Incidence of chronic subdural haematoma: a single-centre exploration of the effects of an ageing population with a review of the literature.

BACKGROUND: Chronic subdural haematoma (cSDH) is a common neurosurgical pathology frequently occurring in older patients. The impact of population ageing on cSDH caseload has not been examined, despite relevance for health system planning. METHODS: This is a single-centre study from the UK. Operated cases of cSDH (n = 446) for 2015-2018 were identified. Crude and directly standardised incidence rates were calculated. Medline and EMBASE were systematically searched to identify studies reporting on the incidence of cSDH by year, so an estimate of rate of incidence change could be determined. Local incidence rates were then applied to population projections for local catchment area to estimate operated cSDH numbers at 5 yearly intervals due to shifting demographics. RESULTS: We identified nine studies presenting incidence estimates. Crude estimates for operative cases ranged from 1.3/100,000/year (1.4-2.2) to 5.3/100,000/year (4.3-6.6). When non-operated cases were included, incidence was higher: 8.2/100,000/year (6.0-11.2) to 48/100,000/year (37.7-61.1). Four pairs of studies demonstrated incidence rate increases of 200-600% over the last 50 years, but data was deemed too heterogeneous to generate formal estimate of incidence change. Local crude incidence of operated cSDH was 3.50/100,000/year (3.19-3.85). Directly standardised incidence was 1.58/100,000/year (1.26-1.90). After applying local incidence rates to population projections, case numbers were predicted to increase by 53% over the next 20 years. CONCLUSIONS: The incidence of cSDH is increasing. We project a 53% increase in operative caseload within our region by 2040. These are important findings for guiding future healthcare planning.

Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians.

BACKGROUND: Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. AIM: To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. METHODS: A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. RESULTS: Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. CONCLUSION: The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Variation in the practice of tracheal intubation in Europe after traumatic brain injury: a prospective cohort study.

Traumatic brain injury patients frequently undergo tracheal intubation. We aimed to assess current intubation practice in Europe and identify variation in practice. We analysed data from patients with traumatic brain injury included in the prospective cohort study collaborative European neurotrauma effectiveness research in traumatic brain injury (CENTER-TBI) in 45 centres in 16 European countries. We included patients who were transported to hospital by emergency medical services. We used mixed-effects multinomial regression to quantify the effects on pre-hospital or in-hospital tracheal intubation of the following: patient characteristics; injury characteristics; centre; and trauma system characteristics. A total of 3843 patients were included. Of these, 1322 (34%) had their tracheas intubated; 839 (22%) pre-hospital and 483 (13%) in-hospital. The fit of the model with only patient characteristics predicting intubation was good (Nagelkerke R2 64%). The probability of tracheal intubation increased with the following: younger age; lower pre-hospital or emergency department GCS; higher abbreviated injury scale scores (head and neck, thorax and chest, face or abdomen abbreviated injury score); and one or more unreactive pupils. The adjusted median odds ratio for intubation between two randomly chosen centres was 3.1 (95%CI 2.1-4.3) for pre-hospital intubation, and 2.7 (95%CI 1.9-3.5) for in-hospital intubation. Furthermore, the presence of an anaesthetist was independently associated with more pre-hospital intubation (OR 2.9, 95%CI 1.3-6.6), in contrast to the presence of ambulance personnel who are allowed to intubate (OR 0.5, 95%CI 0.3-0.8). In conclusion, patient and injury characteristics are key drivers of tracheal intubation. Between-centre differences were also substantial. Further studies are needed to improve the evidence base supporting recommendations for tracheal intubation.

Pressure Reactivity-Based Optimal Cerebral Perfusion Pressure in a Traumatic Brain Injury Cohort.

