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Background The European Network of Medical Residents in Public Health (EuroNet MRPH) is a non-profit, international, independent and non-governmental network of national associations of public health residents around Europe. Objectives To describe the results accomplished by EuroNet MRPH and to show networking opportunities provided to medical residents in public health (MRPH) from 2011 to 2021. Results EuroNet's mission is to improve and facilitate connection between MRPH, to promote pan-European Research, and to facilitate international mobility. Digital and quarterly face-to-face meetings are used as a way of communication. Since 2011, 10 European MRPH associations and 4 individual members have joined the network, representing the UK, France, Spain, Italy, Portugal, Ireland, the Netherlands, Croatia, Slovenia, Turkey, Malta, Poland, Bosnia and Herzegovina, and Austria. In this period, 27 face-to-face meetings have been organised, promoting cooperation and exchanging of ideas between MRPH. Moreover, three working groups (WG) have been established, focusing on research, internships, and communication. Regarding research, studies about e-cigarettes, conflicts of interest, and the impact of COVID-19 on mental health of MRPH have been conducted. When it comes to internships, more than 20 possible destinations and an online form are available on our website, providing MRPH information and support. Finally, thanks to the communication WG, 20 newsletters have been published, sharing experiences and thoughts from members of the network. Moreover, EuroNet has an established presence in social media, with active accounts in Twitter, Instagram and Facebook, where public health information and opportunities for young professionals are promoted. Conclusions In the last ten years, EuroNet MRPH has actively promoted networking opportunities among European Medical Residents in Public Health. Key messages Enhancing international cooperation among young public health professionals is fundamental in order to face current and future public health challenges. EuroNet MRPH represents a useful tool to promote collaboration among young public health professionals.

Background: Understanding the risk factors associated with hospital burden of COVID-19 is crucial for healthcare planning for any future waves of infection. Methods: An observational cohort study is performed, using data on all RT-PCR confirmed cases of COVID-19 in Regione Lombardia, Italy, during the first wave of infection from February-June 2020. A multi-state modelling approach is used to simultaneously estimate risks of progression through hospital to final outcomes of either death or discharge, by pathway (via critical care or not) and the times to final events (lengths of stay). Logistic and time-to-event regressions are used to quantify the association of patient and population characteristics with the risks of hospital outcomes and lengths of stay respectively. Findings: Risks of severe outcomes such as ICU admission and mortality have decreased with month of admission and increased with age. Care home residents aged 65+ are at increased risk of hospital mortality and decreased risk of ICU admission. Being a healthcare worker appears to have a protective effect on mortality risk and length of stay. Lengths of stay decrease with month of admission for survivors, but do not appear to vary with month for non-survivors. Interpretation: Improvements in clinical knowledge, treatment, patient and hospital management and public health surveillance, together with the waning of the first wave after the first lockdown, are hypothesised to have contributed to the reduced risks and lengths of stay over time. Funding: This work has been funded by the Medical Research Council (De Angelis, Jackson, Presanis: Unit programme number MC UU 00002/11; Kunzmann: Unit programme number MC_UU_00002/10); and the UKRI-MRC COVID-19 Rapid Call (Presanis, De Angelis, grant no MC_PC_19074). Declaration of Interests: None to declare.

The pandemic character of coronavirus disease-19 (COVID-19) requires strategy changes designed to guarantee the safety of patients and health-care professionals. We are greatly concerned by the limitations in the operation of pulmonary function test (PFT) laboratories, since there is a high risk of disease progression in patients with chronic pulmonary diseases, and we are now faced by the influx of a new group of individuals in the recovery phase of post-COVID-19-syndrome that requires evaluation and follow-up of their respiratory function. To reestablish the operation of PFT laboratories limiting the risk of cross-contamination, we herein present the consensus reached by a group of experts in respiratory physiology, most of whom work in PFT laboratories in several Latin American countries, on the applicable recommendations for severe acute respiratory syndrome coronavirus 2 pneumonia survivors when undergoing PFT. We present the safety and hygiene measures that must be adopted in laboratories or centers where PFT is conducted in adults and/or children. These recommendations answer the following questions: which PFT is most recommended in subjects that have recovered from COVID-19; what quality control and safety measures should PFT laboratories implement during this pandemic? And how should we approach non-COVID-19 patients requiring PFT?

To enhance the positive predictive value (PPV) of chest digital tomosynthesis (DTS) in the lung cancer detection with the analysis of radiomics features. The investigation was carried out within the SOS clinical trial (NCT03645018) for lung cancer screening with DTS. Lung nodules were identified by visual analysis and then classified using the diameter and the radiological aspect of the nodule following lung-RADS. Haralick texture features were extracted from the segmented nodules. Both semantic variables and radiomics features were used to build a predictive model using logistic regression on a subset of variables selected with backward feature selection and using two machine learning: a Random Forest and a neural network with the whole subset of variables. The methods were applied to a train set and validated on a test set where diagnostic accuracy metrics were calculated. Binary visual analysis had a good sensitivity (0.95) but a low PPV (0.14). Lung-RADS classification increased the PPV (0.19) but with an unacceptable low sensitivity (0.65). Logistic regression showed a mildly increased PPV (0.29) but a lower sensitivity (0.20). Random Forest demonstrated a moderate PPV (0.40) but with a low sensitivity (0.30). Neural network demonstrated to be the best predictor with a high PPV (0.95) and a high sensitivity (0.90). The neural network demonstrated the best PPV. The use of visual analysis along with neural network could help radiologists to reduce the number of false positive in DTS. • We investigated several approaches to enhance the positive predictive value of chest digital tomosynthesis in the lung cancer detection. • Neural network demonstrated to be the best predictor with a nearly perfect PPV. • Neural network could help radiologists to reduce the number of false positive in DTS.

