Effect of Maxillomandibular Advancement Surgery on Pharyngeal Airway Volume and Polysomnography Data in Obstructive Sleep Apnea Patients.
To study volumetric changes in the upper airway in patients with obstructive sleep apnea (OSA) after maxillomandibular advancement (MMA) and compare those findings with polysomnographic (PSG) data of the same patients. The study included 20 patients with OSA (1 woman and 19 men; mean age, 48 yr; range, 31 to 59 yr). Mean values of angles formed by the sella, nasion, and B point and the sella, nasion, and A point before surgery indicated mandibular and maxillary retrognathia, respectively. All patients were treated with MMA and pre- and postoperative orthodontics. Pre- and post-treatment cone-beam computed tomograms were used to measure upper airway volume and PSG data were used to examine the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI-3 or ODI-4). In addition, Epworth Sleepiness Scale (ESS) score, General Health Questionnaire (GHQ-12) score, and amount of MMA were collected from patients' files. Mean maxillary and mandibular advancement was 4.6 ± 1.9 and 9.3 ± 1.7 mm, respectively. A statistically relevant increase (mean, 64.1%) in airway volume was found, with large individual variation. ODI-3 or ODI-4 and AHI values showed statistically relevant improvements from before to after surgery. ODI-3 or ODI-4 score decreased from 12.3 ± 9.8 to 4.0 ± 4.2 and AHI score decreased from 21.4 ± 13.8 to 5.8 ± 7.2. ESS scores showed improvement (lower scores) after surgery for most patients (n = 15), whereas GHQ-12 scores showed improvement (lower scores) for only 6 patients. MMA increases upper airway volume and lessens OSA symptoms according to PSG data. MMA can be considered curative treatment for OSA; however, residual apnea as measured by the AHI can be found in many patients.


Small bowel perforation after radiotherapy for cervical carcinoma.
Radiotherapy is the treatment of choice for carcinoma of the uterine cervix. We report on a 62-year-old Chinese woman with cervical carcinoma, in whom a small bowel perforation developed 5 months after radiotherapy. Ten centimetres of small bowel, including the perforation site, were resected. No bowel adhesion was detected during the operation. The postoperative course was uneventful, and the patient was discharged home 7 days after surgery. Histological examination confirmed post-irradiation injury. The presenting complaints of patients with bowel perforation following radiotherapy vary, and signs of peritonitis may be absent. Emergency physicians must be alert for these complications in patients who have been treated with radiotherapy.


Eukaryotic localization, activation and ubiquitinylation of a bacterial type III secreted toxin.
Type III secretion is a widespread method whereby Gram-negative bacteria introduce toxins into eukaryotic cells. These toxins mimic or subvert a normal cellular process by interacting with a specific target, although how toxins reach their site of action is unclear. We set out to investigate the intracellular localization of a type III toxin of Pseudomonas aeruginosa called ExoU, which has phospholipase activity and requires a eukaryotic factor for activity. We found that ExoU is localized to the plasma membrane and undergoes modification within the cell by addition of two ubiquitin molecules at lysine-178. A region of five amino acids at position 679-683 near the C-terminus of the ExoU protein controls both membrane localization and ubiquitinylation. Site-directed mutagenesis identified a tryptophan at position 681 as crucial for these effects. We found that the same region at position 679-683 was also required for cell toxicity produced by ExoU as well as in vitro phospholipase activity. Localization of the phospholipase ExoU to the plasma membrane is thus required for activation and allows efficient utilization of adjacent substrate phospholipids.


Anti-inflammatory effects of atorvastatin treatment in chronic obstructive pulmonary disease. A controlled pilot study.
Observational studies have suggested that statins may have beneficial effects on outcomes in chronic obstructive pulmonary disease (COPD) patients. These effects may be mediated through an anti-inflammatory effect of statins. The purpose of this pilot-study was to determine whether statins have an anti-inflammatory effect on the lungs of COPD patients. We conducted randomized, controlled, parallel group pilot-study to compare the effects of atorvastatin (n=12) or placebo (n=6) on lung inflammation in patients with mild to moderate COPD. The primary endpoint was change in CD45+ cells expression measured by immunohistochemistry and changes in expression of genes measured using microarrays in lung biopsy (TBB) samples before and after 12 weeks of treatment with atorvastatin 40 mg/day. All subjects had spirometry, lung volumes, diffusing capacity of the lungs for carbon monoxide (DLCO), St George's Respiratory Questionnaire (SGRQ), 6 minute walk distance (6 MWD), serum lipids, hs-CRP, induced sputum (IS), bronchoscopy and TBB carried out at baseline and after treatment. TBB specimens were processed for histology, immunohistochemistry and genome-wide association studies (GWAS) profiling. Seventeen subjects completed the study. There was a significant improvement in SGRQ with mean SGRQ decreased by 12 points after treatment with atorvastatin (P=0.012). Atorvastatin treatment produced a significant 34% reduction in sputum neutrophil count, and a 57% reduction in CD45+ cells in lung biopsies (expressed as integrated optical density -IOD; median IOD 62.51% before, 27.01% after atorvastatin treatment, P=0.008). In patients' lung tissue atorvastatin treatment produced downregulation of key genes involved in inflammatory processes, immune response, and leukocyte activation. These data demonstrate the pulmonary anti-inflammatory effects of atorvastatin in COPD patients with the potential for beneficial clinical effects. ClinicalTrials.gov: NCT01748279.


Protocol for the cultural adaptation of pulmonary rehabilitation and subsequent testing in a randomised controlled feasibility trial for adults with chronic obstructive pulmonary disease in Sri Lanka.
International guidelines recommend pulmonary rehabilitation (PR) should be offered to adults living with chronic obstructive pulmonary disease (COPD), but PR availability is limited in Sri Lanka. Culturally appropriate PR needs to be designed and implemented in Sri Lanka. The study aims to adapt PR to the Sri Lankan context and determine the feasibility of conducting a future trial of the adapted PR in Sri Lanka. Eligible participants will be identified and will be invited to take part in the randomised controlled feasibility trial, which will be conducted in Central Chest Clinic, Colombo, Sri Lanka. A total of 50 participants will be recruited (anticipated from April 2021) to the trial and randomised (1:1) into one of two groups; control group receiving usual care or the intervention group receiving adapted PR. The trial intervention is a Sri Lankan-specific PR programme, which will consist of 12 sessions of exercise and health education, delivered over 6 weeks. Focus groups with adults living with COPD, caregivers and nurses and in-depth interviews with doctors and physiotherapist will be conducted to inform the Sri Lankan specific PR adaptations. After completion of PR, routine measures in both groups will be assessed by a blinded assessor. The primary outcome measure is feasibility, including assessing eligibility, uptake and completion. Qualitative evaluation of the trial using focus groups with participants and in-depth interviews with PR deliverers will be conducted to further determine feasibility and acceptability of PR, as well as the ability to run a larger future trial. Ethical approval was obtained from the ethics review committee of Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka and University of Leicester, UK. The results of the trial will be disseminated through patient and public involvement events, local and international conference proceedings, and peer-reviewed journals. ISRCTN13367735.


Detection of different oxidation states of individual manganese porphyrins during their reaction with oxygen at a solid/liquid interface.
Manganese porphyrins have been extensively investigated as model systems for the natural enzyme cytochrome P450 and as synthetic oxidation catalysts. Here, we report single-molecule studies of the multistep reaction of manganese porphyrins with molecular oxygen at a solid/liquid interface, using a scanning tunnelling microscope (STM) under environmental control. The high lateral resolution of the STM, in combination with its sensitivity to subtle differences in the electronic properties of molecules, allowed the detection of at least four distinct reaction species. Real-space and real-time imaging of reaction dynamics enabled the observation of active sites, immobile on the experimental timescale. Conversions between the different species could be tuned by the composition of the atmosphere (argon, air or oxygen) and the surface bias voltage. By means of extensive comparison of the results to those obtained by analogous solution-based chemistry, we assigned the observed species to the starting compound, reaction intermediates and products.


High-performance source of spectrally pure, polarization entangled photon pairs based on hybrid integrated-bulk optics.
Entangled photon pair sources based on bulk optics are approaching optimal design and implementation, with high state fidelities, spectral purities and heralding efficiencies, but generally low brightness. Integrated entanglement sources, while providing higher brightness and low-power operation, often sacrifice performance in output state quality and coupling efficiency. Here we present a polarization-entangled pair source based on a hybrid approach of waveguiding and bulk optics, addressing every metric simultaneously. We show 96 % fidelity to the singlet state, 82 % Hong-Ou-Mandel interference visibility, 43 % average Klyshko efficiency, and a high brightness of 2.9 × 106 pairs/(mode·s·mW), while requiring only microwatts of pump power.


Human RNA polymerase II-associated protein 2 (RPAP2) interacts directly with the RNA polymerase II subunit Rpb6 and participates in pre-mRNA 3'-end formation.
The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is composed of tandem repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. The CTD of Pol II undergoes reversible phosphorylation during the transcription cycle, mainly at Ser2, Ser5, and Ser7. Dynamic changes in the phosphorylation patterns of the CTD are responsible for stage-specific recruitment of various factors involved in RNA processing, histone modification, and transcription elongation/termination. Human RNA polymerase II-associated protein 2 (RPAP2) was originally identified as a Pol II-associated protein and was subsequently shown to function as a novel Ser5-specific CTD phosphatase. Although a recent study suggested that RPAP2 is required for the efficient expression of small nuclear RNA genes, the role of RPAP2 in controlling the expression of protein-coding genes is unknown. Here, we demonstrate that the C-terminal region of RPAP2 interacts directly with the Pol II subunit Rpb6. Chromatin immunoprecipitation analyses of the MYC and GAPDH protein-coding genes revealed that RPAP2 occupied the coding and 3' regions. Notably, siRNA-mediated knockdown of RPAP2 caused defects in 3'-end formation of the MYC and GAPDH pre-mRNAs. These results suggest that RPAP2 controls Pol II activity through a direct interaction with Rpb6 and participates in pre-mRNA 3'-end formation.


