Physical properties of metal-doped zinc oxide films for surface acoustic wave application.
Metal-doped ZnO [MZO] thin films show changes of the following properties by a dopant. First, group III element (Al, In, Ga)-doped ZnO thin films have a high conductivity having an n-type semiconductor characteristic. Second, group I element (Li, Na, K)-doped ZnO thin films have high resistivity due to a dopant that accepts a carrier. The metal-doped ZnO (M = Li, Ag) films were prepared by radio frequency magnetron sputtering on glass substrates with the MZO targets. We investigated on the optical and electrical properties of the as-sputtered MZO films as dependences on the doping contents in the targets. All the MZO films had shown a preferred orientation in the [002] direction. As the quantity and the variety of metal dopants were changed, the crystallinity and the transmittance, as well as optical band gap were changed. The electrical resistivity was also changed with changing metal doping amounts and kinds of dopants. An epitaxial Li-doped ZnO film has a high resistivity and very smooth surface; it will have the most optimum conditions which can be used for the piezoelectric devices.


Silicon nanosensor for diagnosis of cardiovascular proteomic markers.
A silicon nanosensor technology based on electrical impedance measurements has been developed for the detection of proteins. The nanosensor miniaturizes the high-density, low-volume multiwell plate concept. The scientific core of this technology lies in integrating nanoporous membranes with microfabricated chip platforms. This results in the conversion of individual pores into nanowells of picoliter volume. Monoclonal antibodies were localized and isolated into individual wells. Detection of two cardiac proteomic biomarkers has been demonstrated with this technology. The two proteins, C-reactive protein and NT-pro-brain natriuretic peptide (BNP), are associated with adverse cardiac outcomes in clinical samples when detected in the pg/mL concentration. The formation of the antibody-antigen binding complex occurs in individual wells. The membrane allows for robust separation among individual wells. This technology has the capability to achieve near real-time detection with improved sensitivity at 1 ag/mL for BNP and 1 fg/mL for CRP from human serum.


Rotavirus Infection and Cytopathogenesis in Human Biliary Organoids Potentially Recapitulate Biliary Atresia Development.
Biliary atresia (BA) is a neonatal liver disease characterized by progressive fibroinflammatory obliteration of both intrahepatic and extrahepatic bile ducts. The etiologies of BA remain largely unknown, but rotavirus infection has been implicated at least for a subset of patients, and this causal relation has been well demonstrated in mouse models. In this study, we aim to further consolidate this evidence in human biliary organoids. We obtained seven batches of human biliary organoids cultured from fetal liver, adult liver, and bile duct tissues. We found that these organoids are highly susceptible and support the full life cycle of rotavirus infection in three-dimensional culture. The robust infection triggers active virus-host interactions, including interferon-based host defense mechanisms and injury responses. We have observed direct cytopathogenesis in organoids upon rotavirus infection, which may partially recapitulate the development of BA. Importantly, we have demonstrated the efficacy of mycophenolic acid and interferon alpha but not ribavirin in inhibiting rotavirus in biliary organoids. Furthermore, neutralizing antibody targeting rotavirus VP7 protein effectively inhibits infection in organoids. Thus, we have substantiated the causal evidence of rotavirus inducing BA in humans and provided potential strategies to combat the disease.IMPORTANCE There is substantial evidence indicating the possible involvement of rotavirus in biliary atresia (BA) development, at least in a subset of patients, but concrete proof remains lacking. In a mouse model, it has been well demonstrated that rotavirus can infect the biliary epithelium to cause biliary inflammation and obstruction, representing the pathogenesis of BA in humans. By using recently developed organoids technology, we now have demonstrated that human biliary organoids are susceptible to rotavirus infection, and this provokes active virus-host interactions and causes severe cytopathogenesis. Thus, our model recapitulates some essential aspects of BA development. Furthermore, we have demonstrated that antiviral drugs and neutralizing antibodies are capable of counteracting the infection and BA-like morphological changes, suggesting their potential for mitigating BA in patients.


Treatment of septic thrombocytopenia with immune globulin.
Thrombocytopenia frequently complicates systemic infection and results from multiple possible mechanisms. We and others have demonstrated that platelet-associated IgG (PAIgG) levels are elevated in the majority of patients with septic thrombocytopenia. Corticosteroids may be undesirable as a treatment for thrombocytopenia for patients with severe infection because of their potential for suppressing the immune response. We hypothesized that septic thrombocytopenia is, in most cases, an immune disorder analogous to idiopathic thrombocytopenic purpura (ITP) which might respond to intravenous gamma-globulin as a treatment for increasing the platelet count in this disorder. Intravenous immune globulin (IVIG), 400 mg/kg daily for 3 days, was administered in a randomized double-blind placebo-controlled trial. Twenty-nine patients who developed thrombocytopenia during a documented, septic episode were studied. Patients with disseminated intravascular coagulation (DIC), hypersplenism, or drugs known to cause thrombocytopenia were excluded. Elevated PAIgG levels were documented in 52% of evaluable patients. Mean platelet counts in the IVIG group rose from 43K at study entry to 178K (411% rise) by Day 9. In the placebo group platelets rose from 51K to 125K (261% rise; P = 0.02). Seventy-seven percent of the IVIG group had a minimum peak rise of 35K, vs 56% of the placebo group. Three patients in the placebo group had a serious bleeding episode, vs one in the IVIG group. The use of IVIG to treat septic thrombocytopenia not associated with DIC leads to a more rapid, more sustained, and greater increase in platelet count than placebo. Its use is recommended in the septic patient who is bleeding or is likely to need invasive or surgical procedures.


Disseminated pancreatic adenocarcinoma in an eclectus parrot (Eclectus roratus).
A 15-year-old 0.412-kg (0.906-lb) sexually intact male eclectus parrot (Eclectus roratus) was evaluated because its owners found it lethargic and dyspneic at the bottom of its cage. The parrot was thin and had generalized muscle wasting, diffuse feather loss, pale mucous membranes, and melena. The coelomic cavity was distended and soft on palpation, with coelomic effusion suspected. Results of a CBC indicated leukocytosis with left shift heterophilia, including toxic heterophils, lymphopenia, and anemia. Plasma biochemical analyses revealed severe hyperamylasemia. Radiography revealed no evidence of a metallic foreign body but severe loss of coelomic detail, suggestive of a coelomic mass, coelomic effusion with coelomitis, or both. Ultrasonography and CT revealed severe accumulation of coelomic fluid; a large, heterogeneous, irregularly marginated, and moderately vascularized mass in the caudal aspect of the coelomic cavity; and multiple hepatic, coelomic, and pulmonary nodules. On the basis of a poor prognosis, the parrot was euthanized. Necropsy results confirmed exocrine pancreatic adenocarcinoma, with disseminated metastases in the liver, gastrointestinal tract, coelomic cavity, and lungs. In birds, pancreatic adenocarcinoma is rarely reported but should be considered a differential diagnosis for hyperamylasemia, coelomic mass, coelomic effusion, or abnormal gastrointestinal signs, alone or in combination. Ultrasonography and CT can be useful in further evaluating such patients and should be considered in the diagnostic plan.


Clinical and radiographic predictors of acute compartment syndrome in the treatment of tibial plateau fractures: a retrospective cohort study.
The aim of the study was to evaluate the relation between demographic, injury-related, clinical and radiological factors of patients with tibial plateau fractures and the development of acute compartment syndrome. All consecutive adult patients with intra-articular tibial plateau fractures admitted in our urban academic medical centre between January 2005 and December 2009 were included in this retrospective cohort study. The main outcome measurement was the development of acute compartment syndrome. The charts of 265 patients (mean age 48.6 years) sustaining 269 intra-articular tibial plateau fractures were retrospectively reviewed. Acute compartment syndrome occurred in 28 fractures (10.4%). Four patients presented bilateral tibial plateau fractures; of them, 2 had unilateral, but none had bilateral acute compartment syndrome. Non-contiguous tibia fracture or knee dislocation and higher AO/OTA classification (type 41-C) were statistically significantly associated with the development of acute compartment syndrome in multivariable regression analysis, while younger age (<45 years), male sex, higher Schatzker grade (IV-V-VI), higher tibial widening ratio (≥1.05) and higher femoral displacement ratio (≥0.08) were significantly associated in the analysis adjusted for age and sex. Two parameters related to the occurrence of ACS in tibial plateau fractures were highlighted in this study: the presence of a non-contiguous tibia fracture or knee dislocation, and higher AO/OTA classification. They may be especially useful when clinical findings are difficult to assess (doubtful clinical signs, obtunded, sedated or intubated patients), and should rise the suspicion level of the treating surgeon. In these cases, regular clinical examinations and/or intra-compartmental pressure measurements should be performed before and after surgery, even if acute compartment syndrome seemed unlikely during initial assessment. However, larger studies are mandatory to confirm and refine both factors in predicting the occurrence of acute compartment syndrome.


The Cauliflower Mosaic Virus 35S Promoter: Combinatorial Regulation of Transcription in Plants.
Appropriate regulation of transcription in higher plants requires specific cis elements in the regulatory regions of genes and their corresponding trans-acting proteins. Analysis of the cauliflower mosaic virus (CaMV) 35S promoter has contributed to the understanding of transcriptional regulatory mechanisms. The intact 35S promoter confers constitutive expression upon heterologous genes in most plants. Dissection into subdomains that are able to confer tissue-specific gene expression has demonstrated that the promoter has a modular organization. When selected subdomains are combined, they confer expression not detected from the isolated subdomains, suggesting that synergistic interactions occur among cis elements. The expression patterns conferred by specific combinations of 35S subdomains differ in tobacco and petunia. This indicates that a combinatorial code of cisregulatory elements may be interpreted differently in different species.


