Is There an App for That?: Ethical Issues in the Digital Mental Health Response to COVID-19.
Well before COVID-19, there was growing excitement about the potential of various digital technologies such as tele-health, smartphone apps, or AI chatbots to revolutionize mental healthcare. As the SARS-CoV-2 virus spread across the globe, clinicians warned of the mental illness epidemic within the coronavirus pandemic. Now, funding for digital mental health technologies is surging and many researchers are calling for widespread adoption to address the mental health sequelae of COVID-19. Reckoning with the ethical implications of these technologies is urgent because decisions made today will shape the future of mental health research and care for the foreseeable future. We contend that the most pressing ethical issues concern (1) the extent to which these technologies demonstrably improve mental health outcomes and (2) the likelihood that wide-scale adoption will exacerbate the existing health inequalities laid bare by the pandemic. We argue that the evidence for efficacy is weak and that the likelihood of increasing inequalities is high. First, we review recent trends in digital mental health. Next, we turn to the clinical literature to show that many technologies proposed as a response to COVID-19 are unlikely to improve outcomes. Then, we argue that even evidence-based technologies run the risk of increasing health disparities. We conclude by suggesting that policymakers should not allocate limited resources to the development of many digital mental health tools and should focus instead on evidence-based solutions to address mental health inequalities.


Improving Medication Adherence in Coronary Heart Disease.
The purpose of this review was to synthesize research findings from recently published randomized controlled trials (RCTs) targeting any phase of medication adherence, from initiation to discontinuation, among patients with coronary heart disease (CHD). We identified successful strategies and promising practices for improving medication adherence among patients diagnosed with CHD. Consistent intervention strategies included the following: (1) facilitating patient-provider communication, (2) using mHealth technologies with emphasis on two-way communication, (3) providing patient education in tandem with lifestyle and behavioral counseling, and (4) providing psychosocial support. Regarding medication adherence phases, all studies examined implementation (i.e., taking medications as prescribed over time) and one also addressed treatment initiation (i.e., beginning a new medication). None identified addressed discontinuation. Studies varied by use of objective, self-report, and a combination of outcome measures with a greater number reporting only subjective measures of adherence. Key findings remained mixed in supporting specific intervention designs or delivery formats. This review addresses available data of promising practices for improving CHD medication adherence. Future studies are needed to examine intervention effectiveness, scalability, and durability of observed outcome effects.


Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes.
Nonsteroidal anti-inflammatory drugs are commonly used by athletes to prevent anticipated exercise-induced pain, thereby putatively improving physical performance. However, these drugs may have potentially hazardous effects on the gastrointestinal (GI) mucosa during strenuous physical exercise. The aim of the current study was to determine the effect of oral ibuprofen administration before exercise on GI integrity and barrier function in healthy individuals. Nine healthy, trained men were studied on four different occasions: 1) 400 mg ibuprofen twice before cycling, 2) cycling without ibuprofen, 3) 400 mg ibuprofen twice at rest, and 4) rest without ibuprofen intake. To assess small intestinal injury, plasma intestinal fatty acid binding protein (I-FABP) levels were determined, whereas urinary excretion of orally ingested multisugar test probes was measured using liquid chromatography and mass spectrometry to assess GI permeability. Both ibuprofen consumption and cycling resulted in increased I-FABP levels, reflecting small intestinal injury. Levels were higher after cycling with ibuprofen than after cycling without ibuprofen, rest with ibuprofen, or rest without ibuprofen (peak I-FABP, 875 ± 137, 474 ± 74, 507 ± 103, and 352 ± 44 pg·mL, respectively, P < 0.002). In line, small intestinal permeability increased, especially after cycling with ibuprofen (0-2 h urinary lactulose/rhamnose ratio, 0.08 (0.04-0.56) compared with 0.04 (0.00-0.20), 0.05 (0.01-0.07), and 0.01 (0.01-0.03), respectively), reflecting loss of gut barrier integrity. Interestingly, the extent of intestinal injury and barrier dysfunction correlated significantly (RS = 0.56, P < 0.001). This is the first study to reveal that ibuprofen aggravates exercise-induced small intestinal injury and induces gut barrier dysfunction in healthy individuals. We conclude that nonsteroidal anti-inflammatory drugs consumption by athletes is not harmless and should be discouraged.


Results of an interlaboratory comparison of analytical methods for contaminants of emerging concern in water.
An evaluation of existing analytical methods used to measure contaminants of emerging concern (CECs) was performed through an interlaboratory comparison involving 25 research and commercial laboratories. In total, 52 methods were used in the single-blind study to determine method accuracy and comparability for 22 target compounds, including pharmaceuticals, personal care products, and steroid hormones, all at ng/L levels in surface and drinking water. Method biases ranged from <10% to well over 100% in both matrixes, suggesting that while some methods are accurate, others can be considerably inaccurate. In addition, the number and degree of outliers identified suggest a high degree of variability may be present between methods currently in use. Three compounds, ciprofloxacin, 4-nonylphenol (NP), and 4-tert-octylphenol (OP), were especially difficult to measure accurately. While most compounds had overall false positive rates of ≤5%, bisphenol A, caffeine, NP, OP, and triclosan had false positive rates >15%. In addition, some methods reported false positives for 17β-estradiol and 17α-ethynylestradiol in unspiked drinking water and deionized water, respectively, at levels higher than published predicted no-effect concentrations for these compounds in the environment. False negative rates were also generally <5%; however, rates were higher for the steroid hormones and some of the more challenging compounds, such as ciprofloxacin. The elevated false positive/negative rates of some analytes emphasize the susceptibility of many current methods to blank contamination, misinterpretation of background interferences, and/or inappropriate setting of detection/quantification levels for analysis at low ng/L levels. The results of both comparisons were collectively assessed to identify parameters that resulted in the best overall method performance. Liquid chromatography-tandem mass spectrometry coupled with the calibration technique of isotope dilution were able to accurately quantify most compounds with an average bias of <10% for both matrixes. These findings suggest that this method of analysis is suitable at environmentally relevant levels for most of the compounds studied. This work underscores the need for robust, standardized analytical methods for CECs to improve data quality, increase comparability between studies, and help reduce false positive and false negative rates.


The first high-energy neurtrino experiment.
This article describes the state of knowledge of weak interactions in 1960, the conception and implementation of the first high-energy neutrino experiment, and the not altogether unexpected result that the muon neutrino is different from the electron neutrino.


Microcephaly in Infants, Pernambuco State, Brazil, 2015.
We studied the clinical characteristics for 104 infants born with microcephaly in the delivery hospitals of Pernambuco State, Brazil, during 2015. Testing is ongoing to exclude known infectious causes. However, microcephaly peaked in October and demonstrated central nervous system abnormalities with brain dysgenesis and intracranial calcifications consistent with an intrauterine infection.


Export of beta-lactamase is independent of the signal recognition particle.
In Escherichia coli, three different types of proteins engage the SecY translocon of the inner bacterial membrane for translocation or insertion: 1) polytopic membrane proteins that prior to their insertion into the membrane are targeted to the translocon using the bacterial signal recognition particle (SRP) and its receptor; 2) secretory proteins that are targeted to and translocated across the SecY translocon in a SecA- and SecB-dependent reaction; and 3) membrane proteins with large periplasmic domains, requiring SRP for targeting and SecA for the translocation of the periplasmic moiety. In addition to its role as a targeting device for membrane proteins, a function of the bacterial SRP in the export of SecB-independent secretory proteins has also been postulated. In particular, beta-lactamase, a hydrolytic enzyme responsible for cleavage of the beta-lactam ring containing antibiotics, is considered to be recognized and targeted by SRP. To examine the role of the SRP pathway in beta-lactamase targeting and export, we performed a detailed in vitro analysis. Chemical cross-linking and membrane binding assays did not reveal any significant interaction between SRP and beta-lactamase nascent chains. More importantly, membrane vesicles prepared from mutants lacking a functional SRP pathway did block the integration of SRP-dependent membrane proteins but supported the export of beta-lactamase in the same way as that of the SRP-independent protein OmpA. These data demonstrate that in contrast to previous results, the bacterial SRP is not involved in the export of beta-lactamase and further suggest that secretory proteins of Gram-negative bacteria in general are not substrates of SRP.


Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase.
Myeloid-derived suppressor cell (MDSC) levels are elevated in cancer patients and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton's Tyrosine Kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the anti-tumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of fluorescence activated cell sorting-enriched MDSC from patients with different cancer types (breast, melanoma, head and neck squamous cell cancer - HNSCC). Melanoma patient MDSC were treated in vitro for 4h with 5 µM ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10x Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from breast, melanoma, and HNSCC cancer patients revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from melanoma patients resulted in significant changes in gene expression. GBP1, IL 1β and CXCL8 were among the top downregulated genes while RGS2 and ABHD5 were among the top upregulated genes (p<0.001). Double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes compared to early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL 6 signaling (p<0.004). Implications: ScRNA-seq revealed characteristic gene expression patterns for MDSC from different cancer patients and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.


Prevention, testing, and treatment interventions for hepatitis B and C in refugee populations: results of a scoping review.
Refugees are at higher risk for hepatitis B (HBV) and hepatitis C (HCV), but often face unique healthcare barriers to vaccination, testing, and treatment. This scoping review aimed to identify and characterize HBV and HCV prevention and care services serving refugee populations globally. A literature search was conducted on Embase, Cochrane, and PubMed databases. Research studies published in English between January 2010 to July 2022 describing an HBV or HCV prevention, testing, or treatment intervention for refugees were included. There were a total of 69 articles reporting viral hepatitis prevalence, implementation of services, or economic modelling. Of the 38 implementation studies, 14 were stand-alone HBV and/or HCV interventions, while 24 studies included HBV and/or HCV in an intervention targeting multiple infectious diseases and/or parasitic infections. Interventions commonly included a testing (n = 30) or referral (n = 24) component. Frequently reported features to promote program accessibility included bilingual services (n = 25), community partnerships (n = 21), and multidisciplinary staff members (n = 18), such as cultural and/or linguistic mediators, community health workers, community health leaders, lay health workers, local health staff, members of the refugee community, and social workers. The most commonly reported challenge was the transience of refugees (n = 5). Twenty studies noted funding sources, of which twelve reported governmental funding (not including national health insurance) and eight reported that refugees received national health insurance. This is the first scoping review to characterize the types of hepatitis prevention, screening, and treatment interventions serving refugee populations globally. Published experiences of HBV and HCV services for refugee populations remain limited. Additional efforts are needed to disseminate models of hepatitis interventions for refugees to ensure access to care for this key population. To achieve hepatitis elimination globally, best practices must be identified and shared to expand access to hepatitis services for refugee populations.


