies have shown that improving the patient experience is associated with higher reported patient satisfaction, increased adherence to treatment and clinical outcomes. Whether physician attire can affect the patient experience-and how this influences satisfaction-is unknown. Therefore, we performed a national, cross-sectional study to examine patient perceptions, expectations and preferences regarding physicians dress. 10 academic hospitals in the USA. Convenience sample of 4062 patients recruited from 1 June 2015 to 31 October 2016. We conducted a questionnaire-based study of patients across 10 academic hospitals in the USA. The questionnaire included photographs of a male and female physician dressed in seven different forms of attire. Patients were asked to rate the provider pictured in various clinical settings. Preference for attire was calculated as the composite of responses across five domains (knowledgeable, trustworthy, caring, approachable and comfortable) via a standardised instrument. Secondary outcome measures included variation in preferences by respondent characteristics (eg, gender), context of care (eg, inpatient vs outpatient) and geographical region. Of 4062 patient responses, 53% indicated that physician attire was important to them during care. Over one-third agreed that it influenced their satisfaction with care. Compared with all other forms of attire, formal attire with a white coat was most highly rated (p=0.001 vs scrubs with white coat; p<0.001 all other comparisons). Important differences in preferences for attire by clinical context and respondent characteristics were noted. For example, respondents≥65 years preferred formal attire with white coats (p<0.001) while scrubs were most preferred for surgeons. Patients have important expectations and perceptions for physician dress that vary by context and region. Nuanced policies addressing physician dress code to improve patient satisfaction appear important.


Physicochemical Study of the Self-Disintegration of Calcium Orthosilicate (β→γ) in the Presence of the C12A7 Aluminate Phase.
The β-γ polymorphic transition of calcium orthosilicate (C2S) is a key phenomenon in cement chemistry. During this transition, the compound expands due to structural changes and a significant reduction in its density is observed, leading to its disintegration into a powder with a very high specific surface area. Owing to this tendency of the C2S material to "self-disintegrate", its production is energy-efficient and thus environmentally friendly. A physicochemical study of the self-disintegration process was conducted with the aim of determining how the amount of dodecacalcium hepta-aluminate (C12A7) in calcium orthosilicate (C2S) affects the temperature at which the polymorphic transi-tions from α'L-C2S to β-C2S and from β-C2S to γ-C2S undergo stabilization. The applied techniques included differential thermal analysis (DTA), calorimetry and X-ray diffraction (XRD), and they made it possible to determine what C2S/C12A7 phase ratio in the samples and what cooling rate constitute the optimal conditions of the self-disintegration process. The optimal cooling rate for C2S materials with a C12A7 content of up to 60 wt% was determined to be 5 K·min-1. The optimal mass ratio of C2S/C12A7 was found to be 70/30, which ensures both efficient self-disintegration and desirable grain size distribution.


Proteasome Activity Is Influenced by the HECT_2 Protein Ipa1 in Budding Yeast.
The ubiquitin-proteasome system (UPS) controls cellular functions by maintenance of a functional proteome and degradation of key regulatory proteins. Central to the UPS is the proteasome that adjusts the abundance of numerous proteins, thereby safeguarding their activity or initiating regulatory events. Here, we demonstrate that the essential Saccharomyces cerevisiae protein Yjr141w/Ipa1 (Important for cleavage and PolyAdenylation) belongs to the HECT_2 (homologous to E6-AP carboxyl terminus_2) family. We found that five cysteine residues within the HECT_2 family signature and the C-terminus are essential for Ipa1 activity. Furthermore, Ipa1 interacts with several ubiquitin-conjugating enzymes in vivo and localizes to the cytosol and nucleus. Importantly, Ipa1 has an impact on proteasome activity, which is indicated by the activation of the Rpn4 regulon as well as by decreased turnover of destabilized proteasome substrates in an IPA1 mutant. These changes in proteasome activity might be connected to reduced maturation or modification of proteasomal core particle proteins. Our results highlight the influence of Ipa1 on the UPS. The conservation within the HECT_2 family and the connection of the human HECT_2 family member to an age-related degeneration disease might suggest that HECT_2 family members share a conserved function linked to proteasome activity.


Recent advances in bio-P modelling - a new approach verified by full-scale observations.
This paper summarizes recent developments in biological phosphorus removal modelling, with special attention to side-stream enhanced biological phosphorus removal (S2EBPR) systems on which previous models proved to be ineffective without case-by-case parameter adjustments. Through the research and experience of experts and practitioners, a new bio-kinetic model was developed including an additional group of biomass (glycogen accumulating organisms - GAOs) and new processes (such as aerobic and anoxic maintenance for PAO and GAO; enhanced denitrification processes; fermentation by PAOs which - along with PAO selection - is driven by oxidation-reduction potential (ORP)). This model successfully described various conditions in laboratory measurements and full plant data. The calibration data set is provided by Clean Water Services from Rock Creek Facility (Hillsboro, OR) including two parallel trains: conventional A2O and Westbank configurations, allowing the model to be verified on conventional and side-stream EBPR systems as well.


Apathy in Parkinson's disease: neurophysiological evidence of impaired incentive processing.
Apathy is one of the most common and debilitating nonmotor manifestations of Parkinson's disease (PD) and is characterized by diminished motivation, decreased goal-directed behavior, and flattened affect. Despite its high prevalence, its underlying mechanisms are still poorly understood, having been associated with executive dysfunction, and impaired emotional processing and decision making. Apathy, as a syndrome, has recently been associated with reduced activation in the ventral striatum, suggesting that early- to middle-stage Parkinson's disease patients with this manifestation may have a compromised mesocorticolimbic dopaminergic pathway and impaired incentive processing. To test this hypothesis, we measured the amplitude of the feedback-related negativity, an event-related brain potential associated with performance outcome valence, following monetary gains and losses in human PD patients (12 women) and healthy controls (6 women) performing a gambling task. Early- to middle-stage PD patients presenting clinically meaningful symptoms of apathy were compared with nonapathetic PD patients and healthy controls. Patients with cognitive impairment, depression, and other psychiatric disturbances were excluded. Results showed that the amplitude of the feedback-related negativity, measured as the difference wave in the event-related brain potential between gains and losses, was significantly reduced in PD patients with apathy compared with nonapathetic patients and healthy controls. These findings indicate impaired incentive processing and suggest a compromised mesocorticolimbic pathway in cognitively intact PD patients with apathy.


Small fields: nonequilibrium radiation dosimetry.
Advances in radiation treatment with beamlet-based intensity modulation, image-guided radiation therapy, and stereotactic radiosurgery (including specialized equipments like CyberKnife, Gamma Knife, tomotherapy, and high-resolution multileaf collimating systems) have resulted in the use of reduced treatment fields to a subcentimeter scale. Compared to the traditional radiotherapy with fields > or =4 x 4 cm2, this can result in significant uncertainty in the accuracy of clinical dosimetry. The dosimetry of small fields is challenging due to nonequilibrium conditions created as a consequence of the secondary electron track lengths and the source size projected through the collimating system that are comparable to the treatment field size. It is further complicated by the prolonged electron tracks in the presence of low-density inhomogeneities. Also, radiation detectors introduced into such fields usually perturb the level of disequilibrium. Hence, the dosimetric accuracy previously achieved for standard radiotherapy applications is at risk for both absolute and relative dose determination. This article summarizes the present knowledge and gives an insight into the future procedures to handle the nonequilibrium radiation dosimetry problems. It is anticipated that new miniature detectors with controlled perturbations and corrections will be available to meet the demand for accurate measurements. It is also expected that the Monte Carlo techniques will increasingly be used in assessing the accuracy, verification, and calculation of dose, and will aid perturbation calculations of detectors used in small and highly conformal radiation beams. rican Association of Physicists in Medicine.


Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation: an epigenome-wide association study meta-analysis.
Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials & methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings.


Transcriptomic Analysis of Hidradenitis Suppurativa: A Unique Molecular Signature with Broad Immune Activation.
Hidradenitis suppurativa is a chronic inflammatory skin disease with limited treatment options. The poorly understood pathogenesis hinders the development of effective treatments; therefore, a pressing need exists to further elucidate the molecular mechanisms in hidradenitis suppurativa. This study investigated the underlying inflammatory pathways and cell types in hidradenitis suppurativa using transcriptomic approaches with RNA sequencing of lesional and non-lesional skin biopsies from hidradenitis suppurativa, which was jointly analyzed with previously published transcriptomic data from atopic dermatitis and psoriasis patients. The differential expression and pathway enrichment analyses demonstrated the activation of multiple inflammatory processes, including the innate and adaptive immune systems, implicated in the hidradenitis suppurativa pathogenesis. In agreement, hidradenitis suppurativa exhibited a unique and heterogeneous cell type signature involving lymphoid and myeloid cells such as B cells and macrophages. Furthermore, hidradenitis suppurativa displayed increased expression of TH1/2/17 signatures with no predominant TH signatures unlike psoriasis (TH1/17) and atopic dermatitis (TH2). In summary, our study provides molecular insights into the pathomechanisms in hidradenitis suppurativa, revealing a strong and widespread immune activation, which may benefit from treatment strategies offering a broad immunomodulation of various key inflammatory pathways. Our data not only corroborate previously reported findings but also enhance our understanding of the immune dysregulation in hidradenitis suppurativa, uncovering novel and potential therapeutic targets.


