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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.

Aim: To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic‐ischaemic encephalopathy (HIE). Method: This was a systematic review of randomized controlled trials (RCTs) (with meta‐analysis) and non‐RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long‐term major neurodevelopmental disability). Results: Twenty‐five RCTs (2099 infants) and four non‐RCTs (871 infants) were included, 23 in low‐ and middle‐income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53–0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58–0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34–1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86–10.46; one RCT). No reduction in death or long‐term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14–1.89; one RCT) but reductions in several short‐term adverse outcomes were observed with magnesium sulphate. Evidence was low‐ to very‐low certainty because of risk of bias and imprecision. Interpretation: Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high‐quality studies to determine stand‐alone effects in LMICs and effects with and after therapeutic hypothermia in high‐income countries. [ABSTRACT FROM AUTHOR]

Touch is an essential form of non-verbal communication. While language and its neural basis are widely studied, tactile communication is less well understood. We used fMRI and multivariate pattern analyses in pairs of emotionally close adults to examine the neural basis of human-to-human tactile communication. In each pair, a participant was designated either as sender or as receiver. The sender was instructed to communicate specific messages by touching only the arm of the receiver, who was inside the scanner. The receiver then identified the message based on the touch expression alone. We designed two multivariate decoder algorithms—one based on the sender's intent (sender-decoder), and another based on the receiver's response (receiver-decoder). We identified several brain areas that significantly predicted behavioural accuracy of the receiver. Regarding our a priori region of interest, the receiver's primary somatosensory cortex (S1), both decoders were able to accurately differentiate the messages based on neural activity patterns here. The receiver-decoder, which relied on the receivers' interpretations of the touch expressions, outperformed the sender-decoder, which relied on the sender's intent. Our results identified a network of brain areas involved in human-to-human tactile communication and supported the notion of non-sensory factors being represented in S1. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to describe the surgeon's ability to accurately predict the margin following resection of colorectal liver metastases (CRLMs). Background: The decision to resect CRLM is based on the surgeon's ability to predict tumor-free resection margins. However, to date, no study has evaluated the accuracy of surgeon margin prediction. Methods: In this single-institution prospective study, the operating attending and fellow independently completed a preoperative and postoperative questionnaire describing their expected resection margin in 100 consecutive cases (200 assessments) of CRLM resections. In cases with multiple metastases, the closest margin was assessed as the margin of interest for the primary outcome. Surgeon assessments were compared with the gold-standard histopathologic assessment. Results: After excluding aborted cases, 190 preoperative and 190 postoperative assessments from 95 cases were included in the analysis. The pathologic margin was noted to be wide (=1 cm), 1 mm to 1 cm, narrow (<1 mm), and positive in 28 (29.5%), 55 (57.9%), 5 (5.3%), and 7 (7.4%) cases, respectively. The 88 cases with negative margins were all predicted to be negative. None of the cases with positive margins were predicted to be positive. Ninety-one (48%) preoperative and 104 (55%) postoperative predictions were accurate. The sensitivity of predicting a margin <1 mm was 8.3% preoperatively and 16.7% postoperatively. The positive predictive value for preoperative and postoperative predictions of margin <1 mm was 18.2% and 26.7%, respectively. Conclusions: Surgeons are inaccurate at predicting positive and close surgical margins following resection of CRLM. A predicted close margin should not necessarily preclude resection. [ABSTRACT FROM AUTHOR]

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.

