Management of chronic kidney disease for Maori in Aotearoa New Zealand: a summary of clinical practice guidelines.

AIMS: The kaupapa of the Caring for Australians and New Zealanders with Kidney Impairment (CARI) Clinical practice guidelines for management of chronic kidney disease for Maori in Aotearoa New Zealand is to provide whanau-centred and evidence-based recommendations to healthcare systems, healthcare providers and healthcare workers. The guidelines include screening, identification, management and system-level responses to chronic kidney disease (CKD) to deliver best practice care to Maori affected by CKD across community, primary and secondary services. METHODS: The guidelines are funded by the Ministry of Health - Manatu Hauora and are written by a panel of Maori and non-Maori clinicians and literacy experts across Aotearoa New Zealand from Kaupapa Maori organisations, general practice and nephrology units using standardised methods. The guidelines methodology included consultation with whanau Maori with lived experience of CKD and primary and secondary care practitioners. Additional guideline development would be required to inform management of CKD for non-Maori in Aotearoa New Zealand. RESULTS: The guidelines provide recommendations about equity, governance and accountability, cultural safety, case management, information systems, social determinants of equity and wellbeing and screening. CONCLUSIONS: Recommendations to health services for Maori with CKD are based on giving effect to Te Tiriti o Waitangi and best practice care to prevent CKD, delaying its progression, treating kidney failure through timely transplantation, delivering in community and providing high-quality symptom management.

Causation in cerebral palsy: Parental beliefs and associated emotions.

AIM: To better understand parents' beliefs about causation in cerebral palsy (CP) and the emotions related to those beliefs. METHOD: We surveyed 226 parents of children with CP aged 1 to 18 years, recruited from the Victorian Cerebral Palsy Register, to evaluate their beliefs about the causes of CP, including genetic causes, causes specific to their own child, and their attitudes and emotions in relation to these. RESULTS: Although 92% of participants reported that understanding the causes of their child's CP was important, uncertainty about the cause was expressed by 13%. The most frequently endorsed causal factors, in general and in their own child respectively, were intrapartum hypoxia (81%, 36%) or brain damage (69%, 22%), brain damage during pregnancy (73%, 28%), and preterm birth (66%, 28%). Genetic causes were deemed relevant by 13% of participants and hospital or professional error by 16%. Parents shared related feelings of anger (59%), sadness (80%), guilt (61%), and confusion (53%); parental anger was more likely when their child's CP was attributed to intrapartum events. INTERPRETATION: Substantial parental interest in understanding the causes of CP, together with uncertainty about the causes, parents' causal attributions, and significant emotional sequelae, highlight a strong need for provision of information and support for families of children recently diagnosed with CP. WHAT THIS PAPER ADDS: Understanding the causes of their child's cerebral palsy (CP) was important to parents. Parents most often endorsed intrapartum factors as a cause of CP. Parents reported experiencing strong emotions about the causes of their child's CP.

Distinct manifestations and potential mechanisms of seizures due to cortical versus white matter injury in children.

PURPOSE: To study seizure manifestations and outcomes in children with cortical versus white matter injury, differences potentially explaining variability of epilepsy in children with cerebral palsy. METHODS: In this population-based retrospective cohort study, MRIs of children with cerebral palsy due to ischemia or haemorrhage were classified according to presence or absence of cortical injury. MRI findings were then correlated with history of neonatal seizures, seizures during childhood, epilepsy syndromes, and seizure outcomes. RESULTS: Of 256 children studied, neonatal seizures occurred in 57 and seizures during childhood occurred in 93. Children with neonatal seizures were more likely to develop seizures during childhood, mostly those with cortical injury. Cortical injury was more strongly associated with (1) developing seizures during childhood, (2) more severe epilepsy syndromes (infantile spasms syndrome, focal epilepsy, Lennox-Gastaut syndrome), and (3) less likelihood of reaching > 2 years without seizures at last follow-up, compared to children without cortical injury. Children without cortical injury, mainly those with white matter injury, were less likely to develop neonatal seizures and seizures during childhood, and when they did, epilepsy syndromes were more commonly febrile seizures and self-limited focal epilepsies of childhood, with most achieving > 2 years without seizures at last follow-up. The presence of cortical injury also influenced seizure occurrence, severity, and outcome within the different predominant injury patterns of the MRI Classification System in cerebral palsy, most notably white matter injury. CONCLUSIONS: Epileptogenesis is understood with cortical injury but not well with white matter injury, the latter potentially related to altered postnatal white matter development or myelination leading to apoptosis, abnormal synaptogenesis or altered thalamic connectivity of cortical neurons. These findings, and the potential mechanisms discussed, likely explain the variability of epilepsy in children with cerebral palsy and epilepsy following early-life brain injury in general.