Adult Granulosa Cell Tumor: A Sinister Differential for Clomiphene-resistant Infertility.
Granulosa cell tumors (GCTs) are rare sex cord-stromal tumors of the ovary. They may present with features of hyperestrogenism. We present a case of a 29-year-old nulliparous female, with infertility and oligomenorrhoea, initially managed with a provisional diagnosis of polycystic ovarian syndrome. She did not respond to multiple cycles of ovulation induction with clomiphene citrate. Later, an ovarian mass was detected, and she was initially planned for laparoscopy. Magnetic resonance imaging pelvis revealed a solid-looking mass in the ovary, with increased vascularity. Fine-needle aspiration cytology from the mass suggested GCT. She underwent staging laparotomy with fertility-preserving surgery. Thereafter, she conceived on first cycle of clomiphene citrate. She delivered twins and is presently 8 months postpartum. Thus, a high index of suspicion for underlying androgen- or estrogen-secreting tumor in cases of clomiphene-resistant infertility with ovarian cysts is advisable.


Synovial hypoxia as a cause of tendon rupture in rheumatoid arthritis.
Hypoxia and angiogenesis are now recognized as being important events in the perpetuation of joint destruction in rheumatoid arthritis (RA). In 50% of patients with RA, however, the disease also involves inflammation of the synovial tissue surrounding the tendons, which is associated with multiple ruptures and poor prognosis for long-term hand function. The aim of this study was to determine whether hypoxia and angiogenesis may also play a role in RA tendon disease. Matched in vivo synovial oxygen measurements (invasive and encapsulating tenosynovium and joint synovium) were taken intraoperatively using a microelectrode technique in patients having elective hand surgery for RA. Patients having elective hand surgery for indications other than inflammatory synovitis were recruited as controls. In parallel, RA synovial tissue was harvested and stained for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-2alpha. Tissue was also cultured under either hypoxic (1% O(2)) or normoxic (21% O(2)) conditions to investigate the effect of hypoxia on the expression of VEGF and its soluble receptor, as well as on the key cytokines interleukin (IL)-6, IL-8, IL-10 and the chemokine monocyte chemoattractant protein-1. Invasive tenosynovium was observed to be significantly more hypoxic than either noninvasive tenosynovium or joint synovium in the same patients. Furthermore, RA tenosynovium was shown to be more hypoxic than tenosynovium in patients without RA. This hypoxia was accompanied by expression of VEGF and hypoxia-inducible factor-2alpha. Using in vitro joint synovial cell cultures, upregulation of VEGF expression was shown to be a consequence of this in vivo hypoxia. Furthermore, hypoxia downregulated release of monocyte chemoattractant protein-1 and the immunoregulatory cytokine IL-10. These data demonstrate that hypoxia is a feature of rheumatoid tendon disease and differentially regulates angiogenesis and the inflammatory cascade in RA.


Aloe vera for treating acute and chronic wounds.
Aloe vera is a cactus-like perennial succulent belonging to the Liliaceae Family that is commonly grown in tropical climates. Animal studies have suggested that Aloe vera may help accelerate the wound healing process. To determine the effects of Aloe vera-derived products (for example dressings and topical gels) on the healing of acute wounds (for example lacerations, surgical incisions and burns) and chronic wounds (for example infected wounds, arterial and venous ulcers). We searched the Cochrane Wounds Group Specialised Register (9 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), Ovid MEDLINE (2005 to August Week 5 2011), Ovid MEDLINE (In-Process & Other Non-Indexed Citations 8 September 2011), Ovid EMBASE (2007 to 2010 Week 35), Ovid AMED (1985 to September 2011) and EBSCO CINAHL (1982 to 9 September 2011). We did not apply date or language restrictions. We included all randomised controlled trials that evaluated the effectiveness of Aloe vera, aloe-derived products and a combination of Aloe vera and other dressings as a treatment for acute or chronic wounds. There was no restriction in terms of source, date of publication or language. An objective measure of wound healing (either proportion of completely healed wounds or time to complete healing) was the primary endpoint. Two review authors independently carried out trial selection, data extraction and risk of bias assessment, checked by a third review author. Seven trials were eligible for inclusion, comprising a total of 347 participants. Five trials in people with acute wounds evaluated the effects of Aloe vera on burns, haemorrhoidectomy patients and skin biopsies. Aloe vera mucilage did not increase burn healing compared with silver sulfadiazine (risk ratio (RR) 1.41, 95% confidence interval (CI) 0.70 to 2.85). A reduction in healing time with Aloe vera was noted after haemorrhoidectomy (RR 16.33 days, 95% CI 3.46 to 77.15) and there was no difference in the proportion of patients completely healed at follow up after skin biopsies. In people with chronic wounds, one trial found no statistically significant difference in pressure ulcer healing with Aloe vera (RR 0.10, 95% CI -1.59 to 1.79) and in a trial of surgical wounds healing by secondary intention Aloe vera significantly delayed healing (mean difference 30 days, 95% CI 7.59 to 52.41). Clinical heterogeneity precluded meta-analysis. The poor quality of the included trials indicates that the trial results must be viewed with extreme caution as they have a high risk of bias. There is currently an absence of high quality clinical trial evidence to support the use of Aloe vera topical agents or Aloe vera dressings as treatments for acute and chronic wounds.


Nonspecific B and T cell-stimulatory activity mediated by mast cells is associated with exosomes.
Bone marrow-derived mouse mast cells (BMMC) and mast cell lines P815 and MC9 have recently been shown to induce antigen-independent B and T lymphocyte activation. It has been demonstrated that a physical contact between mast cells and B and T lymphocytes is not necessary since mast cell supernatants contain full activity. Electron microscopy studies revealed the presence in mast cell supernatants of small vesicles called exosomes with a heterogeneous size from 60 to 100 nm of diameter. When cocultured with spleen cells, purified exosomes induce B and T cell blast formation, proliferation as well as IL-2 and IFN-gamma production. In contrast to P815 and MC9 mast cell lines, a pretreatment with IL-4 is required for BMMC to produce active exosomes. Structurally, these exosomes were found to harbor immunologically relevant molecules such as MHC class II, CD86, LFA-1 and ICAM-1. Here we provide for the first time the evidence that mast cells use exosomes as sophisticated messengers to communicate with cells of the immune system.


Aerobic Training Improves Angiogenic Potential Independently of Vascular Endothelial Growth Factor Modifications in Postmenopausal Women.
The purpose of this study is to evaluate the effect of walking-training on the balance between pro- and antiangiogenic signals and on the angiogenic potential in postmenopausal women. Thirty-four postmenopausal women (56.18 ± 4.24 years) participated in a 13 weeks program of walking-training. Anthropometric measures, vascular endothelial growth factor (VEGF), interleukin (IL)-1α, IL-1β, IL-2, IL-8, IL-10, IL-12p70, tumor necrosis factor-α (TNF-α), C-reactive protein, insulin, IGF-1, cortisol, dehydroepiandrosterone sulfate (DHEA-S), leptin, visfatin, resistin, and adiponectin were evaluated before and after training. Moreover, serum samples were tested for their ability to chemo-attract endothelial cells and to support the in vitro formation of capillary-like structures. After training, the levels of IL-8, TNF-α, leptin, and resistin were significantly lower, levels of DHEA-S and adiponectin increased, serum angiogenic properties improved, whereas no changes in anthropometric parameters or VEGF were detected. Walking training reduces inflammatory status and leads to a significant improvement in serum angiogenic properties in the absence of modifications in body composition and VEGF level.


Doctors and Canadian Medicare: Improving Accountability and Performance.
Physician compensation has been a rapidly growing segment of healthcare costs in Canada since the late 1990s. In comparative terms, Canadian physicians are now well compensated compared to physicians in other high-income countries. This has caused provincial governments to begin constraining physician remuneration. However, physician payment should be examined in a larger governance context, including the potentially changing role of physicians, as provincial governments try to improve quality, increase coordination and improve overall health system performance. Although limited progress has been made through primary care reforms in a few jurisdictions, substantive improvement has been hampered by a misalignment between the policy goals and intentions of provincial governments and existing governance and accountability structures. This creates an environment in which both administrators and physicians feel they have limited input or control, seeding an adversarial rather than a collaborative relationship. Effective reform will require addressing governance and accountability at the same time as physician payment.


Punicalagin suppresses the proliferation and invasion of cervical cancer cells through inhibition of the β-catenin pathway.
Natural botanical drugs have attracted attention due to their cancer chemopreventive and chemotherapeutic properties in cancer. Punicalagin (PUN) is the major bioactive component of pomegranate peel, and has been shown to have antioxidant, anti-inflammatory, antiviral, antiproliferation and anticancer properties. PUN has been shown to induce apoptosis in several cancer cell lines. The aim of the present study was to investigate the effect of PUN on HeLa human cervical cancer cells in vitro. The viability of the HeLa cells was assessed following treatment with PUN (0, 12.5, 25, 50, 100 and 200 µM) for 24, 36 and 48 h using a Cell Counting Kit‑8 assay. In addition, the cell cycle distribution, protein expression levels of B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), Bcl‑2, tissue inhibitor of metalloproteinase (TIMP)-2, TIMP‑3 and the β‑catenin pathway, and the activities of matrix metalloproteinase (MMP)‑2 and MMP‑9 were analyzed following treatment with PUN (0, 25, 50 and 100 µM) for 36 h using cell cycle analysis, western blot analysis and gelatin zymography, respectively. In addition, a wound‑healing assay was used to detect cell migration. PUN led to a number of effects on the HeLa cells, including the inhibition of cell proliferation and cell migration, downregulation of MMP‑2 and MMP‑9, upregulation of TIMP‑2 and TIMP‑3, cell‑cycle arrest in the G1 phase, induction of apoptosis via alterations of Bcl‑2 and Bax, and downregulation of β‑catenin and its downstream proteins, cyclin D1 and c-myc. These results suggested that PUN may have chemopreventive and chemotherapeutic effects against cervical cancer in humans through inhibition of the β-catenin signaling pathway.


