Spontaneous hip labrum regrowth after initial surgical débridement.
Anecdotal evidence from second-look hip arthroscopies and animal studies has suggested spontaneous labral regrowth may occur after débridement. However, these observations have not been systematically confirmed. We (1) determined whether labral regrowth occurs after débridement in human hips; (2) if so, described the characteristics of the reconstituted labrum; and (3) determined the association, if any, of age with the presence and quality of labral regrowth. We retrospectively reviewed all 24 patients who previously had open hip surgical dislocation with labral débridement for treatment of femoroacetabular impingement (FAI) and concomitant hip arthroscopy 2 years after index procedure in association with planned removal of trochanteric hardware between January and December 1999. Data recorded included amount of labral resection at the index procedure using the clockface method, presence and quality of any labral regrowth, presence of any labral scarring or inflammation, and WOMAC(®) scores. Minimum clinical followup was 11 years (average, 12 years; range, 11-12 years). All patients demonstrated labral regrowth at arthroscopy at 2 years. Homogeneous regrowth of labral height was seen in 21 of 24 patients, with labral scarring noted in four of 24. Average WOMAC(®) score was 98 points (range, 90-100 points) at the time of hardware removal. Increasing patient age was independently associated with decreased WOMAC(®) score and inhomogeneous regrowth of the labrum. Labral regrowth after resection was seen in all patients at 2 years from index operation. Increasing age, however, was associated with poorer quality of the reconstituted labrum.


Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial.
Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients. Recipients>1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate>30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but <10% in biomarker-led care. The secondary outcomes include the rate of transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes. We have evidence that the biomarker-led care regime will be effective at preventing graft dysfunction and expect this to feed through to graft survival. This trial will confirm the benefit of routine screening and lead to a greater understanding of how to keep kidney transplants working longer. Current Controlled Trials ISRCTN46157828.


Spectral demultiplexing in holographic and fluorescent on-chip microscopy.
Lensfree on-chip imaging and sensing platforms provide compact and cost-effective designs for various telemedicine and lab-on-a-chip applications. In this work, we demonstrate computational solutions for some of the challenges associated with (i) the use of broadband, partially-coherent illumination sources for on-chip holographic imaging, and (ii) multicolor detection for lensfree fluorescent on-chip microscopy. Specifically, we introduce spectral demultiplexing approaches that aim to digitally narrow the spectral content of broadband illumination sources (such as wide-band light emitting diodes or even sunlight) to improve spatial resolution in holographic on-chip microscopy. We also demonstrate the application of such spectral demultiplexing approaches for wide-field imaging of multicolor fluorescent objects on a chip. These computational approaches can be used to replace e.g., thin-film interference filters, gratings or other optical components used for spectral multiplexing/demultiplexing, which can form a desirable solution for cost-effective and compact wide-field microscopy and sensing needs on a chip.


Nitric Oxide-Releasing Aspirin Suppresses NF-κB Signaling in Estrogen Receptor Negative Breast Cancer Cells in Vitro and in Vivo.
Estrogen receptor negative (ER(-)) breast cancer is aggressive, responds poorly to current treatments and has a poor prognosis. The NF-κB signaling pathway is implicated in ER(-) tumorigenesis. Aspirin (ASA) is chemopreventive against ER(+) but not for ER(-) breast cancers. Nitric oxide-releasing aspirin (NO-ASA) is a safer ASA where ASA is linked to an NO-releasing moiety through a spacer. In vitro, we investigated anti-proliferation effects of NO-ASA (para- and meta-isomers) against ER(-) breast cancer cells MDA-MB-231 and SK-BR-23, effects on NF-κB signaling, and reactive oxygen species by standard techniques. In vivo, effects of NO-ASA were evaluated in a mouse xenograft model using MDA-MB-231 cells. p-NO-ASA inhibited the growth of MDA-MB-231 and SK-BR-3 cells at 24 h, the respective IC50s were 13 ± 2 and 17 ± 2 μM; ASA had an IC50 of >3000 μM in both cell lines. The IC50s for m-NO-ASA in MDA-MB-231 and SK-BR-3 were 173 ± 15 and 185 ± 12 μM, respectively, therefore, implying p-NO-ASA as a stronger inhibitor of growth p-NO-ASA reduced cell growth by inhibiting proliferation, inducing apoptosis and causing G0/G1 cell cycle block. Activation of NF-κB was inhibited by both isomers as demonstrated by decreases in NF-κB-DNA binding and luciferase activity at 24 h, However, m-NO-ASA produced transient effects at 3 h such as increased NF-κB-DNA-binding, increased levels of nuclear p50, even though both isomers inhibited IκB degradation. Increase in nuclear p50 by m-NO-ASA was associated with translocation of p50 in to the nucleus as observed by immunoflouresence at 3 h. NO-ASA induced reactive oxygen species (ROS) as evidenced by overall increases in both H2DCFDA (2',7'-dichlorodihydrofluorescein) and DHE (dihydroethidium)-derived fluorescence. Inhibition of ROS by N-acetyl-cysteine reversed the m-NO-ASA-mediated translocation of p50 in to the nucleus. In xenografts, p-NO-ASA inhibited tumor growth by inhibiting proliferation (PCNA and tumor volume), inducing apoptosis (TUNEL positive cells) and reducing NF-κB expression. Both isomers inhibit cancer cells, inhibit NF-κB pathway and induce ROS, and have potential as anticancer compounds.


AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity.
Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure-activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-β-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.


[Clinical features of Guillain-Barré syndrome in 41 patients admitted to a public hospital].
Guillain-Barré syndrome (GBS) is the commonest cause of acute flaccid paralysis worldwide, with an incidence of 0.6-4 per 100.000 inhabitants per year. It affects all age groups and carries an incapacity burden of up to 20%. To describe the features of GBS in adult Chilean patients admitted to a tertiary care hospital. Review of medical records of 41 patients aged 17 to 81 years (30 males) admitted to a public hospital with the diagnosis of GBS between 2003 and 2009. According to clinical and electrophysiological criteria, the patients were classified into different varieties of GBS. The incidence of GBS was higher in males (2.7:1) and the demyelinated GBS variety was found in 66% of cases. According to the Hughes' disability score, patients treated with plasmapheresis, showed non-statistically significant better outcomes than those treated with intravenous immunoglobulin. In this group of patients the demyelinated variety of GBS was more common than the axonal type. Although not statistically significant, the better response to plasmapheresis is encouraging and should prompt a controlled study.


Non-invasive brain stimulation in Parkinson's disease: Exploiting crossroads of cognition and mood.
Cognitive impairments and depression are common non-motor manifestations in Parkinson's disease (PD). Recent evidence suggests that both partially arise via the same frontostriatal network, opening the opportunity for concomitant treatment with non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). In this systematic review, we evaluate the effects of NIBS on cognition and/or mood in 19 placebo-controlled studies involving 561 PD patients. Outcomes depended on the area stimulated and the technique used. rTMS over the dorsolateral-prefrontal cortex (DLPFC) resulted in significant reductions in scores of depressive symptoms with moderate to large effect sizes along with increased performance in several tests of cognitive functions. tDCS over the DLPFC improved performance in several cognitive measures, including executive functions with large effect sizes. Additional effects of tDCS on mood were not detectable; however, only non-depressed patients were assessed. Further confirmatory research is needed to clarify the contribution that NIBS could make in the care of PD patients.


Protein kinase A does not alter unloaded velocity of sarcomere shortening in skinned rat cardiac trabeculae.
Whether beta-adrenergic stimulation affects the cross-bridge cycling rate independently of its effect on Ca2+ handling by the cardiac myocyte is still unknown. An increase in cross-bridge cycling rate may result in increased unloaded velocity of sarcomere shortening (V0). To test this hypothesis directly, skinned rat cardiac trabeculae were attached between a silicon strain gauge (approximately 3.5 kHz resonant frequency) and a fast displacement motor. V0 was measured by a modified "Edman slack test" during a single maximal activation using seven to eight sarcomere-length step releases (measured by laser diffraction) ranging between 0.12 and 0.20 micron (15.0 +/- 0.1 degrees C). beta-Adrenergic stimulation was mimicked by exposing the trabeculae to the catalytic subunit of protein kinase A (PKA). Treatment with PKA (3 micrograms/ml; 45 min) caused a significant (P < 0.01) increase (41 +/- 13%) in the Ca2+ concentration required for half-maximal steady-state tension development. Neither maximum tension nor V0 was affected by treatment with PKA, suggesting that beta-adrenergic stimulation does not affect the rate-limiting step of cross-bridge cycling during unloaded shortening in myocardium.


Update on T cells in the virally infected brain: friends and foes.
The present review will outline neuroprotective and neurotoxic effects of central nervous system (CNS) infiltrating T cells during viral infections. Evidence demonstrating differential roles for antiviral effector and resident memory T-cell subsets in virologic control and immunopathology in the CNS will be discussed. Potential therapeutic targets emanating from a growing understanding of T-cell-initiated neuropathology that impacts learning and memory will also be delineated. The critical role for T cells in preventing and clearing CNS infections became incontrovertible during the era of acquired immunodeficiency syndrome. Recent studies have further defined differential roles of T-cell subsets, including resident memory T cells (Trm), in antiviral immunity and, unexpectedly, in postinfectious cognitive dysfunction. Mechanisms of T-cell-mediated effects include differential innate immune signaling within neural cells that are virus-specific. T-cell cytokines that are essential for cell-mediated virologic control during neurotropic viral infections have recently been identified as potential targets to prevent post-infection memory disorders. Further identification of T-cell subsets, their antigen specificity, and postinfection localization of Trm will enhance the efficacy of immunotherapies through minimization of immunopathology.


Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson's disease.
This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson's disease (PD). Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS. Parkinson's Progression Markers Initiative (PPMI) is a multi-site study of early, untreated PD patients and healthy controls (HCs), the latter with normal cognition. At baseline, participants were assessed with a neuropsychological battery and for symptoms of depression, anxiety, impulse control disorders (ICDs), psychosis, and apathy. Baseline data of 423 PD patients and 196 HCs yielded no between-group differences in demographic characteristics. Twenty-two percent of PD patients met the PD-recommended screening cutoff for CI on the Montral Cognitive Assessment (MoCA), but only 9% met detailed neuropsychological testing criteria for mild cognitive impairment (MCI)-level impairment. The PD patients were more depressed than HCs (P < 0.001), with twice as many (14% vs. 7%) meeting criteria for clinically significant depressive symptoms. The PD patients also experienced more anxiety (P < 0.001) and apathy (P < 0.001) than HCs. Psychosis was uncommon in PD (3%), and no between-group difference was seen in ICD symptoms (P = 0.51). Approximately 10% of PD patients in the early, untreated disease state met traditional criteria of CI, which is a lower frequency compared with previous studies. Multiple dopaminergic-dependent NPS are also more common in these patients compared with the general population, but others associated with dopamine replacement therapy are not or are rare. Future analyses of this cohort will examine biological predictors and the course of CI and NPS. © 2015 International Parkinson and Movement Disorder Society.


Very preterm children who do not cooperate with assessments at three years of age: skill differences at five years.
This study examined skill differences at 5 years of age for very preterm children who were or were not cooperative with developmental testing at 3 years of age. All children born between 1986 and 1991 who were less than 30 weeks of gestation were followed prospectively. Two hundred one children were seen at both the 3- and 5-year assessments. Of the 201 children, 24 (11.9%) who had been uncooperative in the assessment at 3 years were seen at 5 years. Uncooperative children were matched to a group of cooperative children for sex, gestation, and/or birth weight. Nonparametric analyses revealed that scores on the Binet Pattern Analysis (p < .01) and the Bead Memory (p < .01) subtests were significantly different between the groups. The uncooperative children scored significantly more often in the at-risk range for tests of minor neurological dysfunction (MND; p < .01) compared with cooperative matched controls. The authors speculate that in very preterm children, uncooperative behavior shown at 3 years of age associated with poor visual/spatial skills and a high level of MND at 5 years of age may reveal children at risk for the development of nonverbal learning disabilities.


A tissue-specific increase in lipogenesis in rat brown adipose tissue in hypothyroidism.
1. Rats were made hypothyroid by feeding them with propylthiouracil together with a low-iodine diet for 4 weeks. 2. [U-14C]Glucose conversion into fatty acids was substantially enhanced in brown adipocytes isolated from hypothyroid rats. Incorporation of 3H2O into fatty acids in vivo was enhanced in hypothyroidism in interscapular brown fat, but not in epididymal white fat or in liver. Hypothyroidism increased the activities of fatty acid synthase and ATP citrate lyase in brown, but not in white, adipocytes. 3. Glycolytic flux in brown adipocytes, quantified by [3-3H]glucose detritiation, was increased by hypothyroidism. This change was accompanied by increased maximum activity of phosphofructokinase. In white adipocytes a large increase in phosphofructokinase maximum activity was observed in hypothyroidism, but this change was accompanied by only small increases in the rate of glucose detritiation by incubated cells. It is suggested that in the brown adipocyte the overall conversion of glucose into fatty acids is enhanced in thyroid deficiency, but that this change is muted in the white adipocyte, possibly because of limitation of glucose transport. 4. Fatty acid synthesis in brown adipocytes from hypothyroid animals was considerably less sensitive to inhibition by exogenous fatty acids than is the process in cells from euthyroid animals. Consequently, the effect of hypothyroidism to enhance lipogenesis is amplified in the presence of physiological concentrations of fatty acid.


Acetylene hydrogenation over structured Au-Pd catalysts.
AuPd nanoparticles were prepared following a methodology designed to produce core-shell structures (an Au core and a Pd shell). Characterisation suggested that slow addition of the shell metal favoured deposition onto the pre-formed core, whereas more rapid addition favoured the formation of a monometallic Pd phase in addition to some nanoparticles with the core-shell morphology. When used for the selective hydrogenation of acetylene, samples that possessed monometallic Pd particles favoured over-hydrogenation to form ethane. A sample prepared by the slow addition of a small amount of Pd resulted in the formation of a core-shell structure but with an incomplete Pd shell layer. This material exhibited a completely different product selectivity with ethylene and oligomers forming as the major products as opposed to ethane. The improved performance was thought to be as a result of the absence of Pd particles, which are capable of forming a Pd-hydride phase, with enhanced oligomer selectivity associated with reaction on uncovered Au atoms.


Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence.
The tolerance and dependence after chronic medication with morphine are thought to be representative models for studying the plasticity, including the remodeling of neuronal networks. To test the hypothesis that changes in neuronal plasticity observed in opioid tolerance or dependence are derived from increased activity of the anti-opioid nociceptin system, the effects of chronic treatments with morphine were examined using nociceptin receptor knock-out (NOR(-/-)) mice and a novel nonpeptidic NOR antagonist, J-113397, which shows a specific and potent NOR antagonist activity in in vitro [(35)S]GTPgammaS binding assay and in vivo peripheral nociception test. The NOR(-/-) mice showed marked resistance to morphine analgesic tolerance without affecting morphine analgesic potency in tail-pinch and tail-flick tests. The NOR(-/-) mice also showed marked attenuation of morphine-induced physical dependence, manifested as naloxone-precipitated withdrawal symptoms after repeated morphine treatments. Similar marked attenuation of morphine tolerance was also observed by single subcutaneous (10 mg/kg) or intrathecal (1 nmol) injection of J-113397, which had been given 60 min before the test in morphine-treated ddY mice. However, the intracerebroventricular injection (up to 3 nmol) did not affect the tolerance. On the other hand, morphine dependence was markedly attenuated by J-113397 that had been subcutaneously given 60 min before naloxone challenge. There was also observed a parallel enhancement of NOR gene expression only in the spinal cord during chronic morphine treatments. Together, these findings suggest that the spinal NOR system develops anti-opioid plasticity observed on morphine tolerance and dependence.


Skin cancer education for primary care physicians: a systematic review of published evaluated interventions.
Early detection of melanoma may provide an opportunity to positively impact melanoma mortality. Numerous skin cancer educational interventions have been developed for primary care physicians (PCPs) to improve diagnostic accuracy. Standardized training is also a prerequisite for formal testing of melanoma screening in the primary care setting. We conducted a systematic review to determine the extent of evaluated interventions designed to educate PCPs about skin cancer, including melanoma. Relevant studies in the English language were identified through systemic searches performed in MEDLINE, EMBASE, BIOSIS, and Cochrane through December 2010. Supplementary information was obtained from corresponding authors of the included studies when necessary. Studies eligible for inclusion formally evaluated skin cancer education interventions and were designed primarily for PCPs. Excluded studies lacked a specified training intervention, used decision-making software, focused solely on risk factor identification, or did not directly educate or assess participants. Twenty studies met the selection criteria. Data were extracted according to intervention content and delivery format, and study outcomes. All interventions included instructions about skin cancer diagnosis, but otherwise varied in content. Curricula utilized six distinct educational techniques, usually incorporating more than one. Intervention duration varied from 12 min to over 6 h. Eight of the 20 studies were randomized trials. Most studies (18/20, 90%) found a significant improvement in at least one of the following five outcome categories: knowledge, competence, confidence, diagnostic performance, or systems outcomes. Competence was most commonly measured; no study evaluated all categories. Variability in study design, interventions, and outcome measures prevented correlation of outcomes with intervention characteristics. Despite the development of many isolated educational interventions, few have been tested rigorously or evaluated under sufficient standardized conditions to allow for quantitative comparison. Improved and rigorously tested skin cancer educational interventions for PCPs with outcome measures focusing on changes in performance are needed.


Charge-coupled substituted garnets (Y3-xCa0.5xM0.5x)Fe5O12 (M = Ce, Th): structure and stability as crystalline nuclear waste forms.
The garnet structure has been proposed as a potential crystalline nuclear waste form for accommodation of actinide elements, especially uranium (U). In this study, yttrium iron garnet (YIG) as a model garnet host was studied for the incorporation of U analogs, cerium (Ce) and thorium (Th), incorporated by a charge-coupled substitution with calcium (Ca) for yttrium (Y) in YIG, namely, 2Y(3+) = Ca(2+) + M(4+), where M(4+) = Ce(4+) or Th(4+). Single-phase garnets Y3-xCa0.5xM0.5xFe5O12 (x = 0.1-0.7) were synthesized by the citrate-nitrate combustion method. Ce was confirmed to be tetravalent by X-ray absorption spectroscopy and X-ray photoelectron spectroscopy. X-ray diffraction and (57)Fe-Mössbauer spectroscopy indicated that M(4+) and Ca(2+) cations are restricted to the c site, and the local environments of both the tetrahedral and the octahedral Fe(3+) are systematically affected by the extent of substitution. The charge-coupled substitution has advantages in incorporating Ce/Th and in stabilizing the substituted phases compared to a single substitution strategy. Enthalpies of formation of garnets were obtained by high temperature oxide melt solution calorimetry, and the enthalpies of substitution of Ce and Th were determined. The thermodynamic analysis demonstrates that the substituted garnets are entropically rather than energetically stabilized. This suggests that such garnets may form and persist in repositories at high temperature but might decompose near room temperature.


