Estimation of Pediatric Dosage of Antimalarial Drugs, Using Pharmacokinetic and Physiological Approach.

Most of the individuals who die of malaria in sub-Saharan Africa are children. It is, therefore, important for this age group to have access to the right treatment and correct dose. Artemether-lumefantrine is one of the fixed dose combination therapies that was approved by the World Health Organization to treat malaria. However, the current recommended dose has been reported to cause underexposure or overexposure in some children. The aim of this article was, therefore, to estimate the doses that can mimic adult exposure. The availability of more and reliable pharmacokinetic data is essential to accurately estimate appropriate dosage regimens. The doses in this study were estimated using the physiological information from children and some pharmacokinetic data from adults due to the lack of pediatric pharmacokinetic data in the literature. Depending on the approach that was used to calculate the dose, the results showed that some children were underexposed, and others were overexposed. This can lead to treatment failure, toxicity, and even death. Therefore, when designing a dosage regimen, it is important to know and include the distinctions in physiology at various phases of development that influence the pharmacokinetics of various drugs in order to estimate the dose in young children. The physiology at each time point during the growth of a child may influence how the drug is absorbed, gets distributed, metabolized, and eliminated. From the results, there is a very clear need to conduct a clinical study to further verify if the suggested (i.e., 0.34 mg/kg for artemether and 6 mg/kg for lumefantrine) doses could be clinically efficacious.

Evaluation of the diagnostic performance of the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation in people with diabetes: A systematic review.

AIMS: GFR estimated with the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICr ) equation is used to screen for diabetic kidney disease and assess its severity. We systematically reviewed the process and outcome of evaluating CKD-EPICr in estimating point GFR or GFR decline over time in adults with type 1 or type 2 diabetes. METHODS: In this systematic review, MEDLINE, Embase and Cochrane Central Register of Controlled Trials were searched up to August 2019. Observational studies comparing CKD-EPICr with measured GFR (mGFR) in adults with diabetes were included. Studies on people with kidney transplant, non-diabetes related kidney disease, pregnancy, potential kidney donors, and those with critical or other systematic illnesses were excluded. Two independent reviewers extracted data from published papers and disagreements were resolved by consensus. Risk-of-bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. (PROSPERO registration number: CRD42018108776). RESULTS: From the 2820 records identified, 29 studies (14 704 participants) were included. All studies were at risk of bias. Bias (eight different forms) ranged from -26 to 35 ml min-1  1.73 m-2 ; precision (five different forms) ranged between 9 and 63 ml min-1  1.73 m-2 ; accuracy (five different forms) ranged between 16% and 96%; the correlation coefficient between CKD-EPICr and mGFR (four different forms) ranged between 0.38 and 0.86; and the reduced major axis regression slope ranged between 0.8 and 1.8. CONCLUSIONS: Qualitative synthesis of data suggested CKD-EPICr was inaccurate in estimating point GFR or GFR decline over time. Furthermore, a lack of consistency in the methods and processes of evaluating the diagnostic performance of CKD-EPICr limits reliable quantitative assessment. The equation needs to be improved in adults with diabetes.

Radiation protection value to the operator from augmented reality smart glasses in interventional fluoroscopy procedures using phantoms.

INTRODUCTION: Smart glasses can be adapted to display radiographic images to allow clinician's gaze not to be directionally fixed or predetermined by computer monitor location. This study presents an analysis of eye lens dose during interventional fluoroscopy guided procedures, comparing fixed monitor positions against the use of smart glasses. METHODS: Using a head phantom (simulating the clinician), thermoluminescent dosimeters and lead shielded glasses, the dose to the eye was measured for different head 'rotations and tilts' for: gaze directed towards the main scattering source (patient/primary beam) to represent potential gaze direction if smart glasses are used; gaze directed to a range of potential computer monitor positions. An anthropomorphic pelvis phantom was utilised to simulate the patient. Accumulated dose rates (µGy s-1) from five 10-second exposures at 75 kV 25.2 mAs were recorded. RESULTS: An average DAP reading of 758.84 cGy cm2 was measured during each 10 second exposure. Whilst wearing lead shielded glasses a 6.10 - fold reduction in dose rate to the lens is possible (p < 0.05). Influence of the direction of gaze by the clinician demonstrated a wide range of dose rate reduction from 3.13% (p = 0.16) to 143.69% (p < 0.05) when the clinician's gaze was towards the main scattering source. Increased dose rate to the clinician's eyes was received despite wearing lead shielded glasses, as the angle of gaze moved 45° and 90° from 0°. CONCLUSION: If the clinician's gaze is directed towards the main scattering source a potential exists for reducing eye lens dose compared with fixed location computer monitors. Introduction of lead lined smart glasses into interventional radiology may lead to improvements in patient care, reducing the need for the clinician to look away from the patient to observe a radiographic image.

