Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

BACKGROUND: Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. METHODS: We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. RESULTS: Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. CONCLUSIONS: Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.

MLC positional accuracy evaluation through the Picket Fence test on EBT2 films and a 3D volumetric phantom.

The accuracy of MLC positions during radiotherapy is important as even small positional deviations can translate into considerable dose delivery errors. This becomes crucial when radiosensitive organs are located near the treated volume and especially during IMRT, where dose gradients are steep. A test commonly conducted to measure the positional accuracy of the MLCs is the Picket Fence test. In this study two alterations of the Picket Fence test were performed and evaluated, the first one using radiochromic EBT2 films and the second one the Delta4PT diode array phantom and its software. Our results showed that EBT2 films provide a relatively fast, qualitative visual inspection of the significant leaf dispositions. When slight inaccuracies need to be revealed or precise numerical results for each leaf position are needed, Delta4PT provides the desired accuracy of 1 mm. In treatment modalities where a higher accuracy is required in the delivered dose distribution, such as in IMRT, precise numerical values of the measurements for the MLC positional inspection are required.

The first implementation of IMRT technique for head & neck and prostate cancer patients in public sector in Greece: feasibility, treatment planning and dose delivery verification using the delta(4PT) Pre-Treatment volumetric quality assurance system.

PURPOSE: Intensity Modulated Radiation Therapy (IMRT) is nowadays the treatment of choice, in terms of technique, for either head & neck or prostate cancer. With this paper, we are sharing our experience for the first inplementation of IMRT planning in the public sector in Greece, and especially in the Aretaieion University Hospital of Athens. METHODS: From May 2013 until January 2014 four prostate and four head & neck cancer patients were evaluated in the present study. We used the ONCENTRA IMRT treatment planning with a step and shoot technique in a SIEMENS ONCORE Linac. The dose verification method used was based on the delta4(PT) Pre-Treatment volumetric quality assurance system, by Scadidos. RESULTS: In all cases, the Relative Standard Deviation between the prescribed and the calculated average dose received by the target volume was less than 5%, while the γ-index was more than 90%. The acute toxicity was low and equivalent to published data with IMRT technique. CONCLUSION: In conclusion, the first implementation of IMRT technique in the Medical School of Athens was feasible and safe as well as in terms of dose verification. The IMRT technique is already in clinical use and further results with long term radiation induced toxicity will be reported.

End-of-life decisions in Greek intensive care units: a multicenter cohort study.

INTRODUCTION: Intensive care may prolong the dying process in patients who have been unresponsive to the treatment already provided. Limitation of life-sustaining therapy, by either withholding or withdrawing support, is an ethically acceptable and common worldwide practice. The purpose of the present study was to examine the frequency, types, and rationale of limiting life support in Greek intensive care units (ICUs), the clinical and demographic parameters associated with it, and the participation of relatives in decision making. METHODS: This was a prospective observational study conducted in eight Greek multidisciplinary ICUs. We studied all consecutive ICU patients who died, excluding those who stayed in the ICU less than 48 hours or were brain dead. RESULTS: Three hundred six patients composed the study population, with a mean age of 64 years and a mean APACHE II score on admission of 21. Of study patients, 41% received full support, including unsuccessful cardiopulmonary resuscitation (CPR); 48% died after withholding of CPR; 8%, after withholding of other treatment modalities besides CPR; and 3%, after withdrawal of treatment. Patients in whom therapy was limited had a longer ICU (P < 0.01) and hospital (P = 0.01) length of stay, a lower Glasgow Coma Scale score (GCS) on admission (P < 0.01), a higher APACHE II score 24 hours before death (P < 0.01), and were more likely to be admitted with a neurologic diagnosis (P < 0.01). Patients who received full support were more likely to be admitted with either a cardiovascular (P = 0.02) or trauma diagnosis (P = 0.05) and to be surgical rather than medical (P = 0.05). The main factors that influenced the physician's decision were, when providing full support, reversibility of illness and prognostic uncertainty, whereas, when limiting therapy, unresponsiveness to treatment already offered, prognosis of underlying chronic disease, and prognosis of acute disorder. Relatives' participation in decision making occurred in 20% of cases and was more frequent when a decision to provide full support was made (P < 0.01). Advance directives were rare (1%). CONCLUSIONS: Limitation of life-sustaining treatment is a common phenomenon in the Greek ICUs studied. However, in a large majority of cases, it is equivalent to the withholding of CPR alone. Withholding of other therapies besides CPR and withdrawal of support are infrequent. Medical paternalism predominates in decision making.

