Community understanding of the concept of pre-referral treatment and how this impacts on referral related decision-making following the provision of rectal artesunate: a qualitative study in western Uganda.

BACKGROUND: Successful pre-referral treatment with rectal artesunate (RA) for suspected severe malaria requires operational linkages between community health workers (CHWs) and referral facilities, acceptance of pre-referral treatment and adherence to referral practices by CHWs and caregivers. This qualitative study investigated how community understanding of the concept of 'pre-referral treatment' is used in referral related decision-making following provision of RA in Uganda. METHODS: Narrative interviews were conducted with 30 caregivers of children under five who received RA within the previous three months and the 30 associated CHWs who provided the treatment. Nineteen focus group discussions incorporating vignettes from the interviews were held with further caregivers, and 12 with CHWs and women representatives. Twenty traditional healers were targeted for semi-structured interview. Thematic analysis followed a 'meaning-based' approach. RESULTS: CHWs were aware of essential information to be given to caregivers on prescribing RA as indicated by the job aid, specifically urgency for referral, yet there was insufficient emphasis on RA not being a full treatment for severe malaria. Information shared by the CHW appeared to be influenced by the perceived urgency with which the CHW needed to act and the time of day or night the child was seen. Seven of the 32 caregivers did not complete referral post RA administration. Caregivers seemed more likely to adhere to referral advice if they perceived their child's condition to be severe. Previous caregiver experience and CHW comparisons with Artemisinin-based Combination Therapy (ACT) as a treatment for uncomplicated malaria appeared to raise misperceptions that RA is a complete treatment for severe malaria, thus reducing likelihood to complete referral. CHW implication, or caregiver interpretation, of the need to monitor the child, and some prescription of ACT post RA administration, also confused the need for referral. Both CHWs and caregivers requested further information about the role of RA. CONCLUSIONS: CHW advice should emphasise RA as providing temporary relief prior to facility-based treatment, the importance of referral whether or not a change is seen in the child's condition, and the dangers of not completing referral. Social behaviour change communication, training and support supervision activities could help promote these messages.

Recording inpatient weight: implications for medicines administration.

AIM: To identify the proportions of hospital inpatients with recorded weights: among all patients, and among those receiving weight-dosed drug therapy. METHOD: Survey of clinical notes of hospital inpatients across a convenience sample of 11 secondary and tertiary referral hospitals in England and Wales in November 2011. RESULTS: 1068 patients were included, and 1061 patient clinical notes were available (99.3%). Nearly all paediatric patients had recorded weights (77/78; 98.7%). Half of adult inpatients had recorded weights (503/983, 51.2%). The proportion of adult inpatients with recorded weights varied by hospital, ranging from 13.5% to 92.5% (p<0.0001). In those receiving gentamicin or therapeutic-dose low molecular weight heparin (t-LMWH), only 64.5% (71/110) had a recorded weight. CONCLUSIONS: Half of adult inpatients, and two-thirds of those receiving gentamicin or t-LMWH, had recorded weights. There was significant variation in rates of weighing adult inpatients across hospitals. This may put patients at increased risk of side effects and problems resulting from malnutrition.

Antibiotics and evolution: food for thought.

The role of secondary metabolites in effecting and modulating reactions during early biochemical evolution has been largely unappreciated. It is possible that low molecular weight effectors were gradually replaced by polypeptides as polymerizing reactions became more complex, but retained some ability to interact with original receptor sites. Indeed, by reviewing the era of antibiotics in this light we can begin to reconcile the ancient and contemporary activities of these molecules. The corollary being that secondary metabolites participate in a vast array of interactions in nature and investigating their intended receptors will be revealing in both pharmacological and evolutionary terms.

Outcome of a new patient pathway for managing B3 breast lesions by vacuum-assisted biopsy: time to change current UK practice?

