Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

AIMS: Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. METHODS: Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. RESULTS: In Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N = 28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. CONCLUSIONS: The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Complex Language Use in Children With Hearing Loss: A Scoping Review.

PURPOSE: Understanding what is known about the language profiles of children with hearing loss (CHL) is vital so that researchers and teachers can identify the specific complex syntactic structures that CHL may struggle to master. An understanding of which aspects of complex syntax pose difficulties for CHL is necessary to inform the kind of intervention that will facilitate learning complex syntax for this cohort of children. This scoping review aims to identify what is currently known about the complex syntax use of CHL who communicate through spoken language, and uncover gaps in the literature to guide further research. METHOD: Ascoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. The Covidence software was utilized to manage the initial and full-text screening process for the search. RESULTS: From a total of 304 studies, 42 studies were identified that met the eligibility criteria. The review highlights the use of broad-based language assessments and limited use of specific descriptions of the types of complex syntactic structures and skills. CONCLUSIONS: Findings highlight the need for assessment protocols and analysis methods that better support the description of complex syntax profiles for CHL. School-age CHL continue to display challenges with complex syntax development. The review highlighted the need for further research to improve understanding of the complex syntax strengths and vulnerabilities of CHL. Further investigation is needed to better understand their ability to combine ideas and build complexity in their language use, which in turn can inform teaching in schools and interventions for children who require support. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21980177.

Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy.

Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual Bcl-2/Bcl-xL inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-xL inhibitor into clinical development.

Spina bifida and lower limb amputation in Northern Ireland: A retrospective study of demographics and outcome.

BACKGROUND: Spina bifida is an uncommon cause for lower limb amputation. The causes and level of amputation and mobility outcome for these patients have not been reported previously. CASE DESCRIPTION: To identify the causes and level of amputation and the mobility outcome for amputee patients with spina bifida. STUDY DESIGN: Retrospective case series. METHODS: Chart review of patients identified by computer as having an amputation secondary to neurological or congenital cause. Additional patients identified from the Regional Spina Bifida Medical Clinic. Demographics, cause and level of mobility pre- and post-amputation recorded from the prosthetic notes. FINDINGS: In total, 16 patients were identified who had a diagnosis of spina bifida and a lower limb amputation. Mean age at the time of amputation was 28.5 years. In total, 15 patients had a transtibial amputation. In total, 14 patients post-amputation were able to maintain their mobility, wheelchair or walking, without any change in type of aid needed. CONCLUSION: Patients with spina bifida appear to require lower limb amputation at a younger age than patients with peripheral vascular disease. Almost all patients had prior chronic skin infection/osteomyelitis as precursors for amputation. The most common level for amputation was transtibial. Mobility was maintained for all patients, albeit for two in a more supported way. Clinical relevance Spina bifida is an uncommon reason for amputation. Patients, are often younger and medically complicated. Chronic skin ulceration, was the most common indication for amputation. Wheelchair or walking ambulance was maintained at the same level for most patients.

Compliance to service standards for congenital upper limb deficiency: the Northern Ireland experience.

BACKGROUND: In 2003, the British Society of Rehabilitation Medicine (BSRM) published guidelines on amputee and prosthetic rehabilitation, including those with congenital limb deficiency. OBJECTIVES: The aim of the study was to evaluate the service provided by the Regional Disablement Service (RDS) to children with congenital upper limb deficiency, against BSRM guidelines. STUDY DESIGN: Retrospective chart review. METHODS: Chart review. RESULTS: Analysis of the group (n = 44) showed 52% were male, with 61% of children affected on the left side, and 73% having a transverse deficiency. Compliance to individual aspects of the guidelines varied considerably. Only 14 (32%) of children had met with the multidisciplinary team by the recommended age of six months. Analysis of referral sources and timings suggested that children were initially seen elsewhere and later referred to RDS after consultation with a surgeon. CONCLUSIONS: RDS compliance with the BSRM guidelines was variable. Particularly disappointing was the low rate of children and families meeting the multidisciplinary team at an early age (< 6 months). The low rate of early referral prompted us to contact all paediatricians in Northern Ireland highlighting the guidelines, the benefits of early contact with RDS and encouraging referral on diagnosis.

A comparative study of oxygen consumption for conventional and energy-storing prosthetic feet in transfemoral amputees.

OBJECTIVE: To compare oxygen consumption for traumatic high-functioning transfemoral amputees wearing initially a conventional prosthetic foot (Multiflex) and then an energy-storing prosthetic foot (Vari-Flex). SETTING: A regional prosthetic and amputee rehabilitation tertiary referral centre in a teaching hospital. STUDY DESIGN: Experimental crossover trial. SUBJECTS: Six established unilateral transfemoral prosthetic users. INTERVENTIONS: Oxygen consumption breath-by-breath analysis at multiple speeds on a treadmill for each amputee wearing initially the Multiflex foot and then repeated wearing the Vari-Flex foot. RESULTS: Mean oxygen consumption across all subjects was lower for the Vari-Flex foot than for the Multiflex foot at all speeds, although the differences were only significant at speeds of 0.83 and 1.1 m/s (P < 0.05). ANCOVA analysis across all speeds showed that oxygen consumption with the Vari-Flex foot was significantly lower (P < 0.001). The estimated difference across all speeds was 3.54 mL/kg.min. CONCLUSION: A high functioning transfemoral amputee who wears an energy-storing prosthetic foot may have significantly reduced oxygen consumption at normal walking speeds.