Expectations of outcomes in patients with colorectal cancer.

BACKGROUND: Understanding patients' expectations of their treatment is critical to ensure appropriate treatment decisions, and to explore how expectations influence coping, quality of life and well-being. This study aimed to examine these issues related to treatment in patients with colorectal cancer. METHODS: A literature search from January 1946 to September 2016 was performed to identify available data regarding patients' expectations of outcomes following colorectal cancer treatment. A narrative synthesis of the evidence was planned. RESULTS: Of 4337 items initially identified, 20 articles were included in the review. In studies presenting data on overall and short-term survival, patients considerably overestimated prognosis. Patients also had unrealistic expectations of the negative aspects of chemotherapy and stomas. There was marked discordance between patients' and clinicians' expectations regarding chemotherapy, end-of-life care, bowel function and psychosocial outcomes. Level of education was the most consistent factor influencing the accuracy of patients' expectations. CONCLUSION: Patients with colorectal cancer frequently have unrealistic expectations of treatment. Marked disparities exist between patients' and clinicians' expectations of outcomes.

The longitudinal association between weight change and health-related quality of life in adults and children: a systematic review.

This systematic review examined longitudinal associations between weight change (weight gain and loss) and both physical and mental aspects of health-related quality of life (HRQOL) compared with stable weight in adults and children of the general population. MEDLINE, EMBASE, PsycINFO and PubMed databases were searched. Longitudinal observational studies measuring HRQOL with six predefined instruments were synthesized according to type of association: weight change and change in HRQOL (change-on-change association) and weight change and HRQOL at follow-up (predictive association). Twenty studies of adults (n = 15) or children (n = 5) were included. Fifteen studies used the SF-12 or SF-36. Results of nine studies in adults examining the change-on-change association were combined through a tallying of 606 analyses. Weight gain was most often associated with reduced physical, but not mental HRQOL, across all baseline body mass index categories and in both men and women. Weight loss may be associated with improved physical, but not mental HRQOL, among adults with overweight and obesity. Weight gain was more strongly associated with HRQOL than weight loss, implicating a greater need for preventative strategies to tackle obesity. Results in children and for the predictive association generally reflected these findings but require further research.

THE IMPACT OF DEPRESSION ON MATERNAL RESPONSES TO INFANT FACES IN PREGNANCY.

Research has suggested that prenatal depression may be associated with disrupted maternal responses to infant stimuli, with depressed pregnant women not showing the bias toward distressed infants as that observed in nondepressed pregnant women. The current study examined the effects of depression on self- reported responses to infant stimuli, in early pregnancy. Women with clinical depression (n = 38), and nondepressed women (n = 67) were recruited from a wider cognitive behavioral therapy trial. They completed Maternal Response Scales in which they were presented with images of distressed, neutral, and happy infant faces, with no time limit. The women rated their responses to these images along three dimensions--wanting to comfort, wanting to turn away, and feelings of anxiety--using Likert scales via a computerized task. There was evidence that women with depression in pregnancy showed different responses than did women without depression. Women with depression were substantially more likely to be in the highest quartile for ratings of wanting to turn away, odds (OR) ratio = 4.15, 95% confidence intervals (CIs) = 1.63-10.5, p = .003, and also were substantially less likely to be in the highest quartile for wanting to comfort a distressed infant face, OR = 0.22, 95% CIs = 0.09-0.54, p < .001. Findings are consistent with there being both a heightened avoidant and a reduced comforting response toward distressed infants in depressed pregnant women, providing some support that depression disrupts maternal preparations at a conscious level.

Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study.

