Deriving a dose and regimen for anti-glucosaminidase antibody passive-immunisation for patients with Staphylococcus aureus osteomyelitis.

Staphylococcus aureus (S. aureus) osteomyelitis remains a major clinical problem. Anti-glucosaminidase (Gmd) antibodies (1C11) are efficacious in prophylactic and therapeutic murine models. Feasibility, safety and pharmacokinetics of 1C11 passive immunisation in sheep and endogenous anti-Gmd levels were quantified in osteomyelitis patients. 3 sheep received a 500 mg intravenous (i.v.) bolus of 1C11 and its levels in sera were determined by enzyme-linked immunosorbent assay (ELISA) over 52 d. A humanised anti-Gmd monoclonal antibody, made by grafting the antigen-binding fragment (Fab) portion of 1C11 onto the fragment crystallisable region (Fc) of human IgG1, was used to make a standard curve of mean fluorescent intensity versus concentration of anti-Gmd. Anti-Gmd serum levels were determined in 297 patients with culture-confirmed S. aureus osteomyelitis and 40 healthy controls. No complications or adverse events were associated with the sheep 1C11 i.v. infusion and the estimated circulating half-life of 1C11 was 23.7 d. Endogenous anti-Gmd antibody levels in sera of osteomyelitis patients ranged from < 1 ng/mL to 300 µg/mL, with a mean concentration of 21.7 µg/mL. The estimated circulating half-life of endogenous anti-Gmd antibodies in sera of 12 patients with cured osteomyelitis was 120.4 d. A clinically relevant administration of anti-Gmd (500 mg i.v. = 7 mg/kg/70 kg human) was safe in sheep. This dose was 8 times more than the endogenous anti-Gmd levels observed in osteomyelitis patients and was predicted to have a half-life of > 3 weeks. Anti-Gmd passive immunisation has potential to prevent and treat S. aureus osteomyelitis. Further clinical development is warranted.

Matrix stimulation in cancer pain: Methodology, safety and effectiveness.

BACKGROUND: This feasibility study addresses the applicability of matrix electrodes for the reduction of ongoing pain in cancer patients via low-frequency electrical stimulation (LFS). METHODS: Low-frequency matrix stimulation (4 Hz) was applied to the skin within the 'Head's zones' referring to the tumour localization of cancer pain patients. Pain at baseline was compared to a 3-day treatment interval consisting of 5 min of matrix stimulation in the morning and evening followed by a 3-day follow-up period without therapy. Main outcome parameters included numeric rating scale values (rating scale 0-100), painDETECT, HADS, and German pain questionnaire, as well as the opioid intake, calculated as the oral morphine equivalent (OME). RESULTS: Twenty patients with cancer pain (aged 64.4 ± 10.3; 9 women) were examined. In the majority of patients, the pain was classified as nociceptive. The mean pain reduction achieved by matrix therapy was 30%, under stable daily controlled-release opioid doses between 177 and 184 mg/day (OME). Seventeen patients (85%) were responders, defined by a pain reduction of at least 30%, while four responders experienced a pain reduction of over 50%. The only side effect was short-term erythema. CONCLUSION: Findings are consistent with the concept of synaptic long-term depression in cancer pain induced after conditioning LFS. Despite the short, but well-tolerated, treatment duration of 2 × 5 min/day, effects persisted throughout the 3-day follow-up. SIGNIFICANCE: Cutaneous neuromodulation using LFS via a matrix electrode has been shown to be a safe intervention for effectively reducing cancer pain in palliative care patients.

A large animal model for a failed two-stage revision of intramedullary nail-related infection by methicillin-resistant Staphylococcus aureus.

The treatment of chronic orthopaedic device-associated infection (ODRI) often requires multiple surgeries and prolonged antibiotic therapy. Despite this extensive treatment protocol, the procedure is associated with significant failure rates. Currently, no large animal model is available that recapitulates a failed revision. Therefore, our aim was to establish a large animal model for failed treatment of an ODRI in order to serve as a testbed for future interventional strategies. Adult Swiss Alpine sheep received an intramedullary nail in the tibia and a localised inoculum of either a methicillin-sensitive or methicillin-resistant Staphylococcus aureus (MSSA, MRSA respectively). After 8 weeks, when chronic infection had been established, the animals underwent a staged revision with debridement and temporary placement of an antibiotic-loaded cement spacer. Antibiotics were delivered systemically in a standard or pathogen-adapted manner. Debridement and implant exchange alone failed to treat the MSSA infection. Neither local therapy alone nor systemic therapy alone were effective in resolving infection with MSSA, but a combination of local and systemic therapy was effective against it. MRSA infection was not resolved by the combination of local and systemic antibiotics (standard or pathogen-adapted). A model for failed revision of MRSA infection is described despite the use of local and systemic antibiotics. Novel interventions may be assessed using this model, including antibiotic and non-antibiotic interventions.

Weathering and evaporation controls on dissolved uranium concentrations in groundwater - A case study from northern Burundi.

