Search

BackgroundAlthough potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals.MethodsIn the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task.ResultsRelative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects.ConclusionsResults add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

Eosinophilic gastroenteritis is a rare disease with an unknown cause, which can manifest independently or as part of a hyper-eosinophilic syndrome. The severity of the condition depends on the extent of eosinophilic infiltration and damage to the digestive tract. Diagnosis relies on histological examination, which reveals a significant presence of eosinophilic polymorphonuclear leukocytes in the digestive wall. The authors present a new case of eosinophilic gastroenteritis in a 28-year-old patient who exhibited obstructive symptoms but lacked peripheral eosinophilia. Esophagogastroduodenoscopy showed no abnormalities, but barium transit imaging revealed gastro-duodeno-jejunal dilation upstream of a tight jejunal stenosis. Surgical examination of the affected area confirmed a diffuse and transparietal eosinophilic infiltrate, with no evidence of parasitic or granulomatous lesions. Fortunately, the patient had a swift recovery following surgery. Biopsies conducted at other locations, including the gastric, hepatic, and medullary levels, produced negative results, indicating the localized nature of the condition. [ABSTRACT FROM AUTHOR]

Feature-based attention is the ability to selectively attend to a particular feature (e.g., attend to red but not green items while looking for the ketchup bottle in your refrigerator), and steady-state visually evoked potentials (SSVEPs) measured from the human EEG signal have been used to track the neural deployment of feature-based attention. Although many published studies suggest that we can use trial-by-trial cues to enhance relevant feature information (i.e., greater SSVEP response to the cued color), there is ongoing debate about whether participants may likewise use trial-by-trial cues to voluntarily ignore a particular feature. Here, we report the results of a preregistered study in which participants either were cued to attend or to ignore a color. Counter to prior work, we found no attention-related modulation of the SSVEP response in either cue condition. However, positive control analyses revealed that participants paid some degree of attention to the cued color (i.e., we observed a greater P300 component to targets in the attended vs. the unattended color). In light of these unexpected null results, we conducted a focused review of methodological considerations for studies of feature-based attention using SSVEPs. In the review, we quantify potentially important stimulus parameters that have been used in the past (e.g., stimulation frequency, trial counts) and we discuss the potential importance of these and other task factors (e.g., feature-based priming) for SSVEP studies.

Early Check is a voluntary, large‐scale expanded newborn screening study in North Carolina that uses a self‐directed web‐based portal for return of normal individual research results (IRR). Little is known about participant perspectives in using web‐based portals to receive IRR. This study explored user attitudes and behaviors within the Early Check portal using three methods: (1) a feedback survey available to the consenting parent of participating infants (typically mothers), (2) semi‐structured interviews conducted with a subset of parents, and (3) Google Analytics. During an approximate 3‐year period, 17 936 newborns received normal IRR and there were 27 812 visits to the portal. Most surveyed parents reported viewing their baby's results (86%, 1410/1639). Parents largely found the portal easy to use to get results, and helpful in understanding the results. However, 10% of parents said it was difficult to find enough information to understand their baby's results. In Early Check, providing normal IRR via the portal made a large‐scale study practical, and was highly rated by most users. Return of normal IRR may be particularly amenable to web‐based portals, as the consequences to participants from not viewing results are modest, and the interpretation of a normal result is relatively straightforward. [ABSTRACT FROM AUTHOR]

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins.

How statistically non-significant results are reported and interpreted following null hypothesis significance testing is often criticized. This issue is important for animal cognition research because studies in the field are often underpowered to detect theoretically meaningful effect sizes, i.e., often produce non-significant p-values even when the null hypothesis is incorrect. Thus, we manually extracted and classified how researchers report and interpret non-significant p-values and examined the pvalue distribution of these non-significant results across published articles in animal cognition and related fields. We found a large amount of heterogeneity in how researchers report statistically non-significant p-values in the result sections of articles, and how they interpret them in the titles and abstracts. Reporting of the non-significant results as ‘‘No Effect’’ was common in the titles (84%), abstracts (64%), and results sections (41%) of papers, whereas reporting of the results as ‘‘Non-Significant’’ was less common in the titles (0%) and abstracts (26%), but was present in the results (52%). Discussions of effect sizes were rare (<5% of articles). A p-value distribution analysis was consistent with research being performed with low power of statistical tests to detect effect sizes of interest. These findings suggest that researchers in animal cognition should pay close attention to the evidence used to support claims of absence of effects in the literature, and—in their own work—report statistically non-significant results clearly and formally correct, as well as use more formal methods of assessing evidence against theoretical predictions. [ABSTRACT FROM AUTHOR]

Background: Psychosocial interventions for caregivers of patients with Alzheimer disease and relative dementias (ADRD) reported a caregiver burden improvement. Multicomponent intervention integrating pharmaceutical care has not yet been evaluated while ADRD patients and their caregivers are exposed to high risk of drug-related problems. The PHARMAID study aimed to assess the impact of personalized pharmaceutical care integrated to a psychosocial program on the burden of ADRD caregivers at 18 months. Methods: The PHARMAID RCT was conducted between September 2016 and June 2020 [ClinicalTrials.gov: NCT02802371]. PHARMAID study planned to enroll 240 dyads, i.e. ADRD patients and caregivers, whose inclusion criteria were: outpatient with mild or major neurocognitive disorders due to ADRD, living at home, receiving support from a family caregiver. Three parallel groups compared a control group with two interventional groups: psychosocial intervention and integrated pharmaceutical care at a psychosocial intervention. The main outcome was the caregiver burden assessed by the Zarit Burden Index (ZBI, score range 0–88) at 18 months. Results: Overall, 77 dyads were included (32% of the expected sample size). At 18 months, the mean ZBI scores were 36.7 ± 16.8 in the control group, 30.3 ± 16.3 for the group with psychosocial intervention, and 28.8 ± 14.1 in group with integrated pharmaceutical care at psychosocial intervention. No significant difference was demonstrated between the three groups (p = 0.326). Conclusions: The findings suggest that PHARMAID program had no significant impact on caregiver burden at 18 months. Several limitations have been highlighted and discussed by the authors in order to formulate recommendations for further research.