QuickSmart: a basic academic skills intervention for middle school students with learning difficulties.

QuickSmart is a basic academic skills intervention designed for persistently low-achieving students in the middle years of schooling that aims to improve the automaticity of basic skills to improve higher-order processes, such as problem solving and comprehension, as measured on standardized tests. The QuickSmart instructional program consists of three structured, teacher- or teacher aide-directed, 30-minute, small-group lessons each week for approximately 26 weeks. In this study, 42 middle school students experiencing learning difficulties (LD) completed the QuickSmart reading program, and a further 42 students with LD took part in the QuickSmart mathematics program. To investigate the effects of the intervention, comparisons were made between the reading and mathematics progress of the intervention group and a group of 10 high-achieving and 10 average-achieving peers. The results indicated that although the standardized reading comprehension and mathematics scores of QuickSmart students remained below those of comparison students, they improved significantly from pretest to posttest. In contrast, the standardized scores of comparison students were not significantly different from pretest to posttest. On measures of response speed and accuracy gathered using the Cognitive Aptitude Assessment System (CAAS), QuickSmart students were able to narrow the gap between their performance and that of their high- and average-achieving peers. Implications are drawn regarding the importance of interventions that emphasize the automaticity of basic academic skills for students with learning difficulties.

A comparative study of conventional and energy-storing prosthetic feet in high-functioning transfemoral amputees.

OBJECTIVE: To compare the results of gait analysis, timed walking tests, and socket comfort for transfemoral amputees wearing initially a Multiflex conventional prosthetic foot and then a Vari-Flex energy-storing prosthetic foot. DESIGN: Experimental crossover trial. SETTING: A regional prosthetic and amputee rehabilitation tertiary referral center in a teaching hospital. PARTICIPANTS: Six established unilateral transfemoral prosthetic users. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Gait analysis, a timed walking test, and a Prosthetic Socket Fit Comfort Score for each amputee wearing the Multiflex foot and then repeated wearing the Vari-Flex foot. RESULTS: Wearing the Vari-Flex foot, our subjects walked faster in the gait lab (1.38 +/- 0.13 m/s, P < .001) and took more equal step lengths at fast speed (1.063 +/- 0.05, P < .05). They also had greater peak ankle dorsiflexion at push-off on the prosthetic side (18.3 degrees +/-4.73 degrees, P<.001) and 3 times as much power from the prosthetic ankle at push-off (1.13 +/- 0.22 W/kg, P < .001). There were no significant changes in temporal symmetry or loading of the prosthetic limb, in the timed walking test with each foot, or in the comfort score. CONCLUSIONS: A transfemoral amputee who wears an energy-storing foot can have a more symmetric gait with regard to some measures of spatial symmetry, kinetics, and kinematics than one who wears a conventional foot. However, in this study important aspects such as more symmetric loading and comfort did not differ significantly between the 2 foot types.

A study of the physical rehabilitation and psychological state of patients who sustained limb loss as a result of terrorist activity in Northern Ireland 1969-2003.

OBJECTIVE: To benchmark the psychological state and physical rehabilitation of patients who have sustained limb loss as a result of terrorist activity in Northern Ireland and to determine their satisfaction with the period of primary prosthetic rehabilitation and the artificial limb. METHOD: All patients who sustained limb loss as a result of the Troubles and were referred to our rehabilitation centre were sent a questionnaire. The main outcome measures were the SIGAM mobility grades, the General Health Questionnaire (GHQ12) and three screening questions for Post Traumatic Stress Disorder (PTSD). RESULTS: Out of a 66% response rate, 52 (69%) patients felt that the period of primary prosthetic rehabilitation was adequate; 32 (54%) lower limb amputees graded themselves SIGAM C or D; 45 (60%) patients stated that they were still having significant stump pain. Significant stump pain was associated with poorer mobility. Nine (56%) upper limb amputees used their prosthetic limb in a functional way; 33 (44%) patients showed "psychiatric caseness" on the GHQ 12 and 50 (67%) had symptoms of PTSD. CONCLUSIONS: Most patients felt that the period of physical rehabilitation had been adequate; those who did not were more likely to be having ongoing psychological problems. A high percentage of patients continue to have psychological problems and stump pain.

Vegetative and minimally conscious states: serial assessment approaches in diagnosis and management.

Assessment of vegetative (VS) and minimally conscious state (MCS) patients presents clinicians with inherent difficulties (Royal College of Physicians, 2003) in terms of the reliable detection of potential signs of awareness given that all current assessment tools rely on observed behaviour. Recently developed measures such as SMART (Gill-Thwaites & Munday, 1999) and WHIM (Shiel et al., 2000), employing structured operational defined behavioural observations can facilitate the serial assessment of patient awareness, progress and appropriate goal setting particularly as one-off bedside assessments are more likely to be inaccurate. The use of sensitive tailored approaches involving experienced multidisciplinary teams is strongly advocated (Royal College of Physicians and British Society of Rehabilitation Medicine, 2003), notwithstanding clinicians should carefully consider potential confounding clinical factors, which may deleteriously influence patient arousal or ability to respond. Finally, areas for future development and recommendations regarding multidisciplinary assessment approaches with VS and MCS patients are outlined.