The Effects of Three Fixed Ratio Schedules of Reinforcement on Stimulus Generalization

The effects of three different schedules of reinforcement on generalization in rats were investigated. The rats were trained to bar press in the presence of a 2000 hz tone and then participated in tone/no tone discrimination training. Upon completion of discrimination training, the rats were assigned randomly to one of three groups, a FR 10 group, a FR 25 group or a FR 50 group. After seven days on these schedules, generalization testing was started. Six days of generalization testing were done with a 31.5 minute tape of 7 tones in a random sequence. The tones for which the subjects\u27 responses were recorded were: 250 hz, 500 hz. 1000 hz, 2000 hz, 4000 hz, 8000 hz and 16000 hz. The FR 10 group produced the only generalization gradient around the training frequency. The FR 25 and FR 50 groups had their gradients centered about the 1000 hz tone. Generalization gradients were steepest earlier in generalization testing and were flatter as the extinction condition continued. The larger the ratio of the reinforcement schedule the faster the gradients flattened. Thus if the FR schedule is of larger ratio, generalization is evident immediately. The results also indicate that as the density of reinforcement decreases, generalization increases greatly

Indication Alerts Intercept Drug Name Confusion Errors during Computerized Entry of Medication Orders

Background: Confusion between similar drug names is a common cause of potentially harmful medication errors. Interventions to prevent these errors at the point of prescribing have had limited success. The purpose of this study is to measure whether indication alerts at the time of computerized physician order entry (CPOE) can intercept drug name confusion errors. Methods and Findings: A retrospective observational study of alerts provided to prescribers in a public, tertiary hospital and ambulatory practice with medication orders placed using CPOE. Consecutive patients seen from April 2006 through February 2012 were eligible if a clinician received an indication alert during ordering. A total of 54,499 unique patients were included. The computerized decision support system prompted prescribers to enter indications when certain medications were ordered without a coded indication in the electronic problem list. Alerts required prescribers either to ignore them by clicking OK, to place a problem in the problem list, or to cancel the order. Main outcome was the proportion of indication alerts resulting in the interception of drug name confusion errors. Error interception was determined using an algorithm to identify instances in which an alert triggered, the initial medication order was not completed, and the same prescriber ordered a similar-sounding medication on the same patient within 5 minutes. Similarity was defined using standard text similarity measures. Two clinicians performed chart review of all cases to determine whether the first, non-completed medication order had a documented or non-documented, plausible indication for use. If either reviewer found a plausible indication, the case was not considered an error. We analyzed 127,458 alerts and identified 176 intercepted drug name confusion errors, an interception rate of 0.14±.01%. Conclusions: Indication alerts intercepted 1.4 drug name confusion errors per 1000 alerts. Institutions with CPOE should consider using indication prompts to intercept drug name confusion errors

HIV-1 subtype C envelope characteristics associated with divergent rates of chronic disease progression

<p>Abstract</p> <p>Background</p> <p>HIV-1 envelope diversity remains a significant challenge for the development of an efficacious vaccine. The evolutionary forces that shape the diversity of envelope are incompletely understood. HIV-1 subtype C envelope in particular shows significant differences and unique characteristics compared to its subtype B counterpart. Here we applied the single genome sequencing strategy of plasma derived virus from a cohort of therapy naïve chronically infected individuals in order to study diversity, divergence patterns and envelope characteristics across the entire HIV-1 subtype C gp160 in 4 slow progressors and 4 progressors over an average of 19.5 months.</p> <p>Results</p> <p>Sequence analysis indicated that intra-patient nucleotide diversity within the entire envelope was higher in slow progressors, but did not reach statistical significance (p = 0.07). However, intra-patient nucleotide diversity was significantly higher in slow progressors compared to progressors in the C2 (p = 0.0006), V3 (p = 0.01) and C3 (p = 0.005) regions. Increased amino acid length and fewer potential N-linked glycosylation sites (PNGs) were observed in the V1-V4 in slow progressors compared to progressors (p = 0.009 and p = 0.02 respectively). Similarly, gp41 in the progressors was significantly longer and had fewer PNGs compared to slow progressors (p = 0.02 and p = 0.02 respectively). Positive selection hotspots mapped mainly to V1, C3, V4, C4 and gp41 in slow progressors, whereas hotspots mapped mainly to gp41 in progressors. Signature consensus sequence differences between the groups occurred mainly in gp41.</p> <p>Conclusions</p> <p>These data suggest that separate regions of envelope are under differential selective forces, and that envelope evolution differs based on disease course. Differences between slow progressors and progressors may reflect differences in immunological pressure and immune evasion mechanisms. These data also indicate that the pattern of envelope evolution is an important correlate of disease progression in chronic HIV-1 subtype C infection.</p

Tuberculous meningitis is associated with higher cerebrospinal HIV-1 viral loads compared to other HIV-1-associated meningitides.

