Implementation of a new surveillance system for dialysis-associated infection events in outpatient dialysis facilities in Germany.

INTRODUCTION: Patients receiving maintenance haemodialysis are at risk of catheter-related infections. Up to now, there has been no standardized surveillance tool in Germany to evaluate infection events in haemodialysis outpatients. As such, this study aimed to implement an online-based surveillance tool in outpatient dialysis facilities, and to report the first national surveillance data for haemodialysis patients in Germany from October 2019 until September 2021. METHODS: Outpatient dialysis facilities reported three types of dialysis-associated infection event (DAIE): bloodstream infections, intravenous antimicrobial starts, and local access site infections. Denominator data were provided by the number of haemodialysis treatments at each facility per month. DAIE rates stratified by vascular access type were calculated. RESULTS: In total, 43 outpatient dialysis facilities reported 723 DAIEs, including 63 bloodstream infections, 439 intravenous antimicrobial starts, and 221 local access site infections. The overall incidence of DAIEs was 0.51 per 1000 dialysis treatments (723/1,413,457) during the surveillance period. The overall incidence of DAIEs was 0.13 per 1000 dialysis treatments among patients with arteriovenous fistulas (AVFs; 126/990,392), 0.41 per 1000 dialysis treatments among patients with arteriovenous grafts (41/99,499), and 1.68 per 1000 dialysis treatments among patients with central venous catheters (CVCs; 535/318,757). The rate ratio of DAIEs between CVC and AVF rates was 13.2 (95% confidence interval 10.9-16.0; P<0.001). DISCUSSION: These 2-year infection data represent the first standardized data of outpatient dialysis facilities in Germany. Rates of infection were highest among patients with CVCs compared with other vascular access types. This online-based surveillance tool may be helpful to identify effective targets for infection prevention measures in haemodialysis patients.

The OUTREACH study: oncologists of German university hospitals in rotation on a palliative care unit-evaluation of attitude and competence in palliative care and hospice.

PURPOSE: The effect of the duration of an educational rotation presented at a palliative care unit on the palliative care knowledge gain and the increase of palliative care self-efficacy expectations are unclear. METHODS: This national prospective multicenter pre-post survey conducted at twelve German University Comprehensive Cancer Centers prospectively enrolled physicians who were assigned to training rotations in specialized palliative care units for three, six, or twelve months. Palliative care knowledge [in %] and palliative care self-efficacy expectations [max. 57 points] were evaluated before and after the rotation with a validated questionnaire. RESULTS: From March 2018 to October 2020, questionnaires of 43 physicians were analyzed. Physicians participated in a 3- (n = 3), 6- (n = 21), or 12-month (n = 19) palliative care rotation after a median of 8 (0-19) professional years. The training background of rotating physicians covered a diverse spectrum of specialties; most frequently represented were medical oncology (n = 15), and anesthesiology (n = 11). After the rotation, median palliative care knowledge increased from 81.1% to 86.5% (p < .001), and median palliative care self-efficacy expectations scores increased from 38 to 50 points (p < .001). The effect of the 12-month rotation was not significantly greater than that of the 6-month rotation. CONCLUSION: An educational rotation presented in a specialized palliative care unit for at least six months significantly improves palliative care knowledge and palliative care self-efficacy expectations of physicians from various medical backgrounds.

[Patient-specific joint prothesis for ankylotic temporomandibular joints]. / Individueel vervaardigde prothesen voor ankylotische kaakgewrichten.

A 49-year-old woman who suffered from severe obstructive sleep apnea (OSA) was referred to the department of Oral-, Maxillofacial Surgery department due to progressive limitation of the mouth opening and chronic pain in both temporomandibular joints. Based on clinical and radiological examinations, the patient was diagnosed with recurrent ankylosis of the temporomandibular joints. The patient was treated with 2 patient-specific implants of the temporomandibular joint combined with a Le Fort I osteotomy, and a genioplasty including a genioglossus advancement. This treatment may have advantages for the patient such as a lower recurrence rate of ankylosis, improved maximal mouth opening, pain reduction and improved aesthetic results.

Differences in observed and self-reported compliance with 'Five Moments for Hand Hygiene' as a function of the empathy of healthcare workers.