Background:Vitamin D regulates the innate and adaptive immune system responses and low vitamin D levels have been associated with the increased risk of respiratory tract infections (1). Vitamin D deficiency has been recently reported to interfere with the prognosis of COVID-19 (2,3).Objectives:The aim of this study was to correlate the 25OH-vitamin D serum levels with lung involvement and disease severity, in a cohort of elderly patients hospitalized for SARS-CoV-2 infection.Methods:Sixty-five COVID-19 patients (mean age 76±13 years) and sixty-five sex- and age-matched control subjects (CNT) were included in the study. Respiratory parameters (PaO2, SO2, PaCO2, PaO2/FiO2), clinical and laboratory parameters (including 25OH-vitamin D, D-dimer, C-reactive protein) and type of radiological pulmonary involvement were collected at hospital admission. Statistical analysis was performed by non-parametric tests.Results:Vitamin D sufficiency (>30 ng/ml), insufficiency (between 20 and 30 ng/ml), deficiency (between 10 and 20 ng/ml) and severe deficiency (2 (p=0.05), PaO2 (p=0.03), PaO2/FiO2 (p=0.02). A statistically significant negative correlation was found between vitamin D serum levels and severity of radiologic pulmonary involvement: vitamin D was significantly lower in COVID-19 patients with either diffuse/severe interstitial lung involvement (p=0.05) or multiple lung consolidations (p=0.0001) than in those with mild radiological lung involvement. Significantly lower vitamin D serum levels were found in COVID-19 patients who died during hospitalization, compared to those who survived (median 3 vs 8 ng/ml, p=0.05). Finally, a statistically significant negative correlation was found between vitamin D serum levels and D-dimer (p=0.04), C-reactive protein (p=0.04) and disease duration (p=0.05).Conclusion:This study confirms that severe vitamin D deficiency is associated with more severe lung involvement, longer disease duration and risk of death in elderly COVID-19 patients.References:[1]Cutolo M, et al. RMD Open. 2020; 6(3):e001454.[2]Bilezikian JP, et al. Eur J Endocrinol. 2020; 183(5):R133-R147.[3]Weir EK, et al. Clin Med (Lond). 2020; 20:e107-e108.Disclosure of Interests:None declared

Background:COVID-19 is a multifaceted condition with a wide range of clinical manifestations, including microvascular/endothelial dysfunction, that starts in the early phase of the disease and may become dramatically harmful in the late stage, causing a massive pro-thrombotic state. Nailfold videocapillaroscopy (NVC) is the most used tool to identify microvascular status in a large spectrum of diseases [1]. Recently, non-specific NVC abnormalities have been described in a cohort of COVID-19 patients (no controls used) [2].Objectives:To assess microvascular damage in recovered COVID-19 patients (range of 40-270 days from recovery) by considering the previous severity of the disease, and, as mandatory, the comparison with matched individuals suffering from primary Raynaud’s phenomenon (PRP) and healthy volunteers (HV).Methods:NVC investigations were performed during standard clinical assessments in forty-four recovered COVID-19 patients (mean age 58±14 years, mean days from disease onset 129±54, mean days from disease recovery 106±52), twenty-two patients with PRP (mean age 60±15 years, mean years from disease onset 11±10) and twenty-two HV (mean age 60±14 years). COVID-19 patients were divided into two subgroups, according to the need of oxygen supplementation: twenty-two patients with severe lung involvement (need of Continuous Positive Airways Pressure and/or mechanical ventilation, mean age 57±12 years) vs twenty-two patients with mild-moderate lung involvement (need of Venturi mask or no need of oxygen supplementation, mean age 59±15 years). Clinical and demographic data of all the enrolled subjects were collected, during NVC examination. The following capillaroscopic parameters were evaluated: capillary number, dilated capillaries, giant capillaries, microhemorrhages, angiogenesis, disorganization of the microvascular array. A validated semiquantitative scoring (0-3) was adopted for NVC abnormalities [3-5]. Statistical analysis was carried out by non-parametric tests.Results:After COVID-19 recovery, no statistically significant difference was observed between COVID-19 patients and control groups of subjects concerning the score for the following NVC parameters: dilated capillaries, giant capillaries, disorganization of the microvascular array, angiogenesis. However, the capillary number per linear millimeter was significantly lower in COVID-19 patients (8.3±0.9) than in PRP (8.8±0.7, p=0.05) and HV (9.3±0.6, pConclusion:COVID-19 doesn’t seem to significantly induce, in short-term, specific alterations in peripheral microvascular array as evaluated by NVC, despite the severity of the disease, except for a significant reduction of the absolute number of nailfold capillaries. The topic needs longer time of evaluation and larger number of COVID-19 recovered cases to also assess the role of concomitant therapies.References:[1]Ingegnoli F et al. Curr Rheumatol Rev. 2018;14:5-11.[2]Natalello G et al. Microvasc Res. 2021;133:104071.[3]Smith V et al. Autoimmun Rev 2020;19:102458.[4]Cutolo M et al. Clin Rheumatol. 2019;38:2293-2297.[5]Sulli A et al. Ann Rheum Dis. 2008;67:885-7.Disclosure of Interests:None declared

Background: Little is known about the variation in complication rates among U.S. hospitals that perform elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) procedures. The purpose of this study was to use National Quality Forum (NQF)-endorsed hospital-level risk-standardized complication rates to describe variations in, and disparities related to, hospital quality for elective primary THA and TKA procedures performed in U.S. hospitals. Methods: We conducted a cross-sectional analysis of national Medicare Fee-for-Service data. The study cohort included 878,098 Medicare fee-for-service beneficiaries, sixty-five years or older, who underwent elective THA or TKA from 2008 to 2010 at 3479 hospitals. Both medical and surgical complications were included in the composite measure. Hospital-specific complication rates were calculated from Medicare claims with use of hierarchical logistic regression to account for patient clustering and were risk-adjusted for age, sex, and patient comorbidities. We determined whether hospitals with higher proportions of Medicaid patients and black patients had higher risk-standardized complication rates. Results: The crude rate of measured complications was 3.6%. The most common complications were pneumonia (0.86%), pulmonary embolism (0.75%), and periprosthetic joint infection or wound infection (0.67%). The median risk-standardized complication rate was 3.6% (range, 1.8% to 9.0%). Among hospitals with at least twenty-five THA and TKA patients in the study cohort, 103 (3.6%) were better and seventy-five (2.6%) were worse than expected. Hospitals with the highest proportion of Medicaid patients had slightly higher but similar risk-standardized complication rates (median, 3.6%; range, 2.0% to 7.1%) compared with hospitals in the lowest decile (3.4%; 1.7% to 6.2%). Findings were similar for the analysis involving the proportion of black patients. Conclusions: There was more than a fourfold difference in risk-standardized complication rates across U.S. hospitals in which elective THA and TKA are performed. Although hospitals with higher proportions of Medicaid and black patients had rates similar to those of hospitals with lower proportions, there is a continued need to monitor for disparities in outcomes. These findings suggest there are opportunities for quality improvement among hospitals in which elective THA and TKA procedures are performed. Level of Evidence: Therapeutic Level III. See Instruction to Authors for a complete description of levels of evidence.