Neonatal well-being and timing of brain injury in persons with cerebral palsy born at term or late preterm.

AIM: To describe the distribution of neuroimaging patterns in a term/late preterm population-based cohort with cerebral palsy (CP), ascertain associations between neuroimaging patterns and neonatal well-being, estimate the proportion with antenatal or perinatal timing of neuropathology, and apply this information to the understanding of common mechanisms of brain injury and causal pathways. METHOD: The cohort for this observational study comprised 1348 persons born between 1999 and 2017 in Victoria, Australia. Using algorithms designed for the study, neonatal well-being and timing of brain injury were tabulated for the whole cohort and across neuroimaging patterns and birth epochs. RESULTS: Clinical and demographic profiles, neonatal well-being, and timing of brain injury differed across neuroimaging patterns. An estimated 57% of the cohort had a complicated neonatal period. Timing of brain injury was antenatal in 57% and perinatal in 41%. A decrease in the relative proportions of perinatal timing of brain injury was observed over a period when the rates of CP in live births at term decreased. INTERPRETATION: This study begins to bridge the knowledge gap about causation in CP, moving towards better description of the main mechanisms of brain injury and their contribution within CP cohorts, and facilitating the ability to monitor changes over time and the success of preventive measures.

Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs.

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Developmental outcomes for survivors of placental laser photocoagulation for the management of twin-to-twin transfusion syndrome.

BACKGROUND: Fetoscopic laser coagulation of placental anastomoses reverses the pathological process in twin-to-twin transfusion syndrome, thereby increasing survival, but there are a paucity of studies addressing long-term neurodevelopmental outcome of survivors. This study aimed to ascertain the presence of neurodevelopmental disabilities in child survivors of monochorionic pregnancies managed by placental laser photocoagulation in the Australian state of Victoria. METHODS: All pregnancies undergoing placental laser photocoagulation with the Victorian Fetal Therapy Service between 2006-2017 were included. Information on each surviving child, including demographics, perinatal course, and developmental progress was collected from parents, and consent was sought to complete the Child Behaviour Checklist. Interviewers evaluated whether this information was consistent with a diagnosis of any of 14 neurodevelopmental conditions. A three-tiered outcome measure was allocated for each child: (1) unimpaired or developmentally normal, (2) mild or moderate neurological impairment, or (3) severe neurological impairment. Clinical predictors for adverse outcome were identified. RESULTS: Of 116 pregnancies (113 twin, 3 triplet), 96 (83%) resulted in 1 + surviving fetuses. 57/113 (50%) twin pregnancies resulted in 2 survivors, 36 (32%) in 1 survivor, and 20 (18%) in no survivors. Of the 235 fetuses, 154 (65.5%) survived to follow-up. Survival increased from 59% in 2006-2008 to 73% in 2015-2017. 90/154 (58%) survivors were followed up at a mean age of 7.5 [SD 3.0] years. Based on parental interview and Child Behaviour Checklist data, 28/90 (31%) participants were assessed as having neurodevelopmental impairment, 27 of mild-moderate severity and 1 severe. Speech/language disorders, attention deficit (hyperactivity) disorders, and fine motor impairment were most common. Neonatal length of stay conferred the highest risk of impairment. CONCLUSION: Substantial variation exists between fetal therapy services in the type and length of neonatal follow-up following fetoscopic laser coagulation, contributing to a lack of data on long-term outcomes. The findings from this study support increasingly urgent calls to undertake systematic and sustained follow-up of fetoscopic laser coagulation survivors until school age. Information from this study may assist parents in their decision-making when offered fetal surgery. Importantly, it highlights a group for targeted surveillance and early intervention.