Abdominal Computed Tomography Imaging Findings in Hospitalized COVID-19 Patients: A Year-Long Experience and Associations Revealed by Explainable Artificial Intelligence.
The aim of this retrospective study is to assess any association between abdominal CT findings and the radiological stage of COVID-19 pneumonia, pulmonary embolism and patient outcomes. We included 158 adult hospitalized COVID-19 patients between 1 March 2020 and 1 March 2021 who underwent 206 abdominal CTs. Two radiologists reviewed all CT images. Pathological findings were classified as acute or not. A subset of patients with inflammatory pathology in ACE2 organs (bowel, biliary tract, pancreas, urinary system) was identified. The radiological stage of COVID pneumonia, pulmonary embolism, overall days of hospitalization, ICU admission and outcome were registered. Univariate statistical analysis coupled with explainable artificial intelligence (AI) techniques were used to discover associations between variables. The most frequent acute findings were bowel abnormalities (n = 58), abdominal fluid (n = 42), hematomas (n = 28) and acute urologic conditions (n = 8). According to univariate statistical analysis, pneumonia stage > 2 was significantly associated with increased frequency of hematomas, active bleeding and fluid-filled colon. The presence of at least one hepatobiliary finding was associated with all the COVID-19 stages > 0. Free abdominal fluid, acute pathologies in ACE2 organs and fluid-filled colon were associated with ICU admission; free fluid also presented poor patient outcomes. Hematomas and active bleeding with at least a progressive stage of COVID pneumonia. The explainable AI techniques find no strong relationship between variables.


Operative vs Nonoperative Treatment for Atraumatic Rotator Cuff Tears: A Trial Protocol for the Arthroscopic Rotator Cuff Pragmatic Randomized Clinical Trial.
Rotator cuff disorders remain the most common cause of shoulder pain and are among the most common reasons for patients to seek care in primary and specialty settings. Although operative and nonoperative treatments are offered to patients with atraumatic rotator cuff tears, there is a lack of evidence to support operative vs nonoperative treatment. This paucity of evidence has been highlighted by several professional agencies and experts. To perform a pragmatic randomized clinical trial, the Arthroscopic Rotator Cuff trial, comparing pain and functional outcomes in patients undergoing operative vs nonoperative treatment for atraumatic rotator cuff tears, and assessing heterogeneity of treatment effects by age and tear size. Trial protocol of the Arthroscopic Rotator Cuff trial. This pragmatic randomized clinical trial of an estimated 700 patients is adequately powered to accomplish its aims with 488 patients. Primary analysis will be conducted on an intent-to-treat population in the context of a mixed model. The multicenter trial started recruitment in 2018 with a 1-year follow-up duration. Patients aged 50 years or older to younger than 85 years with magnetic resonance imaging-confirmed atraumatic rotator cuff tears that are suitable for either operative or nonoperative treatment will be enrolled. Block randomization will be performed and stratified by site, age, and tear size. Nonoperative treatment consists of an approximately 3-month standardized physical therapy program, whereas operative treatment consists of rotator cuff surgery followed by approximately 4 months of postoperative rehabilitation. The primary outcome is patient-reported Shoulder Pain and Disability Index score, and the secondary outcome is American Shoulder and Elbow Surgeons Standardized Shoulder Form score measured at 1 year of follow-up. The Arthroscopic Rotator Cuff trial is ongoing, and 12 sites with more than 40 physicians are currently recruiting patients. Although there is variation by site, as of May 2, 2019, 13% of all patients screened (787 of 6293) were eligible for the trial, and 9% of eligible patients (74 of 787) were recruited. Results of this study may help patients, clinicians, and policy makers assess the comparative effectiveness of operative vs nonoperative treatment for atraumatic rotator cuff tears. ClinicalTrials.gov identifier: NCT03295994.


Interaction between finger opposition movements and aftereffects of 1Hz-rTMS on ipsilateral motor cortex.
One-hertz repetitive transcranial magnetic stimulation (1Hz-rTMS) over ipsilateral motor cortex is able to modify up to 30 min the motor performance of repetitive finger opposition movements paced with a metronome at 2 Hz. We investigated whether the long-lasting rTMS effect on motor behavior can be modulated by subsequent engagement of the contralateral sensorimotor system. Motor task was performed in different experimental conditions: immediately after rTMS, 30 min after rTMS, or when real rTMS was substituted with sham rTMS. Subjects performing the motor task immediately after rTMS showed modifications in motor behavior < or =30 min after rTMS. On the other hand, when real rTMS was substituted with sham stimulation or when subjects performed the motor task 30 min after the rTMS session, the effect was no longer present. These findings suggest that the combination of ipsilateral 1Hz-rTMS and voluntary movement is crucial to endure the effect of rTMS on the movement itself, probably acting on synaptic plasticity-like mechanism. This finding might provide some useful hints for neurorehabilitation protocols.


The representativeness of eligible patients in type 2 diabetes trials: a case study using GIST 2.0.
The population representativeness of a clinical study is influenced by how real-world patients qualify for the study. We analyze the representativeness of eligible patients for multiple type 2 diabetes trials and the relationship between representativeness and other trial characteristics. Sixty-nine study traits available in the electronic health record data for 2034 patients with type 2 diabetes were used to profile the target patients for type 2 diabetes trials. A set of 1691 type 2 diabetes trials was identified from ClinicalTrials.gov, and their population representativeness was calculated using the published Generalizability Index of Study Traits 2.0 metric. The relationships between population representativeness and number of traits and between trial duration and trial metadata were statistically analyzed. A focused analysis with only phase 2 and 3 interventional trials was also conducted. A total of 869 of 1691 trials (51.4%) and 412 of 776 phase 2 and 3 interventional trials (53.1%) had a population representativeness of <5%. The overall representativeness was significantly correlated with the representativeness of the Hba1c criterion. The greater the number of criteria or the shorter the trial, the less the representativeness. Among the trial metadata, phase, recruitment status, and start year were found to have a statistically significant effect on population representativeness. For phase 2 and 3 interventional trials, only start year was significantly associated with representativeness. Our study quantified the representativeness of multiple type 2 diabetes trials. The common low representativeness of type 2 diabetes trials could be attributed to specific study design requirements of trials or safety concerns. Rather than criticizing the low representativeness, we contribute a method for increasing the transparency of the representativeness of clinical trials.


Thrombotic Risk Determined by Protein C Receptor (PROCR) Variants among Middle-Aged and Older Adults: A Population-Based Cohort Study.
The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequencies (MAFs) <0.1%. Re-sequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2,584 VTE exomes), 11 synonymous, 22 missense, and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease, whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio (HR) of 1.5 (95% confidence interval [CI]: 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF = 0.004) showed an increased VTE risk (HR = 1.3; 95% CI: 1.0-1.9). Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.


Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model.
The blood-tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma. Poor drug entry across the BTB allows infiltrative glioma stem cells to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood-brain barrier in non-tumor-bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. In vitro, A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, downregulation of junctional protein expression by 4 hours, and reestablishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide concentrations, yet no increased survival noted with combined temozolomide therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes among glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance central nervous system treatment delivery to aggressive brain tumors. IMPLICATIONS: This study provides insight on the use of a vasoactive agent to increase exposure of the BTB to chemotherapy with intention to improve glioma treatment efficacy.


Maternal diet-induced obesity programs cardiovascular dysfunction in adult male mouse offspring independent of current body weight.
Obese pregnancies are not only associated with adverse consequences for the mother but also the long-term health of her child. Human studies have shown that individuals from obese mothers are at increased risk of premature death from cardiovascular disease (CVD), but are unable to define causality. This study aimed to determine causality using a mouse model of maternal diet-induced obesity. Obesity was induced in female C57BL/6 mice by feeding a diet rich in simple sugars and saturated fat 6 weeks prior to pregnancy and throughout pregnancy and lactation. Control females were fed laboratory chow. Male offspring from both groups were weaned onto chow and studied at 3, 5, 8, and 12 weeks of age for gross cardiac morphometry using stereology, cardiomyocyte cell area by histology, and cardiac fetal gene expression using qRT-PCR. Cardiac function was assessed by isolated Langendorff technology at 12 weeks of age and hearts were analyzed at the protein level for the expression of the β1 adrenergic receptor, muscarinic type-2 acetylcholine receptor, and proteins involved in cardiac contraction. Offspring from obese mothers develop pathologic cardiac hypertrophy associated with re-expression of cardiac fetal genes. By young adulthood these offspring developed severe systolic and diastolic dysfunction and cardiac sympathetic dominance. Importantly, cardiac dysfunction occurred in the absence of any change in corresponding body weight and despite the offspring eating a healthy low-fat diet. These findings provide a causal link to explain human observations relating maternal obesity with premature death from CVD in her offspring.


Information decomposition of multichannel EMG to map functional interactions in the distributed motor system.
The central nervous system needs to coordinate multiple muscles during postural control. Functional coordination is established through the neural circuitry that interconnects different muscles. Here we used multivariate information decomposition of multichannel EMG acquired from 14 healthy participants during postural tasks to investigate the neural interactions between muscles. A set of information measures were estimated from an instantaneous linear regression model and a time-lagged VAR model fitted to the EMG envelopes of 36 muscles. We used network analysis to quantify the structure of functional interactions between muscles and compared them across experimental conditions. Conditional mutual information and transfer entropy revealed sparse networks dominated by local connections between muscles. We observed significant changes in muscle networks across postural tasks localized to the muscles involved in performing those tasks. Information decomposition revealed distinct patterns in task-related changes: unimanual and bimanual pointing were associated with reduced transfer to the pectoralis major muscles, but an increase in total information compared to no pointing, while postural instability resulted in increased information, information transfer and information storage in the abductor longus muscles compared to normal stability. These findings show robust patterns of directed interactions between muscles that are task-dependent and can be assessed from surface EMG recorded during static postural tasks. We discuss directed muscle networks in terms of the neural circuitry involved in generating muscle activity and suggest that task-related effects may reflect gain modulations of spinal reflex pathways.


