Cholinesterase inhibitor to prevent falls in Parkinson's disease (CHIEF-PD) trial: a phase 3 randomised, double-blind placebo-controlled trial of rivastigmine to prevent falls in Parkinson's disease.

BACKGROUND: Falls are a common complication of Parkinson's disease. There is a need for new therapeutic options to target this debilitating aspect of the disease. Cholinergic deficit has been shown to contribute to both gait and cognitive dysfunction seen in the condition. Potential benefits of using cholinesterase inhibitors were shown during a single centre phase 2 trial. The aim of this trial is to evaluate the effectiveness of a cholinesterase inhibitor on fall rate in people with idiopathic Parkinson's disease. METHODS: This is a multi-centre, double-blind, randomised placebo-controlled trial in 600 people with idiopathic Parkinson's disease (Hoehn and Yahr stages 1 to 4) with a history of a fall in the past year. Participants will be randomised to two groups, receiving either transdermal rivastigmine or identical placebo for 12 months. The primary outcome is the fall rate over 12 months follow-up. Secondary outcome measures, collected at baseline and 12 months either face-to-face or via remote video/telephone assessments, include gait and balance measures, neuropsychiatric indices, Parkinson's motor and non-motor symptoms, quality of life and cost-effectiveness. DISCUSSION: This trial will establish whether cholinesterase inhibitor therapy is effective in preventing falls in Parkinson's disease. If cost-effective, it will alter current management guidelines by offering a new therapeutic option in this high-risk population. TRIAL REGISTRATION: REC reference: 19/SW/0043. EudraCT: 2018-003219-23. ISCRTN: 41639809 (registered 16/04/2019). ClinicalTrials.gov Identifier: NCT04226248 PROTOCOL AT TIME OF PUBLICATION: Version 7.0, 20th January 2021.

Public attitudes to the use of remote data collection in clinical research.

BACKGROUND/AIMS: Coronavirus Disease 2019 (COVID-19) has presented an unprecedented challenge for delivering clinical research. The use of technology-assisted data collection for clinical research is desirable for many practitioners, but the acceptability of use in the general population has not been assessed. The aim of the study was to assess attitudes towards using technology-assisted remote methods in the delivery of clinical research in the UK and to understand the barriers to taking part in research with respect to both remote assessments and traditional research methods across different age ranges. METHODS: The study was conducted as an online anonymous survey with a 4-part questionnaire, between August 2020 and December 2020. Participants living in the UK aged 18 years and above were eligible to take part. RESULTS: A total 351 completed the survey and are included in the data analysis. In all age groups, participants identified that use of online assignments, video calls and telephone calls would make them more likely to take part in clinical research. Overall, the largest barrier to taking part in research was time commitments and timing of the appointment. COVID-19 has had a small, positive influence on the confidence of using technology in the general population. CONCLUSIONS: The study found that there is a large interest in taking part in research using online, telephone and video call appointments, which could facilitate research delivery in light of ongoing COVID-19-related restrictions and also improve the accessibility and inclusivity of research.

The use of continuous electronic prescribing data to infer trends in antimicrobial consumption and estimate the impact of stewardship interventions in hospitalized children.

BACKGROUND: Understanding antimicrobial consumption is essential to mitigate the development of antimicrobial resistance, yet robust data in children are sparse and methodologically limited. Electronic prescribing systems provide an important opportunity to analyse and report antimicrobial consumption in detail. OBJECTIVES: We investigated the value of electronic prescribing data from a tertiary children's hospital to report temporal trends in antimicrobial consumption in hospitalized children and compare commonly used metrics of antimicrobial consumption. METHODS: Daily measures of antimicrobial consumption [days of therapy (DOT) and DDDs] were derived from the electronic prescribing system between 2010 and 2018. Autoregressive moving-average models were used to infer trends and the estimates were compared with simulated point prevalence surveys (PPSs). RESULTS: More than 1.3 million antimicrobial administrations were analysed. There was significant daily and seasonal variation in overall consumption, which reduced annually by 1.77% (95% CI 0.50% to 3.02%). Relative consumption of meropenem decreased by 6.6% annually (95% CI -3.5% to 15.8%) following the expansion of the hospital antimicrobial stewardship programme. DOT and DDDs exhibited similar trends for most antimicrobials, though inconsistencies were observed where changes to dosage guidelines altered consumption calculation by DDDs, but not DOT. PPS simulations resulted in estimates of change over time, which converged on the model estimates, but with much less precision. CONCLUSIONS: Electronic prescribing systems offer significant opportunities to better understand and report antimicrobial consumption in children. This approach to modelling administration data overcomes the limitations of using interval data and dispensary data. It provides substantially more detailed inferences on prescribing patterns and the potential impact of stewardship interventions.

