Doping in sport: an analysis of sanctioned UK rugby union players between 2009 and 2015.
To inform anti-doping policy and practice, it is important to understand the complexities of doping. The purpose of this study was to collate and systematically examine the reasoned decisions published by UK Anti-Doping for doping sanctions in rugby union in the UK since the introduction of the 2009 World Anti-Doping Code. Case files were content analysed to extract demographic information and details relating to the anti-doping rule violation (ADRV), including individuals' explanations for how/why the ADRV occurred. Between 2009 and 2015, 49 rugby union players and one coach from across the UK were sanctioned. Over 50% of the cases involved players under the age of 25, competing at sub-elite levels. Reasons in defence of the ADRV focused on functional use and lifestyle factors rather than performance enhancement. An a priori assessment of the "need", "risk" and "consequence" of using a substance was not commonplace; further strengthening calls for increasing the reach of anti-doping education. The findings also deconstruct the view that "doped" athletes are the same. Consequently, deepening understanding of the social and cultural conditions that encourage doping remains a priority.


Identification and developmental expression of inhibitor of caspase-activated DNase (ICAD) in Drosophila melanogaster.
DNA fragmentation, a hallmark of apoptosis, is regulated by a specific nuclease called caspase-activated DNase (CAD) and its inhibitor (ICAD). When cell lysates from Drosophila S2 cells were chemically denatured and the denatured proteins were removed after dialysis, the supernatant inhibited Drosophila CAD (dCAD). To identify the inhibitor, we tested recombinant DREP-1, which was previously identified using the Drosophila EST data base and found it also inhibited dCAD DNase. An antibody against DREP-1 inhibited the ICAD activity in the S2 cell extracts, confirming the identification of DREP-1 as a Drosophila homolog of ICAD (dICAD). The recombinant DREP-1/dICAD was cleaved at a specific site by human caspase 3 as well as by extracts prepared from S2 cells undergoing apoptosis. Biochemical fractionation and immunoprecipitation of dICAD from S2 cell extracts indicated that dICAD is complexed with dCAD in proliferating cells. The expression of the caspase-resistant form of dICAD/DREP-1 in a Drosophila neuronal cell line prevented the apoptotic DNA fragmentation. Northern hybridization and the immunohistochemical analyses revealed that the expression of the dICAD gene is developmentally regulated.


(2S,3S)-3-(3-Bromo-phen-yl)-6,6-dimethyl-2-nitro-2,3,6,7-tetra-hydro-benzo-furan-4(5H)-one.
The title compound, C16H16BrNO4, has two adjacent chiral C atoms and both have an S configuration. The fused cyclo-hex-2-enone and di-hydro-furan rings both adopt envelope conformations, with the quaternary C atom and the nitro-substituted C atoms as the respective flap. The flap atoms lie 0.607 (3) and -0.253 (2) Å, respectively, from the mean plane of the remaining ring atoms on opposite sides. The dihedral angle between the mean plane of the four coplanar atoms of the di-hydro-furan ring and the phenyl ring is 86.16 (3)°. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming a ladder motif parallel to the b axis.


Measuring Bee Effects on Seed Traits of Hybrid Sunflower.
In hybrid sunflower, bee pollination can improve productivity, but the contribution of bees to productivity may be over or underestimated. To estimate bee effects (seed trait gains from exposure to bees during anthesis), single capitula are commonly covered with a porous material to exclude bees. However, depending on the exclosure porosity, estimates of the magnitude of bee effects will vary. In two studies, porosity size and bee effect gains in two sunflower types were tested. In the exclosure study, Delnet exclosures severely reduced seed set and exclosures with larger porosities and had smaller and similar effects. However, since a few small bees penetrated the largest porosity size tested, exclosures with porosity sizes < 7 mm are recommended. With an exclosure porosity of 5 X 5 mm, the estimated bee effect contribution to the yield was 323 kg per hectare. Effects of exclosures on seed traits were similar in the oilseed and confectionary hybrids tested. Insecticide use did not affect seed traits but did lower insect damage to seeds. Bees from three families, mostly Apidae, were collected while foraging on sunflower. In summary, we recommend the use of exclosures with porosities of about 3 to 5 mm to avoid over or underestimating bee effects. And we recommend holistic insect management for sunflower cropping systems that balances the benefits of bee effects on seed traits with management of pest insects.


Resident-Driven Holistic Lean Daily Management System to Enhance Care Experience at a Safety Net Hospital.
To describe the use of Lean in urology at Zuckerberg San Francisco General, a community safety-net and trauma hospital that serves as a major teaching site for the University of California San Francisco. We examined our process improvement activities from 2016 to 2018. Our Lean Daily Management System (DMS) includes a 15-minute team huddle ("urology Lean work") of service residents, faculty, clinic and operating room nursing staff, and anesthesia liaisons. Our DMS also includes a 5-minute preoperative huddle. Besides team-building, urology Lean work surfaces logistics, safety or equipment improvement ideas, and ensures progress and completion of initiated projects. Over a 2-year period we developed and completed 67 projects. Projects impacted the outpatient setting (57%), followed by the operating room (22%), the Urology service (12%), and inpatient setting (9%). We completed projects in the following domains: safety (26%), quality (22%), care experience (21%), workforce care and development (13%), equity (11%), and financial stewardship (7%). Urology Lean work reduced new patient clinic access time (119-21 days) and Bacillus Calmette-Guérin in clinic treatment time (180-105 minutes). The average proportion of urology on-time surgeries was better than the overall surgery on-time surgeries (71% v 61%). Urology Lean work successfully applied DMS in a service specific yet holistic approach. Urology Lean work improved resident engagement in quality and safety endeavors and served as a DMS model throughout perioperative and clinic areas.


Bone CLARITY: Clearing, imaging, and computational analysis of osteoprogenitors within intact bone marrow.
Bone tissue harbors unique and essential physiological processes, such as hematopoiesis, bone growth, and bone remodeling. To enable visualization of these processes at the cellular level in an intact environment, we developed "Bone CLARITY," a bone tissue clearing method. We used Bone CLARITY and a custom-built light-sheet fluorescence microscope to detect the endogenous fluorescence of Sox9-tdTomato+ osteoprogenitor cells in the tibia, femur, and vertebral column of adult transgenic mice. To obtain a complete distribution map of these osteoprogenitor cells, we developed a computational pipeline that semiautomatically detects individual Sox9-tdTomato+ cells in their native three-dimensional environment. Our computational method counted all labeled osteoprogenitor cells without relying on sampling techniques and displayed increased precision when compared with traditional stereology techniques for estimating the total number of these rare cells. We demonstrate the value of the clearing-imaging pipeline by quantifying changes in the population of Sox9-tdTomato-labeled osteoprogenitor cells after sclerostin antibody treatment. Bone tissue clearing is able to provide fast and comprehensive visualization of biological processes in intact bone tissue.


[Verification of histologic diagnosis in cervical carcinoma in situ with contradictory morphological data].
The medical technology of in situ cervical carcinoma cytological verification using computer-assisted morphometric and density analysis of atypical cells nuclei was developed. The technology is aimed at diagnosis verification in cases with contradictory morphological data. The malignant transformation of cervical epithelium undetectable by conventional morphology methods can be diagnosed using the Felgen-stained samples nuclear DNA distribution data. The right DNA distribution diagram shift with modal class 4C or higher, mean DNA contents higher than 4C, the ratio between aneuploidic and polyploidic cells higher than 0.2 are the signs of cervical epithelium malignant transformation.


Promoting effective communication for patients receiving mechanical ventilation.
Communicating effectively with ventilator-dependent patients is essential so that various basic physiological and psychological needs can be conveyed and decisions, wishes, and desires about the plan of care and end-of-life decision making can be expressed. Numerous methods can be used to communicate, including gestures, head nods, mouthing of words, writing, use of letter/picture boards and common words or phrases tailored to meet individualized patients' needs. High-tech alternative communication devices are available for more complex cases. Various options for patients with a tracheostomy tube include partial or total cuff deflation and use of a speaking valve. It is important for nurses to assess communication needs; identify appropriate alternative communication strategies; create a customized care plan with the patient, the patient's family, and other team members; ensure that the care plan is visible and accessible to all staff interacting with the patient; and continue to collaborate with colleagues from all disciplines to promote effective communication with nonvocal patients.


Late proton MR spectroscopy in children after traumatic brain injury: correlation with cognitive outcomes.
Proton MR spectroscopy has demonstrated reduced levels of N-acetylaspartate (NAA) in normal-appearing occipital and frontal regions of patients with acute nonpenetrating traumatic brain injury (TBI). We studied the relationship of frontoparietal NAA, choline (Cho), and creatine (Cr) to test the hypothesis that reduction in NAA is predictive of cognitive outcome. Proton spectra were collected by using conventional 2D chemical shift imaging in five healthy children and seven children (6 weeks to 3 years) with severe (n=4), moderate (n=2), or mild (n=1) TBI. Spectra in the anterior and posterior regions of the left and right frontoparietal areas were averaged for analysis by using LCModel, with a phantom-established basis function, for quantification of NAA, Cho, and Cr concentrations. Intellectual function, expressive language, and arithmetic capability were measured within 4 months of imaging. NAA/Cho concentration was lower in TBI patients than in control subjects, but no group differences were present for Cho or Cr. Hemispheric levels for NAA, Cho, and Cr were higher on the left than on the right, but we found no effect of region and no interactions. Cognition was lower in the TBI group than the control group and correlated with NAA levels. Left frontal Cho was also correlated with arithmetic scores, whereas Cr was not significantly correlated. NAA levels remain low after TBI and are related to cognitive function. Neurometabolite values are greater in the left frontoparietal region than in the right, and the left frontal Cho level is related to arithmetic ability.


Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L).
This article introduces the new 5-level EQ-5D (EQ-5D-5L) health status measure. EQ-5D currently measures health using three levels of severity in five dimensions. A EuroQol Group task force was established to find ways of improving the instrument's sensitivity and reducing ceiling effects by increasing the number of severity levels. The study was performed in the United Kingdom and Spain. Severity labels for 5 levels in each dimension were identified using response scaling. Focus groups were used to investigate the face and content validity of the new versions, including hypothetical health states generated from those versions. Selecting labels at approximately the 25th, 50th, and 75th centiles produced two alternative 5-level versions. Focus group work showed a slight preference for the wording 'slight-moderate-severe' problems, with anchors of 'no problems' and 'unable to do' in the EQ-5D functional dimensions. Similar wording was used in the Pain/Discomfort and Anxiety/Depression dimensions. Hypothetical health states were well understood though participants stressed the need for the internal coherence of health states. A 5-level version of the EQ-5D has been developed by the EuroQol Group. Further testing is required to determine whether the new version improves sensitivity and reduces ceiling effects.


Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes.
There is evidence that type 2 diabetes mellitus is associated with cognitive impairment. Most studies investigating this association have evaluated elderly individuals, after many years of diabetes, who generally have poor glycaemic control and significant vascular disease. The aim of the current study was to investigate the early cognitive consequences and associated brain correlates of type 2 diabetes. With regard to cognition and brain measures, we compared 23 age-, sex- and education-matched control subjects with 23 mostly middle-aged individuals with relatively well-controlled diabetes of less than 10 years from the time of diagnosis. We found deficits in hippocampal-based memory performance and preservation of other cognitive domains. Relative to control subjects, individuals with diabetes had reductions in brain volumes that were restricted to the hippocampus. There was an inverse relationship between glycaemic control and hippocampal volume; in multivariate regression analysis, HbA(1c) was the only significant predictor of hippocampal volume, accounting for 33% of the observed variance. Other variables commonly associated with type 2 diabetes, such as elevated BMI, hypertension or dyslipidaemia, did not independently contribute to the variance in hippocampal volume. These results suggest that the medial temporal lobe may be the first brain site affected by type 2 diabetes and that individuals in poorer metabolic control may be affected to a greater extent.


The reasons of dropout of sport in Hong Kong school athletes.
Dropout of sport is an issue in sport and public health domains. The aim of this study was to identify the potential dropout reasons of school athletes and to examine if their perception of dropout was affected by the previous dropout experience. There were 50 subjects who were divided into two groups based on their previous dropout experience (Dropout Group=22, No Dropout Group=28). They filled a questionnaire about potential dropout reasons of the current sport. Coach and teammates were two predominated reasons of dropout; Influence of parent and training seemed to affect the termination of the sport to a lesser extent. Moreover, the perception of social value and lost focus were significantly different between two groups. Character of coach and teammates affect the engagement of training in school athletes. However, the parental influence had less influence than expected. Training intensity played little role as the dropout reason. Previous experience of dropout had an impact of potential dropout reasons on their current sport training.


The family check-up with high-risk indigent families: preventing problem behavior by increasing parents' positive behavior support in early childhood.
Seven hundred thirty-one income-eligible families in 3 geographical regions who were enrolled in a national food supplement program were screened and randomized to a brief family intervention. At child ages 2 and 3, the intervention group caregivers were offered the Family Check-Up and linked parenting support services. Latent growth models on caregiver reports at child ages 2, 3, and 4 revealed decreased behavior problems when compared with the control group. Intervention effects occurred predominantly among families reporting high levels of problem behavior at child age 2. Families in the intervention condition improved on direct observation measures of caregivers' positive behavior support at child ages 2 and 3; improvements in positive behavior support mediated improvements in children's early problem behavior.


Spatial-temporal distribution of phthalate esters from riverine outlets of Pearl River Delta in China.
The aquatic environments of the Pearl River Delta (PRD) in China have been contaminated by various industrial chemicals from local industries. In this study, the spatial-temporal distribution of six priority phthalate esters (PAEs) in surface water and sediments from the PRD was investigated. The PAEs were detected with total concentrations (Σ6PAEs) ranging from 0.35 to 20.70 μg L⁻¹ in surface water and dry weight ranging from 0.88 to 5.69 μg g⁻¹ in sediments. The Σ6PAEs concentrations in surface water were higher in the wet season than those in the dry season, while the opposite pattern was observed in sediments. Di(2-ethylhexyl) phthalate (DEHP) was the most abundant congener, which was higher than those reported in the literature. Risk quotients for relevant aquatic organisms were obtained and showed that most of these PAEs, in particular, butyl benzyl phthalate, DEHP and di-n-octyl phthalate, have significant potential health and ecological risks for the aquatic environment studied.


Circumsporozoite protein of Plasmodium berghei: gene cloning and identification of the immunodominant epitopes.
The gene encoding the circumsporozoite (CS) protein of the rodent malaria parasite Plasmodium berghei was cloned and characterized. A cDNA library made from P. berghei sporozoite RNA was screened with a monoclonal antibody for expression of CS protein epitopes. The resulting cDNA clone was used to isolate the CS protein gene from a lambda library containing parasite blood-stage DNA. The CS protein gene contains a central region encoding two types of tandemly repeated amino acid units, flanked by nonrepeated regions encoding amino- and carboxy-terminal signal and anchorlike sequences, respectively. One of the central repeated amino acid unit types contains the immunodominant epitopes.


Second Language Use Facilitates Implicit Emotion Regulation via Content Labeling.
Previous studies reported that negative stimuli induced less affect in bilinguals when stimuli were presented in bilinguals' second, weaker language (L2) than when they were presented in their native language (L1). This effect of L2 use was attributed to increased emotional distance as well as to increased levels of cognitive control during L2 use. Here we investigated how explicit (cognitive reappraisal, i.e., reinterpreting the meaning of the emotional stimulus to alter its emotional impact) and implicit (content labeling, i.e., categorizing the content of the image; and emotion labeling, i.e., naming the emotion induced by the emotional stimulus) emotion regulation strategies are altered in an L2 (English) context in German native speakers with medium to high proficiency in their L2. While previous studies used linguistic stimuli, such as words, to induce affect, here we used images to test whether reduced affect could also be observed for non-linguistic stimuli when presented in an L2 context. We hypothesized that the previously implicated increase in emotional distance and cognitive control in an L2 would result in an L2 advantage in emotion regulation (i.e., leading to less negative emotions compared to an L1 context), by strengthening the effect of linguistic re-evaluation on the evoked emotions. Using a classic emotion regulation paradigm, we examined changes in subjective emotional state ratings during reappraisal, emotion labeling and content labeling in a L1 and L2 context. We found that the strength of evoked affective responses did not depend on the language context in which an image was presented. Crucially, content labeling in L2 was more effective than in L1, whereas emotion labeling did not differ between languages. Overall, evoked responses were regulated most effectively through explicit emotion regulation (reappraisal) in L1 and L2 context. These results demonstrate an L2 advantage effect for emotion regulation through content labeling and suggest that L2 context alters sub-processes implicated in content labeling but not emotion labeling.


Stopping the cardiovascular disease continuum: Focus on prevention.
The cardiovascular disease continuum (CVDC) is a sequence of events, which begins from a host of cardiovascular risk factors that consists of diabetes mellitus, dyslipidemia, hypertension, smoking and visceral obesity. If it is not intervened with early, it inexorably progresses to atherosclerosis, coronary artery disease, myocardial infarction, left ventricular hypertrophy, and left ventricular dilatation, which lead to left ventricular diastolic or systolic dysfunction and eventually end-stage heart failure and death. Treatment intervention at any stage during its course will either arrest or delay its progress. In this editorial, the cardiovascular risk factors that initiate and perpetuate the CVDC are briefly discussed, with an emphasis on their early prevention or aggressive treatment.


Effects of neddylation on viral infection: an overview.
Neddylation is a post-translational modification that plays an important role not only in cancer development but also in regulating viral infection and replication. Upregulation of neddylation occurs in viral infections, and inhibition of neddylation can suppress viral replication. Neddylation is thought to enhance viral protein stability and replication. Neddylation has been reported to enhance the stability of the regulatory hepatitis B virus (HBV) X protein, modulate viral replication, and enhance hepatocarcinogenesis. Inhibition of neddylation using the NEDD8-activating enzyme E1 inhibitor MLN4924 inhibits viral replication, including that of HBV. Understanding of the role of neddylation in viral infections is critical for developing new therapeutic targets and potential treatment strategies. In this review, we discuss recent progress in the understanding of the effects of neddylation during viral infection, particularly in HBV infection, and strategies for curing viral infection by targeting the neddylation pathway.


Fast, super resolution imaging via Bessel-beam stimulated emission depletion microscopy.
A substantial advantage of stimulated emission depletion (STED) microscopy over other super-resolution methods is that images can be acquired in real-time without any post-processing. However imaging speed and photodamage are two major concerns for STED imaging of whole cells. Here we propose a new microscopy method we have termed Bessel-Beam STED (or BB-STED) that overcomes both of these limitations of conventional STED microscopy. In the proposed method, rather than exciting a single STED spot in the sample, an entire line of the sample is illuminated. This line-scanning technique dramatically increases the speed of STED. In addition, plane-illumination by scanning of the line across the focal plane of a detection objective limits the light to a thin layer of the sample and thus significantly reduces photobleaching and photodamage above and below the focal plane compared to epi-illumination. Using the organic dye Atto647N as an example, we calculated the STED power required to break the diffraction limit. The results presented here will be used to guide future experimental designs.


Late domain dependent E-cadherin recruitment into extracellular vesicles.
E-cadherin, a transmembrane protein involved in epithelial cell-cell adhesion and signaling, is found in exosomal fractions isolated from human body fluids. A cellular mechanism for recruitment of E-cadherin into extracellular vesicles (EVs) has not yet been defined. Here, we show that E-cadherin is incorporated into the membrane of EVs with the extracellular domain exposed at the vesicle surface. This recruitment depends on the endosomal sorting complex required for transport I (ESCRT-I) component Tsg101 and a highly conserved tetrapeptide P(S/T)AP late domain motif in the cytoplasmic tail of E-cadherin that mediates interaction with Tsg101. Mutation of this motif results in a loss of interaction and a dramatic decrease in exosomal E-cadherin secretion. We conclude, that the process of late domain mediated exosomal recruitment is exerted by this endogenous non-ESCRT transmembrane protein.