Carboxypeptidase activity common to viridans group streptococci cleaves angiotensin I to angiotensin II: an activity homologous to angiotensin-converting enzyme (ACE).
We have found that Streptococcus gordonii FSS2, an infective endocarditis (IE) isolate, expresses a dipeptidyl-carboxypeptidase with activity homologous to angiotensin-converting enzyme (ACE). The carboxypeptidase activity was purified to homogeneity as a complex/aggregate from a bacterial surface extract and was also active as a 165 kDa monomer. The specific activity for the carboxypeptidase activity was eightfold higher than that for recombinant human ACE. Selected ACE inhibitors, captopril, lisinopril and enalapril, did not inhibit the ACE activity. The carboxypeptidase also hydrolysed the Aα and Bβ-chains of human fibrinogen, which resulted in impaired fibrin formation by thrombin. The gene encoding ACE carboxypeptidase activity was sequenced and the inferred polypeptide product showed 99 % amino acid homology to SGO_0566, sgc, 'challisin' of S. gordonii CL1 Challis, and had no significant amino acid sequence homology to human ACE. Homologues of challisin ACE activity were commonly detected among the viridans group streptococci most often associated with IE.


Evaluation of pancreatic cancer cell migration with multiple parameters in vitro by using an optical real-time cell mobility assay device.
Migration of cancer cell correlates with distant metastasis and local invasion, which are good targets for cancer treatment. An optically accessible device "TAXIScan" was developed, which provides considerably more information regarding the cellular dynamics and less quantity of samples than do the existing methods. Here, we report the establishment of a system to analyze the nature of pancreatic cancer cells using TAXIScan and we evaluated lysophosphatidic acid (LPA)-elicited pancreatic cell migration. Pancreatic cancer cell lines, BxPC3, PANC-1, AsPC1, and MIAPaCa-2, were analyzed for adhesion as well as migration towards LPA by TAXIScan using parameters such as velocity and directionality or for the number of migrated cells by the Boyden chamber methods. To confirm that the migration was initiated by LPA, the expression of LPA receptors and activation of intracellular signal transductions were examined by quantitative reverse transcriptase polymerase reaction and western blotting. Scaffold coating was necessary for the adhesion of pancreatic cancer cells, and collagen I and Matrigel were found to be good scaffolds. BxPC3 and PANC-1 cells clearly migrated towards the concentration gradient formed by injecting 1 μL LPA, which was abrogated by pre-treatment with LPA inhibitor, Ki16425 (IC50 for the directionality ≈ 1.86 μM). The LPA dependent migration was further confirmed by mRNA and protein expression of LPA receptors as well as phosphorylation of signaling molecules. LPA1 mRNA was highest among the 6 receptors, and LPA1, LPA2 and LPA3 proteins were detected in BxPC3 and PANC-1 cells. Phosphorylation of Akt (Thr308 and Ser473) and p42/44MAPK in BxPC3 and PANC-1 cells was observed after LPA stimulation, which was clearly inhibited by pre-treatment with a compound Ki16425. We established a novel pancreatic cancer cell migration assay system using TAXIScan. This assay device provides multiple information on migrating cells simultaneously, such as their morphology, directionality, and velocity, with a small volume of sample and can be a powerful tool for analyzing the nature of cancer cells and for identifying new factors that affect cell functions.


Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development.
Although clinically distinct, schizophrenia and Alzheimer's disease are common and devastating disorders that profoundly impair cognitive function. For Alzheimer's disease, key mechanistic insights have emerged from genetic studies that identified causative mutations in amyloid precursor protein (APP) and presenilin. Several genes have been associated with schizophrenia and other major psychoses, and understanding their normal functions will help elucidate the underlying causes of these disorders. One such gene is disrupted-in-schizophrenia 1 (DISC1). DISC1 and APP have been implicated separately in cortical development, with each having roles in both neuronal migration and neurite outgrowth. Here, we report a previously unrecognized biochemical and functional interaction between DISC1 and APP. Using in utero electroporation in the living rat brain, we show that DISC1 acts downstream of APP and Disabled-1 to regulate cortical precursor cell migration. Specifically, overexpression of DISC1 rescues the migration defect caused by a loss of APP expression. Moreover, knockdown of APP in cultured embryonic neurons results in altered subcellular localization of DISC1. Using transfected cells and normal brain tissue, we show that APP and DISC1 coimmunoprecipitate and that the intracellular domain of APP interacts with the N-terminal domain of DISC1. Based on these findings, we hypothesize that the APP cytoplasmic region transiently interacts with DISC1 to help regulate the translocation of DISC1 to the centrosome, where it plays a key role in controlling neuronal migration during cortical development.


Interaction of fluconazole and human phagocytic cells. Uptake of the antifungal agent and its effects on the survival of ingested fungi in phagocytes.
3H-labelled fluconazole (CAS 86386-73-4) very rapidly penetrated into polymorphonuclear leucocytes (PMNLs) and macrophages (monocytes) isolated from volunteers. The concentration of the antimycotic in the PMNLs was about 28% and in the macrophages even 63% above that in the extracellular medium. At the concentrations examined (5, 10 and 20 micrograms/ml) fluconazole damaged cells of Candida albicans which had been phagocytized by PMNLs or macrophages. There is an evident synergism between therapeutically attainable concentrations of fluconazole and phagocytic cells and this militates against the intracellular survival of the fungus.


Trabecular bone scales allometrically in mammals and birds.
Many bones are supported internally by a latticework of trabeculae. Scaling of whole bone length and diameter has been extensively investigated, but scaling of the trabecular network is not well characterized. We analysed trabecular geometry in the femora of 90 terrestrial mammalian and avian species with body masses ranging from 3 g to 3400 kg. We found that bone volume fraction does not scale substantially with animal size, while trabeculae in larger animals' femora are thicker, further apart and fewer per unit volume than in smaller animals. Finite element modelling indicates that trabecular scaling does not alter the bulk stiffness of trabecular bone, but does alter strain within trabeculae under equal applied loads. Allometry of bone's trabecular tissue may contribute to the skeleton's ability to withstand load, without incurring the physiological or mechanical costs of increasing bone mass.


Differentiating Psychosomatic, Somatopsychic, Multisystem Illnesses, and Medical Uncertainty.
There is often difficulty differentiating between psychosomatic, somatopsychic, multisystem illness, and different degrees of medical uncertainty. Uncommon, complex, and multisystem diseases are commonly misdiagnosed. Two case histories are described, and relevant terms differentiating psychosomatic, somatopsychic, and multisystem illnesses are identified, reviewed, and discussed. Adequate differentiation requires an understanding of the mind/body connection, which includes knowledge of general medicine, psychiatry, and the systems linking the body and the brain. A psychiatric diagnosis cannot be given solely based upon the absence of physical, laboratory, or pathological findings. Medically unexplained symptoms, somatoform disorder, and compensation neurosis are outdated and/or inaccurate terms. The terms subjective, nonspecific, and vague can be used inaccurately. Conversion disorders, functional disorders, psychogenic illness, factitious disorder imposed upon another (Munchausen's syndrome by proxy), somatic symptom disorder, psychogenic seizures, psychogenic pain, psychogenic fatigue, and delusional parasitosis can be over-diagnosed. Bodily distress disorder and bodily distress syndrome are scientifically unsupported and inaccurate. Many "all in your head" conditions may be related to the microbiome and the immune system. Better education concerning the interface between medicine and psychiatry and the associated diagnostic nomenclature as well as utilizing clinical judgment and thorough assessment, exercising humility, and maintaining our roots in traditional medicine will help to improve diagnostic accuracy and patient trust.


[Drug sclerosing of kidney cysts].
A report is given on the medicinal sclerosing of renal cysts by percutaneous treatment of 15 patients of the age of about 50 to 70 years. By intracaval injection of Aethoxysklerol in a solution of 2% the vessels of the cysts wall are obliterated and the tissue is sclerosed. The described technique avoids incorrect application as well as complications and major strain for the patients. True recurrences are obviously seldom. The report indicates that any evidence of a tumour disease apart from the cysts must bei excluded. The successful treatment shows that the percutaneous sclerosing represents a recommendable alternative to surgical operations. The efficacy and compatibility of the sclerosing agent Aethoxysklerol are particularly mentioned.


'Your comments are meaner than your score': score calibration talk influences intra- and inter-panel variability during scientific grant peer review.
In scientific grant peer review, groups of expert scientists meet to engage in the collaborative decision-making task of evaluating and scoring grant applications. Prior research on grant peer review has established that inter-reviewer reliability is typically poor. In the current study, experienced reviewers for the National Institutes of Health (NIH) were recruited to participate in one of four constructed peer review panel meetings. Each panel discussed and scored the same pool of recently reviewed NIH grant applications. We examined the degree of intra-panel variability in panels' scores of the applications before versus after collaborative discussion, and the degree of inter-panel variability. We also analyzed videotapes of reviewers' interactions for instances of one particular form of discourse-Score Calibration Talk-as one factor influencing the variability we observe. Results suggest that although reviewers within a single panel agree more following collaborative discussion, different panels agree less after discussion, and Score Calibration Talk plays a pivotal role in scoring variability during peer review. We discuss implications of this variability for the scientific peer review process.


Medical coordination in airport disasters.
The goals of an Airport Disaster Plan includes the care, treatment and transportation of the wounded with the quality and quantity of care that minimizes the mortality and morbidity of the survivors of a crash. Coordination of the medical aspects of these plans requires participation by physicians, nurses, ambulance and hospital personnel, psychologists, and psychiatrists. To maintain these divers groups in a state of readiness for a potential disaster which may have a frequency of 5-20 years is a challenging problem. This paper addresses methods of accomplishing this goal.


Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17.
Intraoperative fluorescence imaging of the folate-receptor alpha (FRα) could support completeness of resection in cancer surgery. Feasibility of EC17, a FRα-targeting agent that fluoresces at 500nm, was demonstrated in a limited series of ovarian cancer patients. Our objective was to evaluate EC17 in a larger group of ovarian cancer patients. In addition, we assessed the feasibility of EC17 in patients with breast cancer. Two-to-three hours before surgery 0.1mg/kg EC17 was intravenously administered to 12 patients undergoing surgery for ovarian cancer and to 3 patients undergoing surgery for biopsy-proven FRα-positive breast cancer. The number of lesions/positive margins detected with fluorescence and concordance between fluorescence and tumor- and FRα-status was assessed in addition to safety and pharmacokinetics. Fluorescence imaging in ovarian cancer patients allowed detection of 57 lesions of which 44 (77%) appeared malignant on histopathology. Seven out of these 44 (16%) were not detected with inspection/palpation. Histopathology demonstrated concordance between fluorescence and FRα- and tumor status. Fluorescence imaging in breast cancer patients, allowed detection of tumor-specific fluorescence signal. At the 500nm wavelength, autofluorescence of normal breast tissue was present to such extent that it interfered with tumor identification. FRα is a favorable target for fluorescence-guided surgery as EC17 produced a clear fluorescent signal in ovarian and breast cancer tissue. This resulted in resection of ovarian cancer lesions that were otherwise not detected. Notwithstanding, autofluorescence caused false-positive lesions in ovarian cancer and difficulty in discriminating breast cancer-specific fluorescence from background signal. Optimization of the 500nm fluorophore, will minimize autofluorescence and further improve intraoperative tumor detection.


Suppression of repolarization-related arrhythmias in vitro and in vivo by low-dose potassium channel activators.
Marked prolongation of cardiac action potentials and of QT intervals has been associated with early afterdepolarizations and triggered activity in vitro and with ventricular tachycardia in vivo. Because the antihypertensive potassium channel activators pinacidil and cromakalim are known to accelerate repolarization in cardiac tissues, we performed in vitro and in vivo experiments to test the hypothesis that these agents would block the arrhythmogenic effects of delayed repolarization. Early afterdepolarizations and triggered activity were elicited in canine cardiac Purkinje fibers driven at cycle lengths of 4 seconds or more (K0, 2.7 mM) during superfusion with quinidine, cesium, or sematilide, a methylsulfonylamino parasubstituted analogue of procainamide with class III antiarrhythmic activity. The potassium channel activators invariably (17 of 17) abolished this form of abnormal automaticity. This effect was observed at low concentrations that did not alter action potential characteristics at shorter cycle lengths. Intravenous Cs+ (total dose, 4.5 mM/kg) was used to produce ventricular arrhythmias in anesthetized rabbits randomly pretreated in a double-blind fashion with either low-dose pinacidil (0.2 mg/kg) or vehicle. Pinacidil pretreatment resulted in significantly fewer total ventricular ectopic beats (168 +/- 157 versus 582 +/- 448, p less than 0.005) and episodes of ventricular tachycardia (four of nine versus nine of nine, p = 0.057). At this dose, pinacidil did not alter mean blood pressure before Cs+ and maximal hypertensive response after Cs+. In summary, the potassium channel activators pinacidil and cromakalim suppressed triggered activity related to prolonged repolarization at concentrations that did not affect action potential characteristics at normal rates in vitro; pinacidil blunted arrhythmias produced by cesium administration in vivo without lowering blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Pain provocation and low gallbladder ejection fraction with CCK cholescintigraphy are not predictive of chronic acalculous gallbladder disease symptom relief after cholecystectomy.
Chronic acalculous gallbladder disease (CAGD) falls within the spectrum of diseases associated with gallbladder dysmotility. Cholecystokinin-cholescintigraphy (CCK-CS) has been used to evaluate for CAGD, with a gallbladder ejection fraction (GBEF) of <35 % being indicative of gallbladder dysfunction. The reproduction of biliary colic upon administration of CCK has been cited as indicative of CAGD. Our purpose was to determine whether low GBEF or reproduction of pain during CCK-CS was predictor of surgical outcomes related to resolution of symptoms or as a correlate to gallbladder pathology. A retrospective review of patients was performed to evaluate adults with a diagnosis of CAGD who underwent CCK-CS prior to surgical intervention. CPT and ICD-9 coding queries were used to identify the patient population. Patients with cholelithiasis were excluded. Sixty-four patients met inclusion criteria. Two patients were lost to follow-up and were excluded. During CCK-CS, 41 patients (66 %) reported symptoms similar to their presenting complaint. Twenty-one patients reported no symptoms with CCK-CS. There was no significant relationship between gallbladder pathology and either GBEF or reproduction of symptoms with CCK-CS (p = 0.14). About 81 % of patients (n = 50) had relief of symptoms following cholecystectomy. Sixty-six percentage of patients (n = 33) with long-term symptom relief after cholecystectomy had reproduction of symptoms with CCK-CS. Nineteen percentage of all patients (n = 12) had long-term symptom recurrence despite surgery. Eight of these patients (66 %) had symptom reproduction with CCK-CS. There was no significant correlation with either the GBEF or symptoms reproduction with CCK-CS as a predictor of postoperative outcome (p = 0.12). Provocation of pain by CCK-CS and low GBEF are unreliable predictors of postoperative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease.


Amplification of the Y chromosome in three murine tumor cell lines transformed in vivo by different human prostate cancers.
Conventional and molecular cytogenetic analyses of three murine cancer cell lines that had been induced in male athymic mice by the injection of three different human prostate cancer cell lines revealed selective amplification of the Y chromosome. In particular, analysis of metaphase and interphase nuclei by fluorescence in situ hybridization (FISH) with the mouse Y chromosome-specific DNA painting probe revealed the presence of various numbers of Y chromosomes, ranging from one to eight, with a large majority of nuclei showing two copies (46.5-60.1%). In Interphase nuclei, the Y chromosomes showed distinct morphology, allowing identification irrespective of whether the preparations were treated for 15 min or for 5 h with Colcemid, a chemical known to cause chromosome condensation. However, FISH performed on human lymphocyte cultures with chromosome-specific DNA painting probes other than the Y chromosome did not reveal condensed chromosome morphology in interphase nuclei even after 12 h of Colcemid treatment. Our FISH results indicate that (1) the Y chromosome is selectively amplified in all three cell lines; (2) the mouse Y chromosome number is comparable in both interphase and metaphase cells: (3) the Y chromosome number varies between one and eight, with a large majority of cells showing two or three copies in most interphase nuclei; (4) the condensation of the Y chromosome is not affected by the duration of Colcemid treatment but by its inherent DNA constitution; and (5) the number of copies of the Y chromosome is increased and retained not only in human prostate tumor cell lines but also in murine tumors induced by these prostate tumor cell lines.


Verification of a new clinicopathologic staging system for colorectal adenocarcinoma.
Rectal adenocarcinoma is said to have a poorer outcome than colon adenocarcinoma when compared on the basis of Dukes' staging. However a new staging system, determined by a multivariate analysis of 147 patients with rectal adenocarcinoma, has revealed three other variables significantly related to outcome. Therefore this study analyzed the authors' experience with colonic carcinoma during the same time period as they had studied for rectal carcinoma to determine whether the new staging system is valid for colon carcinoma as well, and, if so, to compare the outcome of patients with colon and rectal carcinoma on the basis of this new staging. A total of 603 patients with 611 colonic adenocarcinoma were operated on at the University of Chicago Medical Center between 1965 and 1981. Two hundred seventy-nine adenocarcinomas (45.7%) were located proximal to the splenic flexure and 332 (54.3%) were located between the splenic flexure and the rectosigmoid. Four hundred sixty-two patients underwent segmental colectomy, 46 subtotal colectomy, 26 total colectomy, 18 proctocolectomy, 5 abdominal-perineal resection, 1 appendectomy, while 20 had local excision of the tumor through colotomy and 25 had permanent diverting stoma as the only procedure. The operative mortality rate was 6.1% in the whole group, but was only 2.7% in the group of potentially curable patients. Complete follow-up was obtained in all patients. To validate a previous staging system for Dukes' B and C rectal adenocarcinoma, the authors investigated the correlation between 5-year survival for colonic carcinoma patients and all relevant variables that they had considered potentially meaningful in the previous study with rectal adenocarcinoma. The resulting multivariate analysis using Cox regression showed that the four variables found previously to be significantly related to outcome for rectal adenocarcinoma patients (stage, race, tumor morphology, and vascular and/or lymphatic microinvasion) were the only four variables significantly (p less than 0.05) associated with outcome for colonic adenocarcinoma patients. In addition, by using the results of their previous staging system for rectal adenocarcinoma patients, they 'predicted' the 5-year survival rates of the colon adenocarcinoma patients, divided in 16 staging subgroups. In subgroups of at least 15 patients, the rectal staging system predicted the outcome to within 1 to 6 percentage points of the observed outcome of the colonic adenocarcinoma patients. Thus this study validates this staging system, incorporating stage, race, tumor morphology, and microinvasion to predict 5-year survival rate more accurately than Dukes' staging alone for both colon and rectal adenocarcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)


Management of late cervical esophageal perforation.
We aimed to identify different methods of treating late perforation of the cervical esophagus. Ten late cervical esophageal perforations were caused by foreign bodies. The subjects were divided into three groups according to their diagnosis and treatment as follows: Group I: Cases with cervical abscess were drained by lateral cervical incision and primarily repaired, Group II: Cases with cervical abscess were drained by lateral cervical incision, and any foreign body granulomas found were removed, and Group III: Foreign bodies were removed. All cases were given broad-spectrum antibiotics and were prohibited from any oral food, except Case 5. All patients recovered without mortality and retained normal swallow function. The time for treatment in each group was different. The conservative management of removal of foreign body, prohibition of oral food and administration of broad-spectrum antibiotics is supported. Perforations with the presence of abscess can be surgically treated by debridement closure combined with strip muscle flap repair and irrigation drainage. Granuloma can be removed by lateral cervical incision and vacuum sealing drainage.