Research examining oxytocin and vasopressin in humans has the potential to elucidate neurobiological mechanisms underlying human sociality that have been previously unknown or not well characterized. A primary goal of this work is to increase our knowledge about neurodevelopmental and psychiatric disorders characterized by impairments in social cognition. However, years of research highlighting wide-ranging effects of, in particular, intranasal oxytocin administration have been tempered as the fields of psychology, neuroscience, and other disciplines have been addressing concerns over the reproducibility and validity of research findings. We present a series of behavioral tasks that were conducted using a randomized, double-blind, placebo controlled, between-subjects design, in which our research group found no main effects of oxytocin and vasopressin on a host of social outcomes. In addition to null hypothesis significance testing, we implemented equivalence testing and Bayesian hypothesis testing to examine the sensitivity of our findings. These analyses indicated that 47-83% of our results (depending on the method of post-hoc analysis) had enough sensitivity to detect the absence of a main effect. Our results add to evidence that intranasal oxytocin may have a more limited direct effect on human social processes than initially assumed and suggest that the direct effects of intranasal vasopressin may be similarly limited. Randomized controlled trial registration: NCT01680718.

BackgroundAggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression.ObjectivesTo analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative.MethodsOver up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed.ResultsThe inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan.ConclusionsCSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society.

BackgroundIron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial.MethodsWe did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed.FindingsWe recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related.InterpretationDeferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile.FundingUS National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

How statistically non-significant results are reported and interpreted following null hypothesis significance testing is often criticized. This issue is important for animal cognition research because studies in the field are often underpowered to detect theoretically meaningful effect sizes, i.e., often produce non-significant p-values even when the null hypothesis is incorrect. Thus, we manually extracted and classified how researchers report and interpret non-significant p-values and examined the p-value distribution of these non-significant results across published articles in animal cognition and related fields. We found a large amount of heterogeneity in how researchers report statistically non-significant p-values in the result sections of articles, and how they interpret them in the titles and abstracts. Reporting of the non-significant results as “No Effect” was common in the titles (84%), abstracts (64%), and results sections (41%) of papers, whereas reporting of the results as “Non-Significant” was less common in the titles (0%) and abstracts (26%), but was present in the results (52%). Discussions of effect sizes were rare (

ObjectiveTo explore the relationship between internet use which includes time spent on the internet, internet skills, types of online activities, and depressive symptoms in older adults.MethodsWe used 2020 China Family Panel Studies (CFPS) data with 3,171 older adults aged 60 years. Depression symptoms were measured with the Center for Epidemiologic Studies Depression (CES-D), and internet use was measured by time spent on the internet, internet skills, and types of online activities. Multiple linear regression models were used to explore the relationship between internet use and depressive symptoms in older adults.ResultsLonger time spent on the internet was associated with higher scores of depressive symptoms (β = 0.14). Higher internet skills were associated with lower scores of depressive symptoms (β = −0.42). Watching short-form videos (β = 1.34) was associated with higher depressive symptom scores, and the use of the WeChat function (β = −0.96) was associated with lower depressive symptom scores, while online games and online shopping were not significant.ConclusionThe effect of internet use on depressive symptoms in older adults is a double-edged sword. Controlling the time spent on the internet, improving internet skills, and guiding specific a type of online activities in older adults can improve depressive symptoms through rational use.

Much is known about palliative care needs of persons with dementia and their family. Less is known about how to successfully implement models that address those needs. We present specialist models in the Netherlands (2017-2018) and Northern Ireland (2016-2017) contrasting its evaluations. From implementation failure in the Netherlands compared with successful implementation in Northern Ireland, we learn that recognizing roles and competencies among all involved is essential in developing effective partnership relationships. All of this is facilitated by referral before the end of life and offering various training programs and in-patient and out-patient services and therapies to show benefits early. [ABSTRACT FROM AUTHOR]

Because aphids are global agricultural pests and models for bacterial endosymbiosis, there is a need for reliable methods to study and control their gene function. However, current methods available for aphid gene knockout and knockdown of gene expression are often unreliable and time consuming. Techniques like CRISPR-Cas genome editing can take several months to achieve a single gene knockout because they rely on aphids going through a cycle of sexual reproduction, and aphids often lack strong, consistent levels of knockdown when fed or injected with molecules that induce an RNA interference (RNAi) response. In the hopes of addressing these challenges, we attempted to adapt a new method called symbiont-mediated RNAi (smRNAi) for use in aphids. smRNAi involves engineering a bacterial symbiont of the insect to continuously supply double-stranded RNA (dsRNA) inside the insect body. This approach has been successful in thrips, kissing bugs, and honeybees. We engineered the laboratory Escherichia coli strain HT115 and the native aphid symbiont Serratia symbiotica CWBI-2.3T to produce dsRNA inside the gut of the pea aphid (Acyrthosiphon pisum) targeting salivary effector protein (C002) or ecdysone receptor genes. For C002 assays, we also tested co-knockdown with an aphid nuclease (Nuc1) to reduce RNA degradation. However, we found that smRNAi was not a reliable method for aphid gene knockdown under our conditions. We were unable to consistently achieve the expected phenotypic changes with either target. However, we did see indications that elements of the RNAi pathway were modestly upregulated, and expression of some targeted genes appeared to be somewhat reduced in some trials. We conclude with a discussion of the possible avenues through which smRNAi, and aphid RNAi in general, could be improved in the future. [ABSTRACT FROM AUTHOR]