Purpose The aim of this work was to optimize the Video Assisted Thoracoscopic Surgery (VATS) procedure through a new rotational geometry avoiding also the interference of the flat panel with infusion lines, vital monitoring equipment and intubation instrumentation. Methods The VATS technique was performed in the Hybrid Room environment that can be used at the same time as a diagnostic room and a surgical room. The C-Arm robotic angiography acquires cone beam CT with reduced angle rotation around the patient permitting the lateral decubitus access to thoracic surgeons with two different protocols: 12sDCTLargeVolume (12s) and 5sDRBODYCARE (5s). The first one allows to scan large volumes by twisting twice around the patient. The second protocol allows to shrink the field to the region of interest with a single pass. Organ dose and REID (Risk of Exposure-Induced Death) were estimated with Monte Carlo methods in PCXMC. Results The initial and final positions of the C-Arm rotation were changed from −170, +30 to −100, +100 in the 5s protocol reducing the risk of collision in case of critical cases (external lesions), wherever the bed is located. After optimization we reduced the dose of 80% in the 12s protocol and of 8.5 times in the 5s. the organ dose and REID are shown in the table. Conclusions VATS is a rapidly emerging surgical technique for the excision of lung nodules that permits to perform radical surgery of lung cancers to a larger cohort of patients and with a longer expectancy of life respect to conventional surgery. We optimized the protocol by changing rotational departure and arrival position avoiding collisions and reducing the dose.

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.

Aims To evaluate the comparative efficacy (50% reduction in seizure frequency) and tolerability (premature withdrawal due to adverse events) of anti-epileptic drugs (AEDs) for refractory epilepsy. Methods We searched Cochrane Central Register of Controlled Trials (Cochrane Library 2009, issue 2) including Epilepsy Group's specialized register, MEDLINE (1950 to March 2009), EMBASE (1980 to March 2009), and Current Contents Connect (1998 to March 2009) to conduct a systematic review of published studies, developed a treatment network and undertook a network meta-analysis. Results Forty-three eligible trials with 6346 patients and 12 interventions, including placebo, contributed to the analysis. Only three direct drug comparator trials were identified, the remaining 40 trials being placebo-controlled. Conventional random-effects meta-analysis indicated all drugs were superior in efficacy to placebo (overall odds ratio (OR] 3.78, 95% CI 3.14, 4.55) but did not permit firm distinction between drugs on the basis of the efficacy or tolerability. A Bayesian network meta-analysis prioritized oxcarbazepine, topiramate and pregabalin on the basis of short term efficacy. However, sodium valproate, levetiracetam, gabapentin and vigabatrin were prioritized on the basis of short-term efficacy and tolerability, with the caveat that vigabatrin is recognized as being associated with serious visual disturbance with chronic use. Conclusion Of the wide range of AEDs licensed for the treatment of refractory epilepsy, sodium valproate, levetiracetam and gabapentin demonstrated the best balance of efficacy and tolerability. Until regulators mandate greater use of active comparator trials with longer term follow-up, network meta-analysis provides the only available means to quantify these clinically important parameters.

Background— Variation in outcomes after percutaneous coronary interventions (PCI) may reflect differences in quality of care. To date, however, we lack a methodology to monitor and improve national hospital 30-day mortality rates among patients undergoing PCI. Methods and Results— We developed hierarchical logistic regression models to calculate hospital risk-standardized 30-day all-cause PCI mortality rates. Due to differences in risk, patients were divided into 2 cohorts: those with ST-segment elevation myocardial infarction or cardiogenic shock, and those with no ST-segment elevation myocardial infarction and no cardiogenic shock. The models were derived using 2006 data from the CathPCI Registry linked with administrative claims data, and validated using comparable 2005 data. In the derivation cohort of the ST-segment elevation myocardial infarction or shock model (n=15 123), the unadjusted 30-day mortality rate was 9.2%. The final model included 13 variables with the observed mortality rates ranging from 1.4% to 40.3% across deciles of the predicted patient mortality rates. The 25th and 75th percentiles of the risk-standardized mortality rate were 8.5% and 9.7%, with 5th and 95th percentiles of 7.6% and 11.0%. In the derivation cohort of the no ST-segment elevation myocardial infarction and no shock model (n=110 529), the unadjusted 30-day mortality rate was 1.4%. The final model included 16 variables with the observed predicted mortality rates ranging from 0.1% to 7.0% across deciles of the predicted patient mortality rates. The 25th and 75th percentiles of the risk-standardized mortality rate across 612 hospitals were 1.3% and 1.6%, with 5th and 95th percentiles of 1.0% and 2.0%. Conclusions— These National Quality Forum endorsed registry-based models produce estimates of hospital risk-standardized mortality rates for patients undergoing PCI.

The randomized double-blind controlled clinical trial (RCT) is the undisputed gold-standard for assessing drug efficacy. However the RCT is usually insufficiently powered, or too brief, to detect rare but serious adverse effects or modest but important increases in the risk of common disease outcomes (such as coronary heart disease events) that can have a major population impact in absolute terms. Pooling individual trials via meta-analyses sometimes helps but the reporting of information on adverse effects in clinical trials is often incomplete or poorly quantified, particularly when compared to the efficacy endpoints. Clinically significant and unexpected abnormal laboratory values may not be detected as not all are routinely included in trial protocols. Most RCTs also tend to exclude the elderly, patients with co-morbidity or pregnancy, and this reduces the generalisability of these data. Therefore, at the time of product launch, there are often limited safety data of any new drug, in both the short- and longer-term which is directly applicable to that of the target population. Drugs in use therefore need to remain under constant surveillance (pharmacovigilance) and study by observation (pharmacoepidemiology) Pharmacovigilance systems identify safety signals (signal detection) and thus serve to generate hypothesis. Pharmacoepidemiology tests such hypothesis (signal validation) and quantifies the risk. Both pharmacovigilance and pharmacoepidemiology have limitations, are complementary and only partially overlap.

