Hospital surge capacity in a tertiary emergency referral centre during the COVID-19 outbreak in Italy.

The first person-to-person transmission of the 2019 novel coronavirus in Italy on 21 February 2020 led to an infection chain that represents one of the largest known COVID-19 outbreaks outside Asia. In northern Italy in particular, we rapidly experienced a critical care crisis due to a shortage of intensive care beds, as we expected according to data reported in China. Based on our experience of managing this surge, we produced this review to support other healthcare services in preparedness and training of hospitals during the current coronavirus outbreak. We had a dedicated task force that identified a response plan, which included: (1) establishment of dedicated, cohorted intensive care units for COVID-19-positive patients; (2) design of appropriate procedures for pre-triage, diagnosis and isolation of suspected and confirmed cases; and (3) training of all staff to work in the dedicated intensive care unit, in personal protective equipment usage and patient management. Hospital multidisciplinary and departmental collaboration was needed to work on all principles of surge capacity, including: space definition; supplies provision; staff recruitment; and ad hoc training. Dedicated protocols were applied where full isolation of spaces, staff and patients was implemented. Opening the unit and the whole hospital emergency process required the multidisciplinary, multi-level involvement of healthcare providers and hospital managers all working towards a common goal: patient care and hospital safety. Hospitals should be prepared to face severe disruptions to their routine and it is very likely that protocols and procedures might require re-discussion and updating on a daily basis.

Broadband near-infrared astronomical spectrometer calibration and on-sky validation with an electro-optic laser frequency comb.

The quest for extrasolar planets and their characterization as well as studies of fundamental physics on cosmological scales rely on capabilities of high-resolution astronomical spectroscopy. A central requirement is a precise wavelength calibration of astronomical spectrographs allowing for extraction of subtle wavelength shifts from the spectra of stars and quasars. Here, we present an all-fiber, 400 nm wide near-infrared frequency comb based on electro-optic modulation with 14.5 GHz comb line spacing. Tests on the high-resolution, near-infrared spectrometer GIANO-B show a photon-noise limited calibration precision of < 10 cms as required for Earth-like planet detection. Moreover, the presented comb provides detailed insight into particularities of the spectrograph such as detector inhomogeneities and differential spectrograph drifts. The system is validated in on-sky observations of a radial velocity standard star (HD221354) and telluric atmospheric absorption features. The advantages of the system include simplicity, robustness and turn-key operation, features that are valuable at the observation sites.

Left ventricular systolic function evaluated by strain echocardiography and relationship with mortality in patients with severe sepsis or septic shock: a systematic review and meta-analysis.

BACKGROUND: Sepsis-induced myocardial dysfunction is associated with poor outcomes, but traditional measurements of systolic function such as left ventricular ejection fraction (LVEF) do not directly correlate with prognosis. Global longitudinal strain (GLS) utilizing speckle-tracking echocardiography (STE) could be a better marker of intrinsic left ventricular (LV) function, reflecting myocardial deformation rather than displacement and volume changes. We sought to investigate the prognostic value of GLS in patients with sepsis and/or septic shock. METHODS: We conducted a systematic review (PubMed and Embase up to 26 October 2017) and meta-analysis to investigate the association between GLS and mortality at longest follow up in patients with severe sepsis and/or septic shock. In the primary analysis, we included studies reporting transthoracic echocardiography data on GLS according to mortality. A secondary analysis evaluated the association between LVEF and mortality including data from studies reporting GLS. RESULTS: We included eight studies in the primary analysis with a total of 794 patients (survival 68%, n = 540). We found a significant association between worse LV function and GLS values and mortality: standard mean difference (SMD) - 0.26; 95% confidence interval (CI) - 0.47, - 0.04; p = 0.02 (low heterogeneity, I2 = 43%). No significant association was found between LVEF and mortality in the same population of patients (eight studies; SMD, 0.02; 95% CI - 0.14, 0.17; p = 0.83; no heterogeneity, I2 = 3%). CONCLUSIONS: Worse GLS (less negative) values are associated with higher mortality in patients with severe sepsis or septic shock, while such association is not valid for LVEF. More critical care research is warranted to confirm the better ability of STE in demonstrating underlying intrinsic myocardial disease compared to LVEF.

