Water-flow variation and pharmacoepidemiology of tetracycline hydrochloride administration via drinking water in swine finishing farms.
To evaluate variation of drinking-water flow rates in swine finishing barns and the relationship between drinker flow rate and plasma tetracycline concentrations in pigs housed in different pens. Cross-sectional (phase 1) and cohort (phase 2) studies. 13 swine finishing farms (100 barns with 7,122 drinkers) in phase 1 and 100 finishing-stage pigs on 2 finishing farms (1 barn/farm) in phase 2. In phase 1, farms were evaluated for water-flow variation, taking into account the following variables: position of drinkers within the barn, type of drinker (swing or mounted), pig medication status, existence of designated sick pen, and existence of leakage from the waterline. In phase 2, blood samples were collected from 50 pigs/barn (40 healthy and 10 sick pigs) in 2 farms at 0, 4, 8, 24, 48, and 72 hours after initiation of water-administered tetracycline HCl (estimated dosage, 22 mg/kg [10 mg/lb]). Plasma tetracycline concentrations were measured via ultraperformance liquid chromatography. Mean farm drinker flow rates ranged from 1.44 to 2.77 L/min. Significant differences in flow rates existed according to drinker type and whether tetracycline was included in the water. Mean drinker flow rates and plasma tetracycline concentrations were significantly different between the 2 farms but were not different between healthy and sick pigs. The plasma tetracycline concentrations were typically < 0.3 microg/mL. Many factors affected drinker flow rates and therefore the amount of medication pigs might have received. Medication of pigs with tetracycline through water as performed in this study had questionable therapeutic value.


Is polycystic ovary syndrome associated with high sympathetic nerve activity and size at birth?
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disturbance among women of reproductive age and is proposed to be linked with size at birth and increased prevalence of cardiovascular disease. A disturbance in the sympathetic nervous system may contribute to the etiology of PCOS. This study evaluates sympathetic outflow in PCOS and its relation to size at birth. Directly recorded sympathetic nerve activity to the muscle vascular bed (MSNA) was obtained in 20 women with PCOS and in 18 matched controls. Ovarian ultrasonographic evaluation, biometric, hormonal, and biochemical parameters were measured, and birth data were collected. Women with PCOS had increased MSNA (30 +/- 8 vs. 20 +/- 7 burst frequency, P < 0.0005) compared with controls. MSNA was positively related to testosterone (r = 0.63, P < 0.005) and cholesterol (r = 0.55, P = 0.01) levels in PCOS, which, in turn, were not related to each other. Testosterone level was a stronger predictor of MSNA than cholesterol. Birth size did not differ between the study groups. This is the first study to directly address sympathetic nerve activity in women with PCOS and shows that PCOS is associated with high MSNA. Testosterone and cholesterol levels are identified as independent predictors of MSNA in PCOS, although testosterone has a stronger impact. The increased MSNA in PCOS may contribute to the increased cardiovascular risk and etiology of the condition. In this study, PCOS was not related to size at birth.


Abdominal Pain: A Real Challenge in Novel COVID-19 Infection.
COVID-19 (coronavirus disease 19) is an infectious disease caused by coronavirus 2019-nCoV. Since its detection in China at the end of 2019, the novel coronavirus has rapidly spread throughout the world and has caused an international public health emergency. The most common manifestation is flu-like symptoms. Mild infections usually improve within a few days, but COVID-19 can cause severe pneumonia with acute respiratory distress syndrome and death. Gastrointestinal symptoms are less common but possible and more difficult to recognize as part of a COVID-19 syndrome. In line with the current opinion of the WHO, we strongly believe that preventive measures and early diagnosis of COVID-19 are crucial to interrupt virus spread and avoid local outbreaks. We report the cases of COVID-19 patients admitted to our Emergency Department who complained of gastrointestinal symptoms at admission. The novel COVID-19 infection is a severe public health problem which is causing an increasing number of deaths worldwide.Although uncommon, there may be a relationship between gastrointestinal symptoms and COVID-19, as reported in recent studies.Early detection and isolation of patients with COVID-19 infection is the only way to control and limit the global spread of this virus.


Development of subliminal persuasion system to improve the upper limb posture in laparoscopic training: a preliminary study.
Current training for laparoscopy focuses only on the enhancement of manual skill and does not give advice on improving trainees' posture. However, a poor posture can result in increased static muscle loading, faster fatigue, and impaired psychomotor task performance. In this paper, the authors propose a method, named subliminal persuasion, which gives the trainee real-time advice for correcting the upper limb posture during laparoscopic training like the expert but leads to a lower increment in the workload. A 9-axis inertial measurement unit was used to compute the upper limb posture, and a Detection Reaction Time device was developed and used to measure the workload. A monitor displayed not only images from laparoscope, but also a visual stimulus, a transparent red cross superimposed to the laparoscopic images, when the trainee had incorrect upper limb posture. One group was exposed, when their posture was not correct during training, to a short (about 33 ms) subliminal visual stimulus. The control group instead was exposed to longer (about 660 ms) supraliminal visual stimuli. We found that subliminal visual stimulation is a valid method to improve trainees' upper limb posture during laparoscopic training. Moreover, the additional workload required for subconscious processing of subliminal visual stimuli is less than the one required for supraliminal visual stimuli, which is processed instead at the conscious level. We propose subliminal persuasion as a method to give subconscious real-time stimuli to improve upper limb posture during laparoscopic training. Its effectiveness and efficiency were confirmed against supraliminal stimuli transmitted at the conscious level: Subliminal persuasion improved upper limb posture of trainees, with a smaller increase on the overall workload.


Lethal mutations and genomic instability.
The delayed expression of cell death in progeny of irradiated survivors was christened 'lethal mutations' by Tikvah Alper in 1984. The effect occurs when clones, or populations of cells grown up from irradiated progenitor cells, are replated and reassessed for cloning efficiency or population doubling time. The effect has been shown to be associated with the low dose shoulder region of the survival curve and is due to events occurring in the first two hours post irradiation, i.e. the 'fast repair' period. In this review the lethal mutation data accumulated over the past ten years is discussed in relation to our modern understanding of cellular and molecular events in radiation carcinogenesis and genomic instability research. It is suggested that lethal mutations are associated with a general epigenetic or field effect occurring in all irradiated cells, which makes them more prone to mutations, some of which are lethal. The implications of this for our current approach to risk estimates and therapeutic dose calculation, need to be addressed.


Retrospective analysis of youth evaluated for suicide attempt or suicidal ideation in an emergency room setting.
Suicide is the third leading cause of death in adolescents and a major contributor to morbidity in this age group. The objective of this study was to look at the demographics, major stressors and factors leading to attempting suicide as well as the methods of attempted suicide in adolescents admitted to two hospitals in a medium size city. Medical records were reviewed of adolescents admitted to two area hospitals for attempted suicide between 7/1/97-12/31/99. Coroner's data on completed suicide were also reviewed. In the study period a total of 287 persons aged 21 years or under were admitted for attempted suicide. Mean age was 16.9 years (range 7-21). 53.4% of the total were females and 46.6 were males with the majority of the total being Caucasians (75.6%). Interpersonal conflicts were the most common stressors preceding the attempt; fight with parents 20%, end of a relationship 12%, fight with a significant other 8%. Financial difficulties were the culprit in 10% of the cases. Abuse was not clearly recorded in 64% of cases. In cases where documentation was clear, 60% reported sexual and 67% physical abuse. Nearly half of the patients had a prior psychiatric diagnosis with prior suicide attempt and depression being most common at 27 and 18% respectively. Overdose was the most common method utilized. There were 20 completed adolescent suicides in the area with firearms as the method used in all of them. It is concluded that suicide continues to be a major problem in adolescents. Access to guns may be a detrimental factor in completing suicide. Health care providers may help identify those at risk by routinely screening all adolescents for depression and suicide.


Counselling patients for return to work on immunosuppression: practices of Canadian specialists during the COVID-19 pandemic.
The COVID-19 pandemic has infected over 870,000 Canadians and caused 22,000 deaths. Many patients are attempting to balance health and financial stability. Therefore, we sought to determine how physicians who frequently prescribe immunosuppressive medications are counselling patients on return-to-work prior to widespread vaccine distribution and understand their decision processes. We administered a survey through the Canadian Rheumatology, Gastroenterology and Dermatology Associations. Physicians were asked whether patients have requested counselling on return-to-work during the pandemic and how they decide what advice to provide. They were shown seven clinical scenarios of patients on immunosuppressive medications, then asked whether they would provide a medical note advocating for delayed return-to-work or modified duties to reduce exposure. 151 physicians took the survey. 94% were asked for advice on return-to-work. 33% felt informed enough to provide counselling. When patients requested a medical note, physicians provided one 25% of the time. Factors most associated with providing notes were patient comorbidities, age, glucocorticoids, high risk work and vulnerable co-inhabitants. Conventional synthetic and biologic immunosuppressants did not prompt most physicians to provide a note. Respondents considered patient perspectives and workplace factors. Several requested guidelines to approach these encounters. Almost all rheumatologists, dermatologists and gastroenterologists have been asked to counsel patients on returning to work during the COVID-19 pandemic. Most do not feel informed enough to do so. Medical notes for accommodations are only provided a minority of the time, unless specific factors (e.g. glucocorticoids) are present. Guidance is needed to inform these decisions.


