L’Emprisonnement est censé être une punition, un supplice, si vous voulez, mais pas un lieu de détention où le détenu est indifférent à son sort. Pourtant, on voit dans L’Étranger d’Albert Camus des ...personnages qui se trouvent, ou vont se trouver dans des situations de captivité, mais qui y font face avec honnêteté ou indifférence. On les appelle des anti-prisonniers —des êtres qui renverse l’effet de la psychologie pénale. Au lieu d’en souffrir, ils triomphent sur l’expérience et finissent par se libérer à leur façon. Si l’on observe la psychologie pénale au cours des siècles, on verra que ces personnages reflètent une vraie tranche de la population prisonnière par leur réaction insolite.La mère de Meursault passe les dernières années de sa vie dans un asile de vieillards où elle est contente, ou au moins satisfaite. L’épagneul de Salamano s’évade pour mettre fin à son supplice. Ce faisant, il détruit la joie de punir qu’exerçait Salamano. Meursault, lui-même, finit par complètement bafouer et son avocat et le juge d’instruction aussi bien que le procureur en refusant de jouer le jeu judiciaire, de lutter d’une façon malhonnête pour sauver sa vie. Ces trois personnages ne sont pas des prisonniers, mais des anti-prisonniers. Ils s’échappent de leur geôlier et détruisent la psychologie du processus de punir. Camus a créé des êtres qui peuvent sembler invraisemblables, mais qui signalent la force du révolté qui maintient son amour propre.
Nonhuman primates (NHP) have become a commonly used nonrodent species for general toxicity testing for pharmaceuticals reviewed by CDER. Their increased use in pharmaceutical testing appears to have ...been driven by both increased use in small molecule drug development programs as well as a trend for biologics making up a greater percentage of pharmaceutical development programs. While always in limited supply, the COVID-19 pandemic acutely impaired the availability of NHPs for pharmaceutical testing due to disruptions in the supply and an increased demand to support COVID-19-directed research programs. Because this disruption in the NHP supply had the potential to significantly delay the development of new medications for the treatment of diseases currently without effective treatment options, FDA issued guidance in February of 2022, under its COVID-19 Public Health Emergency authority, that was intended to help mitigate the NHP supply issue by reducing the demand for NHPs. This guidance has been withdrawn with the expiration of the public health emergency. Here we discuss what impact we expect that the withdrawal of this guidance will have on efforts to minimize NHP use.
•Nonhuman primates are a scarce but vital resource in pharmaceutical development.•The COVID-19 pandemic caused persisting disruptions in the nonhuman primate supply.•Nonhuman primates should only be used when other models are not appropriate.•Appropriate use of weight of evidence assessments can reduce NHP use.•There can be legal limitations to the data used in weight of evidence assessments.
There is strong epidemiological association between periodontal disease and cardiovascular disease but underlying mechanisms remain ill-defined. Because the human periodontal disease pathogen, ...Porphyromonas gingivalis (Pg), interacts with innate immune receptors Toll-like Receptor (TLR) 2 and CD36/scavenger receptor-B2 (SR-B2), we studied how CD36/SR-B2 and TLR pathways promote Pg-mediated atherosclerosis. Western diet fed low density lipoprotein receptor knockout (Ldlr°) mice infected orally with Pg had a significant increase in lesion burden compared with uninfected controls.This increase was entirely CD36/SR-B2-dependent, as there was no significant change in lesion burden between infected and uninfected Cd36o/Ldlro mice corrected. Western diet feeding promoted enhanced CD36/SR-B2-dependent IL1β generation and foam cell formation as a result of Pg lipopolysaccharide (PgLPS) exposure. CD36/SR-B2 and TLR2 were necessary for inflammasome activation and optimal IL1ß generation, but also resulted in LPS induced lethality (pyroptosis). Modified forms of LDL inhibited Pg-mediated IL1ß generation in a CD36/SR-B2-dependent manner and prevented pyroptosis, but promoted foam cell formation. Our data show that Pg infection in the oral cavity can lead to significant TLR2-CD36/SR-B2 dependent IL1ß release. In the vessel wall, macrophages encountering systemic release of IL1ß, PgLPS and modified LDL have increased lipid uptake, foam cell formation, and release of IL1ß, but because pyroptosis is inhibited, this enables macrophage survival and promotes increased plaque development. These studies may explain increased lesion burden as a result of periodontal disease, and suggest strategies for development of therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an ...important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio HR, 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
The substitution of p-block heteroatoms into polyaromatic hydrocarbons offers the potential for introducing enhanced molecular properties and advancing material development for electro-optical ...applications. Using density functional theory, we characterize the substitution of boron and nitrogen atoms into a 2,3,6,7,10,11-hexakis(hexathiol)triphenylene (TTP) core, a precursor for a material with a discotic liquid crystal phase, to determine the strength of exciton dissociation and the influence doping has on the formation of a heterojunction with graphene. The substitution of nitrogen and boron into the TTP motif enables tunability of both electron and hole coupling between hetero- and homodyads. The coupling is found to far exceed that of TTP and varied transport behavior with different combinations of doped cores of nitrogen-TTP and boron-TTP is reported. Heterodyads of nitrogen-TTP with boron-TTP appear to be ambipolar in electron/hole coupling, whereas heterodyads of boron- or nitrogen-TTP with TTP form strong electron coupling dyads and homodyads of nitrogen-TTP and boron-TTP form strong hole coupling. Finally, we describe the heterojunction of nitrogen- or boron-TTP with monolayer graphene and observe Ohmic contacts with large hole transport barriers. The presence of induced dipoles occurs at the interface in all heterojunctions, suggesting the possibility of tuning the junction with external potentials and improving exciton dissociation.