AIMS: B3 lesions of the breast represent a difficult management dilemma. The umbrella term 'B3' incorporates lesions with little associated malignancy risk as well as lesions with significant risk of concurrent neoplasia. Diagnosis of B3 lesions in screening populations is largely made on needle core biopsy, which provides little tissue to adequately diagnose pathologically diverse lesions. The advent of vacuum-assisted biopsy (VAB) provides the multidisciplinary team with a more representative pathology sample to direct management. METHODS: In this unit, in 2009, a pathway to guide management of B3 lesions detected on needle core biopsy in screening patients was implemented to assess whether VAB was a safe and viable alternative to surgery in selected cases.Here we present the 5-year follow-up results of this pathway. RESULTS: 398 patients with B3 lesions were suitable for this pathway, of which 321 went on to have second-line VAB. 24% of these patients subsequently required surgery for malignancy or ongoing concerns, and thus 245 avoided surgery being subsequently referred for 5-year mammographic surveillance or back to screening. Median follow-up was 3 years (IQR 2), and no cancers were detected at the original B3 site during follow-up. CONCLUSIONS: We have demonstrated here that with large volume tissue sampling for indeterminate lesions of the breast surgery can be safely avoided in selected B3 lesions with and without atypia.

Polymer incorporation method affects the physical stability of amorphous indomethacin in aqueous suspension.

This study reports the potential of different polymers and polymer incorporation methods to inhibit crystallisation and maintain supersaturation of amorphous indomethacin (IND) in aqueous suspensions during storage. Three different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) and Soluplus® (SP)) were used and included in the suspensions either as a solid dispersion (SD) with IND or dissolved in the suspension medium prior to the addition of amorphous IND. The total concentrations of both IND and the polymer in the suspensions were kept the same for both methods of polymer incorporation. All the polymers (with both incorporation methods) inhibited crystallisation of the amorphous IND. The SDs were better than the predissolved polymer solutions at inhibiting crystallisation. The SDs were also better at maintaining drug supersaturation. SP showed a higher IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. IND in SD with SP did not crystallise, nor did the SD generate any drug supersaturation, whereas IND in the corresponding predissolved SP solution crystallised (into the recently characterised η polymorphic form of the drug) but also led to a more than 20-fold higher IND solution concentration than that observed for crystalline IND. The ranking of the polymers with respect to crystallisation inhibition potential in SDs was SP≫PVP>HPMC. Overall, this study showed that both polymer type and polymer incorporation method strongly impact amorphous form stability and drug supersaturation in aqueous suspensions.

Application of terahertz pulsed imaging to analyse film coating characteristics of sustained-release coated pellets.

Terahertz pulsed imaging (TPI) was employed to explore its suitability for detecting differences in the film coating thickness and drug layer uniformity of multilayered, sustained-release coated, standard size pellets (approximately 1mm in diameter). Pellets consisting of a sugar starter core and a metoprolol succinate layer were coated with a Kollicoat(®) SR:Kollicoat(®) IR polymer blend for different times giving three groups of pellets (batches I, II and III), each with a different coating thickness according to weight gain. Ten pellets from each batch were mapped individually to evaluate the coating thickness and drug layer thickness between batches, between pellets within each batch, and across individual pellets (uniformity). From the terahertz waveform the terahertz electric field peak strength (TEFPS) was used to define a circular area (approximately 0.13 mm(2)) in the TPI maps, where no signal distortion was found due to pellet curvature in the measurement set-up used. The average coating thicknesses were 46 µm, 71 µm and 114 µm, for batches I, II and III respectively, whilst no drug layer thickness difference between batches was observed. No statistically significant differences in the average coating thickness and drug layer thickness within batches (between pellets) but high thickness variability across individual pellets was observed. These results were confirmed by scanning electron microscopy (SEM). The coating thickness results correlated with the subsequent drug release behaviour. The fastest drug release was obtained from batch I with the lowest coating thickness and the slowest from batch III with the highest coating thickness. In conclusion, TPI is suitable for detailed, non-destructive evaluation of film coating and drug layer thicknesses in multilayered standard size pellets.

The impact of surface- and nano-crystallisation on the detected amorphous content and the dissolution behaviour of amorphous indomethacin.

