Get Parkinson's medications on time: the Leeds QI project.

Parkinson's disease (PD) is a common neurodegenerative disease. Delayed administration of PD medications is associated with increased risk of life-threatening complications including choking, aspiration pneumonia and neuroleptic malignant syndrome. In 2016, the spouse of a patient with PD wrote to Leeds Teaching Hospitals Trust (LTHT) to highlight that multiple medication delays and omissions had occurred during his recent admission. In response, LTHT formed a PD quality improvement (QI) Collaborative of multidisciplinary members committed to ensuring timely PD medication administration. The faculty used Institute for Healthcare Improvement Model for Improvement QI methodology. Interventions were tested on pilot wards and the most successful were scaled up and spread across all 90 adult inpatient wards as an 'intervention bundle'. Between January 2016 and June 2020 mean delays in the time from admission to first dose of medication dropped from over 7 to under 1 h. The mean percentage of omitted PD medications reduced from 15.1 to 0.6%. Project success was multifactorial but due to: Simplicity of interventions.Multiprofessional ownership by frontline teams to make changes and take prompt action.The spouse of the patient taking a leading role in the Collaborative, bringing her unique personal insight and experience, which facilitated behavioural change.

Mitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor.

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP. LEARNING POINTS: Adrenocortical carcinoma is an important differential diagnosis for virilization in young childrenMitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosisMitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completedIn our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

A New Evolutionary Algorithm-Based Home Monitoring Device for Parkinson's Dyskinesia.

Parkinson's disease (PD) is a neurodegenerative movement disorder. Although there is no cure, symptomatic treatments are available and can significantly improve quality of life. The motor, or movement, features of PD are caused by reduced production of the neurotransmitter dopamine. Dopamine deficiency is most often treated using dopamine replacement therapy. However, this therapy can itself lead to further motor abnormalities referred to as dyskinesia. Dyskinesia consists of involuntary jerking movements and muscle spasms, which can often be violent. To minimise dyskinesia, it is necessary to accurately titrate the amount of medication given and monitor a patient's movements. In this paper, we describe a new home monitoring device that allows dyskinesia to be measured as a patient goes about their daily activities, providing information that can assist clinicians when making changes to medication regimens. The device uses a predictive model of dyskinesia that was trained by an evolutionary algorithm, and achieves AUC>0.9 when discriminating clinically significant dyskinesia.

Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.

BACKGROUND: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. RESULTS: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. CONCLUSIONS: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.

What to do when people with Parkinson's disease cannot take their usual oral medications.

People with Parkinson's disease have limited brain reserves of endogenous dopamine; thus, their medications must not be omitted or delayed as this may lead to a significant drop in brain dopamine levels. This has two main clinical consequences: first, a deterioration in disease control, with distressing symptoms such as tremor, pain, rigidity, dysphagia and immobility, and second, an increased risk of developing the life-threatening complication of neuroleptic malignant-like syndrome. Common reasons for people with Parkinson's disease being unable to take their oral medications are neurogenic dysphagia from progressive disease or concurrent illness, gastroenteritis, iatrogenic 'nil by mouth' status especially perioperatively, and impaired consciousness level. Here we outline alternative methods to give dopaminergic drugs in the acute setting to people with Parkinson's disease who cannot take their usual oral treatment, namely using dispersible preparations in thickened fluids, an enteral tube, a transdermal patch or subcutaneous injections.

An unusual cause of growth failure in cystic fibrosis: A salutary reminder of the interaction between glucocorticoids and cytochrome P450 inhibiting medication.

A 12 ½ year old male with cystic fibrosis presented with growth failure after itraconazole was added to a treatment regimen including inhaled and intranasal glucocorticoids. Investigations showed severe adrenal suppression. This case demonstrates the potential for exogenous glucocorticoids to accumulate when their degradation is inhibited by a CYP3A4 inhibitor.

The incidence, clinical features, and treatment of type 2 diabetes in children <15 yr in a population-based cohort from Auckland, New Zealand, 1995­2007.