Adoption of Lung Protective ventilation IN patients undergoing Emergency laparotomy: the ALPINE study. A prospective multicentre observational study.

BACKGROUND: Emergency abdominal surgery is associated with a high risk of postoperative pulmonary complications (PPCs). The primary aim of this study was to determine whether patients undergoing emergency laparotomy are ventilated using a lung-protective ventilation strategy employing tidal volume ≤8 ml kg-1 ideal body weight-1, PEEP >5 cm H2O, and recruitment manoeuvres. The secondary aim was to investigate the association between ventilation factors (lung-protective ventilation strategy, intraoperative FiO2, and peak inspiratory pressure) and the occurrence of PPCs. METHODS: Data were collected prospectively in 28 hospitals across London as part of routine National Emergency Laparotomy Audit (NELA). Patients were followed for 7 days. Complications were defined according to the European Perioperative Clinical Outcome definition. RESULTS: Data were collected from 568 patients. The median [inter-quartile range (IQR)] tidal volume observed was 500 ml (450-540 ml), corresponding to a median tidal volume of 8 ml kg-1 ideal body weight-1 (IQR: 7.2-9.1 ml). A lung-protective ventilation strategy was employed in 4.9% (28/568) of patients, and was not protective against the occurrence of PPCs in the multivariable analysis (hazard ratio=1.06; P=0.69). Peak inspiratory pressure of <30 cm H2O was protective against development of PPCs (hazard ratio=0.46; confidence interval: 0.30-0.72; P=0.001). Median FiO2 was 0.5 (IQR: 0.44-0.53), and an increase in FiO2 by 5% increased the risk of developing a PPC by 8% (2.6-14.1%; P=0.008). CONCLUSIONS: Both intraoperative peak inspiratory pressure and FiO2 are independent factors significantly associated with development of a postoperative pulmonary complication in emergency laparotomy patients. Further studies are required to identify causality and to demonstrate if their manipulation could lead to better clinical outcomes.

Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis.

BACKGROUND: Myocardial dysfunction may contribute to circulatory failure in sepsis. There is growing evidence of an association between left ventricular diastolic dysfunction (LVDD) and mortality in septic patients. Utilizing echocardiography, we know that tissue Doppler imaging (TDI) variables e' and E/e' are reliable predictors of LVDD and are useful measurements to estimate left ventricular (LV) filling pressures. METHODS: We conducted a systematic review and meta-analysis to investigate the association of e' and E/e' with mortality of patients with severe sepsis or septic shock. In the primary analysis, we included studies providing transthoracic TDI data for e' and E/e' and their association with mortality. Subgroup analyses were conducted according to myocardial regional focus of TDI assessment (septal, lateral or averaged). Three secondary analyses were performed: one included data from a transoesophageal study, another excluded studies reporting data at a very early (<6 h) or late (>48 h) stage following diagnosis, and the third pooled data only from studies excluding patients with heart valve disease. RESULTS: The primary analysis included 16 studies with 1507 patients with severe sepsis and/or septic shock. A significant association was found between mortality and both lower e' [standard mean difference (SMD) 0.33; 95% confidence interval (CI): 0.05, 0.62; P=0.02] and higher E/e' (SMD -0.33; 95% CI: -0.57, -0.10; P=0.006). In the subgroup analyses, only the lateral TDI values showed significant association with mortality (lower e' SMD 0.45; 95% CI: 0.11, 0.78; P=0.009; higher E/e' SMD -0.49; 95% CI: -0.76, -0.22; P=0.0003). The findings of the primary analysis were confirmed by all secondary analyses. CONCLUSIONS: There is a strong association between both lower e' and higher E/e' and mortality in septic patients.

Effects of arterial load variations on dynamic arterial elastance: an experimental study.

