Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Real-World Treatment Patterns, Outcomes, Resource Utilization and Costs in Treatment-Resistant Major Depressive Disorder: PATTERN, a Retrospective Cohort Study in Belgium.

OBJECTIVE: Treatment-resistant depression (TRD), a subgroup of major depressive disorder (MDD) that does not adequately respond to treatment, has a substantial impact on the quality of life of patients and is associated with higher medical and mental health care costs. This study aimed to report real-world treatment patterns, outcomes, resource utilization, and costs in the management of TRD by psychiatrists in Belgium. METHODS: We conducted a retrospective, non-interventional cohort study of patients ≥ 18 years, with diagnosed MDD who are treatment-resistant, defined as not responding to two different antidepressant treatments in the current moderate to severe major depressive episode (MDE). Data obtained from medical records of patients included patient health state (MDE, response, remission, and recovery) and resource use (number of consultations and emergency room visits, non-drug and drug interventions, and hospitalizations). RESULTS: One hundred and twenty-five patients were enrolled in nine sites, with an average observation period of 34 months. During the MDE, 89.7% of patients were treated with selective serotonin reuptake inhibitors, 63.2% with serotonin-norepinephrine reuptake inhibitors, and 60.8% with anti-psychotics. Twenty-four percent of patients did not respond to any treatment; 76% responded, of whom 61% experienced a relapse; 28% of patients reached recovery, of whom 31.4% experienced recurrence. The average yearly direct cost of a TRD patient is €9012, mainly driven by hospitalization in the MDE. The observed absenteeism relates to a high indirect cost, representing 70% of the total MDE cost. CONCLUSION: TRD is associated with a high unmet need and economic burden for patients and society, with highest costs in the MDE health state driven by absenteeism.

7-Tesla MRI Evaluation of the Knee, 25 Years after Cartilage Repair Surgery: The Influence of Intralesional Osteophytes on Biochemical Quality of Cartilage.

OBJECTIVE: To evaluate the morphological and biochemical quality of cartilage transplants and surrounding articular cartilage of patients 25 years after perichondrium transplantation (PT) and autologous chondrocyte transplantation (ACT) as measured by ultra-high-field 7-Tesla (7T) magnetic resonance imaging (MRI) and to present these findings next to clinical outcome. DESIGN: Seven PT patients and 5 ACT patients who underwent surgery on the femoral condyle between 1986 and 1996 were included. Patient-reported outcome measures (PROMs) were assessed by the clinical questionnaires: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC), and Visual Analogue Scale (VAS) for knee pain. The morphological (MOCART score) and biochemical quality (glycosaminoglycans [GAGs] content and collagen integrity) of cartilage transplants and surrounding articular cartilage were analyzed by 7T MRI. The results of the PT and ACT patients were compared. Finally, a detailed morphological analysis of the grafts alone was performed. RESULTS: No statistically significant difference was found for the PROMs and MOCART scores of PT and ACT patients. Evaluation of the graft alone showed poor repair tissue quality and high prevalence of intralesional osteophyte formation in both the PT and ACT patients. Penetration of the graft surface by the intralesional osteophyte was related to biochemically damaged opposing tibial cartilage; GAG content was significantly lower in patients with an osteophyte penetrating the graft surface. CONCLUSIONS: Both PT and ACT patients have a high incidence of intralesional osteophyte formation 25 years after surgery. The resulting biochemical damage to the opposing tibial cartilage might be dependent on osteophyte morphology.

Efficacy of strategies to increase participation in cervical cancer screening: GPs offering self-sampling kits for HPV testing versus recommendations to have a pap smear taken - A randomised controlled trial.

