Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.

OBJECTIVE: To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. STUDY DESIGN: This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and postrewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. RESULTS: Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs 39% and 50% vs 0%, respectively; P < .001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted P < .001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (OR: 19.9, 95% CI: 4.0-98.1; P < .001). CONCLUSION: The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.

The influence of nutrition on white matter development in preterm infants: a scoping review.

White matter (WM) injury is the most common type of brain injury in preterm infants and is associated with impaired neurodevelopmental outcome (NDO). Currently, there are no treatments for WM injury, but optimal nutrition during early preterm life may support WM development. The main aim of this scoping review was to assess the influence of early postnatal nutrition on WM development in preterm infants. Searches were performed in PubMed, EMBASE, and COCHRANE on September 2022. Inclusion criteria were assessment of preterm infants, nutritional intake before 1 month corrected age, and WM outcome. Methods were congruent with the PRISMA-ScR checklist. Thirty-two articles were included. Negative associations were found between longer parenteral feeding duration and WM development, although likely confounded by illness. Positive associations between macronutrient, energy, and human milk intake and WM development were common, especially when fed enterally. Results on fatty acid and glutamine supplementation remained inconclusive. Significant associations were most often detected at the microstructural level using diffusion magnetic resonance imaging. Optimizing postnatal nutrition can positively influence WM development and subsequent NDO in preterm infants, but more controlled intervention studies using quantitative neuroimaging are needed. IMPACT: White matter brain injury is common in preterm infants and associated with impaired neurodevelopmental outcome. Optimizing postnatal nutrition can positively influence white matter development and subsequent neurodevelopmental outcome in preterm infants. More studies are needed, using quantitative neuroimaging techniques and interventional designs controlling for confounders, to define optimal nutritional intakes in preterm infants.

Clinical Feasibility of Structural and Functional MRI in Free-Breathing Neonates and Infants.

BACKGROUND: Evaluation of structural lung abnormalities with magnetic resonance imaging (MRI) has previously been shown to be predictive of clinical neonatal outcomes in preterm birth. MRI during free-breathing with phase-resolved functional lung (PREFUL) may allow for complimentary functional information without exogenous contrast. PURPOSE: To investigate the feasibility of structural and functional pulmonary MRI in a cohort of neonates and infants with no cardiorespiratory disease. Macrovascular pulmonary blood flows were also evaluated. STUDY TYPE: Prospective. POPULATION: Ten term infants with no clinically defined cardiorespiratory disease were imaged. Infants recruited from the general population and neonatal intensive care unit (NICU) were studied. FIELD STRENGTH/SEQUENCE: T1 -weighted VIBE, T2 -weighted BLADE uncorrected for motion. Ultrashort echo time (UTE) and 3D-flow data were acquired during free-breathing with self-navigation and retrospective reconstruction. Single slice 2D-gradient echo (GRE) images were acquired during free-breathing for PREFUL analysis. Imaging was performed at 3 T. ASSESSMENT: T1 , T2 , and UTE images were scored according to the modified Ochiai scheme by three pediatric body radiologists. Ventilation/perfusion-weighted maps were extracted from free-breathing GRE images using PREFUL analysis. Ventilation and perfusion defect percent (VDP, QDP) were calculated from the segmented ventilation and perfusion-weighted maps. Time-averaged cardiac blood velocities from three-dimensional-flow were evaluated in major pulmonary arteries and veins. STATISTICAL TEST: Intraclass correlation coefficient (ICC). RESULTS: The ICC of replicate structural scores was 0.81 (95% CI: 0.45-0.95) across three observers. Elevated Ochiai scores, VDP, and QDP were observed in two NICU participants. Excluding these participants, mean ± standard deviation structural scores were 1.2 ± 0.8, while VDP and QDP were 1.0% ± 1.1% and 0.4% ± 0.5%, respectively. Main pulmonary arterial blood flows normalized to body surface area were 3.15 ± 0.78 L/min/m2 . DATA CONCLUSION: Structural and functional pulmonary imaging is feasible using standard clinical MRI hardware (commercial whole-body 3 T scanner, table spine array, and flexible thoracic array) in free-breathing infants. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Early neonatal heart rate variability patterns in different subtypes of perinatal hypoxic-ischemic brain injury.

BACKGROUND: This study aims to compare the longitudinal changes in heart rate variability (HRV) during therapeutic hypothermia in neonates with different subtypes of hypoxic-ischemic brain injury. METHODS: HRV was computed from 1 hour time-epochs q6 hours for the first 48 hours. Primary outcome was brain-injury pattern on MRI at 4(3-5) days. We fitted linear mixed-effect regression models with HRV metric, brain injury subtype and postnatal age. RESULTS: Among 89 term neonates, 40 neonates had abnormal brain MRI (focal infarct 15 (38%), basal-ganglia predominant 8 (20%), watershed-predominant 5 (13%), and mixed pattern 12 (30%)). There was no significant difference in the HRV metrics between neonates with normal MRI, focal infarcts and basal ganglia pattern. At any given postnatal age, the degree of HRV suppression (HRV measure in the brain-injury subtype group/HRV measure in Normal MRI group) was significant in neonates with watershed pattern (SDNN(0.63, p = 0.08), RMSSD(0.74, p = 0.04)) and mixed pattern injury (SDNN (0.64, p < 0.001), RMSSD (0.75, p = 0.02)). HRV suppression was most profound at the postnatal age of 24-30 h in all brain injury subtypes. CONCLUSION: Neonates with underlying watershed injury with or without basal-ganglia injury demonstrates significant HRV suppression during first 48 hour of hypothermia therapy. IMPACT: Our study suggests that suppression of heart rate variability in neonates during therapeutic hypothermia varies according to the pattern of underlying hypoxic-ischemic brain injury. Neonates with watershed predominant pattern and mixed pattern of brain injury have the most severe suppression of heart rate variability measures. Heart rate variability monitoring may provide early insights into the pattern of hypoxic-ischemic brain injury in neonates undergoing therapeutic hypothermia earlier than routine clinical MRI.