Long-term clinical, virological and immunological outcomes following planned treatment interruption in HIV-infected children.

OBJECTIVES: Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5 years' follow-up after the end of main trial. METHODS: Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time. RESULTS: In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6 years, including 5.1 years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA < 50 copies/mL (P = 0.26). A persistent increase in CD8 cells was observed in the PTI arm. The sub-study (54 children) suggested that both naïve and memory populations contributed to higher CD8 cells following PTI. Mean CD4/CD8 ratios at 5 years post-trial were 1.22 and 1.08 in CT and PTI arms, respectively [difference (CT - PTI) = -0.15; 95% CI: -0.34-0.05), P = 0.14]. The sub-study also suggested that during the trial and at early timepoints after the end of the trial, reduction in CD4 in the PTI arm was mainly from loss of CD4 memory cells. CONCLUSIONS: Children tolerated PTI with few long-term clinical, virological or immunological consequences.

Paediatric antimicrobial stewardship programmes in the UK's regional children's hospitals.

A survey was conducted in UK regional children's hospitals with paediatric intensive care and paediatric infectious disease (PID) departments to describe the characteristics of paediatric antimicrobial stewardship (PAS) programmes. A structured questionnaire was sent to PAS coordinators. 'Audit and feedback' was implemented in 13 out of 17 centres. Microbiology-led services were more likely to implement antimicrobial restriction (75% vs 33% in PID-led services), to focus on broad-spectrum antibiotics, and to review patients with positive blood cultures. PID-led services were more likely to identify patients from e-prescribing or drug charts and review all antimicrobials. A PAS network has been established.

Dysregulation of the actin scavenging system and inhibition of DNase activity following severe thermal injury.

BACKGROUND: Circulating cell-free DNA (cfDNA) is not found in healthy subjects, but is readily detected after thermal injury and may contribute to the risk of multiple organ failure. The hypothesis was that a postburn reduction in DNase protein/enzyme activity could contribute to the increase in cfDNA following thermal injury. METHODS: Patients with severe burns covering at least 15 per cent of total body surface area were recruited to a prospective cohort study within 24 h of injury. Blood samples were collected from the day of injury for 12 months. RESULTS: Analysis of blood samples from 64 patients revealed a significant reduction in DNase activity on days 1-28 after injury, compared with healthy controls. DNase protein levels were not affected, suggesting the presence of an enzyme inhibitor. Further analysis revealed that actin (an inhibitor of DNase) was present in serum samples from patients but not those from controls, and concentrations of the actin scavenging proteins gelsolin and vitamin D-binding protein were significantly reduced after burn injury. In a pilot study of ten military patients with polytrauma, administration of blood products resulted in an increase in DNase activity and gelsolin levels. CONCLUSION: The results of this study suggest a novel biological mechanism for the accumulation of cfDNA following thermal injury by which high levels of actin released by damaged tissue cause a reduction in DNase activity. Restoration of the actin scavenging system could therefore restore DNase activity, and reduce the risk of cfDNA-induced host tissue damage and thrombosis.