BACKGROUND: The incidence of type 2 diabetes mellitus (T2DM) is increasing in adolescents in most western countries. The time-course of glycemic control and impact of early treatment remain poorly understood. OBJECTIVES: To determine the change in incidence of T2DM, and the time-course of glycemic control in a regional pediatric cohort with T2DM. METHODS: Retrospective analysis of prospectively collected data on 52 patients with T2DM from a population-based treatment referral cohort from 1 January 1995 to 31 December 2007. RESULTS: The annual incidence of new cases of T2DM in children <15 yr increased fivefold in the Auckland region of New Zealand from 1995 [0.5/100,000; 95% confidence interval (CI) 0.0­2.2] to 2007 (2.5/100,000; 95% CI 1.0­5.5). The average annual incidence per 100,000 over the entire period was 1.3 (95% CI 1.0­1.8) overall, 0.1 (0.0­0.4) in Europeans, and 3.4 in both Maori (2.0­5.3) and Pacifica (2.2­5.0). Fifty-seven percent of children were symptomatic at presentation. Fifty-eight percent of patients were treated with insulin from diagnosis, most of whom were symptomatic (p = 0.003). Follow-up data were available for 48 patients with a mean of 2.4 yr. Although insulin therapy was associated with a greater fall in HbA1c values in the first 12 months of treatment (to a nadir of 7.1 vs. 8.1%, p < 0.05), there was a rapid deterioration after 12 months, and subsequent mean HbA1c values were >9% in both groups. Therapy did not affect body mass index standard deviation score (BMI SDS). CONCLUSIONS: The incidence of T2DM in childhood or adolescence increased markedly over a 13-yr period in the Auckland region. Long-

Longitudinal analysis of sleep in relation to BMI and body fat in children: the FLAME study.

OBJECTIVES: To determine whether reduced sleep is associated with differences in body composition and the risk of becoming overweight in young children. DESIGN: Longitudinal study with repeated annual measurements. SETTING: Dunedin, New Zealand. PARTICIPANTS: 244 children recruited from a birth cohort and followed from age 3 to 7. MAIN OUTCOME MEASURES: Body mass index (BMI), fat mass (kg), and fat free mass (kg) measured with bioelectrical impedance; dual energy x ray absorptiometry; physical activity and sleep duration measured with accelerometry; dietary intake (fruit and vegetables, non-core foods), television viewing, and family factors (maternal BMI and education, birth weight, smoking during pregnancy) measured with questionnaire. RESULTS: After adjustment for multiple confounders, each additional hour of sleep at ages 3-5 was associated with a reduction in BMI of 0.48 (95% confidence interval 0.01 to 0.96) and a reduced risk of being overweight (BMI ≥ 85th centile) of 0.39 (0.24 to 0.63) at age 7. Further adjustment for BMI at age 3 strengthened these relations. These differences in BMI were explained by differences in fat mass index (-0.43, -0.82 to -0.03) more than by differences in fat free mass index (-0.21, -0.41 to -0.00). CONCLUSIONS: Young children who do not get enough sleep are at increased risk of becoming overweight, even after adjustment for initial weight status and multiple confounding factors. This weight gain is a result of increased fat deposition in both sexes rather than additional accumulation of fat free mass.

Changes in fat mass and fat-free mass during the adiposity rebound: FLAME study.

OBJECTIVE: To determine the changes in body composition from 3 to 7 years of age in children undergoing adiposity rebound (AR) at different ages. METHODS: Body composition was measured bi-annually by bioelectrical impedance in 229 children from a birth cohort. Age at AR was calculated from changes in weight and height velocity over time. Early AR was defined as < 6.1 years (boys) and < 5.6 years (girls). Differences in fat mass (FM) and fat-free mass (FFM) and the velocity of change in these measures were calculated between early and late rebounders. Physical activity (accelerometry), time in sedentary activity, birth factors, and parental weight were compared. RESULTS: Children with early and late AR did not differ in body composition at 3 years of age, except for greater FFM in boys (by 0.8 kg, P = 0.022). In both sexes, change in body mass index (BMI) was significantly higher in early compared with late AR, and was entirely due to differences in the rate of weight gain, rather than any discrepancy in height velocity. This weight differential is predominantly due to increased deposition of FM in girls and FFM in boys. However, in both sexes, children with early rebound have significantly greater increases in FM velocity from 5 years of age. Few differences in any environmental influences were observed. CONCLUSIONS: Variation in BMI associated with the timing of AR is due to differences in weight rather than height, and sex differences in the relative contribution of FM and FFM to this additional weight gain are apparent.

Stereotypical hand movements in 144 subjects with Rett syndrome from the population-based Australian database.

Stereotypic hand movements are a feature of Rett Syndrome but few studies have observed their nature systematically. Video data in familiar settings were obtained on subjects (n = 144) identified from an Australian population-based database. Hand stereotypies were demonstrated by most subjects (94.4%), 15 categories were observed and midline wringing was seen in approximately 60% of subjects. There was a median of two stereotypies per subject but this number decreased with age. Clapping and mouthing of hands were more prevalent in girls younger than 8 years and wringing was more prevalent in women 19 years or older. Clapping was commoner in those with p.R306C and early truncating mutations, and much rarer in those with p.R106W, p.R270X, p.R168X, and p.R255X. Stereotypies tended to be less frequent in those with more severe mutations. Otherwise, there were no clear relationships between our categories of stereotypies and mutation. Approximately a quarter each had predominantly right and left handed stereotypies and for the remaining half, no clear laterality was seen. Results were similar for all cases and when restricted to those with a pathogenic mutation. Hand stereotypies changed with increasing age but limited relationships with MECP2 mutations were identified.

Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence.

STUDY DESIGN: Modified Delphi technique. OBJECTIVE: To develop guidelines for the clinical management of scoliosis in Rett syndrome through evidence review and consensus expert panel opinion. SUMMARY OF BACKGROUND DATA: Rett syndrome is a rare disorder and clinical expertise is thus with small case series. Scoliosis is a frequent association and the evidence base dealing with scoliosis management in this syndrome is limited. Parents of affected girls and women have expressed needs for more information about scoliosis and Rett syndrome. METHODS: An initial draft of scoliosis guidelines was created based on literature review and open-ended questions where the literature was lacking. Perspectives of four parents of Rett syndrome patients informed this initial draft. Access to an online and a Microsoft Word formatted version of the draft were then sent to an international, multidisciplinary panel of clinicians via e-mail with input sought using a 2-stage modified Delphi process to reach consensus agreement. Items included clinical monitoring and intervention before the diagnosis of scoliosis; monitoring after the diagnosis of scoliosis; imaging; therapy and conservative management; bracing; and preoperative, surgical, and postoperative considerations. RESULTS: The first draft contained 71 statements, 65 questions. The second draft comprised 88 items with agreement to strong agreement achieved on 85, to form the final guideline document. A comprehensive, life-span approach to the management of scoliosis in Rett syndrome is recommended that takes into account factors such as physical activity, posture, nutritional and bone health needs. Surgery should be considered when the Cobb angle is approximately 40 degrees to 50 degrees and must be supported by specialist management of anesthesia, pain control, seizures, and early mobilization. CONCLUSION: Evidence- and consensus-based guidelines were successfully created and have the potential to improve care of a complex comorbidity in a rare condition and stimulate research to improve the current limited evidence base.

Longitudinal study of physical activity and inactivity in preschoolers: the FLAME study.

PURPOSE: To investigate patterns of activity and inactivity in a birth cohort of children followed from 3 to 5 yr and to investigate whether changes in activity occurred over time. METHODS: Two hundred and forty-four children (44% female) were seen annually at 3, 4, and 5 yr. Physical activity and inactivity was measured by questionnaire (parent-proxy) and by Actical accelerometers for five consecutive days (24-h monitoring) each year in children and once in each parent for 7 d (69% with data). RESULTS: Retention of participants was high (92%). Viable accelerometry data were obtained for 76-85% of children at each age. Reliability estimates ranged from 0.80 (3 yr) to 0.84 (5 yr). Day of the week, season, sex, hours of childcare, or birth order did not affect daily average accelerometry counts (AAC) at any age. Parental activity correlated weakly with the child's activity at 3 and 4 yr (r values = 0.17-0.28), but only the father's activity remained a significant predictor of the child's activity after adjustment for confounders. Children spent approximately 90 min.d in screen time (television, videos, DVD, and computers) with an additional 90 min in other sedentary activities (reading, drawing, and music). Physical activity was significantly reduced at 4 and 5 yr compared with 3 yr in both sexes, whether measured as AAC (24-h data, awake time only, weekend days, weekdays), time in moderate or vigorous activity, or from parental reports of activity. CONCLUSION: Levels of physical activity declined in boys and girls between the ages 3 and 4-5 yr, whether using objective measures or parental reports of activity.

The effect of auditory and visual distracters on the useful field of view: implications for the driving task.

PURPOSE: The driving environment is becoming increasingly complex, including both visual and auditory distractions within the in-vehicle and external driving environments. This study was designed to investigate the effect of visual and auditory distractions on a performance measure that has been shown to be related to driving safety, the useful field of view. METHODS: A laboratory study recorded the useful field of view in 28 young visually normal adults (mean 22.6 +/- 2.2 years). The useful field of view was measured in the presence and absence of visual distracters (of the same angular subtense as the target) and with three levels of auditory distraction (none, listening only, listening and responding). RESULTS: Central errors increased significantly (P < 0.05) in the presence of auditory but not visual distracters, while peripheral errors increased in the presence of both visual and auditory distracters. Peripheral errors increased with eccentricity and were greatest in the inferior region in the presence of distracters. CONCLUSIONS: Visual and auditory distracters reduce the extent of the useful field of view, and these effects are exacerbated in inferior and peripheral locations. This result has significant ramifications for road safety in an increasingly complex in-vehicle and driving environment.