Surgical correction of the genital hiatus at the time of sacrocolpopexy - a 7-year Markov analysis: a cost-effectiveness analysis.
To perform a cost-effectiveness analysis of concurrent posterior repair performed at the time of laparoscopic hysterectomy with sacrocolpopexy over a 7-year time period. We hypothesize it is not cost-effective to perform a posterior colporrhaphy. We used TreeAge Pro® to construct a decision model with Markov modeling to compare sacrocolpopexy with and without concurrent posterior repair (SCP and SCP+PR) over a time horizon of 7 years. Outcomes included probability and costs associated with prolapse recurrence, prolapse retreatment, and complications including rectal injury, rectovaginal hematoma requiring reoperation, and postoperative dyspareunia. Cost-effectiveness was defined as an incremental cost-effectiveness ratio (ICER) calculated as ∆ costs /∆ effectiveness and the willingness to pay (WTP) was set at $100,000/QALY. Our model showed that SCP was the dominant strategy, with lower costs (-$ 2681.06) and higher effectiveness (+0.10) compared to SCP+PR over the 7-year period. In two-way sensitivity analyses, we varied the probability of prolapse recurrence after both strategies. Our conclusions would only change if the probability of recurrence after SCP was at least 29.7% higher than after SCP+PR. When varying the probabilities of dyspareunia for both strategies, SCP+PR only became the dominant strategy if the probability of dyspareunia for SCP+PR was lower than the rate of SCP alone. In this 7-year Markov cost-effectiveness analysis, SCP without concurrent PR was the dominant strategy. SCP+PR costs more with lower effectiveness than SCP alone, due to higher surgical cost of SCP+PR and higher probability of dyspareunia after SCP+PR.


Keeping vigil over the profession: a grounded theory of the context of nurse anaesthesia practice.
Nurse anaesthetists in the US have faced continued, repeated challenges to their profession. Regardless, they have met these challenges and have established themselves as major anaesthesia care providers. In this paper we address the research question: How do certified registered nurse anaesthetists (CRNAs) manage the socio-political context in which they provide care for their patients? Grounded theory was used to explore how nurse anaesthetists protect and promote their profession. Purposive, snowball, and theoretical sampling was used and data were collected through participant observation and interviews conducted at a conference of the professional association, an educational program, by telephone, email exchanges, and time spent in operating rooms and an outpatient surgical clinic. Analysis included coding at increasingly abstract levels and constant comparison. The basic social process identified was Keeping Vigil Over the Profession, which explains how nurse anaesthetists protect and promote their profession. It is comprised of three contextual categories: Establishing Public Credibility through regulatory and educational standards, Political Vigilance and taking action in governmental and policy arenas, and Tending the Flock through a continuous information loop between local and administrative/political levels. From our study of the context of nurse anaesthesia practice, it is clear that CRNAs are dedicated to protecting their ability to provide high quality patient care by maintaining constant vigilance over their profession.


Brain level of pentobarbital is the primary determinant for the development of hypnotic of hypnotic tolerance in mice.
Controlling the duration of hypnotic effect of pentobarbital by simultaneously administered bemegride, the relationship between the duration of hypnosis and the degree of developed tolerance after acute or chronic treatment was investigated in mice. Bemegride attenuated the hypnotic effect of pentobarbital, but neither the brain level of pentobarbital nor the development of tolerance was modified by bemegride, indicating that the brain level of pentobarbital is the primary determinant for the production of tolerance and full duration of hypnosis is not essential in this mechanism.


[Feeding and nutrition in Alzheimer's disease].
Dementia is an organic brain disease. The most frequent type of dementia is Alzheimer's and it affects mostly elderly people. Due to the increase in life expectancy and to the ageing of the population, Alzheimer's has recently become an area of research of interest. The eating behaviour and nutrition of elderly people has some special characteristics which become particularly relevant during illness. An Alzheimer's patient suffers a progressive decay in their functional and physical abilities, and these renders them at high nutritional risk. Prevention, rapid intervention and ensuring an adequate nutritional intake is essential in each of the dementia stages. This paper reviews the most important nutrients influencing the development or worsening of dementia and the guidelines for food intake throughout the disease.


A rapid staging system for predicting mortality from HIV-associated community-acquired pneumonia.
Community-acquired pneumonia (CAP) accounts for an increasing proportion of the pulmonary infections in individuals with HIV infection. During the mid-1990s, hospital mortality rates for HIV-associated CAP ranged from 0 to 28%. While hospital differences in case mix may account for mortality rate variation, few methods to evaluate illness severity for HIV-associated CAP have been reported previously. The study objective was to develop a staging system for categorizing mortality risk of patients with HIV-associated CAP using information available prior to hospital admission. Retrospective medical records review of 1,415 patients hospitalized with HIV-associated CAP from 1995 to 1997 at 86 hospitals in seven metropolitan areas. In-patient mortality rate. Hierarchically optimal classification tree analysis was used to develop a preadmission staging system for predicting inpatient mortality. The overall inpatient mortality rate was 9.1%. The significant predictors of mortality included the presence of neurologic symptoms, respiratory rate > or = 25 breaths/min, and creatinine > 1.2 mg/dL. The model identified a five-category staging system, with the mortality rate increasing by stage: 2.3% for stage 1, 5.8% for stage 2, 12.9% for stage 3, 22.0% for stage 4, and 40.5% for stage 5. The classification accuracy of the model was 85.2%. Our staging system categorizes inpatient mortality risk for patients with HIV-associated CAP using three routinely available variables. The staging system may be useful for guiding clinical decisions about the intensity of patient care and for case-mix adjustment in future studies addressing variation in hospital mortality rates.


Exercise training impacts the myocardial metabolism of older individuals in a gender-specific manner.
Aging is associated with decreases in aerobic capacity, cardiac function, and insulin sensitivity as well as alterations in myocardial substrate metabolism. Endurance exercise training (EET) improves cardiac function in a gender-specific manner, and EET has been shown to improve whole body glucose tolerance, but its effects on myocardial metabolism are unclear. Accordingly, we studied the effect of EET on myocardial substrate metabolism in older men and women. Twelve healthy older individuals (age: 60-75 yr; 6 men and 6 women) underwent PET with [(15)O]water, [(11)C]acetate, [(11)C]glucose, and [(11)C]palmitate for the assessment of myocardial blood flow (MBF), myocardial O(2) consumption (MVo(2)), myocardial glucose utilization (MGU), and myocardial fatty acid utilization (MFAU), respectively, at rest and during dobutamine infusion (10 microg.kg(-1).min(-1)). Measurements were repeated after 11 mo of EET. Maximal O(2) uptake (Vo(2max)) increased (P = 0.005) after EET. MBF was unaffected by training, as was resting MVo(2); however, posttraining dobutamine MVo(2) was significantly higher (P = 0.05), as was MGU (P < 0.04). Although overall dobutamine MFAU was unchanged, posttraining dobutamine MFAU increased in women (P = 0.01) but decreased in men (P = 0.03). Thus, EET in older individuals improves the catecholamine response of myocardial glucose metabolism. Moreover, gender differences exist in the myocardial fatty acid metabolic response to training. These findings suggest a role for altered myocardial substrate metabolism in modulating the cardiovascular benefits of EET in older individuals.


[Analysis of two needling techniques in terms of "reinforcing and reducing" and "symptomatic treatment"].
Neijing (Internal Classic) states two kinds of needling techniques, named reinforcing and reducing technique, and the symptomatic treatment technique. The people in the later generations stress on the technique in terms of reinforcing and reducing. The relationship between these two needling techniques, the quantification of reinforcing and reducing technique, the understanding of "reinforcing and reducing" and operation as well as the relevant terminology are expounded in this paper. On the basis of the analysis of the source literatures, the dialectic discussion in association with the clinical practice is condcuted in this paper. It is believed that the view of taking reinforcing and reducing technique as the core should be rectified and the actual value of the needling technique in light of symptomatic treatment be emphasized. It is required to face up to the diversity and opposition of the theories that are exactly existed in the reinforcing and reducing technique and should be explored scientifically. The context and conception ideas should be considered in the explanation of the definition of needling technique and the principle analysis. Concerning the quantification research of needling technique, the factors such as the situation of disease and the body constitution should be taken into account.


Improving Neuromuscular Monitoring and Reducing Residual Neuromuscular Blockade With E-Learning: Protocol for the Multicenter Interrupted Time Series INVERT Study.
Muscle relaxants facilitate endotracheal intubation under general anesthesia and improve surgical conditions. Residual neuromuscular blockade occurs when the patient is still partially paralyzed when awakened after surgery. The condition is associated with subjective discomfort and an increased risk of respiratory complications. Use of an objective neuromuscular monitoring device may prevent residual block. Despite this, many anesthetists refrain from using the device. Efforts to increase the use of objective monitoring are time consuming and require the presence of expert personnel. A neuromuscular monitoring e-learning module might support consistent use of neuromuscular monitoring devices. The aim of the study is to assess the effect of a neuromuscular monitoring e-learning module on anesthesia staff's use of objective neuromuscular monitoring and the incidence of residual neuromuscular blockade in surgical patients at 6 Danish teaching hospitals. In this interrupted time series study, we are collecting data repeatedly, in consecutive 3-week periods, before and after the intervention, and we will analyze the effect using segmented regression analysis. Anesthesia departments in the Zealand Region of Denmark are included, and data from all patients receiving a muscle relaxant are collected from the anesthesia information management system MetaVision. We will assess the effect of the module on all levels of potential effect: staff's knowledge and skills, patient care practice, and patient outcomes. The primary outcome is use of neuromuscular monitoring in patients according to the type of muscle relaxant received. Secondary outcomes include last recorded train-of-four value, administration of reversal agents, and time to discharge from the postanesthesia care unit as well as a multiple-choice test to assess knowledge. The e-learning module was developed based on a needs assessment process, including focus group interviews, surveys, and expert opinions. The e-learning module was implemented in 6 anesthesia departments on 21 November 2016. Currently, we are collecting postintervention data. The final dataset will include data from more than 10,000 anesthesia procedures. We expect to publish the results in late 2017 or early 2018. With a dataset consisting of thousands of general anesthesia procedures, the INVERT study will assess whether an e-learning module can increase anesthetists' use of neuromuscular monitoring. Clinicaltrials.gov NCT02925143; https://clinicaltrials.gov/ct2/show/NCT02925143 (Archived by WebCite® at http://www.webcitation.org/6s50iTV2x).


