Tectonomorphic evolution of Marie Byrd Land - Implications for Cenozoic rifting activity and onset of West Antarctic glaciation

The West Antarctic Rift System is one of the largest continental rifts on Earth. Because it is obscured by the West Antarctic Ice Sheet, its evolution is still poorly understood. Here we present the first low-temperature thermochronology data from eastern Marie Byrd Land, an area that stretches ~ 1000 km along the rift system, in order to shed light on its development. Furthermore, we petrographically analysed glacially transported detritus deposited in the marine realm, offshore Marie Byrd Land, to augment the data available from the limited terrestrial exposures. Our data provide information about the subglacial geology, and the tectonic and morphologic history of the rift system. Dominant lithologies of coastal Marie Byrd Land are igneous rocks that intruded (presumably early Paleozoic) low-grade meta-sedimentary rocks. No evidence was found for un-metamorphosed sedimentary rocks exposed beneath the ice. According to the thermochronology data, rifting occurred in two episodes. The earlier occurred between ~ 100 and 60 Ma and led to widespread tectonic denudation and block faulting over large areas of Marie Byrd Land. The later episode started during the Early Oligocene and was confined to western Pine Island Bay area. This Oligocene tectonic activity may be linked kinematically to previously described rift structures reaching into Bellingshausen Sea and beneath Pine Island Glacier, all assumed to be of Cenozoic age. However, our data provide the first direct evidence for Cenozoic tectonic activity along the rift system outside the Ross Sea area. Furthermore, we tentatively suggest that uplift of the Marie Byrd Land dome only started at ~ 20 Ma; that is, nearly 10 Ma later than previously assumed. The Marie Byrd Land dome is the only extensive part of continental West Antarctica elevated above sea level. Since the formation of a continental ice sheet requires a significant area of emergent land, our data, although only based on few samples, imply that extensive glaciation of this part of West Antarctica may have only started since the early Miocene

Age-specific oncogenic pathways in head and neck squamous cell carcinoma - are elderly a different subcategory?

BACKGROUND: In recent clinical practice, an increasing number of elderly patients suffering from head and neck squamous cell carcinoma (HNSCC) of unknown pathophysiology is observed. The majority of HNSCC patients can roughly be divided into three subcategories. First, a small group of young patients who present with variants of genomic aberrations and inheritable diseases like Fanconi anaemia. Second, an increasing population of HPV-related HNSCCs that are regarded as genomic stable tumours with a more favourable prognosis. Though HPV-related tumours used to be more common among younger males, a notable rise in the elderly population is observed. The third subcategory, that of HPV-negative tumours, has been shown to be more heterogeneous with involvement of a variety of oncogenic pathways related to lifestyle factors like smoking and alcohol consumption, often seen in middle-aged males. Some of these pathways could be related to age, such as TP53 alterations, EGFR activation, apoptotic pathway alterations and field cancerization. CONCLUSIONS: In this narrative review, we provide an overview of established and newly discovered age-specific pathophysiological mechanisms underlying HNSCC. We propose a fourth subcategory of patients with a suspected different pathophysiology: elderly (HPV-negative) HNSCC patients without a history of tobacco and alcohol consumption. In this subcategory, carcinogenesis seems to be a multi-step process based on genomic instability, immunosenescence, cell cycle disruption and telomere shortening. To conclude, we discuss suggestions for future research to fill the knowledge gap about age-dependent HNSCC carcinogenesis

Patient engagement in designing, conducting, and disseminating clinical pain research : IMMPACT recommended considerations