To gain a better understanding of the immunopathogenesis of tuberculous meningitis (TBM) and identify potential diagnostic biomarkers that may discriminate TBM from other HIV-1-associated meningitides, we assessed HIV-1 viral load levels, drug resistance patterns in antiretroviral therapy (ART)-experienced patients with persistent viremia and soluble immunological analytes in peripheral blood and cerebrospinal fluid (CSF) of HIV-1 infected patients with TBM versus other meningitides. One hundred and three matched blood and CSF samples collected from HIV-1 infected patients with TBM or other meningitides presenting at a hospital in Durban, South Africa, from January 2009 to December 2011 were studied. HIV-1 RNA and 28 soluble immunological potential biomarkers were quantified in blood plasma and CSF. Viremic samples were assessed for HIV-1 drug resistance mutations. There were 16 TBM, 46 probable TBM, 35 non-TBM patients, and six unclassifiable patients. TBM and non-TBM patients did not differ in median plasma viral load but TBM patients had significantly higher median CSF viral load than non-TBM participants (p = 0.0005). No major drug resistance mutations were detected in viremic samples. Interleukin (IL)-1β, IL-17, platelet derived growth factor (PDGF)-BB, granulocyte colony stimulating factor (G-CSF) and cathelicidin were significantly elevated in the CNS of TBM participants compared to other patients although these associations were lost after correction for false discovery. Our data suggest that TB co-infection of the CNS is associated with enhanced localized HIV-1 viral replication but none of the evaluated soluble immunological potential biomarkers could reliably distinguish TBM from other HIV-associated meningitides

Reorganization of Atlantic Waters at sub-polar latitudes linked to deep-water overflow in both glacial and interglacial climate states

While a large cryosphere may be a necessary boundary condition for millennial-scale events to persist, a growing body of evidence from previous interglacial periods suggests that high-magnitude climate events are possible during low-cryosphere climate states. However, the full spectrum of variability, and the antecedent conditions under which such variability can occur, have not been fully described. As a result, the mechanisms generating high-magnitude climate variability during low-cryosphere boundary conditions remain unclear. In this study, high-resolution climate records from Deep Sea Drilling Project (DSDP) site 610 are used to portray the North Atlantic climate's progression through low ice, boundary conditions of Marine Isotope Stage (MIS) 11c into the glacial inception. We show that this period is marked by two climate events displaying rapid shifts in both deep overflow and surface climate. The reorganization between Polar Water and Atlantic Water at subpolar latitudes appears to accompany changes in the flow of deep water emanating from the Nordic Seas, regardless of magnitude or boundary conditions. Further, during both intermediate and low ice boundary conditions, we find that a reduction in deep water precedes surface hydrographic change. The existence of surface and deep-ocean events, with similar magnitudes, abruptness, and surface–deep phasing, advances our mechanistic understanding of, and elucidates antecedent conditions that can lead to, high-magnitude climate instability.publishedVersio

Pine Pitch Canker and Insects: Regional Risks, Environmental Regulation, and Practical Management Options

Producción CientíficaPine pitch canker (PPC), caused by the pathogenic fungus Fusarium circinatum (Nirenberg and O’ Donnell), is a serious threat to pine forests globally. The recent introduction of the pathogen to Southern Europe and its spread in Mediterranean region is alarming considering the immense ecological and economic importance of pines in the region. Pines in forests and nurseries can be infected, resulting in severe growth losses and mortality. The pathogen is known to spread in plants for planting and in seeds, and results from recent studies have indicated that F. circinatum may also spread through phoretic associations with certain insects. With this review, we aim to expand the current understanding of the risk of insect-mediated spread of PPC in different parts of Europe. Through the joint action of a multinational researcher team, we collate the existing information about the insect species spectrum in different biogeographic conditions and scrutinize the potential of these insects to transmit F. circinatum spores in forests and nurseries. We also discuss the impact of environmental factors and forest management in this context. We present evidence for the existence of a high diversity of insects with potential to weaken pines and disseminate PPC in Europe, including several common beetle species. In many parts of Europe, temperatures are projected to rise, which may promote the activity of several insect species, supporting multivoltinism and thus, further amplifying the risk of insect-mediated dissemination of PPC. Integrated pest management (IPM) solutions that comply with forest management practices need to be developed to reduce this risk. We recommend careful monitoring of insect populations as the basis for successful IPM. Improved understanding of environmental control of the interaction between insects, the pathogen, and host trees is needed in order to support development of bio-rational strategies to safeguard European pine trees and forests against F. circinatum in future.European Cooperation in Science and Technology (COST Action FP1406 PINESTRENGTH)Ministerio de Economía, Industria y Competitividad - Fondo Europeo de Desarrollo Regional (project AGL2015-69370-R)Portuguese Foundation for Science and Technology (contract IF/00471/2013/CP1203/CT0001)Russian Foundation for Basic Research (grant 17-04-01486)Saint Petersburg State Polytechnical University (project 2019-0420