Molecular Targets of Epigallocatechin-Gallate (EGCG): A Special Focus on Signal Transduction and Cancer.
Green tea is a beverage that is widely consumed worldwide and is believed to exert effects on different diseases, including cancer. The major components of green tea are catechins, a family of polyphenols. Among them, epigallocatechin-gallate (EGCG) is the most abundant and biologically active. EGCG is widely studied for its anti-cancer properties. However, the cellular and molecular mechanisms explaining its action have not been completely understood, yet. EGCG is effective in vivo at micromolar concentrations, suggesting that its action is mediated by interaction with specific targets that are involved in the regulation of crucial steps of cell proliferation, survival, and metastatic spread. Recently, several proteins have been identified as EGCG direct interactors. Among them, the trans-membrane receptor 67LR has been identified as a high affinity EGCG receptor. 67LR is a master regulator of many pathways affecting cell proliferation or apoptosis, also regulating cancer stem cells (CSCs) activity. EGCG was also found to be interacting directly with Pin1, TGFR-II, and metalloproteinases (MMPs) (mainly MMP2 and MMP9), which respectively regulate EGCG-dependent inhibition of NF-kB, epithelial-mesenchimal transaction (EMT) and cellular invasion. EGCG interacts with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which modulates epigenetic changes. The bulk of this novel knowledge provides information about the mechanisms of action of EGCG and may explain its onco-suppressive function. The identification of crucial signalling pathways that are related to cancer onset and progression whose master regulators interacts with EGCG may disclose intriguing pharmacological targets, and eventually lead to novel combined treatments in which EGCG acts synergistically with known drugs.


Caring for women with abortion complications in Ethiopia: national estimates and future implications.
Ethiopia liberalized its abortion law in 2005, primarily to reduce the incidence of unsafe abortion. However, little is known about the current extent and consequences of unsafe abortion. Data were collected in 2007-2008 on 1,932 women seeking postabortion care at a nationally representative sample of 344 public and private health facilities. In addition, staff respondents at 337 facilities provided information on their facility's services and caseload. These data were used to examine patterns of abortion-related morbidity and treatment and to generate national estimates. Almost 58,000 women sought care for complications of induced or spontaneous abortion in 2008. Three-quarters of the women received care in government facilities. Forty-one percent had moderate or severe morbidity, such as signs of infection, that were likely related to an unsafe abortion. Seven percent of all women had signs of a mechanical injury or a vaginally inserted foreign body. More than 13,000 women seeking postabortion care required a hospital stay of at least 24 hours. The case fatality rate among women seeking postabortion care in public hospitals, where the most serious complications were seen, was 628 per 100,000. Postabortion care and safe abortion services should be further expanded and strengthened to make these services more accessible and affordable, which in turn may ease the financial burden on hospitals and allow the resources currently required for postabortion care to be used for other health needs. Ensuring that all women know that safe abortion is available and legal for many indications will further reduce morbidity from unsafe abortions.


Role of Methoprene-tolerant (Met) in adult morphogenesis and in adult ecdysis of Blattella germanica.
Juvenile Hormone (JH) represses metamorphosis of young instars in insects. One of the main players in hormonal signalling is Methoprene-tolerant (Met), which plays the role of JH receptor. Using the Polyneopteran insect Blattella germanica as the model and RNAi for transcript depletion, we have confirmed that Met transduces the antimetamorphic signal of JH in young nymphs and plays a role in the last nymphal instar moult in this species. Previously, the function of Met as the JH receptor had been demonstrated in the Eumetabola clade, with experiments in Holometabola (in the beetle Tribolium castaneum) and in their sister group Paraneoptera (in the bug Pyrrhocoris apterus). Our result shows that the function of Met as JH receptor is also conserved in the more basal Polyneoptera. The function of Met as JH transducer might thus predate the evolutionary innovation of metamorphosis. Moreover, expression of Met was also found in last nymphal instar of B. germanica, when JH is absent. Depletion of Met in this stage provoked deficiencies in wing growth and ecdysis problems in the imaginal moult. Down-regulation of the ecdysone-inducible gene E75A and Insulin-Like-Peptide 1 in these Met-depleted specimens suggest that Met is involved in the ecdysone and insulin signalling pathways in last nymphal instar, when JH is virtually absent.


A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group.
This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene therapy to surgical resection in patients with recurrent glioblastoma multiforme (GBM). The study was open and single-arm, and aimed at assessing the feasibility and safety of the technique and indications of antitumor activity. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resection. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafety assaying. Tumor changes were monitored by magnetic resonance imaging (MRI). Reflux during injection was a frequent occurrence but serious adverse events during the treatment period (days 1-27) were few and of a nature not unexpected in this population. One patient experienced transient neurological disorders associated with postganciclovir MRI enhancement. There was no evidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom remains recurrence free at more than 24 months. Treatment-characteristic images of injection tracks and intracavity hemoglobin were apparent. In conclusion, the gene therapy is feasible and appears to be satisfactorily safe as an adjuvant to the surgical resection of recurrent GBM, but any benefit appears to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.


Direct Visualization of a 26 kDa Protein by Cryo-Electron Microscopy Aided by a Small Scaffold Protein.
Cryo-electron microscopy (cryo-EM)-based structure determination of small proteins is hindered by the technical challenges associated with low signal-to-noise ratios of their particle images in intrinsically noisy micrographs. One solution is to attach the target protein to a large protein scaffold to increase its apparent size and, therefore, image contrast. Here we report a novel scaffold design based on a trimeric helical protein, E. coli ornithine transcarbamylase (OTC), fused to human ubiquitin. As a proof of principle, we demonstrated the ability to resolve a cryo-EM map of a 26 kDa human ubiquitin C-terminal hydrolase (UCHL1) attached to the C-terminus of ubiquitin as part of the trimeric assembly. The results revealed conformational changes in UCHL1 upon binding to ubiquitin, namely, a significant displacement of α-helix 2, which was also observed by X-ray crystallography. Our findings demonstrated the potential of the trimeric OTC scaffold design for studying a large number of ubiquitin interacting proteins by cryo-EM.


Prevalence of Chlamydia trachomatis in young men in north west London.
Chlamydia trachomatis is the most common, treatable, bacterial sexually transmitted infection in England and Wales. Among men, chlamydial infection is an important cause of non-gonococcal urethritis, epididymitis, and proctitis. The case for wider screening among women has been accepted by an expert advisory group. In the absence of estimates of the prevalence of infection in men, its potential impact at the population level is difficult to assess. To estimate the prevalence of Chlamydia trachomatis in young men in clinic and community based samples in north west London. Cross sectional survey in healthcare centres and general practices in north west London. 1002 males aged 18-35 years, living in north west London, were recruited by staff in occupational health departments, general practices, student health services, and a "well man" clinic and by postal recruitment in four GP practices. The men were tested for C trachomatis using the ligase chain reaction assay on urine samples. The main outcome measure was prevalence of C trachomatis infection in men aged 18-35 years. The overall response rate was 51%. Prevalence of confirmed infection was 1.9% (95% CI: 1.14% to 2.96%) in all men. Best estimated minimum prevalence of infection was 1% (95% CI: 0.58% to 1.50%). Estimated prevalence was highest among men aged over 30 years. The estimated prevalence among men is commensurate with that described for female populations in London. The results suggest that recruitment of men to screening programmes would be difficult. However, a higher proportion of chlamydial infection may be detected in men than in women by existing approaches to control through genitourinary medicine clinic based case finding and contact tracing. Screening of young women and the contact tracing of the male partners of positive females may be an efficient approach to improving chlamydia control.


Laboratory corroboration of the pioneer venus gas chromatograph analyses.
Laboratory simulation and tests of the inlet sampling system and columns of the Pioneer Venus gas chromatograph show that the sensitivity to argon is not diminished after the column regeneration step, argon isotopes are not separated, oxygen and sulfur dioxide are not produced in the inlet sampling system from sulfur trioxide, and sulfur trioxide is not formed from sulfur dioxide and oxygen. Comparisons of the volatile inventory of Venus and Earth imply similar efficiencies of early outgassing but a lower efficiency for later outgassing in the case of Venus. The high oxidation state of the Venus atmosphere in the region of cloud formation may prohibit the generation of elemental sulfur particles.


AT1 receptor antagonist candesartan attenuates genomic damage in peripheral blood lymphocytes of patients on maintenance hemodialysis treatment.
Angiotensin II (ANG II) and advanced glycation end products (AGEs) exert genotoxic effects in vitro which were prevented by the ANG II type 1 (AT1) receptor blocker, candesartan. In end-stage renal disease (ESRD) the incidence of genomic damage is increased. A stimulation of the renin-angiotensin system and accumulation of AGEs could be involved. We tested whether oral co-administration of candesartan modulates enhanced DNA damage in ESRD patients. Fifteen maintenance hemodialysis (MHD) patients with mild hypertension were treated with candesartan for 4.5 months. Fourteen MHD patients served as conventionally treated uremic controls. DNA damage was measured as micronucleus frequency (MNF) in peripheral blood lymphocytes and evaluated three times before candesartan therapy and afterwards every 6 weeks. Compared to 14 healthy controls, MNF at baseline was significantly elevated in MHD patients. While in the conventionally treated MHD patients the enhanced DNA damage persisted, the co-administration of candesartan ameliorated the genomic damage significantly and independently of blood pressure changes. Blockade of AT1 receptors with candesartan can reduce DNA damage in MHD patients. Long-term studies in larger patient groups are needed to investigate whether the improved genomic damage lowers atherosclerotic complications and cancer development.