ANTECEDENTES: El ADN libre de las células circulantes (circulating cell-free DNA, cfDNA) no se encuentra en sujetos sanos, pero se detecta fácilmente después de una lesión térmica y puede contribuir al riesgo de fallo multiorgánico. La hipótesis fue que una disminución en la actividad de la proteína/enzima ADNasa tras la lesión térmica podría contribuir a la elevación del cfDNA que ocurre tras la misma. MÉTODOS: Los pacientes con quemaduras graves con una extensión ≥ 15% del área de superficie corporal total (total body surface area, TBSA) se incluyeron en un estudio prospectivo de cohortes durante las primeras 24 horas posteriores a la lesión. Se recogieron muestras de sangre desde el día de la lesión hasta los 12 meses posteriores a la misma. RESULTADOS: El análisis de muestras de sangre de 64 pacientes reveló una reducción significativa de la actividad de la ADNasa en los días 1 a 28 después de la lesión, en comparación con los controles sanos. Los niveles de proteína ADNasa no se vieron afectados, lo que sugiere la presencia de un inhibidor enzimático. Un análisis adicional reveló que la actina (un inhibidor de la ADNasa) estaba presente en las muestras de suero de los pacientes, pero no en los controles, y las concentraciones de la gelsolina, proteína que causa la disociación de la actina, y la proteína de unión a la vitamina D se redujeron significativamente después de la lesión térmica. En un estudio piloto de 10 pacientes con politrauma por lesiones militares, la administración de hemoderivados produjo un aumento en la actividad de la ADNasa y de los niveles de gelsolina. CONCLUSIÓN: Este estudio sugiere un nuevo mecanismo biológico para la acumulación de cfDNA después de una lesión térmica, por el cual los altos niveles de actina liberada por el tejido dañado causarían una reducción en la actividad de la ADNasa. La restauración del sistema eliminador de actina podría, por lo tanto, restaurar la actividad de la ADNasa y reducir el riesgo de daño tisular y trombosis en el huésped inducido por el cfDNA.

Burns objective scar scale (BOSS): Validation of an objective measurement devices based burn scar scale panel.

AIMS: Hypertrophic scars in burn survivors are a major cause of morbidity but the development of evidence based treatments is hampered by the lack of objective measurements of these scars. The objective of our study is to investigate the most accurate parameters for objective scar assessment and to create a combination score to facilitate the use of a panel of objective scar measurement tools. METHODS: Three independent assessors evaluated fifty five scar sites on fifty five burn patients with both the subjective modified Vancouver Scar Scale (mVSS) and a panel of objective measurement tools including the DSM II Colormeter, Cutometer, Dermascan high frequency ultrasound. The sensitivity and specificity of the objective scar parameters in predicting a mVSS score of 6 or more using the Receiving Operator Characteristic Area under the curve (ROC AUC) was then calculated and the most accurate parameters were combined to create an objective global scar score. RESULTS: The ROC AUC values were found to be highest for the Dermascan scar thickness (0.897), dermal intensity and intensity ratio (0.914 and 0.919), Cutometer R0 value (0.942), and R0 ratio (0.944). For colour measurements, ratios of scar to normal skin performed better than the single parameters for both erythema and pigmentation measurements: DSM II Erythema ratio vs Erythema (0.885 vs 0.818), DSM II a* ratio vs a* (0.848 vs 0.741); DSM II Melanin ratio vs Melanin (0.854 vs 0.761), DSM II L* ratio vs L* (0.862 vs 0.767). Analysis of the ROC AUC with chi-square test values showed that the highest AUC (0.786) was obtained with the combination of the Cutometer R0, Dermascan scar thickness, intensity and their respective scar to normal skin ratios. A total score of 5 and above (out of 6 parameters) had the highest combined sensitivity (69.0%) and specificity (83.3%). CONCLUSION: The objective parameters for the DSM II Colormeter, Cutometer and Dermascan high frequency ultrasound were all found to have moderate to strong ROC AUC values and combination of the Cutometer R0 and Dermascan scar thickness and intensity values can be used to create an objective global scar scale that can accurately differentiate patients with hypertrophic burn scarring from non-hypertrophic scars or normal skin.

