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cGAS-STING and PANoptosis: Interplay, Underlying Mechanisms, and Therapeutic Targets.

The cGAS-STING pathway is an essential cytosolic DNA sensing mechanism that activates innate immune responses upon detection of microbial or aberrant self-DNA. This evolutionarily conserved signaling axis plays critical roles in autoimmune diseases, sterile inflammation, and cellular senescence. While its transient activation provides protective immunity, dysregulated cGAS-STING signaling contributes to the pathogenesis of various inflammatory and autoimmune conditions. Growing evidence indicates its functional convergence with multiple cell death pathways-particularly PANoptosis, a distinct inflammatory programmed cell death (PCD) pathway that integrates key features of pyroptosis, apoptosis, and necroptosis. The dynamic interplay between cGAS-STING signaling and PANoptosis has emerged as an important pathogenic mechanism across multiple diseases, revealing new therapeutic opportunities. In this review, we propose a unifying conceptual framework in which cGAS-STING activation functions as a predominant upstream driver of PANoptosis across diverse pathological contexts, orchestrated through a convergent molecular axis involving cytosolic DNA sensing, ZBP1-PANoptosome assembly, and coordinated inflammatory cell death. We begin by outlining the core molecular architecture of the cGAS-STING pathway and its implications in disease. We then examine the mechanisms and pathophysiological consequences of cGAS-STING -PANoptosis crosstalk in various disorders, followed by recent advances in therapeutic strategies specifically targeting this interface. Finally, we discuss translational challenges, such as the poor bioavailability and systemic toxicity of conventional STING agonists, and highlight innovative solutions including nanomedicine-based delivery systems that enable tumor-specific activation while minimizing off-target effects. By highlighting the therapeutic potential of pharmacological modulation at this junction, we identify promising strategies for treating inflammation-associated diseases.

Argininosuccinate lyase deficiency (ASLD), an inborn error of urea synthesis, may present as a neonatal- or late-onset disease. Neonatal-onset ASLD: Characterized by hyperammonemia within the first few days after birth that can manifest as increasing vomiting, lethargy, refusal to feed, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. Late-onset ASLD: Manifestations range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Long-term manifestations of ASLD: Acute hyperammonemia and its associated complications; neurologic and neurocognitive features including attention-deficit/hyperactivity disorder, intellectual and developmental disabilities, learning disabilities, seizures, and abnormalities of motor functioning and coordination; liver disease, including hepatomegaly, hepatitis, steatosis, fibrosis, and cirrhosis; trichorrhexis nodosa (coarse, brittle hair that breaks easily); systemic hypertension; and hypokalemia. The diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine; or identification of biallelic pathogenic variants in ASL by molecular genetic testing. Targeted therapies: Dietary treatment includes protein restriction, supplementation with non-protein-containing formulas to provide age-appropriate caloric requirements, and arginine base supplementation; nitrogen-scavenging medications are required in those with hyperammonemia or suboptimal metabolic control. Treatment of metabolic decompensation: The focus for treatment of metabolic decompensation is to rapidly decrease blood ammonia. Treatment of acute hyperammonemic episodes involves temporary cessation of oral protein intake, intravenous lipids and/or glucose, and intravenous nitrogen-scavenging therapy. Treatment of severe hyperammonemia often requires kidney replacement therapy with hemodialysis or continuous venovenous hemofiltration. Supportive care: Developmental and educational support; treatment of seizures per neurologist; treatment of abnormal motor functioning and coordination per neurologist, physical medicine and rehabilitation specialist, and physical and occupational therapists; orthotopic liver transplantation should be considered in individuals with recurrent hyperammonemia or metabolic decompensations that are resistant to conventional medical therapy; salt restriction, antihypertensive medications, and nitrites and nitrate-containing supplements for hypertension; potassium supplementation as needed; encourage medical alert bracelet; provide letters and written protocol for management in the setting of catabolic stressors; provide family with letters for optimizing social and school functioning; appropriate precautions should be taken during pre- and perioperative periods to prevent catabolic stress that could lead to hyperammonemia. Surveillance: Assessment with metabolic dietitian and clinical biochemical geneticist including height, weight, body mass index, and laboratory indices of nutritional status; plasma ammonia and amino acids with frequency based on age and metabolic status; developmental, educational, and behavioral assessment annually; assess for seizures, abnormal motor function, and problems with coordination at each visit; ALT, AST, albumin, and INR every six to 12 months or as needed; consider liver ultrasound and noninvasive monitoring for hepatic fibrosis every one to two years; blood pressure measurement at each visit; plasma potassium levels at least annually. Agents/circumstances to avoid: Excess protein intake; large boluses of protein or amino acids; less than recommended intake of protein; prolonged fasting or starvation; exposure to communicable diseases; valproic acid; oral or parenteral administration of corticosteroids; hepatotoxic drugs (in those with liver disease). Evaluation of relatives at risk: For at-risk newborn sibs when prenatal testing was not performed: measure plasma amino acids (to specifically assess for argininosuccinate) and plasma ammonia immediately in the newborn period in parallel with newborn screening and molecular genetic testing for the familial ASL pathogenic variants (if known). Pregnancy management: As pregnancy and the postpartum period pose significant stress in females in all urea cycle disorders, close monitoring and management is recommended for prevention of hyperammonemia. ASLD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ASL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ASL pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

10.1021/acs.jcim.5c00972

The dopamine D1 receptor (D1R) is a therapeutic target for a variety of central nervous system disorders including Parkinson's disease (PD). Challenges thus arise in the development of safer D1R therapies in limiting off-target drug activity. This issue is particularly relevant to PD therapy, where L-DOPA has been the "gold standard" drug for decades despite a problematic side-effect profile. Recent studies of G-protein and β-arrestin functionally selective signaling offer new strategies for developing superior D1R orthosteric and allosteric compounds with fewer side effects. We designed a desktop-computer drug-screening platform to examine large virtual chemical libraries for allosteric compounds binding D1R intracellular loop 2 (ICL2) determinants. Two structurally distinct hits were strong enhancers of dopamine-induced β-arrestin recruitment and inhibitors of dopamine-induced G-protein activation. The lead candidate DUSBI-A3 was highly selective for D1R over closely related dopamine receptors when assessed by β-arrestin activation, providing proof-of-concept for pursuing D1R selective, biased compounds in the treatment of PD.

36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.

