Evaluating the performance of the Charlson Comorbidity Index (CCI) in fracture risk prediction and developing a new Charlson Fracture Index (CFI): a register-based cohort study.

The Charlson Comorbidity Index (CCI) may be applicable for predicting fracture risk since several diagnoses from the index are predictors of fracture. Main results were that the CCI was updated to predict risk of hip fracture with fair precision and that the index could be useful in detecting high-risk individuals. PURPOSE: Several of the Charlson Comorbidity Index (CCI) diagnoses are validated predictors of fracture. The purpose of this study was to evaluate the performance of the CCI 1987 by Charlson et al. and of the CCI 2011 by Quan et al. in predicting major osteoporotic fracture (MOF) and hip fracture (HF). Furthermore, it was examined whether the index could be modified to improve fracture risk prediction. METHODS: The study population included the entire Danish population aged 45 + years as per January 1, 2018. The cohort was split randomly 50/50 into a development and a validation cohort. CCI diagnoses and fracture outcomes were identified from hospital diagnoses. The weighting of diagnoses was updated in a new Charlson Fracture Index (CFI) using multivariable logistic regression. Predictive capabilities of the CCI 1987, the updated CCI 2011 and the new Charlson Fracture index were evaluated in the validation cohort by receiver operating characteristics (ROC) curves and area under the curve (AUC). RESULTS: In the validation cohort, the 1987 and 2011 CCIs resulted in AUCs below or around 0.7 in prediction of MOF and HF in both sexes. The CFI resulted in AUCs < 0.7 in prediction of MOF in both sexes. In prediction of HF, the CFI resulted in AUC of 0.755 (95% CI 0.749; 0.761) in women and 0.782 (95% CI 0.772; 0.793) in men. CONCLUSION: The 1987 and 2011 CCIs showed overall poor accuracy in fracture risk prediction. The CFI showed fair accuracy in prediction of HF in women and in men.

A randomized trial of automated intermittent ropivacaine administration vs. continuous infusion in an interscalene catheter.

BACKGROUND: Ultrasound-guided interscalene nerve block with ropivacaine as local anesthetic agent given as boluses or continuous infusion is the preferred pain management after major shoulder surgery. The use of automated intermittent boluses has been shown to be superior to continuous infusion in sciatic and epidural nerve block. HYPOTHESIS: Automated intermittent boluses reduce pain after major shoulder surgery. METHODS: Seventy patients aged 18-75 years, scheduled for major shoulder surgery under general anesthesia with interscalene nerve block were included in this randomized controlled trial. Patients were allocated to either automated intermittent boluses with 16 mg ropivacaine every 2 h combined with patient-controlled administration or to a conventional regimen of continuous infusion of 8 mg/h (4 ml/h) of ropivacaine combined with patient controlled administration (2 ml, lockout time 30 min). Pain (Visual Analog Scale, VAS) was assessed every 8 h postoperatively. RESULTS: Fifty-seven patients completed the study, 29 in the continuous infusion group and 28 in the automated intermittent bolus group. Shoulder arthroplasty was performed in 49 (86%) of the cases. There were no significant differences in VAS score from 8 to 48 h post-operatively. No significant difference in opioid usage was observed. The automated intermittent bolus group reported significantly less force on coughing and more hoarseness. A significantly lower volume of ropivacaine was used in the automated intermittent bolus group. CONCLUSION: Automated intermittent boluses did not reduce pain or rescue opioid consumption compared with continuous infusion of ropivacaine. The automated intermittent bolus group had significantly less force on coughing and more hoarseness.

Protocol for a randomized controlled trial examining multilevel prediction of response to behavioral activation and exposure-based therapy for generalized anxiety disorder.