BACKGROUND.: Dynamic arterial elastance (Ea dyn ), the relationship between pulse pressure variation (PPV) and stroke volume variation (SVV), has been suggested as a functional assessment of arterial load. The aim of this study was to evaluate the impact of arterial load changes during acute pharmacological changes, fluid administration, and haemorrhage on Ea dyn . METHODS.: Eighteen anaesthetized, mechanically ventilated New Zealand rabbits were studied. Arterial load changes were induced by phenylephrine ( n =9) or nitroprusside ( n =9). Thereafter, animals received a fluid bolus (10 ml kg -1 ), followed by stepwise bleeding (blood loss: 15 ml kg -1 ). The influence of arterial load and cardiac variables on PPV, SVV, and Ea dyn was analysed using a linear mixed-effects model analysis. RESULTS.: After phenylephrine infusion, mean ( sd ) Ea dyn decreased from 0.89 (0.14) to 0.49 (0.12), P <0.001; whereas after administration of nitroprusside, Ea dyn increased from 0.80 (0.23) to 1.28 (0.21), P <0.0001. Overall, the fluid bolus decreased Ea dyn [from 0.89 (0.44) to 0.73 (0.35); P <0.01], and haemorrhage increased it [from 0.78 (0.23) to 0.95 (0.26), P =0.03]. Both PPV and SVV were associated with similar arterial factors (effective arterial elastance, arterial compliance, and resistance) and heart rate. Furthermore, PPV was also related to the acceleration and peak velocity of aortic blood flow. Both arterial and cardiac factors contributed to the evolution of Ea dyn throughout the experiment. CONCLUSIONS.: Acute modifications of arterial load induced significant changes on Ea dyn ; vasodilatation increased Ea dyn , whereas vasoconstriction decreased it. The Ea dyn was associated with both arterial load and cardiac factors, suggesting that Ea dyn should be more properly considered as a ventriculo-arterial coupling index.

Haemodynamic monitoring in the peri-operative period: the past, the present and the future.

Over recent years there has been an increase in the implementation of goal-directed therapy using minimally invasive haemodynamic monitoring techniques to guide peri-operative care. Since the introduction of the pulmonary artery flotation catheter in the 1980s, various haemodynamic monitors have been developed, each associated with their own benefits and limitations. Goal-directed therapy has been well-established as a standard of care in the peri-operative period and has largely been associated with a reduction in morbidity and mortality. However, evidence over the last few years from major studies has led us to question: what is the future for goal-directed therapy? Care of the peri-operative patient has significantly evolved over the last decade and this needs to be taken into account when assessing the results of these studies. We should therefore not look at the effects of goal-directed therapy in isolation but as part of a progressive care bundle. Additionally, other markers of haemodynamic status have also begun to be further appreciated and these are worthy of further investigation. We feel that the future for haemodynamic monitoring remains promising with new areas of interest continuously emerging, but further research is still required.

A randomised controlled trial comparing transnasal humidified rapid insufflation ventilatory exchange (THRIVE) pre-oxygenation with facemask pre-oxygenation in patients undergoing rapid sequence induction of anaesthesia.

Pre-oxygenation is an essential part of rapid sequence induction of general anaesthesia for emergency surgery, in order to increase the oxygen reservoir in the lungs. We performed a randomised controlled trial of transnasal humidified rapid insufflation ventilatory exchange (THRIVE) pre-oxygenation or facemask pre-oxygenation in patients undergoing emergency surgery. Twenty patients were allocated to each group. No patient developed arterial oxygen saturation < 90% during attempted tracheal intubation. Arterial blood gases were sampled from an arterial catheter immediately after intubation. The mean (SD) PaO2 was 43.7 (15.2) kPa in the THRIVE group vs. 41.9 (16.2) kPa in the facemask group (p = 0.722); PaCO2 was 5.8 (1.1) kPa in the THRIVE group vs. 5.6 (1.0) kPa in the facemask group (p = 0.631); arterial pH was 7.36 (0.05) in the THRIVE group vs. 7.34 (0.06) in the facemask group (p = 0.447). No airway rescue manoeuvres were needed, and there were no differences in the number of laryngoscopy attempts between the groups. In spite of this, patients in the THRIVE group had a significantly longer apnoea time of 248 (71) s compared with 123 (55) s in the facemask group (p < 0.001). Transnasal humidified rapid insufflation ventilatory exchange is a practicable method for pre-oxygenating patients during rapid sequence induction of general anaesthesia for emergency surgery; we found that it maintained an equivalent blood gas profile to facemask pre-oxygenation, in spite of a significantly longer apnoea time.