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Payne, G. L. Fraser P107 - Unasyn® causes QT prolongation during treatment of intensive care patients B. Tudor, M. Lahner, G. Roth, C. Krenn P108 - Comparative study between teicoplanin and vancomycin in methicillin-resistant staphylococcus aureus (mrsa) infectious of toxicological intensive care unit (ticu) patients – Tehran, Iran H. Talaie P109 - Phage therapy against antimicrobial resistance, design of the first clinical study phagoburn P. Jault, J. Gabard, T. Leclerc, S. Jennes, Y. Que, A. Rousseau, F. Ravat P110 - Antibiotic dosing errors in critically ill patients with severe sepsis or septic shock H. Al-Dorzi, A. Eissa, S. Al-Harbi, T. Aldabbagh, R. Khan, Y. Arabi P111 - Does empiric antifungal therapy improve survival in septic critically ill patients? (immunocompromised excluded) A. Trifi, S. Abdellatif, F. Daly, R. Nasri, S. Ben Lakhal P112 - Neurocysticercosis-Qatar experience F. Paramba, N. Purayil, V. Naushad, O. Mohammad, V. Negi, P. Chandra P113 - Early indicators in acute haemorrhagic shock A. Kleinsasser P114 - Filtering of red blood cells reduces the inflammatory response of pulmonary cells in an in vitro model of mechanical ventilation M. R. Witrz, J. F. Buchner-Doeven, A. M. Tuip-de Boer, J. C. Goslings, N. P. Juffermans P115 - Microparticles from red blood cell transfusion induce a pro-coagulant and pro-inflammatory endothelial cell response M. Van Hezel, M. Straat, A Boing, R Van Bruggen, N Juffermans P116 - The contribution of cytokines on thrombosis development during hospitalization in ICU D. Markopoulou, K. Venetsanou, V. Kaldis, D. Koutete, D. Chroni, I. Alamanos P117 - Prophylactic enoxaparin dosing and adjustment through anti-xa monitoring in an inpatient burn unit L. Koch, J. Jancik, H. Rhodes, E. Walter P118 - Determination of optimal cut-off values of haemoglobin, platelet count and fibrinogen at 24 hours after injury associated with mortality in trauma patients K. Maekawa, M. Hayakawa, S. Kushimoto, A. Shiraishi, H. Kato, J. Sasaki, H. Ogura, T. Matauoka, T. Uejima, N. Morimura, H. Ishikura, A. Hagiwara, M. Takeda P119 - Trauma-induced coagulopathy - prothrombin complex concentrate vs fresh frozen plasma O. Tarabrin, S. Shcherbakow, D. Gavrychenko, G. Mazurenko, V. Ivanova, O. Chystikov P120 - First study to prove the superiority of prothrombin complex concentrates on mortality rate over fresh frozen plasma in patients with acute bleeding C. Plourde, J. Lessard, J. Chauny, R. Daoust P121 - Prothrombin complex concentrate vs fresh frozen plasma in obstetric massive bleeding S. Shcherbakow, O. Tarabrin, D. Gavrychenko, G. Mazurenko, O. Chystikov P122 - Impact of FFP transfusion on VAP in ICU patients A. Vakalos, V. Avramidis P123 - Preoperative platelet function test and the thrombin generation assay are predictive for blood loss after cardiac surgery L. Kropman, L. In het Panhuis, J. Konings, D. Huskens, E. Schurgers, M. Roest, B. De Laat, M. Lance P124 - Rotational thromboelastometry versus standard coagulation tests before surgical interventions M. Durila, P. Lukas, M. Astraverkhava, J. Jonas P125 - Correction of impaired clot quality and stability by fibrinogen and activated prothrombin complex concentrate in a model of severe thrombocytopenia I. Budnik, B. Shenkman P126 - Assessment of point-of-care prothrombin time analyzer as a monitor after cardiopulmonary bypass H. Hayami, Y. Koide, T. Goto P127 - Disseminated intravascular coagulation (dic) is underdiagnosed in critically ill patients: do we need d-dimer measurements? R. Iqbal, Y. Alhamdi, N. Venugopal, S. Abrams, C. Downey, C. H. Toh, I. D. Welters P128 - Validity of the age-adjusted d-dimer cutoff in patients with COPD B. Bombay, J. M. Chauny, R. D. Daoust, J. L. Lessard, M. M. Marquis, J. P. Paquet P129 - A scoping review of strategies for prevention and management of bleeding following paediatric cardiopulmonary bypass surgery K. Siemens, D. Sangaran, B. J. Hunt, A. Durward, A. Nyman, I. A. Murdoch, S. M. Tibby P130 - Nadir hemoglobulin during cardiopulmonary bypass: impact on postoperative morbidity and mortality F. Ampatzidou, D. Moisidou, E. Dalampini, M. Nastou, E. Vasilarou, V. Kalaizi, H. Chatzikostenoglou, G. Drossos P131 - Red blood cell transfusion do not influence the prognostic value of RDW in critically ill patients S. Spadaro, A. Fogagnolo, T. Fiore, A. Schiavi, V. Fontana, F. Taccone, C. Volta P132 - Reasons for admission in the paediatric intensive care unit and the need for blood and blood products transfusions E. Chochliourou, E. Volakli, A. Violaki, E. Samkinidou, G. Evlavis, V. Panagiotidou, M. Sdougka P133 - The implementation of a massive haemorrhage protocol (mhp) for the management of major trauma: a ten year, single-centre study R. Mothukuri, C. Battle, K. Guy, G. Mills, P. Evans P134 - An integrated major haemorrhage protocol for pre-hospital and retrieval medical teams J. Wijesuriya, S. Keogh P135 - The impact of transfusion thresholds on mortality and cardiovascular events in patients with cardiovascular disease (non-cardiac surgery): a systematic review and meta-analysis A. Docherty, R. O’Donnell, S. Brunskill, M. Trivella, C. Doree, L. Holst, M. Parker, M. Gregersen, J. Almeida, T. Walsh, S. Stanworth P136 - The relationship between poor pre-operative immune status and outcome from cardiac surgery is specific to the peri-operative antigenic threat S. Moravcova, J. Mansell, A. Rogers, R. A. Smith, C. Hamilton-Davies P137 - Impact of simple clinical practice guidelines for reducing post-operative atrial fibrillation after cardiac surgery. A. Omar, M. Allam, O. Bilala, A. Kindawi, H. Ewila P138 - Dexamethasone administration during cardiopulmonary bypass has no beneficial effects on elective postoperative cardiac surgery patients F. Ampatzidou, D. Moisidou, M. Nastou, E. Dalampini, A. Malamas, E. Vasilarou, G. Drossos P139 - Intra-aortic balloon counterpulsation in patients undergoing cardiac surgery (IABCS): preliminary results G. Ferreira, J. Caldas, J. Fukushima, E. A. Osawa, E. Arita, L. Camara, S. Zeferino, J. Jardim, F. Gaioto, L. Dallan, F. B. Jatene, R. Kalil Filho, .F Galas, L. A. Hajjar P140 - Effects of low-dose atrial natriuretic peptide infusion on cardiac surgery-associated acute kidney injury C. Mitaka, T. Ohnuma, T. Murayama, F. Kunimoto, M. Nagashima, T. Takei, M. Tomita P141 - Acute kidney injury influence on high sensitive troponin measurements after cardiac surgery A. Omar, K. Mahmoud, S. Hanoura, S. Sudarsanan, P. Sivadasan, H. Othamn, Y. Shouman, R. Singh, A. Al Khulaifi P142 - Complex evaluation of endothelial dysfunction markers for prognosis of outcomes in patients undergoing cardiac surgery I. Mandel, S. Mikheev, I. Suhodolo, V. Kiselev, Y. Svirko, Y. Podoksenov P143 - New-onset atrial fibrillation in intensive care: incidence, management and outcome S. A. Jenkins, R. Griffin P144 - One single spot measurement of the sublingual microcirculation during acute pulmonary hypertension in a pig model of shock M. S. Tovar Doncel, A. Lima, C. Aldecoa, C. Ince P145 - Assessment of levosimendan as a therapeutic option to recruit the microcirculation in cardiogenic shock – initial experience in cardiac ICU A. Taha, A. Shafie, M. Mostafa, N. Syed, H. Hon P146 - Terlipressin vs. norepinephrine in the Potential Multiorgan Donor(PMD) F. Righetti, E. Colombaroli, G. Castellano P147 - Echocardiography in the potential heart donor exposed to substitution hormonotherapy F. Righetti, E. Colombaroli P148 - Machine learning can reduce rate of monitor alarms M. Hravnak, L. C. Chen, A. D. Dubrawski, G. C. Clermont, M. R. Pinsky P149 - Peripherally inserted central catheters placed in the ICU S. Gonzalez, D. Macias, J. Acosta, P. Jimenez, A. Loza, A. Lesmes, F. Lucena, C. Leon P150 - Recordings of abnormal central venous pressure waveform morphology during an episode of pulmonary hypertension in a porcine shock model M. S. Tovar Doncel, C. Ince, C. Aldecoa, A. Lima P151 - Ultrasound guided central venous access technique among French intensivists M. Bastide, J. Richecoeur, E. Frenoy, C. Lemaire, B. Sauneuf, F. Tamion, S. Nseir, D. Du Cheyron, H. Dupont, J. Maizel P152 - Predictive ability of the Pv-aCO2 gap in patients with shock M. Shaban, R. Kolko, N. Salahuddin, M. Sharshir, M. AbuRageila, A. AlHussain P153 - Comparison of echocardiography and pulmonary artery catheter measurements of hemodynamic parameters in critical ill patients P. Mercado, J. Maizel, L. Kontar, D. Titeca, F. Brazier, A. Riviere, M. Joris, T. Soupison, B. De Cagny, M. Slama P154 - The volume clamp method for noninvasive cardiac output measurement in postoperative cardiothoracic surgery patients: a comparison with intermittent pulmonary artery thermodilution J. Wagner, A. Körner, M. Kubik, S. Kluge, D. Reuter, B. Saugel P155 - Hemodynamic monitoring in patients with septic shock (SS) – CPCCO (continuous pulse contour cardiac output) vs. TEE (transesophageal echocardiography) E. Colombaroli, F. Righetti, G. Castellano P156 - Cardiac output measurement with transthoracic echocardiography in critically ill patients: a pragmatic clinical study T. Tran, D. De Bels, A. Cudia, M. Strachinaru, P. Ghottignies, J. Devriendt, C. Pierrakos P157 - Left ventricular outflow tract velocity time integral correlates with stroke volume index in mechanically ventilated patients Ó. Martínez González, R. Blancas, J. Luján, D. Ballesteros, C. Martínez Díaz, A. Núñez, C. Martín Parra, B. López Matamala, M. Alonso Fernández, M. Chana P158 - Transpulmonary thermodilution (TPTD) derived from femoral vs. jugular central venous catheter: validation of a previously published correction formula and a proprietary correction formula for global end-diastolic volume index (GEDVI) W. Huber, M. Eckmann, F. Elkmann, A. Gruber, I. Klein, R. M. Schmid, T. Lahmer P160 - Dynamic arterial elastance calculated with lidcoplus monitor does not predict changes in arterial pressure after a fluid challenge in postsurgical patients D. Bastoni, H. Aya, L. Toscani, L. Pigozzi, A. Rhodes, M. Cecconi P159 - Venous return driving pressure and resistance in acute blood volume changes P. W. Moller, S. Sondergaard, S. M. Jakob, J. Takala, D. Berger P160 - Dynamic arterial elastance calculated with lidcoplus monitor does not predict changes in arterial pressure after a fluid challenge in postsurgical patients D. Bastoni, H. Aya, L. Toscani, L. Pigozzi, A. Rhodes, M. Cecconi P161 - Analysis of duration of post-operative goal-directed therapy protocol C. Ostrowska, H. Aya, A. Abbas, J. Mellinghoff, C. Ryan, D. Dawson, A. Rhodes, M. Cecconi P162 - Hemodynamic optimization – back to square one? M. Cronhjort, O. Wall, E. Nyberg, R. Zeng, C. Svensen, J. Mårtensson, E. Joelsson-Alm P163 - Effectiveness of fluid thoracic content measurement by bioimpedance guiding intravascular volume optimization in patients with septic shock M. Aguilar Arzapalo, L. Barradas, V. Lopez, M. Cetina P164 - A systematic review on the role of internal jugular vein ultrasound measurements in assessment of volume status in critical shock patients N. Parenti, C. Palazzi, L. A. Amidei, F. B. Borrelli, S. C. Campanale, F. T. Tagliazucchi, G. S. Sedoni, D. L. Lucchesi, E. C. Carella, A. L Luciani P165 - Importance of recognizing dehydration in medical Intensive Care Unit M. Mackovic, N. Maric, M. Bakula P166 - Effect of volume for a fluid challenge in septic patients H. Aya, A. Rhodes, R. M. Grounds, N. Fletcher, M. Cecconi P167 - Fluid bolus practices in a large Australian intensive care unit B. Avard, P. Zhang P168 - Liberal late fluid management is associated with longer ventilation duration and worst outcome in severe trauma patients: a retrospective cohort of 294 patients M. Mezidi, J. Charbit, M. Ould-Chikh, P. Deras, C. Maury, O. Martinez, X. Capdevila P169 - Association of fluids and outcomes in emergency department patients hospitalized with community-acquired pneumonia P. Hou, W. Z. Linde-Zwirble, I. D. Douglas, N. S. Shapiro P170 - Association of positive fluid balance with poor outcome in medicosurgical ICU patients A. Ben Souissi, I. Mezghani, Y. Ben Aicha, S. Kamoun, B. Laribi, B. Jeribi, A. Riahi, M. S. Mebazaa P171 - Impact of fluid balance to organ dysfunction in critically ill patients C. Pereira, R. Marinho, R. Antunes, A. Marinho P172 - Volume bolus in ICU patients: do we need to balance our crystalloids? M. Crivits, M. Raes, J. Decruyenaere, E. Hoste P173 - The use of 6 % HES solution do not reduce total fluid requirement in the therapy of patients with burn shock V. Bagin, V. Rudnov, A. Savitsky, M. Astafyeva, I. Korobko, V. Vein P174 - Electron microscopic assessment of acute kidney injury in septic sheep resuscitated with crystalloids or different colloids T. Kampmeier , P. Arnemann, M. Hessler, A. Wald, K. Bockbreder, A. Morelli, H. Van Aken, S. Rehberg, C. Ertmer P175 - Alterations of conjunctival microcirculation in a sheep model of haemorrhagic shock and resuscitation with 0.9 % saline or balanced tetrastarch P. Arnemann, M. Hessler, T. Kampmeier, S. Rehberg, H. Van Aken, C. Ince, C. Ertmer P176 - A single centre nested pilot study