A novel mutation alters the stability of PapA2 resulting in the complete abrogation of sulfolipids in clinical mycobacterial strains.
The analysis of whole genomes has revealed specific geographical distribution of Mycobacterium tuberculosis (Mtb) strains across the globe suggestive of unique niche dependent adaptive mechanisms. We provide an important correlation of a genome-based mutation to a molecular phenotype across two predominant clinical Mtb lineages of the Indian subcontinent. We have identified a distinct lineage specific mutation-G247C, translating into an alanine-proline conversion in the papA2 gene of Indo-oceanic lineage 1 (L1) Mtb strains, and restoration of cell wall sulfolipids by simple genetic complementation of papA2 from lineage 3 (L3) or from H37Rv (lineage 4-L4) attributed the loss of this glycolipid to this specific mutation in Indo-Oceanic L1 Mtb. The investigation of structure of Mtb PapA2 revealed a distinct nonribosomal peptide synthetase (NRPS) C domain conformation with an unconventional presence of a zinc binding motif. Surprisingly, the A83P mutation did not map to either the catalytic center in the N-terminal subdomain or any of the substrate-binding region of the protein. On the contrary, the inherent ability of mutant PapA2 to form insoluble aggregates and molecular simulations with the wild-type/mutant (Wt/mut) PapA2 purports an important role for the surface associated 83rd residue in protein conformation. This study demonstrates the importance of a critical structural residue in the papA2 protein of Mtb and helps establish a link between observed genomic alteration and its molecular consequence in the successful human pathogen Mtb. Significance We demonstrate the effect of a unique SNP in PapA2 gene of Indo-oceanic Mycobacterium tuberculosis (Mtb) strains leading to the loss of sulfolipid from these strains. By X-ray crystallographic analysis and molecular dynamics (MD) simulations, we show the importance of this residue in the global PapA2 structure. The presence of a Zn atom has not been reported before for this class of proteins. Here, we provide an important link between genomic alteration and its molecular consequence in Mtb highlighting one of the many adaptive mechanisms that have contributed to its success as a human pathogen. A high degree of identity with PapA1, 3, or 4 would help in interpreting the structure of these PapA proteins and other acyl transferases of other biological systems.


Treatments for unruptured intracranial aneurysms.
Unruptured intracranial aneurysms are relatively common lesions in the general population, with a prevalence of 3.2%, and are being diagnosed with greater frequency as non-invasive techniques for imaging of intracranial vessels have become increasingly available and used. If not treated, an intracranial aneurysm can be catastrophic. Morbidity and mortality in aneurysmal subarachnoid hemorrhage are substantial: in people with subarachnoid hemorrhage, 12% die immediately, more than 30% die within one month, 25% to 50% die within six months, and 30% of survivors remain dependent. However, most intracranial aneurysms do not bleed, and the best treatment approach is still a matter of debate. To assess the risks and benefits of interventions for people with unruptured intracranial aneurysms. We searched CENTRAL (Cochrane Library 2020, Issue 5), MEDLINE Ovid, Embase Ovid, and Latin American and Caribbean Health Science Information database (LILACS). We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform from inception to 25 May 2020. There were no language restrictions. We contacted experts in the field to identify further studies and unpublished trials. Unconfounded, truly randomized trials comparing conservative treatment versus interventional treatments (microsurgical clipping or endovascular coiling) and microsurgical clipping versus endovascular coiling for individuals with unruptured intracranial aneurysms. Two review authors independently selected trials for inclusion according to the above criteria, assessed trial quality and risk of bias, performed data extraction, and applied the GRADE approach to the evidence. We used an intention-to-treat analysis strategy. We included two trials in the review: one prospective randomized trial involving 80 participants that compared conservative treatment to endovascular coiling, and one randomized controlled trial involving 136 participants that compared microsurgical clipping to endovascular coiling for unruptured intracranial aneurysms. There was no difference in outcome events between conservative treatment and endovascular coiling groups. New perioperative neurological deficits were more common in participants treated surgically (16/65, 24.6%; 15.8% to 36.3%) versus 7/69 (10.1%; 5.0% to 19.5%); odds ratio (OR) 2.87 (95% confidence interval (CI) 1.02 to 8.93; P = 0.038). Hospitalization for more than five days was more common in surgical participants (30/65, 46.2%; 34.6% to 58.1%) versus 6/69 (8.7%; 4.0% to 17.7%); OR 8.85 (95% CI 3.22 to 28.59; P < 0.001). Clinical follow-up to one year showed 1/48 clipped versus 1/58 coiled participants had died, and 1/48 clipped versus 1/58 coiled participants had become disabled (modified Rankin Scale > 2). All the evidence is of very low quality. There is currently insufficient good-quality evidence to support either conservative treatment or interventional treatments (microsurgical clipping or endovascular coiling) for individuals with unruptured intracranial aneurysms. Further randomized trials are required to establish if surgery is a better option than conservative management, and if so, which surgical approach is preferred for which patients. Future studies should include consideration of important characteristics such as participant age, gender, aneurysm size, aneurysm location (anterior circulation and posterior circulation), grade of ischemia (major stroke), and duration of hospitalizations.


Remaining sequelae with modern perinatal care.
The incidence of major sequelae-cerebral palsy (CP), psychomotor retardation (PMR), sensorineural hearing defect, and acquired hydrocephalus--has been studied retrospectively in a nonselected population of 6,5000 3-year-old children born in 1969 and 1970 at one Swedish hospital and treated uniformly according to the principles of modern perinatology. The total incidence of these four types of handicaps was 3.5 per 1,000 when children with congenital malformation syndromes, chromosomal aberrations, verified congenital viral infections, or toxoplasmosis were excluded. The incidence of CP was 1.2 per 1,000. Extreme immaturity, traumatic delivery, postnatal asphyxia, and hyperbilirubinemia were found to be relatively small factors as causes of sequelae in this population. Babies showing various degrees of intrauterine malnutrition were found to be the major remaining group at risk for PMR and/or CP, two thirds of children with these handicaps being recruited from the 16% of newborns with birthweights more than 1 SD below normal in relation to gestational age. The most important further gains can probably be made by earlier intrauterine diagnosis of these cases, induced termination of pregnancy in selected cases, and further studies on the perinatal treatment and adaptation of these infants.


Monitoring COVID-19 where capacity for testing is limited: use of a three-step analysis based on test positivity ratio.
In an effort to monitor coronavirus disease 2019 (COVID-19), many countries have been calculating the ratio of cases confirmed to tests performed (test positivity ratio - TPR). While inferior to sentinel surveillance, TPR has the benefit of being easily calculated using readily available data; however, interpreting TPR and its trends can be complex because both the numerator and the denominator are constantly changing. We describe a three-step process where the ratio of relative increase in cases to relative increase in tests is accounted for in an adjusted TPR. This adjusted value more appropriately reflects the case number and factors out the effect of changes in the number of tests done. Unadjusted and adjusted TPRs are then assessed step-wise with reference to the epidemic curve and the cumulative numbers of cases and tests. Use of this three-step analysis and its potential use in guiding public health interventions are demonstrated for selected countries and subnational areas of the World Health Organization South-East Asia Region, together with the Republic of Korea as a reference. To date, application of the three-step analysis to data from countries of the region has signalled potential inadequacies of testing strategies. Further work is needed on approaches to support countries where testing capacity is likely to remain constrained. One example would be enumeration of the average number of tests needed to detect one COVID-19 case, which could be stratified by factors such as location and population. Such data would allow evidence-informed strategies that best balance the highest detection rate with the prevailing testing capacity.


Regionally decreased gyrification in middle-aged adults with autism spectrum disorders.
To examine changing features of cortical morphology in middle-aged adults with autism spectrum disorders (ASDs) vs typical comparison (TC) participants, hypothesizing regionally decreased local gyrification index (lGI), given our previous findings of accelerated lGI decline during adolescence. After quality assurance, T1-weighted MRI sequences from 20 participants with ASD and 21 TC participants (40-61 years) matched on age were analyzed. lGI, cortical thickness (CT), and surface area (SA) were measured with FreeSurfer version 5.3. Statistical analyses used a general linear model including age, nonverbal IQ, and total brain volume as covariates. Clusters of significant group effects were used as regions of interest for behavioral analyses. Clusters of decreased lGI were observed bilaterally in the ASD group with large effect sizes in insular and anterior cingulate (ACC), left postcentral, and middle frontal and right orbitofrontal and supramarginal regions. lGI was also shown to decline with age across groups in bilateral precentral and right supramarginal clusters. No significant group, age, or group-by-age interaction effects were observed for CT or SA in this age group. lGI showed a significant correlation with Social Responsiveness Scale total scores in a right caudal ACC cluster in the TC group only, while several correlations were found in the ASD group between executive function scores and clusters in the bilateral insula and right orbitofrontal cortex. The pattern of regionally decreased lGI observed here in middle-aged adults with ASDs is consistent with an abnormal trajectory of cortical folding changes across different stages of life in ASDs, as shown in previous studies.


[Carotid stenosis--assessment and treatment].
About 12,000 people suffer an ischemic stroke in Norway every year; 20 % of them may be caused by emboli from precerebral arteries. We discuss the epidemiology of carotid artery stenoses and assessment upon suspicion, and provide an overview of medical treatment and indications for surgery. The article is based on literature identified through non-systematic searches in PubMed, core medical journals and textbooks and the authors' experience from a vascular surgical department and stroke unit. Stroke symptoms or recurrent transient ischemic attacks (TIAs) should lead to direct admission to hospital, while patients with single TIAs should be assessed as out-patients in a hospital within a few days. Risk-factors should be investigated, and the carotid arteries should be examined with duplex ultrasound upon suspicion of stenosis. There is only a weak correlation between a neck bruit and an ipsilateral carotid artery stenosis, but a connection can usually be clarified by use of duplex ultrasound. All patients with a carotid artery stenosis should have medical treatment to prevent complications of atherosclerotic disease; i.e. antithrombotic, and for the majority cholesterol-lowering treatment and possibly antihypertensive medication. Patients with a symptomatic carotid artery stenosis of more than 50 % diameter reduction should be considered for surgical treatment within 14 days. Surgery for asymptomatic carotid artery stenoses seems to have a marginal effect. Patients with stroke-like symptoms should be examined by a doctor as soon as possible. Quick diagnosis and treatment of patients with cerebrovascular events is demanding for the logistics of our hospitals.