With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple process of filling in paperwork, drawing 3 mL of blood in an ethylenediaminetetraacetic acid tube and receiving a test report. This is identical to sending off a full blood count. However, it is far more complex than that. There are many potential pitfalls, as shown by the increasing number of complaints and lawsuits filed against doctors and allied health staff. Furthermore, clinical genetics involves more than just ordering tests; in fact, focusing on genetic tests alone is a potential pitfall. In this review, we discuss the common pitfalls in clinical genetics and how doctors can avoid these pitfalls to ensure patient safety and to safeguard their practice. [ABSTRACT FROM AUTHOR]

Abstract This paper is a report of recommendations for addressing translational challenges in amyloid disease research. They were developed during and following an international online workshop organized by the LINXS Institute of Advanced Neutron and X-Ray Science in March 2021. Key suggestions include improving cross-cultural communication between basic science and clinical research, increasing the influence of scientific societies and journals (vis-à-vis funding agencies and pharmaceutical companies), improving the dissemination of negative results, and strengthening the ethos of science.

Because aphids are global agricultural pests and models for bacterial endosymbiosis, there is a need for reliable methods to study and control their gene function. However, current methods available for aphid gene knockout and knockdown of gene expression are often unreliable and time consuming. Techniques like CRISPR-Cas genome editing can take several months to achieve a single gene knockout because they rely on aphids going through a cycle of sexual reproduction, and aphids often lack strong, consistent levels of knockdown when fed or injected with molecules that induce an RNA interference (RNAi) response. In the hopes of addressing these challenges, we attempted to adapt a new method called symbiont-mediated RNAi (smRNAi) for use in aphids. smRNAi involves engineering a bacterial symbiont of the insect to continuously supply double-stranded RNA (dsRNA) inside the insect body. This approach has been successful in thrips, kissing bugs, and honeybees. We engineered the laboratory Escherichia coli strain HT115 and the native aphid symbiont Serratia symbiotica CWBI-2.3T to produce dsRNA inside the gut of the pea aphid (Acyrthosiphon pisum) targeting salivary effector protein (C002) or ecdysone receptor genes. For C002 assays, we also tested co-knockdown with an aphid nuclease (Nuc1) to reduce RNA degradation. However, we found that smRNAi was not a reliable method for aphid gene knockdown under our conditions. We were unable to consistently achieve the expected phenotypic changes with either target. However, we did see indications that elements of the RNAi pathway were modestly upregulated, and expression of some targeted genes appeared to be somewhat reduced in some trials. We conclude with a discussion of the possible avenues through which smRNAi, and aphid RNAi in general, could be improved in the future.

NMDA receptors (NMDARs) mediate both long-term potentiation and long-term depression (LTD) and understanding how a single receptor can initiate both phenomena remains a major question in neuroscience. A prominent hypothesis implicates the NMDAR subunit composition, specifically GluN2A and GluN2B, in dictating the rules of synaptic plasticity. However, studies testing this hypothesis have yielded inconsistent and often contradictory results, especially for LTD. These inconsistent results may be due to challenges in the interpretation of subunit-selective pharmacology and in dissecting out the contributions of differential channel properties versus the interacting proteins unique to GluN2A or GluN2B. In this study, we address the pharmacological and biochemical challenges by using a single-neuron genetic approach to delete NMDAR subunits in conditional knock-out mice. In addition, the recently discovered non-ionotropic nature of NMDAR-dependent LTD allowed the rigorous assessment of unique subunit contributions to NMDAR-dependent LTD while eliminating the variable of differential charge transfer. Here we find that neither the GluN2A nor the GluN2B subunit is strictly necessary for either non-ionotropic or ionotropic LTD.SIGNIFICANCE STATEMENT NMDA receptors are key regulators of bidirectional synaptic plasticity. Understanding the mechanisms regulating bidirectional plasticity will guide development of therapeutic strategies to treat the dysfunctional synaptic plasticity in multiple neuropsychiatric disorders. Because of the unique properties of the NMDA receptor GluN2 subunits, they have been postulated to differentially affect synaptic plasticity. However, there has been significant controversy regarding the roles of the GluN2 subunits in synaptic long term depression (LTD). Using single-neuron knock-out of the GluN2 subunits, we show that LTD requires neither GluN2A nor GluN2B.

One important assumption in case-control studies is that control selection should be independent of exposure. Nevertheless, it has been hypothesized that virus interference might lead to a correlation between receipt of influenza vaccination and increased risk of infection with other respiratory viruses. We investigated whether such a phenomenon might affect a study design commonly used to estimate influenza vaccine effectiveness (VE). We searched publications in MEDLINE, PubMed, and Web of Science. We identified 12 studies using the test-negative design (2011-2017) that reported VE estimates separately derived by 3 alternative control groups: 1) all patients testing negative for influenza (FLU), VEFLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VEORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VEPAN-. These included VE estimates from 7 countries for all age groups from 2003/2004 to 2013/2014. We observed no difference in vaccination coverage between the ORV-positive and PAN-negative control groups. A total of 63 VEFLU- estimates, 62 VEORV+ estimates, and 33 VEPAN- estimates were extracted. Pooled estimates of the difference in VE (ΔVE) were very similar between groups. In meta-regression, no association was found between the selection of control group and VE estimates. In conclusion, we did not find any differences in VE estimates based on the choice of control group.