Persistence of HIV reservoir following successful haematopoietic stem cell transplant for juvenile myelomonocytic leukaemia in a child with perinatally acquired HIV.

This report describes a case of juvenile myelomonocytic leukaemia (JMML) on a background of both perinatally acquired HIV infection and congenital cytomegalovirus, and management of antiretroviral therapy during haematopoietic stem cell transplant. Peripheral blood HIV viral load remained below the lower limit of detection throughout and following transplant and is currently <20 RNA copies/mL. The child is currently in remission from JMML, but HIV DNA remains detectable despite myeloablative conditioning and sustained plasma HIV viral suppression.

Investigating the intra- and inter-rater reliability of a panel of subjective and objective burn scar measurement tools.

BACKGROUND: Research into the treatment of hypertrophic burn scar is hampered by the variability and subjectivity of existing outcome measures. This study aims to measure the inter- and intra-rater reliability of a panel of subjective and objective burn scar measurement tools. METHODS: Three independent assessors evaluated 55 scar and normal skin sites using subjective (modified Vancouver Scar Scale [mVSS] & Patient and Observer Scar Assessment Scale [POSAS]) and objective tools. The intra-class correlation coefficient was utilised to measure reliability (acceptable when >0.70). Patient satisfaction with the different tools and scar parameter importance were assessed via questionnaires. RESULTS: The inter-rater reliabilities of the mVSS and POSAS were below the acceptable limit. For erythema and pigmentation, all of the Scanoskin and DSM II measures (except the b* value) had acceptable to excellent intra and inter-rater reliability. The Dermascan ultrasound (dermal thickness, intensity) had excellent intra- and inter-rater reliability (>0.90). The Cutometer R0 (firmness) had acceptable reliability but not R2 (gross elasticity). All objective measurement tools had good overall satisfaction scores. Patients rated scar related pain and itch as more important compared to appearance although this finding was not sustained when corrected for multiple comparisons. CONCLUSION: The objective scar measures demonstrated acceptable to excellent intra- and inter-rater reliability and performed better than the subjective scar scales.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Changes in novel haematological parameters following thermal injury: A prospective observational cohort study.

The mortality caused by sepsis is high following thermal injury. Diagnosis is difficult due to the ongoing systemic inflammatory response. Previous studies suggest that cellular parameters may show promise as diagnostic markers of sepsis. The aim of this study was to evaluate the effect of thermal injury on novel haematological parameters and to study their association with clinical outcomes. Haematological analysis was performed using a Sysmex XN-1000 analyser on blood samples acquired on the day of the thermal injury to 12 months post-injury in 39 patients (15-95% TBSA). Platelet counts had a nadir at day 3 followed by a rebound thrombocytosis at day 21, with nadir values significantly lower in septic patients. Measurements of extended neutrophil parameters (NEUT-Y and NEUT-RI) demonstrated that septic patients had significantly higher levels of neutrophil nucleic acid content. A combination of platelet impedance count (PLT-I) and NEUT-Y at day 3 post-injury exhibited good discriminatory power for the identifying septic patients (AUROC = 0.915, 95% CI [0.827, 1.000]). Importantly, the model had improved performance when adjusted for mortality with an AUROC of 0.974 (0.931, 1.000). A combination of PLT-I and NEUT-Y show potential for the early diagnosis of sepsis post-burn injury. Importantly, these tests can be performed rapidly and require a small volume of whole blood highlighting their potential utility in clinical practice.

The influence of paediatric HIV infection on circulating B cell subsets and CXCR5(+) T helper cells.

Antiretroviral therapy (ART) only partially restores HIV-induced alterations in lymphocyte populations. We assessed B and T cell phenotypes in a cohort of children from a single centre in the United Kingdom with perinatally acquired HIV compared to healthy controls. The majority of HIV infected children (44 of 56) were on fully suppressive combination ART. Children with perinatally acquired HIV had significantly lower memory B and CD4(+) CD45RO(+) CXCR5(+) [follicular T helper cell (Tfh)-like] T cell percentages. Detectable viraemia was associated with higher CD21(-) (activated and exhausted/tissue-like memory) B cells. A greater proportion of life spent on suppressive ART was associated with higher memory B cell percentages. These results suggest that early and sustained suppressive ART may preserve B and T cell phenotypes in perinatally acquired HIV and limit deficits in humoral immunity. A lower proportion of circulating Tfh-like cells in HIV infected children appears to be independent of HIV treatment history and ongoing HIV viraemia and warrants further investigation.