Emerging roles for hedgehog-patched-Gli signal transduction in reproduction.
Hedgehog (Hh) proteins are expressed during vertebrate development in some tissues with inductive properties and at epithelial-mesenchymal boundaries in several developing organs, including the lung, gut, hair follicle, and tooth. The Hh signaling pathway is highly conserved, and important clues to understanding the mechanism of Hh signal transduction in vertebrates have come from studies in Drosophila. In recent years, Hh signaling has been recognized during embryonic development and in some cases during postnatal life in several mammalian tissues whose functions are essential for reproduction, including the gonads, uterus, and hormonally responsive accessory sex glands such as the prostate and mammary gland. The role of the pathway in these tissues is highly reminiscent of its role at epithelial-mesenchymal-stromal boundaries in other organ systems, which has provided a framework within which to explore Hh signaling in tissues that function in reproduction. Some features unique to these tissues are emerging, including a role in proliferation and differentiation of male germline cells in mammals and apparent influences of sex steroids on Hh signaling. However, many questions remain about the function of Hh signaling in the gonads, uterus, prostate, and mammary gland, including factors regulating the signal transduction pathway, identification of downstream target genes, and roles for Hh signaling in diseases involving these tissues.


Is the level of education associated with transitions between care settings in older adults near the end of life? A nationwide, retrospective cohort study.
End-of-life transitions between care settings can be burdensome for older adults and their relatives. To analyze the association between the level of education of older adults and their likelihood to experience care transitions during the final months before death. Nationwide, retrospective cohort study using register data. Older adults (⩾65 years) who died in Sweden in 2013 ( n = 75,722). Place of death was the primary outcome. Institutionalization and multiple hospital admissions during the final months of life were defined as secondary outcomes. The decedents' level of education (primary, secondary, or tertiary education) was considered as the main exposure. Multivariable analyses were stratified by living arrangement and adjusted for sex, age at time of death, illness trajectory, and number of chronic diseases. Among community-dwellers, older adults with tertiary education were more likely to die in hospitals than those with primary education (55.6% vs 49.9%; odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.14-1.28), but less likely to be institutionalized during the final month before death (OR = 0.83, 95% CI = 0.76-0.91). Decedents with higher education had greater odds of remaining hospitalized continuously during their final 2 weeks of life (OR = 1.12, 95% CI = 1.02-1.22). Among older adults living in nursing homes, we found no association between the decedents' level of education and their likelihood to be hospitalized or to die in hospitals. Compared with those who completed only primary education, individuals with higher educational attainment were more likely to live at home until the end of life, but also more likely to be hospitalized and die in hospitals.


Treating Japanese Patients With Pembrolizumab for Platinum-Refractory Advanced Urothelial Carcinoma in Real-World Clinical Practice.
Since December 2017, pembrolizumab has been approved in Japan as a second-line treatment for radical unresectable urothelial carcinoma (UC) that has become exacerbated after chemotherapy by the international randomized phase 3 trial, KEYNOTE-045. The aim of this study was to evaluate the oncological efficacy and safety of pembrolizumab after failure of platinum-based chemotherapy in Japanese patients with advanced UC in real-world clinical practice. A total of 34 patients who received pembrolizumab after the failure of platinum-based chemotherapy for advanced urothelial carcinoma at four institutions between January 2018 and August 2019 were retrospectively evaluated. In all patients, UC was histopathologically diagnosed, and disease progression after platinum-based chemotherapy was radiologically confirmed. The median follow-up period was 7.7 months. The objective response rate, median progression-free survival, and median overall survival were 20.6%, 3.3 months, and 11.7 months, respectively. Regarding the toxicities associated with pembrolizumab, adverse events (AEs) of any grade occurred in 61.8%, and grade 3 AEs occurred in 23.5%; grade ≥ 4 AEs did not occur in any patients. Univariate analyses revealed that the Eastern Cooperative Oncology Group Performance Status, neutrophil/lymphocyte ratio, liver metastases, and time from previous chemotherapy were prognostic variables. Multivariate analyses revealed that liver metastases (positive: hazard ratio, 4.23; 95% confidence interval, 1.48 - 12.08; P < 0.01) and time from previous chemotherapy (≥ 3 months: hazard ratio, 5.06; 95% confidence interval, 1.43 - 17.91; P = 0.01) were independent prognostic factors. In this real-world clinical study, these findings concerning the efficacy and safety of pembrolizumab for advanced UC in Japanese patients were comparable to those of the open-label, international, phase 3 trial KEYNOTE-045. Liver metastases and time from previous chemotherapy were independent prognostic factors in the present study.


Tourniquet use in patients undergoing tumour resection and endoprosthetic reconstruction of the knee.
The aim of this study was to determine the prevalence and impact of tourniquet use in patients undergoing limb salvage surgery with endoprosthetic reconstruction for a tumour around the knee. We retrieved data from the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial; specifically, differences in baseline characteristics, surgical details, and postoperative functional outcomes between patients who had undergone surgery under tourniquet and those who had not. A linear regression model was created to evaluate the impact of tourniquet use on postoperative Toronto Extremity Salvage Scores (TESSs) while controlling for confounding variables. A negative-binomial regression model was constructed to explore predictors of postoperative length of stay (LOS). Of the 604 patients enrolled in the PARITY trial, 421 had tumours around the knee joint, of whom 225 (53%) underwent surgery under tourniquet. The tourniquet group was younger (p = 0.014), more likely to undergo surgery for a tumour of the tibia, and had shorter operating times by a mean of 50 minutes (95% confidence interval 30 to 72; p < 0.001). The adjusted linear regression model found that the use of a tourniquet, a shorter operating time, and a higher baseline TESS independently predicted better function at both three- and six-month follow-up. The negative-binomial regression model showed that tourniquet use, shorter operating time, younger age, and intraoperative tranexamic acid administration independently predicted a shorter LOS in hospital. The results of this study show that in patients undergoing resection of a tumour around the knee and endoprosthetic reconstruction, the use of an intraoperative tourniquet is associated with a shorter operating time, a reduced length of stay in hospital, and a better early functional outcome.Cite this article: Bone Joint J 2022;104-B(10):1168-1173.


Is APC hypermethylation a diagnostic biomarker for bladder cancer? A meta-analysis.
Numerous studies have been performed to investigate the association between APC promoter hypermethylation and bladder cancer risk. Nevertheless, the conclusion was uncertain due to small sample size, different ethnicities, and tumor subtype. Hence, to accurately assess the effect of APC promoter hypermethylation on the risk of bladder cancer, we performed the meta-analysis. We retrieved the relevant literatures from electronic databases such as PubMed, Web of Science, Wanfang, Vapp, and CNKI (Chinese National Knowledge Infrastructure). 95% CI and OR were calculated to evaluate the associations of APC promoter hypermethylation with risk and clinical features of bladder cancer. Heterogeneity among studies was assessed with Q test and I 2 statistic. In addition, the diagnostic sensitivity, specificity, and area under the curve (AUC) value of APC hypermethylation for bladder cancer were calculated. In total, 14 articles with 531 controls and 1,293 cases were included to assess the associations of APC promoter hypermethylation with the risk and clinical characteristics of bladder cancer. The significant association between APC promoter hypermethylation and bladder cancer risk was detected (OR =17.01, CI =7.40-39.07). Furthermore, the results revealed that APC promoter hypermethylation was significantly correlated with the grade of bladder tumor (pTNM stage: OR =1.84, CI =0.87-3.93; grade: OR =4.11, CI =1.62-10.43). According to the results of diagnostic evaluation, the diagnostic sensitivity, specificity, and AUC value of APC hypermethylation for bladder cancer risk were 0.52 (95% CI =0.41-0.63), 0.98 (95% CI =0.90-1.00), and 0.80 (95% CI =0.76-0.83), respectively. This meta-analysis revealed that APC promoter hypermethylation was a risk factor for bladder cancer risk. In addition, APC promoter hypermethylation was significantly associated with the grade of bladder cancer. APC hypermethylation might be a useful biomarker for the clinical diagnosis of bladder cancer.


The role of radiation therapy after surgical resection of nonfunctional pituitary macroadenomas.
Radiotherapy after aggressive surgical resection of nonfunctional macroadenoma (NFA) of the pituitary remains controversial. Historically, immediate postoperative radiotherapy has been recommended to decrease risk of recurrence. With the availability of high-resolution imaging, most neurosurgeons now withhold radiation until recurrence. There is relatively little evidence to support this practice, however. This study reviews postoperative results in a large number of patients with NFA, the majority of whom did not undergo prophylactic radiation. Of the 258 patients who underwent surgery from 1979 to 1999 for NFA, medical records were available for 176. Forty-four patients were treated with immediate postoperative radiotherapy after tumor resection, and the remaining 132 patients were followed up with serial imaging studies and treated with radiotherapy only when a recurrence was documented by follow-up imaging. Patients in the group that received immediate postoperative radiotherapy at time of initial diagnosis and surgery did not differ significantly with respect to age or sex from those in the group that was observed. Five- and 10-year recurrence rates were 2.3 and 2.3%, respectively, for patients who received immediate postoperative radiotherapy, as compared with 15.2 and 50.5%, respectively, for patients who were followed up and did not receive radiotherapy unless there was evidence of recurrence or progression. No patient had symptomatic recurrence in the group that was observed if consistent follow-up was performed. Of the 26 patients who received radiotherapy at time of tumor recurrence or progression, 18 had adequate follow-up, and in all cases, the tumors either remained stable or regressed. Withholding radiotherapy after a high-percentage resection of NFA leads to a higher recurrence rate, but it avoids exposing all patients to the risks of radiation. Deferring radiotherapy for patients with complete or near-complete resection seems to be a safe and prudent approach, as our data suggest that recurrences may be detected early with high-resolution imaging and treated effectively with radiation at time of recurrence. Therefore, immediate postoperative radiotherapy may be eliminated for patients with complete or near complete resection of NFA and who agree to undergo close follow-up for a long period.