investigating the effect of using 0.9 % saline or Plasma-Lyte 148 ® as crystalloid fluid therapy on gastrointestinal feeding intolerance in mechanically ventilated patients receiving nasogastric enteral nutrition S. Reddy, M. Bailey, R. Beasley, R. Bellomo, D. Mackle, A. Psirides, P. Young P177 - A single centre nested pilot study investigating the effect on post-operative bleeding of using 0.9 % saline or Plasma-Lyte® 148 as crystalloid fluid therapy in adults in ICU after heart surgery S. Reddy, M. Bailey, R. Beasley, R. Bellomo, D. Mackle, P. Young P178 - Extreme hypernatremia and sepsis in a patient with Huntington’s dementia: a conundrum in fluid management H. Venkatesh, S. Ramachandran, A. Basu, H. Nair P179 - Diagnosis and management of severe hypernatraemia in the critical care setting S. Egan, J. Bates P180 - Correlation between arterial blood gas and electrolyte disturbances during hospitalization and outcome in critically ill patients S. Oliveira, N. R. Rangel Neto, F. Q. Reis P181 - Missing the “I” in MUDPILES – a rare cause of high anion gap metabolic acidosis (HAGMA) C. P. Lee, X. L. Lin, C. Choong , K. M. Eu, W. Y. Sim , K. S. Tee, J. Pau , J. Abisheganaden P182 - Plasma NGAL and urinary output: potential parameters for early initiation of renal replacement therapy K. Maas, H. De Geus P183 - Renal replacement therapy for critically ill patients: an intermittent continuity E. Lafuente, R. Marinho, J. Moura, R. Antunes, A. Marinho P184 - A survey of practices related to renal replacement therapy in critically ill patients in the north of England. T. E. Doris, D. Monkhouse, T. Shipley, S. Kardasz, I Gonzalez P185 - High initiation creatinine associated with lower 28-day mortality in critically ill patients necessitating continuous renal replacement therapy S. Stads, A. J. Groeneveld P186 - The impact of Karnofsky performance scale on outcomes in acute kidney injury patients receiving renal replacement therapy on the intensive care unit I. Elsayed, N. Ward, A. Tridente, A. Raithatha P187 - Severe hypophosphatemia during citrate-anticoagulated CRRT A. Steuber, C. Pelletier, S. Schroeder, E. Michael, T. Slowinski, D. Kindgen-Milles P188 - Citrate regional anticoagulation for post dilution continuous renal replacement therapy S. Ghabina P189 - Citrate 18 mmol/l improves anticoagulation during RRT with adsorbing filters F. Turani, A. Belli, S. Busatti, G. Barettin, F. Candidi, F. Gargano, R. Barchetta, M. Falco P190 - Calcium gluconate instead of calcium chloride in citrate-anticoagulated CVVHD O. Demirkiran, M. Kosuk, S. Bozbay P191 - Enhanced clearance of interleukin-6 with continuous veno-venous haemodialysis (CVVHD) using Ultraflux EMiC2 vs. Ultraflux AV1000S V. Weber, J. Hartmann, S. Harm, I. Linsberger, T. Eichhorn, G. Valicek, G. Miestinger, C. Hoermann P192 - Removal of bilirubin with a new adsorbent system: in vitro kinetics S. Faenza, D. Ricci, E. Mancini, C. Gemelli, A. Cuoghi, S. Magnani, M. Atti P193 - Case series of patients with severe sepsis and septic shock treated with a new extracorporeal sorbent T. Laddomada, A. Doronzio, B. Balicco P194 - In vitro adsorption of a broad spectrum of inflammatory mediators with CytoSorb® hemoadsorbent polymer beads M. C. Gruda, P. O’Sullivan, V. P. Dan, T. Guliashvili, A. Scheirer, T. D. Golobish, V. J. Capponi, P. P. Chan P195 - Observations in early vs. late use of cytosorb therapy in critically ill patients K. Kogelmann, M. Drüner, D. Jarczak P196 - Oxiris membrane decreases endotoxin during rrt in septic patients with basal EAA > 0,6 F. Turani, A. B. Belli, S. M. Martni, V. C. Cotticelli, F. Mounajergi, R. Barchetta P197 - An observational prospective study on the onset of augmented renal clearance: the first report S. Morimoto, H. Ishikura P198 - An ultrasound- guided algorithm for the management of oliguria in severe sepsis I. Hussain, N. Salahuddin, A. Nadeem, K. Ghorab, K. Maghrabi P199 - Ultrasound in acute kidney injury (aki). First findings of farius, an education-programme in structural ultrasonography S. K. Kloesel, C. Goldfuss, A. Stieglitz, A. S. Stieglitz, L. Krstevska, G. Albuszies P200 - Effectiveness of renal angina index score predicting acute kidney injury on critically ill patients M. Aguilar Arzapalo, L. Barradas, V. Lopez, A. Escalante, G. Jimmy, M. Cetina P201 - Time length below blood pressure thresholds and progression of acute kidney injury in critically ill patients with or without sepsis: a retrospective, exploratory cohort study J. Izawa, T. Iwami, S. Uchino, M. Takinami, T. Kitamura, T. Kawamura P202 - Anaemia does not affect renal recovery in acute kidney injury J. G. Powell-Tuck, S. Crichton, M. Raimundo, L. Camporota, D. Wyncoll, M. Ostermann P203 - Estimated glomerular filtration rate based on serum creatinine: actual practice in Dutch ICU’s A. Hana, H. R. De Geus P204 - Comparison of estimated glomerular filtration rate calculated by mdrd, ckd-epi-serum-creatinine and ckd-epi-cystatin-c in adult critically ill patients H. R. De Geus, A. Hana P205 - Early diagnosis of septic acute kidney injury in medical critical care patients with a urine cell cycle arrest marker: insulin like growth factor binding protein-7 (IGFBP-7) M. Aydogdu, N. Boyaci, S. Yuksel, G. Gursel, A. B. Cayci Sivri P206 - Urinary neutrophil gelatinase-associated lipocalin as early biomarker of severe acute kidney injury in intensive care J. Meza-Márquez, J. Nava-López, R. Carrillo-Esper P207 - Shrunken pore syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting A. Dardashti, A. Grubb P208 - The biomarker nephrocheck™ can discriminate the septic shock patients with an akin 1 or 2 acute renal failure who will not progress toward the akin 3 level J. Maizel, M. Wetzstein, D. Titeca, L. Kontar, F. Brazier, B. De Cagny, A. Riviere, T. Soupison, M. Joris, M. Slama P209 - A worldwide multicentre evaluation of acute kidney injury in septic and non-septic critically ill patients: the intensive care over nations (icon) audit E. Peters, H. Njimi, P. Pickkers, J. L. Vincent P210 - Does enhanced recovery after surgery reduce the incidence of acute kidney injury in those undergoing major gynae-oncological surgery? M. Waraich , J. Doyle, T. Samuels, L. Forni P211 - Identification of risk factors for the development of acute kidney injury after lower limb arthroplasty N. Desai, R. Baumber, P. Gunning, A. Sell P212 - Incidences and associations of acute kidney injury after major trauma S. Lin, H. Torrence, M. O’Dwyer, C. Kirwan, J. Prowle P213 - Acute kidney injury of major trauma patients T Kim P214 - Trajectory of serum creatinine after major surgery and the diagnosis of acute kidney injury M. E. O’Connor, R. W. Hewson, C. J. Kirwan, R. M. Pearse, J. Prowle P215 - Epidemiology of acute kidney injury after cardiac surgery. A single center retrospective study S. Hanoura , A. Omar, H. Othamn, S. Sudarsanan , M. Allam, M. Maksoud, R. Singh, A. Al Khulaifi P216 - Post-operative acute kidney injury after major non-cardiac surgery and its association with death in the following year M. E. O’Connor, R. W. Hewson, C. J. Kirwan, R. M. Pearse, J. Prowle P217 - Factors affecting acute renal failure in intensive care unit and effect of these factors on mortality O. Uzundere, D. Memis , M. Ýnal, A. , N. Turan P218 - Results of the live kidney transplantations according to national data of turkish organ and tissue information system M. A. Aydin, H. Basar, I. Sencan, A. Kapuagasi, M. Ozturk, Z. Uzundurukan, D. Gokmen, A. Ozcan, C. Kaymak P219 - Anaesthesia procedure and intensive therapy in patients with neck phlegmon V. A. Artemenko, A. Budnyuk P220 - Nasal high flow oygen for acute respiratory failure: a systematic review R. Pugh , S. Bhandari P221 - Setting optimal flow rate during high flow nasal cannula support: preliminary results T. Mauri, C. Turrini, T. Langer, P. Taccone, C. A. Volta, C. Marenghi, L. Gattinoni, A. Pesenti P222 - Dose to dose consistency across two different gas flow rates using cystic fibrosis and normal adult breathing profiles during nasal high flow oxygen therapy L. Sweeney, A . O’ Sullivan, P. Kelly, E. Mukeria, R. MacLoughlin P223 - Final results of an evaluation of airway medix closed suction system compared to a standard closed suction system M. Pfeffer, J. T. Thomas, G. B. Bregman, G. K. Karp, E. K. Kishinevsky, D. S. Stavi, N. A. Adi P224 - Different cuff materials and different leak tests - one size does not fit all T. Poropat, R. Knafelj P225 - Observational study on the value of the cuff-leak test and the onset of upper airway obstruction after extubation E. Llopart, M. Batlle, C. De Haro, J. Mesquida, A. Artigas P226 - A device for emergency transtracheal lung ventilation D. Pavlovic, L. Lewerentz, A. Spassov, R. Schneider P227 - Long-term outcome and health-related quality of life in patients discharged from the intensive care unit with a tracheostomy and with or without prolonged mechanical ventilation S. De Smet, S. De Raedt, E. Derom, P Depuydt, S. Oeyen, D. Benoit, J. Decruyenaere P228 - Ultrasound-guided percutaneous dilational tracheostomy versus bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients (trachus): a randomized clinical trial A. Gobatto, B. Bese, P. Tierno, L. Melro, P. Mendes, F. Cadamuro, M. Park, L. M. Malbouisson P229 - Is it safe to discharge patients with tracheostomy from the ICU to the ward? B. C. Civanto, J. L. Lopez, A. Robles, J. Figueira, S. Yus, A. Garcia P230 - The application of tracheostomy in children in ICU A. Oglinda, G. Ciobanu, C. Oglinda, L. Schirca, T. Sertinean, V. Lupu P231 - The impact of passive humidifiers on aerosol drug delivery during mechanical ventilation P. Kelly, A. O’Sullivan, L. Sweeney, R. MacLoughlin P232 - Evaluation of vibrating mesh and jet nebuliser performance at two different attachment setups in line with a humidifier nebuliser system A. O’Sullivan, P. Kelly, L. Sweeney, E. Mukeria, M. Wolny , R. MacLoughlin P233 - Psv-niv versus cpap in the treatment of acute cardiogenic pulmonary edema A. Pagano, F. Numis, G. Vison, L. Saldamarco, T. Russo, G. Porta, F. Paladino P234 - Noninvasive ventilation in patients with haematologic malignancy: a retrospective review C. Bell, J. Liu, J. Debacker, C. Lee, E. Tamberg, V. Campbell, S. Mehta P235 - Use of non-invasive ventilation in infectious diseases besides classical indications A. Silva-Pinto, A. Sarmento, L. Santos P236 - The impact of fragility on noninvasive mechanical ventilation application and results in the ICU Ý. Kara, F. Yýldýrým, A. Zerman, Z. Güllü, N. Boyacý, B. Basarýk Aydogan, Ü. Gaygýsýz, K. Gönderen, G. Arýk, M. Turkoglu, M. Aydogdu, G. Aygencel, Z. Ülger, G. Gursel P237 - Effects of metabolic alkalosis on noninvasive ventilation success and ICU outcome in patients with hypercapnic respiratory failure N. Boyacý, Z. Isýkdogan, Ö. Özdedeoglu, Z. Güllü, M. Badoglu, U. Gaygýsýz, M. Aydogdu, G. Gursel P238 - Asynchrony index and breathing patterns of acute exacerbation copd patients assisted with noninvasive pressure support ventilation and neurally adjusted ventilatory assist N. Kongpolprom, C. Sittipunt P239 - High frequency jet ventilation for severe acute hypoxemia A. Eden, Y. Kokhanovsky, S. Bursztein – De Myttenaere, R. Pizov P240 - HFOV revisited: a 7 year retrospective analysis of patients receiving HFOV who met oscillate trial entry criteria L. Neilans, N. MacIntyre P241 - Implementation of a goal-directed mechanical ventilation order set driven by respiratory therapists can improve compliance with best practices for mechanical ventilation M. Radosevich, B. Wanta, V. Weber, T. Meyer, N. Smischney, D. Brown, D. Diedrich P242 - A reduction in tidal volumes for ventilated patients on ICU calculated from IBW. can it minimise mortality in comparison to traditional strategies? A . Fuller, P. McLindon, K. Sim P243 - Predictive value of lung aeration scoring using lung ultrasound in weaning failure M. Shoaeir, K. Noeam, A. Mahrous, R. Matsa, A. Ali P244 - Conventional versus automated weaning from mechanical ventilation using SmartCare™ C. Dridi, S. Koubaji, S. Kamoun, F. Haddad, A. Ben Souissi, B. Laribi, A. Riahi, M. S. Mebazaa P245 - Ultrasonographic evaluation protocol for weaning from mechanichal ventilation A. Pérez-Calatayud, R. Carrillo-Esper, A. Zepeda-Mendoza, M. Diaz-Carrillo, E. Arch-Tirado P246 - Diaphragm ultrasonography: a method for weaning patients from mechanical ventilation S. Carbognin, L. Pelacani, F. Zannoni, A. Agnoli, G. Gagliardi P247 - Dorsal diaphragmatic excursion tracks transpulmonary pressure in ventilated ARDS patients: a potential non-invasive indicator of lung recruitment? R. Cho, A. Adams , S. Lunos, S. Ambur, R. Shapiro, M. Prekker P248 - Pulse oximetry in the icu patient: is the perfusion index of any value? M. Thijssen, L. Janssen, N. Foudraine P249 - Ventilation is a better assessment of respiratory status than EtCO2 C. J. Voscopoulos, J. Freeman P250 - Evaluation of the relationship between non-invasive minute ventilation and end-tidal CO2 in patients undergoing general vs spinal anesthesia C. J. Voscopoulos, J. Freeman, E. George P251 - Respiratory volume monitoring provides early warning