Relationships amongst some bacterial and yeast lactate and mandelate dehydrogenases.
Five yeast strains were isolated by enrichment culture on the basis of their ability to grow on mandelate and two of these strains were identified as Rhodotorula glutinis. In addition, a range of yeasts from culture collections was screened for growth on mandelate. The results suggest that mandelate utilization is a widespread but not universal characteristic within the genus Rhodotorula. Several of the yeasts contained an inducible NAD-dependent D(-)-mandelate dehydrogenase and an inducible dye-linked (presumably flavoprotein) L(+)-mandelate dehydrogenase. All the D(-)-mandelate dehydrogenases from the yeasts showed immunological cross-reactivity with each other (as judged by both immunoinhibition and immunoblotting), as did all the yeast L(+)-mandelate dehydrogenases that were tested. Determination of N-terminal amino acid sequences of several bacterial and yeast lactate and mandelate dehydrogenases, together with the evidence from the immunological studies, confirmed and extended previous proposals that there are several major groups of such dehydrogenases: FMN-dependent, membrane-bound L(+)-lactate and L(+)-mandelate dehydrogenases (M(r) = approx. 44,000) in bacteria, mitochondrial flavocytochrome b2 L(+)-lactate and L(+)-mandelate dehydrogenases (M(r) = approx. 59,000) in yeasts, FAD-dependent, membrane-bound D(-)-lactate and D(-)-mandelate dehydrogenases in bacteria, and soluble NAD-dependent D(-)-mandelate dehydrogenases in both bacteria and yeasts.


CT Navigation for Percutaneous Needle Placement: How I Do It.
CT navigation (CTN) has recently been developed to combine many of the advantages of conventional CT and CT-fluoroscopic guidance for needle placement. CTN systems display real-time needle position superimposed on a CT dataset. This is accomplished by placing electromagnetic (EM) or optical transmitters/sensors on the patient and needle, combined with fiducials placed within the scan field to superimpose a known needle location onto a CT dataset. Advantages of CTN include real-time needle tracking using a contemporaneous CT dataset with the patient in the treatment position, reduced radiation to the physician, facilitation of procedures outside the gantry plane, fewer helical scans during needle placement, and needle guidance based on diagnostic-quality CT datasets. Limitations include the display of a virtual (vs actual) needle position, which can be inaccurate if the needle bends, the fiducial moves, or patient movement occurs between scans, and limitations in anatomical regions with a high degree of motion such as the lung bases. This review summarizes recently introduced CTN technologies in comparison to historical methods of CT needle guidance. A "How I do it" section follows, which describes how CT navigation has been integrated into the study center for both routine and challenging procedures, and includes step-by-step explanations, technical tips, and pitfalls.


Investigations into the sequence-selective binding of mithramycin and related ligands to DNA.
The preferred binding sites for mithramycin on four different DNA fragments have been investigated by DNAase I footprinting. Sites containing at least two contiguous GC base pairs are protected by the antibiotic, the preferred binding site consisting of the dinucleotide step GpG (or CpC). Related antibiotics chromomycin and olivomycin produce similar, but not identical footprinting patterns suggesting that they can recognize other sequences as well. All three antibiotics induce enhanced rates of enzyme cleavage at regions flanking some of their binding sites. These effects are generally observed in runs of A and T and are attributed to DNA structural variations induced in the vicinity of the ligand binding site. The reaction of dimethylsulphate with N7 of guanine was modified by the presence of mithramycin so that we cannot exclude the possibility that these antibiotics bind to DNA via the major groove.


Perceived determinants of risk for breast cancer and the relations among objective risk, perceived risk, and screening behavior over time.
Interrelations among perceived risk for breast cancer, objective risk factors, and both breast self-examination (BSE) and mammography screening were examined across two waves of a longitudinal study of breast cancer screening. Participants were a community sample of 335 predominantly White middle-class women, aged 37 to 77, who had not had breast cancer. Factors believed by women to determine their self-rated risk level for breast cancer were investigated. Women held optimistic biases about their own breast cancer risk; they often erroneously attributed their relatively lower perceived risk to personal actions, including mammography screening. Compliance with mammography screening but not BSE recommendations increased over time. Perceived susceptibility to breast cancer was related to both family history and breast symptomatology; early mammography screening was positively related to perceived susceptibility later in time.


Covid 19 vaccines and the misinterpretation of perceived side effects clarity on the safety of vaccines.
In the era of Covid 19 and mass vaccination programs, the anti-vaccination movement across the world is currently at an all-time high. Much of this anti-vaccination sentiment could be attributed to the alleged side effects that are perpetuated across social media from anti-vaccination groups. Fear mongering and misinformation being peddled by people with no scientific training to terrorise people into staying unvaccinated is not just causing people to remain susceptible to viral outbreaks, but could also be causing more side effects seen in the vaccination process. This brief review will offer data that may demonstrate that misinformation perpetuated by the anti-vaccination movement may be causing more deaths and side effects from any vaccine. A mini review of published literature has been conducted and found that mental stress clearly causes vasoconstriction and arterial constriction of the blood vessels. Therefore, if subjects are panicked, concerned, stressed or scared of the vaccination, their arteries will constrict and become smaller in and around the time of receiving the vaccine. This biological mechanism (the constriction of veins, arteries and vessels under mental stress) is the most likely cause for where there has been blood clots, strokes, heart attacks, dizziness, fainting, blurred vision, loss of smell and taste that may have been experienced shortly after vaccine administration. The extreme mental stress of the patient could most likely be attributed to the fear mongering and scare tactics used by various anti-vaccination groups. This paper does not aim to rule in or out every side effect seen, but it is highly likely that many apparent side effects seen shortly after a subject has received a vaccine could be the result of restricted or congested blood flow from blood vessel or arterial constriction caused by emotional distress or placebo based on fear around vaccines.


Lingual Leiomyomatous Hamartoma in an Adult Male.
An otherwise healthy 20-year-old male presented with an exophytic, polypoid, yellowish lesion involving the dorsal surface of his tongue, which he reported being present since birth and unchanged. This was removed by surgical excision and diagnosed as a leiomyomatous hamartoma. Histological examination revealed a combination of fibrovascular connective tissue, conspicuous smooth-muscle bundles, adipose tissue, minor salivary gland tissue, blood vessels, lymphoid tissue, peripheral nerves, and normal skeletal muscle. This case is exceptional due to the patient's age, as until now, lingual leiomyomatous hamartomas have been reported almost exclusively in a paediatric population. To our knowledge, this is the eldest age at which a LLH has been reported in the literature. This underscores the need for clinicians to consider this rarely reported entity when considering the radiographic and clinical differential diagnoses for these lesions, both in the paediatric and adult populations. We also present a review of the literature regarding lingual leiomyomatous hamartomas.


Epigallocatechin-3-gallate inhibits migration and invasion of human renal carcinoma cells by downregulating matrix metalloproteinase-2 and matrix metalloproteinase-9.
The anticancer properties of epigallocatechin-3-gallate (EGCG) are documented in the treatment of several types of cancer; however, there is no relevant evidence for its efficacy in the treatment of renal cell carcinoma (RCC). In the present study, the therapeutic effects of EGCG in vitro were investigated, with particular attention to the metastatic behavior of human RCC cells. MTT assays and flow cytometry were performed to detect the effects of EGCG on the proliferation and apoptosis of RCC cells. The migration and invasion abilities of RCC cells following treatment with EGCG were assessed by wound-healing and Transwell assays, respectively. Gelatin zymography and western blot analysis were performed to analyze the effect of EGCG on matrix metalloproteinase-2 (MMP-2) and MMP-9 expression levels. The results suggested that EGCG was able to inhibit the proliferation of RCC cells, induce apoptosis and effectively suppressed the migration and invasion of RCC cells. In addition, EGCG treatment resulted in the downregulation of MMP-2 and MMP-9 in RCC cells. We hypothesize that the anticancer effect associated with EGCG may involve the downregulation of MMP-2 and MMP-9. The present results suggest the potential of EGCG as a novel therapeutic agent against RCC.


Three-dimensional reconstruction of aqueous channels in human trabecular meshwork using light microscopy and confocal microscopy.
Conventional two-dimensional imaging of the trabecular meshwork (TM) provides limited information about the size, shape, and interconnection of the aqueous channels within the meshwork. Understanding the three-dimensional (3-D) relationships of the channels within this tissue may give insight into its normal function and possible changes present in the eye disease glaucoma. The purpose of our study was to compare laser scanning confocal microscopy with standard 1 micron Araldite-embedded histologic sections for 3-D analysis of the trabecular meshwork. In addition, the study was done to determine whether computerized 3-D reconstruction could isolate the fluid spaces of the trabecular meshwork and determine the size of interconnections between the fluid spaces. Confocal microscopy appears comparable to 1 micron Araldite-embedded tissue sections and has the advantage of inherent registration of the serial tissue sections. Three-dimensional reconstruction allowed the isolation of the fluid spaces within the trabecular meshwork and revealed the presence of numerous interconnections between larger fluid spaces. The distribution of these interconnections was randomly arranged, with no predilection for specific regions within the trabecular meshwork. This distribution of constrictions and "expansion chambers" may provide a clue to the mechanism by which subtle histologic changes are associated with increased ocular pressure in glaucoma.


N-acetyl-beta-glucosaminidase and albuminuria in acromegaly.
Significantly increased albuminuria and N-acetyl-beta-glucosaminidase activity in serum and urine have been observed in acromegalic patients in comparison with healthy persons (P less than 0.001). No relationship between these biochemical variables and serum growth hormone or insulin concentration was found in our group of patients. Significant correlation was determined between urinary NAG activity and albuminuria of acromegalic patients (r = 0.84).