Paroxysmal Nonepileptic Events in Children With Epilepsy and Cerebral Palsy.

Objective: To determine the frequency of paroxysmal nonepileptic events in children with cerebral palsy due to brain injury who have epilepsy and to describe the factors associated with paroxysmal nonepileptic events. Methods: Retrospective, population-based study of children from the Victorian CP Register born 1999-2006. Neuroimaging, medical records, electroencephalograms (EEG), and EEG requests were analyzed. Results: Of the included 256 children, 87 had epilepsy. EEGs (with video correlation) were available for 82 of 87. Eighteen (18/82, 22%) had epileptic events captured on EEG. Twenty-one (21/82, 26%) had paroxysmal nonepileptic events captured on EEG. The majority (13/18, 77%) of children with epileptic events also had paroxysmal nonepileptic events captured. Ten parents and carers continued to report events as epileptic despite there being no ictal EEG correlate for specific events on multiple EEGs. There were no clear associations to identify which children would have ongoing paroxysmal nonepileptic events reported. Conclusions: Paroxysmal nonepileptic events were captured on EEG in one-fourth of children from this cerebral palsy cohort with epilepsy and available EEG. Half the parents and carers reported previously identified paroxysmal nonepileptic events as epileptic on subsequent EEGs, highlighting the need for clearer counseling so that parents better understand seizure semiology in children with EEG-proven paroxysmal nonepileptic events.

Epilepsy syndromes in cerebral palsy: varied, evolving and mostly self-limited.

Seizures occur in approximately one-third of children with cerebral palsy. This study aimed to determine epilepsy syndromes in children with seizures and cerebral palsy due to vascular injury, anticipating that this would inform treatment and prognosis. We studied a population-based cohort of children with cerebral palsy due to prenatal or perinatal vascular injuries, born 1999-2006. Each child's MRI was reviewed to characterize patterns of grey and white matter injury. Children with syndromic or likely genetic causes of cerebral palsy were excluded, given their inherent association with epilepsy and our aim to study a homogeneous cohort of classical cerebral palsy. Chart review, parent interview and EEGs were used to determine epilepsy syndromes and seizure outcomes. Of 256 children, 93 (36%) had one or more febrile or afebrile seizures beyond the neonatal period and 87 (34%) had epilepsy. Children with seizures were more likely to have had neonatal seizures, have spastic quadriplegic cerebral palsy and function within Gross Motor Function Classification System level IV or V. Fifty-six (60%) children with seizures had electroclinical features of a self-limited focal epilepsy of childhood; we diagnosed these children with a self-limited focal epilepsy-variant given the current International League Against Epilepsy classification precludes a diagnosis of self-limited focal epilepsy in children with a brain lesion. Other epilepsy syndromes were focal epilepsy-not otherwise specified in 28, infantile spasms syndrome in 11, Lennox-Gastaut syndrome in three, genetic generalized epilepsies in two and febrile seizures in nine. No epilepsy syndrome could be assigned in seven children with no EEG. Twenty-one changed syndrome classification during childhood. Self-limited focal epilepsy-variant usually manifested with a mix of autonomic and brachio-facial motor features, and occipital and/or centro-temporal spikes on EEG. Of those with self-limited focal epilepsy-variant, 42/56 (75%) had not had a seizure for >2 years. Favourable seizure outcomes were also seen in some children with infantile spasms syndrome and focal epilepsy-not otherwise specified. Of the 93 children with seizures, at last follow-up (mean age 15 years), 61/91 (67%) had not had a seizure in >2 years. Children with cerebral palsy and seizures can be assigned specific epilepsy syndrome diagnoses typically reserved for normally developing children, those syndromes commonly being age-dependent and self-limited. Compared to typically developing children with epilepsy, self-limited focal epilepsy-variant occurs much more commonly in children with cerebral palsy and epilepsy. These findings have important implications for treatment and prognosis of epilepsy in cerebral palsy, and research into pathogenesis of self-limited focal epilepsy.