Probing binding sites and mechanisms of action of an I(Ks) activator by computations and experiments.
The slow delayed rectifier (IKs) channel is composed of the KCNQ1 channel and KCNE1 auxiliary subunit, and functions to repolarize action potentials in the human heart. IKs activators may provide therapeutic efficacy for treating long QT syndromes. Here, we show that a new KCNQ1 activator, ML277, can enhance IKs amplitude in adult guinea pig and canine ventricular myocytes. We probe its binding site and mechanism of action by computational analysis based on our recently reported KCNQ1 and KCNQ1/KCNE1 3D models, followed by experimental validation. Results from a pocket analysis and docking exercise suggest that ML277 binds to a side pocket in KCNQ1 and the KCNE1-free side pocket of KCNQ1/KCNE1. Molecular-dynamics (MD) simulations based on the most favorable channel/ML277 docking configurations reveal a well-defined ML277 binding space surrounded by the S2-S3 loop and S4-S5 helix on the intracellular side, and by S4-S6 transmembrane helices on the lateral sides. A detailed analysis of MD trajectories suggests two mechanisms of ML277 action. First, ML277 restricts the conformational dynamics of the KCNQ1 pore, optimizing K(+) ion coordination in the selectivity filter and increasing current amplitudes. Second, ML277 binding induces global motions in the channel, including regions critical for KCNQ1 gating transitions. We conclude that ML277 activates IKs by binding to an intersubunit space and allosterically influencing pore conductance and gating transitions. KCNE1 association protects KCNQ1 from an arrhythmogenic (constitutive current-inducing) effect of ML277, but does not preclude its current-enhancing effect.


Antibody responses of red wolves to canine distemper virus and canine parvovirus vaccination.
Twenty captive red wolves (Canis rufus), including 16 intended for release into Great Smoky Mountains National Park, Cades Cove, Tennessee (USA), and four housed at Knoxville Zoological Gardens, Inc., Knoxville, Tennessee, were evaluated for immunologic response to vaccination between June 1994 and April 1995. Wolves were vaccinated with modified-live (MLV) canine distemper virus (CDV) and canine parvovirus type-2 (CPV2). Sera were collected, and immunofluorescent staining was performed for determination of immunoglobulin titers (CDV IgM, CDV IgG, and CPV2 IgG). A capture enzyme-linked immunosorbent assay was performed for validation purposes, to confirm the reactivity of our standard diagnostic reagents with red wolf serum. All wolves produced a measurable antibody response to CDV and CPV2 vaccination. Titers against CDV and CPV2 varied widely among individual wolves, but between-litter differences in mean titers were not significant. No consistent response between the degree of response to CDV versus CPV2 vaccination was observed in individual wolves. No differences were seen between IgG responses of pups vaccinated with univalent vaccines given concurrently or during alternating weeks. Pups had an IgG response to CDV and CPV2 vaccination as early as 9 wk of age. Mean post-vaccination IgG titers against CDV were at or above the level normally measured in vaccinated domestic dogs. Mean post-vaccination IgG titers against CPV2 were below the level normally measured in domestic dogs. Adult previously-vaccinated wolves had measurable CDV and CPV2 IgG titers more than 1 yr after vaccination, but did not have significant IgG titer increases after revaccination. We conclude that red wolves are capable of producing an antibody response after vaccination with commercial canine products but that their response to CPV2 vaccination was minimal. This response can be assayed using tests developed for domestic dogs.


mTORC1 regulates the efficiency and cellular capacity for protein synthesis.
mTORC1 (mammalian target of rapamycin complex 1) is activated by nutrients, growth factors and certain hormones. Signalling downstream of mTORC1 promotes protein synthesis by both activating the processes of translation initiation and elongation, in the short term, and the production of new ribosomes, in the longer term. mTORC1 signalling stimulates the translation of the mRNAs encoding the ribosomal proteins, activates RNA polymerases I and III, which make the rRNAs, and promotes the processing of the precursor for the main rRNAs. Taken together, these effects allow mTORC1 signalling to drive cell growth and proliferation.


Long-term sustained autoimmune response to beta cell specific zinc transporter (ZnT8, W, R, Q) in young adult patients with preserved beta cell function at diagnosis of diabetes.
The aim of this study was to examine whether autoantibodies to: ZnT8-Tryptophan (ZnT8WA), ZnT8-Arginine (ZnT8RA) or ZnT8-Glutamine (ZnT8QA) correlated with C-peptide or other autoantibodies and to assess diagnostic sensitivity of ZnT8WRQA. Specimens from 270 newly diagnosed diabetic subjects (age 15-34 years) and after 5 years duration of disease were examined. Four linear regression models were used to dissect the importance of different factors from diagnosis for the respective difference of (logZnT8WA), (logZnT8RA) and (logZnT8QA); A) unadjusted model for: initial C-peptide, age, BMI, gender, clinical classification, ICA, GADA, IA-2A, (ZnT8WA/ZnT8RA/ZnT8QA); B) C-peptide corrected for clinical factors; C) C-peptide corrected for autoantibodies; D) C-peptide corrected for all factors. The least decrease of ZnT8WA was observed in patients with high initial C-peptide in all models A) p = 0.054; B) p = 0.021; C) p = 0.047 and D) p = 0.017. A less statistically significant decrease of ZnT8RA was observed in patients with high initial C-peptide in A) p = 0.038 and C) p = 0.047, but this finding was not confirmed in B or D. The decrease of ZnT8QA levels was not related to C-peptide in any model but correlated to age D) p = 0.049. Furthermore, patients with unclassifiable diabetes showed the least decrease in D) p = 0.035. ZnT8WA, ZnT8RA or ZnT8QA were identified as a single autoantibody in 3.8% (10/266) of patients, thereby increasing diagnostic sensitivity from 79.3% (211/266) to 83.1% (221/266). In conclusion, high initial C-peptide was the most important factor even after adjusting for other factors in patients positive for ZnT8WA or ZnT8RA to remain autoantibody positive 5 years after diagnosis.


The intrauterine origins of Hodgkin's lymphoma.
Both small and large body size at birth are now known to predict a range of chronic disorders in adult life, including certain cancers. These associations are thought to reflect "fetal programming." This may lead to impairment of a small number of key systems including the immune system. Hodgkin's lymphoma is a disease of the immune system. We have therefore examined the association between Hodgkin's lymphoma and early development. Our hypothesis was that the disease would be associated with markers of poor fetal growth, specifically small body size or small placental size at birth. Using the Finnish Cancer Registry we identified patients with Hodgkin's disease in a cohort of 20,431 people born in Helsinki during 1924-44. Each person has a detailed birth record. There were 12 patients with Hodgkin's disease, giving an incidence comparable to international rates. The disease was associated with prolonged gestation. For every additional week of gestation the hazard ratio was 1.37 (95% CI 1.00-1.87; p = 0.05). The disease was also associated with a short placental surface. After allowing for gestation, for each centimetre increase in surface length, the hazard ratio was 0.70 (0.53-0.92; p = 0.01). The disease was not associated with birth weight or length or maternal body size. We have shown that Hodgkin's lymphoma is associated with prolonged gestation and a short length of the placental surface. We speculate that Hodgkin's lymphoma is initiated by two events in fetal life. One, which is an immune event, is associated with prolonged gestation, while the other is associated with growth faltering.


Small molecule R1498 as a well-tolerated and orally active kinase inhibitor for hepatocellular carcinoma and gastric cancer treatment via targeting angiogenesis and mitosis pathways.
Protein kinases play important roles in tumor development and progression. Lots of kinase inhibitors have entered into market and show promising clinical benefits. Here we report the discovery of a novel small molecule, well-tolerated, orally active kinase inhibitor, R1498, majorly targeting both angiogenic and mitotic pathways for the treatment of hepatocellular carcinoma (HCC) and gastric cancer (GC). A series of biochemical and cell-based assays indicated that the target kinase cluster of R1498 included Aurora kinases and VEGFR2 et al. R1498 showed moderate in vitro growth inhibition on a panel of tumor cells with IC50 of micromole range. The in vivo anti-tumor efficacy of R1498 was evaluated on a panel of GC and HCC xenografts in a parallel comparison with another multikinase inhibitor sorafenib. R1498 demonstrated superior efficacy and toxicity profile over sorafenib in all test models with >80% tumor growth inhibition and tumor regression in some xenogratfts. The therapeutic potential of R1498 was also highlighted by its efficacy on three human GC primary tumor derived xenograft models with 10-30% tumor regression rate. R1498 was shown to actively inhibit the Aurora A activity in vivo, and decrease the vascularization in tumors. Furthermore, R1498 presented good in vivo exposure and therapeutic window in the pharmacokinetic and dose range finding studies. Theses evidences indicate that R1498 is a potent, well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic and antiproliferative profile, and provide strong confidence for further development for HCC and GC therapy.


Use of diagnostic tests and the appropriateness of the treatment decision in patients with suspected urinary tract infection in primary care in Denmark - observational study.
Inappropriate prescription of antibiotics is the leading driver of antimicrobial resistance (AMR). The majority of antibiotics are prescribed in primary care. Understanding how general practitioners (GPs) use diagnostic tests and the effect on treatment decision under daily practice conditions is important to reduce inappropriate prescription of antibiotics. The aim of the study was to investigate the use of diagnostic tests in primary care patients with suspected urinary tract infection (UTI) and to assess the appropriateness of the treatment decision (TD) under daily practice conditions in Denmark. Prospective observational study. Symptomatic adult patients consulting general practice with suspected UTI recruited over 12 months. The diagnostic workup was registered in a standardized form. The appropriateness of the TD was assessed based on the results of a culture performed at a reference microbiological laboratory. TD was considered appropriate if a patient had a positive culture and was prescribed antibiotics or had a negative culture and was not prescribed antibiotics. TD was considered inappropriate if a patient had a negative culture and was prescribed antibiotics (overtreatment) or had a positive culture and was not prescribed antibiotics (undertreatment). Four hundred and eighty-eight patients were included. Dipstick was used in 98% of the patients and urine culture was used in 89% of the patients; 317 had the culture performed in practice and 117 had the culture performed at the hospital. The appropriateness of the final TD was significantly (p = 0.04) lower in patients without culture (55%) than in patients with culture performed in practice (71%) or at hospital (69%). In a context with wide availability of diagnostic tests, GPs use diagnostic tests for the decision-making process in all patients with suspected UTI. Urine culture is used in the majority of the patients and is associated with a higher proportion of appropriate treatment decisions. Performance of urine culture is therefore important in reducing inappropriate antibiotic prescribing in patients with suspected UTI seeking care in general practice in Denmark. ClinicalTrials.gov NCT02249273 .