Prevalence of protective level of hepatitis B antibody 3 years after revaccination in HIV-infected children on antiretroviral therapy.
After responding to highly active antiretroviral therapy (HAART), HIV-infected children had a good response to hepatitis B immunization. However, there are limited data on the durability of antibody to hepatitis B surface antigen (anti-HBs) in these children. The primary objective of this study is to determine the prevalence of protective anti-HBs level 3 years after a 3-dose HBV revaccination among HIV-infected children with immune recovery (CD4 cell ≥ 15%) while on HAART. The secondary objective is to assess immunologic memory among children who had waning of anti-HBs. An anti-HBs level of ≥ 10 mIU/mL was defined as a protective antibody level. Sixty-nine HIV-infected children who had history of a 3-dose HBV revaccination while receiving HAART were enrolled. The mean (SD) of CD4 cell and duration of HAART at time of revaccination was 27.2% (6.7) and 5.9 years (0.4), respectively. The proportion of children with protective anti-HBs level 3 years after the revaccination was 71.0% [95% CI, 58.8-81.3]. The geometric mean titer was 114(SD 5)IU/mL. By multivariate logistic analysis, the predictors for protective anti-HBs level 3 years after revaccination were CD4 cell count ≥ 500 cells/mm³ at the time of vaccination (p = 0.04) and anti-HBs level ≥ 100 IU/mL at 1 month after completion of the 3-dose vaccination (p < 0.001). Anamnestic response after one booster dose was demonstrated among 14 of 17 children who had waning protective anti-HBs level (82.4% [95% CI, 62.2-102.6]). Our findings support the recommendation of giving a 3-dose HBV vaccination to HIV-infected children with immune recovery while receiving HAART.


Simultaneous anterograde labelling of two afferent pathways to the same target area with Phaseolus vulgaris leucoagglutinin and Phaseolus vulgaris leucoagglutinin conjugated to biotin or dinitrophenol.
Anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L) and PHA-L conjugated to either biotin or 2,4-dinitrophenol were used to simultaneously label two populations of axons converging onto the same target area. Using the rat hippocampus as a test system, the septohippocampal and contralateral hilar afferents were labelled with the tracers. Double immunohistochemical procedures and either nickel-enhanced 3,3'-diaminobenzidine (DAB) reaction (blue-black colour) or DAB alone (brown colour) were used to produce contrasting colours for the different tracers in the same section. Both the biotinylated PHA-L and PHA-L conjugated with dinitrophenol were used successfully as anterogradely transported axonal tracers. They produced extensive axonal labelling in the hippocampal formation. Excellent double labelling could be produced with the simultaneous application of PHA-L and biotinylated PHA-L. Biotinylated PHA-L was visualized by a sequence of avidin-biotinylated peroxidase complex (ABC), biotinylated goat antiavidin and ABC again using nickel-enhanced DAB as chromogen yielding a blue-black reaction endproduct. PHA-L alone was detected by the unlabelled antibody enzyme (PAP) method using goat antibodies to PHA-L, and DAB as chromogen for the peroxidase reaction, resulting in brown axons. The combination of biotinylated PHA-L and DNP-conjugated PHA-L gave similar results, although the sensitivity of detection by the latter procedure was inferior to that obtained with the other tracers. These protocols permitted visualization of axons of different origin, together with their terminals, either in a blue-black or brown colour, and also allowed the demonstration of overlapping inputs in strata radiatum and lacunosum moleculare of the hippocampus and stratum moleculare and hilus of the dentate gyrus.


AN X-RAY OF THE NATIONAL MENTAL HEALTH ACT 2021 OF NIGERIA: OPPORTUNITIES, LIMITATIONS AND THE WAY FORWARD.
The Nigerian Mental Health Law originated as a Lunacy ordinance in 1916 and matured into Lunacy Act CAP 524 of the law of Nigeria, 1964. This review of the National Mental Health Act (NMHA) 2021 of Nigeria examines the prospects, challenges, and possible ways forward. This act has a schedule, five parts, fifty-eight sections, and many subsections. It was compared with the WHO Checklist while the limitations were examined with a view to recommending solutions and identifying the tasks ahead. The NMHA 2021 provides for enhancing and regulating Mental Health Services through a Mental health Services Department. Also, a Mental Health Assessment committee is set up as a tribunal to protect the rights of persons with intellectual, cognitive and psychosocial disabilities, including the rights to a legal representative, employment, and housing. Persons with mental health conditions are to enjoy standard services and participate in formulating their medical plans devoid of coercion. The Presidential gazetting of the act is a good starting point in a positive direction. It should be adequately implemented with the coordinated efforts of all stakeholders and domesticated by the state governments. Finally, more advocacy by the Association of Psychiatrists in Nigeria and other key players. A key limitation is the access to the health care facility given the rural-urban access challenges and owing to the wide treatment gap and the low Doctor-patient ratio worsened by the brain drain.


High-conversion-efficiency all-optical wavelength converter based on cascaded highly nonlinear fibers.
All-optical wavelength converters based on parametric processing of highly nonlinear fiber (HNLF) can provide low energy consumption, fast process speed, and modulation format agnosticism. A longer HNLF with a larger nonlinear coefficient and high pump power will contribute to achieve higher conversion efficiency. However, the injected pump power to the fiber is limited by its stimulated Brillouin scattering threshold, where longer fibers always have lower threshold powers. In the paper, we propose an all-optical wavelength converter with higher conversion efficiency by cascading two different HNLFs. We experimentally achieved -8 dB conversion efficiency and good converted signals with negligible power penalties.


Discovery of regulatory motifs in 5' untranslated regions using interpretable multi-task learning models.
The sequence in the 5' untranslated regions (UTRs) is known to affect mRNA translation rates. However, the underlying regulatory grammar remains elusive. Here, we propose MTtrans, a multi-task translation rate predictor capable of learning common sequence patterns from datasets across various experimental techniques. The core premise is that common motifs are more likely to be genuinely involved in translation control. MTtrans outperforms existing methods in both accuracy and the ability to capture transferable motifs across species, highlighting its strength in identifying evolutionarily conserved sequence motifs. Our independent fluorescence-activated cell sorting coupled with deep sequencing (FACS-seq) experiment validates the impact of most motifs identified by MTtrans. Additionally, we introduce "GRU-rewiring," a technique to interpret the hidden states of the recurrent units. Gated recurrent unit (GRU)-rewiring allows us to identify regulatory element-enriched positions and examine the local effects of 5' UTR mutations. MTtrans is a powerful tool for deciphering the translation regulatory motifs.


Active immunization with an octa-valent Staphylococcus aureus antigen mixture in models of S. aureus bacteremia and skin infection in mice.
Proteomic studies with different Staphylococcus aureus isolates have shown that the cell surface-exposed and secreted proteins IsaA, LytM, Nuc, the propeptide of Atl (pro-Atl) and four phenol-soluble modulins α (PSMα) are invariantly produced by this pathogen. Therefore the present study was aimed at investigating whether these proteins can be used for active immunization against S. aureus infection in mouse models of bacteremia and skin infection. To this end, recombinant His-tagged fusions of IsaA, LytM, Nuc and pro-Atl were isolated from Lactococcus lactis or Escherichia coli, while the PSMα1-4 peptides were chemically synthesized. Importantly, patients colonized by S. aureus showed significant immunoglobulin G (IgG) responses against all eight antigens. BALB/cBYJ mice were immunized subcutaneously with a mixture of the antigens at day one (5 μg each), and boosted twice (25 μg of each antigen) with 28 days interval. This resulted in high IgG responses against all antigens although the response against pro-Atl was around one log lower compared to the other antigens. Compared to placebo-immunized mice, immunization with the octa-valent antigen mixture did not reduce the S. aureus isolate P load in blood, lungs, spleen, liver, and kidneys in a bacteremia model in which the animals were challenged for 14 days with a primary load of 3 × 10(5) CFU. Discomfort scores and animal survival rates over 14 days did not differ between immunized mice and placebo-immunized mice upon bacteremia with S. aureus USA300 (6 × 10(5) CFU). In addition, this immunization did not reduce the S. aureus isolate P load in mice with skin infection. These results show that the target antigens are immunogenic in both humans and mice, but in the used animal models do not result in protection against S. aureus infection.


Focal molography is a new method for the in situ analysis of molecular interactions in biological samples.
Focal molography is a next-generation biosensor that visualizes specific biomolecular interactions in real time. It transduces affinity modulation on the sensor surface into refractive index modulation caused by target molecules that are bound to a precisely assembled nanopattern of molecular recognition sites, termed the 'mologram'. The mologram is designed so that laser light is scattered at specifically bound molecules, generating a strong signal in the focus of the mologram via constructive interference, while scattering at nonspecifically bound molecules does not contribute to the effect. We present the realization of molograms on a chip by submicrometre near-field reactive immersion lithography on a light-sensitive monolithic graft copolymer layer. We demonstrate the selective and sensitive detection of biomolecules, which bind to the recognition sites of the mologram in various complex biological samples. This allows the label-free analysis of non-covalent interactions in complex biological samples, without a need for extensive sample preparation, and enables novel time- and cost-saving ways of performing and developing immunoassays for diagnostic tests.


GM foods: is there a way forward?
There are many quality targets in cereals that could generate step-change improvements in nutritional or food-processing characteristics. For instance, levels of acrylamide, soluble and insoluble fibre, antioxidants, allergens and intolerance factors in food are, to a large extent, determined by the genetics of the raw materials used. However, improvements to these traits pose significant challenges to plant breeders. For some traits, this is because the underlying genetic and biochemical basis of the traits is not fully understood but for others, there is simply a lack of natural genetic variation in commercially useful germplasm. One strategy to overcome the latter hindrance is to use wide crosses with more exotic germplasm; however, this can bring other difficulties such as yield loss and linkage drag of deleterious alleles. As DNA sequencing becomes cheaper and faster, it drives the research fields of reverse genetics and functional genomics which in turn will enable the incorporation of desirable traits into crop varieties via molecular breeding and biotechnology. I will discuss the evolution of these techniques from conventional genetic modification to more recent developments in targeted gene editing and the potential of biotechnology to complement conventional breeding methods. I will also discuss the role of risk assessment and regulation in the commercialisation of GM crops.