BACKGROUND: Hand hygiene at critical time-points (as established by the World Health Organization's model 'Five Moments for Hand Hygiene') remains the leading measure for minimizing the risk of healthcare-associated infections. While many interventions have been tested to improve hand hygiene compliance (HHC) of healthcare workers (HCWs), little is known about the relationship between HHC and empathy of HCWs. AIM: To investigate the relationship between moment-specific HHC rates and empathy of HCWs at both individual and ward levels. METHODS: HHC data were collected via observation and self-report, and empathy levels were measured using an established questionnaire. The survey was conducted on 38 wards of three tertiary care hospitals in Germany. Observation data were obtained via in-house observations conducted ≤8 months before or after the survey. FINDINGS: Evidence for the expected correlation between empathy of HCWs and moment-specific HHC was found for both observed HHC (Moment 1: r=0.483, P=0.031; Moment 2: r=588, P=0.006) and self-reported HHC (Moment 1: r=0.093, P=0.092; Moment 2: r=0.145, P=0.008). In analyses of variance, the critical interaction effect between empathy (i.e. lower vs higher empathy) and designated time-point of hand hygiene (i.e. before vs after reference task) was also significant. CONCLUSION: Empathy of HCWs should be considered as an important factor in explaining differences between moment-specific HHC rates. In consequence, empathy comes into focus not only as a crucial factor for high-quality patient care, but also as an important contributor to improving HHC.

No increase in compliance before aseptic procedures in German hospitals. A longitudinal study with data from the national surveillance system over four years.

BACKGROUND: Hand hygiene plays a crucial role in the prevention of healthcare-associated infections and transmission of pathogens. In 2008 the national campaign 'Aktion Saubere Hände' was launched in Germany. It is based on the World Health Organization (WHO) 'Clean Care is Safer Care' initiative. Direct observation and feedback of the results are key components in the improvement of hand hygiene compliance. In 2014 a voluntary national surveillance electronic tool for the documentation of directly observed compliance to hand hygiene was introduced. AIM: Description and evaluation of compliance with the WHO model 'my 5 moments' in German hospitals after implementation. METHODS: Direct observation was performed in the participating hospitals by trained local staff according to the WHO recommendations. We evaluated wards that reported annually at least 150 hand hygiene opportunities (HHOs) of hand hygiene per observation period from January 1st, 2015 until December 31st, 2018. FINDINGS: In all, 1,485,622 HHOs observed on 3337 wards in 525 hospitals were included into analysis. Overall compliance increased from 72% (interquartile range: 61-82) to 76% (66-84). Compliance significantly increased for all individual moments of the WHO model except moment 2. In the multivariate logistic regression analysis the following parameters were independently associated with a high compliance in hand hygiene: intensive care unit, nurse, opportunity observed in 2017 or 2018, as well as all moments except moment 2. CONCLUSION: Overall compliance in German hospitals increased over time. To improve HH compliance 'before aseptic procedures' appears to be difficult and should be addressed explicitly. Underlying reasons need to be the focus of future investigations.

Management of peripheral venous catheters and implementation of guidelines in Germany: a national survey.

BACKGROUND: Due to their frequent use, peripheral venous catheters (PVCs) are of importance in terms of catheter-related infections and their prevention. In 2017, revised national guidelines for the prevention of PVC-related infections were published in Germany. AIM: To describe PVC handling practices and assess the implementation of national guidelines for the prevention of PVC-related infections in German acute care hospitals, 10 months after their release. METHODS: An online survey on the management of PVCs in hospital wards was conducted. For this, 1191 acute care hospitals participating in the national surveillance system for healthcare-associated infections in Germany were invited to participate. Each hospital was asked to complete the survey for an intensive care unit (ICU), as well as a medical ward and a surgical ward. Participation in the survey was voluntary. FINDINGS: In total, 701 hospitals (response rate 59%) participated and provided data on 1449 wards (599 ICUs, 446 medical wards, 404 surgical wards). Approximately 43% of wards reported that they had implemented the new national guidelines where necessary. Structured surveillance for PVC-associated infections was established in only 21% of wards. While 94% of wards reported the inclusion of aspects of PVC handling in their general infection prevention education, questions on the training methods yielded diverse results. Approximately 59% of wards reported that they did not routinely use a combination of alcohol and a remanant disinfectant for skin disinfection before PVC insertion. CONCLUSION: Generally, PVC management in Germany is well organized. However, potential for improvement was identified, particularly considering surveillance and implementation of selected national guidelines.

