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ImportanceCerebral palsy (CP) is the most common childhood physical disability. Early intervention for children younger than 2 years with or at risk of CP is critical. Now that an evidence-based guideline for early accurate diagnosis of CP exists, there is a need to summarize effective, CP-specific early intervention and conduct new trials that harness plasticity to improve function and increase participation. Our recommendations apply primarily to children at high risk of CP or with a diagnosis of CP, aged 0 to 2 years.ObjectiveTo systematically review the best available evidence about CP-specific early interventions across 9 domains promoting motor function, cognitive skills, communication, eating and drinking, vision, sleep, managing muscle tone, musculoskeletal health, and parental support.Evidence reviewThe literature was systematically searched for the best available evidence for intervention for children aged 0 to 2 years at high risk of or with CP. Databases included CINAHL, Cochrane, Embase, MEDLINE, PsycInfo, and Scopus. Systematic reviews and randomized clinical trials (RCTs) were appraised by A Measurement Tool to Assess Systematic Reviews (AMSTAR) or Cochrane Risk of Bias tools. Recommendations were formed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and reported according to the Appraisal of Guidelines, Research, and Evaluation (AGREE) II instrument.FindingsSixteen systematic reviews and 27 RCTs met inclusion criteria. Quality varied. Three best-practice principles were supported for the 9 domains: (1) immediate referral for intervention after a diagnosis of high risk of CP, (2) building parental capacity for attachment, and (3) parental goal-setting at the commencement of intervention. Twenty-eight recommendations (24 for and 4 against) specific to the 9 domains are supported with key evidence: motor function (4 recommendations), cognitive skills (2), communication (7), eating and drinking (2), vision (4), sleep (7), tone (1), musculoskeletal health (2), and parent support (5).Conclusions and relevanceWhen a child meets the criteria of high risk of CP, intervention should start as soon as possible. Parents want an early diagnosis and treatment and support implementation as soon as possible. Early intervention builds on a critical developmental time for plasticity of developing systems. Referrals for intervention across the 9 domains should be specific as per recommendations in this guideline.

Objective: Functional assessments that focus on activity performance and that produce valid outcome measures for people with brachial plexus birth injury are lacking. The primary aim of this study was to re-evaluate the internal scale validity of the Assisting Hand Assessment specifically for children and adolescents with brachial plexus birth injury. Two further aims were investigating whether the scale could be shortened for this group while maintaining psychometric quality, and exploring and presenting its item difficulty hierarchy. Design: A cross-sectional psychometric study. Subjects: A convenience sample of 105 children and adolescents (aged 18 months to 18 years, mean 6 years, 7 months, standard deviation (SD) 4 years, 4 months) from Sweden, Norway, and the Netherlands with brachial plexus birth injury. Methods: Participants were assessed with the Assisting Hand Assessment. Data were analysed with Rasch measurement analysis. Results: The 20 Assisting Hand Assessment items together measured a unidimensional construct with high reliability (0.97) and the 4-level rating scale functioned well. Item reduction resulted in 15 items with good item fit, unidimensionality, reliability and acceptable targeting. Conclusion: Assisting Hand Assessment for people with brachial plexus birth injury, called AHA-Plex, has 15 items and good internal scale validity. A unique item hierarchy for people with brachial plexus birth injury is presented.