Chemokine expression in myocardial ischemia: MIP-2 dependent MCP-1 expression protects cardiomyocytes from cell death.
Chemokines are small molecular weight proteins that play important roles in inflammation. Originally described as chemotactic cytokines, chemokines stimulate the influx of leukocytes into specific tissue compartments. These molecules also modulate gene expression in both infiltrating and resident cells to mediate a vast array of cellular functions, and their importance in disease processes has been well documented. This study examined the expression of chemokines during myocardial ischemia and established a pathway by which two, MIP-2 and JE/MCP-1, modulate cardiac myocyte viability during this process. To focus on the direct effects of chemokines on these cells, a mouse model of ischemia without reperfusion was used. The expression of chemokines and chemokine receptors was induced in the left ventricular free wall as early as 1 h post-ischemia, with the most significant increases in MIP-2 (CXCL2) and JE/MCP-1 (CCL2). Expression of their respective receptors, CXCR2 and CCR2, was also induced. Similar changes in gene expression occurred at the mRNA and protein levels in isolated neonatal mouse cardiac myocytes stimulated by hypoxia. Antibody to MIP-2 inhibited hypoxia-induced JE/MCP-1 expression, demonstrating that MIP-2 is critical for this event. Moreover, in vivo intramyocardial injection of either an adenovirus expressing MIP-2 or the recombinant protein itself was sufficient to upregulate JE/MCP-1 production even in the absence of ischemia. Thus, MIP-2 regulates JE/MCP-1 expression both in cell culture and in vivo. Furthermore, JE/MCP-1 markedly decreased hypoxia-induced cell death in cultured cardiac myocytes. Thus, JE/MCP-1 appears to mediate an unanticipated survival pathway in target cardiac myocytes themselves. These findings indicate an important role for MIP-2 and JE/MCP-1 in regulating the response of cardiac myocytes to myocardial ischemia.


Dramatic increase in HIV prevalence after scale-up of antiretroviral treatment.
To investigate HIV prevalence trends in a rural South African community after the scale-up of antiretroviral treatment (ART) in 2004. We estimated adult HIV prevalence (ages 15-49 years) using data from a large, longitudinal, population-based HIV surveillance in rural KwaZulu-Natal, South Africa, over the period from 2004 (the year when the public-sector ART scale-up started) to 2011. We control for selection effects due to surveillance nonparticipation using multiple imputation. We further linked the surveillance data to patient records from the local HIV treatment program to estimate ART coverage. ART coverage of all HIV-infected people in this community increased from 0% in 2004 to 31% in 2011. Over the same observation period adult HIV prevalence increased steadily from 21 to 29%. The change in overall HIV prevalence is nearly completely explained by an increase of HIV-infected people receiving ART, and it is largely driven by increases in HIV prevalence in women and men older than 24 years. The observed dramatic increase in adult HIV prevalence can most likely be explained by increased survival of HIV-infected people due to ART. Future studies should decompose HIV prevalence trends into HIV incidence and HIV-specific mortality changes to further improve the causal attribution of prevalence increases to treatment success rather than prevention failure.


Predicting microbial protein synthesis in beef cattle: relationship to intakes of total digestible nutrients and crude protein.
Prediction of microbial CP (MCP) synthesis in the rumen is an integral part of the MP system. For the NRC beef model, MCP is calculated as 0.13 multiplied by TDN intake (TDNI), with adjustment for physically effective NDF (peNDF) concentrations less than 20%. Despite its application for nearly 2 decades, MCP predictions using this approach have not been extensively evaluated. We assembled a database of 285 treatment means from 66 published papers using beef cattle and dairy or dairy × beef crossbred steers, fed diets with a wide range of TDN, CP, and ether extract (EE) concentrations, in which MCP synthesis was measured. Fat-free TDN (FFTDN) concentration was calculated by subtracting 2.25 × percent EE from the TDN concentration. Based on initial model selection procedures indicating that DMI and concentrations of TDN, FFTDN, and CP were significantly (P < 0.04) related to MCP synthesis, linear and quadratic effects of TDNI and FFTDN intake (FFTDNI) and CP intake (CPI) were considered as potential independent variables. Mixed model regression methods were used to fit 1-, 2-, and 3-independent-variable models based on either TDNI or FFTDNI (e.g., TDNI only, TDNI and CPI, and TDNI, CPI, and the quadratic effect of TDNI; or FFTDNI only, FFTDNI and CPI, and FFTDNI, CPI, and the quadratic effect of FFTDNI). True ruminal OM digested (TROMD; g/d) was highly related (r(2) = 0.84 using citation-adjusted data) to MCP synthesis. Similarly, both TDNI and FFTDNI were highly related to citation-adjusted TROMD (r(2) > 0.96) and MCP synthesis (r(2) > 0.89). Models with FFTDNI were slightly more precise with slightly smaller prediction errors than those with TDNI. Randomly dividing the citations into Development (60%) and Evaluation (40%) data sets indicated that models such as those derived from the overall database accounted for 46 to 56% of the variation in MCP synthesis, with neither mean nor linear bias (P ≥ 0.26). In contrast, calculating MCP as 0.13 × TDNI, with or without adjustment for peNDF concentration, resulted in overprediction of MCP (P < 0.001 for both mean and linear bias). Cross-validation using 5,000 randomly drawn training and testing data sets yielded results similar to the Development/Evaluation approach. Recommended equations are provided, but the errors of prediction associated with these empirical regression equations were on the order of 25 to 30% of the mean MCP.


Axotomized neonatal motoneurons overexpressing the bcl2 proto-oncogene retain functional electrophysiological properties.
Bcl2 overexpression prevents axotomy-induced neuronal death of neonatal facial motoneurons, as defined by morphological criteria. However, the functional properties of these surviving lesioned transgenic neurons are unknown. Using transgenic mice overexpressing the protein Bcl2, we have investigated the bioelectrical properties of transgenic facial motoneurons from 7 to 20 days after neonatal unilateral axotomy using brain-stem slices and whole cell patch-clamp recording. Nonaxotomized facial motoneurons from wild-type and transgenic mice had similar properties; they had an input resistance of 38 +/- 6 M omega and fired repetitively after injection of positive current pulses. When cells were voltage-clamped at or near their resting membrane potential, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartic acid (NMDA), or vasopressin generated sustained inward currents. In transgenic axotomized mice, facial motoneurons could be found located ipsilaterally to the lesion; they had an input resistance of 150 +/- 30 M omega, indicating that they were smaller in size, fired repetitively, and were also responsive to AMPA, NMDA, and vasopressin. Morphological measurements achieved 1 week after the lesion have shown that application of brain-derived neurotrophic factor prevented the reduction in size of axotomized transgenic motoneurons. These data indicate that Bcl2 not only prevents morphological apoptotic death of axotomized neonatal transgenic motoneurons but also permits motoneurons to conserve functional electrophysiological properties.


Novel sequences of subgroup J avian leukosis viruses associated with hemangioma in Chinese layer hens.
Avian leukosis virus subgroup J (ALV-J) preferentially induces myeloid leukosis (ML) in meat-type birds. Since 2008, many clinical cases of hemangioma rather than ML have frequently been reported in association with ALV-J infection in Chinese layer flocks. Three ALV-J strains associated with hemangioma were isolated and their proviral genomic sequences were determined. The three isolates, JL093-1, SD09DP03 and HLJ09MDJ-1, were 7,670, 7,670, and 7,633 nt in length. Their gag and pol genes were well conserved, with identities of 94.5-98.6% and 97.1-99.5%, respectively, with other ALV-J strains at the amino acid level (aa), while the env genes of the three isolates shared a higher aa identity with the env genes of other hemangioma strains than with those of ML strains. Interestingly, two novel 19-bp insertions in the U3 region in the LTR and 5' UTR, most likely derived from other retroviruses, were found in all the three isolates, thereby separately introducing one E2BP binding site in the U3 region in the LTR and RNA polymerase II transcription factor IIB and core promoter motif ten elements in the 5' UTR. Meanwhile, two binding sites in the U3 LTRs of the three isolates for NFAP-1 and AIB REP1 were lost, and a 1-base deletion in the E element of the 3' UTR of JL093-1 and SD09DP03 introduced a binding site for c-Ets-1. In addition to the changes listed above, the rTM of the 3' UTR was deleted in each of the three isolates. Our study is the first to discovery the coexistence of two novel insertions in the U3 region in the LTR and the 5' UTR of ALV-J associated with hemangioma symptoms, and the transcriptional regulatory elements introduced should be taken into consideration in the occurrence of hemangioma.