Pharmacological and genetic analysis of 90-kDa heat shock isoprotein-aryl hydrocarbon receptor complexes.
The 90-kDa heat shock protein (Hsp90) is an abundant chaperone that regulates a diverse set of intracellular signaling proteins. Drugs that inhibit Hsp90 activity have been useful in the identification of novel Hsp90-dependent signaling pathways. One class of inhibitory compounds disrupts Hsp90-dependent processes by binding to the N-terminal ATPase/p23-binding domain of Hsp90, whereas a second inhibitor class binds within the C-terminal domain. We used signaling by aryl hydrocarbon receptor (AhR), an Hsp90-dependent transcription factor, as a functional probe to study the effects of Hsp90 inhibitors in yeast strains with deletion mutations of individual Hsp90 and p23 cochaperone genes. The more abundant and constitutively expressed Hsp90 isoform, Hsc82, functioned best in supporting AhR signaling. Deletion of the more inducible isoform, Hsp82, had no effect on signaling. AhR complexes containing Hsc82 were preferentially sensitive to the effects of low concentrations of the N-terminal inhibitors radicicol and herbimycin A. However, both Hsp90 isoforms were equally sensitive to the AhR-specific effects of novobiocin, which binds to the C terminus. Hsp90 inhibitors had no preferential effects on AhR signaling in strains that lacked p23, suggesting that the inhibitors exert their effects through a p23-independent mechanism. In contrast, overexpression of p23 buffered the effects of radicicol and herbimycin A, but not novobiocin, on AhR signaling. The data collectively suggest preferential use or function of the Hsc82 isoprotein in AhR signaling and provide new insight into the effects of three structurally unrelated Hsp90 inhibitors.


Regulation of estrogen biosynthesis in human adipose stromal cells. Effects of dibutyryl cyclic AMP, epidermal growth factor, and phorbol esters on the synthesis of aromatase cytochrome P-450.
Using human adipose stromal cells in monolayer culture as a model system for study of the regulation of aromatase activity, as well as polyclonal antibodies raised in this laboratory against aromatase cytochrome P-450 (cytochrome P-450AROM), it was found that the rate of synthesis of cytochrome P-450AROM was stimulated by dibutyryl cyclic AMP. This stimulation was attenuated by epidermal growth factor and was potentiated by phorbol esters. These changes in cytochrome P-450AROM synthesis were associated with comparable changes in the levels of translatable cytochrome P-450AROM mRNA, as well as with changes in the activity of aromatase of these cells. By contrast, there was little change in the synthesis of the reductase component of the aromatase enzyme complex in response to these factors. The increase in mRNA was blocked by cycloheximide, indicative of a requirement for protein synthesis in mediating this inductive response. It is concluded that aromatase activity is regulated primarily by changes in the level of mRNA encoding cytochrome P-450AROM, and that such changes are likely a reflection of changes in the rate of transcription of the gene encoding this enzyme. Increases in the levels of cytochrome P-450AROM mRNA are apparently mediated by a regulatory protein(s), similar to that found for other steroidogenic forms of cytochrome P-450.


Critical appraisal of questionnaires to assess functional impairment in individuals with mild cognitive impairment.
Mild deficits in instrumental activities of daily living (IADLs) have consistently been reported in the individuals with mild cognitive impairment (MCI). A variety of functional assessment tools, including self-and informant report questionnaires and performance-based measures, have been employed in MCI. Previously, a limited focus has been directed at appraising the quality of questionnaires. The goal of this study was to identify the questionnaires that have been validated in the MCI population. Additionally, the quality of validation studies and psychometric attributes of these questionnaires were appraised. Relevant articles were systematically searched in PsychINFO, Ovid MEDLINE, and CINAHL against specific eligibility criteria. To evaluate the methodology of the psychometric studies, the COSMIN checklist was employed. Also, the psychometric properties of the assessment tools were evaluated based upon Terwee's criteria. A total of five psychometric studies and questionnaires were critically evaluated. Varying psychometric properties were available for the chosen tools. None of the studies received the best possible rating for their methodological quality. It was found that questionnaires with high discriminative ability to distinguish MCI from other diagnostic groups were: Disability Assessment in Dementia-6 (DAD-6), Functional Activity Questionnaire (FAQ), and Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for MCI patients (ADCS-MCI-ADL-24). Psychometric studies with strong methodological rigor are required in the future. Considering the fact that IADL decline has been associated with dementia, early detection of functional difficulties in MCI needs to be encouraged as it will allow suitable and timely interventions to prolong functional independence of affected individuals.


A synbio approach for selection of highly expressed gene variants in Gram-positive bacteria.
The market for recombinant proteins is on the rise, and Gram-positive strains are widely exploited for this purpose. Bacillus subtilis is a profitable host for protein production thanks to its ability to secrete large amounts of proteins, and Lactococcus lactis is an attractive production organism with a long history in food fermentation. We have developed a synbio approach for increasing gene expression in two Gram-positive bacteria. First of all, the gene of interest was coupled to an antibiotic resistance gene to create a growth-based selection system. We then randomised the translation initiation region (TIR) preceding the gene of interest and selected clones that produced high protein titres, as judged by their ability to survive on high concentrations of antibiotic. Using this approach, we were able to significantly increase production of two industrially relevant proteins; sialidase in B. subtilis and tyrosine ammonia lyase in L. lactis. Gram-positive bacteria are widely used to produce industrial enzymes. High titres are necessary to make the production economically feasible. The synbio approach presented here is a simple and inexpensive way to increase protein titres, which can be carried out in any laboratory within a few days. It could also be implemented as a tool for applications beyond TIR libraries, such as screening of synthetic, homologous or domain-shuffled genes.


Characterization of mammalian UDP-GalNAc:glucuronide alpha 1-4-N-acetylgalactosaminyltransferase.
We previously reported that cultured cells incubated with beta-xylosides synthesized alpha-GalNAc-capped GAG-related xylosides, GalNAc alpha GlcA beta Gal beta Gal beta Xyl beta-R and GalNAc alpha GlcA beta GalNAc beta GlcA beta Gal beta Gal beta Xyl beta-R, where R is 4-methylumbelliferyl or p-nitrophenyl (Manzi et al., 1995; Miura and Freeze, 1998). In this study, we characterized an alpha-N-acetylgalactosaminyltransferase (alpha-GalNAc-T) that probably adds the alpha-GalNAc residue to the above xylosides. Microsomes from several animal cells and mouse brain contained the enzyme activity which requires divalent cations, and has a relatively broad pH optimal range around neutral. The apparent K(m) values were in the submillimolar range for the acceptors tested, and 19 microM for UDP-GalNAc. 1H-NMR analysis of the GlcA-beta-MU acceptor product showed the GalNAc residue is transferred in alpha 1,4-linkage to the glucuronide, which is consistent with previous results reported on alpha-GalNAc-capped Xyl-MU (Manzi et al., 1995). Various artificial glucuronides were tested as acceptors to assess the influence of the aglycone. Glucuronides with a bicyclic aromatic ring, such as 4-methylumbelliferyl beta-D-glucuronide (GlcA-beta-MU) and alpha-naphthyl beta-D-glucuronide, were the best acceptors. Interestingly, a synthetic acceptor that resembles the HNK-1 carbohydrate epitope but lacking the sulfate group, GlcA beta 1,3Gal beta 1,4GlcNAc beta-O-octyl (delta SHNK-C8), was a better acceptor for alpha-GalNAc-T than the glycosaminoglycan-protein linkage region tetrasaccharyl xyloside, GlcA beta 1,3Gal beta 1,3Gal beta 1,4Xyl beta-MU. GlcA-beta-MU and delta SHNK-C8 competed for the alpha-GalNAc-T activity, suggesting that the same activity catalyzes the transfer of the GalNAc residue to both acceptors. Taken together, the results show that the alpha-GalNAc-T described here is not restricted to GAG-type oligosaccharide acceptors, but rather is a UDP-GalNAc:glucuronide alpha 1-4-N-acetylgalactosaminyltransferase.


Recovery opioid overdose team (ROOT) pilot program evaluation: A community-wide post-overdose response strategy.
Background: Effective interventions for overdose survivors are needed in the emergency departments (EDs). One promising model is the use of peer recovery coaches to engage with survivors in EDs, followed by partnering with community case management navigators to connect survivors to recovery support and treatment services. This paper describes the evaluation of a pilot program, the Recovery Opioid Overdose Team (ROOT), a warm hand-off system that links survivors to treatment services post-ED discharge. Methods: The ROOT program is composed of a peer recovery coach who is in long-term recovery, and a case management navigator who specializes in mental health care and provides guidance for accessing community services. After an overdose reversal, law enforcement contacts a county 24/7 Crisis Team, who then notifies ROOT. The peer recovery coach engages with the survivor in the ED, and then follow up continues with the case management navigator and the peer recovery coach for up to 90 days post-ED discharge. Retrospective chart reviews were conducted to evaluate ROOT in two Midwest EDs from September 2017 through March 2019. Results: Of the 122 referrals, 77.0% (n = 94) of the survivors initially engaged with ROOT in the ED or in the community. The remaining 23.0% (n = 28) left the ED against medical advice or were unengaged. The majority of overdose survivors were male (63.9%; n = 78), White (43.4%; n = 53), had housing (80.2%; n = 48), and access to transportation (48.4%; n = 59). From the 122 referrals, 33.6% (n = 41) received ongoing treatment services (n = 20 outpatient, n = 17 residential, n = 2 detoxification facility, n = 1 recovery housing, n = 1 medication treatment for opioid use disorder), 2.5% (n = 3) were incarcerated, 2.5% (n = 3) died, and 61.5% (n = 75) declined services. Conclusions: The ROOT, a community-wide coordinated program in the EDs, shows promise in linking overdose survivors to recovery support and treatment services post-overdose.