BACKGROUND: Only 40-60% of patients with generalized anxiety disorder experience long-lasting improvement with gold standard psychosocial interventions. Identifying neurobehavioral factors that predict treatment success might provide specific targets for more individualized interventions, fostering more optimal outcomes and bringing us closer to the goal of "personalized medicine." Research suggests that reward and threat processing (approach/avoidance behavior) and cognitive control may be important for understanding anxiety and comorbid depressive disorders and may have relevance to treatment outcomes. This study was designed to determine whether approach-avoidance behaviors and associated neural responses moderate treatment response to exposure-based versus behavioral activation therapy for generalized anxiety disorder. METHODS/DESIGN: We are conducting a randomized controlled trial involving two 10-week group-based interventions: exposure-based therapy or behavioral activation therapy. These interventions focus on specific and unique aspects of threat and reward processing, respectively. Prior to and after treatment, participants are interviewed and undergo behavioral, biomarker, and neuroimaging assessments, with a focus on approach and avoidance processing and decision-making. Primary analyses will use mixed models to examine whether hypothesized approach, avoidance, and conflict arbitration behaviors and associated neural responses at baseline moderate symptom change with treatment, as assessed using the Generalized Anxiety Disorder-7 item scale. Exploratory analyses will examine additional potential treatment moderators and use data reduction and machine learning methods. DISCUSSION: This protocol provides a framework for how studies may be designed to move the field toward neuroscience-informed and personalized psychosocial treatments. The results of this trial will have implications for approach-avoidance processing in generalized anxiety disorder, relationships between levels of analysis (i.e., behavioral, neural), and predictors of behavioral therapy outcome. TRIAL REGISTRATION: The study was retrospectively registered within 21 days of first participant enrollment in accordance with FDAAA 801 with ClinicalTrials.gov, NCT02807480. Registered on June 21, 2016, before results.

Thymidine kinase diversity in bacteria.

Thymidine kinases (TKs) appear to be almost ubiquitous and are found in nearly all prokaryotes, eukaryotes, and several viruses. They are the key enzymes in thymidine salvage and activation of several anti-cancer and antiviral drugs. We show that bacterial TKs can be subdivided into 2 groups. The TKs from Gram-positive bacteria are more closely related to the eukaryotic TK1 enzymes than are TKs from Gram-negative bacteria.

Thymidine kinases in archaea.

Twenty-six fully sequenced archaeal genomes were searched for genes coding for putative deoxyribonucleoside kinases (dNKs). We identified only 5 human-like thymidine kinase 1 genes (TK1s) and none for non-TK1 kinases. Four TK1s were identified in the Euryarchaea and one was found in the Crenarchaea, while none was found in Nanoarchaeum. The identified TK1s have high identity to Gram-positive bacteria TK1s. The TK1s from archaea, Gram-positive bacteria and eukaryotes share the same common ancestor, while the TK1s from Gram-negative bacteria belong to a less-related subgroup. It seems that a functional deoxyribonucleoside salvage pathway is not crucial for the archaeal cell.

Comparison of the acute hemodynamic response to intravenous nisoldipine (Bay k 5552) and intravenous nifedipine for left ventricular dysfunction secondary to myocardial infarction.

Dihydropyridine calcium blocking drugs exert potentially dangerous negative inotropic action in selected patients with severe left ventricular dysfunction. In 10 patients peripheral and central hemodynamic effects of nisoldipine were intraindividually compared with nifedipine using a sequential crossover protocol. The drugs were titrated to a similar steady-state reduction of mean arterial pressure by 15 +/- 3% and 15 +/- 2% and systemic vascular resistance by 25 +/- 5% and 17 +/- 2%, respectively. The equi-effective dosage was 0.17 +/- 0.06 microgram/min/kg for nisoldipine and 0.58 +/- 0.1 microgram/min/kg for nifedipine. In contrast to nifedipine, administration of nisoldipine was associated with increases in cardiac index of 0.45 +/- 0.33 liters/min/m2 (p less than 0.05), stroke volume index of 3.91 +/- 3.0 ml/m2 (p less than 0.05) and left ventricular ejection fraction of 4.6 +/- 2.8% (p less than 0.05). Mean pulmonary capillary wedge pressure decreased with nisoldipine from 11.8 +/- 3.4 to 8.0 +/- 3.4 mm Hg (p less than 0.005) and mean pulmonary arterial pressure from 20.4 +/- 4.06 to 16.1 +/- 3.2 mm Hg (p less than 0.005); these variables were unaffected by nifedipine. Thus, intraindividual comparison revealed no cardiodepressive action of nisoldipine, whereas with nifedipine the conceptually beneficial effect of afterload reduction appears to be offset by intrinsic negative inotropic action. Due to higher vasospecificity and more effective unloading, nisoldipine appears to be superior to nifedipine in patients with left ventricular dysfunction secondary to ischemic heart disease.