Aim: To describe the relationships between outpatient encounters, continuity of care, and unplanned hospital care in children/young people with cerebral palsy (CP). Method: In this population‐based data‐linkage cohort study we included children/young people with CP identified in the New South Wales/Australian Capital Territory CP Register (birth years 1994–2018). We measured the frequency of outpatient encounters and unplanned hospital care, defined as presentations to emergency departments and/or urgent hospital admissions (2015–2020). Continuity of outpatient care was measured using the Usual Provider of Care Index (UPCI). Results: Of 3267 children/young people with CP, most (n = 2738, 83.8%, 57.6% male) had one or more outpatient encounters (123 463 total encounters, median six outpatient encounters per year during childhood). High UPCI was more common in children/young people with mild CP (Gross Motor Function Classification System levels I–III, with no epilepsy or no intellectual disability), residing in metropolitan and areas of least socioeconomic disadvantage. Low UPCI was associated with four or more emergency department presentations (adjusted odds ratio [aOR] 2.34; 95% confidence interval [CI] 1.71–3.19) and one or more urgent hospital admissions (aOR 2.02; 95% CI 1.57–2.61). Interpretation: Children/young people with CP require frequent outpatient services. Improving continuity of care, particularly for those residing in regional/remote areas, may decrease need for unplanned hospital care. What this paper adds: Many children with cerebral palsy use multiple and frequent outpatient services.Better continuity of care is associated with living in metropolitan and less socioeconomically disadvantaged areas.Outpatient service utilization reduces at the time of transition to adult services.High outpatient utilization is associated with unplanned hospital care.Decreased continuity of care is associated with unplanned hospital care. [ABSTRACT FROM AUTHOR]

Aim: To investigate clinicoradiological features associated with epilepsy, its resolution, and drug resistance in children with cerebral palsy (CP). Method: Data were gathered from the New South Wales/Australian Capital Territory CP Register, encompassing children with CP born between 2003 and 2015 (n = 1916). Clinical features and the severity of impairments were compared among three groups: children with current epilepsy (n = 604), those with resolved epilepsy by age 5 years (n = 109), and those without epilepsy (n = 1203). Additionally, a subset of the registry cohort attending Children's Hospital Westmead (n = 256) was analysed to compare epilepsy and treatment characteristics between drug‐responsive (n = 83) and drug‐resistant groups (n = 147) using logistic regression and hierarchical cluster analysis. Results: Manual Ability Classification System levels IV and V, intellectual impairment, and vision impairment were found to be associated with epilepsy in children with CP on multivariable analysis (p < 0.01). Moderate to severe intellectual impairment and bilateral spastic CP were independent positive and negative predictors of epilepsy persistence at the age of 5 years respectively (p < 0.05). Microcephaly and multiple seizure types were predictors of drug‐resistant epilepsy (area under the receiver operating characteristic curve of 0.83; 95% confidence interval 0.77–0.9). Children with a known genetic cause (14%) and CP epilepsy surgery group (4.3%) formed specific clinical subgroups in CP epilepsy. Interpretation: Our study highlights important clinical associations of epilepsy, its resolution, and treatment response in children with CP, providing valuable knowledge to aid in counselling families and identifying distinct prognostic groups for effective medical surveillance and optimal treatment. What this paper adds: Severe motor and non‐motor impairments in cerebral palsy (CP) increase epilepsy risk.Epilepsy more likely resolves in bilateral spastic and milder CP impairments.Epilepsy in CP often manifests at an early age with multiple seizure types and high drug resistance.Children with a known genetic cause and CP epilepsy surgery group represent distinct clinical subgroups. [ABSTRACT FROM AUTHOR]

Aim: To provide a description of cerebral palsy (CP) registers globally, identify which aim to report on CP epidemiology, and report similarities and differences across topics of importance for the sustainability and collaboration between registers. Method: Representatives of all known CP registers globally (n = 57) were invited to participate. The online survey included 68 questions across aims, methodologies, output/impact, and stakeholder involvement. Responses were analysed using descriptive statistics. Results: Forty‐five registers participated, including three register networks. Twenty were newly established or under development, including 12 in low‐ and middle‐income countries (LMICs). An epidemiological aim was reported by 91% of registers. Funding is received by 85% of registers, most often from not‐for‐profit organizations. CP definitions are comparable across registers. While the minimum data set of a register network is used by most registers, only 25% of identified items are collected by all three register networks. Ninety per cent of registers measure research activities/output, and 64% measure research impact. People with lived experience are involved in 62% of registers. Interpretation: There has been a recent surge in CP registers globally, particularly in LMICs, which will improve understanding of CP epidemiology. Ongoing efforts to address identified methodological differences are essential to validate comparison of results and support register collaboration. What this paper adds: Cerebral palsy (CP) registers represent an increasing number of regions, including low‐ and middle‐income, worldwide.Most registers collect the minimum data set of a CP register network.Research activities/output and impact are measured by most registers.The majority of registers involve people with lived experience in operation or research. [ABSTRACT FROM AUTHOR]