Temporal trends, clinical characteristics, and sociodemographic profile of post-neonatally acquired cerebral palsy in Australia, 1973-2012: A population-based observational study.

AIM: To describe post-neonatally acquired (PNN) cerebral palsy (CP) in terms of temporal trends in prevalence, clinical and sociodemographic profiles, known causes and associations between causes, and sociodemographic variables. METHOD: Numerator data, a count of children with PNN-CP confirmed at 5 years of age (n = 523), was drawn from two Australian state CP registers (birth years 1973-2012). Poisson regression was used to investigate temporal trends in the prevalence of PNN-CP by 5-year intervals, calculated per 10 000 live births. Using data from all state and territory Australian CP registers (n = 469), distributions of clinical characteristics, PNN-CP causes, and sociodemographic factors were tabulated (birth years 1995-2012). χ2 and logistic regression analyses were used to assess associations between sociodemographic profile, Australian reference data, and known causes. RESULTS: A significant temporal decline in PNN-CP in Victoria (p = 0.047) and Western Australia (p = 0.033) was observed. The most common proximal causes of PNN-CP were cerebrovascular accidents (34%, n = 158), infection (25%, n = 117), and non-accidental injuries (12%, n = 58). Children born to teenage mothers, Aboriginal and/or Torres Strait Islander mothers, or children born in remote areas were over-represented in this cohort compared with reference data (all p ≤ 0.001). Infectious causes were strongly associated with teenage motherhood (odds ratio 3.0 [95% confidence interval 1.1-8.2], p = 0.028) and remote living (odds ratio 4.5 [95% confidence interval 2.0-10.2], p < 0.001). INTERPRETATION: Although prevalence of PNN-CP has declined, the over-representation of priority populations, and the relative severity of a condition that is largely preventable, suggest the need for more specific primary preventive measures and support. WHAT THIS PAPER ADDS: Prevalence of post-neonatally acquired (PNN) cerebral palsy (CP) in Australia significantly declined between 1973 and 2012. Cerebrovascular accidents are the most common proximal cause of PNN-CP. Children born in remote areas are at greater risk of PNN-CP.

Survival of individuals with cerebral palsy in Victoria, Australia: A longitudinal cohort study spanning four decades.

AIM: To provide an updated description of the rates, trends, and predictors of mortality of individuals with cerebral palsy (CP), born in the Australian state of Victoria between 1970 and 2012. METHOD: Data were extracted for 4807 individuals (2091 females; 2716 males). The probability of survival to 30th June 2017 was calculated using the Kaplan-Meier method. Mortality rates were calculated per 1000 person-years using age strata and compared with population mortality rates to produce mortality ratios. Cox proportional hazards regression was used to calculate hazard ratios for selected demographic and clinical characteristics and to estimate the effect of birth epoch on 15-year survival. RESULTS: There were 666 recorded deaths. Compared to the general population, mortality was higher for all persons with CP and highest for children aged 1 to 15 years (45-62 times). We observed 35% improvement in the probability of survival to 15 years for births in the 2000s relative to the 1970s (hazard ratio 0.65, 95% confidence interval [CI] 0.49, 0.86), but only 4% improvement for the subgroup with complex CP (hazard ratio 0.96, 95% CI 0.69, 1.33). INTERPRETATION: The observed improvements in survival for those born in the 2000s is likely related predominantly to a proportional reduction in complex CP within the cohort. WHAT THIS PAPER ADDS: Length of survival improved for Australians with cerebral palsy (CP) born this millennium. Improved survival was mainly because of a proportional reduction in complex CP. A small improvement in length of survival was seen for children with complex CP.

Ten-year follow-up study found that motor-free intelligence quotient declined in children with mild-to-moderate cerebral palsy.