Direct compressible polymethacrylic acid-starch compositions for site-specific drug delivery.

The purpose of this study was to generate and characterize a direct compressible pH-sensitive excipient composition for controlled drug delivery. In acidic aqueous solutions, polymethacrylic acid (PMAA) forms complexes and precipitates with starch. As the extent of the interaction between PMAA and starch reaches a maximum at a weight ratio of 1:1.38 (PMAA/starch), this composition was used for the direct compression of tablets. These tablets (30 mg) showed no disintegration even after 2 days in a disintegration test apparatus according to the USP XXIII, in simulated gastric fluid at pH 1.2. In contrast, in 100 mM phosphate buffer pH 7.0 they disintegrated within 40.25+/-8.42 min (mean+/-S.D., n=3). Control tablets of starch disintegrated within the first minute at both pH values. Dissolution studies with the model peptide peroxidase demonstrated no release within 120 min at pH 1.2, whereas at pH 7.0, 100% of the peptide was released within 330 min. Similar release profiles were obtained with the model drugs amoxicillin and rifampicin. In addition, the use of a PMAA-starch composition as a carrier matrix for peroxidase and amoxicillin provided a protective effect towards pepsin and hydrolytic degradation at pH 1.2, respectively. According to these results, the PMAA-starch composition may be a useful tool to overcome the very harsh environment of the stomach for future delivery systems.

Purification of monoclonal antibodies from cell culture supernatants using a modified zirconia based cation-exchange support.

A method suitable for the isolation of monoclonal antibodies (Mabs) is described. The protocol utilizes a zirconia based column modified with ethylenediamine-N,N'-tetra(methylenephosphonic) acid to create a novel cation-exchange chromatographic support. Initial experiments using a linear salt gradient demonstrate the ability of this support to efficiently separate Mab from transferrin and bovine serum albumin in a model matrix. Results of the purification of Mab from an actual cell culture supernatant over a range in protein concentrations are also shown. Analyses by enzyme-linked immunosorbent assay and gel electrophoresis demonstrate that Mabs can be recovered from a cell culture supernatant at high yield (92-98%) and high purity (> 95%) in a single chromatographic step.

Thiolated carboxymethylcellulose: in vitro evaluation of its permeation enhancing effect on peptide drugs.

The purpose of this study was to evaluate the effect of sodium carboxymethylcellulose (NaCMC) and carboxymethylcellulose-cysteine (CMC-Cys) conjugates on the intestinal permeation of sodium fluorescein (NaFlu) and model peptide drugs, bacitracin and insulin. Cysteine was covalently linked to carbodiimide activated NaCMC. Iodometric titration of the polymer conjugates was used to determine the extent of immobilised cysteine. Permeation studies were performed on guinea pig small intestinal mucosa mounted in Ussing-type chamber. Unmodified NaCMC (1% m/v) significantly improved the transport ratio (R= P(app) polymer/ P(app) control) of NaFlu to 1.3 and 1% (m/v) NaCMC conjugated with cysteine further enhanced the permeation. Cysteine conjugation at 3.6, 5.3 and 7.3% (m/m) resulted in R-values of 1.4, 1.7 and 1.8, respectively. Decreasing the concentration of CMC-Cys, exhibiting 7.3% (m/m) of immobilised cysteine (CMC-Cys7.3) from 1% (m/v) to 0.5% (m/v) decreased the R-value of NaFlu from 1.8 to 1.2. NaCMC at 1% (m/v) in the presence of free cysteine had no significant effect on the R-value of NaFlu compared to NaCMC alone. Formulation of fluorescence labelled bacitracin and insulin in unconjugated NaCMC (1% m/v) did not significantly improve the permeation, however in the presence of 1% (m/v) CMC-Cys7.3 a significantly improved permeation was observed (R= 1.3). Conjugation at NaCMC with cysteine moieties significantly improves the intestinal permeation of the hydrophilic molecule NaFlu and the model peptide drugs bacitracin and insulin in vitro, therefore this conjugated system maybe useful for peroral administration of peptide drugs in the future.