A survey method for characterizing daily life experience: the day reconstruction method.
The Day Reconstruction Method (DRM) assesses how people spend their time and how they experience the various activities and settings of their lives, combining features of time-budget measurement and experience sampling. Participants systematically reconstruct their activities and experiences of the preceding day with procedures designed to reduce recall biases. The DRM's utility is shown by documenting close correspondences between the DRM reports of 909 employed women and established results from experience sampling. An analysis of the hedonic treadmill shows the DRM's potential for well-being research.


Insulin sensitivity and body composition in children with classical and nonclassical congenital adrenal hyperplasia.
Reduced insulin sensitivity and increased fat mass have been reported in children and adults with congenital adrenal hyperplasia (CAH). To understand the potential mechanisms underlying these differences, we assessed insulin sensitivity and body composition in children with classical or nonclassical (late-presenting) CAH compared with normal controls. Thirty-seven children with CAH (26 classical and 11 nonclassical) median (range) age 9.4 year (0.5-15.8) were compared with 41 healthy control children age 11.0 year (3.2-17.1). All children had an overnight fasting blood sample and body composition assessed by DEXA. Pubertal children (14 CAH and 19 controls) also had an oral glucose tolerance test. Classical and nonclassical CAH groups were each compared with controls, adjusting for age, gender and pubertal status. Results Classical CAH children had more fat mass than controls (P = 0.03), while nonclassical CAH children had more lean mass (P = 0.006) and higher systolic blood pressure (P = 0.003) than control children. Among pubertal children, nonclassical CAH children had higher mean insulin (0-120 min; P = 0.04), stimulated insulin (0-30 min; P = 0.02), 120 min insulin (P = 0.004) and 120 min glucose levels (P = 0.03) than controls, but no difference in disposition index. Greater body fat in classical (early-presenting) CAH children could reflect the effects of lifetime glucocorticoid therapy. In contrast, the greater lean mass and parameters of insulin resistance in nonclassical (late-presenting) CAH children likely indicate the adverse metabolic effects of prolonged postnatal androgen excess.


Background learning for robust face recognition with PCA in the presence of clutter.
We propose a new method within the framework of principal component analysis (PCA) to robustly recognize faces in the presence of clutter. The traditional eigenface recognition (EFR) method, which is based on PCA, works quite well when the input test patterns are faces. However, when confronted with the more general task of recognizing faces appearing against a background, the performance of the EFR method can be quite poor. It may miss faces completely or may wrongly associate many of the background image patterns to faces in the training set. In order to improve performance in the presence of background, we argue in favor of learning the distribution of background patterns and show how this can be done for a given test image. An eigenbackground space is constructed corresponding to the given test image and this space in conjunction with the eigenface space is used to impart robustness. A suitable classifier is derived to distinguish nonface patterns from faces. When tested on images depicting face recognition in real situations against cluttered background, the performance of the proposed method is quite good with fewer false alarms.


The wicked in court: a neuroscientific primer.
The criminal cases of Anders Breivik, the Norwegian shooter, and Bernard Madoff, the fraudulent American financier, are used as prominent examples of the complexity that courts have to explore when judging the severity and responsibility of felonies performed by different types of psychopaths. I outline the brain circuits subserving morally charged decisions in ordinary citizens and in patients with gross lesions in the same areas, along with singularities in these brain systems that have been detected in psychopaths. These neural signatures, combined with thorough neuropsychological examination, will hopefully improve the diagnoses and prognoses of criminals with dangerous psychopathic traits. In this respect, the profiles of incarcerated members of gangs are used to exemplify and distinguish among typical niches and varieties of psychopathy within criminal organizations. A discussion follows, presenting the complexities of novel research that is increasing the sophistication of these challenging but key intersections between neuroscience and law.


Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems.
Amphetamine analogs with a 3,4-methylenedioxy ring-substitution are among the most popular illicit drugs of abuse, exerting stimulant and entactogenic effects. Enzymatic N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to metabolites that may be pharmacologically active. Indeed, previous studies in rats show that specific metabolites of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) can interact with monoaminergic systems. Interactions of metabolites of MDMA, methylone and MDPV with human monoaminergic systems were assessed. The ability of parent drugs and their metabolites to inhibit uptake of tritiated norepinephrine, dopamine and serotonin (5-HT) was assessed in human embryonic kidney 293 cells transfected with human monoamine transporters. Binding affinities and functional activity at monoamine transporters and various receptor subtypes were also determined. MDMA and methylone displayed greater potency to inhibit norepinephrine uptake as compared to their effects on dopamine and 5-HT uptake. N-demethylation of MDMA failed to alter uptake inhibition profiles, whereas N-demethylation of methylone decreased overall transporter inhibition potencies. O-demethylenation of MDMA, methylone and MDPV resulted in catechol metabolites that maintained norepinephrine and dopamine uptake inhibition potencies, but markedly reduced activity at 5-HT uptake. O-methylation of the catechol metabolites significantly decreased norepinephrine uptake inhibition, resulting in metabolites lacking significant stimulant properties. Several metabolites of MDMA, methylone and MDPV interact with human transporters and receptors at pharmacologically relevant concentrations. In particular, N-demethylated metabolites of MDMA and methylone circulate in unconjugated form and could contribute to the in vivo activity of the parent compounds in human users.


Varicella vaccination in Europe: are we ready for a universal childhood programme?
Safe and effective vaccines against varicella zoster virus (VZV), the aetiological agent of varicella and shingles, have been available in Europe for the last 5-10 years. The USA has had a universal childhood vaccination policy since 1995 and this has resulted in a dramatic decrease in the incidence, morbidity and mortality related to varicella. The economic and medical burden of VZV has led to discussions regarding both the desirability and feasibility of a similar routine immunisation policy for all European children. This article examines the epidemiology of varicella in Europe and how the data emerging from the USA can be used to achieve adequate prevention of the disease. It looks into the current evidence of the health economic evaluation of universal varicella vaccination and explores the concerns surrounding such a policy, including the postulated impact on the incidence of zoster. In conclusion, the Society of Independent European Vaccination Experts (SIEVE) recommends that the immunisation of susceptible adolescents needs to be urgently implemented, in addition to the current recommendations targeting high-risk patients, their close contacts with a negative history of varicella and seronegative health-care workers. A universal policy, optimally incorporating a two-dose schedule, will be needed to finally reduce the burden of disease of varicella from a societal point of view. The SIEVE recommends the implementation of such a policy as soon as financially and practically possible.


Eating disorders and quality of life: a review of the literature.
Following recent scientific interest in the quality of life (QoL) of individuals with eating disorders (EDs), this paper aims to provide a summary of the relevant evidence. A literature review on QoL in EDs (EDQoL) was carried out and relevant articles are described in six main sections. Following an introduction to the area and a summary of the methods used in the review, assessment of QoL in EDs is discussed. The third section represents the body of the review and appraises EDQoL in more detail, discussing what idiosyncratic features of EDs might be important in affecting QoL. The review concludes with suggestions for further research in this evolving area and summarizes the main findings. An evidence base is constructed supporting the idea that those with EDs have impaired QoL compared to other psychiatric and physical health conditions. However, what determines impairments in QoL is yet to be delineated although ideas for such variables, such as the presence of bingeing and purging, are suggested. Development of ED-specific measures has aided greatly in the pursuit of clarity, although equivocal conclusions in this complex area necessitate further research.


To the trained eye: perceptual expertise alters visual processing.
Perceptual expertise refers to learning that is specific to a domain, that transfers to new items within the trained domain, and that leads to automatic processing in the sense that expertise effects can be measured across a variety of tasks. It can be argued that most of us possess some degree of perceptual expertise in a least one, if not several domains, thereby giving the study of perceptual expertise broad application. Some object categories may in fact be objects of perceptual expertise to the majority of people: Faces appear to be one such example. Thus, the use of face stimuli, or the comparison of face and object perception, can be a powerful way to ask whether a given process is influenced by perceptual expertise. Here, we emphasize one characteristic way that face processing appears to differ from nonface processing: that is, the degree to which they recruit a "holistic" rather than a "featural" perceptual strategy. This review brings evidence that expertise influences perceptual processing together with recent findings that the capacity of visual short-term memory is greater in perceptual experts and explores the relationship between the two.


Blood contamination of the aerosols produced by in vivo use of ultrasonic scalers.
Disease transmission and barrier techniques during dental treatment have been areas of recent concern in dentistry. Ultrasonic scalers are known to produce aerosols, and these aerosols are often produced from areas of significant disease activity, including bleeding. This study was performed to determine if these aerosols contain blood from the gingival sulcus. Forty areas consisting of two contiguous periodontally involved teeth (probing depth of at least 5 mm on one site of each tooth) were scaled subgingivally with an ultrasonic scaler for 30 seconds. A high volume evacuator (HVE) tip was positioned 3 to 5 cm away from the operating site and utilized to capture the aerosols produced. The water remaining in and on the HVE tube was tested for occult blood by the guiac resin method. Gingival index, mean probing depth, presence of bleeding with scaling, and presence of visible blood in the HVE tip were recorded. All 40 test sites showed a positive result for blood in the captured aerosols despite the wide variation in the measured parameters. It may be concluded that subgingival scaling on periodontally involved teeth with ultrasonic scalers would be expected to produce aerosols containing blood.


