Fragment molecular orbital study of the cAMP-dependent protein kinase catalyzed phosphoryl transfer: a comparison with the differential transition state stabilization method.

The importance of key residues to the activity of the cAMP-dependent protein kinase catalyzed phosphoryl transfer and to the stabilization of the transition state of the reaction has been investigated by means of the fragment molecular orbital (FMO) method. To evaluate the accuracy of the method and its capability of fragmenting covalent bonds, we have compared stabilization energies due to the interactions between individual residues and the reaction center to results obtained with the differential transition state stabilization method (Szarek, et al., J. Phys. Chem. B, 2008, 112, 11819-11826) and observe, despite a size difference in the fragment describing the reaction center, near-quantitative agreement. We have also computed deletion energies to investigate the effect of virtual deletion of key residues on the activation energy. These results are consistent with the stabilization energies and yield additional information as they clearly capture the effect of secondary interactions, i.e. interactions in the second coordination layer of the reaction center. We find that using FMO to calculate deletion energies is a powerful and time efficient approach to analyze the importance of key residues to the activity of an enzyme catalyzed reaction.

Reactivity at the Cu2O(100):Cu-H2O interface: a combined DFT and PES study.

The water-cuprite interface plays an important role in dictating surface related properties. This not only applies to the oxide, but also to metallic copper, which is covered by an oxide film under typical operational conditions. In order to extend the currently scarce knowledge of the details of the water-oxide interplay, water interactions and reactions on a common Cu2O(100):Cu surface have been studied using high-resolution photoelectron spectroscopy (PES) as well as Hubbard U and dispersion corrected density functional theory (PBE-D3+U) calculations up to a bilayer water coverage. The PBE-D3+U results are compared with PBE, PBE-D3 and hybrid HSE06-D3 calculation results. Both computational and experimental results support a thermodynamically favored, and H2O coverage independent, surface OH coverage of 0.25-0.5 ML, which is larger than the previously reported value. The computations indicate that the results are consistent also for ambient temperatures under wet/humid and oxygen lean conditions. In addition, both DFT and PES results indicate that the initial (3,0;1,1) surface reconstruction is lifted upon water adsorption to form an unreconstructed (1 × 1) Cu2O(100) structure.

External validation of the Norwegian survival prediction model in trauma after major trauma in Southern Finland.

BACKGROUND: The Norwegian Survival Prediction Model in Trauma (NORMIT) is a newly developed outcome prediction model for patients with trauma. We aimed to compare the novel NORMIT to the more commonly used Trauma and Injury Severity Score (TRISS) in Finnish trauma patients. METHODS: We performed a retrospective open-cohort study, using the trauma registry of Helsinki university hospital's trauma unit, including severely injured patients (new injury severity score > 15) admitted from 2007 to 2011. We used 30-day in-hospital mortality as the primary outcome, and discharge functional outcome as a secondary outcome of interest. Model performance was evaluated by comparing discrimination (by area under the receiver operating characteristic curve [AUC]), using a re-sample bootstrap technique, and by assessing calibration (GiViTI belt). RESULTS: We identified 1111 patients fulfilling the study inclusion criteria. Overall mortality was 13% (n = 147). NORMIT showed slightly better discrimination for mortality prediction (AUC = 0.83, 95% confidence interval [CI] = 0.80-0.86 vs. AUC = 0.79, 95% CI = 0.75-0.83, P = 0.004) and functional outcome prediction (AUC = 0.78, 95% CI = 0.76-0.82 vs. AUC = 0.75, 95% CI = 0.72-0.78, P < 0.001) than TRISS. Calibration testing revealed poor calibration for both NORMIT and TRISS (P < 0.001), by giving too pessimistic predictions (predicted survival significantly lower than actual survival). CONCLUSION: NORMIT and TRISS showed good discrimination, but poor calibration, in this mixed cohort of severely injured trauma patients from Southern Finland. We found NORMIT to be a feasible alternative to TRISS for trauma patient outcome prediction, but trauma prediction models with improved calibration are needed.

Trauma-registry survival outcome follow up: 30 days is mandatory and appears sufficient.