Should platinum-based chemotherapy be preferred for germline BReast CAncer genes (BRCA) 1 and 2-mutated pancreatic ductal adenocarcinoma (PDAC) patients? A systematic review and meta-analysis.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Recent studies have shown that 4-20% of patients with PDAC have a germline BReast CAncer (gBRCA) genes 1 and 2 mutation (m). Because homologous recombination is impaired in patients with gBRCAm, some reports suggested that these tumors may be more sensitive to platinum compounds. Therefore, this systematic review and meta-analysis focused on benefit of patients with gBRCAm receiving a platinum-based chemotherapy (PtCh) compared with those treated with a non-platinum-based chemotherapy (NPtCh). The following electronic databases were searched from inception to May 12, 2018: PubMed (MEDLINE), EMBASE, and Cochrane Library. Abstracts from conferences were also reviewed for inclusion. Cohort, case-control and randomized studies of patients with PDAC and gBRCAm were eligible for inclusion if they provided data to compare patients receiving PtCh vs NPtCh. The primary endpoint was overall survival (OS) in the PtCh group vs the NPtCh group in patients with clinical stage III (locally advanced) or IV (metastatic) (CS III-IV) PDAC. Of 112 studies identified, 6 were included (total of 108 patients); of these, 4 provided sufficient data for meta-analysis. Half of the patients were males, with a mean age ranging from 58 to 63 years. The OS in the 85 patients with CS III-IV PDAC was higher in the PtCh group (23.7 vs 12.2 months; mean difference of 10.21 months, 95% confidence interval [CI] 5.05-15.37; P < 0.001; very low quality of evidence). PtCh was associated with a lower mortality (62.3 vs 87.5%; relative risk of 0.80, 95%CI 0.66-0.97; P = 0.021; very low quality of evidence). Our study confirmed the hypothesis that patients with CS III-IV gBRCAm preferably benefit from a PtCh compared with NPtCh. However the very low quality of evidence should induce to be careful about the risk of potential biases. The generated hypothesis should be prospectively investigated in homogenous clinical settings.


Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation.
Although hepatic encephalopathy (HE) is linked to the gut microbiota, stool microbiome analysis has not found differences between HE and no-HE patients. This study aimed to compare sigmoid mucosal microbiome of cirrhotic patients to controls, between HE vs. no-HE patients, and to study their linkage with cognition and inflammation. Sixty cirrhotic patients (36 HE and 24 no-HE) underwent cognitive testing, stool collection, cytokine (Th1, Th2, Th17, and innate immunity), and endotoxin analysis. Thirty-six patients (19 HE and 17 no-HE) and 17 age-matched controls underwent sigmoid biopsies. Multitag pyrosequencing (including autochthonous genera, i.e., Blautia, Roseburia, Fecalibacterium, Dorea) was performed on stool and mucosa. Stool and mucosal microbiome differences within/between groups and correlation network analyses were performed. Controls had significantly higher autochthonous and lower pathogenic genera compared with cirrhotic patients, especially HE patients. HE patients had worse MELD (model for end-stage liver disease) score and cognition and higher IL-6 and endotoxin than no-HE. Mucosal microbiota was different from stool within both HE/no-HE groups. Between HE/no-HE patients, there was no difference in stool microbiota but mucosal microbiome was different with lower Roseburia and higher Enterococcus, Veillonella, Megasphaera, and Burkholderia abundance in HE. On network analysis, autochthonous genera (Blautia, Fecalibacterium, Roseburia, and Dorea) were associated with good cognition and decreased inflammation in both HE/no-HE, whereas genera overrepresented in HE (Enterococcus, Megasphaera, and Burkholderia) were linked to poor cognition and inflammation. Sigmoid mucosal microbiome differs significantly from stool microbiome in cirrhosis. Cirrhotic, especially HE, patients' mucosal microbiota is significantly different from controls with a lack of potentially beneficial autochthonous and overgrowth of potentially pathogenic genera, which are associated with poor cognition and inflammation.


A 2.3 A resolution structure of chymosin complexed with a reduced bond inhibitor shows that the active site beta-hairpin flap is rearranged when compared with the native crystal structure.
In the crystal structure of uncomplexed native chymosin, the beta-hairpin at the active site, known as 'the flap', adopts a different conformation from that of other aspartic proteinases. This conformation would prevent the mode of binding of substrates/inhibitors generally found in other aspartic proteinase complexes. We now report the X-ray analysis of chymosin complexed with a reduced bond inhibitor CP-113972 ¿(2R,3S)-isopropyl 3-[(L-prolyl-p-iodo-L-phenylalanyl-S-methyl-cysteinyl)amino-4]-cyclohexy l-2-hydroxybutanoate¿ at 2.3 A resolution in a novel crystal form of spacegroup R32. The structure has been refined by restrained least-squares methods to a final R-factor of 0.19 for a total of 11 988 independent reflections in the resolution range 10 to 2.3 A. The extended beta-strand conformation of the inhibitor allows hydrogen bonds within the active site, while its sidechains make both electrostatic and hydrophobic interactions with residues lining the specificity pockets S4-->S1. The flap closes over the active site cleft in a way that closely resembles that of other previously determined aspartic proteinase inhibitor complexes. We conclude that the usual position and conformation of the flap found in other aspartic proteinases is available to native chymosin. The conformation observed in the native crystal form may result from intermolecular interactions between symmetry-related molecules in the crystal lattice.


Does Toxoplasma gondii infection affect cognitive function? A case control study.
According to studies, latent Toxoplasma gondii infection may affect several functions of the human brain. Here we search for the association between latent toxoplasmosis and cognitive performance. We tested 70 individuals for latent T. gondii infection. There were 26 Toxoplasma-infected subjects and 44 Toxoplasma-free subjects. Within these two groups we assessed cognitive performance using a set of standardized, widely recognized neuropsychological tests: Trail Making Test, Stroop Test, Verbal Fluency Test, Digit Span Test and N-back test. The relationship between chronic toxoplasmosis and cognitive performance was assessed, with adjustment for age and sex. Patients with latent toxoplasmosis performed worse on one neuropsychological test, N-back Test--percentage of correct answers (beta -8.08; 95% CI - 15.64 to -0.53; p < 0.05) compared to seronegative patients. However, after adjustment for age and sex, no statistically significant associations between latent toxoplasmosis and the scores on any cognitive tests were noticed. As statistically significant relationship was not observed, this study does not confirm that chronic latent T. gondii infection affects cognition.


Electrochemical Investigations of Hydrogenases and Other Enzymes That Produce and Use Solar Fuels.
Many enzymes that produce or transform small molecules such as O2, H2, and CO2 embed inorganic cofactors based on transition metals. Their active site, where the chemical reaction occurs, is buried in and protected by the protein matrix, and connected to the solvent in several ways: chains of redox cofactors mediate long-range electron transfer; static or dynamic tunnels guide the substrate, product and inhibitors; amino acids and water molecules transfer protons. The catalytic mechanism of these enzymes is therefore delocalized over the protein and involves many different steps, some of which determine the response of the enzyme under conditions of stress (extreme redox conditions, presence of inhibitors, light), the catalytic rates in the two directions of the reaction and their ratio (the "catalytic bias"). Understanding all the steps in the catalytic cycle, including those that occur on sites of the protein that are remote from the active site, requires a combination of biochemical, structural, spectroscopic, theoretical, and kinetic methods. Here we argue that kinetics should be used to the fullest extent, by extracting quantitative information from the comparison of data and kinetic models and by exploring the combination of experimental kinetics and theoretical chemistry. In studies of these catalytic mechanisms, direct electrochemistry, the technique which we use and contribute to develop, has become unescapable. It simply consists in monitoring the changes in activity of an enzyme that is wired to an electrode by recording an electric current. We have described kinetic models that can be used to make sense of these data and to learn about various aspects of the mechanism that are difficult to probe using more conventional methods: long-range electron transfer, diffusion along gas channels, redox-driven (in)activations, active site chemistry and photoreactivity under conditions of turnover. In this Account, we highlight a few results that illustrate our approach. We describe how electrochemistry can be used to monitor substrate and inhibitor diffusion along the gas channels of hydrogenases and we discuss how the kinetics of intramolecular diffusion relates to global properties such as resistance to oxygen and catalytic bias. The kinetics and/or thermodynamics of intramolecular electron transfer may also affect the catalytic bias, the catalytic potentials on either side of the equilibrium potential, and the overpotentials for catalysis (defined as the difference between the catalytic potentials and the open circuit potential). This is understood by modeling the shape of the steady-state catalytic response of the enzyme. Other determinants of the catalytic rate, such as domain motions, have been probed by examining the transient catalytic response recorded at fast scan rates. Last, we show that combining electrochemical investigations and MD, DFT, and TD-DFT calculations is an original way of probing the reactivity of the H-cluster of hydrogenase, in particular its reactions with CO, O2, and light. This approach contrasts with the usual strategy which aims at stabilizing species that are presumed to be catalytic intermediates, and determining their structure using spectroscopic or structural methods.