Aim: To establish the cost-effectiveness of screen-A ing and treating meticillin-sensitive Staphylococcus aureus (MSSA) carriers, potentially reducing both financial and clinical burdens of managing healthcare-acquired infections. Methods: A decision health economic model analysed the impact of a ‘screen and treat’ strategy for Hospital inpatients from the perspective of the UK National Health Service. Results: Cost savings in excess of £600k and around 840 potential infections could be avoided in a 70,000 patient cohort, at a nasal carriage prevalence of 30%. For 2000 high infection risk cardiothoracic surgery patients, cost savings could reach £8,636 per annum. The dominance of the ‘screen and treat’ strategy holds for plausible variations in the model parameter values and simple modelling of secondary transmission. Conclusion: Adopting rapid screening and treating MSSA nasal carriers should be clinically and financially advantageous, compared to current strategies of not screening, even under conservative assumptions for costs and probabilities of managing infections.

Purpose The aim of this work was to optimize technical and dosimetric aspects of Prostate Artery Embolization (PAE) for Benign Prostatic Hyperplasia (BPH). Methods The radiological procedures in PAE consist of an angio-CT on a Brillance64 (Philips, Eindhoven, The Netherlands) to define the anatomical vascular structure of pelvis and of prostatic arteries and the angiographic procedure on the Integris Allura system (Philips, Eindhoven, The Netherlands) or in the hybrid room with the Zeego system (Siemens, Forchheim, Germany). The latter performs rotational acquisition that permits 3D CT-like reconstructions. Combining the angiographic acquisition with the anatomical 3D reconstruction of CT permits to map the prostatic artery during the procedure. An evaluation of the ESD, pESD, and effective dose was performed based on the dose-area product (DAP), weighting contributions of all the different projections. Results 21 consecutive patients with a mean age of 75.5 (range 56–93) years were studied: 12 with Allura and 9 with Zeego. Effective doses were 54 (range 25–81) mSv during imaging and 46 (range 16–85) mSv during fluoroscopy with Allura and 37 (8–68) mSv during imaging and 80 (33–175) mSv during fluoroscopy with Zeego. Zeego permits a decrease in latero-lateral, contralateral and PA projections, compensated by the rotational acquisition. The effective dose in angio-CT was 7.9 (3.4–18.9) mSv. Optimization by reducing the number of frames per projection and the size of the field in the district of interest pemitted to lower the dose of 35%. Average ESD and pESD were respectively 0.62 Gy and 1.02 Gy on Zeego and respectively 0.44 Gy and 1.49 Gy on Zeego. The rotational dose for Zeego was evaluated 6.8% of the total dose. The angio-CT contributed to the 6.7% of the total dose. Conclusions In this work we gave a first report on the effective dose delivered during PAE on two different generations angiographics system. More patient are needed to understand the advantage of the different technologies.

Background Administrative-claims data enable comparative effectiveness assessment using large numbers of patients treated in real-world settings. Objective To evaluate real-world relapses, healthcare costs and resource use in patients with MS newly initiating subcutaneous interferon beta-1a (sc IFNβ-1a) v. oral disease-modifying drugs (DMDs: dimethyl fumarate, fingolimod, teriflunomide). Methods Patients from an administrative claims database (1 Jan 2012–31 Dec 2015) were selected if they: were 18–63 years old; had an MS diagnosis; had newly initiated sc IFNβ-1a, dimethyl fumarate, fingolimod, or teriflunomide (first claim = index); had no evidence of DMD 12-months pre-index; and had 12-month eligibility pre- and post-index. Relapse was defined as an MS-related inpatient stay, emergency room visit, or outpatient visit with a corticosteroid prescription ± 7 days. Outcomes were evaluated using logistic regression and generalized linear models. Results A total of 4475 patients met inclusion criteria: 21.9% sc IFNβ-1a, 51.0% dimethyl fumarate, 19.7% fingolimod, 7.4% teriflunomide. Teriflunomide patients had 1.357 (95% CI 1.000, 1.831; p = 0.0477) greater odds of 1-year relapse than sc IFNβ-1a patients. Estimated mean all-cause 1-year costs were higher after fingolimod (US$72,376) v. sc IFNβ-1a initiation (US$65,408; p Conclusion Patients initiating sc IFNβ-1a had better relapse outcomes v. teriflunomide, and lower all-cause costs v. fingolimod.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Conflicting studies have raised uncertainty over the vascular effects of the long-acting anticholinergic, tiotropium bromide. WHAT THIS STUDY ADDS • Our results show no increased risk of stroke with tiotropium bromide, or with inhaled anticholinergics in general. AIMS A recent communication from the United States Food and Drug Administration highlighted a possible increased risk of stroke associated with use of the relatively new inhaled anticholinergic drug, tiotropium bromide. Using the United Kingdom General Practice Research Database, we set out to assess the risk of stroke in individuals exposed to inhaled tiotropium bromide and two other inhaled treatments for airways disease. METHODS We used the self-controlled case-series that reduces confounding and minimizes the potential for biases in the quantification of risk estimates. RESULTS Of 1043 people with a diagnosis of incident stroke who had had at least one prescription for tiotropium bromide, 980 satisfied inclusion criteria. The age-adjusted incidence rate ratio for all-cause stoke in individuals exposed to tiotropium bromide (n= 980), ipratropium bromide (n= 4181) and fluticasone propionate/salmeterol xinafoate (n= 1000) was 1.1 [95% confidence interval (CI) 0.9, 1.3], 0.8 (95% CI 0.7, 0.9) and 1.0 (95% CI 0.9, 1.2), respectively. CONCLUSIONS We found no evidence of an increased risk of all-cause stroke for individuals exposed to commonly prescribed inhaled treatments for chronic obstructive pulmonary disease.

Recent research suggests that chocolate, particularly dark chocolate, may benefit cardiovascular health. Chocolate contains over 600 chemicals including flavanoids, magnesium, and theobromine. Flavanoids (including flavanols, flavones, flavanones, and others) are potent antioxidants capable of inducing nitric oxide-dependent vasodilation, as well as having antiplatelet and anti-inflammatory effects.1,2 Magnesium deficits have been linked to hypertension, and other cardiovascular disease.3,4 The methylxanthine theobromine is present in very high quantities, with dark chocolate containing the most.5 The primary pharmacologic effects of theobromine include diuresis, myocardial stimulation, vasodilation, and smooth muscle relaxation,6 and it has been used to treat hypertension, angina, and atherosclerosis.7 Theobromine is widely consumed in the form of chocolate and cocoa products, and although theobromine is one of the 3 primary metabolites of caffeine, it accounts for only about 12% of total metabolized caffeine, compared with 70% to 80% for paraxanthine.6 Thus, theobromine is a useful, specific biomarker for chocolate consumption. In addition, theobromine, along with the other methylxanthines, freely crosses the placental barrier in pregnancy. Preeclampsia is a serious maternal complication of pregnancy that affects 3% to 8% of pregnancies.8 Preeclampsia shares many characteristics and risk factors of cardiovascular disease, including endothelial dysfunction, oxidative stress, hypertension, insulin resistance, and hypertriglyceridemia.9 Cardiovascular manifestations of preeclampsia include changes in vascular reactivity, hypertriglyceridemia, endothelial dysfunction, and hypertension.8,10,11 Women with preeclampsia may also be at increased risk of cardiovascular disease and metabolic disturbances in the years following pregnancy.12–16 We investigate whether chocolate consumption, measured by self-reported maternal intake and fetal cord serum concentrations of theobromine, is associated with preeclampsia.