STUDY OBJECTIVE: To explore the effects of metformin dose on cancer risk reduction in patients with type 2 diabetes. DESIGN: Population-based cohort study. DATA SOURCE: National Health Insurance program Longitudinal Health Insurance Database. PATIENTS: A total of 65,754 age- and gender-matched patients without diabetes and no previous cancer diagnosis were extracted from the database. MEASUREMENTS AND MAIN RESULTS: We compared cancer risk among the subjects who had no diabetes, had type 2 diabetes but were not on diabetes drugs, used metformin only, used antidiabetic drugs other than metformin, or used metformin in combination with other antidiabetic drugs. Our results revealed dose-dependent effects of metformin on cancer risk and cancer onset times. A significant decrease in cancer risk was found in the monotherapy group who received more than 360 defined daily doses (DDDs) of metformin (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.24-0.66). The greatest decrease in cancer risk was observed in patients who took more than 1080 DDDs (HR 0.27, 95% CI 0.09-0.84). Significantly greater dose-dependent effects were seen in patients who used metformin in combination with other antidiabetic drugs. CONCLUSION: The magnitude of cancer risk reduction and prolonged cancer onset times produced by metformin in patients with type 2 diabetes depended on the dose of metformin, regardless of whether metformin was used alone or combined with other antidiabetic drugs.

A pragmatic randomised controlled trial to evaluate the cost-effectiveness of a physical activity intervention as a treatment for depression: the treating depression with physical activity (TREAD) trial.

OBJECTIVE: The TREAting Depression with physical activity (TREAD) study investigated the cost-effectiveness of a physical activity intervention, in addition to usual general practitioner care, as a treatment for people with depression. DESIGN: An individually randomised, pragmatic, multicentre randomised controlled trial with follow-up at 4, 8 and 12 months. A subset of participants took part in a qualitative study that investigated the acceptability and perceived benefits of the intervention. SETTING: General practices in the Bristol and Exeter areas. PARTICIPANTS: Aged 18-69 years with an International Statistical Classification of Diseases and Related Health Problems, 10th Edition (ICD-10) diagnosis of depression and scoring ≥ 14 on the Beck Depression Inventory (BDI). Those who were unable to complete self-administered questionnaires in English, with medical contraindications to physical activity or with psychosis, bipolar disorder or serious drug abuse were excluded. INTERVENTIONS: We devised an intervention designed to encourage choice and autonomy in the adoption of physical activity. It consisted of up to three face-to-face and ten telephone contacts delivered by a trained physical activity facilitator over an 8-month period. MAIN OUTCOME MEASURES: The primary outcome was the BDI score measured at 4 months. Secondary outcomes included depressive symptoms over the 12 months and quality of life, antidepressant use and level of physical activity. RESULTS: The study recruited 361 patients, with 182 randomised to the intervention arm and 179 to the usual care arm; there was 80% retention at the 4-month follow-up. The intervention group had a slightly lower BDI score at 4 months [-0.54, 95% confidence interval (CI) -3.06 to 1.99] but there was no evidence that the intervention improved outcome for depression. Neither was there any evidence to suggest a difference in the prescription of or self-reported use of antidepressants. However, the amount of physical activity undertaken by those who had received the intervention was increased (odds ratio 2.3, 95% CI 1.3 to 3.9) and was sustained beyond the end of the intervention. From a health-care perspective, the intervention group was more costly than the usual care group, with the cost of the intervention £220 per person on average. It is therefore extremely unlikely that the intervention is cost-effective as a treatment for depression using current willingness-to-pay thresholds. CONCLUSIONS: This physical activity intervention is very unlikely to lead to any clinical benefit in terms of depressive symptoms or to be a cost-effective treatment for depression. Previous research has reported some benefit and there are three possible reasons for this discrepancy: first, even though the intervention increased self-reported physical activity, the increase in activity was not sufficiently large to lead to a measurable influence; second, only more vigorous activity might be of benefit; and third, previous studies had recruited individuals with a pre-existing commitment to physical activity. Future research is needed to identify and explain the mechanisms by which depression might be effectively treated, including, in particular, specific guidance on the optimum type, intensity and duration of physical activity required to produce a therapeutic effect. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16900744. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 10. See the HTA programme website for further project information.

A general practice-based prevalence study of epilepsy among adults with intellectual disabilities and of its association with psychiatric disorder, behaviour disturbance and carer stress.