Objective: Reports on negative results of metagenomic next-generation sequencing (mNGS) are scarce. We aimed to explore the diagnostic value of negative results in bronchoalveolar lavage fluid (BALF) mNGS and how to deal with the negative results in patients with severe respiratory disease. Methods: A retrospective analysis was performed on patients suspected severe community-acquired pneumonia who were admitted to the respiratory intensive care unit of the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2021. According to the final diagnosis as the reference standard, the negative results of mNGS were divided into a true negative group and a false negative group. For enrolled patients, we recorded their demographic data, imaging results, laboratory results, therapeutic processes, and prognoses. Results: A total of 21 patients were enrolled in this study, including 16 true negative patients and 5 false negative patients. In the true negative group, interstitial lung diseases were the most and neoplastic diseases were following. In addition to mNGS, 9 patients underwent pathological examination, 7 patients were finally diagnosed by medical history, autoantibodies, and point-of-care (POC) ultrasound. 14 patients eventually discontinued antibiotics, 2 patients underwent antibiotic de-escalation, the average interval time of treatment adjustment was 3.56 ± 2.00 days. In the false negative group, the leading missed pathogen was fungi, followed by tuberculosis bacilli. In contrast to 2 patients underwent pathological examination, 3 patients were confirmed by routine microbiological tests. Conclusions: Negative results of BALF mNGS can help to rule out infection, but missed diagnoses may also exist. It should be re-evaluated with other clinical informations. Pathological examination or repeated mNGS may be viable options when the diagnosis cannot be confirmed. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a neurodegenerative disease with autosomal dominant inheritance, and no radical cure for HD has been established. Qualitative studies are necessary to investigate the psychological state of individuals who underwent predictive testing for HD, because the psychosocial impact on noncarriers remains unclarified in Japan. Herein, we elucidated the psychosocial impact on the noncarriers for HD and the role of genetic counseling for predictive testing and follow-up after testing by examining their experiences with predictive testing. We conducted semi-structured interviews with eight individuals participating in this study. Interview data were transcribed verbatim and evaluated according to thematic analysis. As a result, 4 themes were generated from 21 categories of 46 codes: (1) Diversity of perceptions concerning the test results, (2) Views on life as a noncarrier, (3) Changes in feelings toward and relationships with family members, and (4) Sharing information within the family. After receiving the negative results, the noncarriers felt not only relief but also surprise, doubt, relief from tension, and regret. It was shown that noncarriers felt survivor's guilt toward many unspecified individuals, which was not only a sense of guilt but also a sense of mission or responsibility. Additionally, they conducted altruistic behavior as members of their family and society, that may be related to the Japanese collectivism. Some participants were concerned about sharing information with their siblings. Noncarriers for HD can experience complex psychological states, and Japanese people who prefer high-context communication may find it difficult to express their feelings and thoughts. It is important to understand their true feelings before and after the predictive genetic testing, reconsider the impact of being a noncarrier and whether it is a burden for them from both subjective and objective perspectives, and conduct long-term follow-up as needed., (© 2024 National Society of Genetic Counselors.)

Objectives: To determine the proportions of abdominal US examinations during on-call hours that are negative and that contain an incidentaloma, and to explore temporal changes and determinants. Methods: This study included 1615 US examinations that were done during on-call hours at a tertiary care center between 2005 and 2017. Results: The total proportion of negative US examinations was 49.2% (795/1615). The total proportion of US examinations with an incidentaloma was 8.0% (130/1615). There were no significant temporal changes in either one of these proportions. The likelihood of a negative US examination was significantly higher when requested by anesthesiology [odds ratio (OR) 2.609, P = 0.011], or when the indication for US was focused on gallbladder and biliary ducts (OR 1.556, P = 0.007), transplant (OR 2.371, P = 0.005), trauma (OR 3.274, P < 0.001), or urolithiasis/postrenal obstruction (OR 3.366, P < 0.001). In contrast, US examinations were significantly less likely to be negative when requested by urology (OR 0.423, P = 0.014), or when the indication for US was acute oncology (OR 0.207, P = 0.045) or appendicitis (OR 0.260, P < 0.001). The likelihood of an incidentaloma on US was significantly higher in older patients (OR 1.020 per year of age increase, P < 0.001) or when the liver was evaluated with US (OR 3.522, P < 0.001). Discussion: Nearly 50% of abdominal US examinations during on-call hours are negative, and 8% reveal an incidentaloma. Requesting specialty and indication for US affect the likelihood of a negative examination, and higher patient age and liver evaluations increase the chance of detecting an incidentaloma in this setting. These data may potentially be used to improve clinical reasoning and restrain overutilization of imaging. [ABSTRACT FROM AUTHOR]

Assessing the personality of software engineers may help to match individual traits with the characteristics of development activities such as code review and testing, as well as support managers in team composition. However, self-assessment questionnaires are not a practical solution for collecting multiple observations on a large scale. Instead, automatic personality detection, while overcoming these limitations, is based on off-theshelf solutions trained on non-technical corpora, which might not be readily applicable to technical domains like software engineering. In this article,we first assess the performance of general-purpose personality detection tools when applied to a technical corpus of developers’ e-mails retrieved from the public archives of the Apache Software Foundation.We observe a general low accuracy of predictions and an overall disagreement among the tools. Second, we replicate two previous research studies in software engineering by replacing the personality detection tool used to infer developers’ personalities from pull-request discussions and e-mails. We observe that the original results are not confirmed, i.e., changing the tool used in the original study leads to diverging conclusions. Our results suggest a need for personality detection tools specially targeted for the software engineering domain. [ABSTRACT FROM AUTHOR]

