Second-Order Conditioning and Conditioned Inhibition in Different Moments of the Same Training: The Effect of A+ and AX− Trial Number

The feature negative discrimination (A+/AX−) can result in X gaining excitatory properties (second-order conditioning, SOC) or in X gaining inhibitory properties (conditioned inhibition, CI), a challenging finding for most current associative learning theories. Research on the variables that modulate which of these phenomena would occur is scarce but has clearly identified the trial number as an important variable. In the set of experiments presented here, the effect of trial number was assessed in a magazine training task with rats as a function of both the conditioning sessions and the number of A+ and AX− trials per session, holding constant the total number of trials per session. The results indicated that SOC is most likely to be found at the beginning of training when there are many A+ and few AX− trials, and CI (as assessed by a retardation test) is most likely to be found at the end of training when there are few A+ and many AX− trials. Both phenomena were also found at different moments of training when the number of A+ trials was equal to the number of AX− trials. These results cannot be predicted by acquisition-focused associative models but can be predicted by theories that distinguish between learning and performance.

Identification of human glucocorticoid response markers using integrated multi-omic analysis from a randomized crossover trial

Background:Glucocorticoids are among the most commonly prescribed drugs, but there is no biomarker that can quantify their action. The aim of the study was to identify and validate circulating biomarkers of glucocorticoid action.Methods:In a randomized, crossover, single-blind, discovery study, 10 subjects with primary adrenal insufficiency (and no other endocrinopathies) were admitted at the in-patient clinic and studied during physiological glucocorticoid exposure and withdrawal. A randomization plan before the first intervention was used. Besides mild physical and/or mental fatigue and salt craving, no serious adverse events were observed. The transcriptome in peripheral blood mononuclear cells and adipose tissue, plasma miRNAomic, and serum metabolomics were compared between the interventions using integrated multi-omic analysis.Results:We identified a transcriptomic profile derived from two tissues and a multi-omic cluster, both predictive of glucocorticoid exposure. A microRNA (miR-122-5p) that was correlated with genes and metabolites regulated by glucocorticoid exposure was identified (p=0.009) and replicated in independent studies with varying glucocorticoid exposure (0.01 ≤ p≤0.05).Conclusions:We have generated results that construct the basis for successful discovery of biomarker(s) to measure effects of glucocorticoids, allowing strategies to individualize and optimize glucocorticoid therapy, and shedding light on disease etiology related to unphysiological glucocorticoid exposure, such as in cardiovascular disease and obesity.Funding:The Swedish Research Council (Grant 2015-02561 and 2019-01112); The Swedish federal government under the LUA/ALF agreement (Grant ALFGBG-719531); The Swedish Endocrinology Association; The Gothenburg Medical Society; Wellcome Trust; The Medical Research Council, UK; The Chief Scientist Office, UK; The Eva Madura’s Foundation; The Research Foundation of Copenhagen University Hospital; and The Danish Rheumatism Association.Clinical trial number:NCT02152553.

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial

Purpose To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients. Methods Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety. Results The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%–81%) and 45% (27%–65%) in groups A1 and A2, respectively, and 19% (8%–35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively. Conclusions In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen. Trial registration:The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (http://www.umin.ac.jp/ctr/index-j.htm) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

A stepped-wedge randomised trial on the impact of early ART initiation on HIV-patients’ economic outcomes in Eswatini

Background:Since 2015, the World Health Organisation (WHO) recommends immediate initiation of antiretroviral therapy (ART) for all HIV-positive patients. Epidemiological evidence points to important health benefits of immediate ART initiation; however, the policy’s impact on the economic aspects of patients' lives remains unknown.Methods:We conducted a stepped-wedge cluster-randomised controlled trial in Eswatini to determine the causal impact of immediate ART initiation on patients’ individual- and household-level economic outcomes. Fourteen healthcare facilities were non-randomly matched into pairs and then randomly allocated to transition from the standard of care (ART eligibility at CD4 counts of <350 cells/mm3 until September 2016 and <500 cells/mm3 thereafter) to the ‘Early Initiation of ART for All’ (EAAA) intervention at one of seven timepoints. Patients, healthcare personnel, and outcome assessors remained unblinded. Data were collected via standardised paper-based surveys with HIV-positive adults who were neither pregnant nor breastfeeding. Outcomes were patients’ time use, employment status, household expenditures, and household living standards.Results:A total sample of 3019 participants were interviewed over the duration of the study. The mean number of participants approached at each facility per time step varied from 4 to 112 participants. Using mixed-effects negative binomial regressions accounting for time trends and clustering at the level of the healthcare facility, we found no significant difference between study arms for any economic outcome. Specifically, the EAAA intervention had no significant effect on non-resting time use (RR = 1.00 [CI: 0.96, 1.05, p=0.93]) or income-generating time use (RR = 0.94, [CI: 0.73,1.20, p=0.61]). Employment and household expenditures decreased slightly but not significantly in the EAAA group, with risk ratios of 0.93 [CI: 0.82, 1.04, p=0.21] and 0.92 [CI: 0.79, 1.06, p=0.26], respectively. We also found no significant treatment effect on households’ asset ownership and living standards (RR = 0.96, [CI 0.92, 1.00, p=0.253]). Lastly, there was no evidence of heterogeneity in effect estimates by patients’ sex, age, education, timing of HIV diagnosis and ART initiation.Conclusions:Our findings do not provide evidence that should discourage further investments into scaling up immediate ART for all HIV patients.Funding:Funded by the Dutch Postcode Lottery in the Netherlands, Alexander von Humboldt-Stiftung (Humboldt-Stiftung), the Embassy of the Kingdom of the Netherlands in South Africa/Mozambique, British Columbia Centre of Excellence in Canada, Doctors Without Borders (MSF USA), National Center for Advancing Translational Sciences of the National Institutes of Health and Joachim Herz Foundation.Clinical trial number:NCT02909218 and NCT03789448.