The consensus recommendations are based on the views of IMMPACT meeting participants and do not necessarily represent the views of the organizations with which the authors are affiliated. The following individuals made important contributions to the IMMPACT meeting but were not able to participate in the preparation of this article: David Atkins, MD (Department of Veterans Affairs), Rebecca Baker, PhD (National Institutes of Health), Allan Basbaum, PhD (University of California San Francisco), Robyn Bent, RN, MS (Food and Drug Administration), Nathalie Bere, MPH (European Medicines Agency), Alysha Croker, PhD (Health Canada), Stephen Bruehl, PhD (Vanderbilt University), Michael Cobas Meyer, MD, MBS (Eli Lilly), Scott Evans, PhD (George Washington University), Gail Graham (University of Maryland), Jennifer Haythornthwaite, PhD (Johns Hopkins University), Sharon Hertz, MD (Hertz and Fields Consulting), Jonathan Jackson, PhD (Harvard Medical School), Mark Jensen, PhD (University of Washington), Francis Keefe, PhD (Duke University), Karim Khan, MD, PhD, MBA (Canadian Institutes of Health Research), Lynn Laidlaw (University of Aberdeen), Steven Lane (Patient-Centered Outcomes Research Institute), Karen Morales, BS (University of Maryland), David Leventhal, MBA (Pfizer), Jeremy Taylor, OBE (National Institute for Health Research), and Lena Sun, MD (Columbia University). The manuscript has not been submitted, presented, or published elsewhere. Parts of the manuscript have been presented in a topical workshop at IASP World Congress on Pain in Toronto, in 2022.Peer reviewedPublisher PD

A randomized, double-blind, placebo-controlled trial of deprenyl and thioctic acid in human immunodeficiency virus-associated cognitive impairment

Cognitive impairment is a frequent manifestation of advanced human immunodeficiency virus (HIV) infection. The response to antiretroviral medication is often partial and poorly sustained. Recent studies suggest that free radical production within the CNS and neuronal apoptosis may play important roles in the pathogenesis of HIV dementia. We conducted a randomized double-blind, placebo-controlled trial using a parallel group, 2× 2 factorial design evaluating deprenyl, a monoamine oxidase B inhibitor and putative anti-apoptotic agent, and thioctic acid, an antioxidant, in 36 patients with HIV-associated cognitive impairment. Both deprenyl and thioctic acid were well tolerated with few adverse events. Deprenyl recipients showed significant improvement on tests of verbal memory compared with patients not taking deprenyl. Thioctic acid treatment did not improve cognitive function. These results suggest that deprenyl treatment is associated with cognitive improvement in subjects with mild HIV-associated cognitive impairment, whereas thioctic acid has no benefit. A larger efficacy trial is needed to assess the long-term effect of deprenyl on cognitive performance in patients with HIV infection. Human immunodeficiency virus type 1 (HIV-1)-associated dementia complex(HIV dementia) occurs in 15 to 20% of acquired immunodeficiency syndrome(AIDS) patients and is characterized by cognitive impairment, motor dysfunction, and behavioral changes.1-5 The cognitive impairment includes mental slowing, forgetfulness, and poor concentration. Motor symptoms include loss of fine motor control, clumsiness, unsteady gait, and tremor. Behavioral changes include apathy, lethargy, and depression.2,3,6 HIV dementia is usually a rapidly progressive disorder with a mean survival of about 6 months,2 although recently, patients with slower progression or a stable course have been identified.7 HIV-1-associated minor cognitive motor disorder, a milder syndrome, is estimated to occur in 25% of patients with symptomatic HIV infection.8 Few available antiretroviral agents have been studied for the treatment of HIV dementia. Open label studies with zidovudine (ZDV) in demented patients showed improvements in clinical functioning, neuropsychological performance, and neuroimaging studies.9 ZDV, in a placebo-controlled blinded study, also improved neuropsychological function in AIDS or AIDS-related complex patients without dementia.10 The only placebo-controlled trial of ZDV in HIV dementia demonstrated the greatest neurocognitive improvement only with very high dosages (i.e., 2,000 mg/day).11 Unfortunately, the response to ZDV treatment may be short-lived or associated with intolerable side effects and therefore often unsatisfactory. There is very limited information about the therapeutic effects of other antiretroviral medications (e.g., dideoxynucleosides)12 or protease inhibitors. Neurotoxins from HIV-infected activated macrophages or microglia interacting with astrocytes may play a central pathogenetic role in HIV dementia.13,14 Putative neurotoxins include cytokines (tumor necrosis factor alpha [TNF-α]) and oxygen radicals.2,15 Both TNF-α and hydroxyl free radicals may stimulate apoptosis (programmed cell death), and apoptotic neurons have been demonstrated in the cerebral cortex and basal ganglia of both children and adults with HIV encephalitis.16,17 We hypothesized that these indirect mechanisms of neuronal injury could be modified by deprenyl and thioctic acid to improve or even prevent HIV-associated cognitive impairment. Deprenyl, a selective monoamine oxidase type B inhibitor, at very low dosages in in vitro and in vivo systems has a trophic effect on injured neurons.18-21 Thioctic acid is a naturally occurring enzymatic cofactor for pyruvate dehydrogenase and alpha oxoglutarate dehydrogenase and scavenges harmful hydroxyl radicals and other reactive oxygen species.22,23 We conducted a randomized, double-blind, placebo-controlled clinical trial of deprenyl and thioctic acid to assess their safety and tolerability and to assess their impact on HIV-associated cognitive impairment in HIV seropositive (HIV+) patients