Modified medial minimally invasive double-plating osteosynthesis techniques for the treatment of distal third diaphyseal fracture of humerus.
The optimal surgical approach and placement of plates for the treatment of distal third diaphyseal fracture of the humerus are the subjects of debate. The aim of this retrospective study was to evaluate the clinical and radiographic outcomes of modified medial minimally invasive plate osteosynthesis (MIPO) techniques using a double technique for the treatment of distal third diaphyseal fracture of the humerus. A total of 30 patients with a distal third diaphyseal fracture of the humerus were selected from our hospital. Patients were seen between January 2017 and October 2022. They were treated with a modified medial approach combined with MIPO using a double plate technique. Patient demographics, operation time, bleeding volume, union time, complications, the mean fracture length (FL) and distal cortical length (DCL), and the number of screws in the distal fragment were analyzed. The function of the shoulder and elbow was evaluated using Neer's assessment of the shoulder and Mayo's assessment of the elbow. The FL was 56.1 ± 7.2 mm and the DCL was 38.3 ± 5.3 mm. The mean operative time was 84.8 ± 13.4 min (range 60-110 min). The mean blood loss during surgical treatment was 46.5 ± 10.2 ml (range 30-60 ml). Bone healing was observed in all patients from 10 to 16 weeks (average 12.1 ± 1.7) postoperatively, and one case with poor surgical wound healing was recorded. All the patients had good function of both the shoulder and elbow. The maximum flexibility of the elbow ranged from 130° to 145° (average 138.1 ± 4.8°), with a maximum flexibility straightness ranging from 0° to 5° (average 2.2 ± 1.3°). The Mayo elbow joint function score was 80-100 (average 91.4 ± 5.0). The Neer shoulder joint function score ranged from 85 to 100 (average 92.5 ± 3.9). The modified medial approach was beneficial it did not cause any iatrogenic radial nerve or ulnar nerve injuries. The anterior and the medial side plates are fixed perpendicular to the distal humerus and provide excellent stability at the same time producing better shoulder and elbow joint function.


A simple method to decrease surgical trauma in wire localization procedures.
Minimally invasive breast biopsies of nonpalpable lesions are used for early diagnosis and treatment of breast cancer. This report describes a simple method to decrease surgical trauma in wire localization procedures. After wire localization with mammography or ultrasound, the course of the wire in the breast was marked on the skin to guide the surgeon. As a result, fewer tissue samples were taken and smaller hematomas occurred. This method is particularly useful in deep lesions and in large breasts, leading to shortened surgery time and improved cosmetic results. This technique can be used in any wire-guided procedure.


Increased entropy production in diaphragm muscle of PPAR alpha knockout mice.
Peroxisome proliferator activated receptor alpha (PPAR alpha) regulates fatty acid beta-oxidation (FAO) and plays a central role in the metabolic and energetic homeostasis of striated muscles. The thermodynamic consequences of the absence of PPAR alpha were investigated in diaphragm muscle of PPAR alpha knockout mice (KO). Statistical mechanics provides a powerful tool for determining entropy production, which quantifies irreversible chemical processes generated by myosin molecular motors and which is the product of thermodynamic force A/T (chemical affinity A and temperature T) and thermodynamic flow (myosin crossbridge (CB) cycle velocity upsilon). The behavior of both wild type (WT) and KO diaphragm was shown to be near-equilibrium and in a stationary state, but KO was farther from equilibrium than WT. In KO diaphragm, a substantial decrease in contractile function was associated with an increase in both A/T and upsilon and with profound histological injuries such as contraction band necrosis. There were no changes in PPAR delta and gamma expression levels or myosin heavy chain (MHC) patterns. In KO diaphragm, a marked increase in entropy production (A/T x upsilon) accounted for major thermodynamic dysfunction and a dramatic increase in irreversible chemical processes during the myosin CB cycle.


[The Helium-neon laser effect on skin and oral mucosal tissue].
The biological effects of the helium-neon (He-Ne) laser on skin and oral mucosa were examined for the first time electron microscopically. Canine epidermis, gingiva and sublingual regions were subjected to treatment by the helium-neon laser with varying exposure times. The exposed tissues were excised immediately after radiation and studied with an electron microscope. Depending on the exposure times, ultrastructural alterations were observed such as cytoplasmic vesiculation and vacuolization, mitochondrial changes, dilation of the endoplasmic reticulum, the Golgi cisternae and other endomembranes of the keratinocytes. Furthermore, ultrastructural changes were seen in stromal cells, endothelial cells of the blood and lymphatic vessels, nerves, muscle cells and in the extracellular compartment of the lamina propria. The ultrastructural alterations of different cell and tissue structures following helium-neon laser radiation were compared with the effects induced by other types of lasers. The results are discussed in light of the stimulation of biological cell processes by low-energy lasers.


Collagen Linearization within Tumors.
It is now well appreciated that the tumor microenvironment (TME) surrounding primary tumors impacts tumor growth, progression (invasion and migration), and response to therapy. Broadly speaking, the TME is composed of cells (immune cells, activated fibroblasts, adipocytes, endothelial cells), acellular extracellular matrix (ECM), and cytokines or growth factors, some of which are bound or tethered to the ECM proteins. All these compartments undergo significant changes during tumor development and progression. Changes to the ECM, in particular, can dramatically influence cancer biology. This has stimulated the development of therapies that directly reverse or prevent the structural changes in the TME ECM that facilitate cancer progression. But to do so, in a rational manner, we need to understand how structural changes to tumor ECM arise, are remodeled, and function to facilitate tumor cell invasion and migration that give rise to metastatic disease, which is the main cause of cancer-related deaths. In this issue of Cancer Research, Janjanam and colleagues show that the ratio of WISP1/WISP2 in tumors is critical for ECM collagen fiber linearization and important for metastasis. WISP2 binds ECM collagen directly and can inhibit WISP1-mediated collagen linearization. These new results offer a new approach for targeting the altered collagen ECM in tumors by preventing or reversing collagen linearization.See related article by Janjanam et al., p. 5666.


Late open conversion in ruptured abdominal aortic aneurysm after endovascular repair.
Despite technological advances, the long-term outcomes of endovascular aortic aneurysm repair (EVAR) are still debatable. Although most endograft failures after EVAR can be corrected with endovascular techniques, open conversion may still be required. A 70-year-old male patient presented at the emergency unit with abdominal pain. Twice, in the third and fourth years after the first repair, a stent graft had been placed over a non-adhesive portion of the stent graft due to type Ia endoleaks. In the most recent admission, a CT scan showed type III endoleak and ruptured aneurysm sac. On this occasion the patient underwent late open conversion. The failure was repaired with total preservation of the main endovascular graft body and interposition of a bifurcated dacron graft. This case demonstrates that lifelong radiographic surveillance should be considered in this subset of patients. Late open conversion following EVAR of ruptured abdominal aortic aneurysms can be performed safely.


Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain.
Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.


Unexpected evolution of a monster case of insulin-induced skin lipohypertrophy.
In this journal, in 2020, we published the case of a 74-year-old female outpatient with type-2 diabetes mellitus who self-injected insulin four times a day according to the basal-bolus regimen, with an high glycemic variability and an high rate of severe hypoglycemic episodes. Three years before, we had found two extraordinarily large skin lipohypertrophies, with large underlying fluid collections with high insulin concentration. A long educational and intensive training completely repaired the skin lesions with the disappearance of the subcutaneous insulin reservoirs. Glycemic variability has been reduced dramatically, severe hypoglycemia has almost completely disappeared and the daily dose of insulin has been reduced by 38%. However, this extraordinary, albeit unexpected, result was achieved in five years.


The effectiveness of eugenol against cisplatin-induced ototoxicity.
Ototoxicity refers to cellular damage or function impairment developing in the inner ear in association with any therapeutic agent or chemical substance, and still represents the principal side-effect restricting the use of cisplatin. The aim of this study was to perform a biochemical, functional and histopathological investigation of the potential protective effect of eugenol against cisplatin-induced ototoxicity. The study was performed with 24 female Sprague Dawley rats. Distortion product otoacoustic emissions tests were performed on all animals, which were randomized into four equal groups. A single intraperitoneal dose of 15mg/kg cisplatin was administered to cisplatin group, while the eugenol group received 100mg/kg eugenol intraperitoneal for five consecutive days. 100mg/kg eugenol was administered to cisplatin+eugenol group for 5 days. On the third day, these rats were received a single dose of 15mg/kg cisplatin. The control group was given 8mL/kg/day intraperitoneal saline solution for five days. The distortion product otoacoustic emissions test was repeated 24h after the final drug administration. All animals were sacrificed, and the cochleas were subsequently used for biochemical and histopathological examinations. Cisplatin caused oxidative stress in the cochlea, impaired the cochlear structure and significantly reduced signal noise ratio levels. Administration of eugenol together with cisplatin reversed these effects and provided functional, biochemical and histopathological protection. The study findings represent the first indication in the literature that eugenol may protect against ototoxicity by raising levels of antioxidant enzymes and lowering those of oxidant parameters.


Does G force increase the incidence of varicocele in Air Force pilot cadets?
Air Force pilots are subjected to acceleration (G) forces with a known effect upon the vascular system. Specific training and anti-G maneuvers are used to counteract this effect, and allow pilots to operate at the limits of human endurance. The objective of the present study is to determine whether acceleration affects the incidence of varicocele. The incidence of varicocele during training in 234 Air Force pilots was assessed. Height, weight, BMI and testicular volume were recorded for every participant. A group of 35 pilots with an absence of varicocele, randomly selected, acted as the control group. Left-sided varicocele was confirmed in 23 (9.8%) pilots. Affected pilots tended to be taller (p = 0.073) and had a smaller mean left testicular volume (p < 0.001) than the control group. Eight cases (35%) were grade I, 10 (43%) were grade II, and 5 (22%) were grade III. For grades I and II, there was a trend for the testicular volume to decrease (p = 0.349 and 0.067, respectively). In grade III varicocele, this difference was statistically significant (p < 0.05). The incidence of varicocele in fighter pilots during training is not higher than in other groups of the same age. Affected individuals tend to be taller, with ipsilateral testicular hypotrophy.


[Heterologous induction of the retrotransposon Ty1: reverse transcriptase plays a key role in initiating the retrotransposition cycle].
A new method was developed to study the mechanism of initiation of the retrotransposition cycle: retrotransposons of Drosophila melanogaster, gypsy, copia, and 17.6 were expressed in yeast under the control of potent yeast promoters. Expression of retrotransposons induced formation of viruslike particles (VLPs) associated with full-length Ty1 RNA and DNA sequences. This phenomenon was termed heterologous induction. When the gene for reverse transcriptase of human immunodeficiency virus (HIV) was expressed in yeast, the same results were obtained. These data allowed us to assume the excess of active reverse transcriptase to play the central role in induction of transposition. Possible mechanisms of induction of Ty1 transposition by homologous and heterologous elements are discussed.


