Genetic determinants of co-accessible chromatin regions in activated T cells across humans.

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

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

Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of Critical Care Medicine Task Force 2004-2005.

To develop clinical practice guidelines for the support of the patient and family in the adult, pediatric, or neonatal patient-centered ICU.A multidisciplinary task force of experts in critical care practice was convened from the membership of the American College of Critical Care Medicine (ACCM) and the Society of Critical Care Medicine (SCCM) to include representation from adult, pediatric, and neonatal intensive care units.The task force members reviewed the published literature. The Cochrane library, Cinahl, and MedLine were queried for articles published between 1980 and 2003. Studies were scored according to Cochrane methodology. Where evidence did not exist or was of a low level, consensus was derived from expert opinion.The topic was divided into subheadings: decision making, family coping, staff stress related to family interactions, cultural support, spiritual/religious support, family visitation, family presence on rounds, family presence at resuscitation, family environment of care, and palliative care. Each section was led by one task force member. Each section draft was reviewed by the group and debated until consensus was achieved. The draft document was reviewed by a committee of the Board of Regents of the ACCM. After steering committee approval, the draft was approved by the SCCM Council and was again subjected to peer review by this journal.More than 300 related studies were reviewed. However, the level of evidence in most cases is at Cochrane level 4 or 5, indicating the need for further research. Forty-three recommendations are presented that include, but are not limited to, endorsement of a shared decision-making model, early and repeated care conferencing to reduce family stress and improve consistency in communication, honoring culturally appropriate requests for truth-telling and informed refusal, spiritual support, staff education and debriefing to minimize the impact of family interactions on staff health, family presence at both rounds and resuscitation, open flexible visitation, way-finding and family-friendly signage, and family support before, during, and after a death

Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of Critical Care Medicine Task Force 2004-2005.

To develop clinical practice guidelines for the support of the patient and family in the adult, pediatric, or neonatal patient-centered ICU.A multidisciplinary task force of experts in critical care practice was convened from the membership of the American College of Critical Care Medicine (ACCM) and the Society of Critical Care Medicine (SCCM) to include representation from adult, pediatric, and neonatal intensive care units.The task force members reviewed the published literature. The Cochrane library, Cinahl, and MedLine were queried for articles published between 1980 and 2003. Studies were scored according to Cochrane methodology. Where evidence did not exist or was of a low level, consensus was derived from expert opinion.The topic was divided into subheadings: decision making, family coping, staff stress related to family interactions, cultural support, spiritual/religious support, family visitation, family presence on rounds, family presence at resuscitation, family environment of care, and palliative care. Each section was led by one task force member. Each section draft was reviewed by the group and debated until consensus was achieved. The draft document was reviewed by a committee of the Board of Regents of the ACCM. After steering committee approval, the draft was approved by the SCCM Council and was again subjected to peer review by this journal.More than 300 related studies were reviewed. However, the level of evidence in most cases is at Cochrane level 4 or 5, indicating the need for further research. Forty-three recommendations are presented that include, but are not limited to, endorsement of a shared decision-making model, early and repeated care conferencing to reduce family stress and improve consistency in communication, honoring culturally appropriate requests for truth-telling and informed refusal, spiritual support, staff education and debriefing to minimize the impact of family interactions on staff health, family presence at both rounds and resuscitation, open flexible visitation, way-finding and family-friendly signage, and family support before, during, and after a death

Caenorhabditis elegans processes sensory information to choose between freeloading and self-defense strategies

Hydrogen peroxide is the preeminent chemical weapon that organisms use for combat. Individual cells rely on conserved defenses to prevent and repair peroxide-induced damage, but whether similar defenses might be coordinated across cells in animals remains poorly understood. Here, we identify a neuronal circuit in the nematode Caenorhabditis elegans that processes information perceived by two sensory neurons to control the induction of hydrogen peroxide defenses in the organism. We found that catalases produced by Escherichia coli, the nematode's food source, can deplete hydrogen peroxide from the local environment and thereby protect the nematodes. In the presence of E. coli, the nematode's neurons signal via TGFβ-insulin/IGF1 relay to target tissues to repress expression of catalases and other hydrogen peroxide defenses. This adaptive strategy is the first example of a multicellular organism modulating its defenses when it expects to freeload from the protection provided by molecularly orthologous defenses from another species.Supported by NIH Office of Research Infrastructure Programs (P40 OD010440), and the National BioResources Project, Japan. The research was supported by National Science Foundation CAREER grant 1750065 to JA, a Northeastern University Tier one award to JA, a National Institutes of Health grant R01AG051659 to AG, the MEIC Excelencia award BFU2017-88615-P to NS, the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership to NS, the Centro de Excelencia Severo Ochoa to NS, and the CERCA Programme/Generalitat de Catalunya, and European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 852201) to N