OBJECTIVES: Retrospective data from patients with severe traumatic brain injury (TBI) indicate that deviation from the continuously calculated pressure reactivity-based "optimal" cerebral perfusion pressure (CPPopt) is associated with worse patient outcome. The objective of this study was to assess the relationship between prospectively collected CPPopt data and patient outcome after TBI. METHODS: We prospectively collected intracranial pressure (ICP) monitoring data from 231 patients with severe TBI at Addenbrooke's Hospital, UK. Uncleaned arterial blood pressure and ICP signals were recording using ICM+® software on dedicated bedside computers. CPPopt was determined using an automatic curve fitting procedure of the relationship between pressure reactivity index (PRx) and CPP using a 4-h window, as previously described. The difference between an instantaneous CPP value and its corresponding CPPopt value was denoted every minute as ΔCPPopt. A negative ΔCPPopt that was associated with impaired PRx (>+0.15) was denoted as being below the lower limit of reactivity (LLR). Glasgow Outcome Scale (GOS) score was assessed at 6 months post-ictus. RESULTS: When ΔCPPopt was plotted against PRx and stratified by GOS groupings, data belonging to patients with a more unfavourable outcome had a U-shaped curve that shifted upwards. More time spent with a ΔCPPopt value below the LLR was positively associated with mortality (area under the receiver operating characteristic curve = 0.76 [0.68-0.84]). CONCLUSIONS: In a recent cohort of patients with severe TBI, the time spent with a CPP below the CPPopt-derived LLR is related to mortality. Despite aggressive CPP- and ICP-oriented therapies, TBI patients with a fatal outcome spend a significant amount of time with a CPP below their individualised CPPopt, indicating a possible therapeutic target.

Kinetic modelling of serum S100b after traumatic brain injury.

BACKGROUND: An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury. METHODS: Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling. RESULTS: We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 µg/L (95 % credible interval [0.10, 0.12]). CONCLUSIONS: Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.

Action against vaccine-preventable infectious diseases and tuberculosis in Nomad Camps: the experience of a Local Health Unit in Rome.

In Italy the highest incidence of Tuberculosis (TB) cases is in young adult migrants. In 2011, the sanitarystaff of the Local Health Unit (ASL) Roma A promoted a vaccination campaign conducting several public health interventions in Nomad Camps. After notification of a case of TB in the Camp of Via Salaria, out of 357 Mantoux skin tests performed, 93 were positive (26%); subsequently, 5 subjects with radiographic positivity were hospitalized. The vaccination campaign was carried out to prevent the spread of infectious diseases in immigrant communities at high risk of contagion and to avoid the consequent transmission in the host country. As a result, vaccinations coverage among the residents of the Camps increased: 367 vaccinated subjects (30% more than previous year) and 612 administered vaccinations.

Variation between countries in the frequency of diabetic ketoacidosis at first presentation of type 1 diabetes in children: a systematic review.

AIMS/HYPOTHESIS: Type 1 diabetes is the most frequent endocrine disease in children, with 65,000 children diagnosed worldwide every year. Up to 80% of these children present with diabetic ketoacidosis (DKA), which is associated with both short-term risks and long-term consequences. This study aimed to characterise the worldwide variation in presentation of type 1 diabetes to inform future interventions to reduce this excess morbidity and mortality. METHODS: This was a systematic review of studies indexed on PubMed, EMBASE, Web of Science, Scopus or CINAHL before March 2011 that included unselected groups of children presenting with new-onset type 1 diabetes, reported the proportion presenting with DKA and used a definition of DKA based on measurement of pH or bicarbonate. RESULTS: Sixty-five studies of cohorts comprising over 29,000 children in 31 countries were included. The frequency of DKA at diagnosis ranged from 12.8% to 80%, with highest frequencies in the United Arab Emirates, Saudi Arabia and Romania, and the lowest in Sweden, the Slovak Republic and Canada. Multivariable modelling showed the frequency of DKA was inversely associated with gross domestic product, latitude and background incidence of type 1 diabetes. CONCLUSIONS/INTERPRETATION: This is the first description of the variation in frequency of DKA at presentation of type 1 diabetes in children across countries. It demonstrates large variations that may, at least in part, be explained by different levels of disease awareness and healthcare provision and suggests ways to decrease the excess morbidity and mortality associated with DKA at diagnosis.

Errors during the preparation of drug infusions: a randomized controlled trial.