Current concepts in F18 FDG PET/CT-based radiation therapy planning for lung cancer.
Radiation therapy is an important component of cancer therapy for early stage as well as locally advanced lung cancer. The use of F18 FDG PET/CT has come to the forefront of lung cancer staging and overall treatment decision-making. FDG PET/CT parameters such as standard uptake value and metabolic tumor volume provide important prognostic and predictive information in lung cancer. Importantly, FDG PET/CT for radiation planning has added biological information in defining the gross tumor volume as well as involved nodal disease. For example, accurate target delineation between tumor and atelectasis is facilitated by utilizing PET and CT imaging. Furthermore, there has been meaningful progress in incorporating metabolic information from FDG PET/CT imaging in radiation treatment planning strategies such as radiation dose escalation based on standard uptake value thresholds as well as using respiratory-gated PET and CT planning for improved target delineation of moving targets. In addition, PET/CT-based follow-up after radiation therapy has provided the possibility of early detection of local as well as distant recurrences after treatment. More research is needed to incorporate other biomarkers such as proliferative and hypoxia biomarkers in PET as well as integrating metabolic information in adaptive, patient-centered, tailored radiation therapy.


Antibody in Lymphocyte Supernatant (ALS) responses after oral vaccination with live Shigella sonnei vaccine candidates WRSs2 and WRSs3 and correlation with serum antibodies, ASCs, fecal IgA and shedding.
The levels of antigen-specific Antibodies in Lymphocyte Supernatant (ALS) using an ELISA are being used to evaluate mucosal immune responses as an alternate to measuring the number of Antibody Secreting Cells (ASCs) using an ELISpot assay. A recently completed trial of two novel S. sonnei live oral vaccine candidates WRSs2 and WRSs3 established that both candidates were safe, well tolerated and immunogenic in a vaccine dose-dependent manner. Previously, mucosal immune responses were measured by assaying IgA- and IgG-ASC in peripheral blood mononuclear cells (PBMCs). In this report, the magnitude of the S. sonnei antigen-specific IgA- and IgG-ALS responses was measured and correlated with previously described ASCs, serum antibodies, fecal IgA and vaccine shedding. Overall, the magnitude of S. sonnei anti-Invaplex50 ALS was higher than that of LPS or IpaB, and both vaccines demonstrated a more robust IgA-ALS response than IgG; however, compared to WRSs3, the magnitude and percentage of responders were higher among WRSs2 recipients for IgA- or IgG-ALS. All WRSs2 vaccinees at the two highest doses responded for LPS and Invaplex50-specific IgA-ALS and 63-100% for WRSs3 vaccinees responded. Regardless of the vaccine candidate, vaccine dose or detecting antigen, the kinetics of ALS responses were similar peaking on days 7 to 9 and returning to baseline by day 14. The ALS responses were vaccine-specific since no responses were detected among placebo recipients at any time. A strong correlation and agreement between responders/non-responders were noted between ALS and other mucosal (ASC and fecal IgA) and systemic (serum antibody) immune responses. These data indicate that the ALS assay can be a useful tool to evaluate mucosal responses to oral vaccination, an observation noted with trials of other bacterial diarrheal pathogens. Furthermore, this data will guide the list of immunological assays to be conducted for efficacy trials in different populations. It is hoped that an antigen-specific-ALS titer may be a key mucosal correlate of protection, a feature not currently available for any Shigella vaccines candidates. https://clinicaltrials.gov/show/NCT01336699.


Five decades of genome evolution in the globally distributed, extensively antibiotic-resistant Acinetobacter baumannii global clone 1.
The majority of Acinetobacter baumannii isolates that are multiply, extensively and pan-antibiotic resistant belong to two globally disseminated clones, GC1 and GC2, that were first noticed in the 1970s. Here, we investigated microevolution and phylodynamics within GC1 via analysis of 45 whole-genome sequences, including 23 sequenced for this study. The most recent common ancestor of GC1 arose around 1960 and later diverged into two phylogenetically distinct lineages. In the 1970s, the main lineage acquired the AbaR resistance island, conferring resistance to older antibiotics, via a horizontal gene transfer event. We estimate a mutation rate of ∼5 SNPs genome- 1 year- 1 and detected extensive recombination within GC1 genomes, introducing nucleotide diversity into the population at >20 times the substitution rate (the ratio of SNPs introduced by recombination compared with mutation was 22). The recombination events were non-randomly distributed in the genome and created significant diversity within loci encoding outer surface molecules (including the capsular polysaccharide, the outer core lipooligosaccharide and the outer membrane protein CarO), and spread antimicrobial resistance-conferring mutations affecting the gyrA and parC genes and insertion sequence insertions activating the ampC gene. Both GC1 lineages accumulated resistance to newer antibiotics through various genetic mechanisms, including the acquisition of plasmids and transposons or mutations in chromosomal genes. Our data show that GC1 has diversified into multiple successful extensively antibiotic-resistant subclones that differ in their surface structures. This has important implications for all avenues of control, including epidemiological tracking, antimicrobial therapy and vaccination.


Regulatory roles of phosphorylation in model and pathogenic fungi.
Over the past 20 years, considerable advances have been made toward our understanding of how post-translational modifications affect a wide variety of biological processes, including morphology and virulence, in medically important fungi. Phosphorylation stands out as a key molecular switch and regulatory modification that plays a critical role in controlling these processes. In this article, we first provide a comprehensive and up-to-date overview of the regulatory roles that both Ser/Thr and non-Ser/Thr kinases and phosphatases play in model and pathogenic fungi. Next, we discuss the impact of current global approaches that are being used to define the complete set of phosphorylation targets (phosphoproteome) in medically important fungi. Finally, we provide new insights and perspectives into the potential use of key regulatory kinases and phosphatases as targets for the development of novel and more effective antifungal strategies.


[Biomimetic oxidation of diphenyl sulfide with electrochemical P-450 model system in CH2Cl2 treated with alkaline solution].
Dichloromethane containing metalloporphyrins [meso-tetraphenylporphyrinatomanganese(III) chloride (1) or meso-tetraphenylporphyrinatoiron(III) chloride (2)] and Bu4NClO4 was treated with an aqueous solution of NaOH (5%), and subjected to controlled potential electrolysis at -1.0 V (vs. S.C.E. (saturated calomel electrode)) in a divided cell after addition of diphenyl sulfide (3). Diphenyl sulfoxide (4) and diphenyl sulfone (5) were found in an electrolyzed solution as the reaction products. Results obtained from cyclic voltammetry and visible spectrometry suggested that the treatment of dichloromethane containing metalloporphyrins with the aqueous solution of NaOH did not change the fifth ligand of metalloporphyrins from Cl to OH. On the electrode, dissolved dioxygen was reduced to hydrogen peroxide. Compounds 1 and 2 catalyze the oxidation of 3 by hydrogen peroxide without imidazole. Compound 2 showed higher selectivity than compound 1.


Temperature and trapping characterization of an acoustic trap with miniaturized integrated transducers--towards in-trap temperature regulation.
An acoustic trap with miniaturized integrated transducers (MITs) for applications in non-contact trapping of cells or particles in a microfluidic channel was characterized by measuring the temperature increase and trapping strength. The fluid temperature was measured by the fluorescent response of Rhodamine B in the microchannel. The trapping strength was measured by the area of a trapped particle cluster counter-balanced by the hydrodynamic force. One of the main objectives was to obtain quantitative values of the temperature in the fluidic channel to ensure safe handling of cells and proteins. Another objective was to evaluate the trapping-to-temperature efficiency for the trap as a function of drive frequency. Thirdly, trapping-to-temperature efficiency data enables identifying frequencies and voltage values to use for in-trap temperature regulation. It is envisioned that operation with only in-trap temperature regulation enables the realization of small, simple and fast temperature-controlled trap systems. The significance of potential gradients at the trap edges due to the finite size of the miniaturized transducers for the operation was emphasized and expressed analytically. The influence of the acoustic near field was evaluated in FEM-simulation and compared with a more ideal 1D standing wave. The working principle of the trap was examined by comparing measurements of impedance, temperature increase and trapping strength with impedance transfer calculations of fluid-reflector resonances and frequencies of high reflectance at the fluid-reflector boundary. The temperature increase was found to be moderate, 7°C for a high trapping strength, at a fluid flow of 0.5mms(-1) for the optimal driving frequency. A fast temperature response with a fall time of 8s and a rise time of 11s was observed. The results emphasize the importance of selecting the proper drive frequency for long term handling of cells, as opposed to the more pragmatic way of selecting the frequency of the highest acoustic output. Trapping was demonstrated in a large interval between 9 and 11.5MHz, while the main trapping peak displayed FWHM of 0.5MHz. A large bandwidth enables a more robust manufacturing and operation while allowing the trapping platform to be used in applications where the fluid wavelength varies due to external variations in fluid temperature, density and pressure.


PyRETIS: A well-done, medium-sized python library for rare events.
Transition path sampling techniques are becoming common approaches in the study of rare events at the molecular scale. More efficient methods, such as transition interface sampling (TIS) and replica exchange transition interface sampling (RETIS), allow the investigation of rare events, for example, chemical reactions and structural/morphological transitions, in a reasonable computational time. Here, we present PyRETIS, a Python library for performing TIS and RETIS simulations. PyRETIS directs molecular dynamics (MD) simulations in order to sample rare events with unbiased dynamics. PyRETIS is designed to be easily interfaced with any molecular simulation package and in the present release, it has been interfaced with GROMACS and CP2K, for classical and ab initio MD simulations, respectively. © 2017 Wiley Periodicals, Inc.