of respiratory depression and can be used to reduce false alarms in non-intubated patients C. J. Voscopoulos, D. Eversole, J. Freeman, E. George P252 - P/i index: a predictive edi-derived weaning index during nava S. Muttini, R. Bigi, G. Villani, N. Patroniti P253 - Adequacy of ventilation in patients receiving opioids in the post anesthesia care unit: minute ventilation versus respiratory rate G. Williams, C. J. Voscopoulos, J. Freeman, E. George P254 - Comparison of regional and global expiratory time constants measured by electrical impedance tomography (EIT) A. Waldmann, S. Böhm, W. Windisch, S. Strassmann, C. Karagiannidis P255 - Electrical impedance tomography: robustness of a new pixel wise regional expiratory time constant calculation A. Waldmann, S. Böhm, W. Windisch, S. Strassmann, C. Karagiannidis P256 - Validation of regional and global expiratory time constant measurement by electrical impedance tomography in ards and obstructive pulmonary diseases C. K. Karagiannidis, A. W. Waldmann, S. B. Böhm, S. Strassmann, W. W. Windisch P257 - Transpulmonary pressure in a model with elastic recoiling lung and expanding chest wall P. Persson, S. Lundin, O. Stenqvist P258 - Lactate in pleural and abdominal effusion G. Porta, F. Numis, C. S. Serra, A. P. Pagano, M. M. Masarone, L. R. Rinaldi, A. A. Amelia, M. F. Fascione, L. A. Adinolfi, E. R. Ruggiero P259 - Outcome of patients admitted to the intensive care with pulmonary fibrosis F. Asota, K. O’Rourke, S. Ranjan, P. Morgan P260 - Sedation and analgesia practice in extra-corporeal membrane oxygenation (ECMO)-treated patients with acute respiratory distress syndrome (ARDS): a retrospective study J. W. DeBacker, E. Tamberg, L. O’Neill, L. Munshi, L. Burry, E. Fan, S. Mehta P261 - Characteristics and outcomes of patients deemed not eligible when referred for veno-venous extracorporeal membrane oxygenation (vv-ECMO) S. Poo, K. Mahendran, J. Fowles, C. Gerrard, A. Vuylsteke P262 - The SAVE SMR for veno-arterial ECMO R. Loveridge, C. Chaddock, S. Patel, V. Kakar, C. Willars, T. Hurst, C. Park, T. Best, A. Vercueil, G. Auzinger P263 - A simplified score to predict early (48 h) mortality in patients being considered for VA-ECMO A. Borgman, A. G. Proudfoot, E. Grins, K. E. Emiley, J. Schuitema, S. J. Fitch, G. Marco, J. Sturgill, M. G. Dickinson, M. Strueber, A. Khaghani, P. Wilton, S. M. Jovinge P264 - Lung function six months post extra corporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adult survivors C. Sampson, S. Harris-Fox P265 - Bicarbonate dialysis removes carbon dioxide in hypoventilated rodents. M. E. Cove, L. H. Vu, A. Sen, W. J. Federspiel, J. A. Kellum P266 - Procalcitonin as predictor of primary graft dysfunction and mortality in post-lung transplantation C. Mazo Torre, J. Riera, S. Ramirez, B. Borgatta, L. Lagunes, J. Rello P267 - New molecular biomarkers of acute respiratory distress syndrome in abdominal sepsis A. K. Kuzovlev, V. Moroz, A. Goloubev, S. Polovnikov, S. Nenchuk P268 - Tight junction’s proteins claudin -5 and regulation by tnf in experimental murine lung injury model of ali/ards V. Karavana, C. Glynos, A. Asimakos, K. Pappas, C. Vrettou, M. Magkou, E. Ischaki, G. Stathopoulos, S. Zakynthinos P269 - Cell counts in endobronchial aspirate to assess airway inflammation in ARDS patients: a pilot study S. Spadaro, I. Kozhevnikova, F. Dalla Corte, S. Grasso, P. Casolari, G. Caramori, C. Volta P270 - Epidemiological and clinical profile of patients with acute respiratory distress syndrome in the surgical intensive care unit surgical, hospital JRA, Antananarivo T. Andrianjafiarinoa, T. Randriamandrato, T. Rajaonera P271 - Effect of high PEEP after recruitment maneuver on right ventricular function in ARDS. Is it good for the lung and for the heart? S. El-Dash, ELV Costa, MR Tucci, F Leleu, L Kontar, B. De Cagny, F. Brazier, D. Titeca, G. Bacari-Risal, J. Maizel, M. Amato, M. Slama P272 - Effect of recruitment maneuver on left ventricular systolic strain P. Mercado, J. Maizel, L. Kontar, D. Titeca, F. Brazier, A. Riviere, M. Joris, T. Soupison, B. De Cagny, S. El Dash, M. Slama P273 - Inhaled nitric oxide – is switching supplier cost effective? Remmington, A. Fischer, S. Squire, M. Boichat P274 - Epidemiological study of severe acute pancreatitis in Japan, comparison of the etiology and the patient outcomes on 1159 patients. H. Honzawa, H. Yasuda, T. Adati, S. Suzaki, M. Horibe, M. Sasaki, M. Sanui P275 - Extracorporeal liver support therapy. Experience in an intensive care unit R. Marinho, J. Daniel, H. Miranda, A. Marinho P276 - Accuracy of mortality prediction models in acute versus acute-on-chronic liver failure in the intensive care setting K. Milinis, M. Cooper, G. R. Williams, E. McCarron, S. Simants, I. Patanwala, I. Welters P277 - Risk of coronary artery disease in patients with chronic liver disease: a population based cohort study Y. Su P278 - 20 years of liver transplantation in Santiago de Compostela (Spain). Experience review J. Fernández Villanueva, R. Fernández Garda, A. López Lago, E. Rodríguez Ruíz, R. Hernández Vaquero, S. Tomé Martínez de Rituerto, E. Varo Pérez P279 - Diarrhea is a risk factor for liver injury and may lead to intestinal failure associated liver disease in critical illness N. Lefel, F. Schaap, D. Bergmans, S. Olde Damink, M. Van de Poll P280 - Bowel care on the intensive care unit: constipation guideline compliance and complications K. Tizard, C. Lister, L. Poole P281 - Malnutrition assessed by phase angle determines outcomes in low risk cardiac surgery patients D. Ringaitiene, D. Gineityte, V. Vicka, I. Norkiene, J. Sipylaite P282 - Preoperative fasting times in an irish hospital A. O’Loughlin, V. Maraj, J. Dowling P283 - Costs and final outcome of early x delayed feeding in a private Brazil ICU M. B. Velasco, D. M. Dalcomune, E. B. Dias, S. L. Fernandes P284 - Can ventilator derived energy expenditure measurements replace indirect calorimetry? T. Oshima, S. Graf, C. Heidegger, L. Genton, V. Karsegard, Y. Dupertuis, C. Pichard P285 - Revisiting the refeeding syndrome: results of a systematic review N. Friedli, Z. Stanga, B. Mueller, P. Schuetz P286 - Compliance with the new protocol for parenteral nutrition in our ICU L. Vandersteen, B. Stessel, S. Evers, A. Van Assche, L. Jamaer, J. Dubois P287 - Nutrition may be another treatment in the intensive care unit where less is more? R. Marinho, H. Castro, J. Moura, J. Valente, P. Martins, P. Casteloes, C. Magalhaes, S. Cabral, M. Santos, B. Oliveira, A. Salgueiro, A. Marinho P288 - Should we provide more protein to critically ill patients? R. Marinho, M. Santos, E. Lafuente, H. Castro, S. Cabral, J. Moura, P. Martins, B. Oliveira, A. Salgueiro, S. Duarte, S. Castro, M. Melo, P. Casteloes, A. Marinho P289 Protein provision in an adult intensive care unit S. Gray P290 - Prevalence and clinical outcomes of vitamin d deficiency in the medical critically ill patients in Songklanagarind hospital K. Maipang, R. Bhurayanontachai P291 - Vitamin d deficiency strongly predicts adverse medical outcome across different medical inpatient populations: results from a prospective study L. G. Grädel, P. Schütz P292 - Omega-3 fatty acids in patients undergoing cardiac surgery: a systematic review and meta-analysis P. Langlois, W. Manzanares P293 - Can 5-hydroxytriptophan prevent post-traumatic stress disorder in critically ill patients? R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P294 - Parenteral selenium in the critically ill: an updated systematic review and meta-analysis W. Manzanares, P. Langlois, M. Lemieux, G. Elke, F. Bloos, K. Reinhart, D. Heyland P295 - Probiotics in the critically ill: an updated systematic review and meta-analysis P. Langlois, M. Lemieux, I. Aramendi, D. Heyland, W. Manzanares P296 - Diabetes with hyperglycemic crisis episodes may be associated with higher risk of pancreatic cancer: a population-based cohort study Y. Su P297 - Incidence of hypoglycemia in an intensive care unit depending on insulin protocol R. Marinho, N. Babo, A. Marinho P298 - Severity of the diseases is two-dimensionally correlated to blood glucose, including blood glucose variability, especially in moderately to severely ill patients with glucose intolerance. M. Hoshino, Y. Haraguchi, S. Kajiwara, T. Mitsuhashi, T. Tsubata, M. Aida P299 - A study of glycemic control by subcutaneous glargine injection transition from continuous regular insulin infusion in critically ill patients T. Rattanapraphat, R. Bhurayanontachai, C. Kongkamol, B. Khwannimit P300 - Glycemic control in Portuguese intensive care unit R. Marinho, M. Santos, H. Castro, E. Lafuente, A. Salgueiro, S. Cabral, P. Martins, J. Moura, B. Oliveira, M. Melo, B. Xavier, J. Valente, C. Magalhaes, P. Casteloes, A. Marinho P301 - Impact of hyperglycemia duration on the day of operation on short-term outcome of cardiac surgery patients D. Moisidou, F. Ampatzidou, C. Koutsogiannidis, M. Moschopoulou, G. Drossos P302 - Lactate levels in diabetic ketoacidosis patients at ICU admissions G. Taskin, M. Çakir, AK Güler, A. Taskin, N. Öcal, S. Özer, L. Yamanel P303 - Intensive care implications of merging heart attack centre units in London J. M. Wong, C. Fitton, S. Anwar, S. Stacey P304 - Special characteristics of in-hospital cardiac arrests M. Aggou, B. Fyntanidou, S. Patsatzakis, E. Oloktsidou, K. Lolakos, E. Papapostolou, V. Grosomanidis P305 - Clinical evaluation of ICU-admitted patients who were resuscitated in the general medicine ward S. Suda , T. Ikeda, S. Ono, T. Ueno, Y. Izutani P306 - Serious game evaluation of a one-hour training basic life support session for secondary school students: new tools for future bystanders S. Gaudry, V. Desailly, P. Pasquier, PB Brun, AT Tesnieres, JD Ricard, D. Dreyfuss, A. Mignon P307 - Public and clinical staff perceptions and knowledge of CPR compared to local and national data J. C White, A. Molokhia, A. 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Bertellini P318 Correlation between electroencephalographic findings and serum neuron specific enolase with outcome of post cardiac arrest patients A. Taha, T. Abdullah, S. Abdel Monem P319 Introduction of a targeted temperature management strategy following cardiac arrest in a district general hospital intensive care unit. S. Alcorn, S. McNeill, S. Russell P320 The evolution of cerebral oxygen saturation in post-cardiac arrest patients treated with therapeutic hypothermia W. Eertmans, C. Genbrugge, I. Meex, J. Dens, F. Jans, C. De Deyne P321 Prognostic factors and neurological outcomes of therapeutic hypothermia in comatose survivors from cardiac arrest: 8-year single center experience J. Cholkraisuwat, N. Kongpolprom P322 Adherence to targeted temperature management after out of hospital cardiac arrest B. Avard, R. Burns P323 Implementation of a therapeutic hypothermia protocol for comatose survivors of out-of-hospital cardiac arrest. A. Patarchi, T. 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Shin P329 Brain death and admission diagnosis in neurologic intensive care unit, a correlation? A Marudi, S Baroni, A Gaspari, E Bertellini P330 Brain magnetic resonance imaging findings in patients with septic shock G. Orhun, E. Senturk, P. E. Ozcan, S. Sencer, C. Ulusoy, E. Tuzun, F . Esen P331 Benefits of L-carnitine in valproic acid induced encephalopathy R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P332Automatic analysis of EEG reactivity in comatose patients M. Van Assen, M. M. Admiraal, M. J. Van Putten, M. Tjepkema-Cloostermans, A. F. Van Rootselaar, J. Horn P333 Usefulness of common ICU severity scoring systems in predicting outcome after spontaneous intracerebral hemorrhage M. Fallenius, M. B. Skrifvars, M. Reinikainen, S. Bendel, R. Raj P334 Evalution of patients with suspected subarachnoid haemorrhage and negative ct imaging M. Abu-Habsa, C. Hymers, A. Borowska, H. Sivadhas, S. Sahiba, S. Perkins P335 Timing of endovascular and surgical treatment for aneurysmal subarachnoid haemorrhage: early but not so fast. J. Rubio, J. A. Rubio, R. Sierra P336 Red blood cell transfusion in aneurysmal subarachnoid hemorrhage – the Sahara cohort study S. English, M. Chasse, A. Turgeon, F. Lauzier, D. Griesdale, A. Garland, D. Fergusson, R. Zarychanski, A. Tinmouth, C. Van Walraven, K. Montroy, J. Ziegler, R. Dupont Chouinard, R. Carignan, A. Dhaliwal, C. Lum, J. Sinclair, G. Pagliarello, L. McIntyre P337 - Aneurysmal subarachnoid hemorrhage and anemia: a canadian multi-centre retrospective cohort study S. English, M. Chasse, A. Turgeon, F. Lauzier, D. Griesdale, A. Garland, D. Fergusson, R. Zarychanski, A. Tinmouth, C. Van Walraven, K. Montroy, J. Ziegler, R. Dupont Chouinard, R. Carignan, A. Dhaliwal, C. Lum, J. Sinclair, G. Pagliarello, L. McIntyre P338 - Does the neutrophil-to-lymphocyte (NLR) ratio predict symptomatic vasospasm or delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH)? T. Groza, N. Moreau, D. Castanares-Zapatero, P. Hantson P339 - ICU-acquired infections in aneurysmal subarachnoid hemorrhage patients: impact on ICU and hospital length of stay M. Carbonara , F. Ortolano, T. Zoerle, S. Magnoni, S. Pifferi, V. Conte, N. Stocchetti P340 - Cerebral metabolic effects of normobaric hyperoxia during the acute phase of aneurysmal subarachnoid hemorrhage L. Carteron, T. Suys, C. Patet, H. Quintard, M. Oddo P341 - Postoperative care for elective craniotomy: where is best done? J. A. Rubio, J. Rubio, R. Sierra P342 - 5-year follow-up of patients after transplantation of organs from donors from neurocritical care V. Spatenkova, E. Pokorna, P. Suchomel P343 - Evaluation of levetiracetam pharmacokinetics after severe traumatic brain injury in neurocritical care patients at a level one trauma center N. Ebert, J. Jancik, H. Rhodes P344 - Model based time series cluster analysis to determine unique patient states in traumatic brain injury T. Bylinski, C. Hawthorne, M. Shaw, I. Piper, J. Kinsella P345 - Brain compartment monitoring capabilities from ICP to BI (bioimpedance) during HS (hypertonic saline) administration. State of art simulation outcome depending on brain swelling type A. K. Kink , I. R. Rätsep P346 - Transfusion of red blood cells in patients with traumatic brain injury admitted to Canadian trauma health centers: a multicenter cohort study A. Boutin, L. Moore, M. Chasse, R. Zarychanski, F. Lauzier, S. English, L. McIntyre, J. Lacroix, D. Griesdale, P. Lessard-Bonaventure, A. F. 