Phosphate-related genomic islands as drivers of environmental adaptation in the streamlined marine alphaproteobacterial HIMB59.
These results shed light on the evolutionary strategies of microbes with streamlined genomes to adapt and survive in the oligotrophic conditions that dominate the surface waters of the global ocean. At the individual level, these microbes have been subjected to evolutionary constraints that have led to a more efficient use of nutrients, removing non-essential genes named as "streamlining theory." However, at the population level, they conserve a highly diverse gene pool in flexible genomic islands resulting in polyclonal populations on the same genomic background as an evolutionary response to environmental pressures. Localization of these islands at equivalent positions in the genome facilitates horizontal transfer between clonal lineages. This high level of environmental genomic heterogeneity could explain their cosmopolitan distribution. In the case of the order HIMB59 within the class Alphaproteobacteria, two factors exert evolutionary pressure and determine this intraspecific diversity: phages and the concentration of P in the environment.


Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy.
Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrite nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in the peripheral and subsequent inner layers of multilayered nanocarriers. In vitro and in vivo studies evaluated the nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced the cellular levels of Bcl2 and p53, while increasing the levels of Bim. This delivery system successfully embodies the sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers.


Reading epilepsy in a patient with previous idiopathic focal epilepsy with centrotemporal spikes.
Reading epilepsy (RE) is a form of reflex epilepsy currently classified as an idiopathic localization-related epilepsy (ILAE, 1989). We describe a 30 year-old right-handed male who suffered since the age of 8 from nocturnal partial motor seizures. Clinical features were typical of BECT. We reviewed the EEG recorded at that time which showed centrotemporal spike and waves. He was seizure-free from the age of 12 to the age of 17 when seizures evoked only by reading appeared. No other stimuli provoked seizures. Neurological and neuroradiological (CT and MR) investigations were normal. Baseline video-polygraphic EEG recordings were normal while reading aloud provoked myoclonic jerks in the facial muscles related to bilateral spike and wave discharges. Therapy with carbamazepine and valproic acid strongly reduced seizure frequency. Recent papers have debated the difficulties in classifying RE among the generalized or focal syndromes. Literature reports describe an association with RE and juvenile myoclonic epilepsy, supporting the hypothesis of an idiopathic generalized form. We report the first documented case with a clear-cut idiopathic localization-related epilepsy evolving to a primary reading epilepsy.


Antibiotic resistance among Escherichia coli and Salmonella isolated from dairy cattle feces in Texas.
In several developing countries, studies on antimicrobial resistance among bacteria from food animals are rare mostly because of under-resourced laboratories. The objective of this study was to develop and field-test a low cost protocol to estimate the isolate- and sample-level prevalence of resistance to critically important antibiotics among Escherichia coli and Salmonella isolated from dairy cattle feces. Using a predesigned protocol, fecal samples were collected to isolate non-type-specific E. coli and Salmonella using selective media without antibiotic supplements. Besides, samples were screened for E. coli and Salmonella isolates not susceptible to third-generation cephalosporins and quinolones using selective media supplemented with cefotaxime (1.0 μg/mL) and ciprofloxacine (0.5 μg/mL), respectively. All bacterial isolates were further tested for antibiotic susceptibility using disk diffusion. Bacterial isolates not susceptible to third-generation cephalosporins were tested for extended spectrum beta-lactamase (ESBL) phenotype using the combination disk test. Molecular methods were performed on selected bacterial isolates to identify and distinguish genetic determinants associated with the observed phenotypes. Among 85 non-type-specific E. coli isolated from MacConkey agar without antibiotics, the isolate-level prevalence of resistance to tetracycline was the highest (8.2%). Among 37 E. coli recovered from MacConkey agar with cefotaxime, 56.8% were resistant ceftriaxone. Among 22 E. coli isolates recovered from MacConkey agar with ciprofloxacin, 77.3% and 54.5% were resistant to nalidixic acid and ciprofloxacin, respectively. Sixteen Salmonella were isolated and only one demonstrated any resistance (i.e., single resistance to streptomycin). Among E. coli isolates not susceptible to ceftriaxone, an AmpC phenotype was more common than an ESBL phenotype (29 versus 10 isolates, respectively). Whole genome sequencing showed that phenotypic profiles of antibiotic resistance detected were generally substantiated by genotypic profiles. The tested protocol is suited to detecting and estimating prevalence of antimicrobial resistance in bacteria isolated from food animal feces in resource-limited laboratories in the developing world.


Erythrocyte cellular and membrane deformability in hereditary spherocytosis.
In order to determine whether the relative rigidity of the hereditary spherocytosis (HS) red cell is due to membrane rididity or merely to an altered surface/volume ratio, we investigated the deformability of resealed red cell membranes from patients with HS. Whereas the osmotic fragility of intact red cells of HS patients showed the expected increase, the osmotic fragility of resealed HS membranes was normal, thus indicating that their surface/volume ratio was normal. Measurements with an ektacytometer showed that deformability of intact HS cells was markedly diminished, whereas deformability of resealed HS membranes was normal. These findings indicate that the HS red cell membrane is not intrinsically abnormally rigid, as has been suggested, but that the lack of deformability of the erythrocyte is primarily a function of the altered surface/volume ratio.


Health service use and costs in the last 6 months of life in elderly decedents with a history of cancer: a comprehensive analysis from a health payer perspective.
There is growing interest in end-of-life care in cancer patients. We aim to characterise health service use and costs in decedents with cancer history and examine factors associated with resource use and costs at life's end. We used routinely collected claims data to quantify health service use and associated costs in two cohorts of elderly Australians diagnosed with cancer: one cohort died from cancer (n=4271) and the other from non-cancer causes (n=3072). We used negative binomial regression to examine the factors associated with these outcomes. Those who died from cancer had significantly higher rates of hospitalisations and medicine use but lower rates of emergency department use than those who died from non-cancer causes. Overall health care costs were significantly higher in those who died from cancer than those dying from other causes; and 40% of costs were expended in the last month of life. We analysed health services use and costs from a payer perspective, and highlight important differences in patterns of care by cause of death in patients with a cancer history. In particular, there are growing numbers of highly complex patients approaching the end of life and the heterogeneity of these populations may present challenges for effective health service delivery.


Immunosorbent assay based on recombinant hemagglutinin protein produced in a high-efficiency mammalian expression system for surveillance of measles immunity.
Recombinant hemagglutinin (H) protein of the measles virus (MV) was produced in mammalian cells with a high-yield expression system based on the Semliki Forest virus replicon. Crude membrane preparations of H protein-transfected BHK-21 cells were used to coat microtiter plates to measure specific immunoglobulin G antibodies in 228 serologically defined serum samples mainly from measles late-convalescent adults. The titers by the enzyme-linked immunosorbent assay for the H protein (H-ELISA) closely correlated with neutralization test (NT) titers (R2 = 0.66), hemagglutination inhibition test (HI) titers (R2 = 0.64), with the titers from a certified commercial ELISA based on whole MV-infected cells (MV-ELISA; R2 = 0.45). The correlations described above were better than those of the commercial MV-ELISA titers with the NT (R2 = 0.52) or HI (R2 = 0.48) titers. By using the 2nd International Standard for anti-measles serum, the detection level of the assay corresponds to 215 mIU/ml for undiluted serum, which corresponds to the estimated threshold for protective immunity. The specificity, accuracy, and positive predictive value were, in general, better for the H-ELISA than for a commercial MV-ELISA, independent of whether HI, NT, or HI and NT were used as "gold standards." In contrast, the H-ELISA proved to be slightly less sensitive than the MV-ELISA (sensitivities, 98.6 versus 99.5%, respectively; P was not significant). The assays did not differ significantly in the number of serum samples with positive HI and NT results (n = 212) which measured false negative (H-ELISA, 2 of 212 [0.94%]; MV-ELISA, 1 of 212 [0.47%]), but the H-ELISA detected significantly more measles-susceptible individuals than the MV-ELISA (10 of 11 versus 3 of 11, respectively; P < 0.05) among the individuals whose sera had negative HI and NT results. Our data demonstrate that the H-protein preparation that we describe could be a cost-effective alternative to current whole-virus-based ELISAs for surveillance for immunity to measles and that such an assay could be more efficient in detecting susceptibility to measles. Furthermore, unlike whole MV-based antigens, H-protein would also be suitable for use in the development of a simple field test for the diagnosis of measles.


Clinical utility of 18F-FDG PET/CT in low 18F-FDG-avidity breast cancer subtypes: comparison with breast US and MRI.
The aim of this study was to evaluate the diagnostic performance of fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT in initial axillary lymph node (ALN) staging and tumor recurrence in breast cancer subtypes with low F-FDG avidity in comparison with breast ultrasonography (US) and/or MRI. A total of 491 PET/CT exams from 192 patients with biopsy-proven breast cancer subtypes with low F-FDG avidity were enrolled retrospectively. Nodal status on staging and locoregional recurrence or metastasis on surveillance was confirmed either by pathology or by further clinical follow-up. Comparison was made with recent US and/or MRI. A total of 142 scans were for staging and 349 scans were for surveillance. For the staging, 127 tumors had perceptible F-FDG uptake. For the detection of ALN metastasis, the sensitivity, specificity, and accuracy were calculated to be 51.5, 94.6, and 84.7% for F-FDG PET/CT, 42.4, 90.1, and 79.2% for US, and 51.5, 88.3, and 79.9% for MRI, respectively. PET/CT showed significantly higher specificity than MRI. In the surveillance, the total recurrence rate was 4.3%. There were no cases of recurrence of mucinous or tubular carcinoma. PET/CT showed comparable diagnostic performance for locoregional recurrence compared with US in invasive lobular carcinoma. Distant metastasis developed in five patients (one stage II, four stage III), and all of these were identified by PET/CT alone. PET/CT showed comparable diagnostic performance with US and/or MRI for ALN staging and detecting tumor recurrence even when the primary breast cancer has low F-FDG avidity. F-FDG PET/CT also detected unsuspected distant metastasis in 36.4% of stage III patients. Surveillance PET/CT should be considered in advanced-stage invasive lobular carcinoma for early detection of recurrence.