In vitro evaluation of the permeation-enhancing effect of thiolated polycarbophil.

The objective of this study was to investigate the permeation-enhancing effect of thiolated polycarbophil (PCP) on peptide drugs. Mediated by a carbodiimide, increasing amounts of cysteine (Cys) were covalently bound to sodium neutralized PCP (NaPCP). The extent of covalently attached Cys was determined by quantifying the share of thiol groups on the resulting polymer-Cys conjugates via iodometric titration. The permeation-enhancing effect of polymer-Cys conjugates was evaluated in Ussing-type chambers using intestinal mucosa from guinea pigs. Whereas the transport enhancement ratio (P(app) polymer/P(app) control) for 0.5% (m/v) NaPCP was 1.14 using sodium fluorescein as model drug, it was 1.63 for 0.5% (m/v) PCP-Cys displaying a share of 2.2% (m/m) Cys on the conjugate (PCP-Cys 2.2%). Moreover, the substitution of sodium fluorescein by bacitracin-fluorescein isothiocyanate (bacitracin-FITC) led to ratios of 1.03 and 1.36 and in the case of insulin-fluorescein isothiocyanate (insulin-FITC) to ratios of 1.07 and 1.33, respectively (means; n = 3). Additional permeation studies with 0.5% (m/v) PCP-Cys conjugates exhibiting a share of 1.8% up to 4.2% of cysteine showed enhancement ratios of 1.22 up to 1.47 for sodium fluorescein within 3 h. In contrast, the permeation-enhancing effect of PCP could not be improved by the addition of free unconjugated Cys. Because of their permeation-enhancing effect for the paracellular route of absorption, PCP-Cys conjugates probably represent a new tool for the peroral administration of peptide drugs.

Thiolated polymers: synthesis and in vitro evaluation of polymer-cysteamine conjugates.

The purpose of the present study was to synthesize and characterize novel thiolated polymers. Mediated by a carbodiimide cysteamine was covalently linked to sodium carboxymethylcellulose (CMC) and polycarbophil (PCP). The resulting CMC-cysteamine conjugates displayed 77.9+/-6.7 and 365.1+/-8.7 micromol thiol groups per gram of polymer, whereas the PCP-cysteamine conjugates showed 26.3+/-1.9 and 122.7+/-3.8 micromol thiol groups per gram of polymer (mean+/-S.D.; n=3). In aqueous solutions above pH 5.0 both modified polymers were capable of forming inter- and/or intra-molecular disulfide bonds. The reaction velocity of this oxidation process was accelerated with a decrease in the proton concentration. The oxidation proceeded more rapidly within thiolated CMC than within thiolated PCP. Permeation studies carried out in Ussing-type chambers with freshly excised intestinal mucosa from guinea pigs utilizing sodium fluorescein as model drug for the paracellular uptake revealed an enhancement ratio (R=P(app) (conjugate)/P(app) (control)) of 1.15 and 1.41 (mean+/-S.D.; n=3) for the higher thiolated CMC-cysteamine (0.5%; m/v) and PCP-cysteamine conjugate (1.0%; m/v), respectively. The decrease in the transepithelial electrical resistance values was in good correlation with the enhancement ratios. Due to a high crosslinking tendency by the formation of disulfide bonds stabilizing drug carrier systems based on thiolated polymers and a permeation enhancing effect, CMC- and PCP-cysteamine conjugates represent promising excipients for the development of novel drug delivery systems.

Hypertrophic cardiomyopathy: non-invasive assessment of diastolic and systolic functional parameters in relation to heart rate.

