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Vulnerability, agency, and the research encounter: family members' experiences and perceptions of participating in an observational clinical study in Kenya
No full textPediatric clinical research in low-resourced countries involves individuals defined as "vulnerable" in research ethics guidance. Insights from research participants can strengthen the design and oversight of studies. We share family members' perspectives and experiences of an observational clinical study conducted in one Kenyan hospital as part of an integrated empirical ethics study. Employing qualitative methods, we explored how research encounters featured in family members' care-seeking journeys. Our data reveals that children's vulnerability is intricately interwoven with that of their families, and that research processes and procedures can inadvertently add to hidden burdens for families. In research, the potential for layered and intersecting situational and structural vulnerability should be considered, and participants' agency in constrained research contexts actively recognized and protected
Enhancing the collectivist critique: accounts of the human enhancement debate
No full textIndividualist ethical analyses in the enhancement debate have thus far prioritised or only considered the interests and concerns of parents and the future child. The collectivist critique of the human enhancement debate argues that rather than pure individualism, a focus on collectivist, or group-level ethical considerations is needed for balanced ethical analysis of specific enhancement interventions. Here I defend this argument for the insufficiency of pure individualism. However, existing collectivist arguments tend to take a negative approach in analysis that hinders them from adequately contributing to balanced ethical analysis, and often leading to a prohibitive stance. I argue this is due to two common problems with collectivist arguments: inappropriate acceptance of individualist assumptions, and failure to appropriately weigh individual vs collective ethical considerations. To further develop the collectivist critique in the enhancement debate, I suggest we may look to collectivism in public health ethics collectivism, which avoids these problems
State of the art in adoption of contact tracing apps and recommendations regarding privacy protection and public health: systematic review
No full textBackground: During the outbreak of the COVID-19 pandemic, contact tracing mobile applications have received a lot of public attention. The ongoing debate highlights the challenges with the adoption of data-driven innovation: how to ensure an appropriate level of protection of individual data and maximize public health benefits derivable from the collected data.
Objective: The aim of the study was to analyse available COVID-19 contact tracing applications and verify to what extent public health interests and data privacy standards can be fulfilled simultaneously in the process of the adoption of digital health technologies.
Methods: A systematic review of Pubmed, Medbase, and grey literature was performed to identify available contact tracing applications. Two checklists were developed to evaluate (1) the compliance with the data privacy standards (2) fulfillment of public health interests. Based on both checklists, a scorecard with a selected set of minimum requirements was established as well. It was to estimate whether the balance between the objective of data privacy and public health interests can be achieved to ensure the broad adaptation of digital technologies.
Results: Overall, 21 contact tracing applications were reviewed. In total, 11 criteria were defined to assess the usefulness of each digital technology for public health interests. The most frequently installed features related to the contact alerting and governmental accountability. The least frequent was the availability of the system of medical or organizational support. Only one app provided the threshold for the population coverage needed for the digital solution to be effective. In total, 12 criteria were used to assess the compliance of contact tracing application with data privacy regulations. The explicit user consent, voluntary basis, and the adoption of anonymization techniques were among most frequently fulffiled criteria. The information regarding the personal data breach and data gathered from children was mostly lacking. The balance between standards of data protection and public health benefits were achieved most and least with COVIDSafe, and Alipay Health Code respectively.
Conclusions: The contact tracing application with a high level of compliance with standards of data privacy tend to fulfill public health interests to a limited extend. Simultaneously, the digital technologies with a lower level of data privacy protection used to allow for more data collection. Overall the review indicated that consistent number of applications appeared to be compliant with the standards of data privacy, while their usefulness from the public health perspective can still be maximized
The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia
No full textBackground
Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL.
Methods
Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15–26 years with primary or relapsed T-ALL, using a combination of Genome-Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real-time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1–14 years), 439 TYA (15–24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search.
Results
Genomic characterization of this large cohort of TYA T-ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation – relapsed T-ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways.
Conclusions
All genetic aberrations in TYA T-ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T-ALL exhibits a transitional genomic profile. Analysis of matched presentation – relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub-clones associated with drug resistance (NT5C2 and TP53 mutations) and re-iterative mutation of known key T-ALL drivers, including NOTCH1
Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial
No full textPurpose
We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes.
Methods
In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18–69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline.
Results
At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54–0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress.
Conclusion
Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm
Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines
No full textA one-flask, two-step procedure from 3-amino-2-methyl-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one affords the Streptomyces secondary metabolites legonmycins A and B – three operations overall from methyl N-Boc-prolinate. The key step proceeds in each case via N,O-diacylation, then selective oxidative hydrolysis of the intermediate bicyclic pyrrole and establishes a precedent for the synthesis of related C(7a)-hydroxylated pyrrolizidines
Asociación de Mujeres Afro por la Paz: Feminism with the body and face of a woman
No full textThe Asociación de Mujeres Afro por la Paz (Association of Afro Women for Peace—AFROMUPAZ) is an organization of displaced Afro-Colombian women now based in Bogotá. The organization represents a differential brand of feminism in the face of historical and ongoing violence and provides community, support, and employment opportunities for dozens of women and their families. Its “feminism with a woman’s body and face” is part of the landscape of popular feminism in the region, but its specific social location and its actions cannot be understood without a deliberate and critical understanding of race.