Background: Cervical cancer is preventable by early detection and treatment of pre-cancerous lesions. The current screening policy in Belgium (3-yearly cytology on Pap smears) covers 60% of the target population. Offering self-samples by GPs can overcome barriers for women who are currently not screened. Methods: Women aged 25­64 who did not have a Pap smear since three years and consulted a GP practice in a Flemish municipality between November 2014 and April 2015 were allocated in a 1:1 ratio to either the intervention arm where women were given a vaginal self-sampling kit or control arm where women were encouraged to make an appointment for having a Pap smear taken by a clinician. Results: Eighty-eight consenting women were randomised. 35 (78%) out of 45 women in the self-sampling arm participated in screening compared to 22 (51%) out of 43 women in the control arm (p = 0.009). This difference remained significant after adjusting for covariates (age category, education level, time interval since last Pap smear, past Pap smear-taker). Conclusion: GPs offering self-sampling kits resulted in a high participation. Larger trials should confirm this effect and evaluate feasibility of this approach.4. The authors would also like to include the following sentence in the acknowledgement "The laboratory AML (Antwerp, Belgium) is acknowledged for the free HPV testing on the self-samples."

Nano- and microplastics affect the composition of freshwater benthic communities in the long term.

Given the societal concern about the presence of nano- and microplastics in the environment, our nescience with respect to in situ effects is disturbing. Data on long-term implications under ecologically realistic conditions are particularly important for the risk assessment of nano- and microplastics. Here, we evaluate the long-term (up to 15 months) effects of five concentrations of nano- and microplastics on the natural recolonization of sediments by a macroinvertebrate community. Effects were assessed on the community composition, population sizes and species diversity. Nano- and microplastics adversely affected the abundance of macroinvertebrates after 15 months, which was caused by a reduction in the number of Naididae at the highest concentration (5% plastic per sediment dry weight). For some other taxa, smaller but still significant positive effects were found over time, altogether demonstrating that nano- and microplastics affected the community composition.

Pharmaceutical compounding of orphan active ingredients in Belgium: how community and hospital pharmacists can address the needs of patients with rare diseases.

BACKGROUND: Pharmaceutical compounding of orphan active ingredients can offer cost-effective treatment to patients when no other drug product is available for a rare disease or during periods of drug product shortages. Additionally, it allows customized therapy for patients with rare diseases. However, standardized compounding formulas and procedures, and monographs are required to ensure the patients' safety. RESULTS: Standardized formulas and compounding procedures were developed for seven orphan active ingredients (L-arginine, sodium benzoate, sodium phenylbutyrate, L-carnitine, chenodesoxycholic acid, primaquine phosphate, pyridoxal phosphate) and one non-orphan molecule (sodium perchlorate) regularly compounded by hospital pharmacists for extemporaneous use. The stability of these formulations was evaluated over 3 months at refrigerated (5 °C) and standard storage conditions (25 °C/60%RH) using HPLC-based assays and a suitable shelf life was assigned to the formulations. Additionally, suitable analytical methods for quality control of formulations of pyridoxal phosphate and sodium perchlorate were developed as monographs for these components were not available in the European Pharmacopeia or United States Pharmacopeia. CONCLUSIONS: Availability of compounding formulas and protocols, as well as stability information, for orphan active ingredients can improve patients' access to treatment for rare diseases. Such data were collected for seven orphan active ingredients to treat patients with rare diseases when no other treatment is available. More efforts are needed to develop standardized formulas and compounding procedures for additional orphan active ingredients whose clinical efficacy is well-known but which are not available as products with a marketing authorization. Additionally, a legal framework at EU level is required to enable the full potential of pharmaceutical compounding for orphan active ingredients.