Comparing Eye-tracking Data of Children with High-functioning ASD, Comorbid ADHD, and of a Control Watching Social Videos.
Children with autism spectrum disorders (ASD) are known to have sensory-perceptual processing deficits that weaken their abilities to attend and perceive social stimuli in daily living contexts. Since daily social episodes consist of subtle dynamic changes in social information, any failure to attend to or process subtle human nonverbal cues, such as facial expression, postures, and gestures, might lead to inappropriate social interaction. Traditional behavioral rating scales or assessment tools based on static social scenes have limitations in capturing the moment-to-moment changes in social scenarios. An eye-tracking assessment, which can be administered in a video-based mode, is therefore preferred, to augment clinical observation. In this study, using the single-case comparison design, the eye-tracking data of three participants, a child with autism spectrum disorder (ASD), another with comorbid attention deficit-hyperactive disorder (ADHD), and a neurotypical control, are captured while they view a video of social scenarios. The eye-tracking experiment has helped answer the research question: How does social attention differ between the three participants? By predefining areas of interest (AOIs), their visual attention on relevant or irrelevant social stimuli, how fast each participant attends to the first social stimuli appearing in the videos, for how long each participant continues to attend to those stimuli within the AOIs, and the gaze shifts between multiple social stimuli appearing concurrently in the same social scene are captured, compared, and analyzed in a video-based eye-tracking experiment.


Long-Acting Injectable versus Oral Antipsychotics for Restoration of Competency to Stand Trial.
Treatment with antipsychotics is a mainstay of trial competency restoration, particularly given that most defendants deemed incompetent to stand trial have psychotic illnesses. We explored the association between competency restoration and antipsychotic type in a retrospective sample of defendants diagnosed with psychotic disorders and deemed incompetent to stand trial. Using regression models, we calculated the odds ratio of being competent to stand trial, adjusting for relevant confounders. We found that the use of long-acting injectable antipsychotics was not significantly associated with increased odds of restoration of trial competency. Our results highlight the need for larger, longitudinal studies to further explore the efficacy and tolerability of long-acting injectable drugs compared with oral antipsychotics. Future research will help develop treatment guidelines within the setting of trial competency restoration.


Efficient multiplex mutagenesis by RNA-guided Cas9 and its use in the characterization of regulatory elements in the AGAMOUS gene.
The efficiency of multiplex editing in plants by the RNA-guided Cas9 system is limited by efficient introduction of its components into the genome and by their activity. The possibility of introducing large fragment deletions by RNA-guided Cas9 tool provides the potential to study the function of any DNA region of interest in its 'endogenous' environment. Here, an RNA-guided Cas9 system was optimized to enable efficient multiplex editing in Arabidopsis thaliana. We demonstrate the flexibility of our system for knockout of multiple genes, and to generate heritable large-fragment deletions in the genome. As a proof of concept, the function of part of the second intron of the flower development gene AGAMOUS in Arabidopsis was studied by generating a Cas9-free mutant plant line in which part of this intron was removed from the genome. Further analysis revealed that deletion of this intron fragment results 40 % decrease of AGAMOUS gene expression without changing the splicing of the gene which indicates that this regulatory region functions as an activator of AGAMOUS gene expression. Our modified RNA-guided Cas9 system offers a versatile tool for the functional dissection of coding and non-coding DNA sequences in plants.


Dementia and Dependency vs. Proxy Indicators of the Active Ageing Index in Indonesia.
Dementia prevalence is increasing worldwide and developing countries are expected to carry the highest burden of this. Dementia has high care needs and no current effective long-term treatment. However, factors associated with active ageing (e.g., longer employment; participation in society; independent, healthy and secure living; and enabling environments to allow people to remain psychosocially and physically active) could help maintain independence in older people for longer. We investigated proxy indicators of the Active Ageing Index (AAI), which were offset against dementia and dependency (assessed by Instrumental Activities of Daily Living or IADL) in multi-ethnic urban (Jakarta) and rural (Sumedang and Borobudur) health care districts on Java, Indonesia. Dementia was assessed using validated cognitive dementia screening tests, the IADL and carer reports. Dementia and dependency prevalence showed large interregional differences and were highest in rural Borobudur. Dementia and dependency were associated with an older age, lower education (for dementia), worse physical health (for dependency) and not engaging in psychosocial activities, such as attending community events, reading (for dementia) and sport activities (for dependency). By supporting active ageing activities in Puskesmas (primary health care centers) and improving access to medical care, rural areas could possibly reduce dementia and dependency risk. Our follow-up study planned in 2021 should illustrate whether recent relevant policies have rendered success in these areas. Using active ageing indicators could focus policies to support regions with targeted interventions to compress care needs in older people.


Clinical Evaluation of a 3-D Automatic Annotation Method for Breast Ultrasound Imaging.
The routine clinical breast ultrasound annotation method is limited by the time it consumes, inconsistency, inaccuracy and incomplete notation. A novel 3-D automatic annotation method for breast ultrasound imaging has been developed that uses a spatial sensor to track and record conventional B-mode scanning so as to provide more objective annotation. The aim of the study described here was to test the feasibility of the automatic annotation method in clinical breast ultrasound scanning. An ultrasound scanning procedure using the new method was established. The new method and the conventional manual annotation method were compared in 46 breast cancer patients (49 ± 12 y). The time used for scanning a patient was recorded and compared for the two methods. Intra-observer and inter-observer experiments were performed, and intra-class correlation coefficients (ICCs) were calculated to analyze system reproducibility. The results revealed that the new annotation method had an average scanning time 36 s (42.9%) less than that of the conventional method. There were high correlations between the results of the two annotation methods (r = 0.933, p < 0.0001 for distance; r = 0.995, p < 0.0001 for radial angle). Intra-observer and inter-observer reproducibility was excellent, with all ICCs > 0.92. The results indicated that the 3-D automatic annotation method is reliable for clinical breast ultrasound scanning and can greatly reduce scanning time. Although large-scale clinical studies are still needed, this work verified that the new annotation method has potential to be a valuable tool in breast ultrasound examination.


Diagnostic center for primary care patients with nonspecific symptoms and suspected cancer: compliance to workflow and accuracy of tests and examinations.
To evaluate compliance to workflow and accuracy of tests in Sweden's first fast-track referral pathway for patients with nonspecific symptoms and suspected cancer (SCAN). Prospective cohort study with consecutive inclusion of patients referred to the diagnostic center (DC). Patients with nonspecific symptoms were examined in primary care according to a protocol including two test packages and diagnostic imaging. If symptoms were not explained, patients were referred to the DC and a DC-test package was taken. At the DC, further investigations resulted in diagnosis/no diagnosis. A total of 290 patients, median age 69 years (interquartile range [IQR] 59-76), 48% men, participated. A total of 64 (22%) were diagnosed with cancer, 186 (64%) with non-malignant disease and 40 (14%) had no new disease. Compliance was estimated by percentage of compulsory tests taken. Test accuracy was assessed by likelihood ratios (LRs) regarding cancer. A total of 23 (8%) patients had taken both primary care packages, whereas 150 (52%) patients went through entire diagnostic imaging. Abnormal pulmonary X-ray, peak expiratory flow (PEF) and calcium had the highest LRs in primary care (3.5; 3.2; 2.7). A total of 105 (36%) took the complete DC-package, of which bilirubin and cytomegalovirus had the highest LRs (11.5; 10.9). The median number (IQR) of abnormal primary care tests was 5 (3-6) for cancer, 3 (2-6) for other diagnoses and 1 (0-3) for no diagnosis. Compliance to test packages in primary care was low, which warrants review of the workflow. Few single tests had high accuracy regarding cancer, but the number of abnormal tests can provide guidance in complicated investigations of suspected malignancies.KEY POINTSFast-track referral pathways for patients with nonspecific serious symptoms have been implemented in several countries and are part of the national cancer strategy in all of Scandinavia.Compliance with compulsory tests in primary care was modest in this study; 8% of the patients had taken the entire compulsory test packages.Few single compulsory tests had high accuracy regarding subsequent cancer, which warrants a review of tests and examinations. However, patients diagnosed with cancer had a higher number of abnormal test results compared to the other groups.


[Severe digestive hemorrhage. Place and results of arterial embolization (author's transl)].
Arterial embolization for hemostatic purposes in digestive hemorrhage was carried out in 11 cases of acute hemorrhage and in 2 cases of chronic hemorrhage. In all cases (11) in which selective embolization was possible, immediate hemostasis was obtained. The two hemorrhagic relapses observed later were due to carcinomatous lesions. There was only one serious complication in the form of ischemic stenosis after jejunal embolization. Embolization is the method of choice in all cases in which surgery is contra-indicated. Apart from this category of patients of which the prognosis remains bad in spite of hemostasis, there are other indications in which embolization may permit in spite of a reasonable risk, transformation of emergency surgery into cold surgery with lesser mortality. Finally, in a few cases hemostasis alone and medical treatment may prove to be sufficient and avoid any further surgical operation.


Oxidative responsiveness to multiple stressors in the key Antarctic species, Adamussium colbecki: Interactions between temperature, acidification and cadmium exposure.
High-latitude marine ecosystems are ranked to be among the most sensitive regions to climate change since highly stenothermal and specially adapted organisms might be seriously affected by global warming and ocean acidification. The present investigation was aimed to provide new insights on the sensitivity to such environmental stressors in the key Antarctic species, Adamussium colbecki, focussing also on their synergistic effects with cadmium exposure, naturally abundant in this area for upwelling phenomena. Scallops were exposed for 2 weeks to various combinations of Cd (0 and 40 μgL-1), pH (8.05 and 7.60) and temperature (-1 and +1 °C). Beside Cd bioaccumulation, a wide panel of early warning biomarkers were analysed in digestive glands and gills including levels of metallothioneins, individual antioxidants and total oxyradical scavenging capacity, onset of oxidative cell damage like lipid peroxidation, lysosomal stability, DNA integrity and peroxisomal proliferation. Results indicated reciprocal interactions between multiple stressors and their elaboration by a quantitative hazard model based on the relevance and magnitude of effects, highlighted a different sensitivity of analysed tissues. Due to cellular adaptations to high basal Cd content, digestive gland appeared more tolerant toward other prooxidant stressors, but sensitive to variations of the metal. On the other hand, gills were more affected by various combinations of stressors occurring at higher temperature.