We sought to examine associations among measures of caffeine exposure, including maternal urine, umbilical cord blood, and maternal self report.Pregnant women were recruited from 56 obstetric practices and 15 clinics associated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000; 3633 women were enrolled. Maternal urine throughout pregnancy and umbilical cord blood samples were analyzed for caffeine, paraxanthine, theophylline, and theobromine. Maternal caffeine intake was assessed throughout pregnancy.Urinary and cord blood biomarkers were correlated with reported intake throughout pregnancy (range r = 0.35-0.66; p0.0001). Infants of smokers had greater cord blood concentrations of paraxanthine, reflecting faster caffeine metabolism in smokers, and cord blood paraxanthine levels were more strongly correlated with intake in smokers.Maternal self reported intake may still be the optimal and most valid measure of antenatal caffeine exposure, since biomarkers do not reflect exposure over pregnancy.

Cancer-testis (CT) antigens are immunogenic proteins expressed in normal gametogenic tissues and in different types of tumors. CTSP-1 is a CT antigen frequently expressed in prostate tumors, and capable of eliciting humoral response in prostate cancer patients. Here, we analyzed the presence of anti-CTSP-1 antibodies in 147 patients with localized prostate cancer and determined its prognostic value for predicting biochemical-recurrence after radical prostatectomy. Anti-CTSP-1 antibodies were detected in 25% of the patients and a significant correlation (p = 0.017) between CTSP-1 protein expression and the presence of specific humoral response was observed. No association was found between the presence of antibodies and the pathological variables analyzed. On univariate analysis, patients without antibodies against CTSP-1 had a lower biochemical-recurrence free survival than did those with anti-CTSP-1 antibodies, although the difference between the groups was not statistically significant (57 vs. 75%, p = 0.075). However, the presence of antibodies against CTSP-1 was significantly associated with a better prognosis in patients with higher Gleason score (36 vs. 80%, p = 0.028). On multivariate analysis, antibodies against CTSP-1 were associated with a better prognosis (Hazard ratio = 0.41, 95% IC 0.18-0.90 p = 0.039), being the third most powerful prognostic factor among Gleason score and preoperative PSA levels. CTSP-1 should be considered a promising candidate for prostate cancer immunotherapy, since it is frequently expressed in prostate tumors and capable of eliciting humoral immune response in prostate cancer patients. Our results also suggest that humoral response against CTSP-1 could be used as a prognostic marker, especially among patients with a high Gleason score.

Incidence of head and neck cancer (HNC) due to human papillomavirus (HPV) infection has been increasing. Treatment regimens have evolved. These changes might result in alterations of assumed treatment-related weight changes for HNC patients. We aimed to compare the trajectory of pre- to post-treatment weight changes of oropharyngeal squamous cell carcinoma (OPSCC) versus oral cavity squamous cell carcinoma (OCSCC) patients and to compare weight changes between patients with primary surgery ± adjuvant therapy to patients with primary radiation and/or chemotherapy. This retrospective cohort study examined adult OPSCC and OCSCC patients with initial definitive treatment at the University of Pennsylvania from January 1, 2009 to December 31, 2010. Patient demographics, medical history, treatments, and pre- and post-treatment body weight data were collected from electronic medical records. Mixed-effects modeling was performed. Among 354 patients who met the inclusion criteria, 290 (82 %) survivors were available for inclusion by 24-month follow-up. More than 70 % OPSCC and OCSCC patients were overweight or obese at all pre- and post-treatment time points. The average weight among OPSCC patients was 6.63 kg higher than OCSCC patients at all time points (mean = 6.63, 95 % confidence interval (CI), 2.46–10.79, p = 0.002). After adjusting for potential confounders, patients with primary surgery had significantly more weight gain from pre-treatment to 12–18 month post-treatment follow-up as compared to patients with primary radiation and/or chemotherapy (adjusted mean = 4.01, 95 % CI, 0.16–7.87, p = 0.041). Overweight and obesity may be a new challenge in OPSCC and OCSCC patient care. Further study is needed to evaluate whether exercise and nutritional interventions can improve their survivorship.

Summary Gemcitabine is usually administered at a planned dose-intensity (DI) from 750 to 800 mg/m 2 /week. Preclinical data have suggested a possible dose–response relationship of gemcitabine. A multicenter phase II study was conducted to evaluate the activity in terms of no progression rate (complete responses + partial responses + stable diseases) of gemcitabine administered at an increased DI (1000 mg/m 2 /week) in elderly advanced non-small-cell lung cancer (NSCLC) patients. Secondary endpoints were to evaluate tolerability, progression free survival and overall survival. Elderly (age ≥ 70 years) chemo-naive advanced NSCLC patients, ECOG PS 0–2, were treated with intravenous gemcitabine 1500 mg/m 2 intravenous (30 min infusion) on days 1 and 8 every 21 days for four courses. One hundred and twenty-two patients with a median age of 75 years (range 70-84) entered the study. The following grade 3 (NCI-CTC) haematological toxicities were reported (percent of patients): neutropenia 2.4%, thrombocytopenia 1.6%, anaemia 2.4%. No grades 3–4 non-haematological toxicities were observed. Among 111 evaluable patients 52 (46.8%) no progressions, 17 (15.3%) partial responses (WHO criteria), 35 (31.5%) stable diseases and 59 (53.2%) progressions were observed. Median time to progression was 3.2 months and median duration of survival was 5.4 months. The overall 1-year survival rate was 27%. Although increased dose-intensity of gemcitabine in elderly NSCLC patients is feasible without severe toxicities, this does not seem to be associated with an increased activity and efficacy in comparison to standard gemcitabine regimens with lower dose-intensities.