Midterm outcomes in patients undergoing endovascular repair of thoracic aortic aneurysms and penetrating atherosclerotic ulcers using the RelayPlus stent graft.
The Relay Thoracic Stent-Graft with Plus Delivery System (RelayPlus; Terumo Aortic, Sunrise, Fla) was designed to handle the curvature and tortuosity of the thoracic aorta. It was approved by the Food and Drug Administration in 2012; the postapproval study was stopped early because of adequate safety and efficacy data, and no difference was identified in experienced vs first-time users of RelayPlus. The purpose of this study was to report real-world outcomes of patients with thoracic aortic aneurysms and penetrating atherosclerotic ulcers (PAUs) undergoing thoracic endovascular aortic repair (TEVAR) with RelayPlus. This is a prospective, multicenter, nonrandomized postapproval study that required the use of novice implanters in the United States. Primary and secondary end points included device-related adverse events (deployment failure, conversion to open repair, endoleaks, migration, rupture, and mortality) and major adverse events (stroke, paraplegia/paraparesis, renal failure, respiratory failure, and myocardial infarction), respectively. Continuous and categorical covariates were reported in means or medians and percentages, respectively. Kaplan-Meier survival estimates were used to report long-term TEVAR-related mortality, all-cause mortality, and reinterventions at 3 years. A total of 45 patients with mean age (standard deviation [SD]) of 73.5 (±7.20) years were treated for descending thoracic fusiform aneurysm (56%) or saccular aneurysm/PAU (44%). The patients were predominantly white (80.0%) and male (68.9%). Mean (SD) proximal neck, distal neck, and lesion lengths were 38.2 (±37) mm, 42.1 (±28) mm, and 103.8 (±74) mm, respectively. Mean (SD) aneurysm, proximal neck, and distal neck diameters were 53.9 (±13) mm, 31.3 (±4) mm, and 31.7 (±6) mm, respectively. Technical success was 100%. TEVAR-related mortality at 30 days was 4.4%; two patients died postoperatively, one of shock and the second of bilateral hemispheric stroke. No patient in the study had any conversion to open repair or post-TEVAR rupture. Two patients experienced three major adverse events, which included stroke (2.2%), paraplegia (2.2%), and respiratory failure (2.2%) at 30 days. Three-year freedom from TEVAR-related mortality, all-cause mortality, and reinterventions was 95.6%, 84.0%, and 97.2%, respectively. There were two type I endoleaks at 3 years: one type IB associated with no migration or aneurysm sac increase and one type IA associated with caudal migration of proximal neck and expansion of the proximal aorta. The RelayPlus postapproval study reported low operative mortality and morbidity and supported use of the device as a safe and effective thoracic aortic aneurysm and PAU endovascular treatment. Early midterm follow-up showed sustained freedom from TEVAR-related mortality in real-world practice. Follow-up continues to evaluate the durability of this endograft.


A randomized trial of three marketing strategies to disseminate a screening and brief alcohol intervention programme to general practitioners.
Research findings are of little benefit to patients or society if they do not reach the audience they are intended to influence. A dissemination strategy is needed to target new findings at its user group and encourage a process of consideration and adoption or rejection. To evaluate the effectiveness and cost-effectiveness of different marketing strategies for the dissemination of a screening and brief alcohol intervention (SBI) programme to general practitioners (GPs). Seven hundred and twenty-nine GPs, one per practice, from the former Northern and Yorkshire Regional Health Authority were randomly assigned to one of three marketing strategies: postal marketing (mailing a promotional brochure to GPs), telemarketing (following a script to market the programme over the telephone), and personal marketing (following the same script during face-to-face marketing at GPs' practices). GPs who took up the programme were asked if they would agree to use it. Outcome measures included the proportions of GPs who took up the programme and agreement to use it. Of the 614 GPs eligible for the study, 321 (52%) took the programme. There was a significant difference in the proportions of GPs from the three marketing strategies who took the programme (82% telemarketing, 68% personal marketing, and 22% postal marketing). Of the 315 GPs who took the programme and were eligible to use it, 128 (41%) agreed to use the programme for three months. GPs in the postal marketing group were more likely to agree to use the programme (55% postal marketing, 44% personal marketing, and 34% telemarketing). Personal marketing was the most effective overall dissemination strategy; however, economic analysis revealed that telemarketing was the most cost-effective strategy. Costs for dissemination per GP were: 13 Pounds telemarketing, 15 Pounds postal marketing, and 88 Pounds personal marketing. Telemarketing appeared to be the most cost-effective strategy for dissemination of SBI to GPs.


Design and characterization of dietary assessment in the German National Cohort.
The aim of the study was to describe a novel dietary assessment strategy based on two instruments complemented by information from an external population applied to estimate usual food intake in the large-scale multicenter German National Cohort (GNC). As proof of concept, we applied the assessment strategy to data from a pretest study (2012-2013) to assess the feasibility of the novel assessment strategy. First, the consumption probability for each individual was modeled using three 24 h food lists (24h-FLs) and frequencies from one food frequency questionnaire (FFQ). Second, daily consumed food amounts were estimated from the representative German National Nutrition Survey II (NVS II) taking the characteristics of the participants into account. Usual food intake was estimated using the product of consumption probability and amounts. We estimated usual intake of 41 food groups in 318 men and 377 women. The participation proportion was 100, 84.4, and 68.5% for the first, second, and third 24h-FL, respectively. We observed no associations between the probability of participating and lifestyle factors. The estimated distributions of usual food intakes were plausible and total energy was estimated to be 2707 kcal/day for men and 2103 kcal/day for women. The estimated consumption frequencies did not differ substantially between men and women with only few exceptions. The differences in energy intake between men and women were mostly due to differences in estimated daily amounts. The combination of repeated 24h-FLs, a FFQ, and consumption-day amounts from a reference population represents a user-friendly dietary assessment approach having generated plausible, but not yet validated, food intake values in the pretest study.


S reactivity of an oil sands composite tailings deposit undergoing reclamation wetland construction.
This study is the first to characterize the S stability of a composite tailings (CT) deposit undergoing pilot wetland reclamation in the Athabasca Oil Sands Region (AOSR, Alberta, Canada). As CT is sulfur, organic carbon and bacterially rich, the goal of this study was to characterize the in situ aqueous distribution of sulfur compounds across the wetland, sand cap and underlying CT zones of the deposit, in an effort to establish the potential for microbial sulfur cycling and generation of H2S, an explosive, corrosive and toxicity risk. Porewater samples from three depths spanning the different layers of the deposit, as well as wetland surface ponded water samples were collected for geochemical analyses (July and Sept 2013), and for microbial enrichments (both S reducing and S oxidizing bacteria) in June 2014. While porewater ΣH2S(aq) was detected at all depths across the three zones of the deposit, results identify that the sand cap layer required for construction, acts as a mixing zone generating the highest solution H2S concentrations (>500 uM or 18 mg/L) and H2S gas levels (over 100 and up to 180 ppm) observed. Porewater dissolved sulfate concentrations (0.14-6.97 mM) were orders of magnitude higher and did not correlate to the observed distribution of ΣH2S concentrations throughout the deposit. Unique to the sandcap, dissolved organic carbon positively correlated with the observed maxima of ΣH2S(aq) seen in this layer. The water management of the deposit is a critical factor in the observed S trends. Active dewatering of the CT resulted in migration of S rich water up into the sandcap, while downwelling labile organic carbon from the developing wetland acted in concert to stimulate microbial generation of the H2S in this structural layer to the highest levels observed. Functional enrichments identified that diverse S reducing and oxidizing microbial metabolisms are widespread throughout the deposit, indicating that these waste materials are biogeochemically reactive with implications for longterm stability. These results are of relevance to both the oil sands region, as well as other mine contexts where S rich wastes occur, identifying the need to consider the potential bacterially driven cycling of S and C in the generation of constituents of concern, as well as the water management of such waste deposits to minimize risk.


Tracing amino acid exchange during host-pathogen interaction by combined stable-isotope time-resolved Raman spectral imaging.
This study investigates the temporal and spatial interchange of the aromatic amino acid phenylalanine (Phe) between human retinal pigment epithelial cell line (ARPE-19) and tachyzoites of the apicomplexan protozoan parasite Toxoplasma gondii (T. gondii). Stable isotope labelling by amino acids in cell culture (SILAC) is combined with Raman micro-spectroscopy to selectively monitor the incorporation of deuterium-labelled Phe into proteins in individual live tachyzoites. Our results show a very rapid uptake of l-Phe(D8) by the intracellular growing parasite. T. gondii tachyzoites are capable of extracting l-Phe(D8) from host cells as soon as it invades the cell. l-Phe(D8) from the host cell completely replaces the l-Phe within T. gondii tachyzoites 7-9 hours after infection. A quantitative model based on Raman spectra allowed an estimation of the exchange rate of Phe as 0.5-1.6 × 10(4) molecules/s. On the other hand, extracellular tachyzoites were not able to consume l-Phe(D8) after 24 hours of infection. These findings further our understanding of the amino acid trafficking between host cells and this strictly intracellular parasite. In particular, this study highlights new aspects of the metabolism of amino acid Phe operative during the interaction between T. gondii and its host cell.


Tissue sequestration of 'Candidatus Mycoplasma turicensis'.
'Candidatus Mycoplasma turicensis' ('Candidatus M. turicensis') is a hemoplasma species that infects felids. It differs from other feline hemoplasma species due to its particular infection kinetics and phylogenetic similarity to rodent hemoplasma species. The lower and shorter bacteremia produced by 'Candidatus M. turicensis' suggests a possible tissue sequestration of the organism. The aim of this study was to explore this possibility. Five specified-pathogen free cats were subcutaneously inoculated with 'Candidatus M. turicensis' and sacrificed 86 days after inoculation. Thirty-one selected organs were collected upon necropsy, and samples were analyzed by real-time Taqman(®) PCR. The humoral immune response was monitored by DnaK ELISA. All five cats had detectable 'Candidatus M. turicensis' loads in the majority (52-100%) of the tested tissues. High 'Candidatus M. turicensis' tissue loads (average 3.46×10(4) copies/10 mg) were detected in the samples. The presence of the organisms in the tissues could not be explained by the blood burdens because the blood of four out of five cats tested PCR-negative at the time of necropsy. This is the first study to describe the distribution of 'Candidatus M. turicensis' in various organs; it also demonstrates that, in contrast to other feline hemoplasma species, significant sequestration of 'Candidatus M. turicensis' occurs in many tissues. These results represent an important step toward the understanding of the pathogenesis of 'Candidatus M. turicensis'.


Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane.
Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes.