Three-dimensional macroporous gold electrodes superior to conventional gold disk electrodes in the construction of an electrochemical immunobiosensor for Staphylococcus aureus detection.
Herein, a three-dimensional macroporous gold (3DMG) electrode is demonstrated to be a better choice than a conventional gold disk electrode in the construction of an electrochemical immunobiosensor for Staphylococcus aureus (S. aureus) detection. The 3DMG electrode was prepared on a gold disk electrode by one-step electrodeposition using hydrogen bubbles as dynamic templates. The 3DMG electrode has a high electrochemically active surface area with pore sizes ranging from 20 to 50 μm, and these unique features are conducive to the immobilization of primary antibodies and the capture of S. aureus. Secondary antibodies (Ab2) and alkaline phosphatase (ALP) were immobilized on mesoporous silica nanospheres (MSNs), and the resulting ALP-MSNs-Ab2 composites were utilized as signal tags to construct a sandwich-type electrochemical immunobiosensor. S. aureus was measured based on alkaline phosphatase-catalyzed silver deposition and differential pulse voltammetric detection. The linear range is from 5 to 109 CFU mL-1, and the detection limit is 2 CFU mL-1 for S. aureus detection. Due to the signal amplification of the 3DMG electrode, the sensitivity of the immunobiosensor constructed on the 3DMG electrode is 9 times that of an immunobiosensor constructed on a gold disc electrode. The proposed biosensor was successfully applied for detecting S. aureus in milk samples.


Primary Bone Anaplastic Large Cell Lymphoma Masquerading as Ewing Sarcoma: Diagnosis by Anchored Multiplex PCR.
A 3-year-old boy presented with pathologic fracture of the left proximal femur. Magnetic resonance imaging revealed an aggressive expansile bony mass associated with cortical destruction and surrounding myositis. Computed tomography-guided biopsy revealed a monomorphic small round blue cell tumor by histology. CD99 immunoreactivity and low-level EWSR1 gene translocation by break-apart fluorescent in situ hybridization initially favored a diagnosis of Ewing sarcoma and chemotherapy commenced. Subsequent molecular evaluation by an anchored multiplex polymerase chain reaction-based assay (Archer FusionPlex Sarcoma Panel) revealed a nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) gene fusion. The diagnosis was then amended to primary bone ALK-positive anaplastic large cell lymphoma and the chemotherapy regimen was modified accordingly. This report illustrates the value of this molecular assay in establishing the correct diagnosis of a very rare malignancy masquerading as another tumor type.


Peripheral musculoskeletal manifestations in polymyalgia rheumatica.
The objectives of this study were to evaluate the frequency and characteristics of the peripheral musculoskeletal manifestations in polymyalgia rheumatica (PMR), evaluate if PMR with peripheral synovitis represents a subset with a more severe disease, and examine for clinical and laboratory characteristics at onset of PMR that might later predict rheumatoid arthritis (RA). Patients were diagnosed with PMR according to the 1982 Chuang criteria. Patients were followed up between 1990 and 2002. The following musculoskeletal manifestations at onset and during the follow up were considered: peripheral synovitis, distal extremity swelling with pitting edema, carpal tunnel syndrome, and distal tenosynovitis. Thirty-eight of the 74 patients (51%) showed distal musculoskeletal symptoms: 29 (39%) had peripheral synovitis, 4 (5%) presented pitting edema, 4 (5%) experienced carpal tunnel syndrome, and one (1.3%) had distal tenosynovitis. These manifestations resolved completely after corticosteroid therapy was initiated. Peripheral synovitis was oligoarticular and often transient. The joints most frequently involved were the wrist, metacarpophalangeal, and knee. Erythrocyte sedimentation rate (ESR) was normal in 7 patients. When comparing patients with PMR with and without peripheral synovitis, no statistically significant differences were found in the studied variables. Through the first year of follow up, 7 patients fulfilled the American College of Rheumatology 1987 criteria for RA, 2 patients developed giant cell arteritis, and 3 had associated malignancy. Patients who developed RA had statistically significantly increased presence of persistent synovitis and a smaller decrease in mean ESR after treatment with corticosteroids. Fifty-one percent of the patients with PMR presented distal musculoskeletal manifestations, with peripheral synovitis being the most frequent one. Patients with PMR with peripheral synovitis did not represent a high-risk subgroup with more severe disease. Seven patients who developed criteria for seronegative RA within the first year of follow up had presented statistically significant persistent synovitis compared with those who continued as PMR and also showed a smaller initial decrease in mean ESR after steroid treatment was initiated. The absence of persistent arthritis and the benign course of the arthritis permit the distinction of PMR from other inflammatory arthropathies.


Glutamine supplementation in a child with inherited GS deficiency improves the clinical status and partially corrects the peripheral and central amino acid imbalance.
Glutamine synthetase (GS) is ubiquitously expressed in mammalian organisms and is a key enzyme in nitrogen metabolism. It is the only known enzyme capable of synthesising glutamine, an amino acid with many critical roles in the human organism. A defect in GLUL, encoding for GS, leads to congenital systemic glutamine deficiency and has been described in three patients with epileptic encephalopathy. There is no established treatment for this condition.Here, we describe a therapeutic trial consisting of enteral and parenteral glutamine supplementation in a four year old patient with GS deficiency. The patient received increasing doses of glutamine up to 1020 mg/kg/day. The effect of this glutamine supplementation was monitored clinically, biochemically, and by studies of the electroencephalogram (EEG) as well as by brain magnetic resonance imaging and spectroscopy.Treatment was well tolerated and clinical monitoring showed improved alertness. Concentrations of plasma glutamine normalized while levels in cerebrospinal fluid increased but remained below the lower reference range. The EEG showed clear improvement and spectroscopy revealed increasing concentrations of glutamine and glutamate in brain tissue. Concomitantly, there was no worsening of pre-existing chronic hyperammonemia.In conclusion, supplementation of glutamine is a safe therapeutic option for inherited GS deficiency since it corrects the peripheral biochemical phenotype and partially also improves the central biochemical phenotype. There was some clinical improvement but the patient had a long standing severe encephalopathy. Earlier supplementation with glutamine might have prevented some of the neuronal damage.


The Guttman errors as a tool for response shift detection at subgroup and item levels.
Statistical methods for identifying response shift (RS) at the individual level could be of great practical value in interpreting change in PRO data. Guttman errors (GE) may help to identify discrepancies in respondent's answers to items compared to an expected response pattern and to identify subgroups of patients that are more likely to present response shift. This study explores the benefits of using a GE-based method for RS detection at the subgroup and item levels. The analysis was performed on the SatisQoL study. The number of GE was determined for each individual at each time of measurement (at baseline T0 and 6 months after discharge M6). Individuals showing discrepancies (with many GE) were suspected to interpret the items differently from the majority of the sample. Patients having a large number of GE at M6 only and not at T0 were assumed to present RS. Patients having a small number of GE at T0 and M6 were assumed to present no RS. The RespOnse Shift ALgorithm in Item response theory (ROSALI) was then applied on the whole sample and on both groups. Different types of RS (non-uniform recalibration, reprioritization) were more prevalent in the group composed of patients assumed to present RS based on GE. On the opposite, no RS was detected on patients having few GE. Guttman errors and item response theory models seem to be relevant tools to discriminate individuals affected by RS from the others at the item level.


MicroRNAs as Potential Biomarkers of Environmental Exposure to Polycyclic Aromatic Hydrocarbons and Their Link with Inflammation and Lung Cancer.
Exposure to atmospheric air pollution containing volatile organic compounds such as polycyclic aromatic hydrocarbons (PAHs) has been shown to be a risk factor in the induction of lung inflammation and the initiation and progression of lung cancer. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules of ~20-22 nucleotides that regulate different physiological processes, and their altered expression is implicated in various pathophysiological conditions. Recent studies have shown that the regulation of gene expression of miRNAs can be affected in diseases associated with outdoor air pollution, meaning they could also be useful as biomarkers of exposure to environmental pollution. In this article, we review the published evidence on miRNAs in relation to exposure to PAH pollution and discuss the possible mechanisms that may link these compounds with the expression of miRNAs.


Exploration of an Integrated Active Learning Strategy to Balance Student Workload in a Mixed Level Research Methods Course.
This article was migrated. The article was marked as recommended. Team Base Learning (TBL) and Process Oriented Guided Inquiry Learning (POGIL) are two very distinct active learning and teaching pedagogies, both of which focus on team interactions to facilitate learning. TBL and POGIL literature have both been remiss in addressing their applicability in solving workload imbalance within the team paradigms respective of their individual pedagogy. In this study, we merged integral components of both TBL and POGIL teaching strategies to address perceived imbalance in student workload that were revealed through analysis of initial course evaluations from a mixed level (masters and doctoral level students) Research Methods course. As a result of findings from analyses of initial course evaluations, teams were established based on the integration of TBL and POGIL components in the subsequent course offering.


Diffuse optical tomography & spectroscopy in breast cancer characterization & therapy monitoring at UPENN.
In this paper, I will provide a broad review of breast cancer research conducted at the University of Pennsylvania and collaborative work with other institution. Our group led by Dr. Arjun G. Yodh has been actively exploring functional and physiological information available via the diffuse optical technique and investigate its use in the area of in vivo breast cancer detection, diagnosis, and therapy monitoring. In particular, the recent advances in malignant and benign lesion differentiation from 3D diffuse optical tomography, 3D fluorescence diffuse optical tomography using Indocyanine Green injection, and neoadjuvant chemotherapy monitoring with diffuse correlation spectroscopy will be presented.