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Schuetz P351 - Developing an innovative emergency medicine point-of-care simulation programme T. Brown, J. Collinson, C. Pritchett, T. Slade P352 - The InSim program: an in situ simulation program for junior trainees in intensive care M. Le Guen, S. Hellings, R. Ramsaran P353 - Impact of excessive and inappropriate troponin testing in the emergency setting how good are we A. Alsheikhly P354 - The development of time tracking monitor at emergency department T. Abe P355 - Role of focussed echocardiography in emergency assessment of syncope L. Kanapeckaite, M. Abu-Habsa, R. Bahl P356 - Insertion of an open-ended 14-gauge catheter through the chest wall causes a significant pneumothorax in a self-ventilating swine model M. Q Russell, K. J. Real, M. Abu-Habsa , R. M. Lyon, N. P. Oveland P357 - Ez-io® intraosseous access teaching in the workplace using a mobile ‘tea trolley’ training method J. Penketh, M. Mcdonald, F. 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Hijazi P391 - The incidence and outcome of hyperlactatemia in the post anaesthesia care unit T. Abe, S. Uchino, M. Takinami P392 - Correlation between arterial blood gas disturbances and arterial lactate levels during hospitalization and outcome in critically septic patients N. R. Rangel Neto, S. Oliveira, F. Q. Reis, F. A. Rocha P393 - External validation of saps 3 and mpm iii scores in 48,816 patients from 72 brazilian icus G. Moralez, K. Ebecken, L. S. Rabello, M. F. Lima, R. Hatum, F. V. De Marco, A. Alves, J. E. Pinto, M. Godoy, P. E. Brasil, F. A. Bozza, J. I. Salluh, M. Soares P394 - The frailty penalty: pre-admission functional status confounds mortality prediction models in critically ill patients J. Krinsley, G. Kang P395 - ‘sooner rather than later”: how delayed discharge from critical care leads to increased out of hours discharges and subsequent increase in in-hospital mortality. J. Perry, H. Hines P396 - Identifying poor outcome patient groups in a resource-constrained critical care unit K. M. Wilkinson, C. Tordoff, B. Sloan, M. C. Bellamy P397 - Effects of icu weekend admission and discharge on mortality. E. Moreira, F. Verga, M. Barbato, G. Burghi P398 - Organizational factors, outcomes and resource use in 9,946 cancer patients admitted to 70 ICUs M Soares, U. V. Silva, L. C. Azevedo, A. P. Torelly, J. M. Kahn, D. C. Angus, M. F. Knibel, P. E. Brasil, F. A. Bozza, J. I. Salluh P399 - Evaluation of oncological critically ill patients, severity score and outcome compared to not oncological in a particular hospital cti. M. B. Velasco, D. M. Dalcomune P400 - Outcomes of patients admitted to a large uk critical care department with palliative oncological diagnoses R. Marshall, T. Gilpin, A. Tridente, A. Raithatha P401 - Predictors of mortality in febrile neutropenic patients with haematological malignancies admitted to an intensive care unit of a cancer center D. Mota, B. Loureiro, J. Dias, O. Afonso, F. Coelho, A. Martins, F. Faria P402 - Patients with hematologic malignancies requiring invasive mechanical ventilation: characteristics and predictors of mortality H. Al-Dorzi, H. Al Orainni , F. AlEid, H. Tlaygeh, A. Itani, A. Hejazi, Y. Arabi P403 - Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review S. Gaudry, J. Messika, J. D. Ricard, S. Guillo, B. Pasquet, E. Dubief, D. Dreyfuss, F. Tubach P404 - Alopecia in survivors of critical illness: a qualitative study C . Battle, K. James, P. Temblett P405 - The impact of mental health on icu admission L. Davies, C. Battle, C. Lynch P406 - Cognitive impairment 5 years after ICU discharge S. Pereira, S. Cavaco, J. Fernandes, I. Moreira, E. Almeida, F. Seabra Pereira, M. Malheiro, F. Cardoso, I. Aragão, T. Cardoso P407 - Apache ii versus apache iv for octagenerians in medical icu M. Fister, R. Knafelj P408 - Outcomes of octagenarians in an indian icu P. Muraray Govind, N. Brahmananda Reddy, R. Pratheema, E. D. Arul, J. Devachandran P409 - Mortality and outcomes in elderly patients 80 years of age or older admitted to the icu M. B. Velasco , D. M. Dalcomune P410 - Octagenerians in medical icu - adding days to life or life to days? R. Knafelj, M. Fister P411 - The very elderly admitted to intensive care unit: outcomes and economic evaluation N. Chin-Yee, G. D’Egidio, K. Thavorn, D. Heyland, K. Kyeremanteng P412 - The very elderly in intensive care: relationship between acuity of illness and long-term mortality A. G. Murchison, K. Swalwell, J. Mandeville, D. Stott P413 - Acquired weakness in an oncological intensive care unit I. Guerreiro P414 - Musculoskeletal problems in intensive care unit (ICU) patients post-discharge H. Devine, P. MacTavish, J. McPeake, T. Quasim, J. Kinsella, M. Daniel P415 - Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness C. Goossens M. B. Marques, S. Derde, S. Vander Perre, T. Dufour, S. E. Thiessen, F. Güiza, T. Janssens, G. Hermans, I. Vanhorebeek, K. De Bock, G. Van den Berghe, L. Langouche P416 - Physical outcome measures for critical care patients following intensive care unit (icu) discharge H. Devine, P. MacTavish, T. Quasim, J. Kinsella, M. Daniel, J. McPeake P417 - Improving active mobilisation in a general intensive care unit B. Miles , S. Madden, H. Devine P418 - Mobilization in patients on vasoactive drugs use – a pilot study. M. Weiler, P. Marques, C. Rodrigues, M. Boeira, K. Brenner, C. Leães, A. Machado, R. Townsend, J. Andrade P419 - Pharmacy intervention at an intensive care rehabilitation clinic P. MacTavish, J. McPeake, H. Devine, J. Kinsella, M. Daniel, R. Kishore, C. Fenlon, T. Quasim P420 - Interactive gaming is feasible and potentially increases icu patients’ motivation to be engaged in rehabilitation programs T. Fiks, A. Ruijter, M. Te Raa, P. Spronk P421 - Simulation-based design of a robust stopping rule to ensure patient safety Y. S. Chiew, P. Docherty, J. Dickson, E. Moltchanova, C. Scarrot, C. Pretty, G. M. Shaw, J. G. Chase P422 - Are daily blood tests on the intensive care unit necessary? T. Hall, W. C. Ngu, J. M. Jack, P. Morgan P423 - Measuring urine output in ward patients: is it helpful? B. Avard, A. Pavli, X. Gee P424 - The incidence of pressure ulcers in an adult mixed intensive care unit in turkey C . Bor, E. Akin Korhan, K. Demirag, M. Uyar P425 - Intensivist/patient ratios in closed ICUs in Alexandria, Egypt; an overview M. Shirazy, A. Fayed P426 - Eicu (electronic intensive care unit): impact on ALOS (average length of stay) in a developing country like India S. Gupta, A. Kaushal, S. Dewan, A. Varma P427 - Predicting deterioration in general ward using early deterioration indicator E. Ghosh, L. Yang, L. Eshelman, B. Lord, E. Carlson P428 - High impact enhanced critical care outreach - the imobile service: making a difference E. Helme, R. Broderick, S. Hadfield, R. Loveridge P429 - Impact of bed availability and cognitive load on intensive care unit (ICU) bed allocation: a vignette-based trial J. Ramos, D. Forte P430 - Characteristics of critically ill patients admitted through the emergency department F. Yang, P. Hou P431 - Admission to critical care: the quantification of functional reserve J. Dudziak, J. Feeney, K. Wilkinson, K. Bauchmuller, K. Shuker, M. Faulds, A. Raithatha, D. Bryden, L. England, N. Bolton, A. Tridente P432 - Admission to critical care: the importance of frailty K. Bauchmuller, K Shuker, A Tridente, M Faulds, A Matheson, J. Gaynor, D Bryden, S South Yorkshire Hospitals Research Collaboration P433 - Development of an instrument to aid triage decisions for intensive care unit admission J. Ramos, B. Peroni, R. Daglius-Dias, L. Miranda, C. Cohen, C. Carvalho, I . Velasco, D. Forte P434 - Using selective serotonin re-uptake inhibitors and serotonin-norepinephrine re-uptake inhibitors in critical care: a systematic review of the evidence for benefit or harm J. M. Kelly, A. Neill, G. Rubenfeld, N. Masson, A. Min P435 - Measuring adaptive coping of hospitalized patients with a severe medical condition:the sickness insight in coping questionnaire (sicq) E. Boezeman, J. Hofhuis , A. Hovingh, R. De Vries, P. Spronk P436 - Results of a national survey regarding intensive care medicine training G. Cabral-Campello, I. Aragão, T. Cardoso P437 - Work engagement among healthcare professionals in the intensive care unit M. Van Mol, M. Nijkamp, E . Kompanje P438 - Empowering the intensive care practitioners. is it a burnout ameliorating intervention? P. Ostrowski, A. Omar P439 - Icu patients suffer from circadian rhythm desynchronisation K. Kiss , B. Köves, V. Csernus, Z. Molnár P440 - Noise reduction in the ICU: feasible ? Y. Hoydonckx, S. Vanwing, B. Stessel, A. Van Assche, L. Jamaer, J. Dubois P441 - Accidental removal of invasive devices in the critical patient into the bed-washing. does the presence of professional nurse modify his incidence? V. Medo, R. Galvez, J. P. Miranda P442 - Deprivation of liberty safeguards (dols): audit of compliance in a of a 16-bed specialist cancer critical care unit. C. Stone, T. Wigmore P443 - Use of a modified cristal score to predict futility of critical care in the elderly Y. Arunan, A. Wheeler, K. Bauchmuller, D. Bryden P444 - Improvement of Referral Rate to Palliative Care for Patients with Poor Prognosis in Neurosurgical Intensive Care Unit Y. Wong, C. Poi, C. Gu P445 - Factors associated with limitation of life supporting care (lsc) in a medico-surgical intermediate care unit, and outcome of patients with lsc limitation: a monocentric, six-month study. P. Molmy, N. Van Grunderbeeck, O. Nigeon, M. Lemyze, D. Thevenin, J. Mallat P446 - Palliative care consultation and intensive care unit admission request: a cohort study J. Ramos, M. Correa, R. T. Carvalho, D. Forte P447 - Nursing and medicine together in postsurgical intensive care unit: situations of prognostic conflict at the end of life. our critical care nurses suffer with our medical activism? A. Fernandez, C. McBride P448 - End of life who may decide E. Koonthalloor, C. Walsh P449 - Correctly diagnosing death A. Webber, M. Ashe, K. Smith, P. Jeanrenaud P450 - Skin procurement performed by intensive care physicians: yes, we can. A. Marudi , S. Baroni, F. Ragusa, E. Bertellini P451 - Death analysis in pediatric intensive care patients E. A. Volakli , E. Chochliourou, M. Dimitriadou, A. Violaki, P. Mantzafleri, E. Samkinidou, O. Vrani, A. Arbouti, T. Varsami, M. Sdougka P452 - The potential impact of euthanasia on organ donation: analysis of data from belgium J. A. Bollen, T. C. Van Smaalen, W. C. De Jongh, M. M. Ten Hoopen, D. Ysebaert, L. W. Van Heurn, W. N. Van Mook P453 - Communication within an intensive care setting K. Sim, A. Fuller P454 - Development and implementation of a longitudinal communication curriculum for critical care medicine fellows A. Roze des Ordons, P. Couillard, C. Doig P455 - Staff-family conflict in a multi-ethnic intensive care unit R. V. Van Keer, R. D. Deschepper, A. F. Francke, L. H. Huyghens, J. B. Bilsen P456 - Does the source of admission to critical care affect family satisfaction? B. Nyamaizi, C. Dalrymple, A. Molokhia, A. Dobru P457 - A simple alternative to the family satisfaction survey (fs-icu) E. Marrinan, A. Ankuli, A. Molokhia P458 - A study to explore the experiences of patient and family volunteers in a critical care environment: a phenomenological analysis J. McPeake, R. Struthers, R. Crawford , H. Devine , P. Mactavish , T. Quasim P459 - Prevalence and risk factors of anxiety and depression in relatives of burn patients. P. Morelli, M. Degiovanangelo, F. Lemos, V. MArtinez, F. Verga, J. Cabrera, G. Burghi P460 - Guidance of visiting children at an adult intensive care unit (icu) A. Rutten , S. Van Ieperen, S. De Geer, M. Van Vugt, E. Der Kinderen P461 - Visiting policies in Italian pediatric ICUs: an update A. Giannini, G Miccinesi, T Marchesi, E Prandi

