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Background Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA. Methods We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality. Results Our search identified 6886 studies; 22 studies ( n  = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75–0.96]; p  = 0.008) but not mortality (OR 0.88 [95% CIs 0.62–1.25]; p  = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs. Conclusions Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).

Background The aim of this study was to explore the performance and outcomes for intravascular (IC) versus surface cooling devices (SFC) for targeted temperature management (TTM) after out-of-hospital cardiac arrest. Methods A retrospective analysis of data from the Time-differentiated Therapeutic Hypothermia (TTH48) trial (NCT01689077), which compared whether TTM at 33 °C for 48 h results in better neurologic outcomes compared with standard 24-h duration. Devices were assessed for the speed of cooling and rewarming rates. Precision was assessed by measuring temperature variability (TV), i.e., the standard deviation (SD) of all temperature measurements in the cooling phase. Main outcomes were overall mortality and poor neurological outcome, including death, severe disability, or vegetative status. Results A total of 352 patients had available data and were included in the analysis; of those, 218 (62%) were managed with IC. A total of 114/218 (53%) patients with IC and 61/134 (43%) with SFC were cooled for 48 h ( p  = 0.22). Time to target temperature (≤ 34 °C) was significantly shorter for patients treated with endovascular devices (2.2 [1.1–4.0] vs. 4.2 [2.7–6.0] h, p  < 0.001), but temperature was also lower on admission (35.0 [34.2–35.6] vs. 35.3 [34.5–35.8]°C; p  = 0.02) and cooling rate was similar (0.4 [0.2–0.8] vs. 0.4 [0.2–0.6]°C/h; p  = 0.14) when compared to SFC. Temperature variability was significantly lower in the endovascular device group when compared with SFC methods (0.6 [0.4–0.9] vs. 0.7 [0.5–1.0]°C; p  = 0.007), as was rewarming rate (0.31 [0.22–0.44] vs. 0.37 [0.29–0.49]°C/hour; p  = 0.02). There was no statistically significant difference in mortality (endovascular 65/218, 29% vs. others 43/134, 32%; p  = 0.72) or poor neurological outcome (endovascular 69/218, 32% vs. others 51/134, 38%; p  = 0.24) between type of devices. Conclusions Endovascular cooling devices were more precise than SFC methods in patients cooled at 33 °C after out-of-hospital cardiac arrest. Main outcomes were similar with regard to the cooling methods.

Background Platelet variables, including platelet distribution width (PDW) and mean platelet volume (MPV), have been associated with outcome in critically ill patients. We evaluated these variables in patients after cardiac arrest (CA). Methods All adult CA patients admitted to the intensive care unit (ICU) over an 8-year period (2006–2014) and treated with targeted temperature management were included. We retrieved all data concerning CA characteristics as well as platelet count, PDW and MPV on the first 2 days of admission. Unfavorable 3-month neurological outcome was defined as a cerebral performance category score of 3–5. Results We included 384 patients (age 62 [52–75] years; 270/384 male): 231 patients (60%) died within 30-days and 246 patients (64%) had an unfavorable 3-month neurological outcome. On admission, platelet count, PDW and MPV were 87 [126–261] *10 3 cells/mm 3 , 17 [16.3–17.3]% and 8.3 [7.6–9.2] μm 3 , respectively. Platelet count decreased significantly over the first 2 days, whereas PDW and MPV did not change significantly. There were no significant differences between the values on admission or time-courses of platelet count, PDW or MPV between survivors and non-survivors or between patients with unfavorable and favorable neurological outcome. Conclusions In our cohort of post-CA patients, PDW and MPV were not associated with outcome.

Hyperammonemia (HA) is a potential side-effect of valproate (VPA) treatment, which has been described during long-term administration. The aim of this study was to evaluate the incidence, the impact and the risk factors of HA in critically ill patients. We reviewed the data of all adult patients treated in our mixed 35-bed Department of Intensive Care over a 12-year period (2004–2015) who: a) were treated with VPA for more than 72 h and b) had at least one measurement of ammonium and VPA levels during the ICU stay; patients with Child-Pugh C liver cirrhosis were excluded. HA was defined as ammonium levels above 60 μg/dl. Of a total of 2640 patients treated with VPA, 319 patients met the inclusion criteria (median age 64 years; male gender 55%); 78% of them were admitted for neurological reasons and ICU mortality was 30%. Median ammonium levels were 88 [63–118] µg/dl. HA was found in 245 (77%) patients. For those patients with HA, median time from start of VPA therapy to HA was 3 [2–5] days. In a multivariable analysis, high VPA serum levels, mechanical ventilation and sepsis were independently associated with HA during VPA therapy. In 98/243 (40%) of HA patients, VPA was interrupted; VPA interruption was more frequent in patients with ammonium levels > 100 μg/dl than others (p = 0.001). HA was not an independent predictor of ICU mortality or poor neurological outcome. In this study, HA was a common finding during treatment with VPA in acutely ill patients. VPA levels, sepsis and mechanical ventilation were risk factors for HA. Hyperammonemia did not influence patients’ outcome. •In our cohort of patients who receive valproate, hyperammonemia was observed in 77% of patients•High valproate levels, mechanical ventilation and low creatinine were independent predictors of hyperammonemia during valproate therapy•Hyperammonemia was not independently associated with poor outcome in our patients.