Reactive oxygen species-activated Akt/ASK1/p38 signaling pathway in nickel compound-induced apoptosis in BEAS 2B cells.
Nickel compounds are carcinogenic to humans, possibly through induction of reactive oxygen species (ROS) that damage macromolecules including DNA and proteins. The aim of the present study is to elucidate the role of the ROS-mediated Akt/apoptosis-regulating signal kinase (ASK) 1/p38 pathway in nickel-induced apoptosis. Exposure of human bronchial epithelial cells (BEAS-2B) to nickel compounds induced the generation of ROS and activation of Akt that is associated with the activation of ASK1 and p38 mitogen-activated protein kinase. Immunoblotting suggested a down-regulation of several antiapoptotic proteins, including Bcl-2 and Bcl-xL in the nickel compound-treated cells. Indeed, a notable cell apoptosis following nickel compound treatment is evident as revealed by flow cytometry analysis. N-Acetyl-L-cysteine (NAC, a general antioxidant) and vitamin E or catalase (a specific H(2)O(2) inhibitor) all decreased nickel-induced ROS generation. Scavenging of nickel-induced ROS by NAC or catalase attenuated Akt, ASK1, and p38 MAPK activation and apoptosis, which implies involvement of ROS in the Akt/ASK1/p38 pathway. In addition, nickel-induced activation of p38 MAPK was attenuated by a small interference of RNA specific to ASK1 (siRNA ASK1), implying that p38 MAPK was downstream of ASK1, while ASK1 activation was not reversely regulated by the inhibition of p38 MAPK by SB203580, a widely used p38 MAPK inhibitor. Silencing Akt by siRNA reduced the activation of ASK1 and p38 MAPK and cell apoptosis, whereas without nickel stimulation, siRNA Akt had no effect on the activation of ASK1 and p38 MAPK. Thus, these results suggest that the ROS-dependent Akt-ASK1-p38 axis is important for nickel-induced apoptosis.


Increasing intake of dietary soluble nutrients affects digesta passage rate in the stomach of growing pigs.
The passage rate of solids and liquids through the gastrointestinal tract differs. Increased dietary nutrient solubility causes nutrients to shift from the solid to the liquid digesta fraction and potentially affect digesta passage kinetics. We quantified: (1) the effect of three levels of dietary nutrient solubility (8, 19 and 31 % of soluble protein and sucrose in the diet) at high feed intake level (S) and (2) the effect of low v. high feed intake level (F), on digesta passage kinetics in forty male growing pigs. The mean retention time (MRT) of solids and liquids in the stomach and small intestine was assessed using TiO2 and Cr-EDTA, respectively. In addition, physicochemical properties of digesta were evaluated. Overall, solids were retained longer than liquids in the stomach (2·0 h, P<0·0001) and stomach+small intestine (1·6 h, P<0·001). When S increased, MRT in stomach decreased by 1·3 h for solids (P=0·01) and 0·7 h for liquids (P=0·002) but only at the highest level of S. When F increased using low-soluble nutrients, MRT in stomach increased by 0·8 h for solids (P=0·041) and 0·7 h for liquids (P=0·0001). Dietary treatments did not affect water-binding capacity and viscosity of digesta. In the stomach of growing pigs, dietary nutrient solubility affects digesta MRT in a non-linear manner, while feed intake level increases digesta MRT depending on dietary nutrient solubility. Results can be used to improve predictions on the kinetics of nutrient passage and thereby of nutrient digestion and absorption in the gastrointestinal tract.


Percutaneous internal fixation of selected scaphoid nonunions with an arthroscopically assisted dorsal approach.
Preliminary reports have indicated that selected scaphoid nonunions-i.e., those that are well aligned and without extensive sclerosis or bone resorption at the nonunion site-can be treated effectively with internal fixation alone. We examined the feasibility of percutaneous fixation in a series of such nonunions. A consecutive series of fifteen patients with fibrous union or nonunion of a carpal scaphoid fracture with minimal sclerosis or resorption at the nonunion site were treated with rigid fixation alone (without bone graft) with a headless compression screw inserted with a dorsal percutaneous technique. Clinical examination, standard radiographs, and computed tomography scans confirmed union in all patients at an average of fourteen weeks. Nonunions treated less than six months after the injury healed faster than those treated later (p < 0.02). According to the Mayo modified wrist score, there were twelve excellent and three good results. The results in our series were due to careful examination and grading of the scaphoid nonunions preoperatively. The findings in this small series support the observation in earlier reports that percutaneous repair of selected scaphoid nonunions requires only rigid fixation to achieve healing.


Enhanced electrical properties at boundaries including twin boundaries of polycrystalline CdTe thin-film solar cells.
The effect of grain boundaries (GBs), in particular twin boundaries (TBs), on CdTe polycrystalline thin films is studied by conductive atomic force microscopy (C-AFM), electron-beam-induced current (EBIC), scanning Kelvin probe microscopy (SKPM), electron backscatter diffraction (EBSD), and scanning transmission electron microscopy (STEM). Four types of CdTe grains with various densities of {111} Σ3 twin boundaries (TBs) are found in Cl-treated CdTe polycrystalline thin films: (1) grains having multiple {111} Σ3 TBs with a low angle to the film surface; (2) grains having multiple {111} Σ3 TBs parallel to the film surfaces; (3) small grains on a scale of not more than 500 nm, composed of Cd, Cl, Te, and O; and (4) CdTe grains with not more than two {111} Σ3 TBs. Grain boundaries (including TBs) exhibit enhanced current transport phenomena. However, the {111} Σ3 TB is much more beneficial to micro-current transport. The enhanced current transport can be explained by the lower electron potential at GBs (including TBs) than the grain interiors (GIs). Our results open new opportunities for enhancing solar cell performances by controlling the grain boundaries, and in particular TBs.


Role of procalcitonin use in the management of sepsis.
Important aspects of sepsis management include early diagnosis as well as timely and specific treatment in the first few hours of triage. However, diagnosis and differentiation from non-infectious causes often cause uncertainties and potential time delays. Correct use of antibiotics still represents a major challenge, leading to increased risk for opportunistic infections, resistances to multiple antimicrobial agents and toxic side effects, which in turn increase mortality and healthcare costs. Optimized procedures for reliable diagnosis and management of antibiotic therapy has great potential to improve patient care. Herein, biomarkers have been shown to improve infection diagnosis, help in early risk stratification and provide prognostic information which helps optimizing therapeutic decisions ("antibiotic stewardship"). In this context, the use of the blood infection marker procalcitonin (PCT) has gained much attention. There is still no gold standard for the detection of sepsis and use of conventional diagnostic approaches are restricted by some limitations. Therefore, additional tests are necessary to enable early and reliable diagnosis. PCT has good discriminatory properties to differentiate between bacterial and viral inflammations with rapidly available results. Further, PCT adds to risk stratification and prognostication, which may influence appropriate use of health-care resources and therapeutic options. PCT kinetics over time also improves the monitoring of critically ill patients with sepsis and thus influences decisions regarding de-escalation of antibiotics. Most importantly, PCT helps in guiding antibiotic use in patients with respiratory infection and sepsis by limiting initiation and by shortening treatment duration. To date, PCT is the best studied biomarker regarding antibiotic stewardship. Still, further research is needed to understand optimal use of PCT, also in combination with other remerging diagnostic tests for most efficient sepsis care.


User fees and health service utilization in Vietnam: how to protect the poor?
Vietnam started its health reform process two decades ago, initiated by economic reform in 1986. Economic reform has rapidly changed the socio-economic environment with the transition from a centrally planned economy to a market-oriented economy. Health reform in Vietnam has been associated with the introduction of user fees, the legalization of private medical practices, and the commercialization of the pharmaceutical industry. This paper presents the user fees and health service utilization in Vietnam during a critical period of economic transition in the 1990s. The study is based on two national household surveys: the Vietnam Living Standard Survey 1992-1993 and 1997-1998. The concentration index and related concentration curve were used to measure differences in health service utilization as indicators of health outcomes of income quintiles, ranking from the poorest to the richest. User fees contribute to health resources and have helped to relieve the financial burden on the Government. However, comparisons of concentration indices for hospital stays and community health centre visits show that user fees can drive people deeper into poverty, widen the gap between the rich and the poor, and increase inequality in health outcomes. An effective social protection and targeting system is proposed to protect the poor from the impact of user fees, to increase equity and improve the quality of healthcare services. This cannot be done without taking measures to improve the quality of care and promote ethical standards in health care, including the elimination of unofficial payments.


Adaptive walks and distribution of beneficial fitness effects.
We study the adaptation dynamics of a maladapted asexual population on rugged fitness landscapes with many local fitness peaks. The distribution of beneficial fitness effects is assumed to belong to one of the three extreme value domains, viz. Weibull, Gumbel, and Fréchet. We work in the strong selection-weak mutation regime in which beneficial mutations fix sequentially, and the population performs an uphill walk on the fitness landscape until a local fitness peak is reached. A striking prediction of our analysis is that the fitness difference between successive steps follows a pattern of diminishing returns in the Weibull domain and accelerating returns in the Fréchet domain, as the initial fitness of the population is increased. These trends are found to be robust with respect to fitness correlations. We believe that this result can be exploited in experiments to determine the extreme value domain of the distribution of beneficial fitness effects. Our work here differs significantly from the previous ones that assume the selection coefficient to be small. On taking large effect mutations into account, we find that the length of the walk shows different qualitative trends from those derived using small selection coefficient approximation.


Blood protein concentrations in the first two postnatal weeks that predict bronchopulmonary dysplasia among infants born before the 28th week of gestation.
Lung inflammation contributes to the pathogenesis of bronchopulmonary dysplasia (BPD) and may be accompanied by a systematic inflammatory response. The objective of this study was to investigate the role of systemic inflammation in the development of BPD in a cohort of extremely low GA newborns (ELGANs) by examining the relationships between inflammation-associated proteins in neonatal blood samples and pulmonary outcomes. Proteins were measured in blood specimens collected on postnatal d 1-3, 5-8, and 12-15 from 932 ELGANs. Increased risk of BPD was associated with elevated blood concentrations of a variety of proinflammatory cytokines, adhesion molecules, and proteases. Reduced risk was prominently associated with increased concentrations of one chemokine, RANTES. Elevations of inflammatory proteins associated with BPD risk occurred during the first days after birth and inflammation intensified thereafter. Therefore, exposures that promote inflammation after the first postnatal days may be more critical in the pathogenesis of BPD. Fetal growth restriction, a known BPD risk factor, was not accompanied by proteins elevations and therefore does not seem to be mediated by systemic inflammation. By contrast, mechanical ventilation altered protein levels and may be associated with systemic inflammation


Daily Variation in the Occurrence of Different Subtypes of Stroke.
Three thousand two hundred and ninety-eight patients admitted to our Stroke Unit with hemorrhagic, large artery atherosclerosis, cardioembolic, small-vessel occlusion, and undetermined etiology-cryptogenic strokes were included in the study. The circadian variability in onset in each stroke subgroup and the associations with various risk factors were analyzed. In each subgroup, a significant minority of patients suffered from stroke during sleep. In the ischemic group, hypercholesterolemia, paroxysmal atrial fibrillation, and previous myocardial infarction facilitated the onset during waking. During waking, stroke onset was significantly higher in the morning compared to the afternoon both in the hemorrhagic and in the ischemic type. In hemorrhagic stroke, a previous stroke was associated with a lower early morning occurrence. In large artery atherosclerosis stroke, males were at higher risk of early morning occurrence (p < 0.01). In small-vessel occlusion stroke, hypertension is significantly more present in the morning compared to the afternoon onset (p < 0.005). Circadian patterns of stroke onset were observed both in hemorrhagic and in ischemic stroke, irrespective of the ischemic subgroup. In all groups, stroke was more likely to occur during waking than during sleep and, in the diurnal period, during morning than during afternoon. Moreover, sex and some clinical factors influence the diurnal pattern.