Effectiveness of Food Handler Training and Education Interventions: A Systematic Review and Meta-Analysis.
Improper food handling among those working in retail and food service settings is a frequent contributor to foodborne illness outbreaks. Food safety training and education interventions are important strategies to improve the behaviors and behavioral precursors (e.g., knowledge and attitudes) of food handlers in these settings. We conducted a comprehensive systematic review to identify, characterize, and synthesize global studies in this area to determine the overall effectiveness of these interventions. The review focused on experimental studies with an independent control group. Review methods included structured search strategy, relevance screening of identified abstracts, characterization of relevant articles, risk of bias assessment, data extraction, meta-analysis of intervention effectiveness for four outcome categories (attitudes, knowledge, behavior, and food premise inspection scores), and a quality of evidence assessment. We identified 18 relevant randomized controlled trials (RCTs) and 29 nonrandomized trials. Among RCTs, 25 (64%) unique outcomes were rated as high risk of bias, primarily owing to concerns about outcome measurement methods, while 45 (98%) nonrandomized trial outcomes were rated as serious risk of bias, primarily because of concerns about confounding bias. High confidence was identified for the effect of training and education interventions to improve food handler knowledge outcomes in eight RCT studies (standardized mean difference = 0.92; 95% confidence interval: 0.03, 1.81; I2 = 86%). For all other outcomes, no significant effect was identified. In contrast, nonrandomized trials identified a statistically significant positive intervention effect for all outcome types, but confidence in these findings was very low due to possible confounding and other biases. Results indicate that food safety training and education interventions are effective to improve food handler knowledge, but more evidence is needed on strategies to improve behavior change.


Erythrocyte vitamin E is oxidized at a lower peroxide concentration in neonates than in adults.
Erythrocytes of neonates and adults were incubated with increasing concentrations of H2O2 in the presence of a catalase inhibitor and in the absence of glucose; the pattern of oxidation of vitamin E was analyzed in relationship to that of glutathione, hemoglobin, and polyunsaturated fatty acids (PUFA), and in relationship to hemolysis. The changes of these various parameters were analyzed in function of H2O2 concentration and in relation to incubation time, and were compared in erythrocytes from neonates and adults. In the absence of H2O2, erythrocyte glutathione and tocopherol levels were similar in neonates and adults, despite fourfold lower serum vitamin E level in neonates; alpha-tocopherolquinone, methemoglobin, and malonyldialdehyde (MDA) were not detectable. At 0.375 mmol/L of H2O2, glutathione was completely oxidized. Erythrocyte alpha-tocopherol remained unchanged up to 0.75 mmol/L of H2O2, then decreased linearly, with increasing H2O2 concentrations to 10% of its initial value at 1.5 mmol/L of H2O2 in erythrocytes from neonates, whereas those from adults required 2.0 mmol/L of H2O2 (P less than .05) for the same level of oxidation. The formation of alpha-tocopherolquinone appeared inversely related to the decrease of alpha-tocopherol. The incubation time did not influence the level of vitamin E oxidation. MDA was generated autocatalytically and resulted in hemolysis at 1.5 mmol/L of H2O2 in erythrocytes from neonates and at 3.5 mmol/L of H2O2 in erythrocytes from adults (P less than .001). After four hours of incubation, MDA reached a plateau at a greater level (365 +/- 46 nmol/L) in cells of neonates than in those of adults (208 +/- 37 nmol/L/mL) (P less than .001). Hemoglobin was oxidized in the same pattern in erythrocytes of neonates and adults, and 90% of it was oxidized at 0.625 mmol/L of H2O2. In conclusion, in the experimental conditions used, oxidation of glutathione precedes that of vitamin E, and tocopherol is the last antioxidant to be consumed before the autocatalytic generation of MDA. Differences in the pattern of vitamin E oxidation, MDA generation, and hemolysis in erythrocytes from neonates and adults may be due to a lower erythrocyte vitamin E-PUFA ratio in neonates.


Ixekizumab for treatment of psoriasis.
Psoriasis is a prevalent chronic inflammatory skin disease of unknown etiology. Recent advances in understanding the pathogenesis of psoriasis suggest that IL-17 is a key proinflammatory mediator present in the skin. Several agents targeting IL-17 or its receptor are in clinical trials for the treatment of psoriasis. This review focuses on the biological rationale and the results of clinical trials with ixekizumab, a humanized IgG4 monoclonal antibody. Ixekizumab binds the IL-17A homodimer, thereby blocking the binding of IL-17A to the IL-17 receptor. The currently available Phase I-III data indicate that ixekizumab is a promising drug, although long-term data of efficacy and safety are needed before ixekizumab and other IL-17 targeting therapeutics can find their place in clinical practice.


Ulcerative Colitis in a COVID-19 Patient: A Case Report.
COVID-19 pneumonia is a global viral disease and has been classified as a pandemic by the World Health Organization. The coronavirus that causes it can remain in the stool of some infected patients for a short period, even after recovery from COVID-19 pneumonia. Studies have increasingly reported the involvement of other organs, including the gastrointestinal system, in addition to the respiratory system. Ulcerative colitis is an inflammatory bowel disease with an unknown cause. Emerging data suggest that the gas trointestinal system may be influenced by COVID-19 via the expression of angiotensin-converting enzyme-2 (ACE-2), but data on the association between COVID-19 and inflammatory bowel diseases, including ulcerative colitis, are lacking. In this report, we describe a case of ulcerative colitis diagnosed in a 50-year-old male patient who presented with complaints of bloody diarrhea and abdominal pain following the completion of treatment for COVID-19 pneumonia. It is possible for the novel coronavirus to trigger ulcerative colitis. Hence, patients presenting with gastrointestinal com plaints should also be evaluated for COVID-19.


Microsaccade-related brain potentials signal the focus of visuospatial attention.
Covert shifts of visuospatial attention are traditionally assumed to occur in the absence of oculomotor behavior. In contrast, recent behavioral studies have linked attentional cueing effects to the occurrence of microsaccades, small eye movements executed involuntarily during attempted fixation. Here we used a new type of electrophysiological marker to explore the attention-microsaccade relationship, the visual brain activity evoked by the microsaccade itself. By shifting the retinal image, microsaccades frequently elicit neural responses throughout the visual pathway, scalp-recordable in the human EEG as a microsaccade-related potential (mSRP). Although mSRPs contain similar signal components (P1/N1) as traditional visually-evoked potentials (VEPs), it is unknown whether they are also influenced by cognition. Based on established findings that VEPs are amplified for visual inputs at currently attended locations, we expected a selective gain-modulation also for mSRPs. Eye movements and EEG were coregistered in a classic spatial cueing task with an endogenous cue. Replicating behavioral findings, the direction of early microsaccades 200-400ms after cue onset was biased towards the cued side. However, for microsaccades throughout the cue-target interval, mSRPs were systematically enhanced at occipital scalp sites contralateral to the cued hemifield. This attention effect resembled that in a control condition with VEPs and did not interact with the direction of the underlying microsaccade, suggesting that mSRPs reflect the focus of sustained visuospatial attention, which remains fixed at the cued location, despite microsaccades. Microsaccades are not merely an artifact source in the EEG; instead, they are followed by cognitively modulated brain potentials that can serve as non-intrusive electrophysiological probes of attention.


Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome.
Heterozygous deletions within human chromosome 22q11 are the genetic basis of DiGeorge/velocardiofacial syndrome (DGS/VCFS), the most common deletion syndrome (1 in 4,000 live births) in humans. CRKL maps within the common deletion region for DGS/VCFS (ref. 2) and encodes an SH2-SH3-SH3 adapter protein closely related to the Crk gene products. Here we report that mice homozygous for a targeted null mutation at the CrkL locus (gene symbol Crkol for mice) exhibit defects in multiple cranial and cardiac neural crest derivatives including the cranial ganglia, aortic arch arteries, cardiac outflow tract, thymus, parathyroid glands and craniofacial structures. We show that the migration and early expansion of neural crest cells is unaffected in Crkol-/- embryos. These results therefore indicate an essential stage- and tissue-specific role for Crkol in the function, differentiation, and/or survival of neural crest cells during development. The similarity between the Crkol-/- phenotype and the clinical manifestations of DGS/VCFS implicate defects in CRKL-mediated signaling pathways as part of the molecular mechanism underlying this syndrome.


Meeting or Exceeding Physical Activity Guidelines is Associated with Reduced Risk for Cancer in Mexican-Americans.
Epidemiologic studies have shown that inadequate physical activity was associated with cancers in whites and other ethnic groups, but in Mexican-Americans data are limited. This study aimed to measure the association between physical activity and reported cancer risk in Mexican-Americans. Participants were drawn from the Cameron County Hispanic Cohort (n=3,391), a randomly selected Mexican-American cohort in Texas on the US-Mexico border. Physical activity was assessed using the International Physical Activity Questionnaire. Cancer was self-reported by the participants as being told by a health care provider that they had cancer. Ninety-nine participants of the cohort (2.94%) reported a diagnosis of cancer. Compared to participants who did not meet US physical activity guidelines, subjects who met physical activity guidelines of 150 moderate and vigorous minutes per week (≥ 600 METs) reduced their risk for cancer by 87% (OR=0.13; 95% CI: 0.03-0.54), and subjects with total minutes per week of moderate and vigorous/strenuous activity greater than 745 METs decreased cancer risk by 86% [odds ratio (OR)=0.14; 95% confidence interval (CI): 0.03-0.60] comparing with their counterparts, after adjusting for age, gender, body mass index, smoking and alcohol drinking status, education and total portions of fruit and vegetable intake. Meeting or exceeding recommended levels of moderate and vigorous physical activity was associated with a significantly reduced risk of reporting cancer by Mexican-Americans. Meeting or exceeding recommended levels of physical activity appears to be an effective target for cancer prevention and control among Mexican-Americans independent of BMI and other factors.