Hypertrophic cardiomyopathy (HC) is characterized by reduced left ventricular compliance and subsequent filling abnormalities. To study the pathophysiologic changes in parameters of left ventricular systolic and diastolic performance as a function of increasing heart rate 14 patients with HC (32 +/- 12 yrs; 11 M, 4 F) and 4 normal individuals were subjected to equilibrium radionuclide ventriculography (99mTc-labelled red blood cells) at rest and during incremental right atrial pacing; heart rate was increased in steps of 20 beats per min from basal state to the individual symptom-limited endpoint. Mean symptom-limited heart rate was 141 +/- 28 in HC and 160 in normals (p less than .01.). At each pacing level filling and ejection parameters as well as the left ventricular endsystolic (LVESV) and enddiastolic volume (LVEDV) were determined relative to resting volumes at a heart rate of 78 +/- 8. At the individual maximal pacing rate HC revealed a decline in LVEDV to 61 +/- 4% (p less than .001) and an increase in LVESV to 117 +/- 14% (p less than .001) resulting in decreasing ejection fractions at heart rates above 120. Peak LV filling rates initially increased but subsequently decreased steeply at heart rates above 100; peak LV ejection rates in HC showed a similar pattern with increasing frequency. Time intervals to peak ejection and peak filling rate did not differ from normal. Thus, patients with HC demonstrated combined left ventricular diastolic and systolic abnormalities with increasing heart rate leading into a low-input low-output circulatory state. This probably explains not only the symptoms associated with HC, but also supports the concept of "hemodynamic syncope" in HC.

[Fatal outcome with cerebral edema following abuse of anabolic steroids]. / Letalt forløb med cerebralt ødem efter misbrug af anabolske steroider.

The usual side effects of anabolic steroid abuse are thromboembolic, hepatic, cardiac, reproductive and psychiatric disorders. We report a case of lethal cerebral oedema associated with massive abuse of anabolic steroids in a previously healthy 21 year old man.

[Acute post-infectious Epstein-Barr encephalitis in a young man]. / Akut indsaettende postinfektiøs Epstein-Barr-encefalit hos en yngre mand.

The clinical features of infectious mononucleosis are variable. The course is often asymptomatic and/or atypical. Serious complications are rare. The prognosis is often good, even though there may have been serious neurological symptoms. However, as in the case history presented here, persistent sequelae may be seen.

Population growth and economic and social development.

PIP: This article sets forth 3 positions on population growth: 1) rapid population growth is a central development problem that implies lower living standards for the poor; 2) proposals for reducing population growth raise difficult questions about the proper domain of public policy, yet it is acceptable for governments to attempt to influence private decisions about family size; and 3) the experience in many developing countries shows that quick, effective measures can be taken to reduce fertility. Rapid population growth has slowed development because it exacerbates the difficult choice between higher consumption in the present and the investment needed to bring higher consumption in the future. As populations grow, larger investments are needed just to maintain current capital/person. It further threatens the balance between natural resources and people and creates severe economic and social problems in urban areas. Public policy must provide alternative ways for poor families to secure the benefits provided by large family size. That is, governments need to provide tangible evidence that it really is in the best interests of parents to have fewer children. Also required is greater infomation about and access to fertility control. When family planning services have been widespread and affordable, fertility has decline faster than social and economic progress alone would predict. There is a need for immediate action to improve women's status and to make education, family planning, and primary health care more available. Although economic and social progress help to slow population growth, rapid population growth hinders development. Thus, governments must act simultaneously on both fronts. Accumulating evidence on population growth in developing countries shows that is the combination of social development and family planning that reduces fertility.^ieng

[Implantation of the endo-exo femur prosthesis to improve the mobility of amputees]. / Implantation der Endo-Exo-Femurprothese zur Verbesserung der Mobilität amputierter Patienten.

OBJECTIVE: Improvement of function following above-knee amputation with an osseointegrated, transcutaneous femoral implant as a hard point for the exo prosthesis, the so-called endo-exo femur prosthesis (EEFP). INDICATIONS: Above knee amputation following trauma, tumor, or infection. CONTRAINDICATIONS: Diabetes, PAOD, psychiatric diseases, use of chemotherapeutic or corticosteroid medication, nonconcluded bone growth, lack of compliance, and florid infection at the time of implantation. SURGICAL TECHNIQUE: Performed as a two-step procedure: Stage 1 (implantation): sharp dissection of the end of the residual bone, adequate access to the intramedullar canal, cortical reaming using curettes and a flexible drill followed by cement-free, press-fit implantation of the endoprosthesis itself, closing of the soft tissue coat of the femur stump to reduce the risk of infection, assurance of primary and secondary stability via the metal spongiosa-like surface of the implant (Spongiosa Metal 2®). Stage 2 (exteriorization): 6 weeks postoperatively, opening of the skin at the distal point of the femur stump, the soft tissue between the skin and endoprosthesis is then removed and the double conus and the connecting adapter for the exoprothesis is attached. POSTOPERATIVE MANAGEMENT: Ascending weight bearing depending on bone quality. On average, full weight bearing can be achieved 8-10 weeks after stage 1 surgery. RESULTS: The first endo-exo femur prosthesis (EEFP) was implanted in 1999. Through December 2009, 39 cases were operated in Lübeck, early serosanguinous drainage, soft tissue problems at the stoma, and ascending infections after mobilization of the patients could be minimized by further development of the design of the EEFP. Intramedullary infections were the exception (1 of 39 patients). A total of 4 explantations had to be performed (3 due to infection and 1 due to prosthetic failure). Two of those patients were again provided with an EEFP. Overall, the EEFP improved the gait pattern because of the bone-guided transmission of muscle power, increased osseoperception, and improved economical energy balance. Of the 39 patients, 37 said that they would again undergo operation.