Pulmonary hypertension in HFpEF and HFrEF: Pathophysiology, diagnosis, treatment approaches.

Pulmonary hypertension (PH) is a frequent hemodynamic condition that is highly prevalent in patients with heart failure and reduced (HFrEF) or preserved ejection fraction (HFpEF). Irrespective of left ventricular EF, the presence of PH and right ventricular (RV) dysfunction are highly relevant for morbidity and mortality in patients with heart failure. While elevated left-sided filling pressures and functional mitral regurgitation primarily lead to post-capillary PH, current guidelines and recommendations distinguish between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH), the latter being defined by a pulmonary vascular resistance (PVR) of ≥3 Wood units. Here, we describe the pathophysiology and clinical relevance of these distinct entities, and report on the diagnostic work-up including remote pulmonary artery pressure (PAP) monitoring. Furthermore, we highlight strategies to manage PH and improve RV function in heart failure, which may include optimized management of HFrEF and HFpEF (medical and interventional), sufficient volume control, catheter-based mitral valve repair, and-in selected cases-targeted PH therapy. In this context, we also highlight gaps in evidence and the need for further research.

Decrease of methicillin resistance in Staphylococcus aureus in nosocomial infections in Germany-a prospective analysis over 10 years.

OBJECTIVES: Methicillin resistant Staphylococcus aureus (MRSA) remains an important cause of healthcare-associated infections. Here, we describe the development of methicillin-resistant isolates among nosocomial Staphylococcus aureus (SA) infections in Germany between 2007 and 2016. METHODS: We analyzed data from the voluntary German national nosocomial Infection Surveillance System. Data on bloodstream infections (BSI) and lower respiratory tract infections (LRTI) were derived from intensive care units (ICU), whereas data on surgical site infections (SSI) were collected from surgical departments (SD). Univariate analysis was performed on trend of proportion, while multivariable logistic regression was performed to identify risk factors for MRSA-infections. RESULTS: Data of 1218 ICU and 1,556 SD were included. Overall, a decrease in the proportion of MRSA among all nosocomial SA-infections from 32.8% to 20.0% was noted. MRSA decreased from 37.1% to 21.8% (p = 0.01) for BSI, from 38.7% to 19.2% for LTRI (p < 0.01) and. from 21.1% to 7.4% (p < 0.01) in SSI. Logistic regression revealed that SA-infections in Mecklenburg Western-Pomerania were more likely caused by MRSA (Odds ratio (OR): 2.5; 95% CI: 1.7, 3.6). CONCLUSION: We observed a significant reduction of the proportion of nosocomial Staphylococcus aureus infections due to MRSA in Germany over the course of the last 10 years.

Time-dependent wave packet simulations of transport through Aharanov-Bohm rings with an embedded quantum dot.

We have performed time-dependent wave packet simulations of realistic Aharonov-Bohm (AB) devices with a quantum dot embedded in one of the arms of the interferometer. The AB ring can function as a measurement device for the intrinsic transmission phase through the quantum dot, however, care has to be taken in analyzing the influence of scattering processes in the junctions of the interferometer arms. We consider a harmonic quantum dot and show how the Darwin-Fock spectrum emerges as a unique pattern in the interference fringes of the AB oscillations.

[Pulmonary hypertension associated with left heart disease: recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Linksherzerkrankungen: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more common forms of PH such as PH due to left heart disease. Despite the lack of data, targeted PAH treatments are increasingly being used for PH associated with left heart disease. This development is of concern because of limited ressources and the need to base treatments on scientific evidence. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease, representing an unmet need of targeted PH therapies. It that sense, the practical implementation of the European Guidelines in Germany requires the consideration of several specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, several working groups were initiated, one of which was specifically dedicated to PH associated with left heart disease. This article summarizes the results and recommendations of this working group.