The potential use of groundwater for potable water supply can be severely compromised by natural contaminants such as uranium. The environmental mobility of uranium depends on a suite of factors including aquifer lithology, redox conditions, complexing agents, and hydrological processes. Uranium concentrations of up to 734µg/L are found in groundwater in northern Burundi, and the objective of the present study was to identify the causes for these elevated concentrations. Based on a comprehensive data set of groundwater chemistry, geology, and hydrological measurements, it was found that the highest dissolved uranium concentrations in groundwater occur near the shores of Lake Tshohoha South and other smaller lakes nearby. A model is proposed in which weathering and evapotranspiration during groundwater recharge, flow and discharge exert the dominant controls on the groundwater chemical composition. Results of PHREEQC simulations quantitatively confirm this conceptual model and show that uranium mobilization followed by evapo-concentration is the most likely explanation for the high dissolved uranium concentrations observed. The uranium source is the granitic sand, which was found to have a mean elemental uranium content of 14ppm, but the exact mobilization process could not be established. Uranium concentrations may further be controlled by adsorption, especially where calcium-uranyl­carbonate complexes are present. Water and uranium mass balance calculations for Lake Tshohoha South are consistent with the inferred fluxes and show that high­uranium groundwater represents only a minor fraction of the overall water input to the lake. These findings highlight that the evaporation effects that cause radionuclide concentrations to rise to harmful levels in groundwater discharge areas are not only confined to arid regions, and that this should be considered when selecting suitable locations for water supply wells.

[Update palliative pain therapy]. / Update palliative Schmerztherapie.

Cancer pain and pain associated with non-neoplastic diseases can be associated with pain mechanisms, such as a peripheral or central sensitization or deafferentation. The clarification allows indirect conclusions about the underlying mechanisms based on clinical signs, such as allodynia or hyperalgesia. Non-opioid analgesics are the basis of cancer pain therapy according to the World Health Organization (WHO) pain ladder. In the case of severe cancer pain, treatment can be escalated directly from level 1 to level 3. Opioids are highly effective for the treatment of cancer pain even with a neuropathic component, which can occur in up to 40 % of cases as amixed pain syndrome. Coanalgesics represent a valuable therapeutic adjunct for better pain control and can address treatment of comorbidities, such as anxiety, depression and sleep disorders. When liver and/or renal function is reduced, the dosage of many drugs has to be adapted. Treatment of multimorbid or critically ill patients with opioids and antidepressants/anticonvulsants requires consideration of numerous possible pharmacodynamic and pharmacokinetic interactions.

Scripting MODFLOW Model Development Using Python and FloPy.

Graphical user interfaces (GUIs) are commonly used to construct and postprocess numerical groundwater flow and transport models. Scripting model development with the programming language Python is presented here as an alternative approach. One advantage of Python is that there are many packages available to facilitate the model development process, including packages for plotting, array manipulation, optimization, and data analysis. For MODFLOW-based models, the FloPy package was developed by the authors to construct model input files, run the model, and read and plot simulation results. Use of Python with the available scientific packages and FloPy facilitates data exploration, alternative model evaluations, and model analyses that can be difficult to perform with GUIs. Furthermore, Python scripts are a complete, transparent, and repeatable record of the modeling process. The approach is introduced with a simple FloPy example to create and postprocess a MODFLOW model. A more complicated capture-fraction analysis with a real-world model is presented to demonstrate the types of analyses that can be performed using Python and FloPy.

[ECG changes in patients with chronic non-cancer pain: a prospective observational study]. / EKG-Veränderungen bei Patienten mit chronischen Nichttumorschmerzen : Eine prospektive Beobachtungsstudie.

BACKGROUND: Patients with chronic non-cancer pain not only show reduced quality of life, but also chronic morbidity and increased mortality. However, little is known about prevalence and type of abnormal electrocardiogram (ECG) recordings in these individuals. MATERIAL AND METHODS: A total of 100 consecutive patients (≥ 18 years) with chronic (≥ 3 months) non-cancer pain were examined prospectively using ECG recordings and a questionnaire [German Pain Society (DGSS); further questions]. Data were collected at the first and next two follow-up outpatients' clinic appointments. RESULTS: Participation rate was 98%. Of all patients, 26% had an abnormal ECG, while 5% of these patients had an abnormal ECG first at the follow-up when consuming a different analgesic regimen. Findings were QTc prolongation (16%), ventricular block (7%), artrioventricular block (6%), and atrial fibrillation (4%). CONCLUSION: The prevalence of abnormal ECG recordings should be considered in the pain management of these patients. General ECG screening in this population should be discussed. Future studies should examine a larger population to identify potential risk factors (e.g., medication).

Electrical conductivity as a proxy for groundwater density in coastal aquifers.

Groundwater density is an important parameter in the interpretation of flow patterns. This paper investigates the relationship between electrical conductivity (EC) and groundwater density in coastal aquifers and evaluates the suitability of the UNESCO 1980 equation of state, developed for the world's oceans, for determining the density of groundwater based on its EC. To achieve this aim, a dataset of groundwater samples from four different types of coastal aquifers was collected. It is found that the density of a sample can be estimated to a good approximation on the basis of its EC using the UNESCO 1980 equation of state. Deviations from the equation of state were found to be due to the changes in EC and the density caused by geochemical reactions, such as the dissolution of carbonates, degradation of organic carbon, cation exchange, and sulfate loss. Owing to these deviations, the UNESCO 1980 equation of state may underestimate the density by up to 1.5 kg/m(3). The effect of this uncertainty on the correction terms applied to the hydraulic head required for a proper interpretation of groundwater flow patterns and rates is quantified. It was found that the fresh water head may be wrong by centimeters to a few decimeters. From this it is concluded that, unless the purpose of a groundwater investigation requires great accuracy, the equation of state provides an efficient and inexpensive way to estimate density from EC.