BACKGROUND: Although the elevated occurrence of epilepsy in people with intellectual disabilities (ID) is well recognized, the nature of seizures and their association with psychopathology and carer strain are less clearly understood. The aims were to determine the prevalence and features of epilepsy in a community-based population of adults with ID, and to explore whether the presence of epilepsy was associated with greater psychopathology or carer strain. METHODS: Data were collected on the age, gender, place of residence, adaptive and challenging behaviour, social abilities and psychiatric status of 318 adults from 40 general practices, together with the degree of malaise and strain of family carers. For participants with epilepsy, a nurse collected information on seizures, investigations, treatment and carer concerns by interview. Association between epilepsy and psychiatric morbidity, challenging behaviour and caregiver malaise or strain, was explored by comparing those with epilepsy with a comparison group matched on adaptive behaviour. RESULTS: Fifty-eight participants (18%) had epilepsy: 26% were seizure free, but 34% had extremely poorly controlled seizures. Earlier onset and seizure frequency were associated with adaptive behaviour. Carer concerns were related to seizure frequency and a history of injury. There were no significant differences in psychopathology, carer malaise or caregiver strain between the matched epilepsy and non-epilepsy groups. CONCLUSIONS: This study supports the high occurrence and chronicity of epilepsy among people with ID. While psychopathology and carer strain is common within this population, underlying disability-related factors appear to be more important than the presence of epilepsy per se.

Effect of a specialist eating disorders service on the knowledge and attitudes of local health professionals.

This study investigated the effect of a specialist eating disorders service on the attitudes and knowledge of local healthcare professionals. A questionnaire was sent to fully qualified psychiatrists, postgraduate trainees in psychiatry and general (internal) medicine, general practitioners (family physicians) and dietitians in two comparable cities: Leicester (which had a specialist eating disorders service) and Nottingham (which did not). Psychiatrists in training in Leicester had a greater knowledge of eating disorders than those in Nottingham. There was greater satisfaction with services in Leicester but no difference in attitudes. The presence of a local eating disorders service enhances postgraduate training and increases knowledge.

Quantitative analysis of residual protein contamination on reprocessed surgical instruments.

'Ready-for-use' instruments from surgical instrument trays were examined after routine cleaning and sterilization in a blinded study. These reprocessed instruments originated from five National Health Service hospital trust sterile service departments in England and Wales. Determination of residual protein and peptide contamination was carried out by acid stripping of the instrument surfaces, hydrolysis of the constituent amino acids and quantitative total amino acid analysis. One hundred and twenty instruments were analysed, and the median levels of residual protein contamination per instrument for the individual trays were 267, 260, 163, 456 and 756 microg. Scanning electron microscopy and energy dispersive X-ray spectroscopic analyses of the instruments showed that tissue deposits were localized on surfaces, but there was no significant correlation between overall protein soiling and instrument complexity. The highest levels of residual contamination were found on instruments used for tonsillectomy and adenoid surgery.

Elimination of transmissible spongiform encephalopathy infectivity and decontamination of surgical instruments by using radio-frequency gas-plasma treatment.

It has now been established that transmissible spongiform encephalopathy (TSE) infectivity, which is highly resistant to conventional methods of deactivation, can be transmitted iatrogenically by contaminated stainless steel. It is important that new methods are evaluated for effective removal of protein residues from surgical instruments. Here, radio-frequency (RF) gas-plasma treatment was investigated as a method of removing both the protein debris and TSE infectivity. Stainless-steel spheres contaminated with the 263K strain of scrapie and a variety of used surgical instruments, which had been cleaned by a hospital sterile-services department, were examined both before and after treatment by RF gas plasma, using scanning electron microscopy and energy-dispersive X-ray spectroscopic analysis. Transmission of scrapie from the contaminated spheres was examined in hamsters by the peripheral route of infection. RF gas-plasma treatment effectively removed residual organic residues on reprocessed surgical instruments and gross contamination both from orthopaedic blades and from the experimentally contaminated spheres. In vivo testing showed that RF gas-plasma treatment of scrapie-infected spheres eliminated transmission of infectivity. The infectivity of the TSE agent adsorbed on metal spheres could be removed effectively by gas-plasma cleaning with argon/oxygen mixtures. This treatment can effectively remove 'stubborn' residual contamination on surgical instruments.

Accountability and responsibility.

What can you do if the most appropriate treatment does not comply with a guideline, policy or procedure? A tissue viability team was faced with this dilemma when considering treatment options for an open wound in a woman with cancer.

Epidemiology of diabetic retinopathy and macular oedema: a systematic review.