INTRODUCTION: Thirty-day in-hospital mortality is a common outcome measure in trauma-registry research and benchmarking. However, this does not include deaths after hospital discharge before 30 days or late deaths beyond 30 days since the injury. To evaluate the reliability of this outcome measure, we assessed the timing and causes of death during the first year after major blunt trauma in patients treated at a single tertiary trauma center. METHODS: We used the Helsinki Trauma Registry to identify severely injured (NISS ≥ 16) blunt trauma patients during 2006 to 2015. The Population Register center of Finland provided the mortality data for patients and Statistics Finland provided the cause of death information from death certificates. Disease, work-related disease, medical treatment, and unknown cause of death were considered as non-trauma related deaths. We divided the 1-year study period into the following three categories: in-hospital death before 30 days (Group 1), death after discharge but within 30 days (Group 2), and death 31 to 365 days since admission (Group 3). RESULTS: We included 3557 patients with a median NISS of 29. Altogether, 21.8% (776/3557) patients died during the first year since the injury. Of these non-survivors, 12.7% (450) were in Group 1, 4.0% (141) in Group 2, and 5.2% (185) in Group 3. Non-traumatic deaths not directly related to the injury increased substantially as the time from the injury increased and were 2.0% (9/450) in Group 1, 13.5% (19/141) in Group 2, and 35.7% (66/185) in Group 3. CONCLUSION: Thirty-day mortality is a proper outcome that measures survival after severe blunt trauma. However, applying only in-hospital mortality instead of actual 30-day mortality may exclude non-survivors who die at another facility before day 30. This could result in over-optimistic benchmarking results. On the other hand, extending the follow-up period beyond 30 days increases the rate of non-traumatic deaths. By combining data from different registries, it is possible to address this challenge in current trauma-registry research caused by lack of follow up.

How to Validate Data Quality in a Trauma Registry? The Helsinki Trauma Registry Internal Audit.

BACKGROUND AND AIMS: Trauma registry data are used for analyzing and improving patient care, comparison of different units, and for research and administrative purposes. Data should therefore be reliable. The aim of this study was to audit the quality of the Helsinki Trauma Registry internally. We describe how to conduct a validation of a regional or national trauma registry and how to report the results in a readily comprehensible form. MATERIALS AND METHODS: Trauma registry database of Helsinki Trauma Registry from year 2013 was re-evaluated. We assessed data quality in three different parts of the data input process: the process of including patients in the trauma registry (case completeness); the process of calculating Abbreviated Injury Scale (AIS) codes; and entering the patient variables in the trauma registry (data completeness, accuracy, and correctness). We calculated the case completeness results using raw agreement percentage and Cohen's κ value. Percentage and descriptive methods were used for the remaining calculations. RESULTS: In total, 862 patients were evaluated; 853 were rated the same in the audit process resulting in a raw agreement percentage of 99%. Nine cases were missing from the registry, yielding a case completeness of 97.1% for the Helsinki Trauma Registry. For AIS code data, we analyzed 107 patients with severe thorax injury with 941 AIS codes. Completeness of codes was 99.0% (932/941), accuracy was 90.0% (841/932), and correctness was 97.5% (909/932). The data completeness of patient variables was 93.4% (3899/4174). Data completeness was 100% for 16 of 32 categories. Data accuracy was 94.6% (3690/3899) and data correctness was 97.2% (3789/3899). CONCLUSION: The case completeness, data completeness, data accuracy, and data correctness of the Helsinki Trauma Registry are excellent. We recommend that these should be the variables included in a trauma registry validation process, and that the quality of trauma registry data should be systematically and regularly reviewed and reported.

Blunt Abdominal Trauma in a European Trauma Setting: Need for Complex or Non-Complex Skills in Emergency Laparotomy.

BACKGROUND AND AIMS: Blunt abdominal trauma can lead to substantial organ injury and hemorrhage necessitating open abdominal surgery. Currently, the trend in surgeon training is shifting away from general surgery and the surgical treatment of blunt abdominal trauma patients is often done by sub-specialized surgeons. The aim of this study was to identify what emergency procedures are needed after blunt abdominal trauma and whether they can be performed with the skill set of a general surgeon. MATERIALS AND METHODS: The records of blunt abdominal trauma patients requiring emergency laparotomy (n = 100) over the period 2006-2016 (Helsinki University Hospital Trauma Registry) were reviewed. The organ injuries and the complexity of the procedures were evaluated. RESULTS: A total of 89 patients (no need for complex skills, NCS) were treated with the skill set of general surgeons while 11 patients required complex skills. Complex skills patients were more severely injured (New Injury Severity Score 56.4 vs 35.9, p < 0.001) and had a lower systolic blood pressure (mean: 89 vs 112, p = 0.044) and higher mean shock index (heart rate/systolic blood pressure: 1.43 vs 0.95, p = 0.012) on admission compared with NCS patients. The top three NCS procedures were splenectomy (n = 33), bowel repair (n = 31), and urinary bladder repair (n = 16). In patients requiring a complex procedure (CS), the bleeding site was the liver (n = 7) or a major blood vessel (n = 4). CONCLUSION: The majority of patients requiring emergency laparotomy can be managed with the skills of a general surgeon. Non-responder blunt abdominal trauma patients with positive ultrasound are highly likely to require complex skills. The future training of surgeons should concentrate on NCS procedures while at the same time recognizing those injuries requiring complex skills.

