Insecticidal activity of a basement membrane-degrading protease against Heliothis virescens (Fabricius) and Acyrthosiphon pisum (Harris)

ScathL is a cathepsin L-like cysteine protease derived from the flesh fly Sarcophaga peregrina that functions in basement membrane (BM) remodeling during insect development. A recombinant baculovirus expressing ScathL (AcMLF9.ScathL) kills larvae of the tobacco budworm, Heliothis virescens, significantly faster than the wild-type virus. Here, we show that the occurrence of larval melanization prior to death was closely associated with the onset of high cysteine protease activity of ScathL in the hemolymph of fifth instars infected with AcMLF9.ScathL, but not with AcMLF9.ScathL.C146A, a recombinant baculovirus expressing a catalytic site mutant of ScathL. Fragmented fat body, ruptured gut and malpighian tubules, and melanized tracheae were observed in AcMLF9.ScathL-infected larvae. Phenoloxidase activity in hemolymph was unchanged, but the pool of prophenoloxidase was significantly reduced in virus-infected larvae and further reduced in AcMLF9.ScathL-infected larvae. The median lethal dose (LD50) for purified ScathL injected into fifth-instar H. virescens was 11.0 μg/larva. ScathL was also lethal to adult pea aphids, Acyrthosiphon pisumwith a similar loss of integrity of the gut and fat body. Injection with purified ScathL.C146A or bovine trypsin at 20 μg/larva did not produce any effect in either insect. These results illustrate the potent insecticidal effects of ScathL cysteine protease activity and the potential for use of ScathL in development of insect resistant transgenic plants when combined with an appropriate delivery system

Identifying systems failures in the pathway to a catastrophic event: an analysis of national incident report data relating to vinca alkaloids.

BACKGROUND: Catastrophic errors in healthcare are rare, yet the consequences are so serious that where possible, special procedures are put in place to prevent them. As systems become safer, it becomes progressively more difficult to detect the remaining vulnerabilities. Using inadvertent intrathecal administration of vinca alkaloids as an example, we investigated whether analysis of incident report data describing low-harm events could bridge this gap. METHODS: We studied nine million patient safety incidents reported from England and Wales between November 2003 and May 2013. We searched for reports relating to administration of vinca alkaloids in patients also receiving intrathecal medication, and classified the failures identified against steps in the relevant national protocol. RESULTS: Of 38 reports that met our inclusion criteria, none resulted in actual harm. The stage of the medication process most commonly involved was 'supply, transport and storage' (15 cases). Seven cases related to dispensing, six to documentation, and four each to prescribing and administration. Defences most commonly breached related to separation of intravenous vinca alkaloids and intrathecal medication in timing (n=16) and location (n=8); potential for confusion due to inadequate separation of these drugs therefore remains. Problems involved in six cases did not align with the procedural defences in place, some of which represented major hazards. CONCLUSIONS: We identified areas of concern even within the context of a highly controlled standardised national process. If incident reporting systems include and encourage reports of no-harm incidents in addition to actual patient harm, they can facilitate monitoring the resilience of healthcare processes. Patient safety incidents that produce the most serious harm are often rare, and it is difficult to know whether patients are adequately protected. Our approach provides a potential solution

Retrospective descriptive assessment of clinical decision support medication-related alerts in two Saudi Arabian hospitals

OBJECTIVES: To determine the frequency of clinical decision support system (CDSS) medication-related alerts generated, accepted, or overridden, to assess appropriateness of alert display and overrides, and to characterise the documentation of clinician justification for these overrides in an academic medical centre in Saudi Arabia. MATERIALS AND METHODS: System-generated CDSS reports for the period June 2015 to December 2017 were retrospectively reviewed and analysed. Alerts were classified into different types, and rates of alert overrides calculated as percentages of all generated alerts. A subset of 307 overridden alerts was assessed for appropriateness of display and override by two clinical pharmacists. Physician documentation of reasons for overriding alerts were categorised. RESULTS: A total of 4,446,730 medication-related alerts were generated from both inpatient and outpatient settings, and 4,231,743 (95.2%) were overridden. The most common alert type was 'duplicate drug', accounting for 3,549,736 (79.8%) of alerts. Of 307 alerts assessed for appropriateness, 246 (80%) were judged to be appropriately displayed and 244 (79%) were overridden appropriately. New drug allergy and drug allergy alerts had the highest percentage of being judged as inappropriately overridden. For 1,594,313 alerts (37.7%), 'no overridden reason selected' was chosen from the drop-down menu. CONCLUSIONS: The alert generation and override rate were higher than reported previously in the literature. The small sample size of 307 alerts assessed for appropriateness of alert display and override is a potential limitation. Revision of the CDSS rules for alerts (focusing on specificity and relevance for the local context) is now recommended. Future research should prospectively assess providers' perspectives, and determine patient harm associated with overridden alerts

Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs

Background: Mammalian transcriptomes contain thousands of long noncoding RNAs (lncRNAs). Some lncRNAs originate from intragenic enhancers which, when active, behave as alternative promoters producing transcripts that are processed using the canonical signals of their host gene. We have followed up this observation by analyzing intergenic lncRNAs to determine the extent to which they might also originate from intergenic enhancers. Results: We integrated high-resolution maps of transcriptional initiation and transcription to annotate a conservative set of intergenic lncRNAs expressed in mouse erythroblasts. We subclassified intergenic lncRNAs according to chromatin status at transcriptional initiation regions, defined by relative levels of histone H3K4 mono- and trimethylation. These transcripts are almost evenly divided between those arising from enhancer-associated (elncRNA) or promoter-associated (plncRNA) elements. These two classes of 5′ capped and polyadenylated RNA transcripts are indistinguishable with regard to their length, number of exons or transcriptional orientation relative to their closest neighboring gene. Nevertheless, elncRNAs are more tissue-restricted, less highly expressed and less well conserved during evolution. Of considerable interest, we found that expression of elncRNAs, but not plncRNAs, is associated with enhanced expression of neighboring protein-coding genes during erythropoiesis. Conclusions: We have determined globally the sites of initiation of intergenic lncRNAs in erythroid cells, allowing us to distinguish two similarly abundant classes of transcripts. Different correlations between the levels of elncRNAs, plncRNAs and expression of neighboring genes suggest that functional lncRNAs from the two classes may play contrasting roles in regulating the transcript abundance of local or distal loci

Self Reported Incidence and Morbidity of Acute Respiratory Illness among Deployed U.S. Military in Iraq and Afghanistan

BACKGROUND: Historically, respiratory infections have had a significant impact on U.S. military missions. Deployed troops are particularly at high risk due to close living conditions, stressful work environments and increased exposure to pathogens. To date, there are limited data available on acute respiratory illness (ARI) among troops deployed in support of ongoing military operations, specifically Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). METHODS: Using self-report data from two sources collected from troops deployed to Iraq, Afghanistan and the surrounding region, we analyzed incidence and risk factors for ARI. Military personnel on mid-deployment Rest & Recuperation (R&R) or during redeployment were eligible to participate in the voluntary self-report survey. RESULTS: Overall, 39.5% reported having at least one ARI. Of these, 18.5% sought medical care and 33.8% reported having decreased job performance. The rate of self-reported ARI was 15 episodes per 100 person-months among those taking the voluntary survey, and 24.7 episodes per 100 person-months among those taking the clinic health questionnaire. Negative binomial regression analysis found female sex, Navy branch of service and lack of flush toilets to be independently associated with increased rates of ARI. Deployment to OIF, increasing age and higher rank were also positively associated with ARI risk. CONCLUSIONS: The overall percentage of deployed military personnel reporting at least one acute respiratory illness decreased since earlier parts of OIF/OEF. However, the reported effect on job performance increased tremendously. The most important factors associated with increased respiratory infection are female sex, Navy branch of service, lack of improved latrine facilities, deployment to OIF, increasing age and higher rank

Blue-light-receptive cryptochrome is expressed in a sponge eye lacking neurons and opsin

Many larval sponges possess pigment ring eyes that apparently mediate phototactic swimming. Yet sponges are not known to possess nervous systems or opsin genes, so the unknown molecular components of sponge phototaxis must differ fundamentally from those in other animals, inspiring questions about how this sensory system functions. Here we present molecular and biochemical data on cryptochrome, a candidate gene for functional involvement in sponge pigment ring eyes. We report that Amphimedon queenslandica, a demosponge, possesses two cryptochrome/photolyase genes, Aq-Cry1 and Aq-Cry2. The mRNA of one gene (Aq-Cry2) is expressed in situ at the pigment ring eye. Additionally, we report that Aq-Cry2 lacks photolyase activity and contains a flavin-based co-factor that is responsive to wavelengths of light that also mediate larval photic behavior. These results suggest that Aq-Cry2 may act in the aneural, opsin-less phototaxic behavior of a sponge

Missing Clinical Information in NHS hospital outpatient clinics: prevalence, causes and effects on patient care

In Britain over 39,000 reports were received by the National Patient Safety Agency relating to failures in documentation in 2007 and the UK Health Services Journal estimated in 2008 that over a million hospital outpatient visits each year might take place without the full record available. Despite these high numbers, the impact of missing clinical information has not been investigated for hospital outpatients in the UK.Studies in primary care in the USA have found 13.6% of patient consultations have missing clinical information, with this adversely affecting care in about half of cases, and in Australia 1.8% of medical errors were found to be due to the unavailability of clinical information.Our objectives were to assess the frequency, nature and potential impact on patient care of missing clinical information in NHS hospital outpatients and to assess the principal causes. This is the first study to present such figures for the UK and the first to look at how clinicians respond, including the associated impact on patient care

Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis

Prevention of childhood poisoning in the home: overview of systematic reviews and a systematic review of primary studies

Unintentional poisoning is a significant child public health problem. This systematic overview of reviews, supplemented with a systematic review of recently published primary studies synthesizes evidence on non-legislative interventions to reduce childhood poisonings in the home with particular reference to interventions that could be implemented by Children's Centres in England or community health or social care services in other high income countries. Thirteen systematic reviews, two meta-analyses and 47 primary studies were identified. The interventions most commonly comprised education, provision of cupboard/drawer locks, and poison control centre (PCC) number stickers. Meta-analyses and primary studies provided evidence that interventions improved poison prevention practices. Twenty eight per cent of studies reporting safe medicine storage (OR from meta-analysis 1.57, 95% CI 1.22–2.02), 23% reporting safe storage of other products (OR from meta-analysis 1.63, 95% CI 1.22–2.17) and 46% reporting availability of PCC numbers (OR from meta-analysis 3.67, 95% CI 1.84–7.33) demonstrated significant effects favouring the intervention group. There was a lack of evidence that interventions reduced poisoning rates. Parents should be provided with poison prevention education, cupboard/drawer locks and emergency contact numbers to use in the event of a poisoning. Further research is required to determine whether improving poison prevention practices reduces poisoning rates