The Birmingham Vasculitis Activity Score as a Measure of Disease Activity in Patients with Giant Cell Arteritis.
To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) in the assessment of disease activity in giant cell arteritis (GCA). Patients with GCA enrolled in a prospective, multicenter, longitudinal study with symptoms of active vasculitis during any visit were included. Spearman's rank correlation was used to explore the association of the BVAS with other measures of disease activity. During a mean (SD) followup of 2.3 (1.6) years, symptoms of active GCA were present in 236 visits in 136 subjects (100 female, 74%). Median (range) BVAS1 (new/worse symptoms) was 1 (0-10) and median (range) BVAS2 (persistent symptoms) was 0 (0-5). Median (range) physician's global assessment (PGA) was 4 (0-9) for disease activity in the past 28 days and 2 (0-9) for activity on the day of the visit. Important ischemic manifestations of active vasculitis not recorded by the BVAS included tongue/jaw claudication (27%), upper extremity claudication (15%), lower extremity claudication (5%), carotidynia (7%), and ischemic retinopathy (5%). During 25 visits (11%) with active disease, all symptoms of active vasculitis were placed in the "Other" category yet still resulted in a BVAS1 and BVAS2 of 0. BVAS1 moderately correlated with PGA for the past 28 days (Spearman's correlation 0.50) and physician-rated disease activity for the past 28 days (Spearman's correlation 0.46). The BVAS has limited utility in GCA. Patients with active GCA can have a BVAS of 0. Many important ischemic symptoms attributable to active vasculitis are not included in the composite score.


Signaling states of rhodopsin in rod disk membranes lacking transducin βγ-complex.
To characterize the possible role of transducin Gtβγ-complex in modulating the signaling properties of photoactivated rhodopsin and its lifetime in rod disc membranes and intact rods. Rhodopsin photolysis was studied using UV-visible spectroscopy and rapid scanning spectroscopy in the presence of hydroxylamine in highly purified wild-type and Gtγ-deficient mouse rod disc membranes. Complex formation between photoactivated rhodopsin and transducin was measured by extra-metarhodopsin (meta) II assay. Recovery of dark current and flash sensitivity in individual intact wild-type and Gtγ-deficient mouse rods was measured by single-cell suction recordings. Photoconversion of rhodopsin to meta I/meta II equilibrium proceeds normally after elimination of the Gtβγ-complex. The meta I/meta II ratio, the rate of meta II decay, the reactivity of meta II toward hydroxylamine, and the rate of meta III formation in Gtγ-deficient rod disc membranes were identical with those observed in wild-type samples. Under low-intensity illumination, the amount of extra-meta II in Gtγ-deficient discs was significantly reduced. The initial rate of dark current recovery after 12% rhodopsin bleach was three times faster in Gtγ-deficient rods, whereas the rate of the late current recovery was largely unchanged. Mutant rods also exhibited faster postbleach recovery of flash sensitivity. Photoactivation and thermal decay of rhodopsin proceed similarly in wild-type and Gtγ-deficient mouse rods, but the complex formation between photoactivated rhodopsin and transducin is severely compromised in the absence of Gtβγ. The resultant lower transduction activation contributes to faster photoresponse recovery after a moderate pigment bleach in Gtγ-deficient rods.


Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas.
Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.


Social impacts of living with chronic hepatitis B in South Sudanese community in Australia.
Introduction: Chronic hepatitis B presents significant issues to public health and clinical practices. The infection requires lifelong clinical management and is a leading risk factor for liver cancer and liver cirrhosis. Limited studies currently exist on the social impacts of living with chronic hepatitis B, especially for people from Sub-Saharan Africa. The current study explored the experiences of South Sudanese people living with chronic hepatitis B in Australia.Methods: A qualitative inquiry using face-to-face interviews with fifteen South Sudanese people with chronic hepatitis B in Australia explored the social impacts of living with chronic hepatitis B. The study purposively sampled participants who self-identified as South Sudanese with hepatitis B and over 18 years of age. Interviews were coded and analysed using thematic analysis.Results: The study identified three themes relating to the experiences of living with chronic hepatitis B, and were grouped into psychological, interpersonal and healthcare system levels. Psychological level experiences related to the uncertainty of living with chronic hepatitis B and liver cancer risk, where participants expressed persistent fear of disease progression and anxiety around death related to the disease. Interpersonal level experiences involved the disclosure of hepatitis B and its social impacts including stigma, social distancing and isolation. Healthcare system level experiences included receiving mixed messages about hepatitis B, challenges with regular testing and difficulty receiving hepatitis B treatment.Conclusion: The findings provide valuable insights into the social impacts of hepatitis B. It underlines the importance of integrated public health interventions at the community level to improve knowledge and awareness of hepatitis B which address stigma in the South Sudanese community in Australia.


The mental number line and the human angular gyrus.
To investigate the hemispheric organization of a language-independent spatial representation of number magnitude in the human brain we applied focal repetitive transcranial magnetic stimulation (rTMS) to the right or left angular gyrus while subjects performed a number comparison task with numbers between 31 and 99. Repetitive TMS over the angular gyrus disrupted performance of a visuospatial search task, and rTMS at the same site disrupted organization of the putative "number line." In some cases the pattern of disruption caused by angular gyrus rTMS suggested that this area normally mediates a spatial representation of number. The effect of angular gyrus rTMS on the number line task was specific. rTMS had no disruptive effect when delivered over another parietal region, the supramarginal gyrus, in either the left or the right hemisphere.


Essential role of CCL2 in clustering of splenic ERTR-9+ macrophages during infection of BALB/c mice by Listeria monocytogenes.
Early interactions between pathogens and host cells are often decisive for the subsequent course of infection. Here we investigated early events during infection by Listeria monocytogenes, a ubiquitously occurring facultative intracellular microorganism that exhibits severe pathogenicity, mainly in immunocompromised individuals. We show that the inflammatory chemokine CCL2 is highly up-regulated early after Listeria infection in spleens of BALB/c mice. ERTR-9+ macrophages of the marginal zone were identified as the only infected cells and exclusive producers of CCL2 at the early time point. Consequently, clusters of different cell types were formed around infected ERTR-9+ cells. Metallophilic MOMA-1+ marginal zone macrophages were, however, excluded from the clusters and migrated into the B-cell follicles. Depletion of CCL2 during infection resulted in a different composition of cell clusters in the spleen and increased the mortality rate of treated mice. Interestingly, ERTR-9+ macrophages no longer were part of clusters in such mice but remained at their original location in the marginal zone.


Dydrogesterone exerts endothelial anti-inflammatory actions decreasing expression of leukocyte adhesion molecules.
Clinical observations and basic studies show that progesterone and progestins have a variable influence on endothelial function. Dydrogesterone (DG) is a widely used progestin, but its endothelial actions have not been thoroughly assessed. In this study, we investigated the effects of DG and its metabolite 20-α-dihydro-dydrogesterone (DHD), natural progesterone as well as medroxyprogesterone acetate, on the expression of leukocyte adhesion molecules in human endothelial cells using an in vitro experimental endothelial inflammation system. Our findings show that all progestins significantly suppress endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and inter-cellular adhesion molecule-1 (ICAM-1) induced by bacterial lypopolysaccharide (LPS). These inhibitory effects of DG and DHD require activation of progesterone receptor. DG and DHD decrease adhesion molecule expression associated with LPS administration by preventing nuclear translocation of the pro-inflammatory transcription factor nuclear factor-κB. In addition, DG and DHD do not alter the anti-inflammatory effects of 17β-estradiol. In conclusion, DG and DHD decrease endothelial inflammatory responses induced by LPS, via reduced expression of the pro-atherogenic adhesion molecules VCAM-1 and ICAM-1. These actions may be relevant for the vascular effects of DG.


Upconversion nanoparticles for ratiometric fluorescence detection of nitrite.
We have developed a selective upconversion switching method for the ratiometric fluorescence detection of nitrite using upconversion nanoparticles (UCNPs) and an efficient nitrite reaction. The green emission (λ(em) = 539 nm) of NaYF4:Yb(3+),Er(3+) nanoparticles can be selectively quenched by the neutral red (NR) dye due to the spectral overlap between the emission at 539 nm and the absorption of NR, while its red emission (λ(em) = 654 nm) remains unchanged. Nitrite reacts specifically and strongly with NR to form diazonium salt and lose the diazonium group, which sharply decreases the absorption of NR. Thus, the green emission of NaYF4:Yb(3+),Er(3+) can be recovered by increasing the amount of nitrite, leading to visible color changes from red to orange-yellow and finally green under excitation at 980 nm. The increase in the ratio of emission intensities (I539/I654) is quantitatively correlated to the concentration of nitrite ions. Moreover, the developed method has been successfully applied to nitrite detection in real samples such as drinking water, natural water and meat foods. In particular, the upconversion sensors can efficiently avoid background optical interference and thus show potential for the detection of nitrite salts in complex samples.


Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy.
The aberrant activation of tyrosine kinases represents an important oncogenic mechanism, and yet the majority of such events remain undiscovered. Here we describe a bead-based method for detecting phosphorylation of both wild-type and mutant tyrosine kinases in a multiplexed, high-throughput and low-cost manner. With the aim of establishing a tyrosine kinase-activation catalog, we used this method to profile 130 human cancer lines. Follow-up experiments on the finding that SRC is frequently phosphorylated in glioblastoma cell lines showed that SRC is also activated in primary glioblastoma patient samples and that the SRC inhibitor dasatinib (Sprycel) inhibits viability and cell migration in vitro and tumor growth in vivo. Testing of dasatinib-resistant tyrosine kinase alleles confirmed that SRC is indeed the relevant target of dasatinib, which inhibits many tyrosine kinases. These studies establish the feasibility of tyrosine kinome-wide phosphorylation profiling and point to SRC as a possible therapeutic target in glioblastoma.