Clinical characteristics of responders to treatment with tolvaptan in patients with acute decompensated heart failure: Importance of preserved kidney size.
Recent clinical trials have demonstrated the efficacy of short-term treatment with tolvaptan, an oral vasopressin V2 receptor antagonist, in patients with heart failure. However, the response to tolvaptan varies among patients. The aim of this study was to determine factors associated with response to tolvaptan in patients with acute decompensated heart failure (ADHF). The Tolvaptan Registry, a prospective, observational, multicenter cohort study performed in Japan, aims to determine factors affecting the responsiveness of tolvaptan in patients with ADHF. We enrolled ADHF patients treated with tolvaptan and they were divided into two groups: responders and non-responders. Responders were defined as subjects who met all of the following three conditions: (1) increasing urine volume during a 24-hour period after the start of tolvaptan treatment; (2) improvement in New York Heart Association functional class; and (3) decrease in cardiothoracic ratio assessed by chest X-ray on day 3 of tolvaptan administration. Among the 114 patients, treatment with tolvaptan improved three conditions of heart failure in more than half of all the cohorts (71 patients, 62%). As for baseline characteristics, estimated glomerular filtration rate, urine osmolality, and kidney size were significantly greater in responders than in non-responders. Multivariate logistic analysis revealed that kidney size was independently associated with responders (odds ratio: 1.083, p=0.001, 95% confidence interval 1.031-1.137). The main clinical characteristic of responders to treatment with tolvaptan is that kidney size is preserved.


Direct reconstruction in CT-analogous pharmacokinetic diffuse fluorescence tomography: two-dimensional simulative and experimental validations.
We present a generalized strategy for direct reconstruction in pharmacokinetic diffuse fluorescence tomography (DFT) with CT-analogous scanning mode, which can accomplish one-step reconstruction of the indocyanine-green pharmacokinetic-rate images within in vivo small animals by incorporating the compartmental kinetic model into an adaptive extended Kalman filtering scheme and using an instantaneous sampling dataset. This scheme, compared with the established indirect and direct methods, eliminates the interim error of the DFT inversion and relaxes the expensive requirement of the instrument for obtaining highly time-resolved date-sets of complete 360 deg projections. The scheme is validated by two-dimensional simulations for the two-compartment model and pilot phantom experiments for the one-compartment model, suggesting that the proposed method can estimate the compartmental concentrations and the pharmacokinetic-rates simultaneously with a fair quantitative and localization accuracy, and is well suitable for cost-effective and dense-sampling instrumentation based on the highly-sensitive photon counting technique.


Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors.
Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes.


Cytosolic glutathione S-transferases in various rat tissues differ in stereoselectivity with polycyclic arene and alkene oxide substrates.
The stereoselectivity of cytosolic glutathione S-transferases (GS-T) in rat tissues was determined using (+/-)-benzo(a)pyrene 4,5-oxide (BPO), (+/-)-benz(a)anthracene 5,6-oxide (BAO), pyrene 4,5-oxide (PO), and (+/-)-styrene 7,8-oxide (SO) as substrates. An HPLC system is described which separates the four diastereomeric glutathione (GSH) adducts of BPO. Liver, lung, testis, and heart cytosol were found to be highly selective for catalysis of the reaction of the GSH sulfur atom with R-configured oxirane carbon atoms of BPO; heart was the most stereoselective of these tissues with 93% of the products arising from thiol attack at the R-configured carbons. These same tissues showed identical but lower stereoselectivity with PO or BAO as substrate. With SO as substrate, GSH attack was primarily at the benzylic carbon atom of the R-configured enantiomer in all tissues. In contrast, kidney and spleen cytosol were highly stereoselective for reaction of GSH with S-configured oxirane carbon atoms of all three polycyclic arene oxides (R/S ratio = 0.2-0.3) and showed a greater amount of attack at the terminal carbon atom of (7R)-SO. Enantioselectivity of GS-T from these tissues with BPO as substrate varied substantially; liver, kidney, spleen, and intestine preferentially catalyzed reaction with (4R,5S)-BPO (2.8- to 5.1-fold), but testis, lung, and heart showed little or no enantioselectivity [(4R,5S)-BPO/(4S,5R)-BPO = 1.3, 1.3, and 0.96, respectively]. In general, the differences in stereoselectivity between different rat tissues correlate with known tissue differences in isozyme composition and demonstrate that some rat GS-T isozymes may have markedly different stereo- and enantioselectivities with chiral epoxide substrates.


Novel alleles in classical major histocompatibility complex class II loci of the brushtail possum (Trichosurus vulpecula).
We have investigated the diversity of class II major histocompatibility complex (MHC) loci in the brushtail possum (Trichosurus vulpecula), an important marsupial pest species in New Zealand. Immunocontraceptive vaccines, a method of fertility control that employs the immune system to attack reproductive cells or proteins, are currently being researched as a means of population control for the possum. Variation has been observed in the immune response of individual possums to immunocontraceptives. If this variability is under genetic control, it could compromise vaccine efficacy through preferential selection of animals that fail to mount a significant immune response and remain fertile. The MHC is an important immune region for antigen presentation and as such may influence the response to immunocontraceptives. We used known marsupial MHC sequences to design polymerase chain reaction primers to screen for possum MHC loci. Alpha and beta chains from two class II families, DA and DB, were found in possums throughout New Zealand. Forty new class II MHC alleles were identified in the possum, and the levels of variability in the MHC of this marsupial appear to be comparable to those of eutherian species. Preliminary population surveys showed evidence of clustering/variability in the distribution of MHC alleles in geographically separate locations. The extensive variation demonstrated in possums reinforces the need for further research to assess the risk that such MHC variation poses for long-term immunocontraceptive vaccine efficacy.


Aquatic fungi: targeting the forgotten in microbial ecology.
Fungi constitute important and conspicuous components of aquatic microbial communities, but their diversity and functional roles remain poorly characterized. New methods and conceptual frameworks are required to accurately describe their ecological roles, involvement in global cycling processes, and utility for human activities, considering both cultivation-independent techniques as well as experiments in laboratory and in natural ecosystems. Here we highlight recent developments and extant knowledge gaps in aquatic mycology, and provide a conceptual model to expose the importance of fungi in aquatic food webs and related biogeochemical processes.


Residency Training: Quality improvement projects in neurology residency and fellowship: applying DMAIC methodology.
Teaching quality improvement (QI) is a priority for residency and fellowship training programs. However, many medical trainees have had little exposure to QI methods. The purpose of this study is to review a rigorous and simple QI methodology (define, measure, analyze, improve, and control [DMAIC]) and demonstrate its use in a fellow-driven QI project aimed at reducing the number of delayed and canceled muscle biopsies at our institution. DMAIC was utilized. The project aim was to reduce the number of delayed muscle biopsies to 10% or less within 24 months. Baseline data were collected for 12 months. These data were analyzed to identify root causes for muscle biopsy delays and cancellations. Interventions were developed to address the most common root causes. Performance was then remeasured for 9 months. Baseline data were collected on 97 of 120 muscle biopsies during 2013. Twenty biopsies (20.6%) were delayed. The most common causes were scheduling too many tests on the same day and lack of fasting. Interventions aimed at patient education and biopsy scheduling were implemented. The effect was to reduce the number of delayed biopsies to 6.6% (6/91) over the next 9 months. Familiarity with QI methodologies such as DMAIC is helpful to ensure valid results and conclusions. Utilizing DMAIC, we were able to implement simple changes and significantly reduce the number of delayed muscle biopsies at our institution.


Canopy conundrums: building on the Biosphere 2 experience to scale measurements of inner and outer canopy photoprotection from the leaf to the landscape.
Recognising that plant leaves are the fundamental productive units of terrestrial vegetation and the complexity of different environments in which they must function, this review considers a few of the ways in which these functions may be measured and potentially scaled to the canopy. Although canopy photosynthetic productivity is clearly the sum of all leaves in the canopy, we focus on the quest for 'economical insights' from measurements that might facilitate integration of leaf photosynthetic activities into canopy performance, to better inform modelling based on the 'insights of economics'. It is focussed on the reversible downregulation of photosynthetic efficiency in response to light environment and stress and summarises various xanthophyll-independent and dependent forms of photoprotection within the inner and outer canopy of woody plants. Two main themes are developed. First, we review experiments showing the retention of leaves that grow old in the shade may involve more than the 'payback times' required to recover the costs of their construction and maintenance. In some cases at least, retention of these leaves may reflect selection for distinctive properties that contribute to canopy photosynthesis through utilisation of sun flecks or provide 'back up' capacity following damage to the outer canopy. Second, we report experiments offering hope that remote sensing of photosynthetic properties in the outer canopy (using chlorophyll fluorescence and spectral reflectance technologies) may overcome problems of access and provide integrated measurements of these properties in the canopy as a whole. Finding appropriate tools to scale photosynthesis from the leaf to the landscape still presents a challenge but this synthesis identifies some measurements and criteria in the laboratory and the field that improve our understanding of inner and outer canopy processes.


