Latent factor regression models for grouped outcomes.

We consider regression models for multiple correlated outcomes, where the outcomes are nested in domains. We show that random effect models for this nested situation fit into a standard factor model framework, which leads us to view the modeling options as a spectrum between parsimonious random effect multiple outcomes models and more general continuous latent factor models. We introduce a set of identifiable models along this spectrum that extend an existing random effect model for multiple outcomes nested in domains. We characterize the tradeoffs between parsimony and flexibility in this set of models, applying them to both simulated data and data relating sexually dimorphic traits in male infants to explanatory variables.

Prehospital emergency physicians' experiences with advance directives in Germany: a questionnaire-based multicenter study.

BACKGROUND: Palliative medical emergencies and end-of-life decisions resulting from the exacerbation of cancer account for approximately 3% of all out-of-hospital emergency applications in Germany. Therefore, prehospital emergency physicians (EP) may be confronted with advance directives and ethical and end-of-life decisions. The purpose of the study was to identify EPs' knowledge about ethical and end-of-life decisions and their legal education and experiences concerning advance directives. METHODS: Over a six-month period, we questioned all 150 EPs from three emergency medical services (Braunschweig, Göttingen und Kaiserslautern). An anonymous, self-administered questionnaire with a mixed-methods design was used. The main outcome measures included responses regarding experiences related to advance directives and end-of-life decisions in palliative care patients. For statistical assessment, EPs were divided into three categories: competent, skilled, and unskilled. RESULTS: A total of 104 EPs returned the questionnaire (response rate 69%). Eighty-nine percent of the respondents treated patients who had advance directives. The existence of an advance directive influenced the EP's therapy decision in about 77% of their encounters. Eighty-seven percent of the EPs reported the need for defined end-of-life care pathways and/or standard operating procedures. Eighty-two percent desired educational training concerning end-of-life decisions and the validity of advance directives. CONCLUSION: The prehospital emergency treatment of palliative care patients can be particularly challenging for any EP. A high percentage of the EPs in our study felt insecure in dealing with advance directives and ethical and end-of-life decisions in palliative care patients. Our results suggest that EPs may need more information and education about palliative medical care, legal issues and ethical and end-of-life decisions to provide adequate patient-oriented palliative care in prehospital emergency situations.

[Emergency medical treatment of palliative care patients at the end of life: regulatory emergency medical care framework--a case control investigation of medical intervention and advance directives]. / Notfallmedizinische Betreuung von Palliativpatienten am Lebensende : Juristische Beurteilung notfallmedizinischer Handlungsweisen - retrospektive Fallbetrachtung zur medizinischen Indikation und zum Patientenwillen.

BACKGROUND: The treatment of out-of-hospital palliative emergency care situations during cardiac arrest is a special situation. The prehospital emergency physician (EP) and the paramedic must be informed about the medical, legal, and ethical specifics of these situations, but this knowledge is not integrated within emergency medical curricula at all. We present a case study to discuss such legal and ethical specifics. METHODS: We retrospectively analysed six emergency cases with palliative care patients in the final stages of their illnesses. On the basis of these case studies, we present six different emergency cases with different regulatory frameworks for each EP and paramedic. In accordance with the Declaration of Helsinki, data were collected pseudonymously. RESULTS: The six case studies show therapeutic concepts concerning the emergency medical care of palliative care patients during cardiac arrest. The differences are apparent in the treatment given by EPs and by paramedics (such as whether to start or stop resuscitation). EPs and paramedics differ in their therapeutic approach to these specific situations (e.g. paramedics more often start resuscitation during cardiac arrest even though patients would refuse this according to their advance directives). These differences may be important for the patient and his or her caregivers. CONCLUSIONS: Every EP and paramedic may be involved in the care of palliative care patients who are at the end of their lives. EPs and paramedics do not always adapt their treatment to the will or supposed will of the patient (especially in accordance with the new German law concerning advance directives). The reasons for this usually concern legal uncertainties. Therefore, EPs and paramedics should know that different legal meanings could be important in emergency medical care therapy of palliative care patients. A written "do not resuscitate" order as an advance directive must be evaluated as a desired therapeutic limitation.