Virtual support for paediatric HIV treatment decision making.

OBJECTIVE: The objective of this study is to review clinical outcomes of recommendations made by a multidisciplinary paediatric virtual clinic (PVC) for complex case management of paediatric HIV as a model of care within a tertiary network. DESIGN: A retrospective review of the clinical outcomes of paediatric and adolescent (0-21 years) referrals to the PVC at St. Mary's Hospital, Imperial College Healthcare NHS Trust, London was performed between October 2009 and November 2013. RESULTS: 234 referrals were made for 182 children from 37 centres, discussed in 42 meetings (median age 13 years, IQR 10-15 years). Reasons for referral included virological failure (44%), simplification of the current regimen (24%) and antiretroviral drug complications (24%). At latest follow-up, PVC advice had been instituted in 80% of referrals. Suppression following virological failure was achieved in 48% following first referral and 57% following subsequent discussions and was maintained in 95% of children referred for regimen simplification. Following advice, dyslipidaemia resolved in 42% and liver function normalised in 73% with biochemical hepatitis. Adherence support aided resolution of viraemia in nine children and 12% of referrals resulted in additional support, including psychology, social services and mental health input. CONCLUSIONS: Combined multidisciplinary virtual input with adult expertise in resistance and newer agents, paediatric knowledge of pill swallowing, childhood formulations/weight banding and parental support, assists complex treatment decision making in paediatric HIV infection. The Virtual Clinic model could be applied to the management of other rare complex diseases of childhood within a clinical network.

Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function.

The involvement of mesoaccumbens dopamine in adaptive learning and behaviour is unclear. For example, dopamine may act as a teaching signal to enable learning, or more generally modulate the behavioural expression, or selection, of an already-learned response. The present study investigated the involvement of the mesoaccumbens dopamine system in a fundamental form of learning: Pavlovian conditioning. In this case, the temporal association of a previously neutral visual stimulus and a biologically significant unconditioned stimulus (US), subsequently led to the production of the conditioned response (CR) of discriminated approach behaviour directed toward the conditioned stimulus (CS+), relative to a control (CS-) stimulus. 6-hydroxydopamine lesions of the nucleus accumbens (NAcc), leading to approximately 80% reductions in tissue dopamine, were made at varying time points in four experimental groups of rats, either before or subsequent to the acquisition of the CR. NAcc dopamine depletion produced long-term neuroadaptations in dopamine function 2 months after surgery, and profoundly impaired discriminated Pavlovian approach regardless of when the lesion was made. Thus, NAcc dopamine not only plays a role in conditioned behavioural activation, but also in making the appropriate discriminated response i.e. the direction of response. Further, acquisition lesions produced a far greater impact on discriminated approach than performance lesions. This difference in lesion-induced impairment implies that mesoaccumbens dopamine may play differential roles in the learning and performance of preparatory Pavlovian conditioning.

The preferential induction of apoptosis in multidrug-resistant KB cells by 5-fluorouracil.

It has been previously been shown that multidrug resistance may be associated with biochemical changes which increase the sensitivity of resistant cells to the induction of apoptosis by certain agents. We have shown here that 48 h exposure to 5-fluorouracil (5-FU) induces both a significantly greater proportion of apoptotic cells and much greater cleavage of the apoptosis-related protein poly-(ADP-ribose)-polymerase in the multidrug-resistant (MDR) carcinoma cell line, KB-A1, than in corresponding drug-sensitive control KB-3.1 cells. Exposure to 5-FU also reduced the level of the anti-apoptotic protein, protein kinase B, in the MDR cells, but not in the control cells.