Aim: To characterize motor disorders in children and young people with cerebral palsy (CP). Method: This was a cross‐sectional study of 582 children and young people with CP (mean age 9 years 7 months; range 11 months–19 years 9 months; standard deviation 4 years 11 months; 340 males) attending a rehabilitation clinic at a specialized children's hospital (May 2018–March 2020). Data on motor disorders, topography, functional classifications, and non‐motor features, such as epilepsy, intellectual disability, and sensory impairments, were collected using the Australian Cerebral Palsy Register CP Description Form. Results: Fifty‐five per cent (n = 321) of children and young people with CP presented with multiple motor disorders, often affecting the same limb(s). The most common motor disorders were spasticity and dystonia (50%), spasticity only (36%), and dystonia only (6%), but 18 different combinations were identified, including choreoathetosis, ataxia, and generalized hypotonia with increased reflexes. Children with spasticity only had less severe functional deficits (p < 0.001) and lower rates of associated intellectual disability (p < 0.01) and epilepsy (p < 0.001) than those with both spasticity and dystonia. Interpretation: Multiple motor disorders in children and young people with CP are common and associated with more severe functional impairment. Accurate assessment of motor disorders is essential to guide prognosis and ensure personalized evidence‐based interventions. What this paper adds: More than half of children and young people with cerebral palsy presented with multiple motor disorders.Dystonia was identified in 60% of study participants.Dystonia was associated with more severe functional impairments and rates of non‐motor features. [ABSTRACT FROM AUTHOR]

PURPOSE: Intrahepatic cholangiocarcinoma (ICCA) is characterized by significant phenotypic and clinical heterogeneities and poor response to systemic therapy, potentially related to underlying heterogeneity in oncogenic alterations. We aimed to characterize the genomic heterogeneity between primary tumors and advanced disease in patients with ICCA. METHODS: Biopsy-proven CCA specimens (primary tumor and paired advanced disease [metastatic disease, progressive disease on systemic therapy, or postoperative recurrence]) from two institutions were subjected to targeted next-generation sequencing. Overall concordance (oncogenic driver mutations, copy number alterations, and fusion events) and mutational concordance (only oncogenic mutations) were compared across paired samples. A subgroup analysis was performed on the basis of exposure to systemic therapy. Patients with extrahepatic CCA (ECCA) were included as a comparison group. RESULTS: Sample pairs from 65 patients with ICCA (n = 54) and ECCA (n = 11) were analyzed. The median time between sample collection was 19.6 months (range, 2.7-122.9). For the entire cohort, the overall oncogenic concordance was 49% and the mutational concordance was 62% between primary and advanced disease samples. Subgroup analyses of ICCA and ECCA revealed overall/mutational concordance rates of 47%/58% and 60%/84%, respectively. Oncogenic concordance was similarly low for pairs exposed to systemic therapy between sample collections (n = 50, 53% overall, 68% mutational). In patients treated with targeted therapy for IDH1/2 alterations (n = 6) or FGFR2 fusions (n = 3), there was 100% concordance between the primary and advanced disease specimens. In two patients, FGFR2 (n = 1) and IDH1 (n = 1) alterations were detected de novo in the advanced disease specimens. CONCLUSION: The results reflect a high degree of heterogeneity in ICCA and argue for reassessment of the dominant driver mutations with change in disease status. The low concordance between primary and recurrent/metastatic IHC reflects a high degree of genomic heterogeneity. [ABSTRACT FROM AUTHOR]