A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 ​cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 ​kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 ​cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.

A 2025 update on treatment strategies for the Alzheimer's disease spectrum.

Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder with a continuum of stages ranging from preclinical/asymptomatic phase to severe dementia. Over the past decades, significant advances in diagnostic biomarkers and disease-modifying therapies have reshaped the treatment landscape. This review provides a comprehensive overview of the current treatment paradigm for AD in 2025, incorporating the latest developments in pharmacological and non-pharmacological interventions. The advent of anti-amyloid immunotherapy, including the US Food & Drug Administration (FDA)-approved monoclonal antibodies such as lecanemab and donanemab, has proven efficacy in slowing cognitive decline in early-stage AD. These therapies mark a change in thinking in AD management, emphasizing the importance of early diagnosis and intervention. Cholinesterase inhibitors and memantine remain the standard treatments for mild, moderate to severe dementia, providing symptomatic relief and functional stabilization. Additionally, emerging strategies targeting tau pathology and neuroinflammation are under investigation, offering hope for future breakthroughs. Beyond pharmacotherapy, this review highlights the importance of personalized, multimodal treatment approaches that integrate lifestyle modifications, cognitive training, and caregiver support. The updated diagnostic framework, incorporating fluid and imaging biomarkers, enables more precise staging and individualized treatment plans. Despite these advances, challenges still lie in refining patient selection, addressing treatment-related side effects, and ensuring accessibility to appropriate therapies. As the field moves forward, ongoing clinical trials and real-world evidence will further refine treatment strategies. A proactive approach, combining early detection with disease-modifying and symptomatic therapies, is essential for improving patient outcomes and quality of life. This article synthesizes current knowledge and provides a roadmap for clinicians and researchers navigating the evolving landscape of AD treatment.