Simple Summary: While diagnosing a case of small cell neuroendocrine carcinoma (SCNEC) in the urinary tract, we found that the previous biopsy had been misdiagnosed as urothelial carcinoma (UC) because only chromogranin and synaptophysin were tested to define neuroendocrine differentiation and both tests were negative. This case led us to conduct this present study to define a panel of neuroendocrine markers to ensure the diagnosis of traditional neuroendocrine marker-negative SCNEC. We employed a decision tree classifier algorithm to analyze the expression of 17 immunohistochemical markers and found that the extent of synaptophysin (>5%) and CD117 (>20%) and the intensity of GATA3 (negative or weak) are major parameters. Since SCNEC is an aggressive tumor type and requires therapeutic approaches that differ from those used for UC, an accurate diagnosis of SCNEC is critical and this model may help pathologists accurately diagnose SCNEC in daily practice. Although SCNEC is based on its characteristic histology, immunohistochemistry (IHC) is commonly employed to confirm neuroendocrine differentiation (NED). The challenge here is that SCNEC may yield negative results for traditional neuroendocrine markers. To establish an IHC panel for NED, 17 neuronal, basal, and luminal markers were examined on a tissue microarray construct generated from 47 cases of 34 patients with SCNEC as a discovery cohort. A decision tree algorithm was employed to analyze the extent and intensity of immunoreactivity and to develop a diagnostic model. An external cohort of eight cases and transmission electron microscopy (TEM) were used to validate the model. Among the 17 markers, the decision tree diagnostic model selected 3 markers to classify NED with 98.4% accuracy in classification. The extent of synaptophysin (>5%) was selected as the initial parameter, the extent of CD117 (>20%) as the second, and then the intensity of GATA3 (≤1.5, negative or weak immunoreactivity) as the third for NED. The importance of each variable was 0.758, 0.213, and 0.029, respectively. The model was validated by the TEM and using the external cohort. The decision tree model using synaptophysin, CD117, and GATA3 may help confirm NED of traditional marker-negative SCNEC. [ABSTRACT FROM AUTHOR]

This paper is a report of recommendations for addressing translational challenges in amyloid disease research. They were developed during and following an international online workshop organized by the LINXS Institute of Advanced Neutron and X-Ray Science in March 2021. Key suggestions include improving cross-cultural communication between basic science and clinical research, increasing the influence of scientific societies and journals (vis-à-vis funding agencies and pharmaceutical companies), improving the dissemination of negative results, and strengthening the ethos of science. [ABSTRACT FROM AUTHOR]

Cellular differentiation is pivotal in health and disease. Interfering with the process of differentiation, such as inhibiting the differentiation of adipocytes and inducing the differentiation of cancer cells, is considered a therapeutic approach. Sesquiterpene lactones, primarily found in plants, have been attracted attention as differentiating/dedifferentiating agents tested on various human or animal cells. However, a consensus on sesquiterpene lactones' effects and their mechanism of action is required. In this sense, through a systematic review, we have investigated the differentiating/dedifferentiating effects of sesquiterpene lactones on human or animal cells. 13 different cell lines originated from humans, mice, and rats, in addition to the effects of a total of 21 sesquiterpene lactones, were evaluated in the included studies. These components had either inducing, inhibiting, or no effect on the cells, mediating their effects through JAK-STAT, PI3K-Akt, mitogen-activated protein kinases, NFκB, PPARγ pathways. Although nearly all inducing and inhibiting effects were attributed to cancerous and normal cells, respectively, this is likely a result of a biased study design. Few studies reported negative results along with others, and no study was found reporting only negative results. As a result, not only are the effects and mechanism of action of sesquiterpene lactones not vivid but our knowledge and decisions are also misconducted. Moreover, there is a significant knowledge gap regarding the type of evaluated cells, other sesquiterpene lactones, and the involved signaling pathways. In conclusion, sesquiterpene lactones possess significant effects on differentiation status, leading to potentially efficient therapy of obesity, osteoporosis, and cancer. However, reporting negative results and further investigations on other cells, sesquiterpene lactones, and signaling pathways are highly suggested to pave the path of sesquiterpene lactones to the clinic more consciously. [ABSTRACT FROM AUTHOR]

Cellular differentiation is pivotal in health and disease. Interfering with the process of differentiation, such as inhibiting the differentiation of adipocytes and inducing the differentiation of cancer cells, is considered a therapeutic approach. Sesquiterpene lactones, primarily found in plants, have been attracted attention as differentiating/dedifferentiating agents tested on various human or animal cells. However, a consensus on sesquiterpene lactones’ effects and their mechanism of action is required. In this sense, through a systematic review, we have investigated the differentiating/dedifferentiating effects of sesquiterpene lactones on human or animal cells. 13 different cell lines originated from humans, mice, and rats, in addition to the effects of a total of 21 sesquiterpene lactones, were evaluated in the included studies. These components had either inducing, inhibiting, or no effect on the cells, mediating their effects through JAK-STAT, PI3K-Akt, mitogen-activated protein kinases, NFκB, PPARγ pathways. Although nearly all inducing and inhibiting effects were attributed to cancerous and normal cells, respectively, this is likely a result of a biased study design. Few studies reported negative results along with others, and no study was found reporting only negative results. As a result, not only are the effects and mechanism of action of sesquiterpene lactones not vivid but our knowledge and decisions are also misconducted. Moreover, there is a significant knowledge gap regarding the type of evaluated cells, other sesquiterpene lactones, and the involved signaling pathways. In conclusion, sesquiterpene lactones possess significant effects on differentiation status, leading to potentially efficient therapy of obesity, osteoporosis, and cancer. However, reporting negative results and further investigations on other cells, sesquiterpene lactones, and signaling pathways are highly suggested to pave the path of sesquiterpene lactones to the clinic more consciously.