Structural determination of glycopeptidolipids of Mycobacterium smegmatis by high-resolution multiple-stage linear ion-trap mass spectrometry with electrospray ionization.
Glycopeptidolipids (GPLs) are abundant in the cell walls of different species of mycobacteria and consist of tripeptide-amino-alcohol core of D-Phe-D-allo-Thr-D-Ala-L-alaninol linked to 3-hydroxy or 3-methoxy C(26-34) fatty acyl chain at the N-terminal of D-Phe via amide linkage, and a 6-deoxytalose (6-dTal) and an O-methyl rhamnose residues, respectively, attach to D-allo-Thr and the terminal L-alaninol. They are important cell-surface antigens that are implicated in the pathogenesis of opportunistic mycobacteria belonging to the Mycobacterium avium complex. In this contribution, we described multiple-stage linear ion trap in conjunction with high-resolution mass spectrometry towards structural characterization of complex GPLs as [M + Na](+) ions isolated from Mycobacterium smegmatis, a fast-growing and non-pathogenic mycobacterial species. Following resonance excitation in an ion trap, MS(n) spectra of the [M + Na](+) ions of GPLs contained mainly b and y series ions that readily determine the peptide sequence. Fragment ions from MS(n) also afford locating the 6-dTal and O-methyl rhamnose residues linked to the D-allo-Thr and terminal L-alaninol of the peptide core, respectively, as well as recognizing the modifications of the glycosides, including their acetylation and methylation states and the presence of succinyl group. The GPL families consisting of 3-hydroxy fatty acyl and of 3-methoxy fatty acyl substituents are readily distinguishable. The MS profiles of the GPLs from cells are dependant on the conditions they were grown, and several isobaric isomers were identified for many of the molecular species. These multiple-stage mass spectrometric approaches give detailed structures of GPL in complex mixtures of which the isomeric structures are difficult to define using other analytical methods.


Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death.
The purpose of this study was to analyze the possible effects of machine perfusion (MP) versus cold storage (CS) on delayed graft function (DGF) and early graft survival in expanded criteria donor kidneys (ECD). As part of the previously reported international randomized controlled trial 91 consecutive heart-beating deceased ECDs--defined according to the United Network of Organ Sharing definition--were included in the study. From each donor one kidney was randomized to MP and the contralateral kidney to CS. All recipients were followed for 1 year. The primary endpoint was DGF. Secondary endpoints included primary nonfunction and graft survival. DGF occurred in 27 patients in the CS group (29.7%) and in 20 patients in the MP group (22%). Using the logistic regression model MP significantly reduced the risk of DGF compared with CS (OR 0.460, P=0.047). The incidence of nonfunction in the CS group (12%) was four times higher than in the MP group (3%) (P=0.04). One-year graft survival was significantly higher in machine perfused kidneys compared with cold stored kidneys (92.3% vs. 80.2%, P=0.02). In the present study, MP preservation clearly reduced the risk of DGF and improved 1-year graft survival and function in ECD kidneys. (Current Controlled Trials number: ISRCTN83876362).


Characterization of groundwater quality in three settlement areas of Enugu metropolis, southeastern Nigeria, using multivariate analysis.
Groundwater quality of Enugu metropolis comprising Achara Layout, Abakpa, and Emene settlement areas has been studied and characterized using multivariate statistical techniques. Three principal components (PCs) which explain 77.93 and 88.17% were extracted at Achara Layout and Abakpa, respectively, while two PCs which explain 83.13% were extracted at Emene. PC 1 of all the three areas reflects weathering of the host rock minerals and constitutes the dominant controlling process for all the areas. PC 2 of the three areas and PC 3 of Achara Layout and Abakpa can be attributed to both weathering/leaching of feldspathic minerals of host rocks (giving rise to alkaline earth metals in the groundwater) and anthropogenic activities. Cluster analysis defined groups of groundwater samples with similar hydrochemical characteristics. Two groups in Achara Layout and Emene fell into the high pollution loading class, while only one group in Abakpa fell into this class. The variation in the groundwater quality within each of the three areas may be explained in terms of groundwater flow directions, land use, and well depths. Discriminant analysis showed that the discriminating parameters of the groundwater quality of Achara Layout, Abakpa, and Emene are total dissolved solids, Na and Mg, and Cl, respectively. This study has revealed that the groundwater quality of the areas is controlled by both geogenic and anthropogenic processes and activities. The generated groundwater quality spatial variation models for each area will serve as a tool in the planning and development of groundwater in that region.


Functional analysis of alternatively spliced transcripts of the human histidine decarboxylase gene and its expression in human tissues and basophilic leukemia cells.
L-Histidine decarboxylase (HisDC) is the enzyme catalyzing the formation of histamine from L-histidine. HisDC activity is expressed specifically in mast cells/basophils, endocrine cells in stomach, and histaminergic neurons in brain. As a first step in the analysis of the regulation of HisDC gene expression, we have cloned the cDNA coding for HisDC from a cDNA library of a human basophilic leukemia cell line, KU-812-F. We identified two types of HisDC cDNA, representing the 2.4-kb and 3.4-kb HisDC mRNA constitutively expressed in these cells. Sequence analysis of these cDNA revealed that the 3.4-kb mRNA contains the insert sequence of 824 bases and suggests that both 2.4-kb and 3.4-kb mRNA may represent the alternatively spliced transcripts of the HisDC gene. Using expression plasmids containing a cDNA for each HisDC mRNA, we analyzed the function of possible HisDC isoforms. We show that only the 2.4-kb mRNA encodes functional HisDC and is expressed in human brain and lung. However, we were unable to detect the 3.4-kb mRNA in these tissues. Thus, the 3.4-kb mRNA may be generated by KU-812-F cell-specific splicing of the HisDC gene transcripts. Furthermore, we demonstrated the increase in the level of 2.4-kb HisDC mRNA and HisDC activity in KU-812-F cells following treatment with phorbol 12-myristate 13-acetate.


Resection of malignant brain tumors in eloquent cortical areas: a new multimodal approach combining 5-aminolevulinic acid and intraoperative monitoring.
Several studies have revealed that the gross-total resection (GTR) of malignant brain tumors has a significant influence on patient survival. Frequently, however, GTR cannot be achieved because the borders between healthy brain and diseased tissue are blurred in the infiltration zones of malignant brain tumors. Especially in eloquent cortical areas, resection is frequently stopped before total removal is achieved to avoid causing neurological deficits. Interestingly, 5-aminolevulinic acid (5-ALA) has been shown to help visualize tumor tissue intraoperatively and, thus, can significantly improve the possibility of achieving GTR of primary malignant brain tumors. The aim of this study was to go one step further and evaluate the utility and limitations of fluorescence-guided resections of primary malignant brain tumors in eloquent cortical areas in combination with intraoperative monitoring based on multimodal functional imaging data. Eighteen patients with primary malignant brain tumors in eloquent areas were included in this prospective study. Preoperative neuroradiological examinations included MR imaging with magnetization-prepared rapid gradient echo (MPRAGE), functional MR, and diffusion tensor imaging sequences to visualize functional areas and fiber tracts. Imaging data were analyzed offline, loaded into a neuronavigational system, and used intraoperatively during resections. All patients received 5-ALA 6 hours before surgery. Fluorescence-guided tumor resections were combined with intraoperative monitoring and cortical as well as subcortical stimulation to localize functional areas and fiber tracts during surgery. Twenty-five procedures were performed in 18 consecutive patients. In 24% of all surgeries, resection was stopped because a functional area or cortical tract was identified in the resection area or because motor evoked potential amplitudes were reduced in an area where fluorescent tumor cells were still seen intraoperatively. Grosstotal resection could be achieved in 16 (64%) of the surgeries with preservation of all functional areas and fiber tracts. In 2 patients presurgical hemiparesis became accentuated postoperatively, and 1 of these patients also suffered from a new homonymous hemianopia following a second resection. The authors' first results show that tumor resections with 5-ALA in combination with intraoperative cortical stimulation have the advantages of both methods and, thus, provide additional safety for the neurosurgeon during resections of primary malignant brain tumors in eloquent areas. Nonetheless, more cases and additional studies are necessary to further prove the advantages of this multimodal strategy.


A neural basis for general intelligence.
Universal positive correlations between different cognitive tests motivate the concept of "general intelligence" or Spearman's g. Here the neural basis for g is investigated by means of positron emission tomography. Spatial, verbal, and perceptuo-motor tasks with high-g involvement are compared with matched low-g control tasks. In contrast to the common view that g reflects a broad sample of major cognitive functions, high-g tasks do not show diffuse recruitment of multiple brain regions. Instead they are associated with selective recruitment of lateral frontal cortex in one or both hemispheres. Despite very different task content in the three high-g-low-g contrasts, lateral frontal recruitment is markedly similar in each case. Many previous experiments have shown these same frontal regions to be recruited by a broad range of different cognitive demands. The results suggest that "general intelligence" derives from a specific frontal system important in the control of diverse forms of behavior.


Continuous-wave nonclassical light with gigahertz squeezing bandwidth.
Squeezed states can be employed for entanglement-based continuous-variable quantum key distribution, where the secure key rate is proportional to the bandwidth of the squeezing. We produced a nonclassical cw laser field at the telecommunication wavelength of 1550 nm, which showed squeezing over a bandwidth of more than 2 GHz. The experimental setup used parametric downconversion via a periodically poled potassium titanyl phosphate crystal. We did not use any resonant enhancement for the fundamental wavelength, which should in principle allow a production of squeezed light over the full phase-matching bandwidth of several nanometers. We measured the squeezing to be up to 0.3 dB below the vacuum noise from 50 MHz to 2 GHz limited by the measuring bandwidth of the homodyne detector. The squeezing strength was possibly limited by thermal lensing inside the nonlinear crystal.