Oxytocin-induced Ca2+ responses in human myometrial cells.
Complex spatiotemporal changes in intracellular Ca2+ were monitored in an immortalized human myometrial cell line (PHM1-41) and first-passage human myometrial cells after oxytocin stimulation (1. 0-1000 nM). Laser cytometry revealed intracellular Ca2+ oscillations in both culture systems starting at 1.0 nM, which were followed by repetitive Ca2+ transients by 10-15 min that lasted for at least 90 min. The amplitude of the initial Ca2+ spike was dose dependent, while the frequency of Ca2+ oscillations identified by Fast Fourier Transform (FFT) tended to increase with dose. Removal of oxytocin resulted in termination of oscillations. Analysis of the sources of the Ca2+ involved in oscillations indicated that the major contribution to oscillation frequencies of </= 6 mHz in cells was from the inositol 1,4,5-trisphosphate-sensitive pool, accounting for about 60% of the frequencies. Most of the remaining frequencies were attributable to extracellular Ca2+, which presumably comes from plasma membrane channels other than L-type channels. When oscillation frequencies exceeded 6 mHz, a significant contribution from a ryanodine-sensitive Ca2+ pool was detected. Eight-bromo-cAMP suppressed both the initial Ca2+ spike and the long-term oscillations. Prostaglandin E1 and E2 caused a significant increase in the frequency of oxytocin-induced Ca2+ oscillations. FFT analysis may be of considerable value for study of the mechanisms of rhythmic Ca2+ transients and their function in myometrial cells, as well as the mechanisms by which uterotonins and tocolytic agents impact myometrial Ca2+ regulation.


Ligamentous Reconstruction of the Knee: What Orthopaedic Surgeons Want Radiologists to Know.
Knee ligament injuries are common, and treatment methods are continually evolving. Accurate clinical diagnosis with imaging confirmation is critical to support appropriate treatment. Several imaging pearls allow for improved recognition of injuries. Stress radiographs may be obtained to quantify knee laxity. Magnetic resonance imaging allows assessment of the complex anatomy of the knee and has excellent sensitivity and specificity for many injuries.


Ultrastructure of book gill development in embryos and first instars of the horseshoe crab Limulus polyphemus L. (Chelicerata, Xiphosura).
The transmission electron microscope (TEM) is used for the first time to study the development of book gills in the horseshoe crab. Near the end of the nineteenth century the hypothesis was presented for homology and a common ancestry for horseshoe crab book gills and arachnid book lungs. The present developmental study and the author's recent ones of book gills (SEM) and scorpion book lungs (TEM) are intended to clarify early histological work and provide new ultrastructural details for further research and for hypotheses about evolutionary history and relationships. The observations herein are in agreement with earlier reports that the book gill lamellae are formed by proliferation and evagination of epithelial cells posterior to opisthosomal branchial appendages. A cartilage-like endoskeleton is produced in the base of the opisthosomal appendages. The lamellar precursor cells in the appendage base proliferate, migrate outward and secrete the lamellar cuticle from their apical surface. A series of external, posteriorly-directed lamellae is formed, with each lamella having a central channel for hemolymph and pillar-type space holders formed from cells of the opposed walls. This repeated, page-like pattern results also in water channels (without space holders) between the sac-like hemolymph lamellae. The developmental observations herein and in an earlier study (TEM) of scorpion book lungs show that the lamellae in book gills and book lungs result from some similar activities and features of the precursor epithelial cells: proliferation, migration, alignment and apical/basal polarity with secretion of cuticle from the apical surface and the basal surface in contact with hemolymph. These cellular similarities and the resulting book-like structure suggest a common ancestry, but there are also substantial developmental differences in producing these organs for gas exchange in the different environments, aqueous and terrestrial. For scorpion book lungs, the invaginated precursor cells align in rows and secrete rows of cell fragments that are the basis for the internal, anterior-directed air sacs. The hemolymph sacs of book gills are formed by epithelial evagination or outfolding from the posterior surface of the branchial appendages.


Accuracy of Fractional Flow Reserve Derived From Coronary Angiography.
Measuring fractional flow reserve (FFR) with a pressure wire remains underutilized because of the invasiveness of guide wire placement or the need for a hyperemic stimulus. FFR derived from routine coronary angiography (FFRangio) eliminates both of these requirements and displays FFR values of the entire coronary tree. The FFRangio Accuracy versus Standard FFR (FAST-FFR) study is a prospective, multicenter, international trial with the primary goal of determining the accuracy of FFRangio. Coronary angiography was performed in a routine fashion in patients with suspected coronary artery disease. FFR was measured in vessels with coronary lesions of varying severity using a coronary pressure wire and hyperemic stimulus. Based on angiograms of the respective arteries acquired in ≥2 different projections, on-site operators blinded to FFR then calculated FFRangio using proprietary software. Coprimary end points were the sensitivity and specificity of the dichotomously scored FFRangio for predicting pressure wire-derived FFR using a cutoff value of 0.80. The study was powered to meet prespecified performance goals for sensitivity and specificity. Ten centers in the United States, Europe, and Israel enrolled a total of 301 subjects and 319 vessels meeting inclusion/exclusion criteria which were included in the final analysis. The mean FFR was 0.81 and 43% of vessels had an FFR≤0.80. The per-vessel sensitivity and specificity were 94% (95% CI, 88% to 97%) and 91% (86% to 95%), respectively, both of which exceeded the prespecified performance goals. The diagnostic accuracy of FFRangio was 92% overall and remained high when only considering FFR values between 0.75 to 0.85 (87%). FFRangio values correlated well with FFR measurements ( r=0.80, P<0.001) and the Bland-Altman 95% confidence limits were between -0.14 and 0.12. The device success rate for FFRangio was 99%. FFRangio measured from the coronary angiogram alone has a high sensitivity, specificity, and accuracy compared with pressure wire-derived FFR. FFRangio has the promise to substantially increase physiological coronary lesion assessment in the catheterization laboratory, thereby potentially leading to improved patient outcomes. URL: https://www.clinicaltrials.gov . Unique Identifier: NCT03226262.


The circulatory effects of intravenously administered ephedrine during epidural blockade.
The changes in central circulation following a small dose of intravenously administered ephedrine were studied in middle-aged and elderly patients during high epidural blockade with bupivacaine 0.5% with adrenaline, etidocaine 1% with adrenaline, and etidocaine 1% plain. Itravenously injected ephedrine restored the mean, systolic and diastolic arterial blood pressures to the preanalgesic value independent of the degree of hypotension, and was not followed by marked hypertension in any case. Although the heart rate did not change, the cardiostimulatory effects were more pronounced than after subcutaneous premedication, resulting in increased stroke volume and cardiac output in all groups. Peripheral vascular resistance increased to the preanalgesic value in the groups receiving bupivacaine adrenaline and etidocaine plain. In the etidocaine adrenaline group, peripheral vascular resistance was little changed, as the cardiostimulatory effects were more pronounced than in the other groups.


From particles to spins: Eulerian formulation of supercooled liquids and glasses.
The dynamics of supercooled liquid and glassy systems are usually studied within the Lagrangian representation, in which the positions and velocities of distinguishable interacting particles are followed. Within this representation, however, it is difficult to define measures of spatial heterogeneities in the dynamics, as particles move in and out of any one given region within long enough times. It is also nontransparent how to make connections between the structural glass and the spin glass problems within the Lagrangian formulation. We propose an Eulerian formulation of supercooled liquids and glasses that allows for a simple connection between particle and spin systems, and that permits the study of dynamical heterogeneities within a fixed frame of reference similar to the one used for spin glasses. We apply this framework to the study of the dynamics of colloidal particle suspensions for packing fractions corresponding to the supercooled and glassy regimes, which are probed via confocal microscopy.


The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.
The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. Twenty-seven UK sites. Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. Three and 6 months, and then 6-monthly up to 36 or 42 months. Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. Current Controlled Trials ISRCTN62942668. The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.


Unexpected diversity in northern Europe: trematodes from salmonid fishes in Iceland with two new species of Crepidostomum Braun, 1900.
In 2018 and 2019, salmonid fishes, Salmo trutta L. and Salvelinus alpinus (L.) from lakes in Iceland were assessed for trematodes during a parasitological examination. Combined morphological and molecular analyses revealed the presence of four trematode species, two of which were previously known to parasitise salmonids in Iceland, Crepidostomum farionis (Müller, 1780) and Phyllodistomum umblae (Fabricius, 1780), and the two remaining species were recognised as new to science. Morphologically and genetically, Crepidostomum brinkmanni n. sp. and C. pseudofarionis n. sp. are closely related to two European species, namely C. metoecus and C. farionis. However, C. brinkmanni n. sp. is distinct by the position of maximum body width and arrangement of vitelline follicles; C. pseudofarionis n. sp. is distinct by its stout body, position of maximum body width, size of muscular papillae relative to oral sucker and the anterior extent of vitelline follicles. The new species were previously molecularly detected in their intermediate and definitive hosts in Norway and Ukraine, but their sequences were not supplemented with any morphological characterisation. In the present study, we provide detailed morphological descriptions and molecular sequences (28S rDNA and ITS2) of the four species of trematodes detected in Iceland. The discovery of the two new species of Crepidostomum indicates that the trematode diversity in fishes in the north is higher than previously known; our finding doubles the species spectrum of fish trematodes for Iceland. The record of C. brinkmanni from Ukraine indicates that its distribution might not be limited to northern latitudes.


False-negative Results of Human Immunodeficiency Virus (HIV) Rapid Testing in HIV Controllers.
Serological assays were performed on 85 human immunodeficiency virus-controller samples . 6% presented a negative rapid screening test 7% presented an indeterminate Western blot. The enzyme immunoassay ratio decreased in controllers who had continual negative ultrasensitive HIV RNA results since inclusion.