BACKGROUND: We investigated the extent and frequency of dose errors and treatment delays made as a consequence of preparing drug infusions at the bedside, rather than using pre-filled syringes. METHODS: Forty-eight nurses with critical care experience volunteered to take part in this randomized, blinded, controlled study conducted in the simulation centre of an urban hospital. They assisted in the management of a simulated patient with septic shock. Vasopressor infusions were prepared either by diluting concentrated drugs from ampoules or were provided in syringes pre-filled beforehand by an intensive care unit resident. RESULTS: The time taken for the infusion to be started and the final concentration of the drugs were measured. We also measured the concentration of infusions prepared by a pharmacist and a pharmaceutical company. Nurses took 156 s to start infusions when using pre-filled syringes compared with 276 s when preparing them de novo, a mean delay of 106 s [95% confidence interval (CI) 73-140 s, P<0.0001]. One infusion prepared from ampoules contained one-fifth of the expected concentration of epinephrine; another contained none at all. Medication errors were 17.0 times less likely when pre-filled syringes were used (95% CI 5.2-55.5), and infusions prepared by pharmacy and industry were significantly more likely to contain the expected concentration (P<0.001 for norepinephrine and P=0.001 for epinephrine). CONCLUSIONS: Providing drug infusions in syringes pre-filled by pharmacists or pharmaceutical companies would reduce medication errors and treatment delays, and improve patient safety. However, this approach would have substantial financial implications for healthcare providers, especially in less developed countries.

High intensity training for faster water polo.

AIM: The aim of this study, based on the interaction between two aerobic and anaerobic metabolisms with a parallel production of both aerobic and anaerobic ATP, was to develop a high intensity training programme and increase the aerobic contribution. We examined the applicability of a 16-week training programme with an ergospirometer treadmill and field tests on eight water polo players. METHODS: Tests/retests of repeated exercises to 90V (90% of maximum personal speed over 100 m freestyle) and Speed Endurance Training (SET) after eight weeks were developed. A one-way blocked ANOVA with random blocks was used and each player represented a particular block with two before-after treatments with the aim of reducing error by subtracting both the variance due to the difference between the treatments and that due to the difference between the blocks. RESULTS: A reduction (15.2%) in blood lactate was observed in response to the same absolute workload (before-after). Furthermore the anaerobic contribution to VO2max (ESCAna, Estimated Anaerobic Contribution) after eight weeks of training at 90maxV and the anaerobic contribution to VO2max (ESCAna) after speed endurance training (SET) were very significant (P<0.004) with a reduction in the anaerobic contribution of 16%. The results of the field tests show that there was a very significant reduction (P<0.001) in lactate between 90maxV and maximal aerobic power velocity (MAPv) of 24%. CONCLUSION: With 90maxV and SET, space was gained towards those velocities, which had previously required a considerable anaerobic contribution. In this way match speed was increased.

[Prevention and control of tuberculosis in the hospital setting: the new operative protocol of the polyclinic "Umberto I"]. / Prevenzione e Controllo della Tubercolosi nelle strutture ospedaliere: il nuovo Protocollo Operativo dell'Azienda Policlinico "Umberto I".

The aim of this contribution is to explain a recent tubercolosis "prevention and control" program in health care workers. The same program was implemented in an university hospital since 2007, and revised in 2011 as a result of a new Mycobacterium tubercolosis exposure assessment in the different works environment.

A[H1N1] flu and refractory hypoxaemia: is extracorporeal lung support the holy grail?

There is a call for methodologically robust randomised clinical trials in adult extracorporeal membrane oxygenation for its routine implementation for patients with "failing" conventional ventilation. Adherence to lung protective ventilation strategies, along with fluid balance [if required early renal replacement therapy] and inotropes to support the circulation to minimise ventilator-induced lung injury, may mitigate deterioration requiring extracorporeal lung support. Currently there is no convincing evidence to routinely advocate extracorporeal lung support in failed conventional ventilation, and a prospective trial is needed to define standard best practice and to tailor extracorporeal lung support referral criteria in young patient cohort with severe refractory respiratory failure.

beta-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial cultures.