The association of home-telehealth use and care coordination with improvement of functional and cognitive functioning in frail elderly men.
This study compared health-related outcomes, during a 1-year period, for two groups of frail elders-one that received care coordination via distance monitoring (home-telehealth) and one that received no intervention. A case-control design was employed. The home telehealth intervention group was made up of 111 male veterans who were enrolled in a Veterans Health Administration project. The control group consisted of 115 men who were referred from either senior service agencies or hospital rehabilitation programs, but did not receive home-telehealth. Subjects in both groups had primary diagnoses of hypertension, diabetes, respiratory disease, or heart disease. The two groups were similar in terms of age, race, marital status, and independence in instrumental activities of daily living (IADL) at baseline. A paired t-test was used to study the before-after (baseline to 12-month follow-up) improvements in the outcome measures within each group. Regression models were used to compare the outcome improvements between the two groups. Over 1 year, the intervention group improved 2.2 points more in IADL, 14.4 points more in FIM motor scores, and 2.7 points more in FIM cognitive scores than the control group (p < 0.0001). This evidence supports the use of a specific home-telehealth strategy for care coordination to improve functional independence in non-institutionalized veterans with chronic disease. A randomized controlled trial should be employed to confirm these findings.


Rck2 kinase is a substrate for the osmotic stress-activated mitogen-activated protein kinase Hog1.
Exposure of yeast cells to increases in extracellular osmolarity activates the Hog1 mitogen-activated protein kinase (MAPK). Activation of Hog1 MAPK results in induction of a set of osmoadaptive responses, which allow cells to survive in high-osmolarity environments. Little is known about how the MAPK activation results in induction of these responses, mainly because no direct substrates for Hog1 have been reported. We conducted a two-hybrid screening using Hog1 as a bait to identify substrates for the MAPK, and the Rck2 protein kinase was identified as an interactor for Hog1. Both two-hybrid analyses and coprecipitation assays demonstrated that Hog1 binds strongly to the C-terminal region of Rck2. Upon osmotic stress, Rck2 was phosphorylated in vivo in a Hog1-dependent manner. Furthermore, purified Hog1 was able to phosphorylate Rck2 when activated both in vivo and in vitro. Rck2 phosphorylation occurred specifically at Ser519, a residue located within the C-terminal putative autoinhibitory domain. Interestingly, phosphorylation at Ser519 by Hog1 resulted in an increase of Rck2 kinase activity. Overexpression of Rck2 partially suppressed the osmosensitive phenotype of hog1Delta and pbs2Delta cells, suggesting that Rck2 is acting downstream of Hog1. Consistently, growth arrest caused by hyperactivation of the Hog1 MAPK was abolished by deletion of the RCK2 gene. Furthermore, overexpression of a catalytically impaired (presumably dominant inhibitory) Rck2 kinase resulted in a decrease of osmotolerance in wild-type cells but not in hog1Delta cells. Taken together, our data suggest that Rck2 acts downstream of Hog1, controlling a subset of the responses induced by the MAPK upon osmotic stress.


Genetic Basis of Grain Size and Weight in Rice, Wheat, and Barley.
Grain size is a key component of grain yield in cereals. It is a complex quantitative trait controlled by multiple genes. Grain size is determined via several factors in different plant development stages, beginning with early tillering, spikelet formation, and assimilates accumulation during the pre-anthesis phase, up to grain filling and maturation. Understanding the genetic and molecular mechanisms that control grain size is a prerequisite for improving grain yield potential. The last decade has brought significant progress in genomic studies of grain size control. Several genes underlying grain size and weight were identified and characterized in rice, which is a model plant for cereal crops. A molecular function analysis revealed most genes are involved in different cell signaling pathways, including phytohormone signaling, transcriptional regulation, ubiquitin-proteasome pathway, and other physiological processes. Compared to rice, the genetic background of grain size in other important cereal crops, such as wheat and barley, remains largely unexplored. However, the high level of conservation of genomic structure and sequences between closely related cereal crops should facilitate the identification of functional orthologs in other species. This review provides a comprehensive overview of the genetic and molecular bases of grain size and weight in wheat, barley, and rice, focusing on the latest discoveries in the field. We also present possibly the most updated list of experimentally validated genes that have a strong effect on grain size and discuss their molecular function.


Exposure to prenatal life events stress is associated with masculinized play behavior in girls.
Previous research has shown that prenatal exposure to endocrine-disrupting chemicals can alter children's neurodevelopment, including sex-typed behavior, and that it can do so in different ways in males and females. Non-chemical exposures, including psychosocial stress, may disrupt the prenatal hormonal milieu as well. To date, only one published study has prospectively examined the relationship between exposure to prenatal stress and gender-specific play behavior during childhood, finding masculinized play behavior in girls who experienced high prenatal life events stress, but no associations in boys. Here we examine this question in a second prospective cohort from the Study for Future Families. Pregnant women completed questionnaires on stressful life events during pregnancy, and those who reported one or more events were considered "stressed". Families were recontacted several years later (mean age of index child: 4.9 years), and mothers completed a questionnaire including the validated Preschool Activities Inventory (PSAI), which measures sexually dimorphic play behavior. In sex-stratified analyses, after adjusting for child's age, parental attitudes toward gender-atypical play, age and sex of siblings, and other relevant covariates, girls (n=72) exposed to prenatal life events stress had higher scores on the PSAI masculine sub-scale (β=3.48, p=0.006) and showed a trend toward higher (more masculine) composite scores (β=2.63, p=0.08). By contrast, in males (n=74), there was a trend toward an association between prenatal stress and higher PSAI feminine sub-scale scores (β=2.23, p=0.10), but no association with masculine or composite scores. These data confirm previous findings in humans and animal models suggesting that prenatal stress is a non-chemical endocrine disruptor that may have androgenic effects on female fetuses and anti-androgenic effects on male fetuses.


Association between V4 polymorphism in the ADAM33 gene and asthma risk: a meta-analysis.
In this study, we evaluated the associations between the V4 (rs2787094 G>C) polymorphism in a disintegrin and metalloproteinase domain 33 (ADAM33) gene and asthma risk. We searched Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 2013, without language restrictions. Meta-analysis was performed using the STATA 12.0 software. Crude odds ratios and 95% confidence intervals were calculated. Eight case-control studies were included, with a total of 2128 asthma patients and 3134 healthy controls. Our results suggest that the ADAM33 V4 polymorphism increases the risk of asthma. Subgroup analysis according to the source of controls revealed significant associations between the ADAM33 V4 polymorphism and risk of asthma in population- and hospital-based subgroups under allele and dominant models (all P < 0.05). Further subgroup analysis using the genotyping method suggested that the ADAM33 V4 polymorphism is correlated with asthma risk in the polymerase chain reaction-restriction fragment length polymorphism subgroup. However, no association was found in the non-polymerase chain reaction-restriction fragment length polymorphism subgroup. Meta-regression analyses showed that the genotyping method may be a main source of heterogeneity (P = 0.003). Our meta-analysis suggests that the ADAM33 V4 polymorphism contributes to the risk of asthma and may be utilized as a biomarker for the early diagnosis of asthma.


Bean metal-responsive element-binding transcription factor confers cadmium resistance in tobacco.
Cadmium (Cd) is highly toxic to plants. Modulation of Cd-responsive transcription is an important way for Cd detoxification in plants. Metal-responsive element (MRE) is originally described in animal metallothionein genes. Although functional MREs also exist in Cd-regulated plant genes, specific transcription factors that bind MRE to regulate Cd tolerance have not been identified. Previously, we showed that Cd-inducible bean (Phaseolus vulgaris) stress-related gene2 (PvSR2) produces a short (S) PvSR2 transcript (S-PvSR2) driven by an intronic promoter. Here, we demonstrate that S-PvSR2 encodes a bean MRE-binding transcription factor1 (PvMTF-1) that confers Cd tolerance in tobacco (Nicotiana tabacum). PvMTF-1 expression was up-regulated by Cd at the levels of RNA and protein. Importantly, expression of PvMTF-1 in tobacco enhanced Cd tolerance, indicating its role in regulating Cd resistance in planta. This was achieved through direct regulation of a feedback-insensitive Anthranilate Synthase α-2 chain gene (ASA2), which catalyzes the first step for tryptophan biosynthesis. In vitro and in vivo DNA-protein interaction studies further revealed that PvMTF-1 directly binds to the MRE in the ASA2 promoter, and this binding depends on the zinc finger-like motif of PvMTF-1. Through modulating ASA2 up-regulation by Cd, PvMTF-1 increased free tryptophan level and subsequently reduced Cd accumulation, thereby enhancing Cd tolerance of transgenic tobacco plants. Consistent with this observation, tobacco transiently overexpressing ASA2 also exhibited increased tolerance to Cd. We conclude that PvMTF-1 is a zinc finger-like transcription factor that links MRE to Cd resistance in transgenic tobacco through activation of tryptophan biosynthesis.


Assessing Monkeypox Virus Prevalence in Small Mammals at the Human-Animal Interface in the Democratic Republic of the Congo.
During 2012, 2013 and 2015, we collected small mammals within 25 km of the town of Boende in Tshuapa Province, the Democratic Republic of the Congo. The prevalence of monkeypox virus (MPXV) in this area is unknown; however, cases of human infection were previously confirmed near these collection sites. Samples were collected from 353 mammals (rodents, shrews, pangolins, elephant shrews, a potamogale, and a hyrax). Some rodents and shrews were captured from houses where human monkeypox cases have recently been identified, but most were trapped in forests and agricultural areas near villages. Real-time PCR and ELISA were used to assess evidence of MPXV infection and other Orthopoxvirus (OPXV) infections in these small mammals. Seven (2.0%) of these animal samples were found to be anti-orthopoxvirus immunoglobulin G (IgG) antibody positive (six rodents: two Funisciurus spp.; one Graphiurus lorraineus; one Cricetomys emini; one Heliosciurus sp.; one Oenomys hypoxanthus, and one elephant shrew Petrodromus tetradactylus); no individuals were found positive in PCR-based assays. These results suggest that a variety of animals can be infected with OPXVs, and that epidemiology studies and educational campaigns should focus on animals that people are regularly contacting, including larger rodents used as protein sources.