Treatment of palliative care emergencies by prehospital emergency physicians in Germany: an interview based investigation.

Palliative care medical emergencies as a consequence of advanced cancer account for approximately 3% of all prehospital emergency cases. Therefore, prehospital emergency physicians (EP) are confronted with 'end of life decisions'. No educational content exists concerning palliative medicine in emergency medicine curricula. Over the course of 6 months, we interviewed 150 EPs about their experiences in 'end of life decisions' using a specific questionnaire. The total response rate was 69% (n = 104). Most of the interviewed EPs (89%, n = 93) had been confronted with palliative care medical emergencies and expressed uncertainties in dealing with these difficult situations, especially in the area of psychosocial care of the patients (50%). The emergency treatment of palliative care patients can become a particular challenge for any EP. A large percentage of interviewed EPs felt uncertain about aspects of social care and in the assessment of decisions at the end of life. Further information and training are necessary to amenable EPs to provide adequate patient-oriented care to palliative care patients and their relatives in emergency situations.

[Treatment of oncology patients in the final stadium of disease by prehospital emergency physicians]. / Notärztliche Betreuung von Tumorpatienten in der finalen Krankheitsphase.

BACKGROUND: Presently and even more in the near future more cancer patients will be treated at home especially in the final stage of their disease. For this reason the prehospital emergency system will be confronted with the specific needs of these patients. Palliative care is not part of the German model of post-graduate training regulations for emergency medicine and palliative care teams (PCT) are only involved in the treatment of cancer patients in emergency situations. METHODS: Over a 12-month period we retrospectively analysed all emergency cases that had been categorised as final cancer stage at 2 emergency sites (one air-based, the other ground-based) involving physicians in an out-of-hospital setting. We analysed all cases for indications of emergency call, prehospital treatment and involvement of a PCT in the treatment of symptoms. RESULTS: For this period we analysed 2,765 emergency documents and identified more than 2.5% as emergency calls by cancer patients or their relatives (the majority of patients had been in the final stage of the disease). Most emergency calls occurred at times when no general practitioner was on duty and acute dyspnoea (42.7%) was the prominent diagnosis. After emergency treatment 61.8% patients had been admitted to hospital. In most settings a PCT was not involved in the treatment of palliative care patients or their relatives (92.7%). CONCLUSIONS: Our data demonstrate that care of cancer patients in the final stage of the disease is relevant in emergency medicine. These patients are in need of help based on principles of palliative care. Under these circumstances cooperation of the medical disciplines (emergency and palliative medicine) concerned seems to be necessary. This may increase the possibility for patients to stay at home for the last days of their life. Because of this we are convinced that basic knowledge of palliative care should be integrated into the German model of post-graduate training regulations for emergency care. Combining parts of the curricula (palliative and emergency medicine) it would be possible for emergency physicians to guide their treatment by the ideas and strategies of palliative care. But we are also convinced that the system of PCT should increase and become more involved in prehospital care in emergency cases of palliative care patients.

Simple incorporation of interactions into additive models.

Often, the functional form of covariate effects in an additive model varies across groups defined by levels of a categorical variable. This structure represents a factor-by-curve interaction. This article presents penalized spline models that incorporate factor-by-curve interactions into additive models. A mixed model formulation for penalized splines allows for straightforward model fitting and smoothing parameter selection. We illustrate the proposed model by applying it to pollen ragweed data in which seasonal trends vary by year.

Kriging with nonparametric variance function estimation.