A clinical approach to treatment resistance in depressed patients: What to do when the usual treatments don't work well enough?
Major depressive disorder is a common, recurrent, disabling and costly disorder that is often severe and/or chronic, and for which non-remission on guideline concordant first-line antidepressant treatment is the norm. A sizeable percentage of patients diagnosed with MDD do not achieve full remission after receiving antidepressant treatment. How to understand or approach these 'refractory', 'TRD' or 'difficult to treat' patients need to be revisited. Treatment resistant depression (TRD) has been described elsewhere as failure to respond to adequate treatment by two different antidepressants. This definition is problematic as it suggests that TRD is a subtype of major depressive disorder (MDD), inferring a boundary between TRD and depression that is not treatment resistant. However, there is scant evidence to suggest that a discrete TRD entity exists as a distinct subtype of MDD, which itself is not a discrete or homogeneous entity. Similarly, the boundary between TRD and other forms of depression is predicated at least in part on regulatory and research requirements rather than biological evidence or clinical utility. This paper aims to investigate the notion of treatment failure in order to understand (i) what is TRD in the context of a broader formulation based on the understanding of depression, (ii) what factors make an individual patient difficult to treat, and (iii) what is the appropriate and individualised treatment strategy, predicated on an individual with refractory forms of depression? Expert contributors to this paper were sought internationally by contacting representatives of key professional societies in the treatment of MDD - World Federation of Societies for Biological Psychiatry, Australasian Society for Bipolar and Depressive Disorders, International Society for Affective Disorders, Collegium Internationale Neuro-Psychopharmacologium and the Canadian Network for Mood and Anxiety Treatments. The manuscript was prepared through iterative editing. The concept of TRD as a discrete subtype of MDD, defined by failure to respond to pharmacotherapy, is not supported by evidence. Between 15 and 30% of depressive episodes fail to respond to adequate trials of 2 antidepressants, and 68% of individuals do not achieve remission from depression after a first-line course of antidepressant treatment. Failure to respond to antidepressant treatment, somatic therapies or psychotherapies may often reflect other factors including; biological resistance, diagnostic error, limitations of current therapies, psychosocial variables, a past history of exposure to childhood maltreatment or abuse, job satisfaction, personality disorders, co-morbid mental and physical disorders, substance use or non-adherence to treatment. Only a subset of patients not responding to antidepressant treatment can be explained through pharmacokinetic or pharmacodynamics mechanisms. We propose that non remitting MDD should be personalised, and propose a strategy of 'deconstructing depression'. By this approach, the clinician considers which factors contribute to making this individual both depressed and 'resistant' to previous therapeutic approaches. Clinical formulation is required to understand the nature of the depression. Many predictors of response are not biological, and reflect a confluence of biological, psychological, and sociocultural factors, which may influence the illness in a particular individual. After deconstructing depression at a personalised level, a personalised treatment plan can be constructed. The treatment plan needs to address the factors that have contributed to the individual's hard to treat depression. In addition, an individual with a history of illness may have a lot of accumulated life issues due to consequences of their illness, and these should be addressed in a recovery plan. A 'deconstructing depression' qualitative rubric does not easily provide clear inclusion and exclusion criteria for researchers wanting to investigate TRD. MDD is a polymorphic disorder and many individuals who fail to respond to standard pharmacotherapy and are considered hard to treat. These patients are best served by personalised approaches that deconstruct the factors that have contributed to the patient's depression and implementing a treatment plan that adequately addresses these factors. The existence of TRD as a discrete and distinct subtype of MDD, defined by two treatment failures, is not supported by evidence.


Probing the Effectiveness in Stabilizing Lithium Metal Anodes through Functional Additives.
A variety of electrolyte additives were comprehensively evaluated to understand their relative capability in stabilizing lithium metal anode. Although the Li||Cu test is an effective test to rule out ineffective additives, a reliable assessment of individual additives cannot be obtained just by a single evaluation method. Therefore, various methods must be combined to truly assess the stabilization of a lithium anode. Moreover, it was also discovered that a significant depletion of electrolytes occurred during the end-of-life of the lithium batteries, which partially contributed to the sudden failure of the lithium batteries during cycling. However, the main culprit of the sudden failure was identified as the significant increase in the resistance of the lithium metal anode. When used as an additive, cyclic fluorinated carbonates are the most effective in stabilizing the lithium anode and improving the cycling performance of lithium batteries among all the common additives. Despite its cost-effectiveness, the additive in the conventional electrolyte approach provides insufficient protection for lithium metal due to the complete consumption of the additive materials, which is necessary to repair the solid-electrolyte interphase (SEI). Therefore, it is suggested that a larger ratio (>15 wt %) of the SEI former should be employed to achieve effective lithium stabilization.


Positioning of iris in an ocular prosthesis: A systematic review.
To evaluate different methods, techniques, and concepts documented in the literature to assess iris positioning accurately to the related dimensions needed to effectuate maxillofacial rehabilitation of ocular prosthesis. This systematic review was conducted as per the PRISMA guidelines which is the most opted reporting protocol. Two electronic databases PubMed and Cochrane Library) were searched for manuscripts published from 1969 till September 30, 2019. An electronic search (of peer review restricted to English language dental literature was conducted to identify the relevant scientific article on iris positioning in maxillofacial prostheses. Two observers independently read the abstracts and selected 17 full text articles fulfilling the inclusion criteria. No meta-analysis was conducted due to heterogeneity of data obtained. All the 17 documented articles related to determination of the iris positioning to perform maxillofacial prosthetic rehabilitation depicting the use of a strip of plastic template, a Boley's gauge, a millimeter ruler, a pupillometer, window light, an ocular locator with fixed caliper, inverted anatomic tracings, a transparent graph grid were reviewed systematically. Currently, there is no evidence in the form of a systematic review of the available literature discussing the best technique available for perfectly matching the iris positioning. However, the latest techniques making use of digital technology such as digital photography, is believed to be more precise for iris positioning in the ocular prosthesis.


Using phylogeographic analyses of gene trees to test species status and processes.
A gene tree is an evolutionary reconstruction of the genealogical history of the genetic variation found in a sample of homologous genes or DNA regions that have experienced little or no recombination. Gene trees have the potential of straddling the interface between intra- and interspecific evolution. It is precisely at this interface that the process of speciation occurs, and gene trees can therefore be used as a powerful tool to probe this interface. One application is to infer species status. The cohesion species is defined as an evolutionary lineage or set of lineages with genetic exchangeability and/or ecological interchangeability. This species concept can be phrased in terms of null hypotheses that can be tested rigorously and objectively by using gene trees. First, an overlay of geography upon the gene tree is used to test the null hypothesis that the sample is from a single evolutionary lineage. This phase of testing can indicate that the sampled organisms are indeed from a single lineage and therefore a single cohesion species. In other cases, this null hypothesis is not rejected due to a lack of power or inadequate sampling. Alternatively, this null hypothesis can be rejected because two or more lineages are in the sample. The test can identify lineages even when hybridization and lineage sorting occur. Only when this null hypothesis is rejected is there the potential for more than one cohesion species. Although all cohesion species are evolutionary lineages, not all evolutionary lineages are cohesion species. Therefore, if the first null hypothesis is rejected, a second null hypothesis is tested that all lineages are genetically exchangeable and/or ecologically interchangeable. This second test is accomplished by direct contrasts of previously identified lineages or by overlaying reproductive and/or ecological data upon the gene tree and testing for significant transitions that are concordant with the previously identified lineages. Only when this second null hypothesis is rejected is a lineage elevated to the status of cohesion species. By using gene trees in this manner, species can be identified with objective, a priori criteria with an inference procedure that automatically yields much insight into the process of speciation. When one or more of the null hypotheses cannot be rejected, this procedure also provides specific guidance for future work that will be needed to judge species status.


Sexual behavior suppresses the primary antibody response in the golden hamster.
The possibility that sexual behavior triggers neural or endocrine events that influence immune function was explored in male Golden Hamsters (Mesocricetus auratus). Sexually experienced males showed a 62.8 and 64.9% decrease in antibody response to TNP-ovalbumin compared to virgin and sham-mated males, respectively, as measured by ELISA. Antibody deficiency was associated with copulation on the day of immunization and was highly correlated with ejaculatory behavior and the incidence of prolonged intromissions, an indicator of sexual satiety. Although a single sexual encounter was not sufficient to inhibit antibody levels, prolonged intromissions were inversely correlated with titers. Changes in antibody production were not related to plasma levels of cortisol, corticosteroid-binding globulin activity, or testosterone. These results suggest that sexual behavior is immunosuppressive and may play a role in the communicability of sexually transmitted diseases.


Comparative Transcriptome Analysis Reveals Sex-Biased Gene Expression in Juvenile Chinese Mitten Crab Eriocheir sinensis.
Sex-biased genes are considered to account for most of phenotypic differences between males and females. In order to explore the sex-biased gene expression in crab, we performed the whole-body transcriptome analysis in male and female juveniles of the Chinese mitten crab Eriocheir sinensis using next-generation sequencing technology. Of the 23,349 annotated unigenes, 148 were identified as sex-related genes. A total of 29 candidate genes involved in primary sex determination pathways were detected, indicating the sex determination cascade of the mitten crab might be more complex than previously supposed. Differential expression analysis showed 448 differentially expressed genes (DEGs) between the two transcriptomes. Most of DEGs were involved in processes such as metabolism and immunity, and not associated with obvious sexual function. The pathway predominantly enriched for DEGs were related to lysosome, which might reflect the differences in metabolism between males and females. Of the immune DGEs, 18 up-regulated genes in females were humoral immune factors, and eight up-regulated genes in males were pattern recognition receptors, suggesting sex differences of immune defense might exist in the mitten crab. In addition, two reproduction-related genes, vitellogenin and insulin-like androgenic gland factor, were identified to express in both sexes but with significantly higher level in males. Our research provides the first whole-body RNA sequencing of sex-specific transcriptomes for juvenile E. sinensis and will facilitate further studies on molecular mechanisms of crab sexual dimorphism.