Repetitive negative thinking and interpretation bias in pregnancy

Background: Repetitive negative thinking (RNT; e.g., worry about the future, rumination about the past) and the tendency to interpret ambiguous information in negative ways (interpretation bias) are cognitive processes that play a maintaining role in anxiety and depression, and recent evidence has demonstrated that interpretation bias maintains RNT. In the context of perinatal mental health, RNT has received minimal research attention (despite the fact that it predicts later anxiety and depression), and interpretation bias remains unstudied (despite evidence that it maintains depression and anxiety which are common in this period). Method: We investigated the relationship between RNT, interpretation bias and psychopathology (depression, anxiety) in a pregnant sample (n = 133). We also recruited an age-matched sample of non-pregnant women (n = 104), to examine whether interpretation bias associated with RNT emerges for ambiguous stimuli regardless of its current personal relevance (i.e., pregnancy or non-pregnancy-related). Results: As predicted, for pregnant women, negative interpretation bias, RNT, depression and anxiety were all positively associated. Interpretation bias was evident to the same degree for material that was salient (pregnancy-related) and non-salient (general), and pregnant and non-pregnant women did not differ. RNT was associated with interpretation bias for all stimuli and across the full sample. Conclusion: Our findings highlight the need to further investigate the impact of interpretation bias in pregnant women, and test the effectiveness of interventions which promote positive interpretations in reducing RNT in the perinatal period

PI3K p110δ uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML

Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110α, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ

Looking on the bright side reduces worry in pregnancy: training interpretations in pregnant women

Background Recent evidence suggests that anxiety is more common than depression in the perinatal period, however there are few interventions available to treat perinatal anxiety. Targeting specific processes that maintain anxiety, such as worry, may be one potentially promising way to reduce anxiety in this period. Given evidence that negative interpretation bias maintains worry, we tested whether interpretation bias could be modified, and whether this in turn would lead to less negative thought (i.e., worry) intrusions, in pregnant women with high levels of worry. Method Participants (N = 47, at least 16 weeks gestation) were randomly assigned to either an interpretation modification condition (CBM-I) which involved training in accessing positive meanings of emotionally ambiguous scenarios, or an active control condition in which the scenarios remained ambiguous and unresolved. Results Relative to the control condition, participants in the CBM-I condition generated significantly more positive interpretations and experienced significantly less negative thought intrusions. Conclusions Our findings indicate that worry is a modifiable risk factor during pregnancy, and that it is possible to induce a positive interpretation bias in pregnant women experiencing high levels of worry. Although preliminary, our findings speak to exciting clinical possibilities for the treatment of worry and the prevention of perinatal anxiety

Making Room for Zoom in Focus Group Methods: Opportunities and Challenges for Novice Researchers (During and Beyond COVID-19)

Als die COVID-19-Pandemie über die Welt hereinbrach, waren viele Menschen gezwungen, sich auf online-basierte Routinen einzustellen, darunter auch qualitative Forscher*innen, die nach alternativen Möglichkeiten zur Erhebung aussagekräftiger Daten suchten. Während Fokusgruppen traditionell Face to Face durchgeführt werden, bieten Fortschritte bei Online-Videokonferenzanwendungen neue Methoden zur Datenerhebung, die jedoch bisher nur selten untersucht wurden. In diesem Artikel berichten wir über die Erfahrungen von 12 Doktorand*innen mit der Durchführung von Fokusgruppen unter Verwendung von Zoom im Rahmen eines Kurses zu qualitativen Interviewmethoden. Wir reflektieren Chancen und Herausforderungen, die wir als Moderator*innen und Teilnehmer*innen bei der Nutzung von Zoom erlebten z.B. bei der Vorbereitung oder in Bezug auf Rapport, die Einbindung anderer digitaler Tools und von Internetverbindungen. Zusammenfassend lässt sich sagen, dass die Durchführung von Online-Fokusgruppen unter Verwendung von Zoom insgesamt eine positive Erfahrung war und mit Face-to-Face-Fokusgruppen vergleichbar ist. Möglichkeiten der Teilnehmer*innenrekrutierung, die Sicherheitsmerkmale von Zoom und die Nutzung von Zoom und allgemeiner neuen Technologien sollten auch jenseits der Pandemie weiter erforscht werden.As the COVID-19 pandemic swept through the world, it forced many people to adapt to an online-based routine, including qualitative researchers looking for alternative ways to collect meaningful data. While focus groups are traditionally conducted in-person, advances with online videoconferencing applications present a new method to collect data, however, few studies have explored this. In this article we present 12 doctoral students' experiences with conducting focus groups using the videoconferencing application Zoom during a qualitative methods course on interviewing methods. Through this self-study qualitative analysis, participants reflected on the opportunities and challenges experienced as both moderators and participants using Zoom including: preparation, rapport, incorporating other digital tools, and internet connectivity. In conclusion, doing focus groups online using Zoom was a positive experience overall and comparable to in-person focus groups for collecting qualitative data, despite the introduction of technology. More research on participant recruitment, new technology, Zoom's security features, and Zoom's use outside of a pandemic should be further explored