A method for fitting regression models to data that exhibit spatial correlation and heteroskedasticity is proposed. It is well known that ignoring a nonconstant variance does not bias least-squares estimates of regression parameters; thus, data analysts are easily lead to the false belief that moderate heteroskedasticity can generally be ignored. Unfortunately, ignoring nonconstant variance when fitting variograms can seriously bias estimated correlation functions. By modeling heteroskedasticity and standardizing by estimated standard deviations, our approach eliminates this bias in the correlations. A combination of parametric and nonparametric regression techniques is used to iteratively estimate the various components of the model. The approach is demonstrated on a large data set of predicted nitrogen runoff from agricultural lands in the Midwest and Northern Plains regions of the U.S.A. For this data set, the model comprises three main components: (1) the mean function, which includes farming practice variables, local soil and climate characteristics, and the nitrogen application treatment, is assumed to be linear in the parameters and is fitted by generalized least squares; (2) the variance function, which contains a local and a spatial component whose shapes are left unspecified, is estimated by local linear regression; and (3) the spatial correlation function is estimated by fitting a parametric variogram model to the standardized residuals, with the standardization adjusting the variogram for the presence of heteroskedasticity. The fitting of these three components is iterated until convergence. The model provides an improved fit to the data compared with a previous model that ignored the heteroskedasticity and the spatial correlation.

The bradykinin B2 receptor antagonist Icatibant (HOE 140) corrects avid Na+ retention in rats with CCl4-induced liver cirrhosis: possible role of enhanced microvascular leakage.

Avid Na+ retention is a hallmark of liver cirrhosis. The aim of this study was to investigate whether and how bradykinin is involved in Na+ retention in rats with CCl4-induced liver cirrhosis. To this end the bradykinin B2 receptor antagonist Icatibant (HOE 140) was used. On one hand, bradykinin has a renal natriuretic action. On the other hand, bradykinin is a potent mediator of both vasodilation and microvascular leakage. Both vascular mechanisms, which are reported for cirrhosis, could cause vascular underfilling and Na+ retention by activating the renin-angiotensin-aldosterone system. Icatibant normalised Na+ retention and reduced the hyperactivity of the renin-angiotensin-aldosterone system, suggesting a bradykinin-induced vascular disturbance. Icatibant had no significant effect on the mild hypotension which developed with CCl4 treatment. However, there was indirect evidence for enhanced microvascular leakage that was strongly inhibited by Icatibant. Our experimental results demonstrate that bradykinin is a key mediator of Na+ retention in liver cirrhosis and suggest that a bradykinin-induced increase in microvascular leakage is mainly responsible.

Serum levels of folate and cobalamin in women with recurrent spontaneous abortion.

We evaluated the folate and cobalamin status in 29 non-pregnant women with a history of recurrent spontaneous abortion (three or more consecutive) of unknown aetiology in comparison to 29 healthy nulligravidae of similar reproductive age (controls). Serum concentrations of folate and cobalamin showed no significant differences between the two groups. No correlation between age and vitamin concentrations was found. In the study group there was a significant negative correlation of the number of previous abortions and the concentration of serum folate. Patients with at least four previous miscarriages had significantly lower serum values of folic acid than women with three abortions, but not than controls. The underlying cause of this finding remains unclear. In conclusion, the serum concentrations of folic acid and vitamin B12 are not significantly altered in women with unexplained recurrent spontaneous abortions, and an association between a deficiency of these vitamins and an increased risk of pregnancy loss appears to be questionable in the majority of gestations.

ACE inhibition decreases postoperative mortality in rats with left ventricular hypertrophy and myocardial infarction.