The level of actual functional fitness of men from different living environments in Poland and associations with health - a cross-sectional study.
The study aimed to assess the differences in functional fitness between older men living in social welfare homes (SWH) and men living in society. The study involved 474 men aged 60-84, including 134 men living in social welfare homes and 340 men living in community. The Senior Fitness Test was used to assess functional fitness. Body weight and height were measured. Moreover, data on age, education, taking up physical activity and place of residence were collected. A significantly lower level of functional fitness of SWH residents was demonstrated compared to men living in the society (p < 0.001). A significant percentage of seniors living in SWH did not reach the normal range for the Polish population. Also, the level of education, physical activity and health self-assessment differentiated the institutionalized men from those living in the community. The place of residence is a factor that differentiates seniors' functional fitness levels. The reduced fitness of social welfare home residents may also result from the low level of their daily physical activity, education and health. Introducing physical activity programs for elderly residents in social welfare homes seems reasonable. ISRCTN platform as 18,225,729; December 2020.


Evolutionary divergence and limits of conserved non-coding sequence detection in plant genomes.
The discovery of regulatory motifs embedded in upstream regions of plants is a particularly challenging bioinformatics task. Previous studies have shown that motifs in plants are short compared with those found in vertebrates. Furthermore, plant genomes have undergone several diversification mechanisms such as genome duplication events which impact the evolution of regulatory motifs. In this article, a systematic phylogenomic comparison of upstream regions is conducted to further identify features of the plant regulatory genomes, the component of genomes regulating gene expression, to enable future de novo discoveries. The findings highlight differences in upstream region properties between major plant groups and the effects of divergence times and duplication events. First, clear differences in upstream region evolution can be detected between monocots and dicots, thus suggesting that a separation of these groups should be made when searching for novel regulatory motifs, particularly since universal motifs such as the TATA box are rare. Second, investigating the decay rate of significantly aligned regions suggests that a divergence time of ~100 mya sets a limit for reliable conserved non-coding sequence (CNS) detection. Insights presented here will set a framework to help identify embedded motifs of functional relevance by understanding the limits of bioinformatics detection for CNSs.


Men's social networks and contraception in Ghana.
In this paper, longitudinal data from northern Ghana is used to assess the effects of encouragement to use family planning that men receive from their personal network partners on the adoption of modern contraception by their wives. The study tests a conceptual model that, in addition to the effect of men's network encouragement, incorporates the effect of encouragement to use family planning that women receive from their respective network partners and the effect of spousal communication on reproductive matters and approval of family planning. Results show that encouragement received by men from their social networks significantly increases the likelihood of subsequent contraceptive use by their wives but this effect operates primarily by galvanizing spousal communication on reproductive matters. The effect of encouragement received by women from their respective network partners is largely independent from the effect of male network encouragement but it influences contraceptive adoption both directly and through spousal communication.


Torsional strength of the radius after osteofasciocutaneous free flap harvest with and without primary bone plating.
The osteocutaneous radial forearm free flap (OCRFFF) has not gained widespread popularity in mandibular reconstruction, primarily because of concerns about pathologic fracture of the weakened radius. This study examines the effectiveness of plate fixation of the radius bone after harvest of the OCRFFF as a mechanism to minimize donor-site morbidity and increase the usefulness of the OCRFFF. Matched pairs of fresh human cadaveric radius bones were used in this study. Two study groups were designed. The first group was used to define the amount of strength lost after a typical bone graft harvest. The second group was designed to demonstrate how much torsional strength was regained by the application of an orthopedic reconstruction plate. Statistically significant results were obtained for both groups. In group 1, the strength of the cut bones compared with that of the unaltered bones was significantly decreased by 82% (P = 0.016). In group 2, the cut bones reinforced with a plate were 75% stronger (P = 0.002) than the bones that were only cut. Although the radius bone is significantly weakened by the harvest of a graft, much of this strength can be regained with plate fixation of the radius.


Phosphorylation of choline and ethanolamine in Ehrlich ascites-carcinoma cells.
1. Ehrlich ascites-cell extracts convert choline and ethanolamine approximately equally well into their respective phosphoryl derivatives. 2. Choline is a potent inhibitor of ethanolamine phosphorylation, but ethanolamine has little effect on choline phosphorylation. 3. 2,3-Dimercaptopropanol, cysteine and Ca(2+) inhibit ethanolamine phosphorylation, but have no detectable effect on choline phosphorylation. 4. Choline-phosphorylating activity in Ehrlich ascites-cell extracts is more stable during storage than ethanolamine-phosphorylating activity. 5. Choline phosphorylation is stimulated in the presence of benzoylcholine, succinylcholine, butyrylcholine and propionylcholine, whereas ethanolamine phosphorylation is inhibited. This relationship is reciprocal: the compounds causing the greatest stimulation of choline phosphorylation bring about the greatest inhibition of ethanolamine phosphorylation.


[Bullous pemphigoid in children (author's transl)].
A case of bullous pemphigoid (BP) in a five-year-old girl is reported. IgG deposits at the epidermal-dermal junction and high titres of serum IgG (1/10000) reacting with the epidermal-dermal junction of rabbit esophagus were the two criteria that led to the diagnosis of BP. Clinically and histologically this case had at first been diagnosed as dermatitis herpetiformis or benign chronic bullous disease of childhood. This emphasizes the importance of immunological criteria for classifying chronic bullous diseases in children. Our patient did not respond to sulfones and prednisone was given for thirteen months. No relapse occurred during the first year following prednisone withdrawal. Our observation is the twenty-first case of immunologically proven BP in childhood. The twenty-one cases are reviewed in order to analyze the features of the disease in children.


Rotated Hough filtering for automatically distinguishing the collagen bundles in the most superficial layer of articular cartilage.
The structure of the collagen matrix in the most superficial layer of articular cartilage (AC) is particularly critical to the wear and tensile resistance of AC. Disruption of the collagen network leads to rapid wear of the articular surface, which is a major contributory factor of osteoarthritis. Interwoven fiber bundles have been observed in the most superficial layer of healthy AC under confocal microscopy, but gradually disappear with age and pathological change of AC. The image analysis techniques developed in this paper aimed to provide a quantitative description of the relationship between the presence of the fiber bundles in the lamina splendens and health status of AC. The result of this quantitative study confirmed the existence of fiber bundles in healthy AC, and the accuracy of the identified fiber bundles was up to 90%. With the development of confocal arthroscopy for imaging microstructure of AC without biopsy, the image analysis technique can aid to efficiently assess the physiological status of AC for orthopedic clinics.


Genetic surfing in human populations: from genes to genomes.
Genetic surfing describes the spatial spread and increase in frequency of variants that are not lost by genetic drift and serial migrant sampling during a range expansion. Genetic surfing does not modify the total number of derived alleles in a population or in an individual genome, but it leads to a loss of heterozygosity along the expansion axis, implying that derived alleles are more often in homozygous state. Genetic surfing also affects selected variants on the wave front, making them behave almost like neutral variants during the expansion. In agreement with theoretical predictions, human genomic data reveals an increase in recessive mutation load with distance from Africa, an expansion load likely to have developed during the expansions of human populations out of Africa.


Standardized phenology monitoring methods to track plant and animal activity for science and resource management applications.
Phenology offers critical insights into the responses of species to climate change; shifts in species' phenologies can result in disruptions to the ecosystem processes and services upon which human livelihood depends. To better detect such shifts, scientists need long-term phenological records covering many taxa and across a broad geographic distribution. To date, phenological observation efforts across the USA have been geographically limited and have used different methods, making comparisons across sites and species difficult. To facilitate coordinated cross-site, cross-species, and geographically extensive phenological monitoring across the nation, the USA National Phenology Network has developed in situ monitoring protocols standardized across taxonomic groups and ecosystem types for terrestrial, freshwater, and marine plant and animal taxa. The protocols include elements that allow enhanced detection and description of phenological responses, including assessment of phenological "status", or the ability to track presence-absence of a particular phenophase, as well as standards for documenting the degree to which phenological activity is expressed in terms of intensity or abundance. Data collected by this method can be integrated with historical phenology data sets, enabling the development of databases for spatial and temporal assessment of changes in status and trends of disparate organisms. To build a common, spatially, and temporally extensive multi-taxa phenological data set available for a variety of research and science applications, we encourage scientists, resources managers, and others conducting ecological monitoring or research to consider utilization of these standardized protocols for tracking the seasonal activity of plants and animals.


A Foundation for Vital Academic and Social Support in Clerkships: Learning Through Peer Continuity.
Most medical students on clerkships currently experience lack of continuity of patient care, disjointed learning, and frequent changes in supervisors. Clerkship programs with continuity of care, curriculum, and supervisors appear to benefit student learning and patient-centeredness. A fourth form of continuity is proposed: continuity of peers, in which a stable cohort of students frequently meets to process their experiences on clerkships. This structure builds on benefits previously seen in peer-assisted learning, including enhanced knowledge, technical skills, and collegial peer relationships. Additional advantages of peer continuity in clerkships include facilitated integration into the workplace, social support, and enhanced clinical and professional learning. Practical components required for a successful peer continuity structure include intentional formation of peer cohorts; regular meetings that cover didactic or clinical skills learning; frequent opportunities for reflection on patient care, professional development, and well-being; and skilled facilitators without evaluative roles. Theoretical support for peer continuity comes from social cognitive theory, communities of clinical practice, and social comparison theory. Therefore, in conjunction with empirical programs that have shown benefits of developing these structures, peer continuity should become a formalized educational structure in clerkships.