Deliberate self-poisoning in adolescents.
Adolescent suicide has become increasingly more prevalent in recent years, with self-poisoning being a frequent means of suicide attempt. To investigate the factors associated with adolescent self-poisoning. Data on adolescents referred for intentional self-poisoning to the Adolescent Medical Unit during the years 1990-1998 were evaluated retrospectively. Data were obtained from the hospital medical records and included the following factors: sociodemographic data, educational status, agent and route of intake, motivation for overdose, and the extent of serious suicidal intent. We evaluated 324 cases of adolescent self-poisoners aged 12-18 years (mean +/- SD 14.8 +/- 1.5 years). The female/male ratio was 8:1. Most of the patients were attending school and lived in urban areas. Oral ingestion was the only route of intake; 84.5% of the patients ingested drugs and 10.5% non-medicinal compounds. The drug most commonly taken was acetaminophen. The non-medicinal compounds were mostly pesticides and household materials. The suicide attempts were most frequently associated with transient depression, stemming from defects in child-family communication. As based on clinical psychiatric evaluation, patients who had ingested polydrugs and non-medical compounds evidenced a significantly greater suicidal intent (chi 2 = 11.9, P < 0.001) compared to those who took only one or two kinds of drugs. We found that self-poisoning attempts occur most frequently in depressed females at junior high and high school, usually in the context of family dysfunction. Non-medicinal agents and polydrug ingestion are major risk factors for evaluating the seriousness of the suicidal intent.


Risk factors for recurrence of atrial fibrillation.
Atrial fibrillation (AF) is a progressive disease, associated with increased risk of mortality, stroke, heart failure, and worsens quality of life. There is a high incidence of AF recurrence despite the treatment. The aim of the study was to assess the time to recurrence of AF after sinus rhythm restoration with electrical or pharmacological cardioversion and to identify the risk factors. This study included 101 patients with AF (56% females) at a mean age of 68.02±7 years, after sinus rhythm restoration in a clinical observation of 1-year placebo-controlled treatment with spironolactone (1: 1). The patients were analyzed on the basis of AF recurrence, hospitalization, demographic parameters, comorbidities, embolic risk, and value of biomarker galectin-3 (Gal-3). The average number of AF recurrences was1.62 per patient per year. The median time of occurrence of at least one new episode was 48 days, 95% confidence interval (CI) 14.24-81.76. Female patients experienced significantly more recurrences than male-53.3% vs. 28.6% hazard ration (HR) =1.76, 95% CI 1.02-3.03, p=0.036. The recurrences were more common with increased age, although not significantly. Patients with arterial hypertension had a threefold risk of recurrences than those without hypertension (p=0.025), independently of the treatment. CHA2DS2-VASc score was significantly associated with AF recurrent episodes. Patients with gout had a twofold increased risk, without statistical significance (p=0.15). There was no difference in the AF episodes according to treatment with spironolactone. The levels of Gal-3 did not affect the number of AF recurrences (p=0.9). AF is associated with frequent recurrences after restoration of sinus rhythm in the majority of the patients. Most of them occurred within the first 3 months. Female sex, arterial hypertension, and CHA2DS2-VASc score were significant predictors of AF recurrence. Spironolactone did not reduce AF recurrences.


Co- and counter-transport mechanisms in brush border membranes and basal-lateral membranes of intestine and kidney.
One way to obtain a deeper understanding of the complex function of the small intestinal and renal proximal tubular epithelium is to dissect it into single components and then, having defined the components under well-controlled conditions, try to describe the behaviour of the whole system on the basis of the properties of the single components. Brush border and basal-lateral membranes can be isolated by different methods, including free flow electrophoresis, differential and gradient centrifugation. Transport can be analysed in vesiculated membrane fractions by tracer techniques and spectrophotometric techniques. Different sodium-solute co-transport mechanisms were identified in the brush border membrane. Until now, studies with vesicles failed to document a sodium-chloride co-transport mechanism satisfactorily. On the other hand, a sodium/proton and a chloride/hydroxyl exchange mechanism were documented. These two exchange mechanisms could represent partial reactions of the postulated electroneutral sodium-chloride co-transport. In addition to different sodium-independent transport systems, the basal-lateral membrane contains an ATP-driven transport system for calcium as well as a sodium/calcium exchange mechanism. Studies with membrane vesicles isolated from animals which have been exposed to different dietary conditions or in which the parathyroid hormone or 1.25(OH)2VitD3 level has been altered show altered transport of calcium and inorganic phosphate. Thereby, it might be possible to identify the biochemical mechanisms involved in transport regulation.


Association between recurrent aphthous ulcers and tobacco habits.
The study is a complication of data on oral mucosal lesions collected among 20 333 people aged 15 yr and over. The aim was to calculate the correlation between the prevalence of recurrent aphthous ulcers and various tobacco habits. The prevalence of aphthous ulcers in the population was 17.7% including cases referring to episodes within the last 2 yr. There was a negative correlation between the prevalence of ulcers and tobacco habits. The suppression of ulcers was most evident for those groups smoking pipe or cigarettes without filter and only moderate for those using snuff. Further, heavy smokers had a lower frequency of ulcers than moderate smokers.


Regulation of dendrimer/dextran material performance by altered tissue microenvironment in inflammation and neoplasia.
A "one material fits all" mindset ignores profound differences in target tissues that affect their responses and reactivity. Yet little attention has been paid to the role of diseased tissue on material performance, biocompatibility, and healing capacity. We assessed material-tissue interactions with a prototypical adhesive material based on dendrimer/dextran and colon as a model tissue platform. Adhesive materials have high sensitivity to changes in their environment and can be exploited to probe and quantify the influence of even subtle modifications in tissue architecture and biology. We studied inflammatory colitis and colon cancer and found not only a difference in adhesion related to surface chemical interactions but also the existence of a complex interplay that determined the overall dendrimer/dextran biomaterial compatibility. Compatibility was contextual, not simply a constitutive property of the material, and was related to the extent and nature of immune cells in the diseased environment present before material implantation. We then showed how to use information about local alterations of the tissue microenvironment to assess disease severity. This in turn guided us to an optimal dendrimer/dextran formulation choice using a predictive model based on clinically relevant conditions.


Association of radiotherapy for prostate cancer and second primary colorectal cancer: a US population-based analysis.
Radiotherapy (RT) is a common treatment for prostate cancer, yet the risk of second primary colorectal cancer (SPCRC) in patients with prostate cancer undergoing RT has not been adequately studied. This study employed a population-based cohort design using the US Surveillance, Epidemiology, and End Results (SEER) database to identify individuals diagnosed between January 1975 and December 2015. The cumulative incidence of SPCRC was estimated using Fine-Gray competing risk regression. Poisson regression analysis was used to estimate the risk associated with RT. Survival outcomes of patients with SPCRC were evaluated using the Kaplan-Meier method. A total of 287,607 patients diagnosed with prostate cancer were identified. The cumulative incidences were higher in patients who did not receive RT (2.00%) compared to those who underwent RT (2.47%) after 25 years. After adjustment for multiple variables, RT was associated with an increased risk of developing combined SPCRC (adjusted HR 1.590). Additionally, the overall survival was significantly lower in patients who developed colorectal cancer after receiving RT as compared to those who did not receive RT. These findings underscore the need for diligent long-term monitoring and effective management strategies to detect SPCRC in patients treated with RT for prostate cancer.


Influence of Climate on Radial Growth of Black Pine on the Mountain Regions of Southwestern Turkey.
In this study, we identified the most important climate factors affecting the radial growth of black pine at different elevations of the mountain regions of Southwestern Turkey (Sandıras Mountain, Muğla/Turkey). We used four black pine tree-ring chronologies, which represent upper and lower distribution limits of black pine forest on the South and North slopes of Sandıras Mountain. The relationships between tree-ring width and climate were identified using response function analysis. We performed hierarchical cluster analysis to classify the response functions into meaningful groups. Black pine trees in the mountain regions of Southwestern Turkey responded positively to a warmer temperature and high precipitation at the beginning of the growing season. As high summer temperatures exacerbated drought, radial growth was affected negatively. Hierarchical cluster analysis made clear that elevation differences, rather than aspect, was the main factor responsible for the formation of the clusters. Due to the mountainous terrain of the study area, the changing climatic conditions (air temperature and precipitation) affected the tree-ring widths differently depending on elevation.


C-reactive protein: a novel marker of cardiovascular risk.
Patients without traditional cardiovascular risk factors continue to suffer from cardiovascular events, which has prompted a search for novel markers to better assess cardiovascular risk. Inflammatory biomarkers have surfaced as prime candidates, given the integral role of inflammation in atherosclerosis. C-reactive protein (CRP) measurements in particular have emerged as powerful predictors of cardiovascular risk in a broad spectrum of patient populations. Newer high sensitivity CRP assays now in use are standardized and reproducible, and can detect variations in CRP below the limit of standard assays. In primary prevention populations, studies have shown up to a 2-4-fold increased risk of cardiovascular events in healthy patients with elevated CRP levels. In this population, models incorporating CRP and lipid parameters appear to predict risk significantly better than lipids alone. In patients with established cardiovascular disease and in patients undergoing percutaneous coronary interventions, CRP levels may help predict short- and long-term prognosis, identifying subgroups of patients at increased risk of recurrent events. CRP levels may also prove useful in targeting therapy for primary and secondary prevention, by identifying patients who would most benefit from medications such as statins and aspirin. This review presents an overview of the data regarding CRP measurement for cardiovascular risk assessment.


Preventing pelvic inflammatory disease.
Effective strategies for preventing pelvic inflammatory disease (PID) are crucial to protect women from adverse reproductive consequences and to avoid substantial economic losses. To identify current PID prevention options and assess their efficacy, we conducted a literature search and examined relevant data in published reports. We organized our review by level of participation (ie, individuals, providers, and communities) and prevention (ie, primary, secondary, and tertiary). For individuals, several prevention strategies related to personal protection appear promising, but few have been appropriately evaluated. For providers of health care, five prevention measures are recommended, including such primary prevention activities as counseling and patient education in addition to the usual diagnosis and treatment. Specific evidence supporting the efficacy of these provider practices, however, is limited. For communities, maintaining comprehensive sexually transmitted disease control strategies to prevent lower genital tract chlamydial and gonococcal infection is most important in reducing both symptomatic and asymptomatic PID. We provide specific recommendations for preventing PID and outline research needs.