A 34‐question survey was sent to researchers in chemistry, physics, engineering and environmental sciences, with the aim of identifying their relationship with unsuccessful research results as well as the obstacles to and incentives for their dissemination. Most of the 310 participants were affiliated with French research and teaching institutions. Conducted within the framework of the Datacc project (datacc.org) on research and data management, supported by Lyon and Grenoble Alpes University Libraries, our study fills the gap in literature on the disciplines concerned with reporting negative results in scholarly research. It shows that 81% of the researchers surveyed have already produced relevant negative results and 75% say they are willing to publish this type of data. However, only 12.5% of respondents have had the opportunity to do so in a scientific journal. This gaping contrast between intention and practice raises questions about the barriers and potential solutions. [ABSTRACT FROM AUTHOR]

When reporting concentrations of substances in biological specimens it has been virtually universal practice to suppress negative results, initially by left-censoring negative results to zero and more recently by left-censoring to values such as limit of blank, limit of detection or even limit of quantification. Negative concentrations are obviously nonsensical and current reporting practices place proper emphasis on assisting the clinician. However, it is easily overlooked that negative concentrations are merely artefacts of data reduction and while adjusting them is sensible clinical practice there are potentially adverse consequences for statistical analysis, in particular for those parametric summaries and analyses which rely on reliable estimates of low-end uncertainty. This article puts a case for the availability of negative results, describes complications with respect to estimating variance functions and discusses practical workarounds. [ABSTRACT FROM AUTHOR]

Scientific advance is based on reproducibility, corroboration, and availability of research results. However, large numbers of experimental results that contradict previous work do not get published and many research results are not freely available as they are hidden behind paywalls. As part of COST Action "DARTER", a network of researchers in the field of RNA therapeutics, we have performed a small survey among our members and their colleagues to assess their opinion on the subject of publishing contradictory or ambiguous results and their attitude to open access (OA) publishing. Our survey indicates that, although researchers highly value publication of "negative" results, they often do not publish their own, citing lack of time and the perception that those results may not be as highly cited. OA, on the other hand, seems to be widely accepted, but in many cases not actively sought by researchers due to higher costs associated with it. [ABSTRACT FROM AUTHOR]

Cervical conization is an effective treatment for precancerous lesions. However, in cases where no high-grade lesion is identified in the surgical specimen, managing these patients may be challenging due to the absence of established follow-up protocols for negative conizations. This study aimed to assess the negative conization rates at our institution by histopathological review, identify diagnostic errors, possible risk and recurrence factors and propose follow-up strategies for this group of patients. A retrospective study from January-2010 to December-2020 analyzed patients with negative conization including all surgical techniques and procedure indications. Biopsy and cervical conizations slides were reviewed and patients who kept a negative result underwent deeper levels sectioning of the paraffin blocks with immunohistochemical stains application: p16, Ki-67 and geminin. Data were compared with a control group composed by 29 women with CIN3. Out of 1022 conizations, 186 were negative (18.1%), with 151 cases selected for the study after excluding 35 patients. Following pathology review, 4 patients were excluded due to false-positive cervical biopsy results, 16 for false-negative conization results and 9 for hidden dysplasia identified after deeper sectioning. The remaining 122 patients were considered truly negative cones (11.9%) and exhibited IHC staining with p16 positive in 20.4% of cases, low Ki-67 expression, and low geminin score in most cases. Specimens with CIN 1 had higher prevalence of p16 staining, Ki-67 expression and geminin score when compared to absence of neoplasia, nevertheless geminin had no statistical difference. Older age, higher parity and IHC pattern with negative p16, low Ki-67 and geminin expressions were identified as risk factors for negative cones (p<0.05). Only 10 patients recurred for high-grade lesions, with no statistically significant risk factors identified. The negative conization rate was 11.9%, with diagnostic errors identified across pre-surgical biopsy, cone specimen, and deeper levels. Risk factors included older age, higher parity, low expression of p16, Ki-67 and geminin (p<0.05). Recurrence represented 8.1% of the negative cones, without identification of statistically significant risk factors. Pathological review with deeper level sections and 2-year follow-up are recommended for patients with negative conizations. • Negative conizations are not infrequent, many hypotheses explain their occurrence. • Pathological review and deeper sections are essential to conduct these cases. • Negative conization results require close follow-up. • Hidden dysplasia may recur over one year after the procedure. [ABSTRACT FROM AUTHOR]

Purpose: To investigate temporal changes in the utilization and patient impact of abdominal CT during duty shifts in the past 15 years. Methods: This study included a random sample of 1761 abdominal CT scans that were made during evening and night duty shifts in a tertiary care center between 2005 and 2019. Results: The number of CT scans significantly increased (almost threefold) between 2005 and 2019 (Mann–Kendall tau of 0.829, P < 0.001). The proportion of negative CT scans (i.e., the absence of findings related to the reason that the CT scan was made and no disease deterioration or other new and clinically relevant findings compared to a previous imaging examination when available) was 40.0% (700/1749) in the entire 15-year study frame and did not significantly change over time (Mann–Kendall tau of − 0.219, P = 0.276). The overall frequency of same-day hospital discharge after negative CT was 20.6% (150/729) in the past 15 years and showed a significant increase over time (Mann–Kendall tau of 0.505, P = 0.010). The overall proportion of CT scans with incidental findings was 3.4% (60/1761) and remained statistically stable over the past 15 years (Mann–Kendall tau of − 0.057, P = 0.804). Conclusion: Over the past 15 years, the number of CT scans and the frequency of same-day hospital discharge after negative CT have increased, while the proportions of negative CT scans and incidental findings have remained stable in our tertiary care center. The data from this study can be used for interinstitutional benchmarking to define, monitor, and improve the appropriateness of imaging utilization. [ABSTRACT FROM AUTHOR]