La Asociación de Mujeres Afro por la Paz (AFROMUPAZ) es una organización de mujeres afrocolombianas desplazadas ahora radicadas en Bogotá. La organización representa un tipo distinto de feminismo frente a la violencia histórica y continua, y ofrece oportunidades comunitarias, de apoyo y de empleo para decenas de mujeres y sus familias. Su “feminismo en cuerpo y cara de mujer” es parte del panorama del feminismo popular en la región, pero la comprensión de su ubicación social específica y acciones requiere de un acercamiento deliberado y crítico de la cuestión racial
A catalytic asymmetric cross-coupling approach to the synthesis of cyclobutanes
No full textStereodefined four-membered rings are common motifs in bioactive molecules and versatile intermediates in organic synthesis. However, the synthesis of complex, chiral cyclobutanes is a largely unsolved problem and there is a need for general and modular synthetic methods. Here we report a series of asymmetric cross-coupling reactions between cyclobutenes and arylboronic acids which are initiated by Rh-catalysed asymmetric carbometallation. After the initial carborhodation, Rh–cyclobutyl intermediates undergo chain-walking or C–H insertion so that overall a variety of additions such as reductive Heck reactions, 1,5-addition and homoallylic substitution are observed. The synthetic applicability of these highly stereoselective transformations is demonstrated in the concise syntheses of the drug candidates Belaperidone and PF-04862853. We anticipate this approach will be widely adopted by synthetic and medicinal chemists. While the carbometallation approach reported here is exemplified with Rh and arylboronic acids, it is likely to be applicable to other metals and nucleophiles
Modulation of recognition memory performance by light and its relationship with cortical EEG theta and gamma activities
No full textAcute exposure to light exerts widespread effects on physiology, in addition to its key role in photoentrainment. Although the modulatory effect of light on physiological arousal is well demonstrated in mice, its effect on memory performance is inconclusive, as the direction of the effect depends on the nature of the behavioural task employed and/or the type of stimulus utilised. Moreover, in all rodent studies that reported significant effects of light on performance, brain activity was not assessed during the task and thus it is unclear how brain activity was modulated by light or the exact relationship between light-modulated brain activity and performance. Here we examine the modulatory effects of light of varying intensities on recognition memory performance and frontoparietal waking electroencephalography (EEG) in mice using the spontaneous recognition memory task. We report a light-intensity-dependent disruptive effect on recognition memory performance at the group level, but inspection of individual-level data indicates that light-intensity-dependent facilitation is observed in some cases. Using linear mixed-effects models, we then demonstrate that EEG fast theta (θ) activity at the time of encoding negatively predicts recognition memory performance, whereas slow gamma (γ) activity at the time of retrieval positively predicts performance. These relationships between θ/γ activity and performance are strengthened by increasing light intensity. Thus, light modulates θ and γ band activities involved in attentional and mnemonic processes, thereby affecting recognition memory performance. However, extraneous factors including the phase of the internal clock at which light is presented and homeostatic sleep pressure may determine how photic input is translated into behavioural performance
Progression from external pilot to definitive randomised controlled trial: a methodological review of progression criteria reporting
No full textObjectives Prespecified progression criteria can inform the decision to progress from an external randomised pilot trial to a definitive randomised controlled trial. We assessed the characteristics of progression criteria reported in external randomised pilot trial protocols and results publications, including whether progression criteria were specified a priori and mentioned in prepublication peer reviewer reports.
Study design Methodological review.
Methods We searched four journals through PubMed: British Medical Journal Open, Pilot and Feasibility Studies, Trials and Public Library of Science One. Eligible publications reported external randomised pilot trial protocols or results, were published between January 2018 and December 2019 and reported progression criteria. We double data extracted 25% of the included publications. Here we report the progression criteria characteristics.
Results We included 160 publications (123 protocols and 37 completed trials). Recruitment and retention were the most frequent indicators contributing to progression criteria. Progression criteria were mostly reported as distinct thresholds (eg, achieving a specific target; 133/160, 83%). Less than a third of the planned and completed pilot trials that included qualitative research reported how these findings would contribute towards progression criteria (34/108, 31%). The publications seldom stated who established the progression criteria (12/160, 7.5%) or provided rationale or justification for progression criteria (44/160, 28%). Most completed pilot trials reported the intention to proceed to a definitive trial (30/37, 81%), but less than half strictly met all of their progression criteria (17/37, 46%). Prepublication peer reviewer reports were available for 153/160 publications (96%). Peer reviewer reports for 86/153 (56%) publications mentioned progression criteria, with peer reviewers of 35 publications commenting that progression criteria appeared not to be specified.
Conclusions Many external randomised pilot trial publications did not adequately report or propose prespecified progression criteria to inform whether to proceed to a future definitive randomised controlled trial