We present intersubband absorption in the conduction band of compressively strained germanium quantum wells bounded by Ge-rich SiGe barriers. The measured absorption energies are in the 5-12 THz range depending on the well width. These results may be relevant for the design of SiGe-based THz Quantum Cascade emitters.

Member countries of the North Atlantic Treaty Organization (NATO) initiated a peacekeeping mission in Bosnia-Herzegovina in December 1995. The U.S. Army has deployed field surgical hospitals to the region to provide ongoing medical and surgical care since December 1995. All surgical cases performed at U.S. Army field surgical hospitals in support of the NATO peacekeeping mission in Bosnia-Herzegovina were reviewed to determine the nature of care delivered. Field surgical hospital operative logs served as primary data sources. U.S. Army field surgical hospitals were established in Bosnia-Herzegovina, Croatia, and Hungary. A total of 676 major operations were performed between December 1995 and September 1999. The mean number of operations performed per surgeon per month during this period was 2.13. Surgical procedures performed during this peacekeeping mission reflect procedures commonly performed in garrison. Other lessons include the need to customize field inventories for peacetime care and the fact that the majority of operations were general surgical or orthopedic.

An urgent blood drive in which active duty military field surgical hospital personnel volunteered to donate whole blood was conducted, and administration of warm, whole blood prevented the exsanguination of a normothermic coagulopathic patient who had received a massive transfusion. In austere care settings in which full blood banking capability may not be available, physicians should consider that exsanguinating hemorrhage can potentially be controlled surgically, but nonsurgical bleeding requires specific replacement therapy, and whole blood may be the best selection for repleting deficiencies of components that are otherwise unavailable.

Patent Ductus Arteriosus (PDA) has a prevalence of approximately 25% in neonates of less than 33 weeks gestation. Failure to treat increases the mortality risk in these preterm infants. Intravenous Ibuprofen has recently been licensed in the United Kingdom as a treatment for this condition. This article reviews the clinical efficacy, side effect profile and dosing/administration schedule of this drug and discusses the warnings and precautions currently attributed to this formulation. Ibuprofen provides a further option for neonatologists in the management of PDA.

GRP-type composites (Glass-fibre Reinforced Plastics) have been continuously employed in the oil industry in recent years, often on platforms, especially in pipes for water or oil under moderate temperatures. In this case, the pipes are usually connected through adhesive joints and, consequently, the detection of defects in these joints, as areas without adhesive or adhesive failure (disbonding), gains great importance. One-sided inspection on the joint surface (front side) is a challenging task because the material thickness easily exceeds 10 mm that is far beyond the limits of the capacity of thermography applied to GRP inspection, as confirmed by the experience. Detection limits have been evaluated both theoretically and experimentally as a function of outer wall thickness and defect lateral size. The 3D modeling was accomplished by using the ThermoCalc-6L software. The experimental unit consisted of a FLIR SC640 and NEC TH- 9100 IR imagers and some home-made heaters with the power from 1,5 to 30 kW. The results obtained by applying pulsed heating have demonstrated that the inspection efficiency is strongly dependent on the outer wall thickness with a value of about 8 mm being a detection limit.

OBJECTIVE: To measure the association between use of proton pump inhibitors and a range of harmful outcomes in patients using clopidogrel and aspirin. DESIGN: Observational cohort study and self controlled case series. SETTING: United Kingdom General Practice Research Database with linked data from the Myocardial Ischaemia National Audit Project (MINAP) and the Office for National Statistics (the cardiovascular disease research using linked bespoke studies and electronic records (CALIBER) collaboration) POPULATION: 24,471 patients receiving clopidogrel and aspirin. MAIN OUTCOME MEASURES: The primary outcome was death or incident myocardial infarction. Secondary outcomes were death, incident myocardial infarction, vascular death, and non-vascular death. Comparisons were made between proton pump inhibitor use and non-use. RESULTS: Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton pump inhibitor at some time during the study. Death or incident myocardial infarction occurred in 1419 (11%) patients while they were receiving a proton pump inhibitor compared with 1341 (8%) who were not receiving a proton pump inhibitor. In multivariate analysis, the hazard ratio for the association between proton pump inhibitor use and death or incident myocardial infarction was 1.37 (95% confidence interval 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other 2C19 inhibitors and with non-2C19 inhibitors. With the self controlled case series design to remove the effect of differences between people, there was no association between proton pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01). Similarly, with the self controlled case series there was no association with myocardial infarction for other 2C19 inhibitors/non-inhibitors. CONCLUSION: The lack of a specific association and the discrepancy between findings of the analyses between and within people suggests that the interaction between proton pump inhibitors and clopidogrel is clinically unimportant.

Purpose High-resolution sonography (US) with color Doppler imaging (CDI) is a simple, noninvasive, safe and repeatable technique able to highlight the presence of hyperplastic parathyroid glands and changes in their volume, structure, and vascularization during uremia. The primary aim of this study was to assess the diagnostic accuracy of US and the sensitivity for localizing parathyroid glands with a volume ≥ 500 mm(3). The secondary aim was to assess the parameters that define parathyroid glandular perfusion. Materials and methods The diagnostic use of US was assessed in 40 consecutive uremic patients with severe secondary hyperparathyroidism (sHPT) who were receiving maintenance hemodialysis or conservative therapy with a hypoproteic-hypophosphoric diet and had undergone parathyroidectomy. Prior to surgery (99m)TC-sestamibi scintigraphy (SM) was performed in all patients. Results The sensitivity, specificity, positive predictive value and accuracy of US were 74 %, 75 %, 98 %, and 74 %, respectively. The sensitivity for localizing glands with a volume ≥ 500 mm(3) was 90 %. US and SM had a combined sensitivity of 83 %. The vascularization of parathyroid glands became more evident with increasing glandular volume. With CDI, the signs of hypervascularization (i. e. an enlarged feeding artery at the hilum, a peripheral arc of vascularity and/or ray-like endonodular vessels) were present in 77 % of glands with a volume ≥ 500 mm(3). Conclusion The sensitivity of US is higher than that of SM, but it cannot be compared with that of parathyroidectomy (74 vs. 95 %). However, US/CDI is able to characterize glands with different volumes and vascular patterns. Since glandular volume and vascularization are indicative of the severity of sHPT, this study suggests that the main role of US/CDI in the setting of sHPT should be to complete the diagnosis and to evaluate the morphological changes of enlarged glands during uremia in order to define surgical timing, rather than to assess the presurgical location of glands.