While much of the scholarly work on ethics relating to academic authorship examines the fair distribution of authorship credit, none has yet examined situations where a researcher contributes significantly to the project, but whose contributions do not make it into the final manuscript. Such a scenario is commonplace in collaborative research settings in many disciplines and may occur for a number of reasons, such as excluding research in order to provide the paper with a clearer focus, tell a particular story, or exclude negative results that do not fit the hypothesis. Our concern in this paper is less about the reasons for including or excluding data from a paper and more about distributing credit in this type of scenario. In particular, we argue that the notion 'substantial contribution', which is part of the International Committee of Medical Journal Editors (ICMJE) authorship criteria, is ambiguous and that we should ask whether it concerns what ends up in the paper or what is a substantial contribution to the research process leading up to the paper. We then argue, based on the principles of fairness, due credit, and ensuring transparency and accountability in research, that the latter interpretation is more plausible from a research ethics point of view. We conclude that the ICMJE and other organizations interested in authorship and publication ethics should consider including guidance on authorship attribution in situations where researchers contribute significantly to the research process leading up to a specific paper, but where their contribution is finally omitted. [ABSTRACT FROM AUTHOR]

Increasing interest and pursuit of genetic testing by the general public have raised concerns about their understanding and use of their results. While most research has focused on individuals receiving positive genetic test results, there have been limited investigations assessing the understanding and utility of receiving negative genetic test results. Individuals who receive a negative (or uninformative) genetic test result may not appreciate the limitations of genetic testing and their residual disease risk. The goals of this study were to explore participant understanding and perceived utility of negative non‐diagnostic genetic test results. We conducted semi‐structured interviews with participants who received negative non‐diagnostic genetic test results from the electronic Medical Records and Genomics Network (eMERGE) testing panel at Northwestern University. A total of 17 participants were interviewed. While many expressed a lack of understanding of genetics and the relationship between genes, disease, and environment, most acknowledged that they had residual risk to develop a health problem and should continue with their routine health management. Additionally, participants expressed that their negative results had personal value, by providing them peace of mind and learning additional knowledge about themselves and their health. Participants did not anticipate that results would have an impact on their lifestyle, but felt the results were useful for sharing with their physician and could inform future genetic testing decisions. While mostly positive, some participants were disappointed not to learn more individualized results. While a more thorough exploration is necessary, findings in this study can aid efforts to improve or innovate informed consent for genomic testing, as well as scalable modes of result return that foster comprehension following negative genetic testing. [ABSTRACT FROM AUTHOR]

Abstract An important part of scientific research activities yield negative results – non-confirmatory and null data, inconclusive experiments, unexpected data. These results permeate the entire research cycle and constitute an important part of the full scientific knowledge flow generation. However, despite the acknowledgment that it is the non-confirmatory findings that result in the rejection of consolidated hypotheses that drive the progress of science, most of these investigation routes are not documented. Growing competition for resources, tenure, and impact publications induces researchers to produce “positive” results that are more likely to be published, interfering with the principles of science reproducibility and self-correction and in the scientific communication cycle. This study aims to review negative results incorporation in the traditional academic publication cycle. It also seeks to identify and systematize the main barriers that prevent researchers from publishing negative results. This exploratory study is based methodologically on the scarce literature on the subject. It confirms the initial assumption that few scientific journals accept, edit special issues or are dedicated to the publication of negative results.

Although it has been accepted by most scientists that drugs circulating in blood are eligible to hair incorporation, this cannot be considered as a general statement. A 42-year old man was found dead in his swimming pool. He was living alone, and seen alive 2 days before by a neighbour. Femoral blood, cardiac blood and hair were collected during body examination. Free morphine was identified in femoral blood at 28 ng/mL, corresponding to his treatment for chronic pain (3 × 5 mg daily for 4 months). However, with a limit of quantitation (LOQ) at 10 pg/mg, segmental hair testing (3 × 1 cm) for morphine was negative. In this paper, the author has reviewed the different factors which can be responsible of this discrepancy. Several variables can influence the detection of a drug in hair and the author has listed reasons that can account for the absence of analytical response in hair after drug administration. The drug may not be incorporated in hair. That is the case for large bio-molecules, such as hormones, which cannot be transferred from the blood capillaries to growing cells of hair. Cosmetic treatments (perming, colouring, bleaching) or environmental aggressions (ultraviolet radiation, thermal application) will always reduce the concentrations. In this case, the lack of morphine detection was attributed to the effects of chlorinated water from the swimming pool. A negative hair result is also a result. However, this can be interpreted in three different ways: 1. the owner of the hair did not take or was not exposed to the specific drug, 2. the procedure is not sensitive enough to detect the drug, or 3. something happened after drug incorporation (cosmetic treatment, environmental influence). [ABSTRACT FROM AUTHOR]