AIM: This 10-year follow-up study examined cognitive change in a cohort of children with cerebral palsy from preschool to adolescence at the group and individual levels. METHODS: The Wechsler Preschool and Primary Scale of Intelligence was administered to 80 children with cerebral palsy (mean = 4 years 6 months, standard deviation = 7 months) at baseline (Time 1). At 10-year follow-up (Time 2), 28 adolescents (mean = 14 years 6 months, standard deviation = 9 months) returned for assessment with the Wechsler Intelligence Scale for Children. Motor-free intelligence quotient (IQ) scores were calculated and paired-samples t-tests and the Reliable Change Index (RCI) were used to investigate change in IQ over time. RESULTS: At the group level, nonverbal IQ scores declined significantly. At the individual level, RCI indicated nine and 11 children showed a clinically significant decline in Full Scale IQ (FSIQ) and nonverbal IQ scores, respectively. Decline in FSIQ was related to a history of seizures whereas decline in nonverbal IQ was associated with higher initial IQ. CONCLUSION: Cognitive abilities in children with cerebral palsy evolve over time and selective deficits may not be observable until a later age, highlighting the importance of repeated cognitive assessment throughout childhood and adolescence.

Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.

Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole-exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease cosegregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population-based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP-1 inhibitors may be a potential therapy for some chordoma patients.

Systematic review and meta-analysis of the therapeutic management of patients with cervicogenic dizziness.

BACKGROUND: Patients with cervicogenic dizziness (CGD) present with dizziness, cervical spine dysfunctions, and postural imbalance, symptoms that can significantly impact their daily functioning. OBJECTIVES: To provide evidence-based recommendations for the management of patients with CGD. METHODS: Three databases were searched for randomized controlled trials (RCTs) (last search 15 May 2021). Outcome measures included dizziness, cervical spine, and balance parameters. Cochrane standard methodological procedures were used and included the RoB 2.0 and GRADE. Where possible, RCTs were pooled for meta-analysis. RESULTS: Thirteen RCTs (n = 898 patients) of high (two RCTs), moderate (five RCTs), and low (six RCTs) methodological quality were analyzed. Six RCTs were included in the meta-analysis. Only three RCTs specified the cause of CGD. They showed inconsistent findings for the effectiveness of exercise therapy in patients with traumatic CGD. Manual therapy and manual therapy combined with exercise therapy may reduce CGD, cervical spine, and balance dysfunctions. CONCLUSION: There is moderate quality of evidence that manual therapy reduces CGD, cervical spine, and balance symptoms. When manual therapy is combined with exercise therapy, the positive effect on CGD, cervical spine, and balance symptoms is even stronger. However, the quality of the evidence here is very low.

BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks.

The interaction between tumor suppressor BRCA2 and DSS1 is essential for RAD51 recruitment and repair of DNA double stand breaks (DSBs) by homologous recombination (HR). We have generated mice with a leucine to proline substitution at position 2431 of BRCA2, which disrupts this interaction. Although a significant number of mutant mice die during embryogenesis, some homozygous and hemizygous mutant mice undergo normal postnatal development. Despite lack of radiation induced RAD51 foci formation and a severe HR defect in somatic cells, mutant mice are fertile and exhibit normal RAD51 recruitment during meiosis. We hypothesize that the presence of homologous chromosomes in close proximity during early prophase I may compensate for the defect in BRCA2-DSS1 interaction. We show the restoration of RAD51 foci in mutant cells when Topoisomerase I inhibitor-induced single strand breaks are converted into DSBs during DNA replication. We also partially rescue the HR defect by tethering the donor DNA to the site of DSBs using streptavidin-fused Cas9. Our findings demonstrate that the BRCA2-DSS1 complex is dispensable for RAD51 loading when the homologous DNA is close to the DSB.

Clinical characteristics and diagnostic aspects of cervicogenic dizziness in patients with chronic dizziness: A cross-sectional study.