Changes in functional connectivity of the amygdala during cognitive reappraisal predict symptom reduction during trauma-focused cognitive-behavioral therapy among adolescent girls with post-traumatic stress disorder.

BACKGROUND: While trauma-focused cognitive-behavioral therapy (TF-CBT) is the 'gold standard' treatment for pediatric post-traumatic stress disorder (PTSD), little is known about the neural mechanisms by which TF-CBT produces clinical benefit. Here, we test the hypothesis that PTSD symptom reduction during TF-CBT among adolescent girls with PTSD is associated with changes in patterns of brain functional connectivity (FC) with the amygdala during cognitive reappraisal. METHOD: Adolescent girls with PTSD related to physical or sexual assault (n = 34) were enrolled in TF-CBT, delivered in an approximately 12-session format, in an open trial. Before and after treatment, they were engaged in a cognitive reappraisal task, probing neural mechanisms of explicit emotion regulation, during 3 T functional magnetic resonance imaging. RESULTS: Among adolescent girls completing TF-CBT with usable pre- and post-treatment scans (n = 20), improvements in self-reported emotion from pre- to post-treatment were positively related to improvements in PTSD symptoms. Adolescent girls with greater post-treatment symptom reduction were also able to suppress amygdala-insula FC while re-appraising, which was not evident in girls with less symptom reduction. Pre- to post-treatment changes in right amygdala to left insula FC that scaled with PTSD symptom reduction also scaled with improvements in emotion regulation. CONCLUSIONS: These preliminary results suggest the neurocircuitry mechanisms through which TF-CBT produces clinical outcomes, providing putative brain targets for augmenting TF-CBT response.

Beryllium bis(diazaborolyl): old neighbors finally shake hands.

The synthesis of a linear beryllium bis(diazaborolyl) compound featuring the first non-cluster bond between boron and beryllium has been achieved through the reaction of Yamashita's lithium diazaborolide and BeCl2. In accord with the established chemistry of beryllium, the bonding is polar covalent in character, as determined by structural and spectroscopic analysis, as well as reactivity studies.

Psychological distress and mental health service contact of unaccompanied asylum-seeking children.

BACKGROUND: Evidence is emerging that psychological problems, particularly symptoms of depression and post-traumatic stress disorder, are more prevalent in unaccompanied asylum-seeking children (UASC) than their accompanied peers. However, little is known about help seeking and mental health service (MHS) utilization in this group, and how this relates to their psychological needs. This study aims to describe the level of psychological distress among a group of UASC and the pattern of MHS contact. METHOD: Socio-demographic data on 71 UASC residing in London was obtained and self-report questionnaires were completed regarding trauma events (Harvard Trauma Questionnaire), general psychological distress [Strengths and Difficulties Questionnaire (SDQ)], post-traumatic stress symptoms (Impact of Event Scale), depressive symptoms (Birleson Depression Self-Rating Scale for Children) and contact with MHS (Attitudes to Health and Services Questionnaire). RESULTS: UASC were mainly male (n = 48, 67.6%), Black African (n = 39, 54.9%) and their median age was 17 years (interquartile range = 15; 17). They had been living in the UK for a median of 18 months. Eight (11.3%) scored on the SDQ borderline/abnormal range for total symptoms, but this was 21 (29.6%) using the SDQ emotional subscale. Forty-seven (66.2%) were at high risk for post-traumatic stress disorder and nine (12.7%) at high risk for depressive disorder. Only 12 (17%) had MHS contact. Predictors of MHS contact were depressive symptoms and duration of time in the UK. CONCLUSIONS: UASC had a high level of emotional symptoms, especially post-traumatic stress symptoms. However, only a small proportion of UASC were in contact with MHS. This suggests a high level of MHS under-utilization, and reasons for this are discussed.

Visualization of an alphaherpesvirus membrane protein that is essential for anterograde axonal spread of infection in neurons.