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

Perceived neuropsychological impairment inversely related to self-reported health and employment in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients frequently report cognitive difficulties which impact daily functioning. The objective was to investigate the relationship between patient-reported cognitive impairment and depression, demographic and MS-related variables, and to clarify its impact on self-reported health measures and employment. METHOD: A large two-centre survey included the MS Neuropsychological Screening Questionnaire (MSNQ), the two-question screening tool for depression, vitality, health-related quality of life, the Health-Promoting Lifestyle Profile II and questions assessing social network satisfaction and employment status. RESULTS: Of the 751 respondents (median age 54 years, median Expanded Disability Status Scale 5, 66.2% female), two-thirds reported perceived neuropsychological impairment or depressive symptoms. Whilst depressive symptoms were related to higher MSNQ scores, the MSNQ poorly predicted depression. After correcting for confounders, higher MSNQ scores and depressive symptoms decreased vitality, health-related quality of life and health-promoting behaviours and increased the probability of being socially dissatisfied. In participants below retirement age, higher MSNQ and Expanded Disability Status Scale scores increased the probability of unemployment, whilst depression did not. CONCLUSION: The contribution of the MSNQ to self-reported health measures and its unique explanatory power regarding unemployment suggest that subjective cognitive complaints are connected to subtle, yet meaningful, neuropsychological dysfunction.

Phenotypic plasticity as a clue for invasion success of the submerged aquatic plant Elodea nuttallii.

Two closely related alien submerged aquatic plants were introduced into Europe. The new invader (Elodea nuttallii) gradually displaced E. canadensis even at sites where the latter was well established. The aim of the study was to evaluate the combined effects of environmental factors on several phenotypic characteristics of the two Elodea species, and to relate these phenotypic characteristics to the invasion success of E. nuttallii over E. canadensis. In a factorial design, Elodea plants were grown in aquaria containing five different nitrogen concentrations and incubated at five different light intensities. We used six functional traits (apical shoot RGR), total shoot RGR, relative elongation, root length, lateral spread, branching degree) to measure the environmental response of the species. We calculated plasticity indices to express the phenotypic differences between species. Light and nitrogen jointly triggered the development of phenotypic characteristics that make E. nuttallii a more successful invader in eutrophic waters than E. canadensis. The stronger invader showed a wider range of phenotypic plasticity. The apical elongation was the main difference between the two species, with E. nuttallii being more than two times longer than E. canadensis. E. canadensis formed dense side shoots even under high shade and low nitrogen levels, whereas E. nuttallii required higher light and nitrogen levels. We found that under more eutrophic conditions, E. nuttallii reach the water surface sooner than E. canadensis and through intensive branching outcompetes all other plants including E. canadensis. Our findings support the theory that more successful invaders have wider phenotypic plasticity.

Physical activity after mild traumatic brain injury: What are the relationships with fatigue and sleep quality?

OBJECTIVES: To determine self-reported physical activity (PA) levels and relationships with fatigue and sleep quality in adolescents and young adults after mild traumatic brain injury (mTBI). SETTING: Follow-up 6-18 months after visiting the emergency department of one of 2 general hospitals. PARTICIPANTS: Forty-nine adolescents and young adults aged 12-25 years (mean 18.4 years), 22 (45%) male with mTBI. DESIGN: Cross-sectional survey study. MAIN OUTCOME MEASURES: The Activity Questionnaire for Adults and Adolescents (AQuAA), with results dichotomized into meeting or not meeting Dutch Health Enhancing PA recommendations (D-HEPA), the Checklist Individual Strength (CIS, 4 subscores) and the Pittsburgh Sleep Quality Index (PSQI, total score) were administered. RESULTS: Twenty-five participants (51%) did not meet the D-HEPA recommendations. After adjusting for sex, BMI and age, not meeting the recommendations was associated with a higher CIS Total Score (OR 1.04 95%CI 1.01, 1.07) but not with PSQI Total Score (OR 0.99, 95%CI 0.80, 1.21). CONCLUSIONS: In adolescents and young adults with mTBI the level of reported PA is associated with fatigue but not with sleep quality. It remains to be established whether interventions aiming to promote PA should primarily be focused on PA or fatigue or both.

VALHUDES: A protocol for validation of human papillomavirus assays and collection devices for HPV testing on self-samples and urine samples.