Analyzing brain networks with PCA and conditional Granger causality.
Identifying directional influences in anatomical and functional circuits presents one of the greatest challenges for understanding neural computations in the brain. Granger causality mapping (GCM) derived from vector autoregressive models of data has been employed for this purpose, revealing complex temporal and spatial dynamics underlying cognitive processes. However, the traditional GCM methods are computationally expensive, as signals from thousands of voxels within selected regions of interest (ROIs) are individually processed, and being based on pairwise Granger causality, they lack the ability to distinguish direct from indirect connectivity among brain regions. In this work a new algorithm called PCA based conditional GCM is proposed to overcome these problems. The algorithm implements the following two procedures: (i) dimensionality reduction in ROIs of interest with principle component analysis (PCA), and (ii) estimation of the direct causal influences in local brain networks, using conditional Granger causality. Our results show that the proposed method achieves greater accuracy in detecting network connectivity than the commonly used pairwise Granger causality method. Furthermore, the use of PCA components in conjunction with conditional GCM greatly reduces the computational cost relative to the use of individual voxel time series.


Podoconiosis treatment in northern Ethiopia (GoLBet): study protocol for a randomised controlled trial.
Podoconiosis is one of the forgotten types of leg swelling (elephantiasis) in the tropics. Unlike the other, better-known types of leg swelling, podoconiosis is not caused by any parasite, virus or bacterium, but by an abnormal reaction to minerals found in the clay soils of some tropical highland areas. Non-governmental Organizations (NGOs) have been responsible for the development of simple treatment methods without systematic evaluation of its effectiveness. It is essential that a large scale, fully controlled, pragmatic trial of the intervention is conducted. We aim to test the hypothesis that community-based treatment of podoconiosis lymphoedema reduces the frequency of acute dermatolymphangioadenitis episodes ('acute attacks') and improves other clinical, social and economic outcomes. This is a pragmatic, individually randomised controlled trial. We plan to randomly allocate 680 podoconiosis patients from the East Gojjam Zone in northern Ethiopia to one of two groups: 'Standard Treatment' or 'Delayed Treatment'. Those randomised to standard treatment will receive the hygiene and foot-care intervention from May 2015 for one year, whereas those in the control arm will be followed through 2015 and be offered the intervention in 2016. The trial will be preceded by an economic context survey and a Rapid Ethical Assessment to identify optimal methods of conveying information about the trial and the approaches to obtaining informed consent preferred by the community. The primary outcome will be measured by recording patient recall and using a simple, patient-held diary that will be developed to record episodes of acute attacks. Adherence to treatment, clinical stage of disease, quality of life, disability and stigma will be considered secondary outcome measures. Other outcomes will include adverse events and economic productivity. Assessments will be made at baseline and at 3, 6, 9 and 12 months thereafter. The evidence is highly likely to inform implementation of the new master plan for integrated control of Neglected Tropical Diseases (NTDs), in which podoconiosis is identified as one of eight NTDs prioritised for control. Potentially, an estimated 3 million patients in Ethiopia will therefore benefit from the results of this trial. International Standard Randomised Controlled Trial Number. ISRCTN67805210. Date of registration: 24 January 2013.


Multicenter evaluation of the Elecsys CA 125 II assay.
The technical performance and clinical usefulness of the newly developed Elecsys CA 125 II assay (Boehringer Mannheim) was evaluated in a multicenter study. Imprecision studies were carried out using control sera and human pool sera with CA 125 concentrations from 11 to 1026 U/ml. Within-run CVs between 0.7 to 4.8% (median 1.7%) and between-day CVs between 2.4 to 10.9% (median 5.7%) were found. Method comparison studies with Enzymun-Test CA 125 II carried out in four laboratories yielded slopes between 0.94 to 1.07 and intercepts < 3 U/ml. A good comparability of the Elecsys CA 125 II assay was also found with one MEIA and the Centocor" IRMA. For a second MEIA and a second IRMA the slopes were 1.23 and 1.42, and the corresponding correlation coefficients were 0.987 and 0.977, respectively. The Elecys CA 125 II concentrations are clearly related to the tumor stage of ovarian carcinoma patients. The maximum of diagnostic efficiency of ovarian carcinoma patients compared with patients of benign gynecological diseases is reached at 150 U/ml with a specificity of 93% and a sensitivity of 69%. Follow-up studies of ovarian carcinoma patients reflect the status of the disease and the effect of various therapeutic applications. The technical and clinical evaluation of the Elecsys CA 125 II assay show a superior analytical performance with a broad measuring range up to 5000 U/ml and a short measuring time of 18 minutes.


Early Treatment with Quinidine in 2 Patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) Due to Gain-of-Function KCNT1 Mutations: Functional Studies, Clinical Responses, and Critical Issues for Personalized Therapy.
Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare early-onset developmental epileptic encephalopathy resistant to anti-epileptic drugs. The most common cause for EIMFS is a gain-of-function mutation in the KCNT1 potassium channel gene, and treatment with the KCNT1 blocker quinidine has been suggested as a rational approach for seizure control in EIMFS patients. However, variable results on the clinical efficacy of quinidine have been reported. In the present study, we provide a detailed description of the clinical, genetic, in vitro, and in vivo electrophysiological profile and pharmacological responses to quinidine of 2 EIMFS unrelated patients with a heterozygous de novo KCNT1 mutation: c.2849G>A (p.R950Q) in patient 1 and c.2677G>A (p.E893K) in patient 2. When expressed heterologously in CHO cells, KCNT1 channels carrying each variant showed gain-of-function effects, and were more effectively blocked by quinidine when compared to wild-type KCNT1 channels. On the basis of these in vitro results, add-on quinidine treatment was started at 3 and 16 months of age in patients 1 and 2, respectively. The results obtained reveal that quinidine significantly reduced seizure burden (by about 90%) and improved quality of life in both patients, but failed to normalize developmental milestones, which persisted as severely delayed. Based on the present experience, early quinidine intervention associated with heart monitoring and control of blood levels is among the critical factors for therapy effectiveness in EIMFS patients with KCNT1 gain-of-function mutations. Multicenter studies are needed to establish a consensus protocol for patient recruitment, quinidine treatment modalities, and outcome evaluation, to optimize clinical efficacy and reduce risks as well as variability associated to quinidine use in such severe developmental encephalopathy.


Polyhexamethylene biguanide and calcineurin inhibitors as novel antifungal treatments for Aspergillus keratitis.
To establish polyhexamethylene biguanide (PHMB) as an effective treatment for Aspergillus keratitis in a novel murine model. To determine the ability of the calcineurin inhibitors tacrolimus (FK506) and cyclosporine A (CSA) to enhance the activity of PHMB, amphotericin B (AMB), and voriconazole (VCZ) against Aspergillus keratitis. Broth antifungal susceptibility tests were performed with PHMB, AMB, VCZ, and FK506, individually and in combination against Aspergillus fumigatus. Minimum inhibitory concentrations (MIC) and fractional inhibitory concentration index (FICI) values were used to analyze antifungal activity. In vivo studies: A novel murine model was created to establish Aspergillus keratitis. Infected mice were randomly assigned to treatment groups receiving saline, CSA, AMB, VCZ, PHMB, AMB+CSA, VCZ+CSA, or PHMB+CSA. An ophthalmologist blinded to the treatment groups assessed disease severity daily based on a grading scale. The mean end change in disease score was compared between groups. FK506 in combination with PHMB, VCZ, or AMB enhanced fungal growth inhibition. FICI values showed an additive effect between FK506 and PHMB, AMB, or VCZ. PHMB monotherapy eliminated Aspergillus growth starting at 4 μg/mL. In vivo studies: All treatment groups showed a significant improvement in disease score compared to the control group. CSA significantly worsened VCZ activity against Aspergillus keratitis. PHMB is an effective inhibitor of Aspergillus growth. Further investigation of the role of calcineurin inhibitors in the treatment for Aspergillus keratitis is warranted.


The global move toward Internet shopping and its influence on pollution: an empirical analysis.
This study investigates the influence of Internet retailing on carbon dioxide (CO2) emission in 77 countries categorized into developed and developing countries during the period of 2000-2013. To realize the aims of the study, a model that represents pollution is established utilizing the panel two-stage least square (TSLS) and the generalized method of moments (GMM). The results for both regressions similarly indicated that GDP growth, electricity consumption, urbanization, and trade openness are the main factors that increase CO2 emission in the investigated countries. Although the results show that Internet retailing reduces CO2 emission in general, a disaggregation occurs between developed and developing countries whereby Internet retailing has a significant negative effect on CO2 emission in the developed countries while it has no significant impact on CO2 emission in the developing countries. From the outcome of this study, a number of policy implications are provided for the investigated countries.


If brands are built over years, why are they managed over quarters?
Brands are on the wane. Many consumer-goods companies blame the big-box discount retailers, but the Wharton School's Leonard Lodish and the Fuqua School's Carl Mela have a different explanation. Their research suggests that companies have damaged their brands by investing too much in short-term price promotions and too little in long-term brand building. To rescue their brands and increase profitability, corporate managers must arm themselves with long-term measures of brand performance and use them to make smarter marketing decisions. Several factors explain the short-sightedness of brand management: the increased availability of weekly, or even hourly, scanner data, which show a clear link between discounts and immediate boosts in sales; the relative difficulty of measuring the effects of advertising, new-product development, and distribution--all of which can contribute to a brand's long-term health; the short tenure of most brand managers; and the near-term orientation of Wall Street analysts. Although discounts do increase sales in the short-term, they ultimately lower profit margins. If a product is often discounted, consumers learn to buy it only when it's on sale. Moreover, when one firm increases its discounts, others usually follow suit, lowering everyone's margins. Executives can monitor a brand's long-term performance by watching a dashboard of measures. Only after examining such measures, for example, did managers at Clorox discover that the company's heavy discounting and decreased advertising had caused a steady decline in overall bleach sales and profit margins. In response, Clorox reduced discounting and increased television advertising, moves that ultimately strengthened the brand and reversed the firm's downward trends.