Sudden upper airway obstruction in patients with hereditary angioedema.
Hereditary angioedema (HAE) is clinically characterized by recurrent and self-limiting skin, intestinal, and life-threatening laryngeal edema. This study describes the age at which laryngeal edema first occurred, the time between onset and full development, and the effectiveness of therapy and prophylaxis in 123 HAE patients. 61 (49.7%) patients experienced a total of 596 laryngeal edema episodes. The ratio of laryngeal edema episodes to skin swellings and abdominal pain attacks was approximately 1:70:54 in patients who had laryngeal edema. The mean (SD) age at the first laryngeal edema was 26.2 (15.3) years. Nearly 80% of the laryngeal edemas occurred between age 11 and 45. The mean interval between onset and maximum development of laryngeal edema was 8.3 hours. A total of 354 laryngeal edemas cleared spontaneously without treatment and 208 laryngeal edemas were successfully treated with C1 inhibitor concentrate. Despite long-term prophylactic treatment with danazol, 6 patients developed subsequent laryngeal edemas. Laryngeal edema may occur at any age, although young adults are at greatest risk. In adults, the interval between onset of symptoms and acute risk of asphyxiation is usually long enough to allow for use of appropriate emergency procedures. It is essential to instruct patients and their relatives about the first signs of laryngeal edemas and the necessary procedures to follow.


Four propositions on integrated sustainability: toward a theoretical framework to understand the environment, peace, and sustainability nexus.
The sustainability agenda has evolved around a set of interconnected dilemmas regarding economic, social, and environmental goals. Progress has been made in establishing thresholds and targets that must be achieved to enable life to continue to thrive on the planet. However, much work remains to be done in articulating coherent theoretical frameworks that adequately describe the mechanisms through which sustainability outcomes are achieved. This paper reviews core concepts in the sustainability agenda to develop four propositions on integrated sustainability that collectively describe the underlying mechanisms of sustainable development. We then advance a framework for integrated sustainability and assess its viability through linear regression and principal components analysis of key selected indicators. The results provide preliminary evidence that countries with institutions that enable cooperation and regulate competition perform better in attaining integrated sustainability indicators. Our findings suggest that institutional design is important to sustainability outcomes and that further research into process-oriented mechanisms and institutional characteristics can yield substantial dividends in enabling effective sustainability policy. The online version contains supplementary material available at 10.1007/s11625-021-00925-y.


An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods.
The aim of this study was to systematically compare postprandial insulin responses to isoenergetic 1000-kJ (240-kcal) portions of several common foods. Correlations with nutrient content were determined. Thirty-eight foods separated into six food categories (fruit, bakery products, snacks, carbohydrate-rich foods, protein-rich foods, and breakfast cereals) were fed to groups of 11-13 healthy subjects. Finger-prick blood samples were obtained every 15 min over 120 min. An insulin score was calculated from the area under the insulin response curve for each food with use of white bread as the reference food (score = 100%). Significant differences in insulin score were found both within and among the food categories and also among foods containing a similar amount of carbohydrate. Overall, glucose and insulin scores were highly correlated (r = 0.70, P < 0.001, n = 38). However, protein-rich foods and bakery products (rich in fat and refined carbohydrate) elicited insulin responses that were disproportionately higher than their glycemic responses. Total carbohydrate (r = 0.39, P < 0.05, n = 36) and sugar (r = 0.36, P < 0.05, n = 36) contents were positively related to the mean insulin scores, whereas fat (r = -0.27, NS, n = 36) and protein (r = -0.24, NS, n = 38) contents were negatively related. Consideration of insulin scores may be relevant to the dietary management and pathogenesis of non-insulin-dependent diabetes mellitus and hyperlipidemia and may help increase the accuracy of estimating preprandial insulin requirements.


Interleukin-10 and nerve growth factor have reciprocal upregulatory effects on intestinal epithelial cells.
The intestinal mucosa is in a constant state of controlled inflammation, but the processes whereby this occurs are poorly understood. The aims of this study were to look at the role of IL-10 and nerve growth factor (NGF) in intestinal epithelial cell regulation. The human colon epithelial cell lines T84, HT-29, and CACO-2 were used. RT-PCR, flow cytometry analysis, and immunohistochemistry were applied to measure the cytokine changes in epithelial cells induced by recombinant cholera toxin and its B subunit, IL-10, and NGF. Cholera toxin B subunit caused selective dose-dependent increased mRNA for IL-10 in T84 cells and the protein in T84, HT-29, and CACO-2 cells. IL-10 dose dependently selectively increased NGF mRNA in T84 cells and intracellular protein synthesis in all three epithelial cell lines. The effect of NGF was reciprocal, selective, and dose dependent because it increased mRNA for IL-10 and IL-10 synthesis. Our results suggest that the epithelium may actively participate in downregulation through innate mechanisms involving IL-10 and NGF. The reciprocal interaction suggests for the first time that NGF may be involved in local downregulation by mucosal epithelium and thus may play a potent protective role in response to injury, by prevention of undue inflammation.


Next-generation systematics: An innovative approach to resolve the structure of complex prokaryotic taxa.
Prokaryotic systematics provides the fundamental framework for microbiological research but remains a discipline that relies on a labour- and time-intensive polyphasic taxonomic approach, including DNA-DNA hybridization, variation in 16S rRNA gene sequence and phenotypic characteristics. These techniques suffer from poor resolution in distinguishing between closely related species and often result in misclassification and misidentification of strains. Moreover, guidelines are unclear for the delineation of bacterial genera. Here, we have applied an innovative phylogenetic and taxogenomic approach to a heterogeneous actinobacterial taxon, Rhodococcus, to identify boundaries for intrageneric and supraspecific classification. Seven species-groups were identified within the genus Rhodococcus that are as distantly related to one another as they are to representatives of other mycolic acid containing actinobacteria and can thus be equated with the rank of genus. It was also evident that strains assigned to rhodococcal species-groups are underspeciated with many misclassified using conventional taxonomic criteria. The phylogenetic and taxogenomic methods used in this study provide data of theoretical value for the circumscription of generic and species boundaries and are also of practical significance as they provide a robust basis for the classification and identification of rhodococci of agricultural, industrial and medical/veterinary significance.


Modulation of immune responses to vaccination by the microbiota: implications and potential mechanisms.
The need for highly effective vaccines that induce robust and long-lasting immunity has never been more apparent. However, for reasons that are still poorly understood, immune responses to vaccination are highly variable between different individuals and different populations. Furthermore, vaccine immunogenicity is frequently suboptimal in the very populations who are at most risk from infectious disease, including infants, the elderly, and those living in low-income and middle-income countries. Although many factors have the potential to influence vaccine immunogenicity and therefore vaccine effectiveness, increasing evidence from clinical studies and animal models now suggests that the composition and function of the gut microbiota are crucial factors modulating immune responses to vaccination. In this Review, we synthesize this evidence, discuss the immunological mechanisms that potentially mediate these effects and consider the potential of microbiota-targeted interventions to optimize vaccine effectiveness.


Characteristics of Sexual Abuse Among Individuals With Serious Mental Illnesses.
The deleterious effects of sexual abuse (SA) are well documented, as many studies have found that SA can increase the risk for psychiatric disorders. While SA has been examined in multiple samples, no studies have examined the characteristics of SA in individuals with severe mental illnesses (SMI). This study examined the prevalence rate and characterized the nature of SA among individuals with SMI who were under psychiatric care in three different inpatient facilities. Utilizing data from the MacArthur Violence Risk Assessment Study, 1,136 individuals with SMI were assessed for SA histories, psychiatric diagnoses, and other demographics. Nearly half of this sample ( n = 511) identified SA histories, with almost half indicating that the person was a stranger or someone outside of the family unit. One third reported SA occurred "too many times to count," and approximately a third indicated the abuse consisted of intercourse, occurring at a mean age of 11.22 years. Results found that individuals with SA histories were often never married, Caucasian, female, had children, described themselves as psychologically unwell, and were commonly voluntary psychiatric admissions. Those with SA histories had significantly higher psychopathology and lower functioning, and were more likely to be diagnosed with depression but less likely to be substance dependent. Identifying SA characteristics in individuals with SMI is a critical component to successful treatment. Thorough screening and assessment of this common problem can help clinicians identify accompanying issues that may exacerbate SMI symptomology, and improve the prognosis for long-term outcomes.


Parietal cortex and movement. II. Spatial representation.
Lesions in the two divisions of parietal cortex, 5/7b/MIP and 7a/LIP, produce dissociable reaching deficits. Monkeys with 5/7b/MIP removals were tested on reaching in the dark under two different conditions. All the reaches made on any day were from the same starting position to the same target position in the control condition. In the "transfer" condition, all the reaches were made to the same target position but consecutive reaches were made from different starting positions. The target could be represented as a constant pattern of joint and muscle positions in the control condition. The transfer condition required a representation of the starting position of the hand and/or a representation of the target in terms of its position in space. Removal of areas 5, 7b and MIP produced only a very mild impairment in the control condition and a severe impairment in the transfer condition. This suggests that 5/7b/MIP does not represent the limb in simple sensory or motor coordinates but in terms of its spatial position.


Anodal Transcranial Direct Current Stimulation to the Left Rostrolateral Prefrontal Cortex Selectively Improves Source Memory Retrieval.
Functional neuroimaging studies have consistently implicated the left rostrolateral prefrontal cortex (RLPFC) as playing a crucial role in the cognitive operations supporting episodic memory and analogical reasoning. However, the degree to which the left RLPFC causally contributes to these processes remains underspecified. We aimed to assess whether targeted anodal stimulation-thought to boost cortical excitability-of the left RLPFC with transcranial direct current stimulation (tDCS) would lead to augmentation of episodic memory retrieval and analogical reasoning task performance in comparison to cathodal stimulation or sham stimulation. Seventy-two healthy adult participants were evenly divided into three experimental groups. All participants performed a memory encoding task on Day 1, and then on Day 2, they performed continuously alternating tasks of episodic memory retrieval, analogical reasoning, and visuospatial perception across two consecutive 30-min experimental sessions. All groups received sham stimulation for the first experimental session, but the groups differed in the stimulation delivered to the left RLPFC during the second session (either sham, 1.5 mA anodal tDCS, or 1.5 mA cathodal tDCS). The experimental group that received anodal tDCS to the left RLPFC during the second session demonstrated significantly improved episodic memory source retrieval performance, relative to both their first session performance and relative to performance changes observed in the other two experimental groups. Performance on the analogical reasoning and visuospatial perception tasks did not exhibit reliable changes as a result of tDCS. As such, our results demonstrate that anodal tDCS to the left RLPFC leads to a selective and robust improvement in episodic source memory retrieval.