Mental workload and stress perceived by novice operators in the laparoscopic and robotic minimally invasive surgical interfaces.
High levels of mental workload and stress are experienced by surgeons in the laparoscopic environment. The da Vinci(®) surgical robot was developed to provide surgeons a more user-friendly interface while maintaining the patient benefits associated with laparoscopy. This study examined whether the da Vinci robot reduces mental workload and stress in novice medical students. A detailed understanding of trainees' mental workload and mental stress experiences can aid in the development of training programs that are aimed at facilitating the acquisition of laparoscopic and robotic surgery skills. Fifteen novice first-year medical students performed a standard peg-transfer task at a laparoscopic simulator and the da Vinci Surgical System. Mental workload and stress were assessed with the Multiple Resources Questionnaire (MRQ) and the Dundee Stress State Questionnaire (DSSQ), respectively. Students' mental workload profiles were identical with the two surgical systems and replicated previous MRQ results reported with the laparoscopic system showing high levels of workload. Students experienced a better stress profile with the robotic system, however, when compared wih the laparoscopic system. Our study shows that novice medical students perceive less stress when working with the robotic surgical interface than with the laparoscopic surgery interface. The MRQ and the DSSQ are valuable tools for identifying mental workload and mental stress in the laparoscopic and robotic surgery environments. This information may be useful for facilitating the acquisition of laparoscopic and robotic surgery skills.


Compensating lung cancer patients occupationally exposed to coal tar pitch volatiles.
To investigate the process of deciding on compensation claims by lung cancer patients exposed occupationally to coal tar pitch volatiles. For each case of lung cancer the probability that it was caused (probability of causation (PC)) by coal tar pitch volatiles was expressed as an increasing function of cumulative exposure to benzo-a-pyrene-years. This was assessed from several exposure-response models fitted to data from a large epidemiological study of aluminum production workers. For some models, PC depended also on the smoking habit of the cancer patient. Estimation of relative risk by exposure group indicated that over 50% of lung cancers were attributable to coal tar pitch volatiles (PC > 50%) at exposures above 100 micrograms/m3-years benzo(a)pyrene. A linear relative risk model indicated that 50% PC was first achieved at 342.2 micrograms/m3-years benzo(a)pyrene, or 190.1 micrograms/m3-years benzo(a)pyrene according to the upper 95% confidence limit for risk increment. Corresponding figures for a power curve model were 210.3 and 45.9. With these five figures as compensation criteria compensation would have resulted in 31.4%, 2.7%, 19.2%, 15.7%, and 39.2% of cancers studied, compared with an estimated total proportion of cancers studied attributable to coal tar pitch volatiles of 15%-26%. If risks due to coal tar pitch volatiles and smoking multiply, PC does not depend on the amount smoked. If the two risks are additive, however, PC depends on the amount smoked according to a formula, with the figures mentioned applying to an average smoking history (24.4 pack-years). Because of its simplicity and because it falls within the range of criteria based on several more sophisticated approaches, we prefer the criterion of 100 micrograms/m3-years, based on the relative risks by exposure group. However, the compensation board of the Canadian province of Quebec, on consideration of these alternatives, has proposed as a criterion that the upper 95% confidence limit of PC for the patient be at least 50%, assuming an additive relative risk model and allowing for their smoking habit.


The Influence of Organizational Aspects of the U.S. Agricultural Industry and Socioeconomic and Political Conditions on Farmworkers' COVID-19 Workplace Safety.
Farmworkers in the U.S. experienced high rates of COVID-19 infection and mortality during the COVID-19 pandemic. Their workplace may have been a significant place of exposure to the novel coronavirus. Using political economy of health theory, this study sought to understand how organizational aspects of the agricultural industry and broader socioeconomic and political conditions shaped farmworkers' COVID-19 workplace safety during the pandemic. Between July 2020 and April 2021, we conducted and analyzed fourteen in-depth, semi-structured phone interviews with Latinx farmworkers in California. Findings show that regulatory oversight reinforced COVID-19 workplace safety. In the absence of regulatory oversight, the organization of the agricultural industry produced COVID-19 workplace risks for farmworkers; it normalized unsafe working conditions and the worker-rather than employer-responsibility for workplace safety. Under these conditions, farmworkers enacted personal COVID-19 preventative practices but were limited by financial hardships that were exacerbated by the precarious nature of agricultural employment and legal status exclusions from pandemic-related aid. Unsafe workplace conditions negatively impacted workplace camaraderie. Study findings have implications for farmworkers' individual and collective agency to achieve safe working conditions. Occupational safety interventions must address the organizational aspects that produce workplace health and safety inequities and disempower farmworkers in the workplace.


Targeting IL-27 and/or IL-10 in Experimental Murine Visceral Leishmaniasis.
Interleukin-10 (IL-10) and interleukin-27 (IL-27) both exert counterregulatory immunodeactivation in visceral Leishmania donovani infection. We studied experimental L. donovani infection in the livers of IL-10-/- and IL-27Rα-/- mice and observed that in IL-27Rα-/-, but not IL-10-/- mice, interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) were required for heightened granulomatous inflammation and accelerated control of intracellular parasite replication. This difference in mechanism, along with residual IL-10 activity in IL-27Rα-/- mice, suggested targeting IL-27 in addition to IL-10 in a macrophage-activating, anti-counterregulatory cytokine treatment strategy. In C57BL/6 wild-type mice with established liver infection, a single injection of anti-IL-27 p28 or anti-IL-10R monoclonal antibody enhanced granuloma assembly, enabled macrophage activation, and induced comparable parasite killing (49-56%). However, anti-IL-27 p28 plus anti-IL-10R combination treatment did not increase leishmanicidal effects. These results suggest that IL-27 and IL-10 may operate in a linked deactivating mechanism and that in this intracellular infection, either IL-27 or IL-10 is a suitable immunotherapeutic target.


[IgE-response after administration of pandemic vaccine strain A/California/7/2009 (H1N1)v].
Changes in total and allergy-specific IgE (IgE-antibodies) in 70 healthy volunteers vaccinated with influenza vaccine subunit strain A/California/7/2009/(H1N1)v. Safety of this vaccine was shown. Repeated second dose administration is not accompanied by increase in IgE-antibodies to egg components. Vaccine injection results in decrease of total IgE in patients with elevated IgE at baseline.


"Refractoriness" of airflow obstruction associated with isolated lymphocytic bronchiolitis/bronchitis in pulmonary allografts.
The clinical significance of an isolated "lymphocytic bronchiolitis/bronchitis" (grade B) as detected in transbronchoscopic biopsy specimens (TBB) is unclear. We therefore have reviewed the spirometric responses associated with isolated grade B diagnoses and contrasted them with episodes of "acute cellular rejection" (grade A); the latter are manifested by "perivascular lymphocytic infiltration." Because lymphocytic bronchiolitis/ bronchitis is considered a nonspecific histologic pattern that may be observed with either allograft rejection or respiratory infections, episodes were analyzed with respect to the presence (grade B [+] CMV) or absence (grade B [-] CMV) of cytomegalovirus infection. The maximum forced expiratory volume in 1 second (FEV1) during the preceding 3 months was used as a baseline for computing percent change in FEV1 coincident with transbronchoscopic biopsies (delta %FEV1 PRE) and maximum values obtained during the 3 months subsequent to specific therapies (delta %FEV1 POST). All episodes of acute cellular rejection (grades A1 to 4) and symptomatic lymphocytic bronchiolitis/bronchitis (grade B) were treated with "pulsed-dose" methylprednisolone, whereas intravenous ganciclovir was administered to patients at risk for recrudescence of cytomegalovirus. Between March 1, 1989, and September 1, 1995, 366 TBB procedures were performed for clinical indications in 57 lung transplant recipients. Histologic diagnoses with acceptable serial spirometric values included grade A1 (n = 9), grade A2 (n = 27), grade A3 (n = 2), grade B(-)CMV (n = 25) and grade B(+)CMV (n = 9). The delta %FEV1 PRE coincident with TBB were not statistically different for the different histologic groups. For grade A1, delta %FEV1 PRE was -14.6% +/- 5.2% (X +/- SEM); A2, -7.6% +/- 1.8%; B(-)CMV, -14.8% +/- 3.9%; and B(+)CMV, -14.8% +/- 2.3%. After treatment, the delta %FEV1 POST, relative to baseline values, were for grade A1, -8.8% +/- 7.1%, A2, +0.26% +/- 2.6%; B(-)CMV, -12.0% +/- 3.8%; and B(+)CMV, -6.2% +/- 2.8%. The delta %FEV1 POST values after pulsed methylprednisolone were significantly greater for histologic grade A2 than grade B(-)CMV (unpaired Student's t test, P < 0.01; 95% confidence interval for the difference of means: 3.34% to 21.2%). Grade A2 rejection was associated with spirometric improvement to within 10% of baseline values in 52% of episodes; whereas with grade B(-)CMV, this salutary response was observed in only 32% of episodes. Bronchiolitis obliterans syndrome stage 1b developed in 13 of 20 (65%) recipients, approximately 7.9 +/- 3.4 months after detection of histologic grade B and 21.2 +/- 9.5 months after transplantation. We conclude that the relative "refractoriness" of histologic grade B most likely reflects a continuum of bronchiolitis obliterans after lung transplantation and, hence, may warrant different immunosuppressive strategies. Furthermore, spirometric decrement associated with acute cellular rejection (grade A) may be ameliorated, but often not completely reversed, after pulsed methylprednisolone. We speculate that surveillance TBB may prove rewarding by enabling an earlier detection of these histologic diagnoses before the development of physiologic impairment.