Pasteurella multocida thymidine kinase 1 efficiently activates pyrimidine nucleoside analogs.

In the Pasteurella multocida genome only one putative deoxyribonucleoside kinase encoding gene, for thymidine kinase 1 (PmTK1), was identified. The PmTK1 gene was sub-cloned into Escherichia coli KY895 and it sensitized the host towards 2',2'-difluoro-deoxycytidine (gemcitabine, dFdC), 3'-azido-thymidine (AZT) and 5-fluoro-deoxyuridine (5F-dU). PmTK1 was over-expressed and purified with two different tags. Apparently, deoxyuridine (dU), and not thymidine (dT), is the preferred substrate. We suggest that PmTK1s could be employed as a species-specific activator of uracil-based nucleoside antibiotics.

[The endo-exo femur prosthesis--a new concept of bone-guided, prosthetic rehabilitation following above-knee amputation]. / Die Endo-Exo-Femurprothese--ein neues Konzept zur knochengeführten, prothetischen Versorgung von oberschenkelamputierten Patienten.

AIM: The implantation of an intramedullary transcutaneously conducted femur prosthesis presents a rather new procedure for the rehabilitation of above-knee amputated patients. The aim of the so-called endo-exo prosthesis is to avoid the well-known problems at the interface between the sleeve of the prosthesis and the soft tissue coat of the femur stump which often impedes an inconspicuous and harmonic gait. METHOD: The company ERSKA Implants in Lübeck/Germany has developed an intramedullary femur prosthesis with a spongiosa metal-configurated relief surface which, when implanted cementless, enables a secure osseointegration and allows a more direct transmission of muscle power to the lower leg prosthesis. A minimum length of 16-18 cm and a sufficient soft tissue coverage of the femur stump is needed. The problems at the perforation point of the implant through the soft tissue coat can be handled or even be avoided and they do not necessarily provoke an intramedullary infection. RESULTS: We report on 30 cases that were operated between 1999 and 2008. The design of the prosthesis, aspects of the operative procedure and latest results are presented.

Chromatographic characterization of phosphonate analog EDTA-modified zirconia support for biochromatographic applications.

Zirconium dioxide (zirconia) has a great affinity for inorganic and organic phosphate. Previous work from this laboratory demonstrated the utility of phosphate-modified microparticulate zirconia as a support for protein separations. We have extended this investigation to include the study of ethylenediamine-N,N'-tetramethylphosphonic acid (EDTPA), a phosphonate analog of EDTA, as a surface modifier for zirconia. Our work explores the use of EDTPA-modified zirconia (PEZ) for its potential use as a high-performance inorganic cation-exchange support for the separation of proteins. The phosphate groups in EDTPA very effectively block the sites responsible for strong interactions of hard Lewis bases with zirconia's surface. Modification of zirconia with EDTPA provides a "biocompatible" stationary phase, resulting in high mass recoveries of proteins. We compare PEZ with inorganic phosphate-modified zirconia to show increased efficiency, as well as unique selectivities for chromatography of proteins on the chelator-modified surface. Finally, the selectivity, efficiency, and separation mechanism are reported. The studies show that PEZ is a useful high-performance ion-exchange support for the separation of cationic proteins and for modulating the sites responsible for the high affinity of zirconia toward certain classes of anions.