Photosynthesis and carbon partitioning in transgenic tobacco plants deficient in leaf cytosolic pyruvate kinase
Whole-plant diurnal C exchange analysis provided a noninvasive estimation of daily net C gain in transgenic tobacco (Nicotiana tabacum L.) plants deficient in leaf cytosolic pyruvate kinase (PKc-). PKc- plants cultivated under a low light intensity (100 &mgr;mol m-2 s-1) were previously shown to exhibit markedly reduced root growth, as well as delayed shoot and flower development when compared with plants having wild-type levels of PKc (PKc+). PKc- and PKc+ source leaves showed a similar net C gain, photosynthesis over a range of light intensities, and a capacity to export newly fixed 14CO2 during photosynthesis. However, during growth under low light the nighttime, export of previously fixed 14CO2 by fully expanded PKc- leaves was 40% lower, whereas concurrent respiratory 14CO2 evolution was 40% higher than that of PKc+ leaves. This provides a rationale for the reduced root growth of the PKc- plants grown at low irradiance. Leaf photosynthetic and export characteristics in PKc- and PKc+ plants raised in a greenhouse during winter months resembled those of plants grown in chambers at low irradiance. The data suggest that PKc in source leaves has a critical role in regulating nighttime respiration particularly when the available pool of photoassimilates for export and leaf respiratory processes are low.


Psychological impact of the COVID-19 pandemic on young professionals in blood banks and transfusion services: A global cross-sectional survey.
The COVID-19 pandemic brought about changes to daily life as measures to contain the spread of the virus increased across the world. The aim of this survey was to assess the psychological impact of the pandemic on young professionals (YPs) in transfusion medicine. A cross-sectional web-based survey was distributed electronically to ISBT members inviting YPs (≤40 years) to participate. Statistical analysis was performed using SPSS software. Two hundred and fifty-nine YPs completed the survey, including 107 clinicians/physicians and/or nurses. Almost half of the YPs (52.5%) indicated increased stress levels and 15.4% indicated symptoms of depression. YPs highlighted the loss of social engagement (59.1%) and increased pressure from information seen on media (35.5%) as factors negatively impacting their psychological wellbeing. Further, 20.8% expressed increased economic stress resulting from concerns about job security. Almost half of the YPs indicated that their organization provided moderate/occasional holistic support to them and their families. Sixty percent and 74.4% of YPs reported increased workload and staff absence due to COVID-19 infection, respectively. Only half of clinicians/physicians and/or nurses indicated that they often had sufficient personal protective equipment. The majority of these (76.6%) had family/household members living with them, and 61% indicated that they were significantly worried about infecting them because of the nature of their work. COVID-19 had a major impact on the well-being of YPs working in transfusion medicine. Measures are required to ensure that YPs are protected and mentally supported while undertaking their duties in current and future pandemics.


A computational investigation of thermodynamics, structure, dynamics and solvation behavior in modified water models.
We investigate the properties of geometrically modified water models by performing molecular dynamics simulations of perturbations of the extended simple point charge (SPC/E) model of water over a wide range of temperatures at 1 bar. The geometric modification consists of altering the H-O-H angle in SPC/E. The dipole moment is held constant by altering the O-H bond length, while the electrostatic charges are left unchanged. We find that a H-O-H angle of at least 100 degrees is necessary for the appearance of density anomalies and of solubility extrema with respect to temperature for small apolar solutes. We observe the occurrence of two incompatible types of structural order in these models: Tetrahedral, with waterlike translational order for bent models with H-O-H angles in excess of 100 degrees ; and linear, with Lennard-Jones-like orientationally averaged translational order for smaller H-O-H angles. Increasing the H-O-H angle causes the density to increase, while at the same time shifting waterlike anomalies to progressively higher temperatures. For bent models with H-O-H angle greater than SPC/E's, we observe arrest of translational motion at 300 K (115 degrees) and 330 K (120 degrees).


The origin of parental care in relation to male and female life history.
The evolution of maternal, paternal, and bi-parental care has been the focus of a great deal of research. Males and females vary in basic life-history characteristics (e.g., stage-specific mortality, maturation) in ways that are unrelated to parental investment. Surprisingly, few studies have examined the effect of this variation in male and female life history on the evolution of care. Here, we use a theoretical approach to determine the sex-specific life-history characteristics that give rise to the origin of paternal, maternal, or bi-parental care from an ancestral state of no care. Females initially invest more into each egg than males. Despite this inherent difference between the sexes, paternal, maternal, and bi-parental care are equally likely when males and females are otherwise similar. Thus, sex differences in initial zygotic investment do not explain the origin of one pattern of care over another. However, sex differences in adult mortality, egg maturation rate, and juvenile survival affect the pattern of care that will be most likely to evolve. Maternal care is more likely if female adult mortality is high, whereas paternal care is more likely if male adult mortality is high. These findings suggest that basic life-history differences between the sexes can alone explain the origin of maternal, paternal, and bi-parental care. As a result, the influence of life-history characteristics should be considered as a baseline scenario in studies examining the origin of care.


Computerized video analysis of social interactions in mice.
The study of social interactions in mice is used as a model for normal and pathological cognitive and emotional processes. But extracting comprehensive behavioral information from videos of interacting mice is still a challenge. We describe a computerized method and software, MiceProfiler, that uses geometrical primitives to model and track two mice without requiring any specific tagging. The program monitors a comprehensive repertoire of behavioral states and their temporal evolution, allowing the identification of key elements that trigger social contact. Using MiceProfiler we studied the role of neuronal nicotinic receptors in the establishment of social interactions and risk-prone postures. We found that the duration and type of social interactions with a conspecific evolves differently over time in mice lacking neuronal nicotinic receptors (Chrnb2-/-, here called β2(-/-)), compared to C57BL/6J mice, and identified a new type of coordinated posture, called back-to-back posture, that we rarely observed in β2(-/-) mice.


A PMLRARalpha transgene initiates murine acute promyelocytic leukemia.
The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RAR alpha). To test the hypothesis that the chimera PMLRAR alpha plays a role in leukemogenesis, we expressed a PMLRAR alpha cDNA in myeloid cells of transgenic mice. PMLRAR alpha transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR alpha impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.


Structuring polarity-inverted TBA to G-quadruplex for selective recognition of planarity of natural isoquinoline alkaloids.
Efficient structuring of DNA by small molecules is very crucial in developing DNA-based novel switches with an ideal performance. In this work, we found that inverting only the polarity of the 3' terminal guanine of the thrombin-binding aptamer (3iTBA) totally eradicates the original TBA G-quadruplex (G4) structure in K+. The unstructured 3iTBA can be further refolded upon specifically interacting with small molecules of natural isoquinoline alkaloids (IAs) due to their fruitful binding patterns with variant nucleic acid structures. We identified that 3iTBA can serve as a topology selector for planar IAs. Nitidine (NIT), owing to the planar aromatic ring and coplanar substituents, is the most efficient to restructure the 3iTBA random coil toward the anti-parallel G4 conformation. However, common metal ions can't realize this structuring. The topology selector competency of 3iTBA toward IAs' planarity can be visualized using gold nanoparticles (AuNPs) as the chromogenic readout. Our work expands the G4 repertoire by exploring the polarity inversion regulation and provides a new approach to switch nucleic acid structures toward a small molecule structure-sensitive sensor.


People reporting experiences of mediumship have higher dissociation symptom scores than non-mediums, but below thresholds for pathological dissociation.
Background: Dissociative states exist on a continuum from nonpathological forms, such as highway hypnosis and day-dreaming, to pathological states of derealization and depersonalization. Claims of communication with deceased individuals, known as mediumship, were once regarded as a pathological form of dissociation, but current definitions recognize the continuum and include distress and functional disability as symptoms of pathology. This study examined the relationship between dissociative symptoms and mediumship in a large convenience sample. Methods: Secondary analyses of cross-sectional survey data were conducted. The survey included demographics, the Dissociation Experience Scale Taxon (DES-T, score range 0-100), as well as questions about instances of mediumship experiences. Summary statistics and linear and logistic regressions explored the relationship between dissociative symptoms and mediumship endorsement. Results: 3,023 participants were included and were mostly middle-aged (51 years ± 16; range 17-96), female (70%), Caucasian (85%), college educated (88%), had an annual income over $50,000 (55%), and were raised Christian (71%) but were presently described as Spiritual but not Religious (60%). Mediumship experiences were endorsed by 42% of participants, the experiences usually began in childhood (81%), and 53% had family members who reported similar experiences. The mean DES-T score across all participants was 14.4 ± 17.3, with a mean of 18.2 ± 19.3 for those claiming mediumship experiences and 11.8 ± 15.2 for those who did not (t = -10.3, p < 0.0005). The DES-T threshold score for pathological dissociation is 30. Conclusions: On average, individuals claiming mediumship experiences had higher dissociation scores than non-claimants, but neither group exceeded the DES-T threshold for pathology. Future studies exploring dissociative differences between these groups may benefit from using more comprehensive measures of dissociative symptoms as well as assessments of functional impairment, which would help in discerning between pathological and non-pathological aspects of these experiences.


Effect of different levels of black cumin (Nigella sativa L.) on performance, intestinal Escherichia coli colonization and jejunal morphology in laying hens.
This study was conducted to investigate the effects of different levels of black cumin seeds (Nigella sativa L.) on performance, intestinal Escherichia coli count and morphology of jejunal epithelial cells in laying hens. A total of 100 Leghorn laying hens (Hy-Line W-36) of 49 weeks old were randomly distributed among five cage replicates of five birds each. Experimental diets consisted of different levels (0%, 1%, 2% and 3% of diet) of dietary black cumin inclusion. The experimental period lasted for a total of 10 weeks, and egg quality indexes and laying hens' performance were measured as two 35-day trial periods. At the final day, two hens per replicate were slaughtered to investigate the influence of dietary treatments on intestinal E. coli colonization and morphology of jejunal cells. Although dietary black cumin in all supplementation levels decreased (p < 0.05) the enumeration of ileal E. coli, the morphological and histological alterations in small intestine such as enhancement of villus height to crypt depth ratio, increased goblet cell numbers and proliferation of lamina propria lymphatic follicles were observed after dietary supplementation with at least 2% black cumin. Dietary treatments decreased (p < 0.05) the concentration of serum cholesterol and triglycerides and increased (p < 0.05) serum HDL concentration and relative weight of pancreas; however, the egg yolk cholesterol was not influenced by dietary treatments. In addition, dietary supplementation with black cumin improved (p < 0.05) eggshell quality and Haugh unit. The best feed conversion ratio was obtained when diets were supplemented with 2% black cumin. This improvement was due to the increase (p < 0.05) in egg mass and contemporaneous decrease (p < 0.01) in feed consumption. The present results indicated that regardless of supplementation level, dietary inclusion of black cumin decreased E. coli enumeration in ileal digesta and improved serum lipid profile and eggshell quality, whereas the best intestinal health indices and haying hens' performance were obtained by at least 2% black cumin seeds.