The crystallinity and physical stability of amorphous drugs has previously been studied using different analytical techniques. However, the effect of the measurement method on observed crystallinity and its importance for critical quality attributes, such as dissolution, has not yet been widely investigated. The aim of this study was to (i) qualitatively analyse and understand the recrystallisation behaviour of amorphous indomethacin during storage, (ii) quantify the amorphous content during storage with complementary analytical techniques and (iii) investigate the relationship between observed recrystallisation behaviour and dissolution behaviour. Quench cooled indomethacin was stored and the samples were visualised by scanning electron microscopy to gain spatially resolved information about the recrystallisation behaviour. Crystallisation was quantified by Fourier transform attenuated total reflectance infrared (FT-ATR-IR) spectroscopy, differential scanning calorimetry and X-ray powder diffraction. These techniques resulted in different observed recrystallisation profiles. The physicochemical phenomena detected and sampling geometry for each technique together with the sample recrystallising from the surface and appearance of nano-crystals were used to explain the differences. The dissolution behaviour at the observed recrystallisation endpoints for the different analytical techniques revealed that FT-ATR-IR spectroscopy predicted the changes in dissolution behaviour due to crystallisation best.

Investigations on the effect of different cooling rates on the stability of amorphous indomethacin.

Amorphous forms of indomethacin have previously been prepared using various preparation techniques and it could be demonstrated that the way the material was prepared influenced the physicochemical properties of the amorphous form of the drug. The aim of this study was to use one preparation technique (transformation via the melt) to prepare amorphous indomethacin and to investigate the influence of the cooling rate (as a processing parameter) on the physical stability of the resulting amorphous form. The amorphous materials obtained were analysed for their structural characteristics using Raman spectroscopy in combination with multivariate data analysis. The onset of crystallisation was determined as an indicator of the physical stability of the materials using differential scanning calorimetry (DSC) and polarising light microscopy. The Johnson-Mehl-Avrami (JMA) model and Sestak-Berggren (SB) model were used in this study to describe the non-isothermal crystallisation behaviour. All differently cooled samples were completely X-ray amorphous. Principal component analysis of the Raman spectra of the various amorphous forms revealed that the samples clustered in the scores plot according to the cooling rate, suggesting structural differences between the differently cooled samples. The minimum cooling rate required to obtain amorphous indomethacin was 1.2 K min(-1), as assessed from the time-temperature-transformation (TTT) diagram. The physical stability of the samples was found to increase as a function of cooling rate in the order of 30 K min(-1) > 20 K min(-1) > 10 K min(-1) > 5 K min(-1) > 3 K min(-1) ≈ 1.2 K min(-1) and was in agreement with calculated descriptors for the glass forming ability (GFA), including the reduced glass transition temperature (T(rg)) and the reduced temperature (T(red)). The JMA model could not be applied to describe the crystallisation process for the differently cooled melts of indomethacin in this study. The kinetic exponent M from the autocatalytic SB model however, showed a positive correlation with glass stability.

Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy.

Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the alpha-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.

Analysis of sustained-release tablet film coats using terahertz pulsed imaging.

The coating quality of a batch of lab-scale, sustained-release coated tablets was analysed by terahertz pulsed imaging (TPI). Terahertz radiation (2 to 120 cm(-1)) is particularly interesting for coating analysis as it has the capability to penetrate through most pharmaceutical excipients, and hence allows non-destructive coating analysis. Terahertz pulsed spectroscopy (TPS) was employed for the determination of the terahertz refractive indices (RI) on the respective sustained-release excipients used in this study. The whole surface of ten tablets with 10 mg/cm(2) coating was imaged using the fully-automated TPI imaga2000 system. Multidimensional coating thickness or signal intensity maps were reconstructed for the analysis of coating layer thickness, reproducibility, and uniformity. The results from the TPI measurements were validated with optical microscopy imaging and were found to be in good agreement with this destructive analytical technique. The coating thickness around the central band was generally 33% thinner than that on the tablet surfaces. Bimodal coating thickness distribution was detected in some tablets, with thicker coatings around the edges relative to the centre. Aspects of coating defects along with their site, depth and size were identified with virtual terahertz cross-sections. The inter-day precision of the TPI measurement was found to be within 0.5%.

Influence of sample characteristics on quantification of carbamazepine hydrate formation by X-ray powder diffraction and Raman spectroscopy.