BACK GROUND: Systematic reviews have concluded that hrHPV DNA testing using target-amplification tests is as accurate on vaginal self-samples as on clinician-taken specimens for the detection of cervical precancer. However, insufficient evidence is available for specific HPV assay/self-sample device combinations. OBJECTIVES: The VALHUDES protocol is designed as a diagnostic test accuracy study that aims to compare the clinical sensitivity and specificity of particular hrHPV assay(s) on vaginal self-samples and first-void-urine, collected in agreement with standardized protocols, with hrHPV testing on matched clinician-taken samples. STUDY DESIGN: Five hundred enrolled women referred to a colposcopy clinic are invited to collect a first-void urine sample and one or more vaginal self-samples with particular devices before collection of a cervical sample by a clinician. Sample sets are subsequently analysed in a laboratory accredited for HPV testing. Disease verification for all enrolled patients is provided by colposcopy combined with histological assessment of biopsies. RESULTS: A first VALHUDES study has started in Belgium in December 2017 with enrolment from four colposcopy centres. The following assays are foreseen to be evaluated: RealTime High Risk HPV assay (Abbott), cobas-4800 and -6800 (Roche), Onclarity (BD), Xpert HPV (Cepheid) and Anyplex II HPV HR (Seegene). CONCLUSION: Given empirical evidence that the relative accuracy of HPV-testing on self- vs clinician-samples is robust across clinical settings, the VALHUDES protocol offers a framework for validation of HPV assay/self-sample device combinations that can be translated to a primary screening setting.

Influence of extended dwell time during pre- and main compression on the properties of ibuprofen tablets.

The low melting point, poor flow, physico-mechanical properties (particle size distribution, shape, particle surface roughness) and deformation mechanism of ibuprofen in combination with its high dose in tablets all contribute to the problems observed during the compaction of ibuprofen-based formulations. Since ibuprofen is plastically and elastically deforming, the rate of compaction plays an important role in both the final tablet properties and the risk of capping, laminating and sticking to the punches. While the compaction rate in most tableting machines is only determined by the tableting speed, the high speed rotary tableting machine used in this research project (MODUL™ P, GEA Process Engineering, Halle, Belgium) can adjust and control the dwell time independently from the tableting speed, using an air compensator which allows displacement of the upper (pre-) compression roller. The effect of this machine design on process parameters and tablet properties was investigated. Granules containing 80% ibuprofen were compressed into tablets at 250, 500 and 1000 tablets per minute via double compression (pre- and main compression) with or without extended dwell time. Prior to tableting, granule properties were determined. Process parameters and tablet properties were analyzed using Multivariate Data Analysis. Principal Component Analysis provided an overview of the main phenomena determining the tableting process and Partial Least Squares Analysis unveiled the main variables contributing to the observed differences in the tablet properties.

Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study.

INTRODUCTION: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. METHODS: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. RESULTS: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28-84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). CONCLUSION: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.

Non-motor symptoms and quality of life in dopa-responsive dystonia patients.

BACKGROUND: In patients with GTP-cyclohydrolase deficient dopa-responsive dystonia (DRD) the occurrence of associated non-motor symptoms (NMS) is to be expected. Earlier studies report conflicting results with regard to the nature and severity of NMS. The aim of our study was to investigate the prevalence of psychiatric disorders, sleep problems, fatigue and health-related quality of life (HR-QoL) in a Dutch DRD cohort. METHODS: Clinical characteristics, motor symptoms, type and severity of psychiatric co-morbidity, sleep problems, fatigue and HR-QoL were assessed in DRD patients with a confirmed GCH1 mutation and matched controls. RESULTS: Twenty-eight patients were included (18 adults and 10 children), from 10 families. Dystonia symptoms were well-controlled in all patients. According to the DSM IV patients significantly more often met the criteria for a lifetime psychiatric disorder than controls (61% vs. 29%, p < 0.05). In particular the frequencies of generalized anxiety and agoraphobia were higher in patients (both 29% vs. 4%, p < 0.05). Patients scored significantly higher on daytime sleepiness than controls (ESS, 11.2 vs 5.7, p < 0.05). Adult patients had significantly lower scores on the mental component of the HR-QoL (47 vs. 54, p < 0.05) than controls mainly associated with (worse) quality of sleep. CONCLUSION: NMS were highly prevalent in our cohort of DRD patients, despite adequate treatment of motor symptoms. Our findings support the accumulating evidence of an important non-motor phenotype in DRD, with possible involvement of serotonergic mechanisms. This highlights the need to address NMS and the underlying neurobiology in patients with DRD.