Factors associated with hypertension awareness, treatment, and control in Dallas County, Texas.
Hypertension (HTN) control rates in the United States remain lower in black than white persons, particularly before 65 years of age. Potential sociocultural factors have not been sufficiently addressed. We analyzed data from structured interviews and blood pressure measurements in a population-based sample of 1514 hypertensive (1194 non-Hispanic black and 320 non-Hispanic white) subjects aged 18 to 64 years in Dallas County, Texas, from 2000 to 2002 to identify sociocultural factors associated with low rates of HTN control. We calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) using multivariate logistic regression. Awareness, treatment, and control of HTN were negatively associated with a common perception of good health, with aORs (95% CIs) of 0.37 (0.27-0.50) for awareness, 0.47 (0.36-0.62) for treatment, and 0.66 (0.51-0.86) for control. They were positively associated with having a regular physician, with aORs (95% CIs) of 3.81 (2.86-5.07) for awareness, 8.36 (5.95-11.74) for treatment, and 5.23 (3.30-8.29) for control. Among untreated hypertensive subjects, lack of perceived need for a regular physician was associated with perceived good health (aOR [95% CI], 2.2 [1.2-4.0]), male gender (aOR [95% CI], 2.4 [1.4-4.1]), and black race/ethnicity (aOR [95% CI], 2.1 [1.0-4.4]). The HTN outcomes were unrelated to perceived racism or lay beliefs about the causes, consequences, and treatment of HTN. Among young to middle-aged hypertensive subjects, a perception of good health and the lack of perceived need for a regular physician remain major factors associated with untreated and uncontrolled HTN at the community level-particularly among black men. These factors merit greater emphasis in professional education and public health programs on HTN.


Adsorption removal of Cr(VI) by isomeric FeOOH.
The aim of this work is to study the performances of isomeric α-, β-, and γ-FeOOH (goethite, akaganéite and lepidocrocite, including five samples named as Gth1 and Gth2, Aka1 and Aka2, and Lep, respectively) for removing hexavalent chromium (Cr(VI)) from aqueous solutions. The adsorption mechanisms were explored by kinetic and isothermal experiments. Adsorption efficiencies under the different pH values, anions, and the levels of adsorbate and adsorbent were also measured. Results showed that the Cr(VI) adsorption by isomeric FeOOH could be best described by pseudo-second-order kinetic model. The processes of Cr(VI) isothermal adsorption could be greatly fitted by the Langmuir and Freundlich equations with the high correlation coefficients of R2 (>0.92). Also, there were the optimum pH values of 3.0-8.0 for FeOOH to adsorb Cr(VI), and their adsorption capacities were tightly related with the active sites of adsorbents. Cr(VI) adsorptions by these adsorbents were easily influenced by H2PO4 -, and then SO4 2-, while there were little effects by Cl-, CO3 2- and NO3 -. These obtained results could provide a potentially theoretical evidence for isomeric FeOOH materials applied in the engineering treatment of the polluted chromate-rich waters.


The benefits of incorporating the One Health concept into the organisation of Veterinary Services.
This article analyses the potential benefits of disseminating and implementing the One Health concept at the country level. It explores the need to improve administrative structures, organise inter-agency relationships, build the capacity of the veterinary profession and mainstream the issues of environment and climate change. It also stresses the importance of demographic analysis in disease control and prevention. This article contributes to the discussion by Veterinary Services on how to mainstream the One Health concept.


PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis.
Elucidating mechanisms of hepatitis B virus (HBV)-mediated hepatocarcinogenesis is needed to gain insights into the etiology and treatment of liver cancer. Cells where HBV is replicating exhibit increased expression of Plk1 kinase and reduced levels of two transcription repression factors, SUZ12 and ZNF198. SUZ12 is an essential subunit of the transcription repressive complex PRC2. ZNF198 stabilizes the transcription repressive complex composed of LSD1, Co-REST, and HDAC1. These two transcription repressive complexes are held together by binding the long noncoding RNA HOTAIR. In this study, we linked these regulatory events mechanistically by showing that Plk1 induces proteasomal degradation of SUZ12 and ZNF198 by site-specific phosphorylation. Plk1-dependent ubiquitination of SUZ12 and ZNF198 was enhanced by expression of HOTAIR, significantly reducing SUZ12 and ZNF198 stability. In cells expressing the HBV X protein (HBx), downregulation of SUZ12 and ZNF198 mediated global changes in histone modifications. In turn, HBx-expressing cells propagated an altered chromatin landscape after cell division, as exemplified by changes in histone modifications of the EpCAM promoter, a target of PRC2 and LSD1/Co-REST/HDAC1 complexes. Notably, liver tumors from X/c-myc bitransgenic mice exhibited downregulation of SUZ12 and ZNF198 along with elevated expression of Plk1, HOTAIR, and EpCAM. Clinically, similar effects were documented in a set of HBV-related liver tumors consistent with the likelihood that downregulation of SUZ12 and ZNF198 leads to epigenetic reprogramming of infected hepatocytes. Because both Plk1 and HOTAIR are elevated in many human cancers, we propose that their combined effects are involved in epigenetic reprogramming associated broadly with oncogenic transformation.


Activator protein 2alpha mediates parathyroid TGF-alpha self-induction in secondary hyperparathyroidism.
In secondary hyperparathyroidism, enhanced expression of TGF-alpha in the parathyroid leads to its own upregulation, generating a feed-forward loop for TGF-alpha activation of its receptor, EGFR receptor (EGFR), which promotes parathyroid hyperplasia. These studies examined the role of activator protein 2alpha (AP2), an inducer of TGF-alpha gene transcription, in the upregulation of parathyroid TGF-alpha in secondary hyperparathyroidism. In rat and human secondary hyperparathyroidism, parathyroid AP2 expression strongly correlated with TGF-alpha levels and with the rate of parathyroid growth, as expected. Furthermore, the increases in rat parathyroid content of AP2 and its binding to a consensus AP2 DNA sequence preceded the increase in TGF-alpha induced by high dietary phosphate. More significant, in A431 cells, which provide a model of enhanced TGF-alpha and TGF-alpha self-induction, mutating the core AP2 site of the human TGF-alpha promoter markedly impaired promoter activity induced by endogenous or exogenous TGF-alpha. Important for therapy, in five-sixths nephrectomized rats fed high-phosphate diets, inhibition of parathyroid TGF-alpha self-induction using erlotinib, a highly specific inhibitor of TGF-alpha/EGFR-driven signals, reduced AP2 expression dosage dependently. This suggests that the increases in parathyroid AP2 occur downstream of EGFR activation by TGF-alpha and are required for TGF-alpha self-induction. Indeed, in A431 cells, erlotinib inhibition of TGF-alpha self-induction caused parallel reductions in AP2 expression and nuclear localization, as well as TGF-alpha mRNA and protein levels. In summary, increased AP2 expression and transcriptional activity at the TGF-alpha promoter determine the severity of the hyperplasia driven by parathyroid TGF-alpha self-upregulation in secondary hyperparathyroidism.


Comparison among amoA primers suited for quantification and diversity analyses of ammonia-oxidizing bacteria in soil.
Ammonia monooxygenase subunit A gene (amoA) is frequently used as a functional gene marker for diversity analysis of ammonia-oxidizing bacteria (AOB). To select a suitable amoA primer for real-time PCR and PCR-denaturing gradient gel electrophoresis (DGGE), three reverse primers (degenerate primer amoA-2R; non-degenerate primers amoA-2R-GG and amoA-2IR) were examined. No significant differences were observed among the three primers in terms of quantitative values of amoA from environmental samples using real-time PCR. We found that PCR-DGGE analysis with the amoA-2IR primer gave the best results in this studied soil. These results indicate that amoA-2IR is a suitable primer for community analysis of AOB in the environment.


The Role of the Membrane-Associated Domain of the Export Apparatus Protein, EscV (SctV), in the Activity of the Type III Secretion System.
Diarrheal diseases remain a major public health concern worldwide. Many of the causative bacterial pathogens that cause these diseases have a specialized protein complex, the type III secretion system (T3SS), which delivers effector proteins directly into host cells. These effectors manipulate host cell processes for the benefit of the infecting bacteria. The T3SS structure resembles a syringe anchored within the bacterial membrane, projecting toward the host cell membrane. The entry port of the T3SS substrates, called the export apparatus, is formed by five integral membrane proteins. Among the export apparatus proteins, EscV is the largest, and as it forms a nonamer, it constitutes the largest portion of the export apparatus complex. While there are considerable data on the soluble cytoplasmic domain of EscV, our knowledge of its membrane-associated section and its transmembrane domains (TMDs) is still very limited. In this study, using an isolated genetic reporter system, we found that TMD5 and TMD6 of EscV mediate strong self-oligomerization. Substituting these TMDs within the full-length protein with a random hydrophobic sequence resulted in a complete loss of function of the T3SS, further suggesting that the EscV TMD5 and TMD6 sequences have a functional role in addition to their structural role as membrane anchors. As we observed only mild reduction in the ability of the TMD-exchanged variants to integrate into the full or intermediate T3SS complexes, we concluded that EscV TMD5 and TMD6 are not crucial for the global assembly or stability of the T3SS complex but are rather involved in promoting the necessary TMD-TMD interactions within the complex and the overall TMD orientation to allow channel opening for the entry of T3SS substrates.


Alveolar macrophage subpopulations in bronchoalveolar lavage and induced sputum of asthmatic and control subjects.
Alveolar macrophages (AM) are the most numerous immune cells in the airways and are involved in the immunological homeostasis of the lung. Intriguingly, their role in asthma remains unclear probably, in part, because of their heterogeneity. To characterize AM population from bronchoalveolar lavage (BAL) and induced sputum (IS) of asthmatic and normal subjects using specific biomarkers. Non-asthmatic non-allergic and allergic mild asthmatic subjects were recruited for this study. AM were obtained from BAL and IS and cytospins were prepared. Immunocytochemistry was performed for nine cellular markers (CD68, RFD7, CD14, CD11b, CD83, CD64, CD80, CD86, and FIZZ1). Asthmatic subjects had more AM RFD7(+) in BAL compared with IS, whereas control subjects had more AM RFD7(+) in IS than in BAL. Consequently, there was an increased number of AM RFD7(+) in BAL of asthmatic subjects compared with BAL of control subjects. AM CD11b(+) was higher in BAL than in IS in both groups. The expression of FIZZ1, marker of macrophage alternative activation, was similar in asthmatic and normal subjects. The expression of cellular markers on AM differs according to their localization in the lung. Subpopulations of AM may contribute to the inflammatory profile observed in asthmatic subjects.