PEG-modified nano liposomes co-deliver Apigenin and RAGE-siRNA to protect myocardial ischemia injury.
Ischemic heart disease (IHD) is a cardiac disorder in which myocardial damage occurs as a result of myocardial ischemia and hypoxia. Evidence suggests that oxidative stress and inflammatory responses are critical in the development of myocardial ischemia. Therefore, the combination of antioxidant and anti-inflammatory applications is an effective strategy to combat ischemic heart disease. In this paper, polyethylene glycol (PEG)-modified cationic liposomes were used as carriers to deliver apigenin (Apn) with small interfering RNA (siRNA) targeting the receptor for glycosylation end products (RAGE) (siRAGE) into cardiomyocytes to prevent myocardial ischemic injury through antioxidant and anti-inflammatory effects. Our results showed that we successfully prepared cationic PEG liposomes loaded with Apn and siRAGE (P-CLP-A/R) with normal appearance and morphology, particle size and Zeta potential, and good encapsulation rate, drug loading and in vitro release degree. In vitro, P-CLP-A/R was able to prevent oxidative stress injury in H9C2 cells, downregulate the expression of RAGE, reduce the secretion of cellular inflammatory factors and inhibit apoptosis through the RAGE/NF-κB pathway; In vivo, P-CLP-A/R was able to prevent arrhythmia and myocardial pathological injury, and reduce apoptosis and the area of necrotic myocardium in rats. In conclusion, P-CLP-A/R has a protective effect on myocardial ischemic injury and is expected to be a potential drug for the prevention of ischemic heart disease in the future.


Withdrawal symptoms in internet gaming disorder: A systematic review.
Internet gaming disorder (IGD) is currently positioned in the appendix of the DSM-5 as a condition requiring further study. The aim of this review was to examine the state of current knowledge of gaming withdrawal symptomatology, given the importance of withdrawal in positioning the disorder as a behavioral addiction. A total of 34 studies, including 10 qualitative studies, 17 research reports on psychometric instruments, and 7 treatment studies, were evaluated. The results indicated that the available evidence on Internet gaming withdrawal is very underdeveloped. Internet gaming withdrawal is most consistently referred to as 'irritability' and 'restlessness' following cessation of the activity. There exists a concerning paucity of qualitative studies that provide detailed clinical descriptions of symptoms arising from cessation of internet gaming. This has arguably compromised efforts to quantify withdrawal symptoms in empirical studies of gaming populations. Treatment studies have not reported on the natural course of withdrawal and/or withdrawal symptom trajectory following intervention. It is concluded that many more qualitative clinical studies are needed, and should be prioritised, to develop our understanding of gaming withdrawal. This should improve clinical descriptions of problematic internet gaming and in turn improve the quantification of IGD withdrawal and thus treatments for harmful internet gaming.


Demographic mechanisms underpinning genetic assimilation of remnant groups of a large carnivore.
Current range expansions of large terrestrial carnivores are occurring following human-induced range contraction. Contractions are often incomplete, leaving small remnant groups in refugia throughout the former range. Little is known about the underlying ecological and evolutionary processes that influence how remnant groups are affected during range expansion. We used data from a spatially explicit, long-term genetic sampling effort of grizzly bears (Ursus arctos) in the Northern Continental Divide Ecosystem (NCDE), USA, to identify the demographic processes underlying spatial and temporal patterns of genetic diversity. We conducted parentage analysis to evaluate how reproductive success and dispersal contribute to spatio-temporal patterns of genetic diversity in remnant groups of grizzly bears existing in the southwestern (SW), southeastern (SE) and east-central (EC) regions of the NCDE. A few reproductively dominant individuals and local inbreeding caused low genetic diversity in peripheral regions that may have persisted for multiple generations before eroding rapidly (approx. one generation) during population expansion. Our results highlight that individual-level genetic and reproductive dynamics play critical roles during genetic assimilation, and show that spatial patterns of genetic diversity on the leading edge of an expansion may result from historical demographic patterns that are highly ephemeral.


The evolution and pathology of frontotemporal dementia.
This is a clinicopathologic study of a prospective, clinic-based cohort of patients with frontotemporal dementia (FTD)/Pick complex, who were followed to autopsy. A total of 60 patients with the clinical syndromes of the behavioural variant of FTD (FTD-bv) (n = 32), primary progressive aphasia (PPA) (n = 22), corticobasal degeneration syndrome (CBDS) (n = 4) and progressive supranuclear palsy (PSP) (n = 2) at onset, referred to a cognitive neurology clinic who had subsequent post-mortem examination were included. The most common histological variety was motor neurone disease type inclusion (MNDI) (n = 18), followed by corticobasal degeneration (CBD) (n = 12), then Pick's disease (n = 6), dementia lacking distinctive histology (DLDH) (n = 6) and PSP (n = 3). Others fulfilled the histological criteria for Alzheimer's disease combined with glial pathology (n = 6), Alzheimer's disease only (n = 4), Lewy body variant (n = 2), prion disease (n = 1), vascular dementia (n = 1) and undetermined (n = 1). The most common first syndrome among the MNDI and DLDH (tau negative) pathologies was FTD-bv, but subsequently progressive aphasia (PA), occasionally CBDS and semantic dementia also developed. Tau positive histologies of CBD, PSP and Pick bodies were most frequently associated with PPA onset or CBDS/PSP, but behavioural symptoms were also common. Age of onset was earlier in tau negative cases, but the duration of illness and gender distribution were about the same in all histological variants. Although the tau negative and positive histologies are predicted to some extent by the clinical onset, the extent of the overlap and the convergence of the syndromes in the course of the disease argue in favour of maintaining the clinical and pathological varieties under a single umbrella.


Success habits of long-term gastric bypass patients.
By identifying common habits of the most successful long-term gastric bypass patients, one is able to establish more specific guidelines for new patients to follow. The first postoperative year is a critical time that must be dedicated to changing old behavior and forming new, lifelong habits. 100 gastric bypass patients from 1979 to 1995 participated in a comprehensive survey. Surveys were completed in person, by phone, or in writing. Participants were asked to answer questions regarding their eating, drinking, sleeping, exercise, and personal habits. The survey revealed that specific habits are common in gastric bypass patients who have maintained their weight loss for many years. Identifying and defining the common habits of patients who are successful with long-term weight loss enabled specific guidelines to be established for new patients to implement during the initial weight loss phase, which will contribute to life-long success.


Trends in prostate-specific antigen test use, 2000-2005.
This study examined prostate-specific antigen (PSA) test use among men and identified sociodemographic and health-related characteristics associated with its use over time. The National Health Interview Survey collected information on PSA test use among 16,058 men > or = 40 years of age in 2000 and 2005. We examined two outcomes: (1) having had a recent (within two years) screening PSA test and (2) having had three or more PSA tests in the past five years (to indicate frequent use). Marital status, family history of prostate cancer, and having seen a doctor in the past year differed over time in the unadjusted model. In the adjusted model, recent PSA screening decreased from 2000 to 2005 for single, never-married men, but increased for men with chronic diseases. Frequent PSA test use increased for men with a family history of prostate cancer, men with chronic diseases, and men who had seen a physician in the past year. Significant correlates of higher recent PSA test use included being older, married, and of black race/ethnicity; having higher levels of education and income, health-care coverage, and a usual place of health care; and increased comorbidity. Major organizations are not in agreement about the efficacy of prostate cancer screening; however, men > or = 40 years of age continue to use the PSA test. Both recent screening and frequent testing showed variability during the study period and may have implications for the ongoing randomized clinical trials that are expected to clarify whether early detection of prostate cancer with PSA testing increases survival.


Users' Perceptions of an in-Home Electronic Medication Dispensing System: A Qualitative Study.
Managing and taking multiple medications as prescribed can be a difficult task for older adults. In-home medication dispensing technologies could help enhance care. The objective of the study was to determine users' perspectives on a medication dispensing system (MDS) in supporting medication adherence of individuals living at home with chronic conditions. This analysis is a part of a randomized controlled trial on an MDS in a Western Canadian province. We interviewed participants who were recruited into the intervention group and started using an MDS. A maximum variation purposive sampling was used to select interview participants based on age, number of medications, and health conditions. Thirteen participants were interviewed; most participants were females (n=11) and the average age was 63.7 (SD=8.2) years with an average of 8.9 (SD=3.6) prescribed medications. The most common health conditions were hypertension, diabetes, arthritis, and anxiety and depression. Four main themes emerged from thematic analysis: MDS acceptability, MDS patient support, need for the MDS, and areas of technology improvement. Most of the participants found the MDS to be acceptable and convenient, although privacy and security was an issue for some older adults. Audio and visual reminders and pre-organized medication supported participants' medication adherence and independence in daily routines. The perceived necessity of the MDS was split among participants with cost being one of the main concerns. Areas of technology improvement included the hard-to-open plastic medication packets and the sometimes inexact recording of medication adherence by the MDS if medications were dispensed on behalf of the patients. The MDS is an acceptable tool for improving medication management and adherence in older adults. Increased medication adherence may lead to patient and system-level benefits.


Childhood injury in Tower Hamlets: Audit of children presenting with injury to an inner city A&E department in London.
Childhood injury is a leading cause of mortality and morbidity worldwide with the most socio-economically deprived children at greatest risk. Current routine NHS hospital data collection in England is inadequate to inform or evaluate prevention strategies. A pilot study of enhanced data collection was conducted to assess the feasibility of collecting accident and emergency data for national injury surveillance. To evaluate the reliability and feasibility of supplementary data collection using a paper-based questionnaire and to assess the potential relationship between income deprivation and incidence of paediatric injury. Clinical staff conducted an audit of injuries in all patients under 16 years between June and December 2012 through completion of a questionnaire while taking the medical history. Descriptive statistics were produced for age, sex, time of arrival, activity at time of injury, mechanism and location of injuries. The association between known injury incidence and area level income deprivation (2010 English Index of Multiple Deprivation [IMD] Income Deprivation Domain from home postcode) was assessed using Spearman's rank correlation. Representativeness of the audit was measured using z-test statistics for time of arrival, age, sex and ethnicity. The paper audit captured 414 (6.5%) of the 6358 under-16 injury-related attendances recorded on the NHS Care Record Service Dataset. Comparison of the audit dataset with NHS records showed that the audit was not representative of the larger dataset except for sex of the patient. There was a positive correlation between injury incidence and income deprivation measured using IMD score where data were available (n = 384, p < 0.001). Nearly half of the attendances were due to falls, slips or trips (49.8%) and more than half were due to either leisure (32.9%) or sport (18.1%) activities. There is evidence of area level income inequalities in injury incidence among children attending the Royal London Hospital. The audit failed to capture a high proportion of cases, likely due to the paper-based format used. This study highlights the importance of routinely collecting enhanced injury data in computerized hospital admission systems to provide the necessary evidence base for effective injury prevention. The findings have contributed to plans for implementation.