Preoperative abnormalities in serum sodium concentrations are associated with higher in-hospital mortality in patients undergoing major surgery.

BACKGROUND: Abnormal serum sodium concentrations are common in patients presenting for surgery. It remains unclear whether these abnormalities are independent risk factors for postoperative mortality. METHODS: This is a secondary analysis of the European Surgical Outcome Study (EuSOS) that provided data describing 46 539 patients undergoing inpatient non-cardiac surgery. Patients were included in this study if they had a recorded value of preoperative serum sodium within the 28 days immediately before surgery. Data describing preoperative risk factors and serum sodium concentrations were analysed to investigate the relationship with in-hospital mortality using univariate and multivariate logistic regression techniques. RESULTS: Of 35 816 (77.0%) patients from the EuSOS database, 21 943 (61.3%) had normal values of serum sodium (138-142 mmol litre(-1)) before surgery, 8538 (23.8%) had hyponatraemia (serum sodium ≤137 mmol litre(-1)) and 5335 (14.9%) had hypernatraemia (serum sodium ≥143 mmol litre(-1)). After adjustment for potential confounding factors, moderate to severe hypernatraemia (serum sodium concentration ≥150 mmol litre(-1)) was independently associated with mortality [odds ratio 3.4 (95% confidence interval 2.0-6.0), P<0.0001]. Hyponatraemia was not associated with mortality. CONCLUSIONS: Preoperative abnormalities in serum sodium concentrations are common, and hypernatraemia is associated with increased mortality after surgery. Abnormalities of serum sodium concentration may be an important biomarker of perioperative risk resulting from co-morbid disease.

Noninvasive continuous cardiac output monitoring in perioperative and intensive care medicine.

The determination of blood flow, i.e. cardiac output, is an integral part of haemodynamic monitoring. This is a review on noninvasive continuous cardiac output monitoring in perioperative and intensive care medicine. We present the underlying principles and validation data of the following technologies: thoracic electrical bioimpedance, thoracic bioreactance, vascular unloading technique, pulse wave transit time, and radial artery applanation tonometry. According to clinical studies, these technologies are capable of providing cardiac output readings noninvasively and continuously. They, therefore, might prove to be innovative tools for the assessment of advanced haemodynamic variables at the bedside. However, for most technologies there are conflicting data regarding the measurement performance in comparison with reference methods for cardiac output assessment. In addition, each of the reviewed technology has its own limitations regarding applicability in the clinical setting. In validation studies comparing cardiac output measurements using these noninvasive technologies in comparison with a criterion standard method, it is crucial to correctly apply statistical methods for the assessment of a technology's accuracy, precision, and trending capability. Uniform definitions for 'clinically acceptable agreement' between innovative noninvasive cardiac output monitoring systems and criterion standard methods are currently missing. Further research must aim to further develop the different technologies for noninvasive continuous cardiac output determination with regard to signal recording, signal processing, and clinical applicability.

MYOCLONIC ASTATIC EPILEPSY IN A PATIENT WITH A DE NOVO 4q21.22q21.23 MICRODUPLICATION.

Myoclonicastatic epilepsy (MAE) is a rare form of symptomatic generalized epilepsy of uncertain etiology. To search the possible genetic basis of the disorder, here we investigate a 15 year-old patient with MAE, who is the only person presenting epilepsy in the family. High resolution array-CGH analysis was conducted on DNA extracted from peripheral blood of the patient and the parents. The copy number variant(s) (CNVs) identified were further confirmed by Fluorescent In Situ Hybridization (FISH). The array-CGH identified a de novo microduplication of about 778 Kb in the chromosome region 4q21.22-q21.23, involving 11 genes. This is the first report of a de novo CNV in MAE. The genes involved in the duplication are potential candidates that can be investigated in the future to determine their exact role in the etiopathogenesis of the disorder. However, we suggest performing microarray chromosomal analysis in patients with MAE, since rare de novo CNVs could be identified, and this is known to affect the diagnostic process and recurrence risk assessment.

Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma.

BACKGROUND: Uveal melanoma is the most frequent primary tumour of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight ultraviolet (UV) exposure on the aetiology of uveal melanoma is a matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV-induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma. METHODS: We analysed 50 cases of uveal melanoma obtained from enucleation surgery for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT, measured gene expression using microarrays and analysed gene copy numbers by SNP arrays. RESULTS: We detected a TERT mutation in only one case of a 57-year-old white male patient with clinical and histopathological features typical for uveal melanoma. The tumour showed mutations in GNA11 and EIF1AX that are typical for uveal melanoma and absent from cutaneous melanoma. No mutations were detected in GNAQ, BAP1 and SF3B1 that are frequently mutated in uveal melanoma. Both copies of chromosome 3 were retained. Several tumours among which the one carrying the TERT promoter mutation showed elevated TERT expression. Consistent with previous reports, GNAQ is inversely associated with chromosome 3 monosomy and metastasis. BAP1 mutations are significantly associated with chromosome 3 monosomy but not with relapse. CONCLUSION: These data indicate that TERT mutations are rare in uveal melanoma. No conclusion can be drawn on their potential influence on tumour progression.

Pharmacological management of fluid overload.

BACKGROUND: Standard treatment practice for the hypotensive patient with poor tissue perfusion is rapid volume resuscitation; in some scenarios, such as septic shock, this is performed with targeted goal-directed endpoints within 6 h of presentation. As a result, patients often develop significant positive fluid accumulation, which has been associated with poor outcomes above certain thresholds. METHODS: The aim of the current paper is to provide guidance for active pharmacological fluid management in the patient with, or at risk for, clinically significant positive fluid balance from either resuscitation for hypovolaemic shock or acute decompensated heart failure. RESULTS: We develop rationale for pharmacological fluid management targets (prevention of worsening fluid accumulation, achievement of slow vs rapid net negative fluid balance) in the context of phases of critical illness provided in the earlier Acute Dialysis Quality Initiative 12 papers.

Cardiac complications associated with goal-directed therapy in high-risk surgical patients: a meta-analysis.

Patients with limited cardiopulmonary reserve are at risk of mortality and morbidity after major surgery. Augmentation of oxygen delivery index (DO2I) with i.v. fluids and inotropes (goal-directed therapy, GDT) has been shown to reduce postoperative mortality and morbidity in high-risk patients. Concerns regarding cardiac complications associated with fluid challenges and inotropes may prevent clinicians from performing GDT in patients who need it most. We hypothesized that GDT is not associated with an increased risk of cardiac complications in high-risk, non-cardiac surgical patients. We performed a systematic search of Medline, Embase, and CENTRAL databases for randomized controlled trials (RCTs) of GDT in high-risk surgical patients. Studies including cardiac surgery, trauma, and paediatric surgery were excluded. We reviewed the rates of all cardiac complications, arrhythmias, myocardial ischaemia, and acute pulmonary oedema. Meta-analyses were performed using RevMan software. Data are presented as odds ratios (ORs), [95% confidence intervals (CIs)], and P-values. Twenty-two RCTs including 2129 patients reported cardiac complications. GDT was associated with a reduction in total cardiovascular (CVS) complications [OR=0.54, (0.38-0.76), P=0.0005] and arrhythmias [OR=0.54, (0.35-0.85), P=0.007]. GDT was not associated with an increase in acute pulmonary oedema [OR=0.69, (0.43-1.10), P=0.12] or myocardial ischaemia [OR=0.70, (0.38-1.28), P=0.25]. Subgroup analysis revealed the benefit is most pronounced in patients receiving fluid and inotrope therapy to achieve a supranormal DO2I, with the use of minimally invasive cardiac output monitors. Treatment of high-risk surgical patients GDT is not associated with an increased risk of cardiac complications; GDT with fluids and inotropes to optimize DO2I during early GDT reduces postoperative CVS complications.