Comparison of Unenhanced T1-Weighted Signal Intensities Within the Dentate Nucleus and the Globus Pallidus After Serial Applications of Gadopentetate Dimeglumine Versus Gadobutrol in a Pediatric Population.
The aim of this study was to evaluate and compare changes in T1-weighted signal intensity (SI) within the dentate nucleus (DN) and globus pallidus (GP) in a pediatric population after serial applications of the linear gadolinium-based magnetic resonance contrast medium gadopentetate dimeglumine and the more stable macrocyclic agent gadobutrol. Institutional review board approval was obtained. Two similar pediatric patient cohorts who underwent at least 3 serial contrast-enhanced magnetic resonance imaging (MRI) examinations with sole application of gadopentetate dimeglumine or gadobutrol were analyzed. All MRI examinations were performed on a 1.5 T system acquiring unenhanced T1-weighted spin echo sequences, which were evaluated on the baseline MRI and after the contrast medium administrations. For analysis of SI changes in the DN, the ratios of the DN to the pons (P) and to the middle cerebellar peduncle (MCP) were assessed. The GP was compared with the thalamus (TH) by dividing the SIs between GP and TH (GP-to-TH ratio). Twenty-eight patients (13 boys, 15 girls; mean age, 8.4 ± 6.8 years) who received at least 3 applications of gadopentetate dimeglumine and 25 patients (13 boys, 12 girls; mean age, 9.7 ± 5.4 years) with 3 or more gadobutrol injections were included. After 3 administrations of gadopentetate dimeglumine, the T1-weighted SI ratios significantly increased: mean difference value of 0.036 ± 0.031 (DN-to-P; P < 0.001), 0.034 ± 0.032 (DN-to-MCP; P < 0.001), and 0.025 ± 0.025 (GP-to-TH; P = 0.001). In a subanalysis of 12 patients with more than 3 injections of gadopentetate dimeglumine, the mean differences of the SI ratios were slightly higher: 0.043 ± 0.032 (DN-to-P; P = 0.001), 0.041 ± 0.035 (DN-to-MCP; P = 0.002), and 0.028 ± 0.025 (GP-to-TH; P = 0.003). In contrast, gadobutrol did not show a significant influence on the SI ratios, neither after 3 nor after more than 3 applications. The T1-weighted SI increase within the DN and GP after serial administrations of the linear contrast medium gadopentetate dimeglumine, but not after serial applications of the macrocyclic agent gadobutrol, found in a pediatric population, is consistent with results published for adult patients. The clinical impact of the intracranial T1-hyperintensities is currently unclear. However, in accordance with the recent decision of the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency, intravenous macrocyclic agents should be preferred and MR contrast media should be used with caution and awareness of the pediatric brain development in children and adolescents.


Inter- and intraobserver agreement in interpretation of CT features of medial coronoid process disease.
To evaluate inter- and intraobserver reliability of the assessment of computed tomography features commonly used in the identification and classification of medial coronoid process disease and to assess inter- and intraobserver variability in the identification of the percentage ulna sclerosis from single transverse computed tomography images. Eight observers, on two occasions, reviewed 84 standardised single transverse computed tomography images acquired at the level of the apex of the medial coronoid process. Observers assessed: medial coronoid process disease, coronoid process fragmentation, osteophytes, sclerosis grade and sclerosis delineation with normal bone defined using a sclerometer. Cohen's kappa and intraclass correlation coefficient were calculated. Inter-observer agreement was fair to moderate for identification of computed tomography changes consistent with medial coronoid process disease, moderate to almost perfect for fragmentation, and moderate for osteophyte detection. Agreement was poor for sclerosis grading. Percentage sclerosis measured with a sclerometer had moderate to almost perfect inter- and intraobserver agreement. These findings suggest that subjective assessment of computed tomography images is less repeatable than more quantitative methods.


A Comprehensive Proteomics Analysis of the Human Iris Tissue: Ready to Embrace Postgenomics Precision Medicine in Ophthalmology?
The annual economic burden of visual disorders in the United States was estimated at $139 billion. Ophthalmology is therefore one of the salient application fields of postgenomics biotechnologies such as proteomics in the pursuit of global precision medicine. Interestingly, the protein composition of the human iris tissue still remains largely unexplored. In this context, the uveal tract constitutes the vascular middle coat of the eye and is formed by the choroid, ciliary body, and iris. The iris forms the anterior most part of the uvea. It is a thin muscular diaphragm with a central perforation called pupil. Inflammation of the uvea is termed uveitis and causes reduced vision or blindness. However, the pathogenesis of the spectrum of diseases causing uveitis is still not very well understood. We investigated the proteome of the iris tissue harvested from healthy donor eyes that were enucleated within 6 h of death using high-resolution Fourier transform mass spectrometry. A total of 4959 nonredundant proteins were identified in the human iris, which included proteins involved in signaling, cell communication, metabolism, immune response, and transport. This study is the first attempt to comprehensively profile the global proteome of the human iris tissue and, thus, offers the potential to facilitate biomedical research into pathological diseases of the uvea such as Behcet's disease, Vogt Koyonagi Harada's disease, and juvenile rheumatoid arthritis. Finally, we make a call to the broader visual health and ophthalmology community that proteomics offers a veritable prospect to obtain a systems scale, functional, and dynamic picture of the eye tissue in health and disease. This knowledge is ultimately pertinent for precision medicine diagnostics and therapeutics innovation to address the pressing needs of the 21st century visual health.


Formation of a Au/Au9Ga4 Alloy Nanoshell on a Bacterial Surface through Galvanic Displacement Reaction for High-Contrast Imaging.
The spontaneous electron transfer between GaAs and ionic gold through the galvanic displacement reaction results in the formation of gold nanoparticles and a Au9Ga4 alloy. We investigated this process for decorating Legionella pneumophila and Escherichia coli, aiming at enhanced imaging of these bacteria. The surface of bacteria was modified with gold ions through the electrostatic linkage of ionic liquids with phosphate units of the bacterial cell wall. The modified bacteria were further incubated with an antibody-functionalized GaAs substrate. Due to a large gap in the reduction potential of gold and gallium ions, the induced reaction involving bacteria resulted in a reduction of the gold ions to gold nanoparticles and oxidation of GaAs to Ga2O3 and a Au9Ga4 alloy. The bacteria covered with a Au/AuGa nanoshell, if excited at 377 nm, show a bright emission at 447 nm originating from Au/Au9Ga4. This approach offers a simple and potentially less expensive method for high-contrast imaging of bacteria in comparison to the conventional methods of staining with different dyes or by conjugating green fluorescent proteins.


Treatment of heart failure beyond practice guidelines. Role of cardiac remodeling.
Heart failure (HF) is clinical syndrome that develops and progresses as a result of the overexpression of biologically active molecules that are sufficient to cause deleterious effects on the heart and circulation. Over the past 2 decades the adherence to practice guidelines for treating HF, including the use of angiotensin-converting enzyme inhibitors/angiotensin-receptor antagonists and beta-blockers, has resulted in improved survival for patients. However, despite the use of these evidence-based strategies that block the deleterious effects of neurohormonal activation, the overall mortality for HF remains unacceptably high. Unfortunately, when patients remain symptomatic despite having their medical and/or device therapies optimized, the "next steps" to improving patient morbidity are not at all clear. Thus, there remains an unmet need with respect to the treatment of HF patients. The concept that cardiac remodeling represents an important mechanism for disease progression in HF is reviewed, as well as discussion of several novel treatment strategies with respect to devices that are intended to prevent worsening cardiac remodeling.


Investigation of sex differences in mutation carriers of the Dominantly Inherited Alzheimer Network.
Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD). Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography (11 C-PiB PET) and structural magnetic resonance imaging (MRI). Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences. Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD.


Responses of primate frontal cortex neurons during natural vocal communication.
The role of primate frontal cortex in vocal communication and its significance in language evolution have a controversial history. While evidence indicates that vocalization processing occurs in ventrolateral prefrontal cortex neurons, vocal-motor activity has been conjectured to be primarily subcortical and suggestive of a distinctly different neural architecture from humans. Direct evidence of neural activity during natural vocal communication is limited, as previous studies were performed in chair-restrained animals. Here we recorded the activity of single neurons across multiple regions of prefrontal and premotor cortex while freely moving marmosets engaged in a natural vocal behavior known as antiphonal calling. Our aim was to test whether neurons in marmoset frontal cortex exhibited responses during vocal-signal processing and/or vocal-motor production in the context of active, natural communication. We observed motor-related changes in single neuron activity during vocal production, but relatively weak sensory responses for vocalization processing during this natural behavior. Vocal-motor responses occurred both prior to and during call production and were typically coupled to the timing of each vocalization pulse. Despite the relatively weak sensory responses a population classifier was able to distinguish between neural activity that occurred during presentations of vocalization stimuli that elicited an antiphonal response and those that did not. These findings are suggestive of the role that nonhuman primate frontal cortex neurons play in natural communication and provide an important foundation for more explicit tests of the functional contributions of these neocortical areas during vocal behaviors.


Bidding evidence for primate vocal learning and the cultural substrates for speech evolution.
Speech evolution seems to defy scientific explanation. Progress on this front has been jammed in an entrenched orthodoxy about what great apes can and (mostly) cannot do vocally, an idea epitomized by the Kuypers/Jürgens hypothesis. Findings by great ape researchers paint, however, starkly different and more optimistic landscapes for speech evolution. Over twenty studies qualify as positive evidence for primate vocal (production) learning following accepted terminology. Additionally, the Kuypers/Jürgens hypothesis shows low etymological, empirical, and theoretical soundness. Great apes can produce novel voiced calls and voluntarily control their modification - observations supposedly impossible. Furthermore, no valid pretext justifies dismissing heuristically the production of new voiceless consonant-like calls by great apes. To underscore this point, new evidence is provided for a novel supra-genera voiceless call across all great ape species. Their vocal invention and vocal learning faculties are real and sufficiently potent to, at times, uphold vocal traditions. These data overpower conventional predicaments in speech evolution theory and will help to make new strides explaining why, among hominids, only humans developed speech.