Cavity-Enhanced Room-Temperature Broadband Raman Memory.
Broadband quantum memories hold great promise as multiplexing elements in future photonic quantum information protocols. Alkali-vapor Raman memories combine high-bandwidth storage, on-demand readout, and operation at room temperature without collisional fluorescence noise. However, previous implementations have required large control pulse energies and have suffered from four-wave-mixing noise. Here, we present a Raman memory where the storage interaction is enhanced by a low-finesse birefringent cavity tuned into simultaneous resonance with the signal and control fields, dramatically reducing the energy required to drive the memory. By engineering antiresonance for the anti-Stokes field, we also suppress the four-wave-mixing noise and report the lowest unconditional noise floor yet achieved in a Raman-type warm vapor memory, (15±2)×10^{-3} photons per pulse, with a total efficiency of (9.5±0.5)%.


Analysis of phase I and phase II metabolites of tamoxifen in breast cancer patients.
This study describes the application of LC/MS/MS to the determination of phase I and phase II metabolites of tamoxifen in urine and plasma samples of breast cancer patients. In the plasma extracts, in addition to the parent drug and N-desmethyltamoxifen, a minor metabolite tamoxifen N-oxide was identified for the first time in human. Four intact glucuronides of tamoxifen metabolites were isolated in the 24-hr posttreatment urine sample. They were the glucuronides of 4-hydroxytamoxifen, 4-hydroxy-N-desmethyltamoxifen, dihydroxytamoxifen, and a monohydroxy-N-desmethyltamoxifen. Hydroxylation followed by glucuronidation is a well-established metabolic route of tamoxifen, and this study describes for the first time direct analyses of these metabolites in human urine samples using on-line LC tandem MS.


Accelerated carbonation using municipal solid waste incinerator bottom ash and cold-rolling wastewater: Performance evaluation and reaction kinetics.
Accelerated carbonation of alkaline wastes including municipal solid waste incinerator bottom ash (MSWI-BA) and the cold-rolling wastewater (CRW) was investigated for carbon dioxide (CO2) fixation under different operating conditions, i.e., reaction time, CO2 concentration, liquid-to-solid ratio, particle size, and CO2 flow rate. The MSWI-BA before and after carbonation process were analyzed by the thermogravimetry and differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy equipped with energy dispersive X-ray spectroscopy. The MSWI-BA exhibits a high carbonation conversion of 90.7%, corresponding to a CO2 fixation capacity of 102g perkg of ash. Meanwhile, the carbonation kinetics was evaluated by the shrinking core model. In addition, the effect of different operating parameters on carbonation conversion of MSWI-BA was statistically evaluated by response surface methodology (RSM) using experimental data to predict the maximum carbonation conversion. Furthermore, the amount of CO2 reduction and energy consumption for operating the proposed process in refuse incinerator were estimated. Capsule abstract: CO2 fixation process by alkaline wastes including bottom ash and cold-rolling wastewater was developed, which should be a viable method due to high conversion.


Automatic 3-D breath-hold related motion correction of dynamic multislice MRI.
Magnetic resonance (MR) cine images are often used to clinically assess left ventricular cardiac function. In a typical study, multiple 2-D long axis (LA) and short axis (SA) cine images are acquired, each in a different breath-hold. Differences in lung volume during breath-hold and overall patient motion distort spatial alignment of the images thus complicating spatial integration of all image data in three dimensions. We present a fully automatic postprocessing approach to correct these slice misalignments. The approach is based on the constrained optimization of the intensity similarity of intersecting image lines after the automatic definition of a region of interest. It uses all views and all time frames simultaneously. Our method models both in-plane and out-of-plane translations and full 3-D rotations, can be applied retrospectively and does not require a cardiac wall segmentation. The method was validated on both healthy volunteer and patient data with simulated misalignments, as well as on clinical multibreath-hold patient data. For the simulated data, subpixel accuracy could be obtained using translational correction. The possibilities and limitations of rotational correction were investigated and discussed. For the clinical multibreath-hold patient data sets, the median discrepancy between manual SA and LA contours was reduced from 2.83 to 1.33 mm using the proposed correction method. We have also shown the usefulness of the correction method for functional analysis on clinical image data. The same clinical multibreath-hold data sets were resegmented after positional correction, taking newly available complementary information of intersecting slices into account, further reducing the median discrepancy to 0.43 mm. This is due to the integration of the 2-D slice information into 3-D space.


Gluten-specific T cells cross-react between HLA-DQ8 and the HLA-DQ2α/DQ8β transdimer.
Because susceptibility to celiac disease is associated strongly with HLA-DQ2 (DQA1*05/DQB1*02) and weakly with HLA-DQ8 (DQA1*03/DQB1*03), a subset of patients carries both HLA-DQ2 and HLA-DQ8. As a result, these patients may express two types of mixed HLA-DQ2/8 transdimers (encoded by DQA1*05/DQB1*03 and DQA1*03/DQB1*02) in addition to HLA-DQ2 and HLA-DQ8. Using T cells from a celiac disease patient expressing HLA-DQ8trans (encoded by DQA*0501/DQB*0302), but neither HLA-DQ2 nor HLA-DQ8, we demonstrate that this transdimer is expressed on the cell surface and can present multiple gluten peptides to T cell clones isolated from the duodenum of this patient. Furthermore, T cell clones derived from this patient and HLA-DQ2/8 heterozygous celiac disease patients respond to gluten peptides presented by HLA-DQ8trans, as well as HLA-DQ8, in a similar fashion. Finally, one gluten peptide is recognized better when presented by HLA-DQ8trans, which correlates with preferential binding of this peptide to HLA-DQ8trans. These results implicate HLA-DQ8trans in celiac disease pathogenesis and demonstrate extensive T cell cross-reactivity between HLA-DQ8 and HLA-DQ8trans. Because type 1 diabetes is strongly associated with the presence of HLA-DQ8trans, our findings may bear relevance to this disease as well.


Distinct shed microvesicle and exosome microRNA signatures reveal diagnostic markers for colorectal cancer.
Extracellular vesicle (EV) microRNAs are of major interest as potential diagnostic biomarkers in all cancer types. This study aims to identify miRNA profiles of shed microvesicles (sMVs) and exosomes (Exos) secreted from the isogenic colorectal cancer (CRC) cell lines SW480 and SW620 and evaluate their ability to predict CRC. Deep sequencing of miRNAs in parental cell lysates (CLs) and highly-purified sMVs and Exos was performed. We focused on miRNAs enriched in EVs and dysregulated miRNAs in metastatic cells (SW620) relative to primary cancer cells (SW480). We investigated the ability of EV miRNA signatures to predict CRC tumours using 594 tumours (representing different pathological stages) and 11 normal samples obtained from TCGA. In SW480 and SW620 cells we identified 345 miRNAs, of which 61 and 73 were upregulated and downregulated in SW620-CLs compared to SW480-CLs, respectively. Selective distribution of cellular miRNAs into EVs results in distinct miRNA signatures for sMVs and Exos in each cell line. Cross cell line comparisons of EV miRNA profiles reveal a subset of miRNAs critical in CRC progression from primary carcinoma to metastasis. Many miRNAs non-detectable (<5 TPM) in CLs were significantly enriched (>1000 TPM) in secreted EVs. Strikingly, miR-7641 which is non-detectable in SW480-CL but upregulated in SW620-CL is highly enriched in EVs secreted from both cell lines. Pearson correlation analysis demonstrated that EV miRNA profiles can be used to predict CRC tumours with ~96% accuracy. Our findings suggest that EV miRNA profiles from CRC cell lines may allow prediction of CRC tumours, and that miR-7641 may serve as an attractive candidate for the specific, non-invasive diagnosis and prognosis of CRC.


Utility of the LACE index at the bedside in predicting 30-day readmission or death in patients hospitalized with heart failure.
The Length of stay, Acuity, Comorbidities, Emergency department visits in prior 6 months (LACE) index threshold of 10 predicts readmission or death in general medical patients in administrative databases. We assessed whether the unadjusted LACE index, computed at the bedside, can predict 30-day outcomes in patients hospitalized for heart failure. We used logistic regression with LACE as the continuous predictor and 30-day readmissions and 30-day readmission or death as outcomes. We determined a suitable LACE threshold using logistic regression and the closest-to-(0,1) criterion for dichotomized LACE scores. We assessed model discrimination with C statistics and 95% CI. Of 378 patients, a majority (91%) had LACE scores ≥10. Incremental LACE scores increased the odds of 30-day readmissions (odds ratio [OR] 1.13, 95% CI 1.02-1.24) and 30-day readmissions or death (OR 1.11, 95% CI 1.01-1.22). C statistics for 30-day readmissions (0.59, 95% CI 0.52-0.65) and 30-day readmission or death (0.57, 95% CI 0.51-0.64) were nonsignificantly lower than the Centers for Medicare/Medicaid Services-endorsed readmission risk score (0.61, 95% CI 0.55-0.67 and 0.62, 95% CI 0.55-0.68, respectively). LACE ≥13 predicted 30-day readmissions (OR 1.91, 95% CI 1.17-3.09) and 30-day readmission or death (OR 1.59, 95% CI 1.00-2.54), and met the closest-to-(0,1) criterion for optimal threshold. LACE calculated at the bedside predicts 30-day clinical outcomes in hospitalized heart failure patients. While there is a continuum of risk, a threshold of ≥13 is more suitable than ≥10 to identify high-risk patients. Given its modest discrimination, however, we do not recommend its preferential use over validated risk prediction tools such as readmission risk score.