Testing models of speciation from genome sequences: divergence and asymmetric admixture in Island South-East Asian Sus species during the Plio-Pleistocene climatic fluctuations.
In many temperate regions, ice ages promoted range contractions into refugia resulting in divergence (and potentially speciation), while warmer periods led to range expansions and hybridization. However, the impact these climatic oscillations had in many parts of the tropics remains elusive. Here, we investigate this issue using genome sequences of three pig (Sus) species, two of which are found on islands of the Sunda-shelf shallow seas in Island South-East Asia (ISEA). A previous study revealed signatures of interspecific admixture between these Sus species (Genome biology, 14, 2013, R107). However, the timing, directionality and extent of this admixture remain unknown. Here, we use a likelihood-based model comparison to more finely resolve this admixture history and test whether it was mediated by humans or occurred naturally. Our analyses suggest that interspecific admixture between Sunda-shelf species was most likely asymmetric and occurred long before the arrival of humans in the region. More precisely, we show that these species diverged during the late Pliocene but around 23% of their genomes have been affected by admixture during the later Pleistocene climatic transition. In addition, we show that our method provides a significant improvement over D-statistics which are uninformative about the direction of admixture.


Embodied remorse: Physical displays of remorse increase positive responses to public apologies, but have negligible effects on forgiveness.
Public apologies struggle to communicate genuineness. Previous studies have shown that, in response to public apologies, perceptions of remorse and levels of forgiveness are often low, while skepticism about motive is high. Furthermore, attempts to reduce mistrust of public apologies by manipulating the verbal component of the message have had limited success. Across 6 studies (combined N = 3,818), we examined whether people respond more positively to public apologies if the apologies are accompanied by nonverbal demonstrations of remorse: operationalized as kneeling (Studies 1 and 6) and crying (Studies 2-5). Overall, embodied remorse had small-to-medium effects on perceived remorse, and through this relationship had reliable effects on perceived likelihood of reoffending, empathy, positive appraisals of the transgressor, and satisfaction with the apology. Positive effects of embodiment emerged regardless of whether transgressions were committed by a collective (Studies 1, 2, and 6) or an individual (Studies 3-5), and were equally strong regardless of whether or not the transgressor issued an apology (Studies 4 and 5). Furthermore, embodied remorse appeared to lie beyond suspicion: if anything, those low in dispositional trust were more positively influenced by embodied remorse than those high in dispositional trust. Despite all these positive effects, embodied remorse did not have a significant effect on forgiveness in any of the studies, and an internal meta-analysis revealed a significant effect that was of negligible size. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Otosclerosis and measles virus - association or causation?
Otosclerosis is a frequent condition which occurs exclusively in the human temporal bone. This peculiar disease affects mainly Caucasians and Indians and may cause conductive, mixed conductive-sensorineural or occasionally merely sensorineural hearing loss. Morphological investigations of the otosclerotic focus show all three phases of a chronic inflammation with bone resorption, formation of new bone and finally eburnation. Various hypotheses about the cause of inflammation were proposed in the past. Immunological reactivity to collagen, the existence of otosclerosis genes (OTSC 1-5) including mutations of the collagen gene 1A1 and 1A2 or a measles virus (MV) infection were suggested. The existence of the MV proteins and RNA within the otosclerotic tissue has been shown by several authors. However, due to mainly technical problems, no further progress to elucidate the role of the virus could be made. Epidemiological studies revealed a dramatic decrease of measles and related diseases such as the subacute sclerosing panencephalitis since the introduction of MV vaccination programs in USA and Europe. Indeed, some surgeons reported decreasing numbers of stapes surgery and a shift towards elder patients. Our epidemiological survey of all patients hospitalized with otosclerosis in Germany between 1993 and 2004 demonstrates a highly significant decrease in otosclerosis among the population vaccinated against the MV. The strong correlation makes it most plausible that the MV is at least one triggering factor for the development of otosclerosis.


[PEP-1 multichannel electronic apparatus for electropuncture].
Pep-1 is a 6-channel apparatus for electropuncture, produced in series. It is intended for the following purposes: determination of acupuncture points (AP) by the contact method; diagnosis of the state of different organs according to the value of assymetric currents having positive or negative polarities; for therapeutic action on APs by constant electrical current with definite polarity and frequency, and by alternating current pulses through epicutaneous electrodes or miniclamps connected with acupuncture needles (electropuncture and electroacupuncture), and finally, for therapeutic effect on APs by microelectrophoresis.


TraitRateProp: a web server for the detection of trait-dependent evolutionary rate shifts in sequence sites.
Understanding species adaptation at the molecular level has been a central goal of evolutionary biology and genomics research. This important task becomes increasingly relevant with the constant rise in both genotypic and phenotypic data availabilities. The TraitRateProp web server offers a unique perspective into this task by allowing the detection of associations between sequence evolution rate and whole-organism phenotypes. By analyzing sequences and phenotypes of extant species in the context of their phylogeny, it identifies sequence sites in a gene/protein whose evolutionary rate is associated with shifts in the phenotype. To this end, it considers alternative histories of whole-organism phenotypic changes, which result in the extant phenotypic states. Its joint likelihood framework that combines models of sequence and phenotype evolution allows testing whether an association between these processes exists. In addition to predicting sequence sites most likely to be associated with the phenotypic trait, the server can optionally integrate structural 3D information. This integration allows a visual detection of trait-associated sequence sites that are juxtapose in 3D space, thereby suggesting a common functional role. We used TraitRateProp to study the shifts in sequence evolution rate of the RPS8 protein upon transitions into heterotrophy in Orchidaceae. TraitRateProp is available at http://traitrate.tau.ac.il/prop.


Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells.
A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K(+) channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (I(hERG1)) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher I(hERG1) density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.


Current Available Computer-Aided Detection Catches Cancer but Requires a Human Operator.
This study intends to show that the current widely used computer-aided detection (CAD) may be helpful, but it is not an adequate replacement for the human input required to interpret mammograms accurately. However, this is not to discredit CAD's ability but to further encourage the adoption of artificial intelligence-based algorithms into the toolset of radiologists. This study will use Hologic (Marlborough, MA, USA) and General Electric (Boston, MA, USA) CAD read images provided by patients found to be Breast Imaging Reporting and Data System (BI-RADS) 6 from 2019 to 2020. In addition, patient information will be pulled from our institution's emergency medical record to confirm the findings seen in the pathologist report and the radiology read. Data from a total of 24 female breast cancer patients from January 31st 2019 to April 31st 2020, was gathered from our institution's emergency medical record with restrictions in patient numbers due to coronavirus disease 2019 (COVID-19). Within our patient population, CAD imaging was shown to be statistically significant in misidentifying breast cancer, while radiologist interpretation still proves to be the most effective tool. Despite a low sample size due to COVID-19, this study found that CAD did have significant difficulty in differentiating benign vs. malignant lesions. CAD should not be ignored, but it is not specific enough. Although CAD often marks cancer, it also marks several areas that are not cancer. CAD is currently best used as an additional tool for the radiologist.


Smoking-related interstitial fibrosis (SRIF) and pulmonary hypertension.
Smoking-related interstitial fibrosis (SRIF) is a relatively new term used to describe chronic interstitial fibrosis that can develop in smokers. The association of SRIF with pulmonary hypertension has not been described. We present a 55-year-old man with an extensive smoking history who presented for evaluation of insidious onset of dyspnoea on exertion and hypoxaemic respiratory failure. Physical examination was unremarkable. Pulmonary function testing demonstrated a marked reduction of the diffusion capacity with no obstruction or restriction. Ventilation perfusion scan showed no evidence of thromboembolic disease. High-resolution chest CT revealed minimal biapical pleural parenchymal scarring and subtle dependent atelectasis. Serological markers for connective tissue diseases were negative. Open lung biopsy was consistent with SRIF. Vascular intimal proliferation consistent with pulmonary hypertension was also noted. Right heart catheterisation yielded mild pulmonary hypertension and treatment was initiated with tadalafil and bosentan.


Decreased expression of Drp1 and Fis1 mediates mitochondrial elongation in senescent cells and enhances resistance to oxidative stress through PINK1.
Mitochondria display different morphologies, depending on cell type and physiological situation. In many senescent cell types, an extensive elongation of mitochondria occurs, implying that the increase of mitochondrial length in senescence could have a functional role. To test this hypothesis, human endothelial cells (HUVECs) were aged in vitro. Young HUVECs had tubular mitochondria, whereas senescent cells were characterized by long interconnected mitochondria. The change in mitochondrial morphology was caused by downregulation of the expression of Fis1 and Drp1, two proteins regulating mitochondrial fission. Targeted photodamage of mitochondria induced the formation of reactive oxygen species (ROS), which triggered mitochondrial fragmentation and loss of membrane potential in young cells, whereas senescent cells proved to be resistant. Alterations of the Fis1 and Drp1 expression levels also influenced the expression of the putative serine-threonine kinase PINK1, which is associated with the PARK6 variant of Parkinson's disease. Downregulation of PINK1 or overexpression of a PINK1 mutant (G309D) increased the sensitivity against ROS in young cells. These results indicate that there is a Drp1- and Fis1-induced, and PINK1-mediated protection mechanism in senescent cells, which, when compromised, could contribute to the age-related progression of Parkinson's disease and arteriosclerosis.