Population‐based genomic screening has the potential to improve health outcomes by identifying genetic causes of disease before they occur. While much attention has been paid to supporting the needs of the small percentage of patients who will receive a life‐altering positive genomic screening result that requires medical attention, little attention has been given to the communication of negative screening results. As there are currently no best practices for returning negative genomic screening results, we drew on experiences across the electronic medical records and genomics (eMERGE) III Network to highlight the diversity of reporting methods employed, challenges encountered in reporting negative test results, and "lessons learned" across institutions. A 60‐item survey that consisted of both multiple choice and open‐ended questions was created to gather data across institutions. Even though institutions independently developed procedures for reporting negative results, and had very different study populations, we identified several similarities of approach, including but not limited to: returning results by mail, placing results in the electronic health record via an automated process, reporting results to participants' primary care provider, and providing genetic counseling to interested patients at no cost. Differences in procedures for reporting negative results included: differences in terminology used to describe negative results, definitions of negative results, guidance regarding the meaning of negative results for participants and their family members, and recommendations for clinical follow up. Our findings highlight emerging practices for reporting negative genomic screening results and highlight the need to create patient education and clinical support tools for reporting negative screening results. [ABSTRACT FROM AUTHOR]

Accessible negative results are relevant for researchers and clinicians not only to limit their search space but also to prevent the costly re-exploration of research hypotheses. However, most biomedical relation extraction datasets do not seek to distinguish between a false and a negative relation among two biomedical entities. Furthermore, datasets created using distant supervision techniques also have some false negative relations that constitute undocumented/unknown relations (missing from a knowledge base). We propose to improve the distinction between these concepts, by revising a subset of the relations marked as false on the phenotype-gene relations corpus and give the first steps to automatically distinguish between the false (F), negative (N), and unknown (U) results. Our work resulted in a sample of 127 manually annotated FNU relations and a weighted-F1 of 0.5609 for their automatic distinction. This work was developed during the 6th Biomedical Linked Annotation Hackathon (BLAH6).

We propose a reflection on the construction of scientific knowledge and in so doing an image of this knowledge. This will allow us to develop a comparative analysis of some of the main principles underpinning the constitution of the different sciences. We will highlight the role of critical thought in science, or even "negative results," which pose limits and hence open new trajectories. In particular, we will address a misleading point of view, based on some informal concepts taken from computer science, which dominates the biological imaginary. An "ethics of knowledge" will follow, as a critical and open perspective, capable of taking on the well-intentioned responsibility of proposing universal, though not absolute, principles of knowledge. [ABSTRACT FROM AUTHOR]

Copyright of Perspectivas em Ciência da Informaçao is the property of Nova Economia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Results that do not confirm expectations are generally referred to as 'negative' results. While essential for scientific progress, they are too rarely reported in the literature – Brain–Machine Interface (BMI) research is no exception. This led us to organize a workshop on BMI negative results during the 2018 International BCI meeting. The outcomes of this workshop are reported herein. First, we demonstrate why (valid) negative results are useful, and even necessary for BMIs. These results can be used to confirm or disprove current BMI knowledge, or to refine current theories. Second, we provide concrete examples of such useful negative results, including the limits in BMI-control for complete locked-in users and predictors of motor imagery BMI performances. Finally, we suggest levers to promote the diffusion of (valid) BMI negative results, e.g. promoting hypothesis-driven research using valid statistical tools, organizing special issues dedicated to BMI negative results, or convincing institutions and editors that negative results are valuable. [ABSTRACT FROM AUTHOR]

• We compared the citation counts and citation context of negative results derived from three journals, i.e., journal of negative results in BioMedicine, PLoS One, and BMC research Notes , with those of positive results published by the same first and corresponding authors. • Negative results received 38.6% fewer citations than positive results, even after controlling for bibliographic information. • Negative results were associated with a significantly higher proportion of negative citations when compared to positive results. Negative results are a routine part of the scientific research journey, yet they often receive insufficient attention in scientific publications. In this study, we investigate the scientific impact of negative results by comparing the citations and citation context between negative and positive results. Specifically, we compared 159 negative result papers from three journals: Journal of Negative Results in BioMedicine, PLoS One , and BMC Research Notes , with 1,058 matched positive result papers authored by the same first and corresponding authors. The citation context was categorized according to three dimensions: citation aspect, citation purpose, and citation polarity. The first two were automatically provided by Citation Opinion Retrieval and Analysis (CORA), while citation polarity was manually annotated. Our analysis revealed several key findings. Firstly, negative results received 38.6 % fewer citations than positive results, even after controlling for bibliographic factors. Secondly, negative results were associated with a significantly higher proportion of negative citations when compared to positive results. Lastly, a higher proportion of negative results were negatively cited in the methods section. [ABSTRACT FROM AUTHOR]

The American Phytopathological Society (APS) is launching the new journal PhytoFrontiers™. As with many other gold open access (OA) journals, manuscripts will not be judged on novelty but rather solely on quality and scientific rigor. The expectation therefore is that the manuscripts are based on solid experimental design, robust statistical analyses, and quality technical writing. PhytoFrontiers explicitly encourages publication of negative results because it removes a significant and persistent bias from the literature. PhytoFrontiers establishes a new venue for our plant health colleagues in Europe and elsewhere who are required by their institutions or funders to publish in gold OA journals (i.e., journals that allow immediate access to all content). PhytoFrontiers complements our established journals by providing a new place for manuscripts that do not fit the subject areas currently covered in our five existing journals. These papers might cover subjects as broad as robotics, microbial taxonomy, and those that focus primarily on abiotic stress responses, in addition to all of those plant health subjects typically found in our other APS journals, and potentially other subject areas. We are excited to launch this new journal and hope you will consider PhytoFrontiers for your next submission. Follow us on our new journey on Twitter @PhytoFrontiers.[Figure: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. 2021