To measure housing assistance and homelessness among persons living with HIV (PLWH) and their association with health.
Exposure categories were: experiencing homelessness (per emergency shelter use ...or self-report), receiving housing assistance (per housing subsidy) without homelessness, or neither homelessness nor receiving housing assistance. Outcomes were: engagement (≥1 visit) and retention (≥2 visits ≥90 days apart) in HIV-related medical care and one-time (latest viral load) and durable (≥1 viral load test, all suppressed) HIV viral suppression (<200 copies/mL). Among PLWH in New York City (NYC), we calculated and conducted modified Poisson regressions of the four outcomes according to exposure category.
During 2018, 45% of NYC's 84,053 PLWH received housing assistance, and 8% experienced homelessness. Relative to homelessness, receipt of assistance without homelessness was associated with 3-7% higher adjusted relative risk (ARR) of engagement and retention in care and 31-64% higher ARR of one-time and durable viral suppression. Relative to not receiving assistance, receipt of assistance without homelessness was associated with 6-18% higher ARR of care and 2-5% lower ARR of viral suppression.
Programs promoting housing stability may support HIV care and viral suppression, particularly if preventing homelessness. These may help improve HIV care and suppression rates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during ...whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition.
This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden.
Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95;
= .02). This difference was attributable to less deterioration in executive function at 4 months (23.3%
40.4%;
= .01) and learning and memory at 6 months (11.5%
24.7%
= .049 and 16.4%
33.3%
= .02, respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (
= .04), less difficulty with remembering things (
= .01), and less difficulty with speaking (
= .049) and using imputed data, less interference of neurologic symptoms in daily activities (
= .008) and fewer cognitive symptoms (
= .01).
HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.
Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group ...previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility.
A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively.
Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation (
< .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively.
Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).
Human African trypanosomiasis, caused by the gambiense subspecies of Trypanosoma brucei (gHAT), is a deadly parasitic disease transmitted by tsetse. Partners worldwide have stepped up efforts to ...eliminate the disease, and the Chadian government has focused on the previously high-prevalence setting of Mandoul. In this study, we evaluate the economic efficiency of the intensified strategy that was put in place in 2014 aimed at interrupting the transmission of gHAT, and we make recommendations on the best way forward based on both epidemiological projections and cost-effectiveness. In our analysis, we use a dynamic transmission model fit to epidemiological data from Mandoul to evaluate the cost-effectiveness of combinations of active screening, improved passive screening (defined as an expansion of the number of health posts capable of screening for gHAT), and vector control activities (the deployment of Tiny Targets to control the tsetse vector). For cost-effectiveness analyses, our primary outcome is disease burden, denominated in disability-adjusted life-years (DALYs), and costs, denominated in 2020 US$. Although active and passive screening have enabled more rapid diagnosis and accessible treatment in Mandoul, the addition of vector control provided good value-for-money (at less than $750/DALY averted) which substantially increased the probability of reaching the 2030 elimination target for gHAT as set by the World Health Organization. Our transmission modelling and economic evaluation suggest that the gains that have been made could be maintained by passive screening. Our analysis speaks to comparative efficiency, and it does not take into account all possible considerations; for instance, any cessation of ongoing active screening should first consider that substantial surveillance activities will be critical to verify the elimination of transmission and to protect against the possible importation of infection from neighbouring endemic foci.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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