This study aimed to assess the suitability of two widely utilized solid state characterization techniques namely powder X-ray diffraction (XRPD) and Raman spectroscopy, in polymorph detection and quantification for carbamazepine anhydrate and dihydrate mixtures. The influences of particle size, particle morphology, mixing, and in particular, surface bias on quantitation were investigated. Binary mixtures of carbamazepine anhydrate (form III) and dihydrate were prepared and analyzed using both XRPD and Raman spectroscopy in combination with partial least squares analysis. It was found that in principle both XRPD and Raman spectroscopy could be used to build calibration models for quantitative analysis, and a satisfactory correlation between the two techniques could be achieved. However, Raman spectroscopy appeared to be a more reliable quantification method because problems such as different particle size, morphology, and special distribution of the two solid state forms of the drug seemed to have no significant influence on Raman scattering in this study. The robust nature of Raman analysis greatly facilitates the whole quantification process from the preparation of calibration models to the quantification of in situ CBZ-DH conversion.

Visualizing the conversion of carbamazepine in aqueous suspension with and without the presence of excipients: a single crystal study using SEM and Raman microscopy.

Visual observations of the hydration process of single carbamazepine (CBZ) crystals in water and in various excipient solutions [(1% w/v) - hydroxypropyl cellulose (HPC), poly(vinyl pyrrolidone) (PVP), sodium carboxymethylcellulose (CMC) at pH 7.5 and 3.0, and polyethylene glycol (PEG)] using scanning electron microscopy (SEM) are reported in this paper. Raman microscopy was used to confirm the chemical structures of the unconverted CBZ and the CBZ dihydrate (DH) needles. It was found that defect structures were a more important driving force than the nature of crystal faces for the initiation of the hydration, but face differences became obvious after 6 h immersion. The biggest crystal face grown from methanol, (100), was the slowest one to be covered with DH needles. A comparison of the molecular arrangements along the three crystal faces [(100), (010) and (001)] was carried out using crystal structure visualization software, and fewer polar groups exposed on the (100) face than on the (001) and (010) faces were found, explaining the comparatively weak interaction of the (100) face with water during hydration. Furthermore, investigation of the influence of excipients on the hydration of CBZ showed that both HPC and PVP strongly inhibited conversion, and no conversion of CBZ to DH was found after 18 h immersion in water. PEG and CMC (pH 7.5) were less potent inhibitors than HPC and PVP, and DH needles were observed on all the faces except the (100) face after 18 h immersion. No conversion was detected for the crystal immersed in CMC solution at pH 3.0. This is likely to be caused by the decreased polarity of CMC in water at pH 3.0 (pKa,cmc = 4.3), and thus a higher surface adsorption of CMC to the CBZ crystals in dispersion. The influence of excipients on the conversion of CBZ observed in this study agreed well with our previous quantitative studies using Raman spectroscopy. In this study, visual observation using electron microscopy has been demonstrated to be a unique and powerful tool to improve our understanding of polymorphic conversions of CBZ in aqueous suspension.

Analysis of lecithin-cholesterol mixtures using Raman spectroscopy.

FT-Raman spectroscopy has been used to investigate interactions between lecithin and cholesterol. Raman spectra of lecithin show multiple peaks which can be classified into three regions: hydrophobic chain, interfacial, and headgroup regions. Binary lipid mixtures (1:1, w/w, lecithin:cholesterol) were prepared by physical mixing, granulation, coprecipitation, hydration and heating (65 degrees C), and heating (120 degrees C). Regardless of the preparation method, no changes in the spectra were observed in the hydrophobic region. A shift in the wavenumber of the choline methyl asymmetric stretching mode was observed when the samples were prepared by coprecipitation, hydration and heating (65 degrees C), and heating (120 degrees C). This may indicate a modification of phospholipids in the headgroup region in these samples. The difference in degrees of frequency shift (physical mixing approximately granulation

Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy.