Pseudogene recoding revealed from proteomic analysis of salmonella serovars.
Recoding refers to the reprogramming of mRNA translation by nonstandard read-out rules. In this study, we used stable isotope labeling with amino acids in cell culture (SILAC) technology to investigate the proteome of host-adapted Salmonella serovars, which are characteristic of accumulation of pseudogenes. Interestingly, a few annotated pseudogenes were indeed able to express peptides downstream of the inactivation site, suggesting the occurrence of recoding. Two mechanisms of recoding, namely, programmed frameshifting and codon redefinition, were both found. We believe that the phenomena of recoding are not rare in bacteria. More studies are required for a better understanding of bacterial translation and the implication of pseudogene recoding in Salmonella serovars.


Parents' narratives about their experiences of their child's reconstructive genital surgeries for ambiguous genitalia.
The aim of this study was to initiate an exploration of parents' understanding and experiences of their child's reconstructive genital surgeries for ambiguous genitalia. The determination of gender for a child born with ambiguous genitalia is a complex medical and social process influenced by biological, psychological, social and cultural factors. Two main approaches exist; one promotes interventions (optimal gender policy) while the other suggests delaying interventions (informed consent policy) until the child can contribute to the decision. An exploratory narrative inquiry design was chosen. Data were collected through narrative interviews with a purposive non-random sample of 10 parents of eight children (aged 0-11 years) who had ambiguous genitalia. Parents' stories reflected strong protective instincts towards their children along with feelings of shock and disbelief. Parents' social construction of gender influenced their attitudes and beliefs about their child's ambiguous genitalia and the need for surgery. Parents' desired to be 'good parents' and do what they perceived as 'right' for their child. They considered genital surgery as a necessity primarily relying on medical advice to guide them at times of uncertainty and confusion. Parents rarely shared stories about their child's surgeries/genitalia outside of the couple relationship and these stories were often referred to as 'secrets'. Having a child with ambiguous genitalia was perceived as problematic and brought about changes in roles, responsibilities, goals and social status as a parent beyond those usually associated with parenthood. These early findings help increase awareness of parents' experiences and of the problems and emotional challenges that parents face when their child is born with genital ambiguity.


A clinical pathway for pediatric gastroenteritis.
Gastroenteritis is one of the most common reasons for hospitalization in the United States for children under the age of 5 years. Second only to respiratory problems, the cost of providing care for these children is estimated to exceed $2 billion dollars annually ( Burkhart, 1999; Prescilla, 2002). This article reviews the causes of gastroenteritis as well as the 1996 American Academy of Pediatrics Guidelines for treatment of gastroenteritis. These guidelines and more recently published literature were used to develop a clinical pathway to improve the care of pediatric patients admitted to the hospital with gastroenteritis. The article discusses the importance of clinical pathways and the process of implementation of a pathway for pediatric gastroenteritis. Additionally, the article provides a parent teaching tool to address recurrent questions parents have related to home management of a child with gastroenteritis. Useful web sites for resource information related to gastroenteritis are provided as well.


Intrapulmonary schwannoma presenting as an asymptomatic lung mass: a case report.
Schwannomas are solitary well-circumscribed encapsulated benign tumors that exhibit Schwann cell differentiation, and arise directly from myelinated peripheral or central nerves. Although they are usually asymptomatic and found incidentally, schwannomas can cause symptoms due to compression of nearby structures which, depending on the location, can make clinical presentations widely variable. Despite their rarity, schwannomas have been documented in a number of locations including the limbs, cerebellopontine angle, posterior mediastinum, and, far more infrequently, the lungs. In this article, we report an incidental finding of an intrapulmonary schwannoma in a 59-year-old Pakistani woman who was grossly asymptomatic upon presentation to the cardiothoracic surgery clinic. An [18F]fluorodeoxyglucose positron emission tomography/computed tomography scan revealed a lobulated soft-tissue lesion measuring 23 mm × 23 mm in the lower lobe of the right lung. A computed tomography-guided core biopsy of the mass was performed, which revealed a benign spindle cell lesion based on histopathological examination and immunohistochemical staining. The mass was surgically resected via a right lower lobectomy, and subsequently confirmed to be an encapsulated neoplastic lesion composed of well-differentiated Schwann cells. There were no short- or long-term complications, morbidities, or recurrences based on 1-year follow-up. This report underscores the predominantly asymptomatic nature of schwannomas and reemphasizes the efficacy of surgical resection as a safe and curative procedure for a tumor of this nature. Albeit very rare, intrapulmonary schwannomas can be considered a differential diagnosis when encountering solitary asymptomatic pulmonary nodules or masses.


SEL1L is required for endoplasmic reticulum-associated degradation of misfolded luminal proteins but not transmembrane proteins in chicken DT40 cell line.
Proteins misfolded in the endoplasmic reticulum (ER) are degraded in the cytosol by a ubiquitin-dependent proteasome system, a process collectively termed ER-associated degradation (ERAD). Unraveling the molecular mechanisms of mammalian ERAD progresses more slowly than that of yeast ERAD due to the laborious procedures required for gene targeting and the redundancy of components. Here, we utilized the chicken B lymphocyte-derived DT40 cell line, which exhibits an extremely high homologous recombination frequency, to analyze ERAD mechanisms in higher eukaryotes. We disrupted the SEL1L gene, which encodes the sole homologue of yeast Hrd3p in both chickens and mammals; Hrd3p is a binding partner of yeast Hrd1p, an E3 ubiquitin ligase. SEL1L-knockout cells grew only slightly more slowly than the wild-type cells. Pulse chase experiments revealed that chicken SEL1L was required for ERAD of misfolded luminal proteins such as glycosylated NHK and unglycosylated NHK-QQQ but dispensable for that of misfolded transmembrane proteins such as NHK(BACE) and CD3-δ, as in mammals. The defect of SEL1L-knockout cells in NHK degradation was restored by introduction of not only chicken SEL1L but also mouse and human SEL1L. Deletion analysis showed the importance of Sel1-like tetratricopeptide repeats but not the fibronectin II domain in the function of SEL1L. Thus, our reverse genetic approach using the chicken DT40 cell line will provide highly useful information regarding ERAD mechanisms in higher eukaryotes which express ERAD components redundantly.


Transcatheter aortic valve replacement: transapical resection of the aortic valve in vivo.
The resection of pulmonary valves has already been demonstrated in an experimental beating-heart model. The aim of this study was to analyse the transapical laser-assisted resection of aortic valves in an in vivo porcine model in a non-beating heart. The resection was performed in a porcine model (n = 10) using a Thullium:YAG laser. After establishing a standard extracorporeal circulatory support, the aortic valve isolation chamber (AVIC) system was inserted transapically. The resection of the aortic leaflets was carried out step-by-step in the arrested heart. The AVIC implantation, the resection process, and the gross anatomy of intracardiac lesions were analysed. The procedure for installing the AVIC took 5.8 ± 1.5 min. A sealed chamber was achieved in 9/10 cases. The resection of the valves was performed in 8/10 and completed in 7/10 cases. The resection took, on average, 7.4 ± 2.7 min/cusp. In 9/10 cases, the sealing was sufficient. Gross anatomy and histological analysis demonstrated only superficial damage to the surrounding tissue. In this study, the in vivo on-pump isolation of the left ventricular outflow tract and the laser resection of the native aortic valve could be demonstrated successfully. Nevertheless, this model is the next step towards a beating-heart resection of the aortic valve using the isolation chamber.


Modest association of joint hypermobility with disabling and limiting musculoskeletal pain: results from a large-scale general population-based survey.
To determine the population prevalence of joint hypermobility (JH) and to test the hypothesis that JH would be associated with reporting musculoskeletal pain. We conducted a cross-sectional population survey in Aberdeen and Cheshire. A total of 45,949 questionnaires were mailed that assessed JH and the presence, distribution, duration, and severity of musculoskeletal pain. Based on their pain reports, participants were classified as having chronic widespread pain (CWP), some pain, or no pain. Multinominal logistic regression tested the relationship between JH and pain status. Associations were adjusted for age, sex, and other putative confounders. Participants with no pain were the referent category. A total of 12,853 participants (28.0%) returned a questionnaire with complete data; 2,354 participants (18.3%) were classified as hypermobile. A total of 2,094 participants (16.3%) had CWP, 5,801 participants (45.1%) had some pain, and 4,958 participants (38.6%) reported no pain. JH participants were significantly more likely to report CWP than non-JH participants (18.5% versus 15.8%; P < 0.001). After adjusting for age and sex, hypermobile participants were 40% more likely to report the most severe CWP (relative risk ratio [RRR] 1.4, 95% confidence interval [95% CI] 1.1-1.7; P < 0.00). After further adjustments for employment status, smoking, alcohol, and physical activity, JH remained significantly associated with the most severe CWP (RRR 1.6, 95% CI 1.3-2.1; P < 0.000) and some pain (RRR 1.3, 95% CI 1.02-1.6; P = 0.03). JH was associated with severe pain; however, this relationship was not specific to CWP. The relationship was relatively modest and may be explained by unmeasured confounding factors such as psychological distress.


High-resolution mapping of infraslow cortical brain activity enabled by graphene microtransistors.
Recording infraslow brain signals (<0.1 Hz) with microelectrodes is severely hampered by current microelectrode materials, primarily due to limitations resulting from voltage drift and high electrode impedance. Hence, most recording systems include high-pass filters that solve saturation issues but come hand in hand with loss of physiological and pathological information. In this work, we use flexible epicortical and intracortical arrays of graphene solution-gated field-effect transistors (gSGFETs) to map cortical spreading depression in rats and demonstrate that gSGFETs are able to record, with high fidelity, infraslow signals together with signals in the typical local field potential bandwidth. The wide recording bandwidth results from the direct field-effect coupling of the active transistor, in contrast to standard passive electrodes, as well as from the electrochemical inertness of graphene. Taking advantage of such functionality, we envision broad applications of gSGFET technology for monitoring infraslow brain activity both in research and in the clinic.