BACKGROUND:Although targeted temperature management (TTM) is recommended in comatose survivors after cardiac arrest (CA), the optimal method to deliver TTM remains unknown. We performed a meta-analysis to evaluate the effects of different TTM methods on survival and neurological outcome after adult CA.METHODS:We searched on the MEDLINE/PubMed database until 22 February 2019 for comparative studies that evaluated at least two different TTM methods in CA patients. Data were extracted independently by two authors. We used the Newcastle-Ottawa Scale and a modified Cochrane ROB tools for assessing the risk of bias of each study. The primary outcome was the occurrence of unfavorable neurological outcome (UO); secondary outcomes included overall mortality.RESULTS:Our search identified 6886 studies; 22 studies (n = 8027 patients) were included in the final analysis. When compared to surface cooling, core methods showed a lower probability of UO (OR 0.85 [95% CIs 0.75-0.96]; p = 0.008) but not mortality (OR 0.88 [95% CIs 0.62-1.25]; p = 0.21). No significant heterogeneity was observed among studies. However, these effects were observed in the analyses of non-RCTs. A significant lower probability of both UO and mortality were observed when invasive TTM methods were compared to non-invasive TTM methods and when temperature feedback devices (TFD) were compared to non-TFD methods. These results were significant particularly in non-RCTs.CONCLUSIONS:Although existing literature is mostly based on retrospective or prospective studies, specific TTM methods (i.e., core, invasive, and with TFD) were associated with a lower probability of poor neurological outcome when compared to other methods in adult CA survivors (CRD42019111021).

Background: The aim of the study was to assess the coherence between systemic hemodynamic and microcirculatory response to a fluid challenge (FC) in critically ill patients. Methods: We prospectively collected data in patients requiring a FC whilst cardiac index (CI) and microcirculation were monitored. The sublingual microcirculation was assessed using the incident dark field (IDF) CytoCam device (Braedius Medical, Huizen, The Netherlands). The proportion of small perfused vessels (PPV) was calculated. Fluid responders were defined by at least a 10% increase in CI during FC. Responders according to changes in microcirculation were defined by at least 10% increase in PPV at the end of FC. Cohen’s kappa coefficient was measured to assess the agreement to categorize patients as “responders” to FC according to CI and PPV. Results: A total of 41 FC were performed in 38 patients, after a median time of 1 (0–1) days after ICU admission. Most of the fluid challenges (39/41, 95%) were performed using crystalloids and the median total amount of fluid was 500 (500–500) mL. The main reasons for fluid challenge were oliguria (n = 22) and hypotension (n = 10). After FC, CI significantly increased in 24 (58%) cases; a total of 19 (46%) FCs resulted in an increase in PPV. Both CI and PPV increased in 13 responders and neither in 11; the coefficient of agreement was only 0.21. We found no correlation between absolute changes in CI and PPV after fluid challenge. Conclusions: The results of this heterogenous population of critically ill patients suggest incoherence in fluid responsiveness between systemic and microvascular hemodynamics; larger cohort prospective studies with adequate a priori sample size calculations are needed to confirm these findings.

Laser synthesis emerges as a suitable technique to produce ligand-free nanoparticles, alloys and functionalized nanomaterials for catalysis, imaging, biomedicine, energy and environmental applications. In the last decade, laser ablation and nanoparticle generation in liquids has proven to be a unique and efficient technique to generate, excite, fragment and conjugate a large variety of nanostructures in a scalable and clean way. In this work, we give an overview on the fundamentals of pulsed laser synthesis of nanocolloids and new information about its scalability towards selected applications. Biomedicine, catalysis and sensing are the application areas mainly discussed in this review, highlighting advantages of laser-synthesized nanoparticles for these types of applications and, once partially resolved, the limitations to the technique for large-scale applications.

IntroductionAntidepressant overprescribing and unnecessary long-term use are common and can increase the risk of adverse effects and withdrawal symptoms on discontinuation. Although gradual tapering strategies have been proposed, empirical evidence from randomised trials is lacking. This study will compare the efficacy of two antidepressant discontinuation strategies—linear and hyperbolic tapering—in adults with remitted depressive disorders.Methods and analysisThis pragmatic, multicentre, open-label, parallel-group superiority randomised controlled trial will recruit adults (≥18 years) with remitted depressive disorders who have been taking an antidepressant for at least 6 months. During an 8-month recruitment period, participants in outpatient psychiatric and primary care settings will be randomised (1:1) to (a) linear tapering (dose reduced by 50% of the minimum effective dose every 2 weeks until cessation) or (b) hyperbolic tapering (dose reduced by 20–25% every 2 weeks until cessation). The primary outcome is the proportion of participants who fail to discontinue the antidepressant by the end of the predefined tapering schedule or who re-initiate antidepressant therapy within 16 weeks of discontinuation. Secondary outcomes include safety, tolerability (including withdrawal symptoms), acceptability, clinical effectiveness, social functioning, quality of life and cost-effectiveness. Recruiters and participants will be aware of their treatment allocation; however, outcome assessors and the biostatistician will remain blinded throughout follow-up. Validated rating scales measuring depression, anxiety, withdrawal symptoms and social functioning will be administered at baseline and at scheduled follow-up visits up to 36 weeks. Based on observational data, we aim to recruit 150 participants (75 per arm).Ethics and disseminationThe study was approved by institutional Ethics Committees and regulatory authorities. Written informed consent will be obtained from all participants and data processed in accordance with General Data Protection Regulation. Study insurance and pharmacovigilance procedures are in place. Findings will be published in open-access journals, presented at scientific meetings and communicated to policy and regulatory stakeholders.Trial registrationNCT07393919.

Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence. Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response. By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients. In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.