BACKGROUND AND OBJECTIVES: Chronic dizziness can significantly affect quality of life, but identifying the underlying cause remains challenging. This study focuses on proprioceptive cervicogenic dizziness (CGD) and aims: (1) to compare clinical test results between patients with CGD, dizzy patients without CGD, and healthy controls; and (2) to evaluate the diagnostic value of the clinical tests for CGD in patients with chronic dizziness. METHODS: Sixty patients with chronic dizziness (18 with CGD and 42 without CGD), and 43 healthy controls underwent clinical tests evaluating neck function (mobility, proprioception, muscle function and disability), balance control, and the presence of visually induced dizziness. Data were analysed through one-way ANOVA, chi-square, independent samples t-test, and logistic regression analyses. RESULTS: Patients with CGD had significantly more neck pain-related disability (Neck Bournemouth questionnaire (NBQ), p = 0.006), but better static (Static Balance, p = 0.001) and dynamic balance (Tandem Gait, p = 0.049), compared to dizzy patients without CGD. Univariable analyses revealed that increased NBQ (OR 1.05 [1.01; 1.09], p = 0.017), Joint Position Error (JPE) after extension (OR 1.52 [1.00; 2.32], p = 0.050), and Tandem Gait scores (OR 1.09 [1.01; 1.18], p = 0.046) were individually associated with higher odds of having CGD. Their optimal cut-off level (based on the maximum Youden index) had high sensitivity but low specificity for CGD. The multivariable model, including NBQ and Tandem Gait, had fair discriminative ability (AUC = 0.74, 95% CI [0.61; 0.87]). CONCLUSION: The combined use of the NBQ and Tandem Gait tests had the highest discriminative ability to detect CGD in patients with chronic dizziness.

iSelf-Help: a co-designed, culturally appropriate, online pain management programme in Aotearoa.

INTRODUCTION: Current best practice recommends group-based pain management programmes for long-term improvements in persistent pain-related disability. However, there are barriers for people to access in-person delivered pain management programmes in Aotearoa. AIMS: To develop a co-designed, culturally responsive, online group-based pain management programme (iSelf-help) for people with persistent pain. METHODS: A modified participatory action research (PAR) framework was used to co-design contents and cultural-appropriateness of iSelf-help. The PAR team included: (1) seven end-users living with persistent pain, who had previously attended an in-person delivered group pain management programme, (2) two pain management clinicians, (3) two health researchers, (4) two digital health experts, and (5) a health literacy expert. Five meetings were held with the PAR group and a Nominal Group Technique was used to rank order the preferred features of content delivery. In parallel, to ensure cultural appropriateness of iSelf-help, three focus groups (n = 15) were held with Maori (the Indigenous population of Aotearoa) living with persistent pain in collaboration with a Maori community health trust. All contents were reviewed by a Maori Health literacy expert and core contents were translated into Te Reo (Maori language). All contents were finalised by iterative discussion among the PAR team and consultation with Maori stakeholders. The preliminary version of iSelf-help was pilot tested with the PAR group participants and Maori community members living with persistent pain and their feedback was included. The iterative co-design process occurred over a period of nine months. RESULTS: The finalised version of iSelf-help included a total of 130 resources organised in to 12 content relevant online modules plus a dedicated welcoming page and an online community forum. Each module included: short videos, animations explaining main concepts, patient stories, written content to accompany visual content, podcasts of relaxation techniques, illustrated texts, and evidence-summaries. A dedicated module of videos demonstrating cardiovascular and strengthening exercises of varying intensity was also included. CONCLUSIONS: This is the first co-created, culturally appropriate, on-line group pain management programme for people with persistent pain, developed in Aotearoa. The next step is to evaluate the clinical and cost-effectiveness of iSelf-help compared to in-person delivered pain management programme.

Pain management programmes delivered in a group format are best practice to support people living with persistent non-cancer pain to live well. Some people can find accessing these programmes hard due to lack of referral, transportation costs and lack of trained health professionals. Further, people from Indigenous and non-Western backgrounds are poorly represented in these programmes despite having a high prevalence of persistent pain. One way of improving access is delivering services via technology. We aimed to co-design an online version of an existing hospital-based pain management programme (iSelf-help) and to ensure cultural appropriateness of the iSelf-help for Maori. Maori are the Indigenous population of Aotearoa (an accepted Maori word to describe New Zealand). We used a modified participatory action research (PAR) framework for our co-design process. This framework actively encouraged people with lived experience of pain and community partners to have a voice in the content design. The PAR team included: (1) seven end-users living with persistent pain, who had previously attended hospital-based pain management programme, (2) two pain management clinicians, (3) two health researchers, (4) two digital health experts, and (5) a health literacy expert. Five meetings were held with the PAR team. We used a Nominal Group Technique, whereby PAR team members ranked their preferences on content design and delivery, until concensus was reached. In parallel, three focus groups (n = 15) were held with Maori living with persistent pain in collaboration with a Maori community health trust. All contents were reviewed by a Maori Health literacy expert and core contents were translated into Te Reo (Maori language). The finalised version of iSelf-help included 130 resources, tested for accessibility, organised in to 12 online modules plus a dedicated welcoming page and an online community forum. Each module included: short videos, animations, patient stories, podcasts of relaxation techniques, illustrated texts, and evidence-summaries. This is the first co-created, culturally appropriate, on-line group pain management programme for people with persistent pain, developed in Aotearoa. We are currently evaluating if iSelf-help is acceptable to users, and clinically and cost effective as compared to the hospital-based pain management programme.