A Phase II Study of First-line Afatinib For Patients Aged ≥ 75 Years With EGFR Mutation-positive Advanced Non-small Cell Lung Cancer: North East Japan Study Group Trial NEJ027

Background: We investigated afatinib in elderly patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC).Patients and Methods: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥ 75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review.Results: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology group performance status of 0 or 1, and 60.5% had Del19-positive disease. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade III/IV treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and 8 (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported.Conclusion: First-line afatinib administered at a starting dose of 40 mg was well tolerated with dose adjustments and was associated with encouraging activity in Japanese patients aged ≥ 75 years with EGFR mutation-positive NSCLC.Trial Registration: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

Investigating the role of attention in the identification of associativity shortcuts using a microgenetic measure of implicit shortcut use

Many mathematics problems can be solved in different ways or by using different strategies. Good knowledge of arithmetic principles is important for identifying and using strategies that are more sophisticated. For example, the problem “6 + 38 − 35” can be solved through a shortcut strategy where the subtraction “38 − 35 = 3” is performed before the addition “3 + 6 = 9,” a strategy that is derived from the arithmetic principle of associativity. However, both children and adults make infrequent use of this shortcut and the reasons for this are currently unknown. To uncover these reasons, new sensitive measures of strategy identification and use must first be developed, which was one goal of our research. We built a novel method to detect the time-point when individuals first identify an arithmetic strategy, based on trial-by-trial response time data. Our second goal was to use this measure to investigate the contribution of one particular factor, attention, in the identification of the associativity shortcut. In two studies, we found that manipulating visual attention made no difference to the number of people who identified the shortcut, the trial number on which they first identified it, or their accuracy and response time for solving shortcut problems. We discuss the theoretical and methodological contribution of our findings and argue that the origin of people’s difficulty with associativity shortcuts may lie beyond attention.

Naloxon – Medizinische Grundlagen und internationale Erfahrungen

Zusammenfassung. Hintergrund: Die Abhängigkeit von Opioiden ist mit erheblichen gesundheitlichen Gefährdungen der Betroffenen und einer hohen Mortalität assoziiert. Derzeit werden insbesondere die dramatisch gestiegenen Mortalitätsraten in den USA diskutiert (‚opioid crisis‘), aber auch in Deutschland war in den letzten Jahren ein kontinuierlicher Anstieg der Drogentoten, überwiegend verursacht durch Opioide, zu verzeichnen. Die Risiken einer Opioid Überdosierung bzw. Intoxikation resultiert vor allem aus der hemmenden Wirkung der Opioide auf den Atemantrieb, die durch andere gleichzeitig konsumierte Substanzen noch verstärkt werden kann. Neben Erstmaßnahmen (Notruf, lebensrettende Basismaßnahmen der Ersten Hilfe) kommt auch der Einsatz des Opioidantagonisten Naloxon in Betracht. Methode: Literaturrecherche in PubMed, Cochrane Library und im International Standard Randomized Controlled Trial Number (ISRCTN) Register. Ergebnisse: Auch aus ethischen Gründen liegen bislang eher wenig systematische Untersuchungen zum nicht-ärztlichen Einsatz von Naloxon bei Opioidüberdosierung vor. Trotzdem kann nach aktuellem Stand geschlussfolgert werden, dass die intranasale Verabreichung vergleichbar wirksam mit einer intramuskulären Anwendung zu sein scheint. Bei Überdosierten, die nach erfolgreichem Naloxon-Einsatz aus unterschiedlichen Gründen nicht in einer Klinik gebracht wurden, wurden in ca. 1 %. Todesfälle dokumentiert. Falls 60 min nach Naloxongabe unauffällige Vitalparameter und auf der Glasgow Coma Scale mind. 15 Punkte erreicht werden, besteht wohl ein sehr niedriges Rebound-Risiko. Im Vergleich dazu ist das Auftreten von Naloxon-induzierten Entzugssyndromen deutlich häufiger, hängen jedoch von der Dosis und dem konsumierten Opioid ab, wie auch von der verabreichten Naloxon-Dosis. Schlussfolgerungen: Naloxon kann mittlerweile auch in Deutschland als zugelassenes Nasalspray verabreicht werden und ist daher im Prinzip auch für den Einsatz durch Ersthelfer geeignet. Verbesserte Rahmenbedingungen, wie z. B. spezifische Schulungen könnten dazu beitragen, Take-Home Naloxon als erfolgreichen Baustein zur Reduktion von Drogentod zu implementieren.