ImportanceCerebral palsy describes the most common physical disability in childhood and occurs in 1 in 500 live births. Historically, the diagnosis has been made between age 12 and 24 months but now can be made before 6 months' corrected age.ObjectivesTo systematically review best available evidence for early, accurate diagnosis of cerebral palsy and to summarize best available evidence about cerebral palsy-specific early intervention that should follow early diagnosis to optimize neuroplasticity and function.Evidence reviewThis study systematically searched the literature about early diagnosis of cerebral palsy in MEDLINE (1956-2016), EMBASE (1980-2016), CINAHL (1983-2016), and the Cochrane Library (1988-2016) and by hand searching. Search terms included cerebral palsy, diagnosis, detection, prediction, identification, predictive validity, accuracy, sensitivity, and specificity. The study included systematic reviews with or without meta-analyses, criteria of diagnostic accuracy, and evidence-based clinical guidelines. Findings are reported according to the PRISMA statement, and recommendations are reported according to the Appraisal of Guidelines, Research and Evaluation (AGREE) II instrument.FindingsSix systematic reviews and 2 evidence-based clinical guidelines met inclusion criteria. All included articles had high methodological Quality Assessment of Diagnostic Accuracy Studies (QUADAS) ratings. In infants, clinical signs and symptoms of cerebral palsy emerge and evolve before age 2 years; therefore, a combination of standardized tools should be used to predict risk in conjunction with clinical history. Before 5 months' corrected age, the most predictive tools for detecting risk are term-age magnetic resonance imaging (86%-89% sensitivity), the Prechtl Qualitative Assessment of General Movements (98% sensitivity), and the Hammersmith Infant Neurological Examination (90% sensitivity). After 5 months' corrected age, the most predictive tools for detecting risk are magnetic resonance imaging (86%-89% sensitivity) (where safe and feasible), the Hammersmith Infant Neurological Examination (90% sensitivity), and the Developmental Assessment of Young Children (83% C index). Topography and severity of cerebral palsy are more difficult to ascertain in infancy, and magnetic resonance imaging and the Hammersmith Infant Neurological Examination may be helpful in assisting clinical decisions. In high-income countries, 2 in 3 individuals with cerebral palsy will walk, 3 in 4 will talk, and 1 in 2 will have normal intelligence.Conclusions and relevanceEarly diagnosis begins with a medical history and involves using neuroimaging, standardized neurological, and standardized motor assessments that indicate congruent abnormal findings indicative of cerebral palsy. Clinicians should understand the importance of prompt referral to diagnostic-specific early intervention to optimize infant motor and cognitive plasticity, prevent secondary complications, and enhance caregiver well-being.

The aim is to evaluate the feasibility of an intervention model with a client-centered goal-directed approach with the aim to enhance the child’s participation in leisure activities, self-efficacy, and activity performance. A pilot intervention using a client-centered goal-directed approach and a single-subject design was performed. Two Swedish boys with neuropsychiatric diagnosis aged 12 and 14 years old were included, and 3 leisure activity goals were identified. The intervention was carried out over 8 weeks and took place in the adolescent’s everyday environment and at the pediatric rehabilitation center. The goal attainment of participation goals (GAS), the perceived performance ability according to the Canadian Occupational Performance Measure (COPM), the self-efficacy, and the participants’ satisfaction were used to study the effect. The participants succeeded in attaining their leisure goals as specified by the GAS by achieving +2 on one goal and +1 on the other two goals. They estimated higher performance ability and self-efficacy in their goal performance. Participants, parents, and therapists were overall satisfied and found the intervention to be applicable and helpful in optimizing leisure participation. The intervention model with a client-centered goal-directed approach in which participants define their own leisure activity goals appears to be effective in increasing participation in leisure activities.

Aim: The aim of this study was to describe how the usefulness of the hemiplegic hand develops in children with unilateral cerebral palsy (CP) aged between 18 months and 8 years. Method: A prospective longitudinal study of 43 children (22 males, 21 females) with unilateral CP was conducted. Inclusion age was 18 months to 5 years 4 months (mean 2y 8mo [SD 1y 1mo]). Children were assessed with the Assisting Hand Assessment (AHA) 3 to 11 times per child over a mean period of 4 years 6 months. Two models were used for grouping children: by AHA score at 18 months and by Manual Ability Classification System (MACS) levels. Estimated average motor development curves were fitted with a nonlinear mixed-effects model. Results: Children with a high AHA score (high ability level) at 18 months reached a significantly higher ability level and at a higher progression rate than children with a low 18-month AHA score. Limits of development differed between the three MACS levels. Interpretation: Results indicate that the AHA score at 18 months can be used to discuss future development of affected hand use in bimanual tasks in children with unilateral CP.