UNLABELLED: In male Sprague Dawley rats with left ventricular hypertrophy (LVH) and hypertension induced by aortic constriction (AC) and subsequent myocardial infarction (MI) by occlusion of the left coronary artery the effects of ACE inhibition with ramipril (RA 1 mg/kg/day via the drinking water during 6 weeks) on survival as well as cardiac function and metabolism were investigated. Respective groups (sham AC; AC; AC + sham MI; normotensive animals with sham MI; MI; MI + RA) served as comparisons. Following MI hypertensive rats with AC and LVH revealed an increased postoperative mortality (68%) when compared to normotensives without AC (28%). ACE inhibition with ramipril significantly reduced mortality in hypertensive rats by 26%. Untreated hypertensive animals with LVH clearly showed reduced MI size (6.2 +/- 2.3%) in comparison with untreated normotensive animals and MI (31.0 +/- 3.3%). In hypertensive rats with MI which died during the study a significant increase in infarct size was found compared to those which survived MI. In normotensive animals ramipril reduced infarct size by 50%. Due to the quite small infarct size observed in hypertensive rats, ACE inhibition did not further reduce MI in these animals. LVH as well as hydroxyproline/proline ratio was diminished by ACE inhibitor treatment. In the isolated hearts of ramipril treated rats contractility was improved when compared to the respective untreated groups with MI. In the coronary effluent of isolated hearts from rats with AC and MI lactate dehydrogenase and creatine kinase activities as well as lactate levels were increased. Ramipril treatment starting one week before MI normalized these parameters and in addition increased prostacyclin output. Hearts with MI from treated normotensive animals contained increased energy rich phosphates when compared to hearts from untreated rats with MI. CONCLUSIONS: Hypertensive rats with LVH undergoing MI experience increased postoperative mortality probably due to a reduced tolerance to myocardial ischemia and occurrence of arrhythmias. In these animals ACE inhibition with ramipril increased survival. Both, increased survival in hypertensive and reduction in infarct size in normotensive rats by ACE inhibition with ramipril was accompanied by an improved myocardial metabolism.

[The computed tomographic morphology of Crohn's disease and ulcerative colitis]. / Computertomographische Morphologie von Morbus Crohn und Colitis ulcerosa.

PURPOSE: To assess the value of computed tomography for the diagnosis of Crohn's disease and ulcerative colitis. METHOD: We analysed the CT examinations of 109 patients with 197 involved bowel locations. 81 patients suffered from Crohn's disease, 28 from ulcerative colitis. Diagnosis was based on the combination of clinical, endoscopic and histopathologic findings. Three radiologists evaluated the CT series concerning the presence of morphologic changes analogous to conventional radiographic findings. RESULTS: In Crohn's disease, we found irregular outer contours in 26% of cases. The bowel wall was thickened in 82%. In acute phases, the bowel wall was thickened in 100%. Abscess and fistula as complications of inflammatory disease were present in 26 and 14% respectively. In ulcerative colitis, a target sign of the bowel wall was present in 40%, whereas in Crohn's disease a homogeneous wall density was present in all but two cases. Reduced attenuation due to submucosal fat deposits was found in 16% and mucosal tunneling in 27% of cases with ulcerative colitis. Even if severe mucosal destructions were found, the outer contour of the gut was smooth and regular in 95% of the ulcerative colitis cases. CONCLUSION: CT can provide additional information on acuity, extent and complications in inflammatory bowel disease. In combination with conventional radiographic findings a three-step classification for Crohn's disease and ulcerative colitis (early changes, acute and chronic phase) can be proposed.

HIV protease inhibitor HOE/BAY 793, structure-activity relationships in a series of C2-symmetric diols.

A detailed structure-activity relationship of C2-symmetric diol inhibitors of HIV-1 protease leads to inhibitor 6 (HOE/BAY 793) which is outstanding in the inhibition of the enzyme and in the inhibition of viral replication in HIV infected cell culture (IC50: 0.3 nM; EC50: 3 nM). There are well defined steric requirements for the design of the side chains P1-P3 of the inhibitors. In addition, all three side chains need to be lipophilic. While the enzyme tolerates hydrophilic substituents in some cases, drastic reductions in anti-HIV activity are observed in cell culture, most likely due to insufficient cell penetration.

Effects of the renin inhibitor N-[N-(3-(4-amino-1-piperidinyl-carbonyl)-2(R)-benzylpropionyl)-L- histid inyl] -(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6(2-pyridyl)-hexane-2-amide acetate in anesthetized rhesus monkeys.

