Mindfulness and Pain Regulation: The Role of Acceptance and Commitment Therapy for Individuals with Chronic Pain

Chronic pain is a significant and widely prevalent health condition which requires comprehensive care to address the many facets contributing to symptomatology. In 2016, 20% of American adults (about 50 million) reported experiencing chronic pain, of which 7.4% indicated that chronic pain frequently limited their life and participation in activities within the past 3 months (CDC, 2018). As a result, many individuals with chronic pain turn to opioid-based medication for pain relief, but long-term use of opioids actually increases pain sensation (Tobin, 2019). Moreover, opioid medication is unable to target underlying mental health components which emerge as part of chronic pain conditions. Thus, non-pharmacological treatment is needed to relieve the burden of chronic pain and improve cognitive and emotional processing as well as views of self (Skelly et al., 2018). Acceptance and Commitment Therapy (ACT) is a highly effective transdiagnostic intervention used to treat chronic pain by teaching individuals coping skills through mindfulness and behavioral activation (Bai et al., 2020; Dindo et al., 2017). Based on extensive data, ACT is shown to correlate with an increase in psychological flexibility, pain acceptance, and reductions in feelings of pain-related stigma (Aytur et al., 2022; Ding & Zheng, 2022; Meier et al., 2021; Feliu-Soler, 2018). Given the necessity of remote healthcare intervention, especially relevant during the recent pandemic, there is an urgent need to evaluate the efficacy of ACT in a tele-practice delivery model which will broaden the availability of the treatment to reach far larger numbers of patients. As a complement to ACT, recreational therapy (RT) is likely efficacious for treatment of chronic pain and associated symptoms. Similar to the underlying goals of ACT, RT focuses on personal values, improved functioning, quality of life, independence, and recovery (Froutan, 2022). The purpose of this paper is to expand upon a prior pilot study assessing feasibility of a non-pharmacological approach to chronic pain treatment using a tele-practice intervention that combines ACT with RT (TeleACT-RT). Specifically, this paper will evaluate the efficacy of the TeleACT-RT intervention on improving mindfulness in participants with chronic pain. With a focus on the concept of mindfulness, this study aims to extend the previous findings from the TeleACT-RT study by quantifying the impact of ACT on metrics of mindfulness using the Five Facet Mindfulness Questionnaire (FFMQ; Baer et al., 2004, 2008). Results suggest that TeleACT-RT was associated with a significant increase in mindfulness scores after the intervention, as well as improved scores in numerous other domains (e.g., psychological flexibility, pain acceptance, and social role participation) (Roy, 2022). These findings complemented prior research suggesting that TeleACT-RT was associated with a wide range of improvements in chronic pain. (Roy, 2022). Roy et al. (2022) explored the feasibility of administering this intervention through a 6-week tele-practice TeleACT-RT modality within the context of the COVID-19 pandemic through a pilot-study. Findings from this study revealed positive behavior outcomes, encompassing increased psychological flexibility, pain acceptance, and lower extremity function, while simultaneously showing decreased feelings of pain-related stigma (Roy, 2022). Additionally, participants reported being satisfied with the tele-practice modality of delivery and provided positive feedback regarding their overall quality of life post-treatment with ACT

Modelling the COVID-19 pandemic in context : An international participatory approach

Funding RA is funded by the Bill and Melinda Gates Foundation (OPP1193472). LW is funded by the Li Ka Shing Foundation. CF is funded by grant #2017/26770-8, São Paulo Research Foundation (FAPESP). The CoMo Consortium has support from the Oxford University COVID-19 Research Response Fund (ref: 0009280). Scientific writing assistance and editorial support was provided by Adam Bodley, according to Good Publication Practice guidelines.Peer reviewedPublisher PD

Potential health and economic impacts of dexamethasone treatment for patients with COVID-19

Acknowledgements We thank all members of the COVID-19 International Modelling Consortium and their collaborative partners. This work was supported by the COVID-19 Research Response Fund, managed by the Medical Sciences Division, University of Oxford. L.J.W. is supported by the Li Ka Shing Foundation. R.A. acknowledges funding from the Bill and Melinda Gates Foundation (OPP1193472).Peer reviewedPublisher PD

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, <scp>genotype–phenotype</scp> correlations and common mechanisms

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (&gt;60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS‐like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or “DTRs”). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype–phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Implementation of human papillomavirus video education for women participating in mass cervical cancer screening in Tanzania.

BACKGROUND: Because the global disease burden of cervical cancer is greatest in Africa, the World Health Organization has endorsed visual inspection with acetic acid screening with cryotherapy triage for the screen-and-treat approach. With the lowest doctor-to-patient ratio worldwide (1:50,000), Tanzania has nearly 10,000 new cases of cervical cancer and 7000 deaths annually. OBJECTIVE: We report on the feasibility of visual inspection with acetic acid in the severely resource-limited Mwanza district and on the impact of intervening education on baseline human papillomavirus and cervical cancer knowledge. STUDY DESIGN: Two 5-day free visual inspection with acetic acid (VIA) clinics in urban Buzuruga and rural Sangabuye on the shores of Lake Victoria were approved by our university institutional review board and local Tanzanian health authorities. Participants completed a demographic survey and a 6-question (1 point per question) multiple choice test written in Kiswahili to assess baseline knowledge. A 15-minute educational video in Kiswahili (MedicalAidFilms: Understanding screening, treatment, and prevention of cervical cancer) was followed by repeated assessment using the same test, visual inspection with acetic acid screening, and optional HIV testing. Pre- and postvideo scores and change of score were analyzed via t test, analysis of variance, and multivariate regression. Significance was considered at P\u3c.05. RESULTS: From July 2, 2018 to July 6, 2018, 825 women were screened, and 207 women (25.1%) were VIA positive (VIA+). One hundred forty-seven VIA+ nonpregnant women received same-day cryotherapy. Seven hundred sixty women participated in an educational intervention-61.6% of whom were from an urban site and 38.2% from a rural site. The mean age was 36.4 (standard deviation, 11.1). Primary languages were Kiswahili (62.2%) and Kisukuma (30.6%). Literacy was approximately 73%, and average education level was equivalent to the seventh grade (United States). Less than 20% of urban and rural women reported access to healthcare providers. Mean score of the participants before watching the video was 2.22 (standard deviation, 1.76) and was not different between VIA+ and VIA negative groups. Mean score of the participants after watching the video was 3.86 (standard deviation, 1.78). Postvideo scores significantly improved regardless of age group, clinic site, primary language, education level, literacy, or access to healthcare provider (P CONCLUSION: Visual inspection with acetic acid screening for cervical cancer is feasible and accepted in northern Tanzania. Short video-based educational intervention improved baseline knowledge on the consequences of human papillomavirus infection in the studied populations. The impact was greater in the urban setting than in the rural setting

Equity for excellence in academic institutions: a manifesto for change

Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output