The parasitoid, Verticia fasciventris causes morphological and behavioral changes in infected soldiers of the fungus-growing termite, Macrotermes carbonarius.
The larval parasitoid Verticia fasciventris Malloch (Diptera: Calliphoridae) develops in the head of soldiers of the fungus-growing termite Macrotermes carbonarius (Hagen) (Isoptera: Termitidae). Morphological and behavioral changes in the host were evaluated and the termite castes and stages that were parasitized were identified. The larval emergence process is also described and possible mechanisms for the parasitoid fly's entry into the host body are discussed based on qualitative observations. Only a single larva per host was found. The mature larva pupated outside the host's body by exiting between the abdominal cerci. Parasitized soldiers possess a short and square-shaped head capsule, a pair of notably short mandibles, and a pair of 18-segmented antennae. Although parasitized soldiers were statistically less aggressive than healthy soldiers (P < 0.05), they expressed varying levels of aggression. Both minor and major soldiers can be parasitized and based on evidence from presoldiers, parasitization may begin during the precursor stages of soldiers. However, the stage at which parasitism first occurs has not been determined.


Optimisation of positive and expiratory pressure for maximal delivery of oxygen to tissues using oesophageal Doppler ultrasonography.
To assess oesophageal Doppler ultrasonography as a convenient means of optimising positive end expiratory pressure for maximal delivery of oxygen to tissues. Measurements of blood flow, arterial oxygen saturation, and cardiac output by thermodilution (when available) at baseline and at 20-30 minutes after each incremental increase (2.5-5.0 cm H2O) in positive and expiratory pressure to a maximum of 20.0 cm H2O. If the cardiac output fell by more than 15% measurements were repeated after stepwise decreases in positive end expiratory pressure. No other manoeuvre such as endotracheal suction or changing ventilator settings, drug or fluid dosage, or the patient's position was performed for at least one hour before the start of the study or during it. Intensive care unit. 10 Patients being mechanically ventilated for acute respiratory failure who had stable haemodynamic and blood gas values and required a fractional inspired oxygen concentration of greater than or equal to 0.45. They were assessed on a total of 11 occasions. Incremental increases in positive end expiratory pressure followed when indicated by stepwise decreases. The positive end expiratory pressure providing maximal delivery of oxygen to tissues. Arterial oxygen saturation increased with positive end expiratory pressure in all patients by an average of 6.1%. In nine of the 11 studies, however, cardiac output fell by 15% to 30% after the second increment. On the two other occasions cardiac output and oxygen delivery rose by up to 54%. Positive end expiratory pressure was decreased on seven occasions; there was considerable individual variation in the time taken for cardiac output to rise and arterial oxygen saturation to fall. In six patients good agreement was seen between the results from Doppler ultrasonography and thermodilution, the mean of the differences being -0.3% with narrow limits of agreement (-14.4% to 13.9%). Oesophageal Doppler ultrasonography is a rapid, safe, and reliable technique for optimising positive end expiratory pressure to obtain maximal delivery of oxygen to tissues. The results show the need to consider haemodynamic consequences when altering positive end expiratory pressure.


Addressing dementia challenges through international networks: Evidence from the Latin American and Caribbean Consortium on Dementia (LAC-CD).
LAC-CD has recently reported that challenges faced by LAC countries are very similar to those experienced by HIC, and that regional networks will be needed to bridge gaps. ReDLat is a US-LAC multi-partner consortium aimed at expanding dementia research in LAC. The UK-Latin America Brain Connectivity Research Network (UL-BCRN) focuses on developing new affordable EEG-based biomarkers for dementia. The Language and Brain Health Network (LBHN) integrate international multidisciplinary efforts to reveal linguistic markers of neurodegenerative diseases. ReDLat is collecting genomic, neuroimaging, clinical, cognitive, and socioeconomic data from a first-in-class cohort anchored in six LAC (Argentina, Chile, Colombia, Brazil, Mexico, and Peru) and will compare these to US data (> 4200 participants, including 2100 controls, 1050 AD patients, and 1050 FTD patients). The 5-year project will develop innovative, harmonized, and cross-nation approaches on two of the most prevalent neurodegenerative diseases, Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). The UL-BCRN currently links seven EEG labs from Colombia, Argentina, Chile, Brazil and the UK. The network's vision is to forge strong relationships between labs through which new methodologies, EEG plus multidimensional datasets, and experience will be developed and shared. The LBHN will analyze speech samples from massive AD, FTD, and control cohorts across LAC, Spain, and the US. This effort aims to identify low-cost disease-specific markers in diverse Latino and English-speaking patients. ReDLat will aims to reveal unique risk factors for AD and FTD in LAC compared to US populations. Data collection strategies have been adapted to face the challenges brought by the COVID-19 pandemic. The UL-BCRN has now standardised recording protocols across LAC and UK labs and is collecting data from longitudinal cohorts of patients at risk of dementia relying on novel culture-free cognitive paradigms. Preliminary LBHN data shows that, automated speech analyses can identify Latinos with AD and FTD, with good generalization across socio-biological profiles, dialects, and languages. By broadening our understanding of dementia phenotypes, risk factors, and affordable diagnostic approaches in LAC, adding new evidence on variability across HIC and LMIC, the above networks will contribute unique knowledge that will help enhance future global dementia strategies.


The centrality of social ties to climate migration and mental health.
Climate change-related hazards and disasters, known to adversely impact physical and mental health outcomes, are also expected to result in human migration above current levels. Environmentally-motivated migration and displacement may lead to the disruption of existing social ties, with potentially adverse consequences for mobile populations as well as their family members who remain in places of origin. We propose that the disruption of social ties is a key mechanism by which climate-related migration may negatively impact mental health, in particular. Existing social ties may provide social and material resources that buffer mental health stressors related to both prolonged and acute climate events. Preparation for such events may also strengthen these same ties and protect mental health. Communities may leverage social ties, first to mitigate climate change, and second, to adapt and rebuild post-disaster in communities of origin. Additionally, social ties can inform migration decisions and destinations. For example, scholars have found that the drought-motivated adaptive migration of West African Fulbe herders only occurred because of the long-term development of social networks between migrants and non-migrants through trade and seasonal grazing. On the other hand, social ties do not always benefit mental health. Some migrants, including those from poor regions or communities with no formal safety net, may face considerable burden to provide financial and emotional resources to family members who remain in countries of origin. In destination communities, migrants often face significant social marginalization. Therefore, policies and programs that aim to maintain ongoing social ties among migrants and their family and community members may be critically important in efforts to enhance population resilience and adaptation to climate change and to improve mental health outcomes. Several online platforms, like Refugee Start Force, serve to integrate refugees by connecting migrants directly to people and services in destination communities. These efforts may increasingly draw upon novel technologies to support and maintain social networks in the context of population mobility due to climatic and other factors.


Diverging mRNA and Protein Networks in Activated Microglia Reveal SRSF3 Suppresses Translation of Highly Upregulated Innate Immune Transcripts.
Uncontrolled microglial activation may lead to the development of inflammation-induced brain damage. Here, we uncover a ribosome-based mechanism/checkpoint involved in control of the innate immune response and microglial activation. Using an in vivo model system for analysis of the dynamic translational state of microglial ribosomes, with mRNAs as input and newly synthesized peptides as an output, we find a marked dissociation of microglia mRNA and protein networks following innate immune challenge. Highly upregulated and ribosome-associated mRNAs were not translated, resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA signature and an immunomodulatory/homeostatic protein signature. We find that this is due to specific translational suppression of highly expressed mRNAs through a 3' UTR-mediated mechanism involving the RNA-binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia.


Utilizing a crossover reverse sural artery flap for soft tissue reconstruction of the plantar forefoot after a severe degloving injury.
Extensive soft tissue defects involving the weight-bearing areas of the plantar aspect of the foot often require coverage with flaps. The options often include free flaps, free muscle flaps with split-thickness skin grafting, or local flaps. When presented with high-energy-induced soft tissue injuries of the foot, choices become narrow, secondary to the associated zone of injury. Free flaps require a viable recipient vessel suitable for microvascular anastomosis. Split-thickness skin grafts applied to the plantar aspect of the foot are prone to persistent breakdown. Local flaps if available are useful for coverage of plantar soft tissue defects. However, when local flaps of the affected limb are compromised or extension is not sufficient for coverage, crossover leg and foot flaps become invaluable. The reported cases of crossover sural artery flaps are sparse. To the best of the authors' knowledge, the few reported cases of crossover leg and sural artery flaps were described to provide soft tissue coverage over the heel and leg. The authors report a case of a crossover reverse sural artery flap for soft tissue coverage to the plantar aspect of the forefoot after a high-energy-induced degloving injury.


In Vivo Precipitation of Poorly Soluble Drugs from Lipid-Based Drug Delivery Systems.
Precipitation of poorly water-soluble drugs from lipid-based drug delivery systems (LbDDS) has been studied extensively during in vitro lipolysis but has never been shown in vivo. The aim of this study was therefore to investigate if drug precipitation can occur from LbDDS during transit of the gastrointestinal tract in vivo. Rats were administered 300 μL of either of two LbDDS (LbDDS I and LbDDS II) loaded with danazol or fenofibrate (or paracetamol to assess gastric emptying). The rats were euthanized at various time points after administration of both LbDDS containing either drug, and the contents of the stomach and proximal part of the small intestine were harvested. The contents were analyzed for crystalline drug by X-ray powder diffraction and polarized light microscopy. No drug precipitation was evident in the stomach or the intestine after administration of LbDDS I containing danazol at the tested time points. Fenofibrate precipitation was absent in the stomach initially after administration of LbDDS I, but was evident in the stomach 90 min after dosing. No crystalline fenofibrate was observed in the intestine. Danazol and fenofibrate precipitation was evident in the stomach following administration of LbDDS II containing either drug, but not in the intestine at the tested time point. Drug precipitation from LbDDS was observed in the stomach, but not in the intestine, which is contrary to what in vitro lipolysis data (obtained under human GI conditions) suggests. Thus, precipitation of drugs from LbDDS in vivo in rats is much lower than might be anticipated from in vitro lipolysis data.