Development of clinical tools to estimate the breathing effort during high-flow oxygen therapy: A multicenter cohort study.

INTRODUCTION AND OBJECTIVES: Quantifying breathing effort in non-intubated patients is important but difficult. We aimed to develop two models to estimate it in patients treated with high-flow oxygen therapy. PATIENTS AND METHODS: We analyzed the data of 260 patients from previous studies who received high-flow oxygen therapy. Their breathing effort was measured as the maximal deflection of esophageal pressure (ΔPes). We developed a multivariable linear regression model to estimate ΔPes (in cmH2O) and a multivariable logistic regression model to predict the risk of ΔPes being >10 cmH2O. Candidate predictors included age, sex, diagnosis of the coronavirus disease 2019 (COVID-19), respiratory rate, heart rate, mean arterial pressure, the results of arterial blood gas analysis, including base excess concentration (BEa) and the ratio of arterial tension to the inspiratory fraction of oxygen (PaO2:FiO2), and the product term between COVID-19 and PaO2:FiO2. RESULTS: We found that ΔPes can be estimated from the presence or absence of COVID-19, BEa, respiratory rate, PaO2:FiO2, and the product term between COVID-19 and PaO2:FiO2. The adjusted R2 was 0.39. The risk of ΔPes being >10 cmH2O can be predicted from BEa, respiratory rate, and PaO2:FiO2. The area under the receiver operating characteristic curve was 0.79 (0.73-0.85). We called these two models BREF, where BREF stands for BReathing EFfort and the three common predictors: BEa (B), respiratory rate (RE), and PaO2:FiO2 (F). CONCLUSIONS: We developed two models to estimate the breathing effort of patients on high-flow oxygen therapy. Our initial findings are promising and suggest that these models merit further evaluation.

Goal-directed therapy in cardiac surgery: a systematic review and meta-analysis.

BACKGROUND: Perioperative mortality after cardiac surgery has decreased in recent years although postoperative morbidity is still significant. Although there is evidence that perioperative goal-directed haemodynamic therapy (GDT) may reduce surgical mortality and morbidity in non-cardiac surgical patients, the data are less clear after cardiac surgery. The objective of this review is to perform a meta-analysis on the effects of perioperative GDT on mortality, morbidity, and length of hospital stay in cardiac surgical patients. METHODS: We conducted a systematic review using Medline, EMBASE, and the Cochrane Controlled Clinical Trials Register. Additional sources were sought from experts. The inclusion criteria were randomized controlled trials, mortality reported as an outcome, pre-emptive haemodynamic intervention, and cardiac surgical population. Included studies were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. Data synthesis was obtained by using odds ratio (OR) and mean difference (MD) for continuous data with 95% confidence interval (CI) utilizing a random-effects model. RESULTS: From 4986 potential studies, 5 met all the inclusion criteria (699 patients). The quantitative analysis showed that the use of GDT reduced the postoperative complication rate (OR 0.33, 95% CI 0.15-0.73; P=0,006) and hospital length of stay (MD -2.44, 95% CI -4.03 to -0.84; P=0,003). There was no significant reduction in mortality. CONCLUSION: The use of pre-emptive GDT in cardiac surgery reduces morbidity and hospital length of stay.

Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome.

Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome is a unique example of primary immunodeficiency characterized by autoimmune manifestations due to defective regulatory T (Treg) cells, in the presence of FOXP3 mutations. However, autoimmune symptoms phenotypically resembling IPEX often occur in the absence of detectable FOXP3 mutations. The cause of this "IPEX-like" syndrome presently remains unclear. To investigate whether a defect in Treg cells sustains the immunological dysregulation in IPEX-like patients, we measured the amount of peripheral Treg cells within the CD3(+) T cells by analysing demethylation of the Treg cell-Specific-Demethylated-Region (TSDR) in the FOXP3 locus and demethylation of the T cell-Specific-Demethylated-Region (TLSDR) in the CD3 locus, highly specific markers for stable Treg cells and overall T cells, respectively. TSDR demethylation analysis, alone or normalized for the total T cells, showed that the amount of peripheral Treg cells in a cohort of IPEX-like patients was significantly reduced, as compared to both healthy subjects and unrelated disease controls. This reduction could not be displayed by flow cytometric analysis, showing highly variable percentages of FOXP3(+) and CD25(+)FOXP3(+) T cells. These data provide evidence that a quantitative defect of Treg cells could be considered a common biological hallmark of IPEX-like syndrome. Since Treg cell suppressive function was not impaired, we propose that this reduction per se could sustain autoimmunity.

Raised serum cardiac troponin I concentrations predict hospital mortality in intensive care unit patients.

BACKGROUND: Recent work suggests that increased plasma concentrations of cardiac troponin I (cTnI) are common in critically ill patients and are associated with poor outcome. We measured the frequency of increased plasma cTnI concentrations during patients' stay in a mixed medical/surgical intensive care unit (ICU) and compared our findings with hospital mortality. METHODS: Basic details, organ support, and hospital mortality were recorded for all patients treated in ICU during a 6 month period. cTnI concentrations were sampled daily for all patients, using 0.04 µg litre(-1) as the upper limit of normal, and 0.12 µg litre(-1) as an additional stratification point. RESULTS: Of 663 patients, 54% were male, with a mean (sd) age of 60 (18) yr, 65% were surgical patients, and the median Acute Physiology and Chronic Ill Health II (APACHE II) score was 15 (inter-quartile range 12-20). Increased cTnI concentrations were found in 345 patients (52%) while in ICU. One hundred and twenty patients (18%) died in hospital. cTnI concentration >0.04 µg litre(-1) was associated with reduced odds of hospital survival, independent of age, medical admission, unplanned admission, APACHE II score, mechanical ventilation, and haemofiltration (adjusted odds ratio 0.25, 95% confidence interval 0.08-0.75, P=0.014). Stratification by the degree of cTnI increase revealed an incremental trend towards a lower odds of hospital survival, including for patients with 'minor' elevations of cTnI (0.05-0.12 µg litre(-1)). CONCLUSIONS: Increased serum cTnI concentrations during ICU stay independently predicts hospital mortality, even when the threshold is low. We found a trend towards an association between 'minor' elevations in cTnI and higher in-hospital mortality.

Mutations in GDI1 and X-linked non-specific mental retardation.

Mental retardation (MR) is a complex phenotype characterized by suboptimal functioning of the central nervous system (CNS). It is estimated that from 1 to 3% of the general population is affected with MR. MR or "intellectual disability" can be caused by genetic as well as environmental causes that act on the development and functioning of the CNS prenatally, perinatally or postnatally. Genetic causes of MR include chromosome aneusomies, chromosome structural abnormalities, genomic disorders and monogenic diseases. Amongst children, acute MR (QI < 50) is estimated at 0.4% and faint MR is about 2.5-3%. To determine the etiology of the MR, many diagnostic studies have been conducted and they show that MR is very heterogeneous and its etiology is not yet known in 20-50% of the group of patients with severe MR. This percentage increases up to 75-80% in the group of individuals with mild or "borderline" forms of MR. In light of the literature results, we tried to carry out a screening of 41 subjects with nonspecific MR for the detection of mutations in the gene GDI1 using the DHPLC methodology. This technique has the following advantages: low cost, high sensitivity (> 95%), and it can be done quickly. We have found 3 nucleotide (nt) substitutions: an intronic polymorphism at nt 107877 A --> C, a polymorphism in exon 3 at nt 109259 T --> C (Asn73Asn), and an intronic polymorphism at nt 110314 G --> C. The mutations in this gene are common and do not seem to influence the gene expression so as to cause a change in phenotype. These results therefore do not encourage the research of a diagnostic protocol designed for mutational analysis of the GDI1 human gene as the only responsible factor for a complex disease as Mental Retardation X-linked (MRX).