The effect of genetic and non-genetic factors for carcass, breast meat and leg weights, and yields of a commercial broiler line were investigated using the restricted maximum likelihood method, considering four different animal models, including or excluding maternal genetic effect with covariance between direct and maternal genetic effects, and maternal permanent environmental effect. The likelihood ratio test was used to determine the most adequate model for each trait. For carcass, breast, and leg weight, and for carcass and breast yield, maternal genetic and permanent environmental effects as well as the covariance between direct and maternal genetic effects were significant. The estimates of direct and maternal heritability were 0.17 and 0.04 for carcass weight, 0.26 and 0.06 for breast weight, 0.22 and 0.02 for leg weight, 0.32 and 0.02 for carcass yield, and 0.52 and 0.04 for breast yield, respectively. For leg yield, maternal permanent environmental effect was important, in addition to direct genetic effects. For that trait, direct heritability and maternal permanent environmental variance as a proportion of the phenotypic variance were 0.43 and 0.02, respectively. The results indicate that ignoring maternal effects in the models, even though they were of small magnitude (0.02 to 0.06), tended to overestimate direct genetic variance and heritability for all traits.

Today's SoCs are composed of a high variety of modules, such as microprocessor cores, memories, peripherals, and customized blocks directly related to the targeted application. Testing a peripheral core embedded in a SoC requires two correlated phases: module configuration and module operation. The first one prepares the peripheral on the different operation modes, whereas, the second one is in charge of exciting the whole device and observing its behavior. Different testing strategies based on the execution of assembly programs have been proposed by the research community to test the embedded blocks in a SoC, however, testing highly embedded peripherals (e.g., DMA controllers) is still a challenging task, since their observability and controllability are even more reduced compared to peripherals devoted to I/O communication. In this paper we describe an approach to develop functional tests for DMA controllers embedded in SoCs that can first be used for design validation, and then exploited for testing, adding observability features. Preliminary experimental results demonstrating the method suitability are finally reported.

Sixty-six patients, surgically treated for head and neck cancer and free of disease, were interviewed at the outpatient clinic from 6 months to 8 years after surgery. The patients were divided by the physician into two groups, according to the patients' degree of disfigurement, i.e., minor (24 patients, 36%, minor disfigurement group = MDG) or extensive (42 patients, 64%, extensive disfigurement group = EDG). Subsequently, the patients were interviewed with close-ended questions. The following subjective aspects were assessed: self-image; relationship with the partner, family, and friends; and the overall impact of the therapy. The results of the study showed a significantly higher impact in the EDG versus the MDG as regards a changed self-image (57% vs 25%, P less than 0.05), a worsened relationship with the partner (27% vs 0%, P less than 0.05), a reduced sexuality (74% vs 39%, P less than 0.01), and an increased social isolation (36% vs 12%, P less than 0.05). On the whole, 18% of the subjects stated that the disadvantages of therapy outweighed the advantages, and 30% fell that the difficulties encountered were "too harsh." In such cases, the opportunity of setting up a rehabilitation program offering psychosocial support should be considered.

Background: A recent trial unexpectedly reported that atrial fibrillation, when defined as serious, occurred more often in participants randomized to an annual infusion of the relatively new parenteral bisphosphonate, zoledronic acid, than among those given placebo, but had limited power. Two subsequent population-based case-control studies of patients receiving a more established oral bisphosphonate, alendronic acid, reported conflicting results, possibly due to uncontrolled confounding factors.Methodology/Principal Findings: We used the United Kingdom General Practice Research Database to assess the risk of atrial fibrillation and flutter in women exposed to the oral bisphosphonates, alendronic acid and risedronate sodium. The self-controlled case-series method was used to minimise the potential for confounding. The age-adjusted incidence rate ratio for atrial fibrillation or flutter in individuals during their exposure to these oral bisphosphonates (n = 2195) was 1.07 (95% CI 0.94 - 1.21). The age-adjusted incidence rate ratio for alendronic acid (n = 1489) and risedronate sodium (n = 649) exposed individuals were 1.09 (95% CI 0.93 - 1.26) and 0.99 (95% CI 0.78 - 1.26) respectively. In post-hoc analyses, an increased risk of incident atrial fibrillation or flutter was detected for patients during their first few months of alendronic acid therapy.Conclusions/Significance: We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies.

Background: Percutaneous vertebroplasty (PV) is largely employed in vertebral body compression fractures (VCF). Purpose: To evaluate the efficacy of PV on pain relief and functional status, and its complications rate. Materials and methods: A prospective observational study was conducted by the Division of Internal Medicine of St. Croce and Carle Hospital. Inclusion criteria: Diagnosis of osteoporosis, intense back pain, unresponsive to conservative treatment, associated with radiological evidence of recent VCF. Pain control and functional improvement were respectively assessed using Visual Analogue Scale (VAS) and Activity of Daily Living scale (ADL) on admission, 24 h after PV and at follow-up. PV complications were detected by an immediate computed tomography (CT) scan on the vertebra treated as well as the vertebrae above and below the treated level(s) and by CT chest scan to exclude pulmonary emboli. A magnetic resonance imaging (MRI) follow-up at 6 or 12 months was performed. Results: Fifty-two (46 with primary osteoporosis) patients were enrolled (mean age 73.18 yr, range 44–92). Median follow-up was 20.4 months (range 6–24). Treated vertebrae were 124. VAS, mean value was 9.05 (range 6–10) before treatment, 5.95 (range 2–8) at 24 h after PV and 4.94 (range 2–9) at follow-up (p

Studies investigating antenatal caffeine consumption and reproductive outcomes show conflicting results, and most studies have used maternal self-reported caffeine consumption to estimate fetal exposure. This study (n=1,606) was specifically designed to test the association of caffeine and its primary metabolites in umbilical cord blood with intrauterine growth restriction (IUGR). Pregnant women were recruited from 56 obstetric practices and 15 clinics affiliated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000. In an adjusted model including caffeine only, levels in all quartiles were associated with reduced risk of IUGR. In adjusted analyses including paraxanthine and caffeine, serum paraxanthine levels in the highest quartile were associated with increased risk of IUGR (adjusted odds ratio=3.29, 95% confidence interval: 1.17, 9.22); caffeine remained protective. These conflicting findings suggest that cytochrome P-450 1A2 (CYP1A2) metabolic activity may be associated with IUGR, so the ratio of paraxanthine to caffeine was then modeled. The likelihood of IUGR increased 21% for every one standard deviation change in the ratio (adjusted odds ratio=1.21, 95% confidence interval: 1.07, 1.37), suggesting that CYP1A2 activity, and not the absolute levels of paraxanthine, influences fetal growth. No associations were observed between caffeine or any metabolites and preterm delivery.

