Public health system challenges in the Free State, South Africa: a situation appraisal to inform health system strengthening.

BACKGROUND: Since the advent of democracy, the South African government has been putting charters, policies, strategies and plans in place in an effort to strengthen public health system performance and enhance service delivery. However, public health programme performance and outcomes remained poor while the burden of disease increased. This was also the case in the Free State Province, where major public health system challenges occurred around 2012. Assessment was necessary in order to inform health system strengthening. METHODS: The study entailed a multi-method situation appraisal utilising information collated in 44 reports generated in 2013 through presentations by unit managers, subdistrict assessments by district clinical specialist teams, and group discussions with district managers, clinic supervisors, primary health care managers and chief executive and clinical officers of hospitals. These data were validated through community and provincial health indabas including non-governmental organisations, councils and academics, as well as unannounced facility visits involving discussions with a wide range of functionaries and patients. The reports were reviewed using the World Health Organization health system building blocks as a priori themes with subsequent identification of emerging subthemes. Data from the different methods employed were triangulated in a causal loop diagram showing the complex interactions between the components of an (in) effective health system. RESULTS: The major subthemes or challenges that emerged under each a priori theme included: firstly, under the 'service delivery' a priori theme, 'fragmentation of health services' (42 reports); secondly, under the 'health workforce' a priori theme, 'staff shortages' (39 reports); thirdly, under the 'health financing' a priori theme, 'financial/cash-flow problems' (39 reports); fourthly, under the 'leadership and governance' a priori theme, 'risk to patient care' (38 reports); fifthly, under the 'medical products/technologies' a priori theme, 'dysfunctional communication technology' (27 reports); and, sixthly, under the 'information' a priori theme, 'poor information management' (26 reports). CONCLUSION: The major overall public health system challenges reported by stakeholders involved fragmentation of services, staff shortages and financial/cash-flow problems. In order to effect health systems strengthening there was particularly a need to improve integration and address human and financial deficiencies in this setting.

[Terrorist attack training exercise-What can be learned? : Baden-Württemberg counterterrorism exercise (BWTEX)]. / Terrorismusabwehrübung ­ Was können wir daraus lernen? : Baden-Württembergische Terrorismusabwehr Exercise (BWTEX).

BACKGROUND: There is a risk of terror attacks in the Federal Republic of Germany, which might increase in the future. A timely comprehensive strategy for treatment and care of a large number of casualties helps minimize chaos and improve the outcome of patients. Adequate training is vital for successful implementation of an emergency plan. Therefore, the effectiveness of training should be assessed and evaluated; however, data collection capabilities for training events are extremely limited, so that publications on the topic are almost impossible to find. OBJECTIVE: This study aimed to collect data from a simulated terrorist attack in order to draw conclusions from a clinical point of view concerning the improvement of preclinical and clinical management, taking interface problems into consideration. MATERIAL AND METHODS: On 19 October 2019 the Ministry of the Interior, Digitalization and Migration of Baden-Württemberg conducted a large-scale simulation of a terrorist attack in the city center of Constance, called the Baden-Württemberg counterterrorism exercise (BWTEX). The simulation included an explosion of a car bomb as well as the use of firearms by terrorists. The large scale of the simulation with the high number of participants in combination with close cooperation between military and civil forces was unprecedented. The police force, the armed forces, civil protection forces, air rescue teams and staff from Constance, Friedrichshafen and Sigmaringen regional hospitals in southwest Germany worked together to treat simulated injuries to victims of the attack. The following parameters were recorded when the injured patients arrived at the hospital: prehospital triage time, prehospital triage score, initial treatment and quality of documentation on site as well as triage time, triage score, injury severity scale (ISS) score based on the specified injury pattern, treatment, and quality of documentation on hospital arrival. RESULTS: Out of a total of 84 "injured patients" 55 were admitted to hospital and 80% were triaged at the scene. Injured patients of triage category 1 (TK1 red: life-threatening injury, immediate treatment) arrived at the hospital 198 ± 50 min after the attack, injured patients of triage category 2 (TK2 yellow: severely injured, urgent treatment) after 131 ± 44 min and injured patients of triage category 3 (TK3 green: slightly injured, non-urgent treatment) arrived after 157 ± 46 min. There was no significant difference in terms of arrival time at the hospital between the triage scores (r = 0.2) or between the ISS scores (r = 0.43). The authors assume that approximately 44% of TK1 patients would have died due to avoidable time delays. Prehospital medical documentation was insufficient in 78% and insufficient in 65% in the hospitals. CONCLUSION: A mass casualty incident resulting from a terrorist attack differs greatly from a conventional mass casualty incident. The scene of the attack has to be evacuated as quickly as possible, which means that a large number of patients arrive untreated at the nearest hospitals. The setting up of treatment facilities in city centers and areas close to the city seems to be counterproductive because the time delay may result in higher mortality rates of victims. The particularities of mass casualties caused by a terrorist attack have to be incorporated into terrorist attack training.