Current advances in Candida tropicalis: Yeast overview and biotechnological applications.
Candida tropicalis is a nonconventional yeast with medical and industrial significance, belonging to the CTG clade. Recent advancements in whole-genome sequencing and genetic analysis revealed its close relation to other unconventional yeasts of biotechnological importance. C. tropicalis is known for its immense potential in synthesizing various valuable biomolecules such as ethanol, xylitol, biosurfactants, lipids, enzymes, α,ω-dicarboxylic acids, single-cell proteins, and more, making it an attractive target for biotechnological applications. This review provides an update on C. tropicalis biological characteristics and its efficiency in producing a diverse range of biomolecules with industrial significance from various feedstocks. The information presented in this review contributes to a better understanding of C. tropicalis and highlights its potential for biotechnological applications and market viability.


A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity.
Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. We evaluated the efficacy and safety of 24-week treatment of mazdutide up to 6 mg in Chinese overweight adults or adults with obesity, as an interim analysis of a randomised, two-part (low doses up to 6 mg and high dose of 9 mg), double-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov, NCT04904913). Overweight adults (body-mass index [BMI] ≥24 kg/m2) accompanied by hyperphagia and/or at least one obesity-related comorbidity or adults with obesity (BMI ≥ 28 kg/m2) were randomly assigned (3:1:3:1:3:1) to once-weekly mazdutide 3 mg, 4.5 mg, 6 mg or matching placebo at 20 hospitals in China. The primary endpoint was the percentage change from baseline to week 24 in body weight. A total of 248 participants were randomised to mazdutide 3 mg (n = 62), 4.5 mg (n = 63), 6 mg (n = 61) or placebo (n = 62). The mean percentage changes from baseline to week 24 in body weight were -6.7% (SE 0.7) with mazdutide 3 mg, -10.4% (0.7) with 4.5 mg, -11.3% (0.7) with 6 mg and 1.0% (0.7) with placebo, with treatment difference versus placebo ranging from -7.7% to -12.3% (all p < 0.0001). All mazdutide doses were well tolerated and the most common adverse events included diarrhoea, nausea and upper respiratory tract infection. In summary, in Chinese overweight adults or adults with obesity, 24-week treatment with mazdutide up to 6 mg was safe and led to robust and clinically meaningful body weight reduction.


Thromboelastographic evaluation of dogs with congenital portosystemic shunts.
On plasma-based assays, dogs with congenital portosystemic shunts (CPSS) have changes in serum concentrations of both pro- and anticoagulant proteins, but how these abnormalities affect whole blood coagulation assays (eg, thromboelastography) are unknown. To conduct kaolin-activated thromboelastography (TEG) analysis in dogs with CPSS and to compare TEG coagulation status with clinical presentation, routine serum biochemistry, and plasma-based coagulation tests. Twenty-one client-owned dogs with CPSS confirmed by ultrasound examination or nuclear scintigraphy. In a prospective study, signalment, clinical presentation, TEG analysis, CBC, serum biochemistry, and hemostatic tests (platelet count, prothrombin time [PT], activated partial thromboplastin time [aPTT], quantitative fibrinogen, antithrombin [AT] activity, protein C [PC] activity, d-dimers, and factor VIII activity) were analyzed in dogs with CPSS. Dogs with CPSS had significantly shorter K values and increased angle, maximum amplitude (MA), and G values compared with the reference population. On plasma-based coagulation testing, dogs with CPSS had significantly prolonged PT, lower platelet counts, lower AT and PC activities, and increased d-dimers and factor VIII activity. Evaluation of G value defined 9/21 dogs with CPSS as hypercoagulable. These dogs were more likely to have hepatic encephalopathy (HE) than CPSS dogs that had normal coagulation. TEG analysis detected hemostatic abnormalities consistent with a hypercoagulable state in some dogs with CPSS. The presence of a hypercoagulable state was 40 times more likely in dogs with symptomatic HE.


Interventions to improve children's access to mental health care: a systematic review and meta-analysis.
Mental disorders in children are a significant and growing cause of morbidity worldwide. Although interventions to help overcome barriers along the pathway to accessing health care for children with mental disorders exist, there is no overview of randomised controlled trials (RCTs) on these interventions as yet. This study aimed to systematically identify RCTs of interventions to improve access to mental health care for children and synthesise them using a conceptual framework of access to health care. This systematic review was performed following a predefined protocol registered with PROSPERO (ID: CRD42018081714). We searched the databases MEDLINE, EMBASE, PsycINFO and CENTRAL for RCTs up to 15 May 2019 using terms related to the concepts 'young people,' 'mental disorders' and 'help-seeking interventions' and scanned reference lists from relevant studies. Two reviewers independently screened all identified articles in a two-stage process, extracted results on outcomes of interest (knowledge, attitudes, intentions, help-seeking, accessing care, mental health outcomes and satisfaction), assessed the risk of bias and conducted meta-analyses where deemed appropriate. After screening 5641 identified articles, 34 RCTs were eligible for inclusion. Eighty per cent of universal school-based interventions measuring knowledge (n = 5) and 67% measuring attitudes (n = 6) reported significantly better results compared with controls on those outcomes, whereas 20% measuring access to care (n = 5) and none measuring mental health outcomes (n = 7) did. In contrast, 71% of interventions targeting at-risk individuals (n = 21) reported better access to care compared with controls, while just 33% (n = 6) did for mental health outcomes. For satisfaction with care, this proportion was 80% (n = 5). Meta-analyses of interventions measuring initial appointment attendance yielded combined odds ratios of 3.11 (2.07-4.67) for appointment reminder interventions and 3.51 (2.02-6.11) for treatment engagement interventions. The outcomes for universal school-based interventions were heterogeneous and could not be summarised quantitatively through meta-analysis. To have a population-level effect on improving children's access to mental health care, two-stage interventions that identify those in need and then engage them in the health-care system may be necessary. We need more evidence on interventions to target contextual factors such as affordability and infrastructural barriers.


Multipole plasmon resonances of submicron silver particles.
Single crystal, silver particles of 215 +/- 10 nm size were synthesized in solution using the hydrogen reduction method and were characterized by UV-visible extinction spectroscopy and electron microscopy. The extinction spectra reveal the presence of higher order multipoles of the plasmon resonance, such as quadrupole, octupole, and hexadecapole, in addition to the dipole. The formation of higher order multipoles was continuously monitored during the particles growth. Mie extinction calculations were performed and are in good agreement with the measured extinction spectra. The frequency shift of all plasmon modes was measured as a function of the refractive index of the surrounding dielectric medium.


Ancient divisions, recent expansions: phylogeography and population genetics of the round goby Apollonia melanostoma.
During the past two decades, the round goby Apollonia melanostoma (=Neogobius melanostomus) has expanded its range via shipping transport and canals, extending north and west from the Ponto-Caspian region of Eurasia and to the North American Great Lakes. Exotic populations of the round goby have been very successful in the Baltic Sea and the Great Lakes regions, exerting significant ecological changes. Our study evaluates the population genetic and biogeographical structure of the round goby across its native and nonindigenous ranges, in light of geological history and its expansion pathways. We analyzed seven new nuclear microsatellite loci and mitochondrial DNA cytochrome b gene sequences from 432 individuals in 22 locations. Population structure was tested using F(ST)-analogs, phylogenetic trees, clustering diagrams, Bayesian assignment tests and nested clade analyses. Results show that native populations in the Black vs. the Caspian Sea basins diverge by 1.4% and c. 350,000 years, corresponding to closure of their prior connections and supporting the taxonomic separation of the Black Sea A. m. melanostoma from the Caspian Sea A. m. affinis. Their within-basin populations diverge by approximately 0.4% and 100,000 years. Nonindigenous populations in the Baltic Sea and Danube and Dnieper Rivers trace to separate northern Black Sea origins, whereas the upper Volga River system houses mixed populations of A. m. melanostoma and A. m. affinis. Native populations average twice the genetic diversity of most exotic sites; however, sites in the Volga River system have high diversity due to mixing of the two taxa. Our results highlight how vicariance and anthropogenic disturbances have shaped a rapidly expanding species' genetic heritage.


Development of the ReaxFF reactive force field for describing transition metal catalyzed reactions, with application to the initial stages of the catalytic formation of carbon nanotubes.
With the aim of developing a computationally inexpensive method for modeling the high-temperature reaction dynamics of transition metal catalyzed reactions we have developed a ReaxFF reactive force field in which the parameters are fitted to a substantial quantum mechanics (QM) training set, containing full reaction pathways for relevant reactions. In this paper we apply this approach to reactions involving carbon materials plus Co, Ni, and Cu atoms. We find that ReaxFF reproduces the QM reaction data with good accuracy while also reproducing the binding characteristics of Co, Ni, and Cu atoms to hydrocarbon fragments. To demonstrate the applicability of ReaxFF we performed high-temperature (1500 K) molecular dynamics simulations on a nonbranched all-carbon feedstock in the presence and absence of Co, Ni, and Cu atoms. We find that the presence of Co and Ni leads to substantial amounts of branched carbon atoms, leading eventually to the formation of carbon-nanotube-like species. In contrast, we find that under the same simulation conditions Cu leads to very little branching and leads to products with no nanotube character. In the absence of metals no branching is observed at all. These results suggest that Ni and Co catalyze the production of nanotube-like species whereas Cu does not. This is in excellent agreement with experimental observations, demonstrating that ReaxFF can provide a useful and computational tractable tool for studying the dynamics of transition metal catalytic chemistry.