Restorative effect of atrial natriuretic peptide or chronic neutral endopeptidase inhibition on blunted cardiopulmonary vagal reflexes in aged rats.
Arterial baroreflex function diminishes with age, but whether cardiopulmonary vagal reflexes are similarly altered with physiological aging has not been fully elucidated. In this study, predominantly cardiac high pressure mechanoreceptor-activated (ramp baroreflex) and cardiopulmonary chemoreceptor-activated (von Bezold-Jarisch reflex) vagal reflexes in conscious, instrumented rats were impaired by 30% to 40% (P<0.05) in 24-month-old (n=12) compared with 6-month-old rats (n=12). To determine whether this is a restorable deficit, the influence of atrial natriuretic peptide (ANP), either by infusion or blockade of its breakdown, was studied. ANP infusion was previously shown to enhance Bezold-Jarisch reflex and ramp baroreflex bradycardia in young adult rats. The present study confirmed that vagal reflex augmentation by ANP (50 pmol/kg per minute) also occurs in old rats (increased by 60+/-18% (Bezold-Jarisch reflex) and 91+/-15% (ramp baroreflex; P<0.05). Direct vagal stimulation in anesthetized animals showed that the target for ANP was not the cardiac vagus itself in old rats (n=7), although in young rats only, we confirmed the published finding that ANP enhances vagal bradycardia (by 58+/-14%, n=7). Neutral endopeptidase 24.11 degrades ANP and several other peptides. The neutral endopeptidase inhibitor candoxatrilat (5 mg/kg per day IV for 7 to 9 days) restored vagal reflex bradycardia in old rats (n=6) to levels similar to those in young neutral endopeptidase inhibitor-treated rats (n=6). Impaired cardiopulmonary vagal reflex control of heart rate is thus a feature of normal aging, and this deficit may be ameliorated by either ANP infusion or chronic neutral endopeptidase inhibition.


Selective Runx2-II deficiency leads to low-turnover osteopenia in adult mice.
Runx2 transcribes Runx2-II and Runx2-I isoforms with distinct N-termini. Deletion of both isoforms results in complete arrest of bone development, whereas selective loss of Runx2-II is sufficient to form a grossly intact skeleton with impaired endochondral bone development. To elucidate the role of Runx2-II in osteoblast function in adult mice, we examined heterozygous Runx2-II (Runx2-II(+/-)) and homozygous Runx2-II (Runx2-II(-/-))-deficient mice, which, respectively, lack one or both copies of Runx2-II but intact Runx2-I expression. Compared to wild-type mice, 6-week-old Runx2-II(+/-) had reduced trabecular bone volume (BV/TV%), cortical thickness (Ct.Th), and bone mineral density (BMD), decreased osteoblastic and osteoclastic markers, lower bone formation rates, impaired osteoblast maturation of BMSCs in vitro, and significant reductions in mechanical properties. Homozygous Runx2-II(-/-) mice had a more severe reduction in BMD, BV/TV%, and Ct.Th, and greater suppression of osteoblastic and osteoclastic markers than Runx2-II(+/-) mice. Non-selective Runx2(+/-) mice, which have an equivalent reduction in Runx2 expression due to the lack one copy of Runx2-I and II, however, had an intermediate reduction in BMD. Thus, selective Runx2-II mutation causes diminished osteoblastic function in an adult mouse leading to low-turnover osteopenia and suggest that Runx2-I and II have distinct functions imparted by their different N-termini.


Limits on a muon flux from neutralino annihilations in the sun with the IceCube 22-string detector.
A search for muon neutrinos from neutralino annihilations in the Sun has been performed with the IceCube 22-string neutrino detector using data collected in 104.3 days of live time in 2007. No excess over the expected atmospheric background has been observed. Upper limits have been obtained on the annihilation rate of captured neutralinos in the Sun and converted to limits on the weakly interacting massive particle (WIMP) proton cross sections for WIMP masses in the range 250-5000 GeV. These results are the most stringent limits to date on neutralino annihilation in the Sun.


Climbing fiber afferent modulation during treadmill locomotion in the cat.
The relationship of the climbing fiber afferent discharge to the unperturbed and perturbed step cycle was evaluated in the cat. Following a precollicular-premamillary decerebration, cats walked spontaneously on a motorized treadmill. Purkinje cells were recorded extracellularly and simple and complex spikes were discriminated. Right forelimb displacement, biceps and triceps EMG activity, as well as treadmill velocity, were also monitored. In some animals pressure measurements of the contact of the footpad with the treadmill were obtained. Cells were studied during both "normal" and perturbed locomotion. The perturbation consisted of a braking of the treadmill at different phases in the step cycle. Histograms of the simple and complex spike activity, and averages of the right forelimb displacement, biceps, and triceps EMG activity and treadmill velocity were constructed. The complex spike activity of 163 Purkinje cells was averaged through a minimum of 50 sweeps in either normal and/or perturbed locomotion. Statistical analysis revealed that the probability of the climbing fiber afferent discharge in 54% of the cells (36/67) studied during normal locomotion was significantly modulated with the step cycle. For most Purkinje cells the onset of the increase in climbing fiber afferent discharge was coupled to triceps activity and the onset of stance phase. A group of cells exhibited complex spike discharge in association with biceps onset and swing. These observations suggest that complex spike discharge occurs preferentially at the phase transition periods in the step cycle when the trajectory of the forelimb changes from swing to stance or stance to swing. During treadmill braking 51% of the cells exhibited complex spike modulation (70/137). A number of different patterns of climbing fiber afferent modulation occurred. The most common pattern was an increase in complex spike discharge with the resumption of the treadmill movement and locomotion. Analysis of the time of these periods of increased climbing fiber activity suggests that, although in some cells the response is coupled to the treadmill onset, in other cells the modulation occurs at longer latencies. Subsequent analysis aligning the EMG, displacement, and treadmill velocity signals with the times of the climbing fiber afferent discharge suggested some responses were coupled to the reinitiation of the locomotor cycle. The second most common pattern was an increase in climbing fiber afferent discharge at the onset of the perturbation. Also, in some cells, complex spike discharge decreased during the period in which the step cycle was arrested.(ABSTRACT TRUNCATED AT 400 WORDS)


Risk of transmission via medical employees and importance of routine infection-prevention policy in a nosocomial outbreak of Middle East respiratory syndrome (MERS): a descriptive analysis from a tertiary care hospital in South Korea.
In 2015, South Korea experienced an outbreak of Middle East respiratory syndrome (MERS), and our hospital experienced a nosocomial MERS infection. We performed a comprehensive analysis to identify the MERS transmission route and the ability of our routine infection-prevention policy to control this outbreak. This is a case-cohort study of retrospectively analysed data from medical charts, closed-circuit television, personal interviews and a national database. We analysed data of people at risk of MERS transmission including 228 in the emergency department (ED) and 218 in general wards (GW). Data of personnel location and movement, personal protection equipment and hand hygiene was recorded. Transmission risk was determined as the extent of exposure to the index patient: 1) high risk: staying within 2 m; 2) intermediate risk: staying in the same room at same time; and 3) low risk: only staying in the same department without contact. The index patient was an old patient admitted to our hospital. 11 transmissions from the index patient were identified; 4 were infected in our hospital. Personnel in the ED exhibited higher rates of compliance with routine infection-prevention methods as observed objectively: 93% wore a surgical mask and 95.6% washed their hands. Only 1.8% of personnel were observed to wear a surgical mask in the GW. ED had a higher percentage of high-risk individuals compared with the GW (14.5% vs. 2.8%), but the attack rate was higher in the GW (16.7%; l/6) than in the ED (3%; 1/33). There were no transmissions in the intermediate- and low-risk groups in the ED. Otherwise 2 patients were infected in the GW among the low-risk group. MERS were transmitted to them indirectly by staff who cared for the index patient. Our study provide compelling evidence that routine infection-prevention policies can greatly reduce nosocomial transmission of MERS. Conventional isolation is established mainly from contact tracing of patients during a MERS outbreak. But it should be extended to all people treated by any medical employee who has contact with MERS patients. NCT02605109 , date of registration: 11th November 2015.


Pharmacological evidence that captopril possesses an endothelium-mediated component of vasodilation: effect of sulfhydryl groups on endothelium-derived relaxing factor.
Captopril, an angiotensin-converting enzyme inhibitor, reportedly can scavenge superoxide anion (O2-), a property attributed to its sulfhydryl group. The present investigation, using rabbit aortic rings precontracted with either norepinephrine or clonidine, was designed to determine whether captopril possesses an endothelium-dependent component of vasodilation related to its ability to protect endothelium-derived relaxing factor (EDRF) from superoxide-mediated destruction. Also studied were enalaprilat, a nonsulfhydryl angiotensin-converting enzyme-inhibitor, superoxide dismutase, and the sulfhydryl compounds glutathione (GSH), N-2-mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC). Captopril, but not enalaprilat, caused dose-dependent relaxations in preconstricted aortic rings containing an intact endothelium. Rings denuded of endothelium were unresponsive to any dose of captopril. Captopril's vasodilation was not related to prostaglandin influence but was associated with an increase in cyclic GMP. Superoxide dismutase, GSH, MPG and NAC also produced endothelium-dependent relaxations similar to captopril. It was also demonstrated that endothelium-dependent relaxations to acetylcholine were enhanced by captopril, GSH, MPG and NAC but not by enalaprilat. In another set of experiments, the ability of captopril to inhibit superoxide-mediated inactivation of EDRF was examined. Pyrogallol, a potent generator of O2-, and superoxide dismutase, a scavenger of O2-, were used as a basis for comparing a possible scavenging effect of captopril. In preconstricted rings, pyrogallol elicited endothelium-dependent contractions that were attenuated by both captopril and superoxide dismutase. Similar effects were found with GSH, MPG and NAC but not with enalaprilat. These results suggest that captopril's endothelium-dependent vasodilation is due to its sulfhydryl group and the ability of the latter to scavenge O2-, thereby protecting EDRF.