Bacterial sepsis : Diagnostics and calculated antibiotic therapy.

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective calculated antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed infection and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account during the selection of anti-infective treatment. Many pathophysiologic alterations influence the pharmacokinetics (PK) of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of ß­lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM, but for continuous infusion, TDM is generally necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug-resistant (MDR) pathogens in the intensive care unit. For effective treatment, antibiotic stewardship teams (ABS teams) are becoming more established. Interdisciplinary cooperation of the ABS team with infectious disease (ID) specialists, microbiologists, and clinical pharmacists leads not only to rational administration of antibiotics, but also has a positive influence on treatment outcome. The gold standards for pathogen identification are still culture-based detection and microbiologic resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction(PCR)-based procedures for pathogen identification and resistance determination are currently only an adjunct to routine sepsis diagnostics, due to the limited number of studies, high costs, and limited availability. In complicated septic courses with multiple anti-infective therapies or recurrent sepsis, PCR-based procedures can be used in addition to treatment monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically (still) absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation). (Contribution available free of charge by "Free Access" [ https://link.springer.com/article/10.1007/s00101-017-0396-z ].).

[S2k guidelines of the PEG on calculated parenteral initial treatment of bacterial diseases in adults : Focussed summary and supplementary information on antibiotic treatment of critically ill patients]. / S2k-Leitlinie der PEG zur kalkulierten parenteralen Initialtherapie bakterieller Erkrankungen bei Erwachsenen : Fokussierte Zusammenfassung und ergänzende Informationen zur Antibiotikatherapie kritisch kranker Patienten.

In January 2018 the recent revision of the S2k guidelines on calculated parenteral initial treatment of bacterial diseases in adults-update 2018 (Editor: Paul Ehrlich Society for Chemotherapy, PEG) was realized. It is a helpful tool for the complex infectious disease setting in an intensive care unit. The present summary of the guidelines focuses on the topics of anti-infective agents, including new substances, pharmacokinetics and pharmacodynamics as well as on microbiology, resistance development and recommendations for calculated drug therapy in septic patients. As in past revisions the recent resistance situation and results of new clinical studies are considered and anti-infective agents are summarized in a table.

[Adequate anti-infective treatment : Importance of individual dosing and application]. / Adäquate Antiinfektivatherapie : Bedeutung der individuellen Dosierung und Applikation.

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (Vd) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beta-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

Cysteamine revisited: repair of arginine to cysteine mutations.

Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

[Bacterial sepsis : Diagnostics and calculated antibiotic therapy]. / Bakterielle Sepsis : Diagnostik und kalkulierte Antibiotikatherapie.

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. METHODS: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. RESULTS: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. CONCLUSION: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials.

Correction of disease-causing CBS mutations in yeast.

Mutations in cystathionine beta-synthase (CBS) are known to cause homocystinuria, a recessive disorder characterized by excessive levels of total homocysteine (tHcy) in plasma. The primary cause of mortality is thromboembolism induced by the excessive tHcy levels. Mild increases in tHcy levels are a significant risk factor in the development of vascular disease in the general population. This can result from heterozygosity at the CBS locus or polymorphic variation in other enzymes involved in homocysteine re-methylation. We report here that a mutation which deletes the carboxy-terminal 145 amino acids of CBS can functionally suppress the phenotype of several CBS mutant alleles found in homocystinurics when expressed in yeast. This C-terminal domain of CBS acts to inhibit enzymatic activity and is in turn regulated by S-adenosylmethionine (AdoMet), a positive effector of CBS. Our results indicate that most mutations found in homocystinurics do not cause dysfunction of the catalytic domain, but rather interfere with the activation of the enzyme. These findings suggest a new drug target to treat homocystinuria and homocysteine-related vascular disease.

Diagnosis of invasive fungal infections in hematology and oncology--guidelines from the Infectious Diseases Working Party in Haematology and Oncology of the German Society for Haematology and Oncology (AGIHO).