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection.

INTRODUCTION: Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time. METHODS: The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer. RESULTS: Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis. CONCLUSIONS: Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

Accuracy and precision of cardiac output estimation by an automated, brachial cuff-based oscillometric device in patients with shock.

Non-invasive monitoring of cardiac output is a technological and clinical challenge, especially for critically ill, surgically operated, or intensive care unit patients. A brachial cuff-based, automated, oscillometric device used for blood pressure and arterial stiffness ambulatory monitoring (Mobil-O-Graph) provides a non-invasive estimation of cardiac output values simultaneously with regular blood pressure measurement. The aim of the study was to evaluate the feasibility of this apparatus to estimate cardiac output in intensive care unit patients and to compare the non-invasive estimated cardiac output values with the respective gold standard method of thermodilution during pulmonary artery catheterization. Repeated sequential measurements of cardiac output were performed, in random order, by thermodilution (reference) and Mobil-O-Graph (test), in 24 patients hospitalized at intensive care unit. Reproducibility and accuracy of the test device were evaluated by Bland-Altman analysis, intraclass correlation coefficient, and percentage error. Mobil-O-Graph underestimated significantly the cardiac output by -1.12 ± 1.38 L/min (p < 0.01) compared to thermodilution. However, intraclass correlation coefficient was >0.7 indicating a fair agreement between the test and the reference methods, while percentage error was approximately 39% which is considered to be within the acceptable limits. Cardiac output measurements were reproducible by both Mobil-O-Graph (intraclass correlation coefficient = 0.73 and percentage error = 27.9%) and thermodilution (intraclass correlation coefficient = 0.91 and percentage error = 26.7%). We showed for the first time that cardiac output estimation in intensive care unit patients using a non-invasive, automated, oscillometric, cuff-based apparatus is reproducible (by analyzing two repeated cardiac output measurements), exhibiting similar precision to thermodilution. However, the accuracy of Mobil-O-Graph (error compared to thermodilution) could be considered fairly acceptable. Future studies remain to further examine the reliability of this technology in monitoring cardiac output or stroke volume acute changes which is a more clinically relevant objective.

Enhancement of Flux Performance in PTFE Membranes for Direct Contact Membrane Distillation.

This work focused on enhancing the flux on hydrophobic polymeric membranes aimed for direct contact membrane distillation desalination (DCMD) process without compromising salt rejection efficiency. Successful coating of commercial porous poly-tetrafluoroethylene membranes with poly(vinyl alcohol) (PVA) was achieved by solution dipping followed by a cross-linking step. The modified membranes were evaluated for their performance in DCMD, in terms of water flux and salt rejection. A series of different PVA concentration dipping solutions were used, and the results indicated that there was an optimum concentration after which the membranes became hydrophilic and unsuitable for use in membrane distillation. Best performing membranes were achieved under the specific experimental conditions, water flux 12.2 L·m-2·h-1 [LMH] with a salt rejection of 99.9%. Compared to the pristine membrane, the flux was enhanced by a factor of 2.7. The results seemed to indicate that introducing hydrophilic characteristics in a certain amount to a hydrophobic membrane could significantly enhance the membrane distillation (MD) performance without compromising salt rejection.

Adaptive information processing of network modules to dynamic and spatial stimuli.