Risk analysis for deterioration of renal function after pancreas alone transplant.
The risk of progression to renal replacement after pancreas transplant alone (PTA) is a concern in patients with pre-transplant estimated glomerular filtration rate (eGFR) < 70 mL/min/1.73 m(2). This is a retrospective, single-center risk analysis of potential factors affecting renal function after PTA. Twenty-four patients, transplanted over a three-yr period, with functioning pancreatic grafts at the study's end point were included. High tacrolimus levels (> 12 mg/dL) at six months post-transplant was the only independent risk factor identifying a substantial decline in native renal function by Cox regression analysis (HR = 14.300, CI = 1.271-160.907, p = 0.031). The presence of severe pre-transplant proteinuria (urine Pr/Cr ≥ 100 mg/mmol) marginally failed to reach significance (p = 0.056). Low eGFR levels alone (≤ 45 and ≤ 40 mL/min/1.73 m(2)) at the time of transplant did not correlate with substantial decline in renal function. Our data suggest that PTA is a justifiable therapy for patients with hypoglycemia unawareness or other life-threatening diabetic complications, even in those with borderline renal function, provided that they do not suffer from severe proteinuria and appropriate monitoring and tailoring of immunosuppression is ensured.


Optimistic biases in observational learning of value.
Action-outcome contingencies can be learnt either by active trial-and-error, or vicariously, by observing the outcomes of actions performed by others. The extant literature is ambiguous as to which of these modes of learning is more effective, as controlled comparisons of operant and observational learning are rare. Here, we contrasted human operant and observational value learning, assessing implicit and explicit measures of learning from positive and negative reinforcement. Compared to direct operant learning, we show observational learning is associated with an optimistic over-valuation of low-value options, a pattern apparent both in participants' choice preferences and their explicit post-hoc estimates of value. Learning of higher value options showed no such bias. We suggest that such a bias can be explained as a tendency for optimistic underestimation of the chance of experiencing negative events, an optimism repressed when information is gathered through direct operant learning.


Historical Meiotic Crossover Hotspots Fueled Patterns of Evolutionary Divergence in Rice.
Recombination plays an integral role in the creation of novel genetic variation in sexually reproducing species. Despite this important role, the determinants and evolution of crossover hotspots have remained poorly understood in plants. Here, we present a comparative analysis of two rice (Oryza sativa) historical recombination maps from two subspecies (indica and japonica) using 150 resequenced genomes. Fine-scale recombination rates and crossover hotspots were validated by comparison with a consensus genetic map and empirically derived crossovers, respectively. Strikingly, nearly 80% of crossover hotspots were unique to each subspecies, despite their relatively recent divergence and broad-scale correlated recombination rates. Crossover hotspots were enriched with Stowaway and P instability factor (PIF)/Harbinger transposons and overlapped accessible chromatin regions. Increased nucleotide diversity and signatures of population differentiation augmented by Stowaway and PIF/Harbinger transposons were prevalent at subspecies-specific crossover hotspots. Motifs derived from lineage-specific indica and japonica crossover hotspots were nearly identical in the two subspecies, implicating a core set of crossover motifs in rice. Finally, Stowaway and PIF/Harbinger transposons were associated with stabilized G/C bias within highly active hotspots, suggesting that hotspot activity can be fueled by de novo variation. These results provide evolutionary insight into historical crossover hotspots as potentially powerful drivers of sequence and subspecies evolution in plants.


The surgical management of hidradenitis suppurativa in the United Kingdom: a national survey of care pathways informing the THESEUS study.
The evidence-base underpinning treatment efficacy and effectiveness for hidradenitis suppurativa (HS) is limited, as has been highlighted in the wide-ranging research priorities established by a James Lind Alliance priority-setting partnership (PSP). Understanding the landscape of surgical practice is a key step towards tackling undesired variation in care and resolving treatment uncertainties. This survey of current surgical practice aimed to describe care pathways involving surgeons for the management of HS and surgical approaches to management. In the development of the prospective cohort Treatment of Hidradenitis Suppurativa Evaluation Study (THESEUS), a bespoke electronic surgeon survey was conducted to describe variation in care pathways and surgical preferences in the management of HS. This was disseminated to a pre-defined denominator list of surgeons using local collaborators through the reconstructive surgery trials network (RSTN). Key results were small numbers of surgeons working in formal multidisciplinary teams (MDTs) (8/198, 4%), heterogeneity of first-line intervention, low rates of guideline endorsed treatments (laser and deroofing in particular), variation in wound closure methods and follow-up length, and that over half of respondents do not use well-validated outcome instruments to determine treatment success/failure (110/198, 56%). This survey demonstrated variation in care, which is likely to be undesirable. Surgeons treating HS patients might consider developing MDTs or referring patients to those with an interest in HS and considering routine outcome measurement. Such steps might reduce variation, increase standardisation of care and improve access to specific treatments.


Impact of the consideration of serrated polyps to the interval of colonoscopic surveillance in the NHS Bowel Cancer Screening Programme.
Most international post polypectomy surveillance guidelines do not recommend surveillance for serrated polyps. In the present study the additional impact of serrated polyps on surveillance intervals from international adenoma surveillance guidelines was investigated. Endoscopic and pathology records were audited of participants in the NHS Bowel Cancer Screening Programme (guaiac faecal occult blood test, gFOBT) in 2011. Surveillance intervals were calculated for current guidelines and also for serrated polyps based on previously described aggressive and conservative strategies. In total, 389 patients were included of whom 141 (36.2%) were high risk (advanced adenoma: adenoma ≥ 10 mm, villous elements, high grade dysplasia, or adenoma ≥ 3 in number) needing surveillance at ≤ 3 years. Thirty-three (8.5%) had significant serrated polyps, of whom 18 (4.6% of the total) had significant serrated lesions and simultaneous advanced adenoma or ≥ 3 adenomas. Adopting an aggressive surveillance strategy, the mean overall absolute additional proportion of all such patients in the surveillance group at 3 years or less was 4.0% (3.9% - 4.1%; 4.2% women; 3.8% men). These proportions varied according to endoscopist from 2.3% to 4.7%. For more conservative strategies the increase was only 1%. The impact of including serrated polyps in current guidelines would result in a small increase in surveillance intervals for FOBT based bowel cancer screening. About half of those who might need surveillance for serrated polyps would already receive surveillance for being in a high risk adenoma group.


Crystal structure of poxvirus thymidylate kinase: an unexpected dimerization has implications for antiviral therapy.
Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer.


Medical students' experiences of shame in professional enculturation.
Despite the intentions of caregivers not to harm, medical encounters may involve intimidation and induce emotions of shame. Reflection is a critical part of professional learning and training. However, the role of shame in medical education has scarcely been studied. The aim of this study was to explore medical students' reflections on shame-related experiences in clinical situations and to examine how they tackled these experiences. A 24-credit course in Professional Development is held at the Medical School of Umeå University, Sweden. A 1-day seminar on the theme of shame, which involves individual reflections and group discussions, is held in term 9. Medical students were invited to individually consider and write down their memories of situations in which they had experienced shame in clinical encounters. Of a total of 133 students, 75 were willing to share their written reflections anonymously. Their essays were transcribed to computer text and analysed by means of qualitative content analysis. Three themes emerged. These included: Difficulties in disclosing shame; Shame-inducing circumstances, and Avoiding or addressing shame. Initially, students experienced problems in recalling shameful incidents, but successively described various situations which related to being taken by surprise, being exposed, and being associated with staff imprudence. Students disclosed shame avoidance behaviours, but also gave examples of how addressing shame provided them with new insights and restored their dignity. Students' reflections on shameful experiences elucidated the importance of attitudes, manners, standards and hierarchies in clinical situations. These are important issues to highlight in the professional enculturation of medical students; our emphasising of them may encourage medical teachers elsewhere to organise similar activities. Opportunities for mentoring medical students in tackling shame and adverse feelings, and in resolving conflict, are needed in medical curricula.


Impact of adherence counseling dose on antiretroviral adherence and HIV viral load among HIV-infected methadone maintained drug users.
Adherence counseling can improve antiretroviral adherence and related health outcomes in HIV-infected individuals. However, little is known about how much counseling is necessary to achieve clinically significant effects. We investigated antiretroviral adherence and HIV viral load relative to the number of hours of adherence counseling received by 60 HIV-infected drug users participating in a trial of directly observed antiretroviral therapy delivered in methadone clinics. Our adherence counseling intervention combined motivational interviewing and cognitive-behavioral counseling, was designed to include six 30 minute individual counseling sessions with unlimited "booster" sessions, and was offered to all participants in the parent trial. We found that, among those who participated in adherence counseling, dose of counseling had a significant positive relationship with antiretroviral adherence measured after the conclusion of counseling. Specifically, a liner mixed-effects model revealed that each additional hour of counseling was significantly associated with a 20% increase in post-counseling adherence. However, the number of cumulative adherence counseling hours was not significantly associated with HIV viral load, also measured after the conclusion of counseling. Our findings suggest that more intensive adherence counseling interventions may have a greater impact on antiretroviral adherence than less intensive interventions; however, it remains unknown how much counseling is required to impact HIV viral load.