The objective of the study was to investigate the feasibility of modified constraint-induced (CI) therapy provided in a 2-week day-camp model with and without intramuscular botulinum toxin type A (BoNT-A) injections for children with congenital cerebral palsy. Sixteen children with congenital hemiplegia, Manual Ability Classification System (MACS) level I and II, aged 8-17 years, participated in a CI therapy day camp; of whom five participants (aged 11-16 years) received intramuscular BoNT-A prior to CI therapy. Assessments were conducted 4 months and 2 weeks before (baselines 1 and 2), immediately after, and 6 months after the day camp. For the children who received BoNT-A, no statistical analyses were conducted due to the small size of the sample. In this group, consistent improvement was only found according to the Melbourne Unilateral Limb Assessment. The children who received only the CI therapy demonstrated improvements in the Jebsen-Taylor Hand Function Test (p = 0.04) at posttest, but improvements were not sustained at 6-month follow-up. No significant improvement was obtained for the Melbourne Assessment or the Assisting Hand Assessment. Children in both groups improved on specially trained tasks: frisbee golf, stacking blocks, and in-hand manipulation. Feedback from the participants suggests that the day-camp model is a feasible intervention following intramuscular BoNT-A injections. The results suggest that children with congenital hemiplegia with varying severity of impairment in hand function may benefit from CI therapy, but not every child demonstrates improvements in hand function. The characteristics of children who respond the best to CI therapy are not clear. (Contains 3 tables and 5 figures.)

To reduce expression of gene products not required under stress conditions, eukaryotic cells form large and complex cytoplasmic aggregates of RNA and proteins (stress granules; SGs), where transcripts are kept translationally inert. The overall composition of SGs, as well as their assembly requirements and regulation through stress-activated signaling pathways remain largely unknown. We have performed a genome-wide screen of S. cerevisiae gene deletion mutants for defects in SG formation upon glucose starvation stress. The screen revealed numerous genes not previously implicated in SG formation. Most mutants with strong phenotypes are equally SG defective when challenged with other stresses, but a considerable fraction is stress-specific. Proteins associated with SG defects are enriched in low-complexity regions, indicating that multiple weak macromolecule interactions are responsible for the structural integrity of SGs. Certain SG-defective mutants, but not all, display an enhanced heat-induced mutation rate. We found several mutations affecting the Ran GTPase, regulating nucleocytoplasmic transport of RNA and proteins, to confer SG defects. Unexpectedly, we found stress-regulated transcripts to reach more extreme levels in mutants unable to form SGs: stress-induced mRNAs accumulate to higher levels than in the wild-type, whereas stress-repressed mRNAs are reduced further in such mutants. Our findings are consistent with the view that, not only are SGs being regulated by stress signaling pathways, but SGs also modulate the extent of stress responses. We speculate that nucleocytoplasmic shuttling of RNA-binding proteins is required for gene expression regulation during stress, and that SGs modulate this traffic. The absence of SGs thus leads the cell to excessive, and potentially deleterious, reactions to stress.

Abstract Objective To investigate interrater and intrarater reliability, measurement error, and convergent and discriminative validity of the Adult Assisting Hand Assessment Stroke (Ad-AHA Stroke). Design Cross-sectional observational study. Setting A total of 7 stroke rehabilitation centers. Participants Stroke survivors (reliability sample: n=30; validity sample: N=118) were included (median age 67y; interquartile range [IQR], 59-76); median time poststroke 81 days (IQR 57-117). Interventions N/A. Main Outcome Measures Ad-AHA Stroke, Action Research Arm Test (ARAT), upper extremity Fugl-Meyer Assessment (UE-FMA). The Ad-AHA Stroke is an observation-based instrument assessing the effectiveness of the spontaneous use of the affected hand when performing bimanual activities in adults poststroke. Reliability of Ad-AHA Stroke was examined using intraclass correlation coefficients (ICCs), Bland–Altman plots, and weighted kappa statistics for reliability on item level. SEM was calculated based on Ad-AHA units. Convergent validity was assessed by calculating Spearman rank correlation coefficients between Ad-AHA Stroke and ARA test and UE-FMA. Comparison of Ad-AHA Stroke scores between subgroups of patients according to hand dominance, neglect, and age evaluated discriminative validity. Results Intrarater and interrater agreement showed an ICC of 0.99 (95% confidence interval, 0.99-0.99), an SEM of 2.15 and 1.64 out of 100, respectively, and weighted kappa for item scores were all above 0.79. The relation between Ad-AHA and other clinical assessments was strong (ρ=0.9). Patients with neglect had significantly lower Ad-AHA scores compared to patients without neglect (P =.004). Conclusions The Ad-AHA Stroke captures actual bimanual performance. Therefore, it provides an additional aspect of upper limb assessment with good to excellent reliability and low SEM for patients with subacute stroke. High convergent validity with the ARA test and UE-FMA and discriminative validity were supported. [ABSTRACT FROM AUTHOR]