Accuracy and Coverage of Diagnosis and Procedural Coding of Severely Injured Patients in the Finnish Hospital Discharge Register: Comparison to Patient Files and the Helsinki Trauma Registry.

BACKGROUND AND AIMS: The Finnish Hospital Discharge Register data are frequently used for research purposes. The Finnish Hospital Discharge Register has shown excellent validity in single injuries or disease groups, but no studies have assessed patients with multiple trauma diagnoses. We aimed to evaluate the accuracy and coverage of the Finnish Hospital Discharge Register but at the same time validate the data of the trauma registry of the Helsinki University Hospital's Trauma Unit. MATERIALS AND METHODS: We assessed the accuracy and coverage of the Finnish Hospital Discharge Register data by comparing them to the original patient files and trauma registry files from the trauma registry of the Helsinki University Hospital's Trauma Unit. We identified a baseline cohort of patients with severe thorax injury from the trauma registry of the Helsinki University Hospital's Trauma Unit of 2013 (sample of 107 patients). We hypothesized that the Finnish Hospital Discharge Register would lack valuable information about these patients. RESULTS: Using patient files, we identified 965 trauma diagnoses in these 107 patients. From the Finnish Hospital Discharge Register, we identified 632 (65.5%) diagnoses and from the trauma registry of the Helsinki University Hospital's Trauma Unit, 924 (95.8%) diagnoses. A total of 170 (17.6%) trauma diagnoses were missing from the Finnish Hospital Discharge Register data and 41 (4.2%) from the trauma registry of the Helsinki University Hospital's Trauma Unit data. The coverage and accuracy of diagnoses in the Finnish Hospital Discharge Register were 65.5% (95% confidence interval: 62.5%-68.5%) and 73.8% (95% confidence interval: 70.4%-77.2%), respectively, and for the trauma registry of the Helsinki University Hospital's Trauma Unit, 95.8% (95% confidence interval: 94.5%-97.0%) and 97.6% (95% confidence interval: 96.7%-98.6%), respectively. According to patient records, these patients were subjects in 249 operations. We identified 40 (16.1%) missing operation codes from the Finnish Hospital Discharge Register and 19 (7.6%) from the trauma registry of the Helsinki University Hospital's Trauma Unit. CONCLUSION: The validity of the Finnish Hospital Discharge Register data is unsatisfactory in terms of the accuracy and coverage of diagnoses in patients with multiple trauma diagnoses. Procedural codes provide greater accuracy. We found the coverage and accuracy of the trauma registry of the Helsinki University Hospital's Trauma Unit to be excellent. Therefore, a special trauma registry, such as the trauma registry of the Helsinki University Hospital's Trauma Unit, provides much more accurate data and should be the preferred registry when extracting data for research or for administrative use, such as resource prioritizing.

The Effect of Evolving Fluid Resuscitation on the Outcome of Severely Injured Patients: An 8-year Experience at a Tertiary Trauma Center.

BACKGROUND AND AIMS: Fluid resuscitation of severely injured patients has shifted over the last decade toward less crystalloids and more blood products. Helsinki University trauma center implemented the massive transfusion protocol in the end of 2009. The aim of the study was to review the changes in fluid resuscitation and its influence on outcome of severely injured patients with hemodynamic compromise treated at the single tertiary trauma center. MATERIAL AND METHODS: Data on severely injured patients (New Injury Severity Score > 15) from Helsinki University Hospital trauma center's trauma registry was reviewed over 2006-2013. The isolated head-injury patients, patients without hemodynamic compromise on admission (systolic blood pressure > 90 or base excess > -5.0), and those transferred in from another hospital were excluded. The primary outcome measure was 30-day in-hospital mortality. The study period was divided into three phases: 2006-2008 (pre-protocol, 146 patients), 2009-2010 (the implementation of massive transfusion protocol, 85 patients), and 2011-2013 (post massive transfusion protocol, 121 patients). Expected mortality was calculated using the Revised Injury Severity Classification score II. The Standardized Mortality Ratio, as well as the amounts of crystalloids, colloids, and blood products (red blood cells, fresh frozen plasma, platelets) administered prehospital and in the emergency room were compared. RESULTS: Of the 354 patients that were included, Standardized Mortality Ratio values decreased (indicating better survival) during the study period from 0.97 (pre-protocol), 0.87 (the implementation of massive transfusion protocol), to 0.79 (post massive transfusion protocol). The amount of crystalloids used in the emergency room decreased from 3870 mL (pre-protocol), 2390 mL (the implementation of massive transfusion protocol), to 2340 mL (post massive transfusion protocol). In these patients, the blood products' (red blood cells, fresh frozen plasma, and platelets together) relation to crystalloids increased from 0.36, 0.70, to 0.74, respectively, in three phases. CONCLUSION: During the study period, no other major changes in the protocols on treatment of severely injured patients were implemented. The overall awareness of damage control fluid resuscitation and introduction of massive transfusion protocol in a trauma center has a significant positive effect on the outcome of severely injured patients.