BACKGROUND: Adaptation and homeostasis are basic features of information processing in cells and seen in a broad range of contexts. Much of the current understanding of adaptation in network modules/motifs is based on their response to simple stimuli. Recently, there have also been studies of adaptation in dynamic stimuli. However a broader synthesis of how different circuits of adaptation function, and which circuits enable a broader adaptive behaviour in classes of more complex and spatial stimuli is largely missing. RESULTS: We study the response of a variety of adaptive circuits to time-varying stimuli such as ramps, periodic stimuli and static and dynamic spatial stimuli. We find that a variety of responses can be seen in ramp stimuli, making this a basis for discriminating between even similar circuits. We also find that a number of circuits adapt exactly to ramp stimuli, and dissect these circuits to pinpoint what characteristics (architecture, feedback, biochemical aspects, information processing ingredients) allow for this. These circuits include incoherent feedforward motifs, inflow-outflow motifs and transcritical circuits. We find that changes in location in such circuits where a signal acts can result in non-adaptive behaviour in ramps, even though the location was associated with exact adaptation in step stimuli. We also demonstrate that certain augmentations of basic inflow-outflow motifs can alter the behaviour of the circuit from exact adaptation to non-adaptive behaviour. When subject to periodic stimuli, some circuits (inflow-outflow motifs and transcritical circuits) are able to maintain an average output independent of the characteristics of the input. We build on this to examine the response of adaptive circuits to static and dynamic spatial stimuli. We demonstrate how certain circuits can exhibit a graded response in spatial static stimuli with an exact maintenance of the spatial mean-value. Distinct features which emerge from the consideration of dynamic spatial stimuli are also discussed. Finally, we also build on these results to show how different circuits which show any combination of presence or absence of exact adaptation in ramps, exact mainenance of time average output in periodic stimuli and exact maintenance of spatial average of output in static spatial stimuli may be realized. CONCLUSIONS: By studying a range of network circuits/motifs on one hand and a range of stimuli on the other, we isolate characteristics of these circuits (structural) which enable different degrees of exact adaptive and homeostatic behaviour in such stimuli, how they may be combined, and also identify cases associated with non-homeostatic behaviour. We also reveal constraints associated with locations where signals may act to enable homeostatic behaviour and constraints associated with augmentations of circuits. This consideration of multiple experimentally/naturally relevant stimuli along with circuits of adaptation of relevance in natural and engineered biology, provides a platform for deepening our understanding of adaptive and homeostatic behaviour in natural systems, bridging the gap between models of adaptation and experiments and in engineering homeostatic synthetic circuits.

Pre-intensive care unit intubation and subsequent delayed intensive care unit admission is independently associated with increased occurrence of ventilator-associated pneumonia.

INTRODUCTION: Critically ill intubated patients are at risk for ventilator-associated pneumonia. However, intubation may not occur in intensive care unit (ICU) and subsequent ICU admission may be delayed. OBJECTIVES: To evaluate whether intubation >24 h prior ICU admission and delay in ICU admission is associated with ventilator-associated pneumonia (VAP) in non-trauma critically ill patients. MATERIALS AND METHODS: Prospective observational study conducted in a medical-surgical ICU of a tertiary hospital. Consecutive patients with >48 h of invasive mechanical ventilation and >72 h hospitalization, were recruited in the study. Pre-ICU intubation and delay in ICU admission, demographical, clinical, microbiological data and ICU interventions were assessed as risk factors for VAP and ICU mortality. RESULTS: 100 patients were included in the study. Pre-ICU intubation and delayed (>24 h) ICU admission (PDA patients) (P = 0.014, OR = 3.294, confidence interval 1.268-8.557) and SOFA score on ICU admission (P = 0.045, OR = 1.154, confidence interval 1.003-1.328) were independent risk factors for VAP in ICU care setting. Yet, PDA patients, presented significantly increased incidence of VAP due to MDR bacteria, mainly from Acinetobacter baumannii. Acinetobacter baumannii infection was the only independent risk factor for ICU mortality (P = 0.049, OR = 3.253, confidence interval 1.006-10.521). SOFA score on ICU admission, presented a fair prognostic accuracy of overall ICU mortality (SOFA ≥ 8.5, AUC = 0.850, P < 0.001). CONCLUSIONS: Pre-ICU intubation and delayed ICU admission was independent risk factor for VAP Acinetobacter baumannii infection and a high SOFA score on ICU admission were predictors of increased ICU mortality.

Fatal post-traumatic zygomycosis in an immunocompetent young patient.

Zygomycosis, a relatively uncommon infection, usually occurs among immunocompromised individuals. It has been reported only rarely in trauma patients. A fatal case is reported of pulmonary and rapidly progressive cutaneous zygomycosis in a young, otherwise healthy farmer, with multiple bone fractures, wounds and soft tissue injuries after an accident with an agricultural machine in the field. Rhizopus spp. was isolated from both cultures of bronchial washings and wound samples. The diagnosis was confirmed by histopathological examination of tissue specimens from a large wound. Despite systemic antifungal therapy and surgical debridement, the patient's condition deteriorated and he died from refractory septic shock.

Primary right atrium angiosarcoma mimicking pericarditis.