Background and Purpose: Longitudinal information regarding the prevalence of upper limb somatosensory deficits and the association with motor impairment and activity limitations is scarce. The aim of this prospective cohort study was to map the extent and distribution of somatosensory deficits, and to determine associations over time between somatosensory deficits and motor impairment and activity limitations. Methods: We recruited 32 participants who were assessed 4 to 7 days after stroke, and reassessed at 6 months. Somatosensory measurements included the Erasmus-modified Nottingham sensory assessment (Em-NSA), perceptual threshold of touch, thumb finding test, 2-point discrimination, and stereognosis subscale of the NSA. Evaluation of motor impairment comprised the Fugl-Meyer assessment, Motricity Index, and Action Research Arm Test. In addition, at 6 months, activity limitation was determined using the adult assisting hand assessment stroke, the ABILHAND, and hand subscale of the Stroke Impact Scale. Results: Somatosensory impairments were common, with 41% to 63% experiencing a deficit in one of the modalities within the first week and 3% to 50% at 6 months. In the acute phase, there were only very low associations between somatosensory and motor impairments (r = 0.03-0.20), whereas at 6 months, low to moderate associations (r = 0.32-0.69) were found for perceptual threshold of touch, thumb finding test, and stereognosis with motor impairment and activity limitations. Low associations (r = 0.01-0.29) were found between somatosensory impairments in the acute phase and motor impairments and activity limitations at 6 months. Discussion and Conclusions : This study showed that somatosensory impairments are common and suggests that the association with upper limb motor and functional performance increases with time after stroke. [ABSTRACT FROM AUTHOR]

Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of bicyclic diols to their diacetates was highly enantio- and diastereoselective to give the corresponding diacetates in high yield with high enantioselectivity (99.9 % ee). The enantiomerically pure diols are accessible by simple hydrolysis (NaOH, MeOH), but an alternative enzyme-catalyzed ester cleavage was also used to give the trans-diol (R,R)-1 b in extremely high diastereomeric purity (trans/cis=99.9:0.1, >99.9 % ee). It was demonstrated that the diols can be selectively oxidized to the ketoalcohols in a ruthenium-catalyzed Oppenauer-type reaction. A formal enantioselective synthesis of sertraline from a simple racemic cis/trans diol 1 b was demonstrated.

Chemoenzymatic dynamic kinetic resolution (DKR) via combined ruthenium and enzyme catalysis was used in the key step of a synthesis of a neonicotinoid pesticide derivative (S)-3. The DKR was carried out under mild conditions with low catalyst loading. The method gives (S)-3 in high enantiomeric excess (98%).

An efficient method for the preparation of beta,gamma-unsaturated delta-lactones has been developed. The starting materials for the synthesis of these compounds are allene-substituted malonates which undergo gold-catalyzed cyclization by means of nucleophilic attack of the ester moiety on the allene. It is worth mentioning that this is the first example where an ester group attacks as a nucleophile in a gold-catalyzed transformation of allenes.

Directed evolution of Pseudomonas aeruginosa lipase by the use of combinatorial active site saturation test (CAST) criteria provided a highly enantioselective mutant (Leu162Phe) for kinetic resolution of an axially chiral allene, p-nitrophenyl 4-cyclohexyl-2-methylbuta-2,3-dienoate (E=111); the high enantioselectivity of the Leu162Phe mutant was rationalized by pi-pi stacking.