Coffee and its metabolite caffeine are widely studied for their health effects but with inconclusive results. Caffeine is particularly difficult to assess, and therefore we explore heterogeneity of caffeine exposure.We categorized caffeine exposure among 2,478 pregnant women in southern New England during 1996-2000 by the traditional laboratory-based methods of M. Bunker and M. McWilliams. A subsample was examined to ascertain caffeine levels of brewed or purchased beverages actually consumed.More than half (56.6%) of women drank coffee since becoming pregnant. Serving sizes ranged from 2 to 32 oz and are considerably larger than laboratory standards, which are typically 8-10 oz, as compared with the standard of 5 to 6 oz. Conversely, caffeine content per serving of coffee was one-third the laboratory standard, eg, 100 mg caffeine compared with 300 mg for a 10-oz cup. Tea brewed more than 3 minutes contained 42 mg caffeine as compared with the standard of 94 mg. When the amount of caffeine actually consumed was measured, one-quarter (24.8%) of subjects traditionally classified as consuming 300+ gm caffeine daily were reclassified as consuming 150-299 mg.Misclassification of caffeine consumption increases difficulty in identifying health effects from caffeine. Some combination of more precise consumption data and a biomarker such as paraxanthine may more precisely estimate exposure.

This study estimates the effect of maternal caffeine consumption throughout pregnancy on fetal growth. We studied 2,714 women who delivered a liveborn infant between 1988 and 1991. Detailed information regarding coffee, tea, and soda drinking during the first and third trimesters of pregnancy was obtained. Average caffeine intake during month 1 of pregnancy was higher than for month 7 (72.4 vs 54.0 mg per day). Consumption of >300 mg caffeine per day during month 1 (adjusted odds ratio = 0.91; 95% confidence interval = 0.44-1.90) and during month 7 (adjusted odds ratio = 1.00; 95% confidence interval = 0.37-2.70) was not associated with intrauterine growth retardation. There was little evidence for any effect modification due to cigarette smoking on the caffeine associations. This study provides evidence that antenatal caffeine consumption has no adverse effect on fetal growth.

Background The pineal hormone melatonin (MLT) exerts a variety of effects on the immune system. MLT activates Th1 lymphocytes and monocytes; moreover MLT enhances the production of inflammatory cytokines, like IL-1, IL-6, IL-12 and TNFa, as well as nitric oxide production. Objectives Several symptoms of rheumatoid arthritis (RA), i.e. morning gelling, stiffness and swelling, are more evident in the early morning and might be related to the neuroimmunomodulatory effects exerted by MLT on synovitis. On the other hand, it is well known that MLT reaches its physiological serum peak level during the first hours of the morning. Methods Nocturnal MLT serum levels (8 pm, 12 pm, 2 am, 4 am, 6 am, 8 am o’clock) were evaluated in ten RA patients (pts) (mean age 57 ± 13 SD ys) and in six healthy controls (cnts) (mean age 50 ± 18 SD ys). RA pts were taking only nonsteroidal antiinflammatory drugs and the mean disease duration was 4 ± 2 SD ys. MLT assay was performed by RIA and statistical analysis was carry out by nonparametric tests. Results MLT serum levels at 8 pm and 8 am o’clock resulted higher in RA pts than in cnts (p 60 ys) when compared to the younger ones (age Conclusion The results of this study confirm the existence of a nocturnal rhythm of MLT also in RA pts, with the peak level in the early morning. However, RA pts showed higher mean MLT serum levels, that reached earlier the peak of concentration, and maintained the high levels for longer time when compared to cnts. The imbalance between cortisol serum levels (notably lower in RA pts) and MLT serum levels (higher in RA pts) might explain several clinical aspects related to the neuroimmunomodulatory effects on RA synovitis, such as morning gelling, stiffness and swelling.

The predominant theme of modern literature reviews and textbook chapters regarding intensive care medicine consists primarily of care as it is delivered in tertiary medical centers. High technology equipment is rapidly transforming the mode in which critical care is delivered, and patients can enjoy an increasingly favorable outcome and survival at the dawn of the new millennium.

Purpose To examine the association between IUGR and preterm delivery (PTD) and fetal caffeine exposure when estimated by serum caffeine and paraxanthine in umbilical cord. Methods Prospective cohort study conducted in Connecticut and Massachusetts specifically testing the relation of caffeine and its metabolites, measured in cord blood (ng/ml) to IUGR (N = 1606) and PTD (N = 1609). Important covariates were controlled for in logistic regression models. Ridge regression for generalized linear models was used to control for collinearity among metabolites. All metabolite analyses were done blind to consumption data and reproductive outcomes. Results We observed a 24% increase in risk for IUGR per paraxanthine quartile change (Ridge adjusted OR 1.24; 95% CI 1.10, 1.39), while caffeine was protective for IUGR: Ridge adjusted OR 0.87 (95% CI 0.78, 0.97) per quartile change. When the ratio of paraxanthine:caffeine was modeled, there was a 6-fold increase in risk for IUGR for every one-unit increase in the ratio (MLE adjusted OR 6.03; 95% CI 2.14, 17.03). There was an 18% increase in risk for preterm delivery per paraxanthine quartile change (Ridge adjusted OR 1.18; 95% CI 1.05, 1.33). Caffeine was not associated with PTD nor was the paraxanthine:caffeine ratio. Maternal self-reported caffeine consumption during the third trimester was not associated with either outcome. Conclusions Paraxanthine, rather than caffeine, may increase risk for IUGR and PTD. These findings may explain the equivocal literature evaluating reported consumption only. More research to replicate and extend these findings which have relevance to other health outcomes is warranted.

Pulmonary embolism (PE) is a frequent event, especially in certain patient groups, and carries a high mortality rate in affected individuals (1). It has been estimated that early diagnosis and start of an adequate therapeutic regimen is responsible for a 50% reduction of immediate mortality (2). Acute PE, untreated, causes approximately 30% mortality, of which about one third of deaths occurring within the first hour. Immediate death is essentially due to massive embolism causing critical obstruction of the pulmonary arterial bed.