Loss of TDP-43 Inhibits Amyotrophic Lateral Sclerosis-Linked Mutant SOD1 Aggresome Formation in an HDAC6-Dependent Manner.
Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, and progressive neurodegenerative disorder with no cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS; and aggresome formation of misfolded SOD1 is closely associated with ALS pathogenesis. HDAC6, one of the histone deacetylase family members, has already been demonstrated to play an important role in regulating aggresome formation of misfolded proteins and protecting cells against the toxicity induced by misfolded proteins. In this study, we found that in a cellular model with impaired proteasome activity, the TAR DNA-binding protein 43, which is closely linked with ALS and associated with various neurodegenerative disorders such as frontotemporal lobar degeneration, Alzheimer's disease, and Parkinson's disease, can regulate mutant SOD1 aggresome formation through an HDAC6-dependent manner. TDP-43 deficiency did not affect poly-ubiquitination of mutant SOD1, whereas it greatly decreased the expression level of HDAC6, which is required for aggresome formation of ALS-linked mutant SOD1. Moreover, overexpression of siRNA-resistant HDAC6 restored mutant SOD1 aggresome formation in TDP-43-knockdown cells. Thus, our data provide evidence that TDP-43 plays an important role in mutant SOD1 aggresome formation through its regulation of HDAC6.


Comparison between overground and dynamometer manual wheelchair propulsion.
Laboratory-based simulators afford many advantages for studying physiology and biomechanics; however, they may not perfectly mimic wheelchair propulsion over natural surfaces. The goal of this study was to compare kinetic and temporal parameters between propulsion overground on a tile surface and on a dynamometer. Twenty-four experienced manual wheelchair users propelled at a self-selected speed on smooth, level tile and a dynamometer while kinetic data were collected using an instrumented wheel. A Pearson correlation test was used to examine the relationship between propulsion variables obtained on the dynamometer and the overground condition. Ensemble resultant force and moment curves were compared using cross-correlation and qualitative analysis of curve shape. User biomechanics were correlated (R ranging from 0.41 to 0.83) between surfaces. Overall, findings suggest that although the dynamometer does not perfectly emulate overground propulsion, wheelchair users were consistent with the direction and amount of force applied, the time peak force was reached, push angle, and their stroke frequency between conditions.


Longitudinal effects of an antibacterial oral rinse on gingivitis and dental plaque.
The purpose of this study was to determine what effect oral rinse containing alexidine dihydrochloride (Calgon Consumer Products Company, a Subsidiary of Merck & Co.) would have on gingivitis and plaque. Following a dental prophylaxis, 167 male and female, 7-12-year-old students in Puerto Rican elementary school rinsed twice daily for 60 sec. with 10 ml of either a placebo oral rinse or one containing alexidine dihydrochloride. All students brushed their teeth daily in school. Gingivitis and plaque were scored on all buccal and lingual tooth surfaces prior to the prophylaxis and on days 30, 90, and 160. On these dates, blood and urine analysis were also made. A second prophylaxis was given at the end of the study. The adjusted mean gingivitis and plaque scores were compared between the treatment and placebo groups at 30, 90, and 160 days using analysis of covariance. The alexidine dihydrochloride oral rinse was found to reduce significantly gingivitis after 160 days (p less than 0.02) of treatment and plaque scores 30 days (p less than 0.01), 90 days (p less than 0.001), and 160 days (p less than 0.001) after treatment. No blood or urine changes were attributed to the active ingredient oral rinse.


Special concerns in defining, studying, and treating dystonia in children.
Dystonia is movement disorder with many diverse underlying etiologies. Some of those etiologies manifest at specific stages of development or at specific ages. Others may present early in life and evolve as the individual develops. The appearance of symptoms during a time of nervous system development poses special challenges to the neurologist. Normal functions change appearance, dysfunction may manifest in an age-dependent manner, and age-dependent differences in beneficial and toxic effects of treatments all introduce complexities to the process of diagnosis, functional assessment, and therapeutics. Consideration of these developmental differences is essential in assuring a universal definition of dystonia, and for developing valid and reliable assessment tools that can be compared across the lifespan, and more effective therapeutics. © 2013 Movement Disorder Society.


GAIN domain-mediated cleavage is required for activation of G protein-coupled receptor 56 (GPR56) by its natural ligands and a small-molecule agonist.
Adhesion G protein-coupled receptors (aGPCRs) represent a distinct family of GPCRs that regulate several developmental and physiological processes. Most aGPCRs undergo GPCR autoproteolysis-inducing domain-mediated protein cleavage, which produces a cryptic tethered agonist (termed Stachel (stinger)), and cleavage-dependent and -independent aGPCR signaling mechanisms have been described. aGPCR G1 (ADGRG1 or G protein-coupled receptor 56 (GPR56)) has pleiotropic functions in the development of multiple organ systems, which has broad implications for human diseases. To date, two natural GPR56 ligands, collagen III and tissue transglutaminase (TG2), and one small-molecule agonist, 3-α-acetoxydihydrodeoxygedunin (3-α-DOG), have been identified, in addition to a synthetic peptide, P19, that contains seven amino acids of the native Stachel sequence. However, the mechanisms by which these natural and small-molecule agonists signal through GPR56 remain unknown. Here we engineered a noncleavable receptor variant that retains signaling competence via the P19 peptide. We demonstrate that both natural and small-molecule agonists can activate only cleaved GPR56. Interestingly, TG2 required both receptor cleavage and the presence of a matrix protein, laminin, to activate GPR56, whereas collagen III and 3-α-DOG signaled without any cofactors. On the other hand, both TG2/laminin and collagen III activate the receptor by dissociating the N-terminal fragment from its C-terminal fragment, enabling activation by the Stachel sequence, whereas P19 and 3-α-DOG initiate downstream signaling without disengaging the N-terminal fragment from its C-terminal fragment. These findings deepen our understanding of how GPR56 signals via natural ligands, and a small-molecule agonist may be broadly applicable to other aGPCR family members.


Demographic characteristics, presentations and treatment outcome of patients with prolactinoma.
Prolactinomas are the most common type of functional pituitary tumours. The objective of this study was to determine demographic profile of patients with prolactinomas, and to compare the outcomes in patients treated with Cabergoline versus those receiving Bromocriptine treatment. This descriptive study was conducted at Endocrinology Section, Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan. We reviewed the medical record of 68 patients with prolactinoma. Data about demographic characteristics, clinical presentation and treatment were entered on a pre-designed pro forma. Out of the total 68 patients, 36.8% were males and 63.2% were females, with a mean age of 34±10.7 years. The most frequent presenting complaint amongst the patients was of headache, present in 57.4% patients. Galactorrhea, amenorrhea and infertility were next highest reported symptoms. Results of the tumour size on initial MRI showed macroprolactinomas 52.9% (36), microprolactinomas in 33.8% (23), and giant prolactinomas in 13.3 % (9) patients. Decreasing trend of prolactin levels were also seen on follow up visits at 9 months and 12 months. Tumour size was decreased in 48.53% (33) patients and lesion completely disappeared in 16.18% (11) patients after 6 months of treatment and also almost similar trend in tumour size change was seen after one year. There was no significant difference between the two drugs in bringing prolactin to, normal range at each follow up duration. Most of the prolactinoma patients were females and the common the most frequent presenting complaint was headache. The decreasing trend of serum prolactin and tumour size reduction in patients was noted, suggesting the beneficial impact of medical therapy as it is the first line treatment modality in these patients.


[Reasons for an intercultural perspective of bioethics].
Bioethics must have an intercultural perspective. This is based on three facts: The principles and values around which reflection is made are related to world views and traditions, human beings are cultural beings, and current societies are considerably diverse. Based on this, bioethics will seek an adequate balance between ethical universalism and contextualism. This is a fundamental step for unconditional respect for human dignity and mutual recognition, dialogue, correlation and complementarity among diverse cultures.


Electrically guided versus imaging-guided implant of the left ventricular lead in cardiac resynchronization therapy: a study protocol for a double-blinded randomized controlled clinical trial (ElectroCRT).
Cardiac resynchronization therapy (CRT) is an established treatment in patients with heart failure and prolonged QRS duration where a biventricular pacemaker is implanted to achieve faster activation and more synchronous contraction of the left ventricle (LV). Despite the convincing effect of CRT, 30-40% of patients do not respond. Among the most important correctable causes of non-response to CRT is non-optimal LV lead position. We will enroll 122 patients in this patient-blinded and assessor-blinded, randomized, clinical trial aiming to investigate if implanting the LV lead guided by electrical mapping towards the latest LV activation as compared with imaging-guided implantation, causes an excess increase in left ventricular (LV) ejection fraction (LVEF). The patients are randomly assigned to either the intervention group: preceded by cardiac computed tomography of the cardiac venous anatomy, the LV lead is placed according to the latest LV activation in the coronary sinus (CS) branches identified by systematic electrical mapping of the CS at implantation and post-implant optimization of the interventricular pacing delay; or patients are assigned to the control group: placement of the LV lead guided by cardiac imaging. The LV lead is targeted towards the latest mechanical LV activation as identified by echocardiography and outside myocardial scar as identified by myocardial perfusion (MP) imaging. The primary endpoint is change in LVEF at 6-month follow up (6MFU) as compared with baseline measured by two-dimensional echocardiography. Secondary endpoints include relative percentage reduction in LV end-systolic volume, all-cause mortality, hospitalization for heart failure, and a clinical combined endpoint of response to CRT at 6MFU defined as the patient being alive, not hospitalized for heart failure, and experiencing improvement in NYHA functional class or/and > 10% increase in 6-minute walk test. We assume an absolute increase in LVEF of 12% in the intervention group versus 8% in the control group. If an excess increase in LVEF can be achieved by LV lead implantation guided by electrical mapping, this study supports the conduct of larger trials investigating the impact of this strategy for LV-lead implantation on clinical outcomes in patients treated with CRT. ClinicalTrials.gov, NCT02346097 . Registered on 12 January 2015. Patients were enrolled between 16 February 2015 and 13 December 2017.