HISTORICAL EXAMINATION OF DELAYED PLUMAGE MATURATION IN THE SHOREBIRDS (AVES: CHARADRIIFORMES).
Delayed plumage maturation refers to the presence of nonadultlike immature plumages (juvenal plumage excluded). It is usually considered the result of selection for distinctive first-winter or first-summer appearance. In the present study, evolution of delayed plumage maturation is examined in the shorebirds: the sandpipers, plovers, gulls, and their allies. Nine plumage-maturation characters were identified, and their states were superimposed onto topologies generated during two recent investigations of shorebird relationships (Sibley and Ahlquist; revised Strauch). The characters were then optimized so as to assign character states to interior nodes of the trees in the most parsimonious way. Reconstructions of character evolution on six of the shortest revised Strauch trees were ambiguous with respect to delayed plumage maturation in the hypothetical ancestral shorebird. If plumage maturation was not delayed in the shorebird ancestor, optimization indicated that delay appeared when nonadultlike juvenal feathers were acquired. In contrast, on the single Sibley and Ahlquist tree, absence of delayed plumage maturation in the shorebird ancestor was indicated unambiguously, with three evolutionary novelties (nonadultlike juvenal feathers, seasonal plumage change, and a reduced first-spring molt) implicated in its acquisition. Optimization indicated that delayed plumage maturation in shorebirds can be explained plausibly without invoking selection for distinctive first-winter or first-summer appearance. Two of the novel conditions generating delayed plumage maturation (modified juvenal feathers and seasonal plumage change) did so only because they were acquired in a taxon possessing restricted first-year molts, which are primitive. Given these observations, it seems simplest to explain the delay in plumage maturation as an incidental consequence of the phylogenetic inertia of shorebird molts. The third novelty that generates delayed plumage maturation, a reduced first-spring molt, may have been acquired to reduce molt-associated energetic demands in young birds.


Wide-field en face swept-source optical coherence tomography angiography using extended field imaging in diabetic retinopathy.
To examine the feasibility of wide-field en face swept-source optical coherence tomography angiography (SS-OCTA) with extended field imaging (EFI) for evaluation of the retinal vasculature in diabetic retinopathy (DR). This study included 37 eyes of 27 patients (age, 65±10 years; male patients, 18; female patients, 9) with DR. All patients underwent comprehensive ophthalmological examination, including OCTA and fluorescein angiography (FA). The imaging methods were compared for visible field of view, presence and extent of non-perfused areas (NPAs), presence and number of new blood vessels (NVs), vessel density (VD) and patient comfort level measured by Visual Analogue Scale. SS-OCTA with EFI allowed capture of larger areas (by 1.80±0.18 times on average) of the fundus than SS-OCTA without EFI. Compared with FA, the sensitivities of SS-OCTA with EFI for detection of NPAs and NVs were 96% and 79%, respectively, with specificities of 100% and 96%, respectively. There was no significant difference in extent of NPAs (61.2±45.8 vs 61.5±55.0 disc areas, P=0.99) or number of NVs (1.5±3.3 vs 0.9±1.8, P=0.68) between FA and SS-OCTA with EFI. VD showed significantly lower values in EFI SS-OCTA than in those acquired without EFI (31.6%±4.3% vs 34.2%±4.3%, P<0.001). Wide-field OCTA with EFI was significantly more comfortable for patients than FA (P<0.001). SS-OCTA with EFI allows acquisition of wide-field en face images of the retinal vasculature in patients with DR, with greater patient comfort than FA.


Frequency tuning of basilar membrane and auditory nerve fibers in the same cochleae.
Responses to tones of a basilar membrane site and of auditory nerve fibers innervating neighboring inner hair cells were recorded in the same cochleae in chinchillas. At near-threshold stimulus levels, the frequency tuning of auditory nerve fibers closely paralleled that of basilar membrane displacement modified by high-pass filtering, indicating that only relatively minor signal transformations intervene between mechanical vibration and auditory nerve excitation. This finding establishes that cochlear frequency selectivity in chinchillas (and probably in mammals in general) is fully expressed in the vibrations of the basilar membrane and renders unnecessary additional ("second") filters, such as those present in the hair cells of the cochleae of reptiles.


Behind the subcutaneous trastuzumab hype: evaluation of benefits and their transferability to Central Eastern European countries.
Trastuzumab, the standard treatment for HER-2 positive breast cancer, may be associated with access restrictions in countries with severe economic constraints. This study aimed to compare intravenous (IVT) and subcutaneous trastuzumab (SCT) forms and to explore the transferability of value propositions to Central and Eastern European (CEE) countries. Areas covered: After screening 376 abstracts, 42 articles were included in the final review. Statistical test results were rarely reported; therefore, the similarity of adverse event profiles of SCT and IVT could not be validated. Potential time savings for patients due to subcutaneous administration was not validated in CEE settings, where patient's waiting time for treatment administration is fairly long. Standard patient reported outcome instruments were rarely used to confirm the preference of patients/health care professionals to SCT over IVT. Moreover, feasibility of self/home administration of SCT, especially in case of concomitant intravenous chemotherapies, was not considered. Cost comparisons considered neither the patent expiry of IVT nor the incremental cost of potential differences in adverse events. Expert commentary: Potential benefits of SCT were not tested by any studies in CEE countries. The main policy objective should be to facilitate the uptake of multisource biologicals in lower income countries with access barriers.


Researchers' participation in and motivations for engaging with research information management systems.
This article examined how researchers participated in research information management systems (RIMSs), their motivations for participation, and their priorities for those motivations. Profile maintenance, question-answering, and endorsement activities were used to define three cumulatively increasing levels of participation: Readers, Record Managers, and Community Members. Junior researchers were more engaged in RIMSs than were senior researchers. Postdocs had significantly higher odds of endorsing other researchers for skills and being categorized as Community Members than did full and associate professors. Assistant professors were significantly more likely to be Record Managers than were members of any other seniority categories. Finally, researchers from the life sciences showed a significantly higher propensity for being Community Members than Readers and Record Managers when compared with researchers from engineering and the physical sciences, respectively. When performing activities, researchers were motivated by the desire to share scholarship, feel competent, experience a sense of enjoyment, improve their status, and build ties with other members of the community. Moreover, when researchers performed activities that directly benefited other members of a RIMS, they assigned higher priorities to intrinsic motivations, such as perceived self-efficacy, enjoyment, and building community ties. Researchers at different stages of their academic careers and disciplines ranked some of the motivations for engaging with RIMSs differently. The general model of research participation in RIMSs; the relationships among RIMS activities; the motivation scales for activities; and the activity, seniority, and discipline-specific priorities for the motivations developed by this study provide the foundation for a framework for researcher participation in RIMSs. This framework can be used by RIMSs and institutional repositories to develop tools and design mechanisms to increase researchers' engagement in RIMSs.


Intestinal mucus affinity and biological activity of an orally administered antibacterial and anti-inflammatory peptide.
Antimicrobial peptides (AMP) provide protection from infection by pathogenic microorganisms and restrict bacterial growth at epithelial surfaces to maintain mucosal homeostasis. In addition, they exert a significant anti-inflammatory activity. Here we analysed the anatomical distribution and biological activity of an orally administered AMP in the context of bacterial infection and host-microbial homeostasis. The anatomical distribution as well as antibacterial and anti-inflammatory activity of the endogenous AMP cryptdin 2 and the synthetic peptide Pep19-2.5 at the enteric mucosal surface were analysed by immunostaining, functional viability and stimulation assays, an oral Salmonella enterica subsp. enterica sv. Typhimurium (S. Typhimurium) model and comparative microbiota analysis. Endogenous cryptdin 2 was found attached to bacteria of the enteric microbiota within the intestinal mucus layer. Similarly, the synthetic peptide Pep19-2.5 attached rapidly to bacterial cells, exhibited a marked affinity for the intestinal mucus layer in vivo, altered the structural organisation of endotoxin in a mucus matrix and demonstrated potent anti-inflammatory and antibacterial activity. Oral Pep19-2.5 administration induced significant changes in the composition of the enteric microbiota as determined by high-throughput 16S rDNA sequencing. This may have contributed to the only transient improvement of the clinical symptoms after oral infection with S. Typhimurium. Our findings demonstrate the anti-inflammatory activity and mucus affinity of the synthetic AMP Pep19-2.5 and characterise the influence on microbiota composition and enteropathogen infection after oral administration.


Caregiver burden and health-related quality of life among primary family caregivers of individuals with schizophrenia: a cross-sectional study.
This study aimed to examine correlates of caregiver burden and health-related quality of life (HRQoL) among primary family caregivers of individuals with schizophrenia in inpatient psychiatric rehabilitation facilities. A cross-sectional study was conducted with 157 Taiwanese primary family caregivers of individuals with schizophrenia residing in inpatient psychiatric facilities. Measures included socio-demographic questionnaires and clinical information, Mutuality Scale, Family Crisis-Oriented Personal Evaluation Scales, Zarit Burden Interview, and World Health Organization Quality of Life-brief version. To describe the degree of caregiver burden and domains of HRQoL, descriptive statistics were computed. Independent sample t test, one-way analysis of variance, and Pearson's correlation analysis followed by multiple regression analyses were performed to determine correlations and relationships between characteristics of patients and primary family caregivers with caregiver burden and domains of HRQoL. Primary family caregivers experienced mild to moderate caregiver burden and poor HRQoL. Primary family caregivers who were older and unemployed, caring for patient's severe psychiatric symptoms, and had low monthly incomes, decreased mutuality, and fewer family coping strategies were associated with greater caregiver burden and poor HRQoL. Greater mutuality and family coping strategies of reframing and seeking spiritual support were the most significant factors in improving caregiver burden and all domains of HRQoL, respectively. Family-focused interventions for caregivers of institutionalized persons with schizophrenia that include psychological support and peer support groups are recommended to enhance mutuality and family coping strategies, reduce caregiver burden, and improve HRQoL.