The renin inhibitory effect of the non-peptide renin inhibitor S 2864 (N-[N-(3-(4-Amino-1-piperidinyl-carbonyl)-2(R)-benzylpropionyl)-L- histidinyl]-(2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy-6(2-pyridyl)-hexane-2- amide acetate, CAS 135683-92-0) was characterized in vitro and in vivo in primates. In vitro, S 2864 inhibited the activity of purified human plasma renin with an IC50 of 3.8 x 10(-10) mol/l and did not affect related human aspartyl proteases like human cathepsin E, cathepsin D or pepsin. In vivo, in anesthetized sodium depleted rhesus monkeys S 2864 decreased mean arterial blood pressure after intraduodenal (i.d.) administration of 2 mg/kg significantly by 27% from 94 +/- 8 to 62 +/- 6 mmHg for 90 min. Heart rate was not changed. Cumulative intravenous (i.v.) administration of S 2864 or remikiren in doses of 1, 10 and 30 micrograms/kg significantly decreased systemic blood pressure, dP/dtmax and cardiac output while heart rate was not changed. Plasma angiotensin II (ANG II) levels as well as renin activity were dose dependently reduced after 10, 30 and 60 min. It is concluded that S 2864 is an effective specific inhibitor of human renin eliciting marked blood pressure lowering activities in primates.

Renin inhibitors containing a pyridyl amino diol derived C-terminus.

Based on the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected inhibitors were evaluated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduodenal administration of a dose of 2 mg/kg. Compound 38 (S 2864) containing an amino piperidyl succinic acid derived N-terminal is the most promising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decreased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetized, sodium-depleted rhesus monkeys.

Inhibition of HIV-1 protease by short peptides derived from the terminal segments of the protease.

The active HIV-1 protease is a homodimeric enzyme. A beta-sheet consisting of N- and C-terminal segments provides the main driving force for dimerization of the inactive protomers. Several short peptides with sequences derived from the N- and C-termini of the protease were tested for inhibition of protease activity and for inhibition of HIV-1 replication in lymphocytes. Medium inhibitory activity was found with each of the peptides in the enzyme test and no inhibition of the lymphocytes was found up to 200 micrograms/ml. The enzyme tests indicate that HIV-1 protease is the target of the inhibitory action. Synergistic action could not be found with pairs of the peptides derived from the two different termini. Prolonged incubation with one of the peptides increased inhibition indicating a slow dissociation of the protease dimers. No cytotoxic effect of the inhibitors could be found below 200 micrograms/ml.

Renin inhibitory pentols showing improved enteral bioavailability.

Incorporation of a C-terminal pentahydroxy functionality led to potent, low molecular weight hydrophilic renin inhibitors lacking the P1' side chain. As these compounds are easy to synthesize and have sufficient water solubility, they were chosen for further study. Compound 33 was transported across rabbit intestinal brush border membrane vesicles and yielded a hypotensive effect in sodium-depleted rhesus monkeys which lasted for 90 min when dosed at 2 mg/kg id.

Fitting heteroscedastic regression models to individual pharmacokinetic data using standard statistical software.

In the analysis of individual pharmacokinetic data by nonlinear regression it is important to allow for possible heterogeneity of variance in the response. Two common methods of doing this are weighted least squares with appropriate weights or data transformation using a suitable transform. With either approach it is appealing to let the data determine the appropriate choice of weighting scheme or transformation. This article describes two methods of doing this which are easy to compute using standard statistical software. The first method is a generalized least squares scheme for the case where the variance is assumed proportional to an unknown power of the mean. The second involves applying a power transformation to both sides of the regression equation. It is shown that both techniques may be implemented using only nonlinear regression routines. Sample code is provided for their implementation using the SAS software package. However, the proposed methods are feasible using any software package that incorporates a nonlinear least squares routine, and are thus well suited to routine use.

Hoe 263, a new substance with calcium channel antagonistic activity.

Hoe 263 inhibited the contraction of the potassium-depolarized pulmonary artery of the guinea pig. In this experiment it was slightly more active than verapamil. The calcium uptake of the potassium-depolarized pulmonary artery was inhibited by Hoe 263 more effectively than by prenylamine. The upstroke velocity of the potassium-depolarized papillary muscle of the guinea pig was depressed with similar concentrations of Hoe 263 and verapamil. In the (3H)-nitrendipine binding test, Hoe 263 was effective at similar concentrations as prenylamine and verapamil. The positive inotropic effect of K-strophanthin was depressed by Hoe 263 at concentrations which were comparable with those necessary for verapamil.