Do physical interventions improve outcomes following concussion: a systematic review and meta-analysis?

OBJECTIVE: To investigate the effect of physical interventions (subthreshold aerobic exercise, cervical, vestibular and/or oculomotor therapies) on days to recovery and symptom scores in the management of concussion. DESIGN: A systematic review and meta-analysis. DATA SOURCES: Medline, CINAHL, Embase, SportDiscus, Cochrane library, Scopus and PEDro. ELIGIBILITY CRITERIA: Randomised controlled trials of participants with concussion that evaluated the effect of subthreshold aerobic exercise, cervical, vestibular and/or oculomotor therapies on days to recovery/return to activity, symptom scores, balance, gait and/or exercise capacity. RESULTS: Twelve trials met the inclusion criteria: 7 on subthreshold aerobic exercise, 1 on vestibular therapy, 1 on cervical therapy and 3 on individually tailored multimodal interventions. The trials were of fair to excellent quality on the PEDro scale. Eight trials were included in the quantitative analysis. Subthreshold aerobic exercise had a significant small to moderate effect in improving symptom scores (standardised mean difference (SMD)=0.43, 95% CI 0.18 to 0.67, p=0.001, I2=0%) but not in reducing days to symptom recovery in both acutely concussed individuals and those with persistent symptoms (SMD=0.19, 95% CI -0.54 to 0.93, p=0.61, I2=52%). There was limited evidence for stand-alone cervical, vestibular and oculomotor therapies. Concussed individuals with persistent symptoms (>2 weeks) were approximately 3 times more likely to have returned to sport by 8 weeks (relative risk=3.29, 95% CI 0.30 to 35.69, p=0.33, I2=83%) if they received individually tailored, presentation-specific multimodal interventions (cervical, vestibular and oculo-motor therapy). In addition, the multimodal interventions had a moderate effect in improving symptom scores (SMD=0.63, 95% CI 0.11 to 1.15, p=0.02, I2=0%) when compared with control. CONCLUSIONS: Subthreshold aerobic exercise appears to lower symptom scores but not time to recovery in concussed individuals. Individually tailored multimodal interventions have a worthwhile effect in providing faster return to sport and clinical improvement, specifically in those with persistent symptoms. PROSPERO REGISTRATION NUMBER: CRD42020108117.

Assessing IQ in adolescents with mild to moderate cerebral palsy using the WISC-V.

Objective: To examine the influence of subtests that require fine motor responses on measures of intellectual ability, and compare three approaches to minimizing motor demands while assessing cognitive abilities in adolescents with cerebral palsy (CP) to the traditional method of the Wechsler Intelligence Scale for Children - Fifth edition (WISC-V). Method: Seventy adolescents with CP (M = 14 years 6 months, SD = 10 months) who were able to provide either a verbal or point response were assessed using the WISC-V administered via Q-interactive. The pencil-to-paper version of Coding was also administered. Performance on Block Design and pencil-to-paper Coding was compared to Visual Puzzles and Coding on Q-interactive, respectively. Full Scale IQ (FSIQ) scores derived according to the Traditional method of the WISC-V were compared to alternative estimates of FSIQ derived according to the Q-interactive, Nonmotor, and Motor-free methods, which minimized motor demands. Results: An additional 7-12% of participants were able to respond to Visual puzzles and Coding on Q-interactive compared to Block Design and pencil-to-paper Coding, respectively, and performance was marginally but significantly better. For 54 adolescents (Gross Motor Function Classification System (GMFCS) Level I-III) who were able to obtain FSIQ scores, the Traditional method underestimated FSIQ by 3-6 points compared to the alternative methods and the difference was most pronounced for those with more severe CP as measured by the GMFCS. Conclusion: Adolescents with CP are at an inherent disadvantage when cognitive ability is assessed using the Traditional method of the WISC-V. Findings suggest clinicians should employ the Nonmotor or Motor-free methods when assessing IQ in adolescents with CP.