BACKGROUND: Primary cardiac neoplasms occur rarely and most of them are benign. Malignant tumors including angiosarcoma are extremely rare and have a non specific clinical presentation and a poor prognosis. CASE PRESENTATION: We present a case of a young male who was transferred to our hospital because of shock and multiple organ failure after a complicated pericardial biopsy. During the previous seven months he presented with recurrent episodes of pericardial effusions and tamponade. Chest computed tomography revealed a mass in the right atrium, infiltrating the myocardium and pericardium. During emergency surgery that followed, the patient died because of uncontrolled hemorrhage. Autopsy revealed the mass of the right atrium, which was identified on histological examination as primary cardiac angiosarcoma. CONCLUSION: This case highlights the difficulties both in early diagnosis and in the management of patients with cardiac angiosarcoma.

Evaluation of Intensity Modulated Radiation Therapy Delivery System using a Volumetric Phantom on the Basis of the Task Group 119 Report of American Association of Physicists in Medicine.

The current work describes the implementation of the American Association of Physicists in Medicine (AAPM)'s Task Group 119 report on a volumetric phantom (Delta4, Scandidos, Uppsala, Sweden) following the stated dose goals, to evaluate the step-and-shoot intensity modulated radiation therapy (IMRT) system. Delta4 consists of diode detectors, lying on two crossed planes, measuring the delivered dose, and providing two-dimensional dosimetric information. Seven plans of different goals and complexity were performed, with individual structure sets. TG199 structure sets and plans were transferred and implemented on the Delta4 phantom taking into account its cylindrical geometry. All plans were delivered with a 6 MV linear accelerator equipped with multileaf collimator of 1 cm thickness. Plan results for each test met the recommended dose goals. The evaluation was performed in terms of dose deviation, distance to agreement, and gamma index passing rate. In all test cases, the gamma index passing rate was measured >90%. Delta4 phantom has proven to be fast, applicable, and reliable for the step-and-shoot IMRT commissioning following TG119's recommended tests. Although AAPM's TG119 report is referring to the implementation of test plans that do not correspond to patient plans, it could be used as an evaluation tool of various IMRT systems, considering the local treatment planning system and the delivery system.

Effect of median sternotomy on respiratory system compliance in humans: evaluation without sophisticated instrumentation.

To evaluate the effect of median sternotomy on the static compliance of the respiratory system (C(RS)) in humans, we used a new technique for pressure-volume (PV) curve tracing without sophisticated instrumentation. The accuracy and the reproducibility of the new technique were tested in a lung simulator, while its agreement with multiple-occlusion (MO) technique (the technique most often used in the ICU for C(RS) measurement) was evaluated in 12 mechanically ventilated patients. Finally, the NCI technique was used in 13 cardiosurgical patients to measure C(RS) before and after median sternotomy. Measurements provided by the NCI technique were at least as accurate as standard measurements in the bench study. In ICU patients, we observed a good agreement of C(RS) measurements provided by the two techniques (bias 0.8, 95% limits of agreement -5.6 to 7.2 ml/cm H(2)O) and a similar reproducibility. In cardiosurgical patients we observed a significant (P=0.037) increase in C(RS) with an upward and leftward shift of the PV-curve after median sternotomy. No adverse effect was observed during PV-curve tracing maneuvers. The simplicity of NCI technique allowed for the first time, to our knowledge, PV-curve tracing in humans during cardiosurgery and revealed 5% increase in C(RS) immediately after median sternotomy.

Monocytes as a site of production of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the septic host.

The role of blood monocytes in the secretion of soluble triggering receptor expressed on myeloiod cells (sTREM-1) was studied in 90 patients with septic syndrome due to ventilator-associated pneumonia. Blood monocytes were isolated on 7 consecutive d after initiation of symptoms. Monocytes were incubated in the absence or presence of LPS and concentrations of sTREM-1 and TNFalpha in cell supernatants and serum were estimated by an enzyme-immunoassay. sTREM-1 and TNFalpha were consistently present at detectable levels in the cell supernatants. LPS induced increased levels of TNFalpha but not of sTREM-1. Supernatants recovered from monocytes on d 1 showed levels of sTREM-1 higher than those recovered on any of the following 6 d (p<0.05); these levels were higher in non-survivors than in survivors. Supernatants recovered from monocytes on d 1 of patients with severe sepsis had elevated concentrations of sTREM-1 compared to patients with septic shock and similar to patients with sepsis. A negative correlation was found between levels of sTREM-1 in the cell supernatants and the percentage of apoptotic monocytes. In essence, the above results suggest that monocytes contribute to the production of sTREM-1 in the event of septic syndrome.