AIMS: To systematically review the literature on the prevalence and incidence of diabetic retinopathy (DR) and macular oedema (MO). METHODS: A search of the bibliographic databases (Medline, Embase, CINAHL) was conducted up to October 2001. Selected relevant studies were scrutinized and included in the review. RESULTS: A total of 359 studies were included. The studies were reported in nearly 100 different journals and in over 50 countries. The majority of the studies were US-based, with large studies such as the Wisconsin Epidemiologic Study of Diabetic Retinopathy dominating the literature. The studies were quite dated and highly heterogeneous in nature in terms of patient selection with variable inclusion criteria (age range, gender, diabetes duration and type, ethnicity, comorbidity, and DR status, assessment, and classification). CONCLUSIONS: There are inconsistencies between epidemiological studies, and differences in study methods may contribute to conflicting reports of prevalence and incidence of DR and MO in diabetic populations. As new therapies for DR and its associated complications emerge, the need to capture and monitor new epidemiological data becomes increasingly important to be able to assess the impact and effectiveness of these therapies. Robust, longitudinal capture of patient data is, therefore, essential to evaluate the impact of current practice on the epidemiology of diabetic eye complications.

Plasma cleaning of dental instruments.

The theoretical risk of prion transmission via surgical instruments is of current public and professional concern. These concerns are further heightened by reports of the strong surface affinity of the prion protein, and that the removal of organic material by conventional sterilization is often inadequate. Recent reports of contamination on sterilized endodontic files are of particular relevance given the close contact that these instruments may make with peripheral nerve tissue. In this paper, we report the effective use of a commercial gas plasma etcher in the cleaning of endodontic files. A representative sample of cleaned, sterilized, files was screened, using scanning electron microscopy and energy-dispersive X-ray analysis, to determine the level of contamination before plasma cleaning. The files were then exposed for a short-term to a low-pressure oxygen-argon plasma, before being re-examined. In all cases, the amount of organic material (in particular that which may have comprised protein) was reduced to a level below the detection limit of the instrument. This work suggests that plasma cleaning offers a safe and effective method for decontamination of dental instruments, thus reducing the risk of iatrogenic transmission of disease during dental procedures. Furthermore, whilst this study focuses on dental files, the findings indicate that the method may be readily extended to the decontamination of general surgical instruments.

Sedation effects on responsiveness: evaluating the reduction of antipsychotic medication in people with intellectual disability using a conditional probability approach.

BACKGROUND: The impact of the withdrawal of long-term antipsychotic medication prescribed to adults with intellectual disabilities on behavioural functioning has been investigated using a real-time direct observation methodology. Previous authors have reported a significant post-reduction difference in engagement in activity between the successful drug reduction and control groups. METHOD: In the present study, sequential analysis of the relationship between staff:resident interaction and behavioural engagement was used to give a more precise measure of the extent to which user responsiveness is affected by drug withdrawal. Responsiveness was measured by calculating the likelihood of engagement occurring given the occurrence of staff interaction. This likelihood was represented by the statistic Yule's Q-value. RESULTS: High Yule's Q-value results pre- and post-baseline were found, indicating that clients were highly responsive to staff interaction. However, Yule's Q-value did not significantly increase following drug withdrawal. CONCLUSION: The present study provides no evidence of greater responsiveness following the withdrawal of psychotropic medication.

Specificity of 14-3-3 isoform dimer interactions and phosphorylation.

Proteins that interact with 14-3-3 isoforms are involved in regulation of the cell cycle, intracellular trafficking/targeting, signal transduction, cytoskeletal structure and transcription. Recent novel roles for 14-3-3 isoforms include nuclear trafficking the direct interaction with cruciform DNA and with a number of receptors, small G-proteins and their regulators. Recent findings also show that the mechanism of interaction is also more complex than the initial finding of the novel phosphoserine/threonine motif. Non-phosphorylated binding motifs that can also be of high affinity may show a more isoform-dependent interaction and binding of a protein through two distinct binding motifs to a dimeric 14-3-3 may also be essential for full interaction. Phosphorylation of specific 14-3-3 isoforms can also regulate interactions. In many cases, they show a distinct preference for a particular isoform(s) of 14-3-3. A specific repertoire of dimer formation may influence which of the 14-3-3-interacting proteins could be brought together. Mammalian and yeast 14-3-3 isoforms show a preference for dimerization with specific partners in vivo.