By promoting cell proliferation, survival and maturation insulin-like growth factor (IGF)-I is essential to the normal growth and development of the central nervous system. It is clear that IGF-I actions are primarily mediated by the type I IGF receptor (IGF1R), and that phosphoinositide 3 (PI3)-Akt kinases and MAP kinases signal many of IGF-I-IGF1R actions in neural cells, including oligodendrocyte lineage cells. The precise downstream targets of these signaling pathways, however, remain to be defined. We studied oligodendroglial cells to determine whether beta-catenin, a molecule that is a downstream target of glycogen synthase kinase-3beta (GSK3beta) and plays a key role in the Wnt canonical signaling pathway, mediates IGF-I actions. We found that IGF-I increases beta-catenin protein abundance within an hour after IGF-I-induced phosphorylation of Akt and GSK3beta. Inhibiting the PI3-Akt pathway suppressed IGF-I-induced increases in beta-catenin and cyclin D1 mRNA, while suppression of GSK3beta activity simulated IGF-I actions. Knocking-down beta-catenin mRNA by RNA interference suppressed IGF-I-stimulated increases in the abundance of cyclin D1 mRNA, cell proliferation, and cell survival. Our data suggest that beta-catenin is an important downstream molecule in the PI3-Akt-GSK3beta pathway, and as such it mediates IGF-I upregulation of cyclin D1 mRNA and promotion of cell proliferation and survival in oligodendroglial cells.

Histone deacetylase 11 regulates oligodendrocyte-specific gene expression and cell development in OL-1 oligodendroglia cells.

Both in vivo and in vitro studies indicate a correlation between reduced acetylation of histone core proteins and oligodendrocyte development. The nature of these histone modifications and the mechanisms mediating them remain undefined. To address these issues, we utilized OL-1 cells, a rat nontransformed oligodendrocyte cell line, and primary oligodendrocyte cultures. We found that the acetylated histone H3 at lysine 9 and lysine 14 (H3K9/K14ac) is reduced in both the myelin basic protein (MBP) and proteolipid protein (PLP) genes of maturing oligodendroglial OL-1 cells, and furthermore, this temporally correlates with increases in MBP, PLP, and histone deacetylase (HDAC) 11 expression. Disruption of developmentally-regulated histone H3 deacetylation within the MBP and PLP genes by the HDAC inhibitor trichostatin A blunts MBP and PLP expression. With its increased expression, interaction of HDAC 11 with acetylated histone H3 and recruitment of HDAC 11 to the MBP and PLP genes markedly increases in maturing OL-1 cells. Moreover, suppressing HDAC 11 expression with small interfering RNA significantly (1) increases H3K9/K14ac globally and within the MBP and PLP genes, (2) decreases MBP and PLP mRNA expression, and (3) blunts the morphological changes associated with oligodendrocyte development. Our data strongly support a specific role for HDAC 11 in histone deacetylation and in turn the regulation of oligodendrocyte-specific protein gene expression and oligodendrocyte development.

Type 1 insulin-like growth factor receptor signaling is essential for the development of the hippocampal formation and dentate gyrus.

Type 1 insulin-like growth factor receptor (IGF1R) signaling in neuronal development was studied in mutant mice with blunted igf1r gene expression in nestin-expressing neuronal precursors. At birth [postnatal (P) day 0] brain weights were reduced to 37% and 56% of controls in mice homozygous (nes-igf1r(-/-)) and heterozygous (nes-igf1r(-/Wt)) for the null mutation, respectively, and this brain growth retardation persisted postnatally. Stereological analysis demonstrated that the volumes of the hippocampal formation, CA fields 1-3, dentate gyrus (DG), and DG granule cell layer (GCL) were decreased by 44-54% at P0 and further by 65-69% at P90 in nes-igf1r(-/Wt) mice. In nes-igf1r(-/-) mice, volumes were 29-31% of controls at P0 and, in the two mice that survived to P90, 6-19% of controls, although the hilus could not be identified. Neuron density did not differ among the mice at any age studied; therefore, decreased volumes were due to reduced cell number. In postnatal nes-igf1r(-/Wt) mice, the percentage of apoptotic cells, as judged by activated caspase-3 immunostaining, was increased by 3.5-5.3-fold. The total number of proliferating DG progenitors (labeled by BrdU incorporation and Ki67 staining) was reduced by approximately 50%, but the percentage of these cells was similar to the percentages in littermate controls. These findings suggest that 1) the postnatal reduction in DG size is due predominantly to cell death, pointing to the importance of the IGF1R in regulating postnatal apoptosis, 2) surviving DG progenitors remain capable of proliferation despite reduced IGF1R expression, and 3) IGF1R signaling is necessary for normal embryonic brain development.

Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus.

The somatomedins or insulin-like growth factors (IGFs) are synthesized in many organs and tissues, but the specific cells that synthesize them in vivo have not been defined. By in situ hybridization histochemistry, IGF I (somatomedin C) and IGF II messenger RNAs were localized to connective tissues or cells of mesenchymal origin in 14 organs and tissues from human fetuses. IGF messenger RNAs were localized to perisinusoidal cells of liver, to perichondrium of cartilage, to sclera of eye, and to connective tissue layers, sheaths, septa, and capsules of each organ and tissue. All of the hybridizing regions are comprised predominantly of fibroblasts or other cells of mesenchymal origin. Because these cells are widely distributed and anatomically integrated into tissues and organs, they are ideally located for production of IGFs, which may exert paracrine effects on nearby target cells.

Modelling the impact of an influenza A/H1N1 pandemic on critical care demand from early pathogenicity data: the case for sentinel reporting.

Projected critical care demand for pandemic influenza H1N1 in England was estimated in this study. The effect of varying hospital admission rates under statistical uncertainty was examined. Early in a pandemic, uncertainty in epidemiological parameters leads to a wide range of credible scenarios, with projected demand ranging from insignificant to overwhelming. However, even small changes to input assumptions make the major incident scenario increasingly likely. Before any cases are admitted to hospital, 95% confidence limit on admission rates led to a range in predicted peak critical care bed occupancy of between 0% and 37% of total critical care bed capacity, half of these cases requiring ventilatory support. For hospital admission rates above 0.25%, critical care bed availability would be exceeded. Further, only 10% of critical care beds in England are in specialist paediatric units, but best estimates suggest that 30% of patients requiring critical care will be children. Paediatric intensive care facilities are likely to be quickly exhausted and suggest that older children should be managed in adult critical care units to allow resource optimisation. Crucially this study highlights the need for sentinel reporting and real-time modelling to guide rational decision making.

Serum sodium and intracranial pressure changes after desmopressin therapy in severe traumatic brain injury patients: a multi-centre cohort study.

BACKGROUND: In traumatic brain injury (TBI) patients desmopressin administration may induce rapid decreases in serum sodium and increase intracranial pressure (ICP). AIM: In an international multi-centre study, we aimed to report changes in serum sodium and ICP after desmopressin administration in TBI patients. METHODS: We obtained data from 14 neurotrauma ICUs in Europe, Australia and UK for severe TBI patients (GCS ≤ 8) requiring ICP monitoring. We identified patients who received any desmopressin and recorded daily dose, 6-hourly serum sodium, and 6-hourly ICP. RESULTS: We studied 262 severe TBI patients. Of these, 39 patients (14.9%) received desmopressin. Median length of treatment with desmopressin was 1 [1-3] day and daily intravenous dose varied between centres from 0.125 to 10 mcg. The median hourly rate of decrease in serum sodium was low (- 0.1 [- 0.2 to 0.0] mmol/L/h) with a median period of decrease of 36 h. The proportion of 6-h periods in which the rate of natremia correction exceeded 0.5 mmol/L/h or 1 mmol/L/h was low, at 8% and 3%, respectively, and ICPs remained stable. After adjusting for IMPACT score and injury severity score, desmopressin administration was independently associated with increased 60-day mortality [HR of 1.83 (1.05-3.24) (p = 0.03)]. CONCLUSIONS: In severe TBI, desmopressin administration, potentially representing instances of diabetes insipidus is common and is independently associated with increased mortality. Desmopressin doses vary markedly among ICUs; however, the associated decrease in natremia rarely exceeds recommended rates and median ICP values remain unchanged. These findings support the notion that desmopressin therapy is safe.

Correction to: Serum sodium and intracranial pressure changes after desmopressin therapy in severe traumatic brain injury patients: a multi-centre cohort study.

Following publication of the original article [1], we were notified that the collaborators' names part of the "The TBI Collaborative" group has not been indexed in Pubmed. Below the collaborators names full list.