Unconscious trauma patients: outcome differences between southern Finland and Germany-lesson learned from trauma-registry comparisons.

PURPOSE: International trauma registry comparisons are scarce and lack standardised methodology. Recently, we performed a 6-year comparison between southern Finland and Germany. Because an outcome difference emerged in the subgroup of unconscious trauma patients, we aimed to identify factors associated with such difference and to further explore the role of trauma registries for evaluating trauma-care quality. METHODS: Unconscious patients [Glasgow Coma Scale (GCS) 3-8] with severe blunt trauma [Injury Severity Score (ISS) ≥16] from Helsinki University Hospital's trauma registry (TR-THEL) and the German Trauma Registry (TR-DGU) were compared from 2006 to 2011. The primary outcome measure was 30-day in-hospital mortality. Expected mortality was calculated by Revised Injury Severity Classification (RISC) score. Patients were separated into clinically relevant subgroups, for which the standardised mortality ratios (SMR) were calculated and compared between the two trauma registries in order to identify patient groups explaining outcome differences. RESULTS: Of the 5243 patients from the TR-DGU and 398 from the TR-THEL included, nine subgroups were identified and analyzed separately. Poorer outcome appeared in the Finnish patients with penetrating head injury, and in Finnish patients under 60 years with isolated head injury [TR-DGU SMR = 1.06 (95 % CI = 0.94-1.18) vs. TR-THEL SMR = 2.35 (95 % CI = 1.20-3.50), p = 0.001 and TR-DGU SMR = 1.01 (95 % CI = 0.87-1.16) vs. TR-THEL SMR = 1.40 (95 % CI = 0.99-1.81), p = 0.030]. A closer analysis of these subgroups in the TR-THEL revealed early treatment limitations due to their very poor prognosis, which was not accounted for by the RISC. CONCLUSION: Trauma registry comparison has several pitfalls needing acknowledgement: the explanation for outcome differences between trauma systems can be a coincidence, a weakness in the scoring system, true variation in the standard of care, or hospitals' reluctance to include patients with hopeless prognosis in registry. We believe, however, that such comparisons are a feasible method for quality control.

Trauma registry comparison: six-year results in trauma care in Southern Finland and Germany.

PURPOSE: To compare the treatment and survival of trauma patients in Germany and Southern Finland. METHODS: Data from Helsinki University Hospital trauma registry (TR-THEL) and TraumaRegister DGU(®) (TR-DGU) were compared in a period from 2006 until 2011. From TR-DGU level-one trauma centers treating annually >50 injury severity score (ISS) >15 patients were included. The inclusion criterion was ISS >15. Patients under 16 years with penetrating trauma without head injury and transferred in with isolated head injury were excluded. The compared parameters were age, sex, pre-injury ASA, injury scoring, injury pattern, mechanism of injury, injury distribution, pre-hospital timings, transportation method, pre-hospital intubation, treatment at hospital, discharge destination, and 30-day hospital mortality. Expected mortality was defined with the Revised Injury Severity Classification score (RISC). RESULTS: Eighty-five German level-one trauma centers were included. A total of 15,306 and 1,274 patients were included in the outcome analysis from TR-DGU and TR-THEL, respectively. The difference between the observed and expected mortality of all patients was -4.1% (standardized mortality ratio [SMR] 0.82) at German hospitals and -4.0% (SMR 0.79) in Helsinki. Differences in the pre- and in-hospital treatment between the two countries were noted (transportation method, intubation rate, intensive care unit treatment, ventilation time, length of stay). CONCLUSION: The overall outcome results of the Helsinki University Hospital trauma unit were similar to those of the German level-one trauma centers. Registry comparison is a feasible method of quality control in a trauma centre.

Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study.