Glenoid bone deficiency in recurrent anterior shoulder instability: diagnosis and management.
Recurrent anterior shoulder instability may result from a spectrum of overlapping, often coexistent factors, one of which is glenoid bone loss. Untreated, glenoid bone loss may lead to recurrent instability and poor patient satisfaction. Recent studies suggest that the glenoid rim is altered in up to 90% of shoulders with recurrent instability, thus underscoring the need for careful diagnosis, quantification, and preoperative evaluation. Biomechanical and clinical studies offer criteria that may be used in both primary and revision settings to judge whether shoulder stability is compromised by a bony defect. Along with patient activity level, these criteria can help guide the surgeon in selecting treatment options, which range from nonsurgical care to isolated soft-tissue repair as well as various means of bony reconstitution.


Morphologic predictive factors for development of optic disc hemorrhages in glaucoma.
To evaluate which optic disc parameters are predictive factors for the development of disc hemorrhages in chronic open-angle glaucoma. The prospective comparative clinical observational study included 432 eyes of 281 white patients with chronic open-angle glaucoma. Mean follow-up time was 38.8 months (median, 31.5). Eyes in the whole study group were divided into those with an optic disc hemorrhage during the follow-up period (hemorrhagic group; n = 38; 8.8%), those without disc hemorrhages and with neuroretinal rim loss as sign of progression of glaucoma (rim loss group; n = 42; 9.7%), and those with neither disc hemorrhages nor neuroretinal rim loss (stable group; n = 352; 81.5%). Color stereo optic disc photographs were obtained repeatedly in all patients and subjected to qualitative and morphometric evaluation. At baseline, neuroretinal rim area was significantly (P < 0.03) smaller and the beta zone of parapapillary atrophy (temporal lower sector) was significantly (P < 0.03) larger in the hemorrhagic group than in the stable group. Both study groups did not vary significantly (P > 0.05) in optic disc size and shape, optic cup depth, alpha zone of parapapillary atrophy, and retinal vessel diameter. In multivariate analysis, the neuroretinal rim area was the only significant predictor of hemorrhages. The hemorrhagic group and the rim loss group did not differ significantly (P > 0.05) in any optic disc parameter measured. In chronic open-angle glaucoma, morphologic predictive factors for the development of disc hemorrhages are small size of neuroretinal rim and, possibly, a large parapapillary beta zone. Development of disc hemorrhages is independent of optic disc size and shape, size of alpha zone of parapapillary atrophy, retinal vessel diameter, and optic cup depth. Optic nerve heads in eyes with eventual development of disc hemorrhages and in eyes with eventual progressive rim loss without observed disc hemorrhages do not differ markedly in appearance.


The effect of irradiance on virus sterilization and photodynamic damage in red blood cells sensitized by phthalocyanines.
Phthalocyanines are being studied as photosensitizers for virus sterilization of red blood cells (RBC). During optimization of the reaction conditions, we observed a marked effect of the irradiance on production of RBC damage. Using a broad-band light source (600-700 nm) between 5 and 80 mW/cm2, there was an inverse relationship between irradiance and rate of photohemolysis. This effect was observed with aluminum sulfonated phthalocyanine (AlPcSn) and cationic silicon (HOSiPc-OSi[CH3]2[CH2]3N+[CH3]3I- phthalocyanine (Pc5) photosensitizers. The same effect occurred when the reduction of RBC negative surface charges was used as an endpoint. Under the same treatment conditions, vesicular stomatitis virus inactivation rate was unaffected by changes in the irradiance. Reduction in oxygen availability for the photochemical reaction at high irradiance could explain the effect. However, theoretical estimates suggest that oxygen depletion is minimal under our conditions. In addition, because the rate of photohemolysis at 80 mW/cm2 was not increased when irradiations were carried out under an oxygen atmosphere this seems unlikely. Likewise, formation of singlet oxygen dimoles at high irradiances does not appear to be involved because the effect was unchanged when light exposure was in D2O. While there is no ready explanation for this irradiance effect, it could be used to increase the safety margin of RBC virucidal treatment by employing exposure at high irradiance, thus minimizing the damage to RBC.


Response to nitrogen addition reveals metabolic and ecological strategies of soil bacteria.
The nitrogen (N) cycle represents one of the most well-studied systems, yet the taxonomic diversity of the organisms that contribute to it is mostly unknown, or linked to poorly characterized microbial groups. While new information has allowed functional groups to be refined, they still rely on a priori knowledge of enzymes involved and the assumption of functional conservation, with little connection to the role the transformations, plays for specific organisms. Here, we use soil microcosms to test the impact of N deposition on prokaryotic communities. By combining chemical, genomic and transcriptomic analysis, we are able to identify and link changes in community structure to specific organisms catalysing given chemical reactions. Urea deposition led to a decrease in prokaryotic richness, and a shift in community composition. This was driven by replacement of stable native populations, which utilize energy from N-linked redox reactions for physiological maintenance, with fast responding populations that use this energy for growth. This model can be used to predict response to N disturbances and allows us to identify putative life strategies of different functional and taxonomic groups, thus providing insights into how they persist in ecosystems by niche differentiation.


Homeopathic Plumbum metallicum for lead poisoning: a randomized clinical trial.
Poisoning due to lead and its compounds has short and long-term effects primarily on the nervous, hematopoietic, gastrointestinal, cardiovascular, musculoskeletal, renal and reproductive systems. It can manifest in acute or chronic symptoms. Measuring serum concentration is the primary method for diagnosing and monitoring exposed workers. Presently, elevated lead levels are treated by drugs whose effectiveness is contested on various fronts. Experimental studies suggest that homeopathic preparations may be in controlling blood lead levels in laboratory animals, creating the need for controlled studies to evaluate the effectiveness and safety of these preparations in humans. To evaluate the effectiveness of the homeopathic preparation Plumbum metallicum in reducing the blood lead level of workers exposed to this metal. Double-blind randomized trial. Workers' clinic in the Ajax battery plant, which employs 900 workers with varying degrees of lead exposure in Bauru, São Paulo State, Brazil. 131 workers exposed to lead. Plumbum metallicum 15 cH or placebo, orally for 35 days. The percentage of workers who demonstrated a reduction in lead counts by a percentage greater than or equal to 25% following treatment was the same for both groups: 20.3% in the homeopathic groups versus 21% in the control group [Relative Risk (RR) = 0.95, confidential interval (CI) 95%: 0.47-1.92)]. Analysis by intention-to-treat also did not show any difference between the groups: 18.2% in the treated group versus 20% in the placebo group (RR = 0.91, CI 95%: 0.45-1.84). The homeopathic preparation Plumbum metallicum had no effect, in this study, in terms of reducing serum lead in workers exposed to lead.


Factors Associated With Urgent Care Reliance and Outpatient Health Care Use Among Children Enrolled in Medicaid.
Urgent care (UC) centers are a growing option to address children's acute care needs, which may cause unanticipated changes in health care use. To identify factors associated with high UC reliance among children enrolled in Medicaid and examine the association between UC reliance and outpatient health care use. A retrospective cohort study used deidentified data on 4 133 238 children from the Marketscan Medicaid multistate claims database to calculate UC reliance and outpatient health care use. Children were younger than 19 years, with 11 months or more of continuous Medicaid enrollment and 1 or more UC, emergency department (ED), primary care provider (PCP; physician, advanced practice nurse, or physician assistant; well-child care [WCC] or non-WCC), or specialist outpatient visit during the 2017 calendar year. Statistical analysis was conducted from November 11 to 26, 2019. Urgent care, ED, PCP (WCC and non-WCC), and specialist visits based on coded location of services. Urgent care reliance, calculated by the number of UC visits divided by the sum of total outpatient (UC, ED, PCP, and specialist) visits. High UC reliance was defined as UC visits totaling more than 33% of all outpatient visits. Of 4 133 238 children in the study, 2 090 278 (50.6%) were male, with a median age of 9 years (interquartile range, 4-13 years). A total of 223 239 children (5.4%) had high UC reliance. Children 6 to 12 years of age were more likely to have high UC reliance compared with children 13 to 18 years of age (adjusted odds ratio, 1.07; 95% CI, 1.06-1.09). Compared with white children, black children (adjusted odds ratio, 0.81; 95% CI, 0.81-0.82) and Hispanic children (adjusted odds ratio, 0.61; 95% CI, 0.60-0.61) were less likely to have high UC reliance. Adjusted for age, sex, race/ethnicity, and presence of chronic or complex conditions, children with high UC reliance had significantly fewer PCP encounters (WCC: adjusted rate ratio, 0.60; 95% CI, 0.60-0.61; and non-WCC: adjusted rate ratio, 0.41; 95% CI, 0.41-0.41), specialist encounters (adjusted rate ratio, 0.31; 95% CI, 0.31-0.31), and ED encounters (adjusted rate ratio, 0.68; 95% CI, 0.67-0.68) than children with low UC reliance. High UC reliance occurred more often in healthy, nonminority, school-aged children and was associated with lower health care use across other outpatient settings. There may be an opportunity in certain populations to ensure that UC reliance does not disrupt the medical home model.


Effect of a pathological scapular tilt after total shoulder arthroplasty.
Total shoulder arthroplasty (TSA) is an accepted and most successfully used treatment for different shoulder pathologies. Different risk factors for the failure of the prosthesis are known. A pathological scapular orientation, observed in elderly people or in patients suffering from neuromuscular diseases, could be a cause of failure, which has not been investigated yet. To test this hypothesis, a numerical musculoskeletal model of the glenohumeral joint was used to compare two TSA cases: a reference normal case and a case with a pathological anterior tilt of the scapula. An active abduction of 150° was simulated. Joint force, contact pattern, polyethylene and cement stress were evaluated for both cases. The pathological tilt slightly increased the joint force and the contact pressure, but also shifted the contact pattern. This eccentric contact increased the stress level within the polyethylene of the glenoid component and within the surrounding cement layer. This adverse effect occurred mainly during the first 60° of abduction. Therefore, a pathological orientation of the scapula may increase the risk of a failure of the cement layer around the glenoid component. These preliminary numerical results should be confirmed by a clinical study.


Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial.
Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified. In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents. A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258–0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206–2.588]). The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.