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"Grit, J"
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The best American science & nature writing. 2023
\"Twenty science and nature essays that represent the best examples of the form published in 2022.\" -- Provided by publisher.
Book
Institutional work to maintain, repair, and improve the regulatory regime: How actors respond to external challenges in the public supervision of ongoing clinical trials in the Netherlands
National regulatory regimes for supervising ongoing clinical trials are affected by external challenges, both international, such as harmonization of EU legislation, and national, such as critical reviews of incidents. This study examines how supervisory bodies dealing with ongoing trials respond to external challenges of the past two decades and engage in institutional work to maintain, repair, or improve the Dutch regulatory regime. International and national regulatory documents were analyzed and interviews (n = 27) were conducted with various actors, including public supervisory bodies, hospital staff, and boards of directors. In the Netherlands, EU harmonization directed at centralizing and coordinating the regulatory regime for good clinical trial practice in Member States has paradoxically led to further fragmentation. The resulting ambiguity and inefficiency remained largely unresolved until a serious incident in a university hospital became a catalyst to clarify both the interconnected responsibilities and working relationships of various supervisory bodies. New legislation and regulatory methods were implemented, and actors outside the legislative framework became active in the field in order to strengthen supervision of ongoing trials, further multiplying yet also aligning with existing regulatory regimes. Public supervision of ongoing trials is fragmented in the Netherlands because the responsibilities and resources are unevenly distributed. In countries like the Netherlands, public supervisory bodies must do a great deal of institutional work to align with new EU regulations and still safeguard their traditional regulatory mechanisms that protect human safety. However, national regulatory traditions also offer new opportunities to strengthen the quality assurance of clinical trials.
Journal Article
An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation
Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an
N
-methyl-
d
-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (
P
<0.001) and blood (
P
=0.001 and
P
<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
Journal Article
Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study
Because survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy.
195 patients with low-grade glioma (of whom 104 had received radiotherapy 1–22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability.
Low-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function.
Our findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.
Journal Article
Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: a comparative study
Investigates the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy. Some 195 patients with low-grade glioma (of whom 104 had received radiotherapy 1-22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention. (Original abstract - amended)
Journal Article
NEW LIGHT ON NEGRO RIGHTS
During the war of the Revolution, that primitive era of the nation's life, that golden age of public and private virtue, as we are accustomed to regard it, free Negroes voted in all the...
Newspaper Article
Negro Poet of Royal Lineage
Alexander Sergejewitch Poushkin, the Russian Negro poet, was born in the Schwarzhaus on the German street in Moscow on Ascension day, May (Russian calendar) 26, June 7, 1799.
Book Review
Delocalization of exciton and electron wavefunction in non-fullerene acceptor molecules enables efficient organic solar cells
A major challenge for organic solar cell (OSC) research is how to minimize the tradeoff between voltage loss and charge generation. In early 2019, we reported a non-fullerene acceptor (named Y6) that can simultaneously achieve high external quantum efficiency and low voltage loss for OSC. Here, we use a combination of experimental and theoretical modeling to reveal the structure-property-performance relationships of this state-of-the-art OSC system. We find that the distinctive π–π molecular packing of Y6 not only exists in molecular single crystals but also in thin films. Importantly, such molecular packing leads to (i) the formation of delocalized and emissive excitons that enable small non-radiative voltage loss, and (ii) delocalization of electron wavefunctions at donor/acceptor interfaces that significantly reduces the Coulomb attraction between interfacial electron-hole pairs. These properties are critical in enabling highly efficient charge generation in OSC systems with negligible donor-acceptor energy offset.
Y6, as a non-fullerene acceptor for organic solar cells, has attracted intensive attention because of the low voltage loss and high charge generation efficiency. Here, Zhang et al. find that the delocalization of exciton and electron wavefunction due to strong π-π packing of Y6 is the key for the high performance.
Journal Article
Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.
Blocking immune checkpoints is a promising strategy to treat lung cancer, but patients often become resistant to the therapy. Here, the authors analyse resistance in mouse models of lung cancer and show in mice and two patients, an increase in the expression of TIM3, which is also involved in the immune response to cancer.
Journal Article
Physical activity and prevalence and incidence of mental disorders in adolescents and young adults
Although positive effects of physical activity on mental health indicators have been reported, the relationship between physical activity and the development of specific mental disorders is unclear.
A cross-sectional (12-month) and prospective-longitudinal epidemiological study over 4 years in a community cohort of 2548 individuals, aged 14-24 years at outset of the study. Physical activity and mental disorders were assessed by the DSM-IV Composite International Diagnostic Interview (CIDI) with an embedded physical activity module. Multiple logistic regression analyses controlling for age, gender and educational status were used to determine the cross-sectional and prospective associations of mental disorders and physical activity.
Cross-sectionally, regular physical activity was associated with a decreased prevalence of any and co-morbid mental disorder, due to lower rates of substance use disorders, anxiety disorders and dysthymia. Prospectively, subjects with regular physical activity had a substantially lower overall incidence of any and co-morbid mental disorder, and also a lower incidence of anxiety, somatoform and dysthymic disorder. By contrast, the incidence of bipolar disorder was increased among those with regular physical activity at baseline. In terms of the population attributable fraction (PAF), the potential for preventive effects of physical activity was considerably higher for men than for women.
Regular physical activity is associated with a substantially reduced risk for some, but not all, mental disorders and also seems to reduce the degree of co-morbidity. Further examination of the evidently complex mechanisms and pathways underlying these associations might reveal promising new research targets and procedures for targeted prevention.
Journal Article