[Electromyographic characteristics of recovery of motor function in patients with lesions of the cervical division of the spinal cord].
Electromyographic examination used for determining spontaneous activity of the muscles in patients with an injury at the level of C3-C6 showed that at the first stage the most significant sign was the presence of at least weak activity in the muscles of the lower extremities. This was usually a precursor of the successful restoration of motor functions and indicated the smallest volume of the injury and the absence of complications. At the later stages of treatment of these patients EMG revealed considerable activity in all major muscle groups ensuring walking and the maximum independence of the patient.


Exploring experiences of infertility amongst women and men in low-income and middle-income countries: protocol for a qualitative systematic review.
Infertility is increasingly recognised as a global public health issue for women and men that merits further investigation to support policy and programming. While research in high-income settings has examined the consequences of infertility and access to services, there has been limited synthesis of how individuals experience infertility in low-income and middle-income countries (LMICs). This protocol describes a systematic review that will synthesise qualitative evidence on experiences of infertility among women and men in LMICs. The review will follow the Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) guidelines for reporting on qualitative evidence syntheses. The study team will search for published literature in PubMed, CINAHL and Scopus and PsycINFO databases and review available grey literature. Using Covidence software, two independent reviewers will conduct title and abstract screening based on inclusion and exclusion criteria, followed by full-text reviews and extraction by a larger team. Quality will be appraised using an adapted version of the Critical Appraisal Skills Programme guidelines. We will conduct thematic synthesis to characterise individual experiences and related factors at the individual, interpersonal, community and health system levels. We will develop a conceptual framework to describe evidence on experiences of infertility in LMICs and to help inform interventions across settings. This protocol has been internally approved as exempt by the Institutional Review Board of the Population Council, as it does not involve contact with human subjects or personally identifying data. Results of the review will be published in a peer-reviewed journal and will be used to inform future infertility research and programming in LMICs. CRD42021227742.


Heart failure in African Americans: unique etiology and pharmacologic treatment responses.
After reading the article, "Heart Failure in African Americans: Unique Etiology and Pharmacologic Treatment Responses," the learner should be able to complete the following quiz and evaluation questions.Accredidation:NMA is accredited by the Accredidation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. NMA designates this continuing medical education activity for one credit hour in category one of the Physician's Recognition Award of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. The Journal of the National Medical Association (JNMA) has been approved by the American Academy of Family Physicians (AAFP) as having educational content acceptable for five prescribed credit hours. This article has been approved for one credit hour. Term of approval is from January 1, 2003, through December 31, 2003. Credit may be claimed for one year from date of individual use.Expiration:The quiz must be completed, postmarked and mailed by Feb. 25, 2003, for eligibility to receive continuing medical education credit for this CME activity.


Reduction of multidrug-resistant and drug-susceptible Salmonella in ground beef and freshly harvested beef briskets after exposure to commonly used industry antimicrobial interventions.
Two separate studies were conducted to examine the differences in survivability of multidrug-resistant (MDR) and drug-susceptible Salmonella in fresh meats in a simulated industry environment. Beef trim from a commercial facility was inoculated with either MDR (AmpC phenotype) or drug-susceptible Salmonella (SUS) cocktails (10(6) CFU/ml). Antimicrobial interventions included 3% lactic acid (LA), 1,000 ppm of acidified sodium chloride (ASC), ambient water (AW), and an inoculated control with no intervention (CTRL). Each aliquot was ground and formed into patties and packaged using high-O(2) modified atmosphere packaging. Samples for microbiological evaluation were collected on days 0, 7, 10, and 14. In the second study, beef briskets were collected immediately after harvest. Inoculation and antimicrobial application were the same, except treatments were heated and there was an additional hot water treatment. All beef briskets were refrigerated, and samples were collected at 0, 6, and 24 h. For the first study, the overall effectiveness of the treatments (from most effective to least effective) was LA, ASC, CTRL, and AW. Significant differences were observed only between MDR and SUS Salmonella when AW was applied (P = 0.02), and bacterial loads with AW were significantly greater (P < 0.01) for MDR Salmonella. In the second study, the intervention effectiveness ranked LA, ASC, hot water, AW, and CTRL. Significant differences between MDR and SUS Salmonella levels were not detected for any intervention or sampling time point. These data indicate that MDR and SUS variants of Salmonella behave similarly in response to the antagonistic action of antimicrobials commonly used in beef facilities.


Efficacy of neoadjuvant chemoradiotherapy in resectable esophageal squamous cell carcinoma--a single institutional study.
A prospective phase II study of neoadjuvant chemoradiotherapy (CRT) for resectable esophageal squamous cell carcinoma was conducted from May 1993 to March 1996. A total of 88 patients fitted the eligibility criteria and were treated with two courses of induction chemotherapy (cisplatin 60 mg/m2/day on day 1 and 5-fluorouracil (5-FU) 1000 mg/m2/day on days 2-6) with concurrent hyperfractionated radiotherapy (48 Gy/40 fractions/4 weeks) followed by esophagectomy or definitive CRT comprising 4 cycles of cisplatin/5-FU and hyperfractionated radiotherapy (additional 12 Gy) with intracavitary brachytherapy (9 Gy). Clinical response and downstaging were achieved in 83% and 42% of the patients, respectively. With a median follow-up of 77 months, median survival time was 18 months with a 5-year survival rate of 23%. The clinical responses to CRT and surgery were independent prognostic factors for overall survival. Among the intended surgery group (n = 52), 41 (79%) patients underwent surgery and 36 had a resection with a pathologic complete response rate of 43%. When compared with a matched historical control (n = 40), there was a significant survival benefit in the multimodality arm (p = 0.04). This multimodality therapy was feasible and its efficacy was promising, especially when surgical resection was performed. The therapeutic benefit of neoadjuvant CRT remains to be assessed in large well-designed randomized trials, one of which is ongoing at our institution.


Ca2+ release from platelet intracellular stores by thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone: relationship to Ca2+ pools and relevance in platelet activation.
The effects of the Ca(2+)-ATPase inhibitors thapsigargin (Tg) and 2,5-di-(t-butyl)-1,4-benzohydroquinone (tBuBHQ) were examined by using Ca(2+)-regulatory systems of platelet mixed membranes, saponin-permeabilized and intact platelets. Both agents inhibit Ca(2+)-ATPase activities of platelet mixed membranes, without any effect on the basal Mg(2+)-ATPase activity. Tg is more effective (EC50 = 35 nM) than tBuBHQ (EC50 = 580 nM). The effect of the two inhibitors on 45Ca2+ release from saponin-permeabilized platelets has also been characterized. 45Ca2+ uptake into non-mitochondrial intracellular stores occurs via an ATP-dependent mechanism, and if added at equilibrium the second messenger Ins(1,4,5)P3 releases 50% of the accumulated 45Ca2+. Maximally effective concentrations of Tg (1 microM) and tBuBHQ (50 microM) release 77% and 68% of the accumulated 45Ca2+. Addition of Ins(1,4,5)P3 together with either Tg or tBuBHQ resulted in a non-additive release which was the same as with either Tg or tBuBHQ alone, indicating that the Ins(1,4,5)P3-sensitive Ca2+ pool was a subset of the pool that is sensitive to the Ca(2+)-ATPase inhibitors. Release of 45Ca2+ by either Tg or tBuBHQ was not affected by heparin, which totally blocked Ins(1,4,5)P3-induced Ca2+ release, and Tg was found not to affect [32P]Ins(1,4,5)P3 binding to its receptor on mixed membranes. Thus both Tg and tBuBHQ release Ca2+ from a pool that totally overlaps the Ins(1,4,5)P3-sensitive pool without affecting Ins(1,4,5)P3 function. In intact indomethacin-treated Fura 2-loaded platelets, Tg and tBuBHQ cause Ca2+ elevation, arising from release from intracellular stores and influx from the outside. Both Tg and tBuBHQ elevated Ca2+ to similar levels, which were less and slower than those observed with thrombin. Addition of thrombin to cells already treated with Tg or tBuBHQ produced further elevation of Ca2+, indicating agonist utilization of a Ca(2+)-ATPase inhibitor-insensitive pool. In aggregation experiments Tg and tBuBHQ showed different functional effects. In indomethacin-treated cells Tg induces slow aggregation and secretion responses, whereas tBuBHQ only induces shape change. Both agents show synergistic secretory responses with the protein kinase C activator dioctanoylglycerol (DiC8). Tg also showed greater ability than tBuBHQ to release [3H]arachidonic acid (AA) from [3H]AA-labelled platelets. Additionally, in [32P]Pi-labelled platelets both Tg and tBuBHQ induced phosphorylation of myosin light chain, a 27 kDa protein and the 45 kDa protein pleckstrin, but Tg showed a greater ability than tBuBHQ to cause phosphorylation of pleckstrin. These studies indicate that Tg and tBuBHQ are effective in releasing the Ins(1,4,5)P3-sensitive Ca2+ pool in platelets.(ABSTRACT TRUNCATED AT 400 WORDS)