Research objectives and general considerations for pragmatic clinical trials of pain treatments: IMMPACT statement

Many questions regarding the clinical management of people experiencing pain and related health policy decision-making may best be answered by pragmatic controlled trials. To generate clinically relevant and widely applicable findings, such trials aim to reproduce elements of routine clinical care or are embedded within clinical workflows. In contrast with traditional efficacy trials, pragmatic trials are intended to address a broader set of external validity questions critical for stakeholders (clinicians, healthcare leaders, policymakers, insurers, and patients) in considering the adoption and use of evidence-based treatments in daily clinical care. This article summarizes methodological considerations for pragmatic trials, mainly concerning methods of fundamental importance to the internal validity of trials. The relationship between these methods and common pragmatic trials methods and goals is considered, recognizing that the resulting trial designs are highly dependent on the specific research question under investigation. The basis of this statement was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) systematic review of methods and a consensus meeting. The meeting was organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership. The consensus process was informed by expert presentations, panel and consensus discussions, and a preparatory systematic review. In the context of pragmatic trials of pain treatments, we present fundamental considerations for the planning phase of pragmatic trials, including the specification of trial objectives, the selection of adequate designs, and methods to enhance internal validity while maintaining the ability to answer pragmatic research questions

Exhumation history along the eastern Amundsen Sea coast, West Antarctica, revealed by low-temperature thermochronology

West Antarctica experienced a complex tectonic history, which is still poorly documented, in part due to extensive ice cover. Here we reconstruct the Cretaceous to present thermotectonic history of Pine Island Bay area and its adjacent coasts, based on a combination of apatite and zircon fission track and apatite (U-Th-Sm)/He thermochronology. In addition, we report petrographic information for the catchments of Pine Island, Thurston Island, and Thwaites glaciers. Our data suggest that the underlying bedrock of the Pine Island and Thwaites Glacier catchments are very different and vary from granitoids to (Cenozoic?) volcanogenic sequences and low-grade metamorphics. Our thermochronology data show that the upper crustal rocks of Pine Island Bay experienced very rapid cooling during the late Cretaceous. We attribute this rapid cooling of basement rocks and associated reduction in mean elevation to tectonic denudation driven by gravitational collapse of the Cretaceous orogen along the proto-Pacific Gondwana margin. Rapid Cretaceous crustal cooling was followed by very slow cooling during the Cenozoic, with no erosional response—within the limits of thermochronological methods—to the onset of glaciation and subsequent climatic changes. Cenozoic rifting within the West Antarctic Rift appears to have had little effect on erosion processes around Pine Island Bay; instead, our data suggest Cenozoic crustal tilting toward Pine Island Trough, a major geomorphic feature previously suggested to be a branch of the rift system