UNLABELLED: Pseudorabies virus (PRV), an alphaherpesvirus with a broad host range, replicates and spreads in chains of synaptically connected neurons. The PRV protein Us9 is a small membrane protein that is highly conserved among alphaherpesviruses and is essential for anterograde axonal spread in neurons. Specifically, the Us9 protein is required for the sorting of newly assembled PRV particles into axons. However, the molecular details underlying the function of Us9 are poorly understood. Here we constructed PRV strains that express functional green fluorescent protein (GFP)-Us9 fusion proteins in order to visualize axonal transport of viral particles in infected rat superior cervical ganglion neurons. We show that GFP-Us9-labeled structures are transported exclusively in the anterograde direction within axons. Additionally, the vast majority of anterograde-directed capsids (labeled with VP26-monomeric red fluorescent protein) and a viral membrane protein (labeled with glycoprotein M fused to mCherry) are cotransported with GFP-Us9 in the anterograde direction. In contrast, during infection with PRV strains that express nonfunctional mutant GFP-Us9 proteins, cotransport of mutant GFP-Us9 with capsids in axons is abolished. These findings show that axonal sorting of progeny viral particles is dependent upon the association of viral structures with membranes that contain functional Us9 proteins. This association is required for anterograde spread of infection in neurons. IMPORTANCE: Alphaherpesviruses, such as pseudorabies virus (PRV), are parasites of the mammalian nervous system. These viruses spread over long distances in chains of synaptically connected neurons. PRV encodes several proteins that mediate directed virion transport and spread of infection. Us9 is a highly conserved viral membrane protein that is essential for anterograde neuronal spread of infection. In the absence of Us9, newly replicated viral particles are assembled in the cell body but are not sorted into or transported within axons. Here, we constructed and characterized novel PRV strains that express functional green fluorescent protein (GFP)-Us9 fusion proteins in order to visualize its localization in living neurons during infection. This enabled us to better understand the function of Us9 in facilitating the spread of infection. We show that all viral particles moving in the anterograde direction are labeled with GFP-Us9, suggesting that the presence of Us9 determines the capacity for directed transport within axons.

Proteomic characterization of pseudorabies virus extracellular virions.

Pseudorabies virus (PRV), a member of the Alphaherpesvirinae, has a complex multilayered extracellular virion that is structurally conserved among other herpesviruses. PRV virions contain a double-stranded DNA genome within a proteinaceous capsid surrounded by the tegument, a layer of viral and cellular proteins. The envelope layer, which encloses the capsid and tegument, contains viral transmembrane proteins anchored in a phospholipid bilayer. The viral and host proteins contained within virions execute important functions during viral spread and pathogenesis, but a detailed understanding of the composition of PRV virions has been lacking. In this report, we present the first comprehensive proteomic characterization of purified PRV virions by mass spectrometry using two complementary approaches. To exclude proteins present in the extracellular medium that may nonspecifically associate with virions, we also analyzed virions treated with proteinase K and samples prepared from mock-infected cells. Overall, we identified 47 viral proteins associated with PRV virions, 40 of which were previously localized to the capsid, tegument, and envelope layers using traditional biochemical approaches. Additionally, we identified seven viral proteins that were previously undetected in virions, including pUL8, pUL20, pUL32, pUL40 (RR2), pUL42, pUL50 (dUTPase), and Rsp40/ICP22. Furthermore, although we did not enrich for posttranslational modifications, we detected phosphorylation of four virion proteins: pUL26, pUL36, pUL46, and pUL48. Finally, we identified 48 host proteins associated with PRV virions, many of which have known functions in important cellular pathways such as intracellular signaling, mRNA translation and processing, cytoskeletal dynamics, and membrane organization. This analysis extends previous work aimed at determining the composition of herpesvirus virions and provides novel insights critical for understanding the mechanisms underlying PRV entry, assembly, egress, spread, and pathogenesis.

Soft x-ray continuum radiation transmitted through metallic filters: an analytical approach to fast electron temperature measurements.

A new set of analytic formulas describes the transmission of soft x-ray continuum radiation through a metallic foil for its application to fast electron temperature measurements in fusion plasmas. This novel approach shows good agreement with numerical calculations over a wide range of plasma temperatures in contrast with the solutions obtained when using a transmission approximated by a single-Heaviside function [S. von Goeler et al., Rev. Sci. Instrum. 70, 599 (1999)]. The new analytic formulas can improve the interpretation of the experimental results and thus contribute in obtaining fast temperature measurements in between intermittent Thomson scattering data.

