Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Adjunctive therapies for severe sepsis.

Severe sepsis-associated mortality may still be improved by earlier recognition, faster and adequate source control, and targeted resuscitation. Patients who may benefit from the administration of drotrecogin alfa (activated) are currently those at high risk of death, and other indications should be better defined by ongoing trials. Use of low-dose steroids for the treatment of severe sepsis must be re-clarified by new studies and should be restricted to patients with refractory septic shock. Trials exploring the role of natural anticoagulants and Toll-like receptor inhibitors are ongoing and should be completed in the coming 3 years. Future trials in severe sepsis should target more homogeneous populations with a well-defined focus of infection and severity, receiving appropriate standard of care, and the tested intervention should be administered in a timely fashion according to the expected host response

Fertility preservation in the male pediatric population: factors influencing the decision of parents and children.

Abstract STUDY QUESTION How can the decision process for fertility preservation (FP) in adolescents and prepubertal boys be improved based on patient and parent feelings about FP counseling? SUMMARY ANSWER The content of information given to patients and parents and hope for future parenthood appeared to positively impact on the decision to preserve fertility in the pediatric population and, therefore, deserves special attention to improve FP care. WHAT IS KNOWN ALREADY A vast body of literature on adult cancer patients shows that reproductive capacity is a major quality-of-life issue. Patients also have a strong desire to be informed of available FP options with a view to future parenthood of their own genetic child, considering that 12 years considered the information to be clear (72%), complete (80%) and understandable (90.9%), only 33.3% of boys aged <12 years were able to comprehend the information. Pressure from doctors to reduce the delay between diagnosis and cancer treatment increased the number of refusals (P<0.01), while hope for future parenthood favored acceptance (P < 0.01). Family support was considered important for 75% of adolescents and 58% of children, and medical support for 50% of adolescents and 42% of children. LIMITATIONS, REASON FOR CAUTION This single-center survey does not allow extrapolation of the information to other settings. Recall bias and lack of full external validation of the questionnaires are further limitations. Modification of the current MCCP should be further evaluated according to our results. WIDER IMPLICATIONS OF THE FINDINGS Acknowledging the issues faced and familiarizing oneself with the care of patients undergoing fertility-threatening therapies supply primary care providers with the appropriate quality management tools in the field of FP in centers for reproductive medicine. Expectations reported in the survey allow appropriate support to be included within the MCCP design

Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance

Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome

Effect of Moderate Electropulsing on Nb Multiterminal Transport Bridges

peer reviewedWe investigate targeted and localized material modifications produced by electropulsing of Al-capped Nb microbridges with a multiterminal configuration. The affected regions of the Nb/Al bilayer terminals are revealed by an in-lens secondary-electron detector in a scanning electron microscope and by Kelvin-probe force microscopy, both suggesting a decrease in the work function in the modified areas. In contrast, the affected areas are neither apparent through an Everhart-Thornley secondary-electron detector nor through atomic force microscopy, which indicates little morphological change in the microstructure. In addition, we demonstrate that the extent of the electroannealed regions is strongly influenced by the terminal geometry. These results are captured by complementary finite-element modeling, which permits us to estimate that a threshold temperature of 435±35 K is needed to induce material modifications. These findings provide further insights into the subtle modifications produced by gentle electroannealing of Nb/Al microstructures and represent a step forward towards mastering this emerging nanofabrication technique

ESMO Congress 2021: highlights from the EORTC gastrointestinal tract cancer group's perspective

International audienceThere has been no major change of practice in gastrointestinal oncology at the European Society for Medical Oncology (ESMO) symposium 2021, but confirmation that immunotherapy in combination with chemotherapy has become standard of care in several indications. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Track Cancer Group has selected important phase II and III trials presented during the symposium across all gastrointestinal cancers as well as early reports on new drugs or new combinations that may change practice in the future