Comparing cost and print time estimates for six commercially-available 3D printers obtained through slicing software for clinically relevant anatomical models.
3D printed patient-specific anatomical models have been applied clinically to orthopaedic care for surgical planning and patient education. The estimated cost and print time per model for 3D printers have not yet been compared with clinically representative models across multiple printing technologies. This study investigates six commercially-available 3D printers: Prusa i3 MK3S, Formlabs Form 2, Formlabs Form 3, LulzBot TAZ 6, Stratasys F370, and Stratasys J750 Digital Anatomy. Seven representative orthopaedic standard tessellation models derived from CT scans were imported into the respective slicing software for each 3D printer. For each printer and corresponding print setting, the slicing software provides a print time and material use estimate. Material quantity was used to calculate estimated model cost. Print settings investigated were infill percentage, layer height, and model orientation on the print bed. The slicing software investigated are Cura LulzBot Edition 3.6.20, GrabCAD Print 1.43, PreForm 3.4.6, and PrusaSlicer 2.2.0. The effect of changing infill between 15% and 20% on estimated print time and material use was negligible. Orientation of the model has considerable impact on time and cost with worst-case differences being as much as 39.30% added print time and 34.56% added costs. Averaged across all investigated settings, horizontal model orientation on the print bed minimizes estimated print time for all 3D printers, while vertical model orientation minimizes cost with the exception of Stratasys J750 Digital Anatomy, in which horizontal orientation also minimized cost. Decreasing layer height for all investigated printers increased estimated print time and decreased estimated cost with the exception of Stratasys F370, in which cost increased. The difference in material cost was two orders of magnitude between the least and most-expensive printers. The difference in build rate (cm3/min) was one order of magnitude between the fastest and slowest printers. All investigated 3D printers in this study have the potential for clinical utility. Print time and print cost are dependent on orientation of anatomy and the printers and settings selected. Cost-effective clinical 3D printing of anatomic models should consider an appropriate printer for the complexity of the anatomy and the experience of the printer technicians.


Long-term efficacy and safety of 12 months of valganciclovir prophylaxis compared with 3 months after lung transplantation: a single-center, long-term follow-up analysis from a randomized, controlled cytomegalovirus prevention trial.
The optimal approach to cytomegalovirus (CMV) prevention after lung transplantation is controversial. We recently completed a prospective, randomized, placebo-controlled study of CMV prevention in lung transplantation that demonstrated the short-term efficacy and safety of extending valganciclovir prophylaxis to 12 months vs 3 months of therapy. In the current analysis, we monitored a single-center subset of patients enrolled in the CMV prevention trial to determine if extended prophylaxis conferred a sustained long-term benefit and to assess its hematologic safety. The sub-analysis included 38 randomized patients from Duke University Medical Center. All patients underwent consistent serial serum CMV monitoring and surveillance bronchoscopies. CMV was defined by viremia (≥ 500 CMV DNA copies/ml) or pneumonitis. The safety assessment included a review of all complete blood counts obtained from transplant onward. During a mean follow-up of 3.9 years in each group, extended-course compared with short-course prophylaxis provided a sustained protective benefit with a lifetime CMV incidence of 12% vs 55%, respectively (hazard ratio, 0.13; 95% confidence interval, 0.03-0.61; p = 0.009), an effect that persisted after adjustment for clinical risk factors. Patients in each group underwent a comparable number of peripheral blood draws and bronchoscopies. Post-transplant white blood cell, neutrophil, and platelet counts were similar between each treatment group during the course of follow-up. Extending valganciclovir prophylaxis to 12 months provides a durable long-term CMV protective benefit compared with short-course therapy, without increasing adverse hematologic effects.


Impact of putamen inhibition by DREADDs on schedule-induced drinking in rhesus monkeys.
The putamen is a nucleus within the sensory-motor striatal network that is involved in automatic, habitual actions. Schedule-induced polydipsia (SIP) is highly automated behavior, reliably occurring under intermediate interval schedules of reinforcement. The effect of putamen inhibition in mediating SIP of water and ethanol (4% w/v) under a Fixed Time 5-min (FT-5 min) schedule for food delivery was tested in 12 rhesus monkeys (6 male, 6 female). Water and ethanol SIP sessions ended after set volumes were consumed. Baseline patterns of SIP intake differed between water and ethanol SIP in volume but not in pattern of drinking. Activation of the designer receptor exclusively activated by designer drug (DREADD: hM4Di) with deschloroclozapine (DCZ; 300 μg/kg, i.m.) administered 30 min prior to the onset of the SIP session, for four consecutive sessions. DCZ administration increased the postpellet drink volume and reduced the time to drink both water and ethanol. Although the effect of DCZ treatment was similar for increasing SIP with either water or ethanol, post-DCZ return to baseline SIP rates of differed, perhaps highlighting the effect of a state dependency with ethanol SIP. Overall, the study shows that targeting the putamen with the inhibitory DREADD produces a reversible, reproducible and reliable increase in adjunctive drinking.


Vitamin K Deficiency in the Setting of Blenderized Tube Feeding Regimen in a Teenager: A Case Report.
Vitamin K acts a cofactor for the gamma-carboxylation of several proteins in the coagulation cascade. The clinical spectrum of vitamin K deficiency (VKD) can be asymptomatic to a significant bleeding. VKD is classically seen in newborns. However, this can manifest later in patients with risks such as sub-optimal nutrition, fat malabsorption, medications including antibiotics. A 17-year-old male with spinal muscular atrophy (SMA) Type 1, tracheostomy with ventilator dependent, gastrostomy tube feeding was seen by the gastroenterologist following treatment for small intestinal bacterial overgrowth (SIBO). Investigations showed coagulopathy following which he was transferred to the Pediatric ICU. Labs revealed prothrombin time (PT) 114 s [Normal 9.4-12.5 s], INR (International normalized ratio) 12.6 [Normal < 1.1] and partial thromboplastin time (PTT) 90 s [Normal 25.1-36.5 s]. Mixing studies and coagulation assays were consistent with VKD (low Factor VII and Factor IX with normal Factor V). His home blenderized feeding regimen met the caloric requirement but not the adequate intake (AI) values for vitamin K and other minerals. He received intravenous vitamin K (phytonadione) for five consecutive days with resolution of the coagulopathy (PT 13.2 s, PTT 37.1 s, INR 1.2). The patient was discharged on enteral vitamin K and additional supplements following dietary review by a nutritionist. Clinicians should be cognizant of VKD in patients on blenderized tube feeds which may not meet the adequate intake (AI) goals. In patients who are not receiving nutritionally complete formulas or receiving inadequate volumes, it is important to monitor macro and micronutrients.


A practical guide to social networks.
Saying that networks are important is stating the obvious. But harnessing the power of these seemingly invisible groups to achieve organizational goals is an elusive undertaking. Most efforts to promote collaboration are haphazard and built on the implicit philosophy that more connectivity is better. In truth, networks create relational demands that sap people's time and energy and can bog down entire organizations. It's crucial for executives to learn how to promote connectivity only where it benefits an organization or individual and to decrease unnecessary connections. In this article, the authors introduce three types of social networks, each of which delivers unique value. The customized response network excels at framing the ambiguous problems involved in innovation. Strategy consulting firms and new-product development groups rely on this format. By contrast, surgical teams and law firms rely mostly on the modular response network, which works best when components of the problem are known but the sequence of those components in the solution is unknown. And the routine response network is best suited for organizations like call centers, where the problems and solutions are fairly predictable but collaboration is still needed. Executives shouldn't simply hope that collaboration will spontaneously occur in the right places atthe right times in their organization. They need to develop a strategic, nuanced view of collaboration, and they must take steps to ensure that their companies support the types of social networks that best fit their goals. Drawing on examples from Novartis, the FAA, and Sallie Mae, the authors offer managers the tools they need to determine which network will deliver the best results for their organizations and which strategic investments will nurture the right degree of connectivity.


The Impact of a Soiled Airway on Intubation Success in the Emergency Department When Using the GlideScope or the Direct Laryngoscope.
The objective was to determine the impact of a soiled airway on firstpass success when using the GlideScope video laryngoscope or the direct laryngoscope for intubation in the emergency department (ED). Data were prospectively collected on all patients intubated in an academic ED from July 1, 2007, to June 30, 2016. Patients ≥ 18 years of age, who underwent rapid sequence intubation by an emergency medicine resident with the GlideScope or the direct laryngoscope, were included in the analysis. Data were stratified by device used (GlideScope or direct laryngoscope). The primary outcome was firstpass success. Patients were categorized as those without blood or vomitus (CLEAN) and those with blood or vomitus (SOILED) in their airway. Multivariate regression models were developed to control for confounders. When using the GlideScope, the firstpass success was lower in the SOILED group (249/306; 81.4%) than the in CLEAN group (586/644, 91.0%; difference = 9.6%; 95% confidence interval [CI] = 4.7%-14.5%). Similarly, when using the direct laryngoscope, the firstpass success was lower in the SOILED group (186/284, 65.5%) than in the CLEAN group (569/751, 75.8%; difference = 10.3%; 95% CI = 4.0%-16.6%). The SOILED airway was associated with a decreased firstpass success in both the GlideScope cohort (adjusted odds ratio [aOR] = 0.4; 95% CI = 0.3-0.7) and the direct laryngoscope cohort (aOR = 0.6; 95% CI = 0.5-0.8). Soiling of the airway was associated with a reduced firstpass success during emergency intubation, and this reduction occurred to a similar degree whether using either the GlideScope or the direct laryngoscope.