[Activities of the consortium Gesundheitsziele.de concerning the health target "Reduce tobacco consumption"]. / Aktivitäten der Akteure im Kooperationsverbund gesundheitsziele.de zum nationalen Gesundheitsziel "Tabakkonsum reduzieren".

The consortium gesundheitsziele.de develops, together with all relevant actors in health care, exemplary national health targets and recommends concrete measures to achieve these goals. Implementation takes place based on voluntary agreements of the actors. The success of gesundheitsziele.de is assessed yearly based on the activities undertaken by the actors in order to achieve the six health targets. Evaluation of the health target "Reduce tobacco consumption" shows that numerous interventions were undertaken in 2008 geared towards not only the promotion of quitting, prevention of take-up or protection against passive smoking, but also the fostering of effective tobacco control policies. The number of behavioural, individual-oriented interventions is almost twice as high as the number of structural/legislative measures.

Depressive symptoms and behavioural health risks in young women attending an urban sexual health clinic.

BACKGROUND: Adolescence is a time of increased health risk behaviours and depressive symptoms and disorders. Most young people with depressive disorders, however, are not under the care of specialist child and adolescent mental health services, and there is increasing interest in identifying alternative appropriate settings which are acceptable for young people and may attract those at high risk for depressive disorders. AIM: To assess depressive and behavioural health risks in attendees to a sexual health clinic (SHC) for young people. METHOD: Cross-sectional controlled study of women attending a SHC and school attendees, using questionnaires on depressive symptoms and mental health problems, sexual activity and substance use. RESULTS: 115/178 attendees 14-19 years old completed questionnaires. In the comparison between 66 women aged 16-18 years and 49 socio-demographically group-matched school controls, SHC attendees reported higher levels of sexual activity and substance use. They were significantly more at risk for depression (20/65 or 30% vs. 4/46 or 8%; chi(2)P < 0.01) on the Beck Depression Inventory, for emotional (12/66 or 18% vs. 1/49 or 2%; chi(2)P < 0.01), hyperactivity (11/66 or 16% vs. 2/46 or 4%; chi(2)P < 0.05) and conduct (8/66 or 12% vs. 0/49; chi(2)P < 0.05) problems on the Strengths and Difficulties Questionnaire. High depressive scores were significantly associated with a history of self-harm, earlier alcohol use and having tried cannabis, but not with sexual risk behaviours. Earlier age at first sexual intercourse was linked to higher sexual and substance use risks. CONCLUSION: We have found high levels of depressive symptoms among attendees to a SHC for young people, which seem an appropriate setting for screening and providing guidance for depression and other health risk behaviours.

A procedure to optimize scale-up for the primary drying phase of lyophilization.

This article describes a procedure to facilitate scale-up for the primary drying phase of lyophilization using a combination of empirical testing and numerical modeling. Freeze dry microscopy is used to determine the temperature at which lyophile collapse occurs. A laboratory scale freeze-dryer equipped with manometric temperature measurement is utilized to characterize the formulation-dependent mass transfer resistance of the lyophile and develop an optimized laboratory scale primary drying phase of the freeze-drying cycle. Characterization of heat transfer at both lab and pilot scales has been ascertained from data collected during a lyophilization cycle involving surrogate material. Using the empirically derived mass transfer resistance and heat transfer data, a semi-empirical computational heat and mass transfer model originally developed by Mascarenhas et al. (Mascarenhas et al., 1997, Comput Methods Appl Mech Eng 148: 105-124) is demonstrated to provide predictive primary drying data at both the laboratory and pilot scale. Excellent agreement in both the sublimation interface temperature profiles and the time for completion of primary drying is obtained between the experimental cycles and the numerical model at both the laboratory and pilot scales. Further, the computational model predicts the optimum operational settings of the pilot scale lyophilizer, thus the procedure discussed here offers the potential to both reduce the time necessary to develop commercial freeze-drying cycles by eliminating experimentation and to minimize consumption of valuable pharmacologically active materials during process development.