AADC deficiency: occurring in humans, modeled in rodents.

Aromatic l-amino acid decarboxylase (AADC) is a homodimeric pyridoxal phosphate-dependent enzyme responsible for the syntheses of dopamine and serotonin. Defects in the AADC gene result in neurotransmitter deficiencies. Patients with AADC deficiency have severe motor and autonomic dysfunctions. A mouse model of AADC deficiency was recently established. These mice grow poorly and move awkwardly during infancy. They also show high anxiety when they grow up. Because drug therapy provides little or no benefit for many patients with AADC deficiency, a gene therapy has been attempted. The gene therapy employed an adeno-associated virus viral vector that can express the human AADC protein. The vector was injected to the brain of several children with AADC deficiency. The therapy was well tolerated, and all treated patients showed improvement. In the future, the mouse model will also help the development of treatments for AADC deficiency.

[A Case of Advanced Breast Cancer with Altered Biology by Eribulin Chemotherapy].

In the treatment of advanced breast cancer, onlya few drugs confer overall survival(OS)benefit. Eribulin is a drug that was shown to extend OS in an international phase Ⅲtrial; however, the underlying mechanism is thought to involve cancer microenvironment regulation. The concept of "breast cancer subtype discordance" implies the biological changes that accompany treatment. Herein, we encountered a case of advanced breast cancer in a 54-year-old woman that showed biological changes after eribulin chemotherapy. The patient noticed a lump in her left breast and visited a nearby doctor, who referred her to our hospital for close examination and treatment. Ultrasonographyrevealed a large mass at the center of the left mammarygland and axillaryly mph node swelling. Core-needle biopsyconfirmed an invasive ductal carcinoma(ER stronglypositive, PgRnegative, HER-2 negative, Ki-67 low expression). CT findings showed multiple lung metastases. Letrozole was administered for cT4N2M1, stage Ⅳ, Luminal A, which showed progression to the left side with advances in breast cancer. Six months later, the primarytumor and axillaryly mph nodes showed progression. Subsequent treatment with eribulin was started, and partial response was obtained; however, new lymph node metastasis developed in the axilla after 11 cycles. The primary tumor and axillaryly mph nodes showed stronglypositive ER expression, were PgR-negative and HER2-positive, and showed Ki-67 low expression and HER2-positive conversion.

Accelerating Alzheimer's therapeutic development: The past and future of clinical trials.

Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.

A comprehensive head-to-head comparison of key plasma phosphorylated tau 217 biomarker tests.

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarker for reliable detection of Alzheimer's disease pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET and cognition as outcomes and benchmarked them against CSF biomarker tests. Samples from 998 individuals [mean (range) age 68.5 (20.0-92.5) years, 53% female] from the Swedish BioFINDER-2 cohort, including both cognitively unimpaired and cognitively impaired individuals, were analysed. Plasma p-tau217 was measured with mass spectrometry assays [the ratio between phosphorylated and non-phosphorylated (%p-tau217WashU) and p-tau217WashU] and with immunoassays (p-tau217Lilly, p-tau217Janssen and p-tau217ALZpath). CSF biomarkers included p-tau217Lilly, the US Food and Drug Administration-approved p-tau181/Aβ42Elecsys, and p-tau181Elecsys. All plasma p-tau217 tests exhibited a high ability to detect abnormal Aβ-PET [area under the curve (AUC) range: 0.91-0.96] and tau-PET (AUC range: 0.94-0.97). Plasma %p-tau217WashU had the highest performance, with significantly higher AUCs than all the immunoassays (Pdiff < 0.007). For detecting Aβ-PET status, %p-tau217WashU had an accuracy of 0.93 (immunoassays: 0.83-0.88), sensitivity of 0.91 (immunoassays: 0.84-0.87) and a specificity of 0.94 (immunoassays: 0.85-0.89). Among immunoassays, p-tau217Lilly and plasma p-tau217ALZpath had higher AUCs than plasma p-tau217Janssen for Aβ-PET status (Pdiff < 0.006), and p-tau217Lilly outperformed plasma p-tau217ALZpath for tau-PET status (Pdiff = 0.025). Plasma %p-tau217WashU exhibited stronger associations with all PET load outcomes compared with immunoassays; baseline Aβ-PET load (R2: 0.72; immunoassays: 0.47-0.58; Pdiff < 0.001), baseline tau-PET load (R2: 0.51; immunoassays: 0.38-0.45; Pdiff < 0.001), longitudinal Aβ-PET load (R2: 0.53; immunoassays: 0.31-0.38; Pdiff < 0.001) and longitudinal tau-PET load (R2: 0.50; immunoassays: 0.35-0.43; Pdiff < 0.014). Among immunoassays, plasma p-tau217Lilly was more associated with Aβ-PET load than plasma p-tau217Janssen (Pdiff < 0.020) and with tau-PET load than both plasma p-tau217Janssen and plasma p-tau217ALZpath (all Pdiff < 0.010). Plasma %p-tau217 also correlated more strongly with baseline cognition (Mini-Mental State Examination) than all immunoassays (R2: %p-tau217WashU: 0.33; immunoassays: 0.27-0.30; Pdiff < 0.024). The main results were replicated in an external cohort from Washington University in St Louis (n = 219). Finally, p-tau217NULISA showed similar performance to other immunoassays in subsets of both cohorts. In summary, both mass spectrometry- and immunoassay-based p-tau217 tests generally perform well in identifying Aβ-PET, tau-PET and cognitive abnormalities, but %p-tau217WashU performed significantly better than all the examined immunoassays. Plasma %p-tau217 may be considered as a stand-alone confirmatory test for Alzheimer's disease pathology, whereas some immunoassays might be better suited as triage tests where positive results are confirmed with a second test, which needs to be determined by future reviews incorporating results from multiple cohorts.

Acquisition of neurodegenerative features in isogenic OPTN(E50K) human stem cell-derived retinal ganglion cells associated with autophagy disruption and mTORC1 signaling reduction.

The ability to derive retinal ganglion cells (RGCs) from human pluripotent stem cells (hPSCs) has led to numerous advances in the field of retinal research, with great potential for the use of hPSC-derived RGCs for studies of human retinal development, in vitro disease modeling, drug discovery, as well as their potential use for cell replacement therapeutics. Of all these possibilities, the use of hPSC-derived RGCs as a human-relevant platform for in vitro disease modeling has received the greatest attention, due to the translational relevance as well as the immediacy with which results may be obtained compared to more complex applications like cell replacement. While several studies to date have focused upon the use of hPSC-derived RGCs with genetic variants associated with glaucoma or other optic neuropathies, many of these have largely described cellular phenotypes with only limited advancement into exploring dysfunctional cellular pathways as a consequence of the disease-associated gene variants. Thus, to further advance this field of research, in the current study we leveraged an isogenic hPSC model with a glaucoma-associated mutation in the Optineurin (OPTN) protein, which plays a prominent role in autophagy. We identified an impairment of autophagic-lysosomal degradation and decreased mTORC1 signaling via activation of the stress sensor AMPK, along with subsequent neurodegeneration in OPTN(E50K) RGCs differentiated from hPSCs, and have further validated some of these findings in a mouse model of ocular hypertension. Pharmacological inhibition of mTORC1 in hPSC-derived RGCs recapitulated disease-related neurodegenerative phenotypes in otherwise healthy RGCs, while the mTOR-independent induction of autophagy reduced protein accumulation and restored neurite outgrowth in diseased OPTN(E50K) RGCs. Taken together, these results highlighted that autophagy disruption resulted in increased autophagic demand which was associated with downregulated signaling through mTORC1, contributing to the degeneration of RGCs.

Activation of the γ-secretase/NICD-PXR/Notch pathway induces Taxol resistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is currently the only subtype lacking efficient targeted therapies. Taxol is the primary chemotherapeutic agent for TNBC. However, Taxol resistance often develops in the treatment of TNBC patients, which importantly contributes to high mortality and poor prognosis in TNBC patients. Recent preclinical studies have shown that the inhibition of Notch pathway by γ-secretase inhibitors can slow down the progression of TNBC. Our studies in bioinformatic analysis of breast cancer patients and TNBC/Taxol cells in vitro showed that there was high correlation between the activation of Notch pathway and Taxol resistance in TNBC. Increased γ-secretase activity (by the overexpression of catalytic core PSEN-1) significantly reduced Taxol sensitivity of TNBC cells, and enhanced biological characteristics of malignancy in vitro, and tumour growth in vivo. Mechanistically, increased γ-secretase activity led to the accumulation of NICD in the nucleus, promoting the interaction between NICD and PXR to activate PXR, which triggered the transcription of PXR downstream associated drug resistance genes. Furthermore, we showed that pharmacological inhibition of γ-secretase with γ-secretase inhibitors (Nirogacestat and DAPT) can reverse Taxol resistance in vivo and in vitro. Our results for the first time demonstrate that the activation of γ -secretase/NCD-PXR/Notch pathway is one of important mechanisms to cause Taxol resistance in TNBC, and the blockades of this pathway may represent a new therapeutic strategy for overcoming Taxol resistance in TNBC.

Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance.

Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show that GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

Addiction as a stress surfeit disorder.

Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-κ opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-κ opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the κ opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Advances and Therapeutic Potential of Anthraquinone Compounds in Neurodegenerative Diseases: A Comprehensive Review.