Duplication of teichoic acid biosynthetic genes in Staphylococcus aureus leads to functionally redundant poly(ribitol phosphate) polymerases.
Wall teichoic acids are anionic phosphate-rich polymers that are part of the complex meshwork of carbohydrates that make up the gram-positive cell wall. These polymers are essential to the proper rod-shaped morphology of Bacillus subtilis and have been shown to be an important virulence determinant in the nosocomial opportunistic pathogen Staphylococcus aureus. Together, sequence-based studies, in vitro experiments with biosynthetic proteins, and analyses of the chemical structure of wall teichoic acid have begun to shed considerable light on our understanding of the biogenesis of this polymer. Nevertheless, some paradoxes remain unresolved. One of these involves a putative duplication of genes linked to CDP-ribitol synthesis (tarI'J' and tarIJ) as well as poly(ribitol phosphate) polymerization (tarK and tarL) in S. aureus. In the work reported here, we performed careful studies of the dispensability of each gene and discovered a functional redundancy in the duplicated gene clusters. We were able to create mutants in either of the putative ribitol phosphate polymerases (encoded by tarK and tarL) without affecting teichoic acid levels in the S. aureus cell wall. Although genes linked to CDP-ribitol synthesis are also duplicated, a null mutant in only one of these (tarI'J') could be obtained, while tarIJ remained essential. Suppression analysis of the tarIJ null mutant indicated that the mechanism of dysfunction in tarI'J' is due to poor translation of the TarJ' enzyme, which catalyzes the rate-limiting step in CDP-ribitol formation. This work provides new insights into understanding the complex synthetic steps of the ribitol phosphate polymer in S. aureus and has implications on specifically targeting enzymes involved in polymer biosynthesis for antimicrobial design.


Reliability criteria for steroid radioimmunoassay.
The principle of radioimmunoassay has been applied to every hormonal steroid and many steroids without known biological activity. The validation of steroid radioimmunoassay requires the evaluation of reliability criteria. These criteria involve the degree of relative specificity of the assay, the sensitivity which dictates the volume of biological fluid required for accurate and precise measurement, and the precision and accuracy of the assay which should be evaluated in every batch of assays as quality control. The use of steroid radioimmunoassay in physiological and clinical studies requires prior validation of these assays by proper evaluation of the reliability criteria.


Circulation of two Enterovirus C105 (EV-C105) lineages in Europe and Africa.
The coding sequences of five human enterovirus (HEV)-C genotype 105 strains recovered in Italy, Romania and Burundi from patients with upper and lower respiratory tract infections were analysed and phylogenetically compared with other circulating HEV-C strains. The EV-C105 was closely related to EV-C109 and EV-C118 strains. The European strains were similar to other circulating EV-C105 strains, while the two African EV-C105 clustered in separate bootstrap-supported (>0.90) branches of the P2 and P3 region trees. Minor inconsistencies in the clustering pattern of EV-C105 in the capsid region (P1) and non-capsid region (P3) suggest that recombination may have occurred in EV-C105 group B viruses. In conclusion, phylogenetic analysis revealed the circulation of two distinct EV-C105 lineages in Europe and Africa. A different pattern of evolution could be hypothesized for the two EV-C105 lineages.


Prospective follow-up study of youth and adults with onset of functional tic-like behaviours during the COVID-19 pandemic.
Very little is known about the long-term prognosis of patients with functional tic-like behaviours (FTLBs). We sought to characterize the trajectory of symptom severity over a 12-month period. Patients with FTLBs were included in our prospective longitudinal child and adult clinical tic disorder registries at the University of Calgary. Patients were prospectively evaluated 6 and 12 months after their first clinical visit. Tic inventories and severity were measured with the Yale Global Tic Severity Scale (YGTSS). Eighty-three youths and adults with FTLBs were evaluated prospectively until April 2023. Mean YGTSS total tic severity scores were high at baseline, with a mean score of 29.8 points (95% confidence interval [CI] = 27.6-32.1). Fifty-eight participants were reevaluated at 6 months, and 32 participants were reevaluated at 12 months. The YGTSS total tic severity score decreased significantly from the first clinical visit to 6 months (raw mean difference = 8.9 points, 95% CI = 5.1-12.7, p < 0.0001), and from 6 to 12 months (raw mean difference = 6.4 points, 95% CI = 0.8-12.0, p = 0.01). Multivariable linear regression demonstrated that tic severity at initial presentation and the presence of other functional neurological symptoms were associated with higher YGTSS total tic scores at 6 months, whereas younger age at baseline, receiving cognitive behavioural therapy for anxiety and/or depression, and prescription of selective serotonin reuptake inhibitors were associated with lower YGTSS total tic scores at 6 months. We observed a meaningful improvement in tic severity scores in youth and adults with FTLBs over a period of 6-12 months.


Retrospective Study on Implantation of Autologous-Cultured Osteoblasts for the Treatment of Patients with Avascular Necrosis of the Femoral Head.
Osteonecrosis of the femoral head is a progressive and debilitating disease that causes pain, osteoarthritis and hip joint collapse, eventually necessitating hip replacement. This study evaluated the long-term outcomes of autologous adult live-cultured osteoblasts (AALCO) implantation in patients with osteonecrosis of femoral head. In this retrospective multicenter study, we collated and analyzed data of patients ≥12 years of age who underwent AALCO (OSSGROW®) between 2010 and 2015 for the treatment of osteonecrosis of the femoral head. Data from 64 patients (101 hip joints) were assessed in this study. The mean ±SD duration of disease since diagnosis of osteonecrosis was 7.4±1.6 years. The mean follow-up duration was 6.3±1.4 years. The mean VAS score (n=98 hips) reduced significantly from 58.8 ± 13.8 to 32.2 ± 32.1 post-operatively (mean difference: -26.5±35.2, p=0.001) and Harris hip score (n=97 hips) also significantly improved from 47.1±12.3 to 63.7±27.7 post-operatively (mean difference:16.7±28.7, p=0.0001). Following the AALCO treatment, 29 hips in 13 patients (28.7%) underwent total hip replacement (THA), indicating that AALCO treatment could delay THA for 71.3% of hips. A total of 39.1% of hips diagnosed in early stage versus 60.8% in the late stage of osteonecrosis required THA. Overall, 60.4% of hips improved, 2% remained stable, and 37.6% progressed following the AALCO implantation. The condition of disease was found to have improved in 71.1% of patients in early stage (Grades I and II) versus 58% in the late stage (Grades III and IV) of osteonecrosis. Patients with osteonecrosis who received implantation of autologous-cultured osteoblasts using AALCO showed improvement in joint function and decrease in pain. Treatment with AALCO halted progression of osteonecrosis, preserved the natural hip, and eliminated the need for hip replacement surgeries in 7 out of 10 patients.


Recurrent respiratory papillomatosis in pregnancy: a case of emergent airway management.
Recurrent respiratory papillomatosis is a benign neoplastic process involving squamous epithelium of the respiratory tract, typically the vocal folds. In cases of aggressive growth, or uncontrolled disease, airway compromise and respiratory distress can occur. Human papillomavirus (HPV) is known to be the etiologic agent in this disease process, as well as in condyloma acuminata, or genital warts. Studies have shown that HPV-induced condyloma acuminata can worsen during pregnancy. We present a case of airway obstruction requiring emergent tracheostomy in a pregnant patient with known laryngeal recurrent respiratory papillomatosis. The management of this condition and some theories regarding its response to certain hormonal states are discussed.


Potential intercellular futile cycling of carbohydrates in diabetes.
Diabetes was induced by treating rats with alloxan, and was confirmed by blood glucose values greater than 250 mg/dl. In perfused livers from both normal and diabetic rats, basal rates of O2 uptake were similar (120-130 mumol/h per g). In livers from diabetic rats, basal rates of glucose output of 60 mumol/h per g declined to around 20 mumol/h per g during 1 h of perfusion. Basal glucose production was abolished by pretreatment with an inhibitor of glycogen synthesis, galactosamine (1.5 g/kg), injected 3 h before perfusion. The subsequent infusion of lactate (2 mM) increased O2 uptake and glucose production about 40-50 mumol/h per g in both groups; however, the average maximal increase in glucose output was nearly twice as high in livers from normal (33 mumol/h per g) as from diabetic (18 mumol/h per g) rats. Rates of lactate uptake were also about 50% lower in livers from diabetic than from normal rats, yet rates of ketone-body formation were similar. Miniature O2 electrodes placed on periportal and pericentral regions of the liver lobule were employed to measure local rates of O2 uptake before, during and after infusion of lactate by stopping the flow of perfusate through the liver and measuring the decrease in local [O2]. Local rates of glucose production were calculated from the extra O2 consumed and the known stoichiometry between O2 uptake and glucose production from lactate. In livers from normal rats, glucose was synthesized predominantly in periportal regions of the liver lobule; however, glucose was produced exclusively in periportal regions in livers from diabetic rats. In pericentral regions, O2 uptake increased slightly in livers from normal rats, but declined significantly by 10 mumol/h per g in livers from diabetic rats. These data are consistent with the hypothesis that gluconeogenesis from lactate occurs exclusively in periportal regions of the liver lobule in livers from diabetic rats. A portion of this glucose is metabolized back to lactate in pericentral areas, leading to increased rates of glycolytic ATP production, thereby decreasing the demands for O2. This production of glucose from lactate in periportal regions, followed by conversion of glucose back into lactate in pericentral areas, raises the possibility of intercellular futile cycling, stimulated by diabetes.