Electronic visual analogue scales for pain, fatigue, anxiety and quality of life in people with multiple sclerosis using smartphone and tablet: a reliability and feasibility study.

OBJECTIVE: To explore the reliability and feasibility of electronic visual analogue scales in people with multiple sclerosis (MS) and healthy individuals. DESIGN: Cross-sectional observational study Setting: Clinical setting Subjects: Convenience sample of 52 people with MS and 52 matched healthy controls Interventions: NA Main measures: Participants scored 15 statements assessing fatigue, pain, anxiety and quality of life on an electronic visual analogue scale (eVAS), either using a smartphone or a tablet (randomly allocated). To check for test-retest reliability, statements were administered in two separate randomly ordered groups. Subjects completed a feasibility questionnaire. RESULTS: Mean (SD) eVAS scores ranged from 35 (28.1) to 80 (22.1) in MS group, and from 57 (28.0) to 86 (13.2) in controls. Intra Class Correlations ranged from 0.73 to 0.95 in MS sample; 0.61 to 0.92 in controls. For most statements, Bland-Altman plots indicated no systematic error, but relatively large random error of the eVAS scores (exceeding 20mm). Considerable ceiling effects (i.e. better health) were found in healthy controls. Similar reliability was found among smartphone or tablet, different demographic groups and the experience-groups. CONCLUSION: Electronic visual analogue scales are reliable and useful for people with MS to register fatigue, pain, anxiety and quality of life.

Improved tabletability after a polymorphic transition of delta-mannitol during twin screw granulation.

In most formulations processed via continuous twin screw granulation microcrystalline cellulose (MCC) and/or lactose are used as excipients, but mannitol is also a preferred excipient for wet granulation and tableting due to its non-hygroscopicity and inertness. Therefore, the aim of the current study was to investigate the influence of process parameters on critical quality attributes of granules (moisture content, solid state, morphology, size distribution, specific surface area, friability, flowability and hygroscopicity) and tablets (tensile strength and friability) after twin screw granulation of δ-mannitol. The δ-polymorph was selected since a moisture-induced transformation to ß-mannitol was observed during batch wet granulation, which exhibited a unique morphology with a large surface area and improved tabletability. A full factorial experimental design was performed, varying screw speed (400-900rpm), granulation temperature (25-40°C), number of kneading elements (6 or 12) and liquid-to-solid (L/S) ratio, on the granulation unit of a ConsiGma™-25 line (a continuous powder-to-tablet manufacturing system). After tray drying the granules were milled and tableted. The results showed that the polymorphic transition from δ- to ß-mannitol also occurred during twin screw granulation, although the residence time and L/S ratios were much lower in continuous twin screw granulation compared to batch processing. However, the polymorphic transition was not complete in all experiments and depended on the L/S ratio, screw speed and number of kneading elements. Nevertheless all granules exhibited the unique morphology linked to the polymorphic transition and had a superior tabletability compared to granules produced with ß-mannitol as starting material. This was attributed to enhanced plastic deformation of the granules manufactured using δ-mannitol as starting material. In addition, it was concluded that mannitol was granulated via a different mechanism than other, less-soluble, excipients (e.g. lactose, microcrystalline cellulose) due to its high solubility and dissolution rate as the influence of process parameters on the mannitol granule characteristics was different.

Continuous manufacturing of delta mannitol by cospray drying with PVP.

Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of mannitol has superior tabletability in comparison to α- and ß-mannitol, the latter are most commonly used because large-scale production of δ-mannitol is difficult. Therefore, a continuous method for production of δ-mannitol was developed in the current study. Spray drying an aqueous solution of mannitol and PVP in a ratio of 4:1 resulted in formation of δ-mannitol. The tabletability of a physical mixture of spray dried δ-mannitol with PVP (5%) and paracetamol (75%) was clearly superior to the tabletability of physical mixtures consisting of spray dried α- and ß-mannitol with PVP (5%) and paracetamol (75%) which confirmed the excellent tableting properties of the δ-polymorph. In addition, a coprocessing method was applied to coat paracetamol crystals with δ-mannitol and PVP. The tabletability of the resulting coprocessed particles consisting of 5% PVP, 20% δ-mannitol and 75% paracetamol reached a maximal tensile strength of 2.1 MPa at a main compression pressure of 260 MPa. Moreover the friability of tablets compressed at 184 MPa was only 0.5%. This was attributed to the excellent compression properties of δ-mannitol and the coating of paracetamol crystals with δ-mannitol and PVP during coprocessing.

The impact of hot-melt extrusion on the tableting behaviour of polyvinyl alcohol.

There is evidence that processing techniques like hot-melt extrusion (HME) could alter the mechanical properties of pharmaceuticals, which may impede further processability (e.g. tableting). The purpose of this study was to evaluate if HME has an impact on the tableting behaviour of polyvinyl alcohol (PVA)-formulations. Mixtures of partially hydrolysed PVA grades (with a hydroxylation degree of 75 and 88%) and sorbitol (0, 10 and 40%) were extruded, (cryo-) milled and compressed into compacts of 350 ± 10 mg. Before compression all intermediate products were characterized for their solid-state (Tg, Tm, crystallinity) and material properties (particle size, moisture content, moisture sorption). Because both PVA-grades required higher extrusion temperatures (i.e. 180 °C), sorbitol was added to PVA as plasticizing agent to allow extrusion at 140 °C. Compaction experiments were performed on both physical mixtures and cryo-milled extrudates of PVA-sorbitol. By measuring tablet tensile strength and porosity in function of compaction pressure, tableting behaviour was compared before and after HME by means of the CTC-profiles (compressibility, tabletability, compactibility). A higher amorphous content in the formulation (as a result of HME) negatively influenced the tableting behaviour (i.e. lower tablet tensile strength). HME altered the mechanical properties towards more elastically deforming materials, thereby increasing tablet elastic recovery during decompression. The lower tensile strengths resulted from a combined effect of less interparticulate bonding areas (because of higher elastic recovery) and weaker bonding strengths per unit bonding area (between glassy particles).

Analysis of the safety and efficacy of diabetic ketoacidosis management in a Community General Hospital, 2001-2010: a descriptive study.

BACKGROUND: The recommended place for treatment of diabetic ketoacidosis in children is a paediatric High Dependency Unit. This facility is not available in all areas where children with type 1 diabetes mellitus are cared for. AIMS: This study investigates the safety and efficacy of diabetic ketoacidosis management in a community general hospital without a paediatric high dependency unit. METHODS: Data from children with diabetic ketoacidosis were collected from all diabetes related admissions in Dr Gray's Hospital, Elgin from 2001 to 2010. Observations were compared with safety indicators (pH, bicarbonate, glucose, electrolytes and cerebral oedema) and were reviewed for the recovery to normal values (pH, bicarbonate), without abnormal fluctuation (electrolytes, glucose) and without neurological complications (cerebral oedema). RESULTS: The 114 patients generated 251 diabetes-related admissions, 118 for diabetic ketoacidosis treatment of whom 99 patients were treated with intravenous fluids and insulin. The mean time to recover to a pH of at least 7.30 was 655 minutes (120-1410 min). There were 79 (4.37% of 1808) glucose readings dropping more than 5.0 mmol/l per hour. There were six hypoglycaemic events (2.3-2.9 mmol/l) and in one case potassium dropped to 2.2 mmol/l. There was no case which developed into cerebral oedema. CONCLUSION: Treatment of diabetic ketoacidosis in a community general hospital managed with a protocol for fluids, insulin and strict monitoring has shown to be effective in achieving recovery and to safely avoid complications.