We included 43 patients with migraine without aura in a triple-blind, placebo- and dose-controlled, crossover study of the prophylactic effect of slow-release sodium valproate; 34 patients completed the trial. The number of days with migraine was 3.5 per 4 weeks during treatment with sodium valproate and 6.1 during placebo (p = 0.002). The severity and duration of the migraine attacks that did occur were not affected by sodium valproate when compared with placebo. Fifty percent of the patients were responders, ie, their initial migraine frequency was reduced to 50% or less during sodium valproate as compared with 18% during placebo. The number of responders increased during the trial to 65% in the last 4 weeks of the active treatment period. There were no serious side effects requiring withdrawal of patients from the study. We conclude that sodium valproate is an effective and well-tolerated prophylactic medication for migraine without aura.

[Treatment of anorexia nervosa]. / Behandling af anorexia nervosa.

Anorexia nervosa is a common disorder, that is becoming an increasing burden on health care institutions. It has complicated biological and psychological symptoms that reinforce each another. The treatment is of long duration and is often difficult. Patients are ambivalent about treatment and the treating doctor must actively motivate them to continue treatment. An important part of the treatment is the re-establishment of normal body weight. Uncomplicated cases should be treated by the general practitioner.

A theoretical study of the uncatalyzed and BF3-assisted Baeyer-Villiger reactions.

The mechanisms for the uncatalyzed and boron trifluoride (BF3) assisted Baeyer-Villiger reactions between acetone and hydrogen peroxide have been investigated using high level ab initio [MP2 and CCSD(T)] and density functional theory (B3LYP) methods. Both steps in the uncatalyzed reaction are found to have very high transition state energies. It is clear that detectable amounts of the Crieege intermediate or the products cannot be formed without the aid of a catalyst. The main function of BF3 in both the addition step and the rearrangement (migration) step is to facilitate proton transfer. In the addition step the complexation of hydrogen peroxide with BF3 leads to an increased acidity of the attacking OH group, while in the rearrangement step BF3 takes active part in the proton-transfer process. This latter step is found to be rate determining with an activation free energy of 17.7 kcal/mol in organic solution. The products of the reaction are BF2OH, hydrogen fluoride, and methyl acetate. Thus, BF3 is not directly regenerated from the reaction.

Headache resembling tension-type headache as the single manifestation of Lyme neuroborreliosis.

We present two patients with monosymptomatic headache resembling chronic tension-type headache as the first manifestation of Lyme neuroborreliosis. The headache developed over a few days in both cases and lasted for three months in the first case and for two and a half years in the second case before the diagnosis of Lyme neuroborreliosis was made. Neuroimaging and many laboratory investigations did not lead to the diagnosis, which was only established after lumbar puncture. The CSF in both cases showed high protein, lymphocytic pleocytosis and Borrelia burgdorferi-specific intrathecal antibody synthesis. The headache disappeared completely after treatment with penicillin G. In patients suffering from daily headaches which have developed subacutely, Lyme neuroborreliosis should be considered even in the absence of signs of meningeal irritation. A lumbar puncture should be performed more often than is presently customary and the CSF should be examined for pleocytosis as well as Borrelia burgdorferi-specific intrathecal antibody synthesis.

The use of the electrostatic potential at the molecular surface in recognition interactions: dibenzo-p-dioxins and related systems.

An ab initio self-consistent-field molecular orbital approach was used to compute the electrostatic potentials of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), two analogues of the latter, and two isomeric benzoflavones on a three-dimensional molecular surface corresponding to the contour of constant electronic density equal to 0.002 electrons/bohr3. The results are discussed in relation to the biological activities of the respective molecules. It is shown that the electrostatic potential graphically depicted on the molecular surface is well suited for the study of recognition interactions, such as are believed to be involved in the initial receptor-mediated step leading to toxicity in the dibenzo-p-dioxins. The surface potential has the advantage of clearly showing steric features that may play a role in understanding the recognition process being investigated.

Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers.

The sensitivity to nitroglycerin-induced dilatation of large intracranial arteries was studied in 17 patients with migraine without aura, 17 age and sex-matched healthy subjects and 9 patients with episodic tension-type headache. Nitroglycerin in the doses of 0.015, 0.03, 0.25 microgram/kg/min was successively infused for 15 min per dose. Blood velocity (Vmean) in the middle cerebral artery (MCA) was recorded with transcranial Doppler before and at the end of every infusion period, and 30 and 60 min after end of the last infusion. In all three groups Vmean decreased with increasing doses (p < 0.001). The response was more pronounced in migraine patients at the two higher doses (p < 0.05). Since nitroglycerin acts as an exogenous source of nitric oxide (NO), these data support that NO supersensitivity may be an important molecular mechanism of migraine pain.