BACKGROUND: Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms. OBJECTIVE: This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of NDDs. METHODS: A comprehensive search of PubMed, Web of Science, and Google Scholar was conducted for articles on the intervention of anthraquinones in NDDs in the past 20 years. The collected information was then summarized and analyzed. RESULTS: Anthraquinones ameliorate NDDs through multiple mechanisms. They exhibit antioxidant and anti-inflammatory effects, protect mitochondria, and regulate microglial polarization. Furthermore, anthraquinones inhibit pyroptosis, apoptosis, tau phosphorylation, Aβ/α-synuclein aggregation, and acetylcholinesterase activity, while restoring metal homeostasis, activating estrogen receptors, modulating gut microbiota, increasing BDNF levels, and preserving blood-brain barrier permeability. More notably, these compounds play a neuroprotective role by mediating multiple signaling pathways and targets, including Nrf2, ERK1/2, PI3K/mTOR, ROS/TXNIP, SIRT1/PCG-1α, NLRP3, PI3K/Akt, MAPK, TLR4-NFκB, CaM/CaMKIV, and Ca2+/EGFR/PLCγ. CONCLUSION: The pleiotropic actions of anthraquinones highlight their potential as therapeutic candidates for NDDs, yet clinical validation remains essential. Future studies should emphasize rigorously designed clinical trials and optimized brain-targeted delivery platforms. This review consolidates current evidence to support their translational development.

Advances in HER2-Targeted Therapies: From monoclonal antibodies to dual inhibitors developments in cancer treatment.

HER2 receptors, overexpressed in certain human cancers, have drawn significant attention in cancer research due to their correlation with poor survival rates. Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer. However, ongoing research is investigating their potential use in other types of cancer, often in combination with other medications. EGFR/HER2 dual-targeted drugs have overcome drug resistance associated with HER2-targeted monotherapy. This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.

Advancing Alzheimer's disease treatment: A literature review on senolytic intervention.

Alzheimer's disease (AD) is a leading cause of dementia, currently affecting over 50 million people globally. Despite decades of research, therapeutic development has continued to face high failure rates due to an incomplete understanding of the underlying disease mechanisms. Current drugs like rivastigmine focus on managing cognitive symptoms since there is no known cure to halt the disease's progression. However, recent research has suggested that advanced biological age, particularly the accumulation of senescent cells, is the most significant risk factor for AD pathology, and targeting these aging mechanisms may prove more effective in altering the disease progression. Senescent cells accumulate with age, contributing to inflammatory states and neurodegenerative diseases such as AD. Senolytic drugs, such as dasatinib and quercetin (D + Q), have shown promise in animal models by clearing senescent cells, delaying aging-related decline, and improving AD-related outcomes. This literature review aims to provide a comprehensive overview of the therapeutic potential of senolytic interventions for AD by examining the mechanisms of cellular senescence based on evidence of its accumulation in the human brain, critically analyzing the preclinical and clinical trials involving senolytic compounds, and discussing the implications and limitations of this approach. The findings from recent studies indicate that senolytics may pave the way for effective AD treatments, though further clinical validation is needed.

African swine fever virus hijacks lipolysis induced by chaperone-mediated autophagy to upregulate fatty acid β-oxidation and promote viral replication.

Lipid metabolism plays a crucial role in cellular signal transduction, affects the structural integrity of cell membranes, and regulates energy metabolism. However, various viruses, including African swine fever virus (ASFV), usurp lipid metabolism to enhance their replication. The mechanism for the positive role of lipid metabolism in ASFV infection is unclear. Here, we present data that ASFV infection concurrently upregulates both fatty acid synthesis (FAS) and fatty acid β-oxidation (FAO) to enhance viral replication. Pharmacological inhibition of FAS significantly suppresses ASFV replication, an effect that can be markedly reversed by exogenous palmitate (the end product of FAS). Similarly, inhibition of FAO also impairs viral replication. Lipidomic profiling revealed that ASFV infection dramatically alters lipid droplet (LD) lipid composition, particularly triglycerides (TG) and diacylglycerols (DAG). ASFV infection triggers the accumulation of LDs, which in turn promote viral replication. Mechanistically, we discovered that ASFV exploits chaperone-mediated autophagy (CMA) to degrade perilipin 2 (PLIN2), a protein on the LD surface, thereby stimulating lipolysis. Furthermore, ASFV infection induces LD-mitochondrion contacts, facilitating the transfer of LD-derived fatty acids to mitochondria. These data indicate that LDs provide lipids to fuel ASFV-induced FAO upregulation. Collectively, our study reveals that ASFV orchestrates a complex metabolic network involving FAS, LD biogenesis, lipolysis, and FAO to optimize viral replication. These findings elucidate the pivotal role of lipid metabolism in ASFV replication, revealing a mechanism through which the virus manipulates cellular lipid pathways to facilitate its replication. This insight not only advances our understanding of ASFV pathogenesis but also presents potential therapeutic avenues for inhibiting viral production by modulating lipid metabolic processes.IMPORTANCEAfrican swine fever (ASF), caused by African swine fever virus (ASFV), represents a catastrophic threat to the global swine industry, with no safe and effective vaccines or antiviral therapies currently available except in Vietnam. Understanding how ASFV reprograms host lipid metabolism is critical for developing targeted interventions. Our study reveals a novel metabolic hijacking strategy employed by ASFV to reprogram lipid metabolism pathways, including fatty acid synthesis (FAS), lipid droplet (LD) biogenesis, chaperone-mediated autophagy (CMA)-mediated lipolysis, and mitochondrial β-oxidation (FAO), to support viral replication. Notably, we provide evidence that ASFV exploits CMA to degrade perilipin 2 (PLIN2), a key protein stabilizing lipid droplets, thereby promoting lipolysis. This mechanism resolves the paradox of concurrent upregulation of FAS and FAO by facilitating lipid shuttling through LD-mitochondrion contacts. Our findings offer new insights into how ASFV exploits host lipid networks and may pave the way for designing vaccines or targeted drugs to control ASF.

Agile delivery of protein therapeutics to CNS.

A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.

Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism

Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouse(TM) platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.

AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3-6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

AKT as a therapeutic target in multiple myeloma.

INTRODUCTION: Multiple myeloma remains an incurable malignancy with poor survival. Novel therapeutic approaches capable of improving outcomes in patients with multiple myeloma are urgently required. AKT is a central node in the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin signaling pathway with high expression in advanced and resistant multiple myeloma. AKT contributes to multiple oncogenic functions in multiple myeloma which may be exploited therapeutically. Promising preclinical data has lent support for pursuing further development of AKT inhibitors in multiple myeloma. Lead drugs are now entering the clinic. AREAS COVERED: The rationale for AKT inhibition in multiple myeloma, pharmacological subtypes of AKT inhibitors in development, available results of clinical studies of AKT inhibitors and suitable drug partners for further development in combination with AKT inhibition in multiple myeloma are discussed. EXPERT OPINION: AKT inhibitors are a welcome addition to the armamentarium against multiple myeloma and promising clinical activity is being reported from ongoing trials in combination with established and/or novel treatment approaches. AKT inhibitors may be set to improve patient outcomes when used in combination with synergistic drug partners.

AKT/PKB Signaling: Navigating the Network.

The Ser and Thr kinase AKT, also known as protein kinase B (PKB), was discovered 25 years ago and has been the focus of tens of thousands of studies in diverse fields of biology and medicine. There have been many advances in our knowledge of the upstream regulatory inputs into AKT, key multifunctional downstream signaling nodes (GSK3, FoxO, mTORC1), which greatly expand the functional repertoire of AKT, and the complex circuitry of this dynamically branching and looping signaling network that is ubiquitous to nearly every cell in our body. Mouse and human genetic studies have also revealed physiological roles for the AKT network in nearly every organ system. Our comprehension of AKT regulation and functions is particularly important given the consequences of AKT dysfunction in diverse pathological settings, including developmental and overgrowth syndromes, cancer, cardiovascular disease, insulin resistance and type 2 diabetes, inflammatory and autoimmune disorders, and neurological disorders. There has also been much progress in developing AKT-selective small molecule inhibitors. Improved understanding of the molecular wiring of the AKT signaling network continues to make an impact that cuts across most disciplines of the biomedical sciences.

Alcohol sipping patterns, personality, and psychopathology in Children: Moderating effects of dorsal anterior cingulate cortex (dACC) activation.

Alcohol, the most consumed drug in the United States, is associated with various psychological disorders and abnormal personality traits. Despite extensive research on adolescent alcohol consumption, the impact of early alcohol sipping patterns on changes in personality and mental health over time remains unclear. There is also limited information on the latent trajectory of early alcohol sipping, beginning as young as 9-10 years old. The dorsal anterior cingulate cortex (dACC) is crucial for cognitive control and response inhibition. However, the role of the dACC remains unclear in the relationship between early alcohol sipping and mental health outcomes and personality traits over time. Utilizing the large data from the Adolescent Brain Cognitive Development study (N = 11,686, 52% males, 52% white, mean [SD] age 119 [7.5] months, 9807 unique families, 22 sites), we aim to comprehensively examine the longitudinal impact of early alcohol sipping patterns on psychopathological measures and personality traits in adolescents, filling crucial gaps in the literature. We identified three latent alcohol sipping groups, each demonstrating distinct personality traits and depression score trajectories. Bilateral dACC activation during the stop-signal task moderated the effect of early alcohol sipping on personality and depression over time. Additionally, bidirectional effects were observed between alcohol sipping and personality traits. This study provides insights into the impact of early alcohol consumption on adolescent development. The key finding of our analysis is that poor response inhibition at baseline, along with increased alcohol sipping behaviors may accelerate the changes in personality traits and depression scores over time as individuals transition from childhood into adolescence.

Allosteric Activation of Transglutaminase 2 via Inducing an "Open" Conformation for Osteoblast Differentiation.

Osteoblasts play an important role in the regulation of bone homeostasis throughout life. Thus, the damage of osteoblasts can lead to serious skeletal diseases, highlighting the urgent need for novel pharmacological targets. This study introduces chemical genetics strategy by using small molecule forskolin (FSK) as a probe to explore the druggable targets for osteoporosis. Here, this work reveals that transglutaminase 2 (TGM2) served as a major cellular target of FSK to obviously induce osteoblast differentiation. Then, this work identifies a previously undisclosed allosteric site in the catalytic core of TGM2. In particular, FSK formed multiple hydrogen bonds in a saddle-like domain to induce an "open" conformation of the β-sandwich domain in TGM2, thereby promoting the substrate protein crosslinks by incorporating polyamine. Furthermore, this work finds that TGM2 interacted with several mitochondrial homeostasis-associated proteins to improve mitochondrial dynamics and ATP production for osteoblast differentiation. Finally, this work observes that FSK effectively ameliorated osteoporosis in the ovariectomy mice model. Taken together, these findings show a previously undescribed pharmacological allosteric site on TGM2 for osteoporosis treatment, and also provide an available chemical tool for interrogating TGM2 biology and developing bone anabolic agent.