Constitutive expression of a 92-kD gelatinase (type V collagenase) by rheumatoid synovial fibroblasts and its induction in normal human fibroblasts by inflammatory cytokines.
Synovial fibroblasts freshly isolated from the rheumatoid joint are characterized by their marked connective tissue degradative ability. This phenotype includes the ability to secrete large amounts of the matrix-degrading metalloproteinases, collagenase, and stromelysin. We have found that another aspect of this phenotype is the constitutive expression at both protein and mRNA levels of a 92-kD gelatinolytic metalloproteinase, which is not secreted by normal dermal or lung fibroblasts and is immunologically cross-reactive with a type V collagenase expressed by activated macrophages and neutrophils. Expression of this 92-kD metalloproteinase confers upon the fibroblasts the capacity to degrade collagenase- and stromelysin-resistant interstitial elements, such as collagen types IV, V and XI. In contrast to the 92-kD metalloproteinase, a 68-kD gelatinase (type IV collagenase) was expressed by all fibroblast types studied, indicating that its regulation is distinct from that of the 92-kD gelatinase. To identify what cytokines may be important in the induction of the rheumatoid synovial phenotype, including expression of the 92-kD gelatinase, we exposed normal dermal fibroblasts to a number of cytokines including many known or considered likely to be present in rheumatoid synovial fluid and tissue. Although IL-1 beta, tumor necrosis factor-alpha, lymphotoxin, platelet-derived growth factor, and basic fibroblast growth factor were capable of stimulating fibroblasts to secrete collagenase, only tumor necrosis factor-alpha, lymphotoxin, and IL-1 beta were able to induce expression of the 92-kD gelatinase, demonstrating discordant regulation of the two metalloproteinases. Expression of the 68-kD gelatinase was independent of that of the 92-kD gelatinase, as demonstrated at the protein and mRNA levels. Late passage rheumatoid synovial fibroblasts, which no longer constitutively expressed the 92-kD gelatinase, displayed an accentuated response to IL-1 beta when compared to normal dermal fibroblasts. Thus, in addition to IL-1 beta, tumor necrosis factor-alpha or lymphotoxin may contribute to the expression of a specific rheumatoid synovial phenotype in vivo that is associated with progressive matrix destruction.


[Minimally invasive methods for treatment of cholelithiasis, complicated by choledocholithiasis].
Disease of the common bile duct (choledochal duct) was revealed in 18 from 531 patients with bile tract lithiasis (3.4%), who underwent laparoscopic cholecystectomy and in 3 of 72 patients (5.4%), who underwent cholecystectomy through minilaparotomy approach. Stenosis of the large duodenal papilla was observed in 14 patients, choledocholithiasis in 9 patients. Endoscopic papillosphincterotomy (EPST) was performed in all cases. There were no complications. In 2 cases moderate amylasemia was detected. Laparoscopic cholecystectomy was performed 5 days after the procedure on the large duodenal papilla (5.1 days mean). Intervention with the use of mini-approach after EPST was carried out in patient with concrement of gall bladder duct stump, which was revealed 3 months after laparoscopic cholecystectomy. Mini-approach made it possible to perform reconstructive operations on bile ducts in combination with cholecystectomy in 3 patients. At present there are many tools which enable combined treatment of the bile tract lithiasis complicated by bile ducts pathology with low-invasive technique.


In vivo estimation and repeatability of force-length relationship and stiffness of the human achilles tendon using phase contrast MRI.
To devise a method using velocity encoded phase contrast MRI and MR-compatible dynamometry, for in vivo estimation of elastic properties of the human Achilles tendon and to assess within-session and day-to-day repeatability of this technique. Achilles tendon force and calcaneus-movement-adjusted displacement were measured during a submaximal isometric plantarflexion in 4 healthy subjects, four repeated trials each. The measured force-length (F-L) relationship was least-squares fitted to a cubic polynomial. Typical error was calculated for tendon displacement at multiple force levels, stiffness from the "linear region," and transition point from the displacement point separating the linear and nonlinear parts of the curve. Displacements of the tendon were determined up to a maximum force of 500 N, with mean stiffness of 234 +/- 53 N/mm, mean transition point of 2.70 +/- 0.23 mm and maximum tendon displacement of 3.38 mm. Variability of tendon displacement was not dependent on the force level. Overall typical errors were 0.09 mm and 0.16 mm for within-session and between days, respectively. Typical error of transition point was 0.05 mm and 0.14 mm. Stiffness had typical errors of 47.24 N/mm and 51.95 N/mm. The tendon cross-sectional area and calcaneus displacement were found to be very significant factors in minimizing the individual differences in F-L curves. The method yielded F-L relationships, stiffness, and transition point values that showed good within and day-to-day repeatability. The technique compared well with the more conventional one using ultrasonography. Its reliability indicates potential for measuring tendon structural changes after an injury, disease, and altered loading.


The interpretation of disjunction in universal grammar.
Child and adult speakers of English have different ideas of what 'or' means in ordinary statements of the form 'A or B'. Even more far-reaching differences between children and adults are found in other languages. This tells us that young children do not learn what 'or' means by watching how adults use 'or'. An alternative is to suppose that children draw upon a priori knowledge of the meaning of 'or'. This conclusion is reinforced by the observation that all languages adopt the same meaning of 'or' in certain structures. For example, statements of the form 'not S[A or B]' have the same meanings in all languages, and disjunctive statements receive a uniform interpretation in sentences that contain certain focus expressions, such as English 'only'. These observations are relevant for the long-standing "nature versus nurture" controversy. A linguistic property that (a) emerges in child language without decisive evidence from experience, and (b) is common to all human languages, is a likely candidate for innate specification. Experience matters, of course. As child speakers grow up, they eventually learn to use 'or' in the same way as adults do. But, based on findings from child language and cross-linguistic research, it looks like certain aspects of language, including the interpretation of disjunction, are part of the human genome.


Surgical ventricular restoration versus cardiac transplantation: a comparison of cost, outcomes, and survival.
Cardiac transplantation is the accepted standard treatment for end-stage heart disease but is donor limited. Surgical ventricular remodeling is an established treatment for patients with ischemic cardiomyopathy. We sought to compare charges, outcomes, and survival in patients undergoing surgical ventricular restoration (SVR) versus cardiac transplantation (CTx). We retrospectively analyzed hospital charges, length of stay (LOS), and survival for 69 SVR and 53 CTx patients at our institution between January 2002 and June 2005. We also compared New York Heart Association (NYHA) status and Kaplan-Meier survival of our SVR patients with CTx patients with ischemic cardiomyopathy from the International Society of Heart & Lung Transplantation (ISHLT) registry. Median total LOS (12 days vs. 17 days, P = .01) and median postoperative LOS (10 days vs. 15 days, P = .02) were shorter for SVR patients than our CTx patients. Median total hospital charges ($45,506 vs. $137,679, P < .0001) and median total drug charges ($2,625 vs. $15,930, P < .0001) were lower for SVR patients. Significant improvements in ejection fraction were seen after both SVR (27% vs. 37%; P < .0001) and CTx (14% vs. 62%, P < .0001). Furthermore, 91% (49/54) of surviving SVR patients, 98% (44/45) of surviving CTx patients, and 91% of ISHLT CTx patients improved to NYHA Class I/II at follow-up. Survival did not differ between groups. SVR patients demonstrate cost-effective clinical improvements that lead to good overall survival. SVR is an excellent surgical option for CHF patients who are not transplant candidates, and should be considered for ischemic cardiomyopathy patients who qualify for transplantation. This strategy may help relieve donor shortage and improve allocation of donor organs.


Data on benthic species assemblages and seafloor sediment characteristics in an offshore windfarm in the southeastern North Sea.
The German Bight (North Sea) is a centre of development of offshore wind energy. In the near future, windfarms will cover a significant part (about 25%) of the German Exclusive Economic Zone. In order to understand and assess potential effects of the construction and early operational phase of offshore wind turbines on the marine environment, an extensive research programme was carried out at Germany's first offshore windfarm alpha ventus. Here, data are presented on macroinfauna and local sediment characteristics collected as part of this programme. Grab samples were taken annually in autumn in 2008 (baseline), 2009 (construction phase) and 2010 and 2011 (early operational phase). Sampling stations were located along transects between adjacent turbines inside the windfarm and in two reference areas with similar environmental conditions in terms of sediment characteristics and water depth. A total of 336 samples were taken inside the windfarm and 192 samples in the reference areas. Sediment characteristics were described in terms of grain size distribution and organic content. The infauna was taxonomically analysed and quantified in terms of abundance and biomass. One-hundred three infauna taxa were identified, mainly belonging to the polychaetes, crustaceans and bivalves, living in fine to medium sandy soft bottom in water depths ranging from -27 m to -30 m. The data can be useful in meta-analyses of renewable energies impacts. Additionally, the data can support species distribution modelling to gain a better understanding of species' requirements and habitats as a basis for spatial planning scenarios and the evaluation of the ecological status of the marine environment. Moreover, the data can serve as baseline data for future monitoring and management of nearby protected areas where environmental conditions are comparable to those of the present study area.


Strong inbreeding depression in a Daphnia metapopulation.
The deleterious effects of inbreeding have long been known, and inbreeding can increase the risk of extinction for local populations in metapopulations. However, other consequences of inbreeding in metapopulations are still not well understood. Here we show the presence of strong inbreeding depression in a rockpool metapopulation of the planktonic freshwater crustacean Daphnia magna, which reproduces by cyclical parthenogenesis. We conducted three experiments in real and artificial rockpools to quantify components of inbreeding depression in the presence and the absence of competition between clonal lines of selfed and outcrossed genotypes. In replicated asexual populations, we recorded strong selection against clones produced by selfing in competition with clones produced by outcrossing. In contrast, inbreeding depression was much weaker in single-clone populations, that is, in the absence of competition between inbred and outbred clones. The finding of a competitive advantage of the outbred genotypes in this metapopulation suggests that if rockpool populations are inbred, hybrid offspring resulting from crosses between immigrants and local genotypes might have a strong selective advantage. This would increase the effective gene flow in the metapopulation. However, the finding of low inbreeding depression in the monoclonal populations suggests that inbred and outbred genotypes might have about equal chances of establishing new populations.