Human Papillomavirus (HPV) Self-Sampling among Never-and Under-Screened Indigenous Maori, Pacific and Asian Women in Aotearoa New Zealand: A Feasibility Study.

In Aotearoa, New Zealand, the majority of cervical cancer cases occur in women who have never been screened or are under-screened. Wahine Maori, Pacific and Asian women have the lowest rate of cervical screening. Self-sampling for human papillomavirus (HPV-SS) has been shown to increase participation in cervical cancer screening. A whole-of-system approach, driven by evidence in the most effective delivery of HPV-SS, is required to mitigate further widening of the avoidable gap in cervical screening access and outcomes between groups of women in Aotearoa. This single-arm feasibility and acceptability study of HPV self-sampling invited never- and under-screened (≥5 years overdue) 30-69-year-old women from general practices in Auckland, Aotearoa. Eligible women were identified by data matching between the National Cervical Programme (NCSP) Register and practice data. Focus groups were additionally held with eligible wahine Maori, Asian and Pacific women to co-design new patient information materials. Questionnaires on HPV knowledge and post-test experience were offered to women. Our follow-up protocols included shared decision-making principles, and we committed to follow-up ≥90% of women who tested positive for HPV. Data matching identified 366 eligible never- and under-screened wahine Maori, Pacific and Asian women in participating practices. We were only able to contact 114 women, and 17, during the discussion, were found to be ineligible. Identifying and contacting women overdue for a cervical screen was resource-intensive, with a high rate of un-contactability despite multiple attempts. We found the best uptake of self-sampling was at focus groups. Of the total 84 HPV-SS tests, there were five positive results (6%), including one participant with HPV18 who was found to have a cervical Adenocarcinoma at colposcopy. In our feasibility study, self-sampling was acceptable and effective at detecting HPV and preventing cervical cancer in under-screened urban wahine Maori, Pacific and Asian women in Aotearoa. This is the first report of cervical Adenocarcinoma (Grade 1B) as a result of an HPV-18 positive self-sample in Aotearoa. We co-designed new patient information materials taking a health literacy and ethnicity-specific approach. This work provides policy-relevant information to the NCSP on the resources required to implement an effective HPV self-sampling programme to improve equity in national cervical cancer screening.

A novel mouse model of PMS2 founder mutation that causes mismatch repair defect due to aberrant splicing.

Hereditary non-polyposis colorectal cancer, now known as Lynch syndrome (LS) is one of the most common cancer predisposition syndromes and is caused by germline pathogenic variants (GPVs) in DNA mismatch repair (MMR) genes. A common founder GPV in PMS2 in the Canadian Inuit population, NM_000535.5: c.2002A>G, leads to a benign missense (p.I668V) but also acts as a de novo splice site that creates a 5 bp deletion resulting in a truncated protein (p.I668*). Individuals homozygous for this GPV are predisposed to atypical constitutional MMR deficiency with a delayed onset of first primary malignancy. We have generated mice with an equivalent germline mutation (Pms2c.1993A>G) and demonstrate that it results in a splicing defect similar to those observed in humans. Homozygous mutant mice are viable like the Pms2 null mice. However, unlike the Pms2 null mice, these mutant mice are fertile, like humans homozygous for this variant. Furthermore, these mice exhibit a significant increase in microsatellite instability and intestinal adenomas on an Apc mutant background. Rectification of the splicing defect in human and murine fibroblasts using antisense morpholinos suggests that this novel mouse model can be valuable in evaluating the efficacy aimed at targeting the splicing defect in PMS2 that is highly prevalent among the Canadian Inuits.