Left-right temporal region asymmetry in infants and children.
Thirty-two consecutive cranial computed tomographic (CT) scans in normal infants ranging from 1 day to 3 years of age were evaluated for asymmetry of the temporal lobes as evidenced by differences in the size of the sylvian fissures. The left sylvian fissure was larger than the right in 23 of the 32 cases, which was statistically significant (p less than 0.0001). In five other cases the two sides were equal; in the four remaining cases, the right side was larger than the left. The results show that asymmetry of the temporal lobes can be demonstrated in vivo even at birth and that this asymmetry is a normal developmental difference between the two hemispheres and not secondary to an acquired abnormality.


Complete Glucose Electrooxidation Enabled by Coordinatively Unsaturated Copper Sites in Metal-Organic Frameworks.
The electrocatalytic oxidation of glucose plays a vital role in biomass conversion, renewable energy, and biosensors, but significant challenges remain to achieve high selectivity and high activity simultaneously. In this study, we present a novel approach for achieving complete glucose electrooxidation utilizing Cu-based metal-hydroxide-organic framework (Cu-MHOF) featuring coordinatively unsaturated Cu active sites. In contrast to traditional Cu(OH)2 catalysts, the Cu-MHOF exhibits a remarkable 40-fold increase in electrocatalytic activity for glucose oxidation, enabling exclusive oxidation of glucose into formate and carbonate as the final products. The critical role of open metal sites in enhancing the adsorption affinity of glucose and key intermediates was confirmed by control experiments and density functional theory simulations. Subsequently, a miniaturized nonenzymatic glucose sensor was developed showing superior performance with a high sensitivity of 214.7 μA mM-1 cm-2 , a wide detection range from 0.1 μM to 22 mM, and a low detection limit of 0.086 μM. Our work provides a novel molecule-level strategy for designing catalytically active sites and could inspire the development of novel metal-organic framework for next-generation electrochemical devices.


The importance of symbolic and engaged participation in evidence-based quality improvement in a complex integrated healthcare system: response to "The science of stakeholder engagement in research".
In this commentary, we respond to the commentary provided by Goodman and Sanders Thompson regarding our paper on multilevel stakeholder engagement in a VA implementation trial of evidence-based quality improvement (EBQI) in women's health primary care. We clarify our overall approach to engagement (comprised of both symbolic and engaged participation, according to the authors' classification rubric), highlighting that symbolic participation is of more import and value than the authors suggest, especially in the context of a hierarchical healthcare system. We contend that the issue of power-and how power matters in stakeholder engagement-needs to be considered in this context rather than in global "community" terms. In response to the authors' call for greater detail, we clarify our planning processes as well as our approach to veteran engagement. We concur with Goodman and Sanders Thompson that the science of stakeholder engagement necessitates a broader understanding of best practices as well as the impact of engagement on implementation outcomes.


Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history.
From 1960 to 1987, 1209 patients with colorectal liver metastases were recorded, and followed until 1 January 1990. In 242 cases the diagnosis was based on external imaging, whereas 967 patients had operative confirmation and staging of their liver disease. Three groups of patients were analysed: group 1 involved 921 cases, of whom 902 were deemed non-resectable whereas 19 could not be unequivocally classified. Only 21 patients lived for longer than 3 years, seven survived for 4 years, but there were no 5-year survivors. Group 2 comprised 62 highly selected patients who at laparotomy demonstrated resectable metastatic spread confined to the liver, but this was not treated mainly because of a formerly different therapeutic approach. These patients had a significantly longer median survival time (14.2 versus 6.9 months), but also failed to achieve 5-year survival. The 226 patients forming group 3 underwent hepatic resection with intent to cure. Nine of them had minimal macroscopic disease left, and 34 with all gross tumour removed had positive margins. Survival of patients with these 43 eventually non-radical resections followed an identical course as in group 2 (median survival 13.3 months, maximum 42 months). Of the 183 patients with potentially curative resection ten died after surgery (5.5 per cent). Actuarial 5 and 10-year survival rates in the remaining 173 patients were 40 and 27 per cent with 25 and seven patients alive at respective periods of time. Until 1 January 1990, 64 patients remained free from recurrent disease for up to 24 years. In three patients the tumour status at death was unclear. The other 106 patients developed definite cancer relapse. Nevertheless they demonstrated a prolongation of survival time by a median of 1 year when compared with the 43 non-radically resected patients or the 62 untreated patients with resectable liver-only metastases, and accomplished a maximum survival time of 8 years. Radical excision of colorectal secondaries to the liver therefore offers effective palliation, and in a small number the chance of a cure.


Expression of African swine fever virus envelope protein j13L inhibits vaccinia virus morphogenesis.
The African swine fever virus (ASFV) strain Malawi LIL20/1 open reading frame (ORF) j13L was expressed in vaccinia virus (VV) from a strong synthetic late promoter as either a complete ORF (vSJ1) or lacking codons 1-31 (vSJ2). Each recombinant VV produced a small plaque which rapidly reverted to a normal size upon passage. The yield of infectious virus from a single cycle infection with vSJ1 or vSJ2 was reduced 50- to 100-fold compared to wild-type (wt) and a revertant virus (vSJ5) in which the j13L ORF was removed and the VV thymidine kinase gene restored. PCR analysis of nine spontaneous large plaque revertant viruses, recovered after passage of vSJ1 in BSC-40 cells, showed that six had lost the j13L ORF and the co-inserted beta-galactosidase gene. Three viruses retained the j13L and beta-galactosidase genes, but in each case the j13L protein was not expressed due to a different single base deletion near the 5' end of the j13L coding region which introduced a stop codon a short distance downstream. The formation of intracellular mature virus (IMV) and extracellular enveloped virus was reduced 50- to 75-fold in cells infected with vSJ1 compared to wt VV and revertant vSJ5. Electron microscopy showed aberrant IMV precursor structures in vSJ1-infected cells, and immunoelectron microscopy demonstrated that these structures contained j13L protein. These results indicate that expression of the j13L protein is toxic for VV replication due to interference with VV morphogenesis prior to IMV formation.


Reovirus-associated meningoencephalomyelitis in baboons.
Baboon orthoreovirus (BRV) is associated with meningoencephalomyelitis (MEM) among captive baboons. Sporadic cases of suspected BRV-induced MEM have been observed at Southwest National Primate Research Center (SNPRC) for the past 20 years but could not be confirmed due to lack of diagnostic assays. An immunohistochemistry (IHC)-based assay using an antibody against BRV fusion-associated small transmembrane protein p15 and a conventional polymerase chain reaction (PCR)-based assay using primers specific for BRV were developed to detect BRV in archived tissues. Sixty-eight cases of suspected BRV-induced MEM from 1989 through 2010 were tested for BRV, alphavirus, and flavivirus by IHC. Fifty-nine of 68 cases (87%) were positive for BRV by immunohistochemistry; 1 tested positive for flavivirus (but was negative for West Nile virus and St Louis encephalitis virus by real-time PCR), and 1 virus isolation (VI) positive control tested negative for BRV. Sixteen cases (9 BRV-negative and 7 BRV-positive cases, by IHC), along with VI-positive and VI-negative controls, were tested by PCR for BRV. Three (of 9) IHC-negative cases tested positive, and 3 (of 7) IHC-positive cases tested negative by PCR for BRV. Both IHC and PCR assays tested 1 VI-positive control as negative (sensitivity: 75%). This study shows that most cases of viral MEM among baboons at SNPRC are associated with BRV infection, and the BRV should be considered a differential diagnosis for nonsuppurative MEM in baboons.


Time to Colonoscopy and Risk of Colorectal Cancer in Patients With Positive Results From Fecal Immunochemical Tests.
In patients with positive results from a fecal immunochemical test (FIT), failure to receive a timely follow-up colonoscopy may be associated with higher risks of colorectal cancer (CRC) and advanced-stage CRC. We evaluated the prevalence of any CRC and advanced-stage CRC associated with delays in follow-up colonoscopies for patients with positive results from a FIT. We collected data from 39,346 patients (age, 50-69 years) who participated in the Taiwanese Nationwide Screening Program from 2004 through 2012 and had completed a colonoscopy more than 1 month after a positive result from a FIT. Risks of any CRC and advanced-stage CRC (stage III-IV) were evaluated using logistic regression models and results expressed as adjusted odds ratios (aORs) and corresponding 95% CIs. In our cohort, 2003 patients received a diagnosis of any CRC and 445 patients were found to have advanced-stage disease. Compared with colonoscopy within 1-3 months (cases per 1000 patients: 50 for any CRC and 11 for advanced-stage disease), risks were significantly higher when colonoscopy was delayed by more than 6 months for any CRC (aOR, 1.31; 95% CI, 1.04-1.64; 68 cases per 1000 patients) and advanced-stage disease (aOR, 2.09; 95% CI, 1.43-3.06; 24 cases per 1000 patients). The risks continuously increased when colonoscopy was delayed by more than 12 months for any CRC (aOR, 2.17; 95% CI, 1.44-3.26; 98 cases per 1000 patients) and advanced-stage disease (aOR, 2.84; 95% CI, 1.43-5.64; 31 cases per 1000 patients). There were no significant differences for colonoscopy follow up at 3-6 months for risk of any CRC (aOR, 0.98; 95% CI, 0.86-1.12; 49 cases per 1000 patients) or advanced-stage disease (aOR, 0.95; 95% CI, 0.72-1.25; 10 cases per 1000 patients). In an analysis of data from the Taiwanese Nationwide Screening Program, we found that among patients with positive results from a FIT, risks of CRC and advanced-stage disease increase with time. These findings indicate the importance of timely colonoscopy after a positive result from a FIT.