In an aqueous environment, polymorphic forms I-III of carbamazepine all convert to the dihydrate. This study investigated the conversion of each polymorphic form individually and of a mixture of forms III and I to the dihydrate. Two batches of form I with different crystal morphology were used. Samples were dispersed independently in water at 23+/-1 degrees C and recovered at various timepoints varying from 10 to 210 min. Scanning electron microscopy, X-ray powder diffraction and Raman spectroscopy were used to characterize the initial polymorphic forms and the recovered samples after 210 min. Raman spectroscopy combined with partial least squares analysis was used to generate quantitative models of binary and ternary mixtures of the different polymorphic forms with the dihydrate. On the basis of these models the conversion kinetics of the polymorphic forms I-III were characterized. First-order kinetics with an unconverted portion were used to model the data (R2> or =0.95). The unconverted portions ranged from 16 to 51% after dispersion for 210 min. The conversion kinetics were similar between polymorphic forms with comparable crystal morphology, but differed significantly between batches of the same polymorph (form I) with different crystal morphology. Furthermore, the conversion of forms III and I in the aqueous suspension was not influenced by the presence of the other polymorph when dispersed together.

Who bounces back? Physiologic and other predictors of intensive care unit readmission.

OBJECTIVE: To determine the influence of changes in acute physiology scores (APS) and other patient characteristics on predicting intensive care unit (ICU) readmission. DESIGN: Secondary analysis of a prospective cohort study. SETTING: Single large university medical intensive care unit. PATIENTS: A total of 4,684 consecutive admissions from January 1, 1994, to April 1, 1998, to the medical ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The independent influence of patient characteristics, including daily APS, admission diagnosis, treatment status, and admission location, on ICU readmission was evaluated using logistic regression. After accounting for first ICU admission deaths, 3,310 patients were "at-risk" for ICU readmission and 317 were readmitted (9.6%). Hospital mortality was five times higher (43% vs. 8%; p < .0001), and length of stay was two times longer (16 +/- 16 vs. 32 +/- 28 days; p < .001) in readmitted patients. Mean discharge APS was significantly higher in the readmitted group compared with the not readmitted group (43 +/- 19 vs. 34 +/- 18; p > .01). Significant independent predictors of ICU readmission included discharge APS >40 (odds ratio [OR] 2.1; 95% confidence interval [CI] 1.6-2.7; p < .0001), admission to the ICU from a general medicine ward (Floor) (OR 1.9; 95% CI 1.4-2.6; p < .0001), and transfer to the ICU from other hospital (Transfer) (OR 1.7; 95% CI 1.3-2.3; p < .01). The overall model calibration and discrimination were (H-L chi2 = 3.8, df = 8; p = .85) and (receiver operating characteristic 0.67), respectively. CONCLUSIONS: Patients readmitted to medical ICUs have significantly higher hospital lengths of stay and mortality. ICU readmissions may be more common among patients who respond poorly to treatment as measured by increased severity of illness at first ICU discharge and failure of prior therapy at another hospital or on a general medicine unit. Tertiary care ICUs may have higher than expected readmission rates and mortalities, even when accounting for severity of illness, if they care for significant numbers of transferred patients.

The prevention of orthopaedic implant and vascular graft infections.

The infection rate for any surgical prosthesis insertion should be less than 1% in the first postoperative year. If infection occurs the patients will lose their new found mobility, lose their independence, be hospitalized with sepsis, both local and systemic, and perhaps die. Preoperative and intraoperative measures to prevent infection are well established in orthopaedic surgery but less scientifically applied in peripheral vascular surgery. In both specialties the problem of late infection has promoted research on the protection of the peri-prosthetic environment against both bacteria and biofilm. In orthopaedics, the incorporation of various antibiotics into bone cement is well accepted in revision surgery, but still debated for the primary operation. On-going research on bioresorbable ceramics and the incorporation of antibiotics more effective against coagulase-negative staphylococci should eventually counter late infections. As HIV-positive patients increasingly present with sepsis around implanted prostheses this need will increase. In vascular surgery as the risk factors for biomaterial infection are better understood, new generations of protein-sealed grafts are permitting ionically compatible antibiotic coatings. Large well-designed clinical trials have begun and are needed to confirm the forecast of improved long-term clinical outcomes.