Infrared reflectance imaging in age-related macular degeneration.
The purpose of this article is to describe the appearance of age-related macular degeneration (AMD) phenotypes using infrared (IR) reflectance imaging. IR reflectance imaging of the retina has the potential to highlight specific sub-retinal features and pathology. However, its role in macular disease, specifically AMD, is often underestimated and requires clarification. Recent advances in clinical methods, imaging and scientific knowledge may be integrated to improve the accuracy of disease stratification in AMD. In particular, IR imaging holds an underutilised sensitivity to detect reticular pseudodrusen, which have been repeatedly described as a high-risk sign for late AMD. This article provides clinically relevant descriptions of AMD phenotypes using IR reflectance imaging. The findings are integrated with images from cases seen at the Centre for Eye Health. As primary eye-care providers assume a critical role in the detection, diagnosis and management of AMD, we also provide a chair-side reference to assist clinicians in interpreting IR images in AMD.


Neuroprotective effect of paeonol on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat.
Diabetic encephalopathy (DE) has been characterized by the impaired cognition and the abnormalities of neurochemistry and neurostructure. The study was conducted to evaluate the neuroprotective effect of paeonol on STZ-induced DE rats. Paeonol of 25, 50, 100mg/kg (p.o.) could decrease the latency time and path length, and enhance significantly the spent time in the target quadrant and platform crossings in Morris water maze test. The treatment with paeonol could also increase significantly Na(+)-K(+)-ATP enzyme and ChAT activities, as well as decreasing significantly AchE activity in hippocampal tissue. Immunohistochemistry and TUNEL staining showed that paeonol could attenuate apoptosis of neurons and caspase 3 expression, improve two neurotrophic factors BDNF and IGF expressions, and also ameliorate Aβ deposition in the hippocampus and cerebral cortex. In conclusion, the present study demonstrated diabetic rats treated with paeonol could ameliorate the cognition deficits. These findings indicated paeonol might act as a beneficial agent for the prevention and treatment of DE.


Pregnancy and breastfeeding in patients with Crohn's disease.
Crohn's disease commonly affects women of childbearing age. Available data on Crohn's disease and pregnancy show that women with Crohn's disease can expect to conceive successfully, carry to term and deliver a healthy baby. Control of disease activity before conception and during pregnancy is critical, to optimize both maternal and fetal health. Generally speaking, pharmacological therapy for Crohn's disease during pregnancy is similar to pharmacological therapy for nonpregnant patients. Patients maintained in remission by way of pharmacological therapy should continue it throughout their pregnancy. Sulfasalazine, mesalazine and corticosteroids are safe, azathioprine and 6-mercaptopurine are reasonably safe with few discordant data, infliximab seems safe as well, whereas methotrexate is contraindicated during pregnancy. During breastfeeding, mesalazine and prednisone are considered safe, azathioprine/6-mercaptopurine, budesonide and infliximab probably safe and methotrexate is contraindicated.


Remission and recurrence of depression in the maintenance era: long-term outcome in a Cambridge cohort.
Long-term studies of severe depression have described high rates of non-recovery, recurrence, chronic incapacity and mortality. A more recent cohort was followed-up to ascertain whether the course had improved given developments in pharmacological and psychological treatments in the last 15 years. Subjects from a cohort of 70 mainly severe recurrent depressives originally recruited to a shorter follow-up study from 1990-1992 were followed-up after 8-11 years. Data included longitudinal information on course of depression and other psychiatric disorders, pharmacological and psychological treatment and social functioning during follow-up. Sixty-nine (99%) subjects were successfully followed-up, with 61 of 66 living subjects interviewed and detailed follow-up data obtained in total on 65. Sixty (92%) of 65 subjects recovered during follow-up, with two-thirds subsequently suffering a recurrence. Eleven (17%) suffered from an episode of chronic depression of at least 2 years duration during follow-up. Social function at follow-up was good and there were high levels of pharmacological and psychological treatment. Greater severity of illness was the most consistent predictor of poor outcome. Times to recovery and recurrence and recovery and recurrence rates were very similar to older studies. The long-term outcome of depression still shows high recurrence rates and does not appear to have changed in the last 20 years.


Neurocytotoxicity: pharmacological implications.
Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy-compromised cells since the NMDA receptor-linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy-deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Furthermore the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium-related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks "fast" excitation and Na+ influx, an "upstream" event which causes "downstream" calcium influx via multiple pathways. In the perifocal ("penumbra") zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium-carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.


Systemic Sclerosis Associated Interstitial Lung Disease and Nintedanib: A Rare Disease and a Promising Drug.
Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a rare disease with a progressive nature, eventually leading to lung fibrosis. Nintedanib, a tyrosine kinase inhibitor, is a widely accepted drug for treating idiopathic pulmonary fibrosis (IPF), a disease that shares some similarities with SSc-ILD regarding pathological disease processes. In this review, we aim to discuss the pathogenesis of SSc-ILD and the overall role of nintedanib in the management of SSc-ILD. SSc-ILD involves multiple pathological mediators contributing to various pathways that ultimately cause lung fibrosis. The pathogenesis of SSc-ILD is a complex phenomenon and still needs further study. Nintedanib has demonstrated its efficacy in the treatment of SSc-ILD by reducing the progression of the pathological process. It has also proven its clinical significance in the management of SSc-ILD. However, the currently available literature does not have any evidence to compare the effectiveness of nintedanib with the already available treatment modalities such as cyclophosphamide (CYC), mycophenolate mofetil (MMF), and azathioprine (AZT). The current literature also lacks information about nintedanib's long-term consequences on patients with SSc-ILD. Therefore, to create better evidence-based treatment guidelines, we recommend that researchers conduct randomized clinical trials comparing nintedanib to MMF, CYC, AZT, etc., and continue surveillance to explore the long-term consequences of nintedanib.


Is there a role for virtual reality in objective structured clinical examinations (OSCEs)?
This article was migrated. The article was marked as recommended. Virtual reality is an area with fascinating possibilities. It has already revolutionised the entertainment industry, and over the last ten years, it has advanced similarly within the medical field. We have already seen virtual reality make a difference in a variety of ways. This ranges from improving the way surgical training is delivered, having a role in the management of chronic pain and now, it is even being considered in the treatment of psychiatric diseases. Currently, the application of virtual reality towards the training of health care professionals and medical education are concepts that are being explored. Within medical education and more specifically medical student training, the benefits of virtual reality have so far been limited to studies assessing its role in teaching. Very few studies exist looking at the role of virtual reality in the assessment of medical students. Therefore, in this article, we discuss the idea of utilising virtual reality for objective structured clinical examinations (OSCEs) and analyse the potential benefits and pitfalls of implementing this technology.


Is testing a more effective learning strategy than note-taking?
The testing effect is both robust and generalizable. However, most of the underlying studies compare testing to a rather ineffective control condition: massed repeated reading. This article therefore compares testing with note-taking, which has been shown to be more effective than repeated reading. Experiment 1 is based on a 3 × 3 between-participants design with the factors learning condition (repeated reading vs. repeated testing vs. repeated note-taking) and final test delay (5 min vs. 1 week vs. 2 weeks). It shows that in the immediate condition, learning performance is best after note-taking. After 1 week, both the note-taking and the testing groups outperform the rereading group, and after 2 weeks, testing is superior to both note-taking and rereading. Since repeated notetaking may not be the most effective (and common) operationalization of note-taking, Experiment 2 contrasts repeated testing with 2 other note-taking conditions: note-taking plus note-reading and note-taking plus testing (with only a 2-week final test delay). Both conditions that include a testing phase result in better long-term learning than note-taking plus note-reading. In summary, our findings indicate that-in the long run-testing is a powerful learning tool both in isolation and in combination with note-taking. (PsycINFO Database Record


Performance Characteristics of Body Fluid Cytology Analysis of 344 380 Responses From the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology.
- Body fluid cytology is an important diagnostic tool used to identify various conditions. However, an accurate diagnosis in this setting can sometimes be challenging. - To identify the performance characteristics of body fluid cytology by analyzing participant responses from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytopathology. - Participant responses from 5102 slides were analyzed for concordance to the general category (GC) and to the reference diagnosis (RD). Nonlinear mixed models were used to analyze concordance. - The overall GC concordance was 95.2%. The GC type, participant type, and preparation type were significantly associated with GC concordance ( P < .001). Concordance for malignant cases was higher than it was for benign cases. Cytotechnologists had better GC concordance compared to pathologists. ThinPrep (Hologic, Marlborough, Massachusetts) slides had the highest GC concordance. Participant type, fluid type, preparation type, and participant interpretation were significantly associated with RD concordance ( P < .001). Pathologists performed better than cytotechnologists did for RD concordance. Pericardial fluid had the lowest RD concordance, especially for cases with normal or reactive findings. Modified Giemsa-stained slides performed best for lymphoma and hematopoietic malignancy. Small cell carcinoma had the highest GC concordance, and its RD concordance was higher in pleural than in peritoneal fluids. Adenocarcinoma showed the highest concordance rates for both GC and RD. - This study illustrates the challenges associated with interpreting body fluid cytology, particularly in pericardial fluid, and the factors that may affect accurate diagnoses. The results also highlight the value of using multiple preparation types in challenging cases.