Invasive fungal infections (IFIs) are a primary cause of morbidity and mortality in patients with hematological malignancies. Establishing a definite diagnosis of IFI in immunocompromised patients is particularly challenging and time consuming, but delayed initiation of antifungal treatment increases mortality. The limited overall outcome has led to the strategy of initiating either 'empirical' or 'preemptive' antifungal therapy before the final diagnosis. However, diagnostic procedures have been vastly improved in recent years. Particularly noteworthy is the introduction of newer imaging techniques and non-culture methods, including antigen-based assays, metabolite detection and molecular detection of fungal DNA from body fluid samples. Though varying widely in cancer patients, the risk of IFI is highest in those with allogeneic stem cell transplantation and those with acute leukemia. The AGIHO presents recommendations for the diagnosis of IFIs with risk-adapted screening concepts for febrile episodes in patients with haemato-oncological disorders.

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hamatologie und Onkologie OSHO-53 phase II study.

BACKGROUND: We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. PATIENTS AND METHODS: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. RESULTS: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. CONCLUSIONS: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

[Prevention and follow-up care of sepsis. 1st revision of S2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V., DSG) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin, DIVI)]. / Prävention und Nachsorge der Sepsis. 1. Revision der S2k-Leitlinien der Deutschen Sepsis-Gesellschaft e.V. (DSG) und der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI).

The 1st revision of the S2k guideline on the prevention and follow-up care of sepsis, provided by the German Sepsis Society in collaboration with 17 German medical scientific societies and one self-help group provides state-of-the-art information on the effective and appropriate medical care of critically ill patients with severe sepsis or septic shock. The guideline recommendations may not be applied under all circumstances. It rests with the clinician to decide whether a certain recommendation should be adopted or not, taking into consideration the unique set of clinical facts presented in connection with each individual patient as well as the available resources.

A comparative proteomic analysis of Gluconacetobacter diazotrophicus PAL5 at exponential and stationary phases of cultures in the presence of high and low levels of inorganic nitrogen compound.

A proteomic view of G. diazotrophicus PAL5 at the exponential (E) and stationary phases (S) of cultures in the presence of low (L) and high levels (H) of combined nitrogen is presented. The proteomes analyzed on 2D-gels showed 131 proteins (42E+32S+29H+28L) differentially expressed by G. diazotrophicus, from which 46 were identified by combining mass spectrometry and bioinformatics tools. Proteins related to cofactor, energy and DNA metabolisms and cytoplasmic pH homeostasis were differentially expressed in E growth phase, under L and H conditions, in line with the high metabolic rate of the cells and the low pH of the media. Proteins most abundant in S-phase cells were stress associated and transporters plus transferases in agreement with the general phenomenon that binding protein-dependent systems are induced under nutrient limitation as part of hunger response. Cells grown in L condition produced nitrogen-fixation accessory proteins with roles in biosynthesis and stabilization of the nitrogenase complex plus proteins for protection of the nitrogenases from O(2)-induced inactivation. Proteins of the cell wall biogenesis apparatus were also expressed under nitrogen limitation and might function in the reshaping of the nitrogen-fixing G. diazotrophicus cells previously described. Genes whose protein products were detected in our analysis were mapped onto the chromosome and, based on the tendency of functionally related bacterial genes to cluster, we identified genes of particular pathways that could be organized in operons and are co-regulated. These results showed the great potential of proteomics to describe events in G. diazotrophicus cells by looking at proteins expressed under distinct growth conditions.

PDGF mediates a neuron-astrocyte interaction in the developing retina.

Astrocytes invade the developing retina from the optic nerve head, over the axons of retinal ganglion cells (RGCs). RGCs express the platelet-derived growth factor A-chain (PDGF-A) and retinal astrocytes the PDGF alpha-receptor (PDGFR alpha), suggesting that PDGF mediates a paracrine interaction between these cells. To test this, we inhibited PDGF signaling in the eye with a neutralizing anti-PDGFR alpha antibody or a soluble extracellular fragment of PDGFR alpha. These treatments inhibited development of the astrocyte network. We also generated transgenic mice that overexpress PDGF-A in RGCs. This resulted in hyperproliferation of astrocytes, which in turn induced excessive vasculogenesis. Thus, PDGF appears to be a link in the chain of cell-cell interactions responsible for matching numbers of neurons, astrocytes, and blood vessels during retinal development.

Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up.

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and >/=10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m(2)), cyclophosphamide (600 mg/m(2)) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m(2)), thiotepa (150 mg/m(2)) and mitoxantrone (10 mg/m(2)) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), 5-fluorouracil 600 mg/m(2), i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.

Dilute Russel Viper Venom Time analysis in a Haematology Laboratory: An audit.

INTRODUCTION: To determine whether the current set of evaluation criteria used for dilute Russel Viper Venom Time (dRVVT) investigations in the routine laboratory meet expectation and identify possible shortcomings. METHODS: All dRVVT assays requested from January 2015 to December 2015 were appraised in this cross-sectional study. The raw data panels were compared with the new reference interval, established in 2016, to determine the sequence of assays that should have been performed. The interpretive comments were audited, and false-negative reports identified. Interpretive comments according to three interpretation guidelines were compared. The reagent cost per assay was determined, and reagent cost wastage, due to redundant tests, was calculated. RESULTS: Only ~9% of dRVVT results authorized during 2015 had an interpretive comment included in the report. ~15% of these results were false-negative interpretations. There is a significant statistical difference in interpretive comments between the three interpretation methods. Redundant mixing tests resulted in R 7477.91 (~11%) reagent cost wastage in 2015. CONCLUSIONS: We managed to demonstrate very evident deficiencies in our own practice and managed to establish a standardized workflow that will potentially render our service more efficient and cost effective, aiding clinicians in making improved treatment decisions and diagnoses. Furthermore, it is essential that standard operating procedures be kept up to date and executed by all staff in the laboratory.

[Therapeutic drug monitoring and individual dosing of antibiotics during sepsis : Modern or just "trendy"?] / Therapeutisches Drug Monitoring und individualisierte Dosierung von Antibiotika bei der Sepsis : Modern oder nur "modisch"?

Pharmacokinetic variability of anti-infective drugs due to pathophysiological changes by severe sepsis and septic shock is a well-known problem for critically ill patients resulting in suboptimal serum and most likely tissue concentrations of these agents.To cover a wide range of potential pathogens, high concentrations of broad spectrum anti-infectives have to reach the site of infection. Microbiological susceptibility testing (susceptible, intermediate, resistant) don't take the pharmacokinetic variability into account and are based on data generated by non-critically ill patients. But inter-patient variability in distribution and elimination of anti-infective drugs in ICU patients is extremely high and also highly unpredictable. Drug clearance of mainly renally eliminated drugs and thus the required dose can differ up to 10-fold due to the variability in renal function in patients with severe infections. To assure a timely and adequate anti-infective regime, individual dosing and therapeutic drug monitoring (TDM) seem to be appropriate tools in the setting of pathophysiological changes in pharmacokinetics (PK) and pharmakodynamics (PD) due to severe sepsis. In the case of known minimal inhibitory concentration, PK/PD indices (time or peak concentration dependent activity) and measured serum level can provide an optimal target concentration for the individual drug and patient.Modern anti-infective management for ICU patients includes more than the choice of drug and prompt application. Individual dosing, optimized prolonged infusion time and TDM give way to new and promising opportunities in infection control.

A negative regulator of HO transcription, SIN1 (SPT2), is a nonspecific DNA-binding protein related to HMG1.

The SIN1 gene was initially identified because mutations in SIN1 bypass the need for SWI1 to activate transcription of the yeast HO gene. We show here that transcription of HO in swi1 sin1 cells efficiently utilizes the normal start site. We have cloned SIN1 and found that it is identical to the previously identified gene SPT2, mutations in which allow transcription from certain mutated regulatory regions. The predicted SIN1/SPT2 protein has a distinctive amino acid composition (45% charged residues, 25% basic and 20% acidic) and has similarity to the mammalian HMG1 protein, a nonhistone component of chromatin. We show that SIN1 is concentrated in the nucleus and binds to DNA with little or no sequence specificity in vitro. It thus exhibits properties of an HMG protein. Addition of random DNA segments to a test promoter alters regulation by SIN1 in a manner similar to addition of a segment from the HO upstream region. Functional analysis of certain SIN1 mutations suggests that SIN1 may be part of a multiprotein complex. On the basis of these results, we propose that SIN1 is a nonhistone component of chromatin which creates the proper context for transcription. Because sin1 mutants exhibit increased loss of chromosome III, SIN1 may also play a role in fidelity of chromosome segregation.