Demineralization of dentine grooves in vitro.
Caries mainly occurs at retention sites for plaque such as pits, fissures, margins of restorations and interproximal sites. An in vitro model was developed to investigate dentine caries in narrow gaps. Forty bovine coronal dentine discs were covered with bonding agent. In 20 discs, two grooves, 200 and 340 mu m wide and 500 mu m deep, were sawn to mimic fissures. In the 20 other discs, a 1-mm-wide groove was made and, after polyester sheets were placed against both walls, filled with composite. After curing of the composite and removal of the sheets, grooves of 22 mu m remained at the borders of the restoration. All grooves were exposed to 8% methylcellulose gel 0.1 M lactic acid at pH 4.8 for 1 week. Demineralization was determined by microradiography of sections sawn out of the center of the discs. The walls of the grooves showed subsurface lesions, which decreased in size towards the base of the grooves. The average mineral losses (vol % x mu m) at the entrance of the 22-, 200- and 340-mu m-wide grooves were 1,112 (SD 370), 1,277 (293) and 1,277 (255), halfway down the groove 218 (150), 659 (244) and 797 (207) and at the base of the groove 140 (88), 285 (145) and 504 (205), respectively. Analysis of variance and Tukey's B test showed that the average mineral losses from grooves of different width and from sites at different depth were all significantly different at p<0.05 level, but not for the mineral losses from the entrance of the two wider grooves and from the two lower sites in the narrowest groove. The reduced mineral loss in the two narrower groove widths is assumed to be caused by the more limited inward diffusion of acids and outward diffusion of mineral ions through the methylcellulose gel.


Nosocomial coagulase-negative staphylococcal infections in bone marrow transplantation recipients with central vein catheter. A 5-year prospective study.
The purpose of this study was to examine coagulase-negative staphylococcal infections in bone marrow transplantation (BMT) patients with central vein catheters by investigating incidence, clinical relevance, risk factors, methicillin resistance, clinical impact of initial empiric antimicrobial therapy without vancomycin, and management of documented catheter-related infections. A 5-year prospective study was conducted with daily evaluation of 242 BMT patients during hospitalization, including clinical assessment and blood culture via the Hickman/Broviac catheter. If fever or infected appearance occurred, peripheral blood cultures or exit site cultures, respectively, were done. Results showed a septicemia incidence of 7.0%, including in 6 patients following colonization, in 1 patient with tunnel infection, in 1 patient with thrombophlebitis, in 1 patient with exit site infection, and in 8 patients with septicemia of unknown origin. Total colonization incidence was 7%, with colonization only in 11 patients who had 16 episodes; incidence of exit site infection was 3.7%. Age > or = 18 years was the only identified risk factor for developing staphylococcal infection (P = 0.03). Despite a methicillin resistance rate of 45% and omission of vancomycin from the routine initial empiric antimicrobial regimen, the clinical course of coagulase-negative staphylococcal infections was relatively benign. A single patient, who experienced marrow rejection, died on day +31 with septicemia and only one patient experienced microbiological failure with recurrent colonization. Bacteria grown in both aerobic and anaerobic bottles were more likely true bacteremia than contaminant (P = 0.03). We conclude that the hazard of coagulase-negative staphylococcal infection does not mandate inclusion of a glycopeptide in the initial empiric antimicrobial regimen in BMT patients, even during febrile neutropenia. Hickman/Broviac-related staphylococcal infections, except for tunnel infection or thrombophlebitis, can usually be treated successfully without removing the catheter.


Analysis of factors that influence neurosurgical length of hospital stay among newly diagnosed pediatric brain tumor patients.
Postoperative length of stay (LOS) carries a high burden of healthcare costs. In resource-intense specialties such as neurosurgery, it is imperative to identify factors that influence LOS to improve care. The current study investigates the potential for variables that affect clinical presentation, tumor characteristics, treatment modalities, and postoperative complications to impact overall LOS in pediatric brain tumor patients. A retrospective cohort study design was used with patients enrolled in the McMaster Pediatric Brain Tumor Study Group database. All patients up to 18 years of age, presenting with a newly diagnosed brain tumor admitted to and discharged from neurosurgery, were included. Patients were sorted into three cohorts: short LOS (≤3 days), extended LOS (≥20 days), and control LOS (4-19 days). Of the 124 patients included, 20 (65% male; median age: 9.1 years; range, 0.8-17.4 years) were considered short LOS, 28 (61% male; median age: 4.7 years; range, 0.4-14.7 years) were considered extended LOS, and 76 (57% male; median age: 8.5 years; range, 0.3-17.9 years) were considered control LOS. Variables that prolonged LOS were emesis at presentation (P < 0.001), developmental delay (P = 0.02), multiple surgeries (P = 0.004), tumor location (P < 0.05), subtotal resection (P = 0.02), feeding tube (P < 0.001), adjuvant chemoradiotherapy (P < 0.001), and posterior fossa syndrome (P = 0.004). This study identifies variables related to clinical presentation, tumor characteristics, treatment modalities, and postoperative complications associated with extended LOS. These findings uncover novel predictors of LOS that can be used to guide future research and improve health resource management.


Phosphoinositide 5-phosphate and phosphoinositide 4-phosphate trigger distinct specific responses of Arabidopsis genes: genome-wide expression analyses.
Phosphoinositide phosphates, PtdInsP, are important components of the cell lipid pool that can function as messengers in diverse cellular processes. Lack of information on downstream targets, however, has impeded our understanding of the potential of lipid-signaling to influence gene activity. Our goals here were to identify genes that altered expression in the presence of two isomeric monophosphate lipid messengers (Phosphoinositide 5-Phosphate, PtdIns(5)P, and Phosphoinositide 4-Phosphate, PtdIns(4)P) and to establish whether the two lipids influence distinct or overlapping gene-sets. Our results indicated that PtdIns(5)P and PtdIns(4)P affected genes within shared gene-families but that each messenger influenced the expression of different members within the same family. These results suggested that PtdIns(5)P and PtdIns(4)P participate in separate pathways that, ultimately, may control gene expression. The pathways may have points of convergence but may also counteract each other's effects. A significant fraction ( approximately 40%) of the PtdIns(5)P-stimulated genes belong to various families of wall-modifying genes. Wall-modifying activities are recognized as factors affecting cell extension and plant growth. Elevated PtdIns(5)P concentration influenced stem growth and the effects were different from those triggered by PtdIns(4)P. The data allow insights into plants' response to two related PtdInsP at whole-plant/genome-wide levels and demonstrate that PtdIns(5)P-and PtdIns(4)P-involving mechanisms are distinct, selective and specific.


Novel dabigatran etexilate hemisuccinate-loaded polycap: Physicochemical characterisation and in vivo evaluation in beagle dogs.
The purpose of this study was to develop a novel dabigatran etexilate hemisuccinate (DEH) salt-loaded polycap with bioequivalence to the dabigatran etexilate mesylate (DEM)-loaded commercial product. DEH prepared with dabigatran etexilate base (DE) and succinic acid was less hygroscopic but less soluble than DEM. Numerous micronized DEHs and DEH-loaded solid dispersions were prepared employing the spiral jet-milling and spray-drying techniques, respectively. Among the formulations prepared, a micronized DEH prepared with the injection air at 1.5bar and the grinding air at 2bar, and a DEH-loaded solid dispersion prepared with 6g HPMC most improved the drug solubility, respectively. Moreover, the micronized DEH provided more increased drug solubility and dissolution compared with the solid dispersion, even though its drug solubility was still lower than that of DEM. Unlike the situation in other studies, the enhanced solubility and dissolution of DEH was more due to particle size reduction than to a change to the amorphous form. The micronized DEH prepared with Myrj 52S had greater drug solubility than preparations with other surfactants. Among the organic acids investigated, only fumaric acid (128.8mg) showed a similar pattern in pH changes to the DEM-loaded commercial product. Furthermore, in order to make the environment acidic while preventing the direct contact of the drug with fumaric acid, the polycap was composed of a tablet containing the micronized DEH, Myrj 52S and other ingredients, and separate fumaric acid. This micronized DEH-loaded polycap was dissolution- and bio-equivalent to the DEM-loaded commercial product in beagle dogs. Thus, the novel micronized DEH-loaded polycap would be a promising alternative to the DEM-loaded commercial product.


KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses.
Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study, we aimed to evaluate to the utility of aberrant promoter hypermethylation for detection in a panel of 10 genes (KIF1A, EDNRB, CDH4, TERT, CD44, NISCH, PAK3, VGF, MAL and FKBP4) in head and neck squamous cell carcinoma (HNSCC) via a candidate gene approach. We investigated methylation of the gene promoters by bisulfite modification and quantitative methylation-specific PCR (Q-MSP) in a preliminary study of a limited cohort of salivary rinses from healthy subjects (n = 61) and patients with HNSCC (n = 33). The methylation status of 2 selected genes (EDNRB and KIF1A) were then analyzed in 15 normal mucosa samples from a healthy population, 101 HNSCC tumors and the corresponding salivary rinses from 71 out of the 101 HNSCC patients were collected before treatment. The promoter regions of CDH4, TERT, VGF, MAL, FKBP4, NISCH and PAK3 were methylated in normal salivary rinses while no methylation of CD44 was observed in either normal salivary rinses or tumor samples. However, KIF1A and EDNRB were methylated in 98 and 97% of primary HNSCC tissues respectively and were only methylated in 2 and 6.6% of normal salivary rinses. In addition, KIF1A and EDNRB were methylated in 38 and 67.6% of salivary rinses from HNSCC patients, respectively. Promoter hypermethylation of KIF1A and EDNRB is a frequent event in primary HNSCC, and these genes are preferentially methylated in salivary rinses from HNSCC patients. KIF1A and EDNRB are potential biomarkers for HNSCC detection.