Optic Perineuritis Associated With Cryptococcal Meningitis Presenting With a "Hot Orbit" in a Patient With Chronic Lymphocytic Leukemia.

ABSTRACT: A 75-year-old man presented with 3 days of progressive left retro-orbital pain, eyelid swelling, tearing, and pain with extraocular movement. His medical history was significant for type II diabetes mellitus and chronic lymphocytic leukemia, stable on no therapy since diagnosis 8 years prior. The initial examination was significant for diffuse restriction of left ocular motility, marked lid edema, and mild dyschromatopsia. Computed tomography demonstrated asymmetric left periorbital soft tissue swelling and intraconal fat stranding with an irregular left optic nerve sheath complex and clear paranasal sinuses. He was hospitalized for orbital cellulitis and treated empirically with broad-spectrum intravenous antibiotics, but his visual acuity declined over the ensuing 2 days. Subsequent MRI demonstrated left-greater-than-right circumferential optic nerve sheath enhancement, and leptomeningeal enhancement. An orbital biopsy demonstrated monoclonal B-cell lymphocyte aggregation, whereas a lumbar puncture was positive for Cryptococcus antigen with subsequent demonstration of abundant Cryptococcus by Papanicolaou stain. The final diagnosis was optic perineuritis secondary to cryptococcal meningitis presenting with orbital inflammation. Although his clinical course was complicated by immune reconstitution inflammatory syndrome, symptoms and signs of optic neuropathy ultimately resolved after 1 month of intensive antifungal therapy.

Location and Size of Preterm Cerebellar Hemorrhage and Childhood Development.

OBJECTIVE: To examine the association between cerebellar hemorrhage (CBH) size and location and preschool-age neurodevelopment in very preterm neonates. METHODS: Preterm magnetic resonance images of 221 very preterm neonates (median gestational age = 27.9 weeks) were manually segmented for CBH quantification and location. Neurodevelopmental assessments at chronological age 4.5 years included motor (Movement Assessment Battery for Children, 2nd Edition [MABC-2]), visuomotor integration (Beery-Buktenica Developmental Test of Visual-Motor Integration, 6th Edition), cognitive (Wechsler Primary and Preschool Scale of Intelligence, 3rd Edition), and behavioral (Child Behavior Checklist) outcomes. Multivariable linear regression models examined the association between CBH size and 4.5-year outcomes accounting for sex, gestational age, and supratentorial injury. Probabilistic maps assessed CBH location and likelihood of a lesion to predict adverse outcome. RESULTS: Thirty-six neonates had CBH: 14 (6%) with only punctate CBH and 22 (10%) with ≥1 larger CBH. CBH occurred mostly in the inferior aspect of the posterior lobes. CBH total volume was independently associated with MABC-2 motor scores at 4.5 years (ß = -0.095, 95% confidence interval = -0.184 to -0.005), with a standardized ß coefficient (-0.16) that was similar to that of white matter injury volume (standardized ß = -0.22). CBH size was similarly associated with visuomotor integration and externalizing behavior but not cognition. Voxelwise odds ratio and lesion-symptom maps demonstrated that CBH extending more deeply into the cerebellum predicted adverse motor, visuomotor, and behavioral outcomes. INTERPRETATION: CBH size and location on preterm magnetic resonance imaging were associated with reduced preschool motor and visuomotor function and more externalizing behavior independent of supratentorial brain injury in a dose-dependent fashion. The volumetric quantification and localization of CBH, even when punctate, may allow opportunity to improve motor and behavioral outcomes by providing targeted intervention. ANN NEUROL 2020;88:1095-1108.

Training in neonatal neurocritical care: a proposal for a hybrid model of competence by design and time-based methods.

BACKGROUND: Neonatal neurocritical care (NNCC) is a rapidly advancing field with limited fellowship training available in locally developed, non-accredited programs. A standardized survey aimed to understand the training backgrounds of individuals practicing NNCC, the structure of existing clinical NNCC services/training programs, and suggested clinical competencies for new graduates. METHODS: We developed an anonymous survey electronically sent to members of societies related to NNCC. Using the survey results as a guide, we discuss a competence by design (CBD) curriculum as a complementary approach to traditional time-based training. RESULTS: There were 82 responses to the survey from 30 countries; 95% of respondents were physicians. Thirty-one (42%) institutions reported having an NNCC service, 24 (29%) individuals reported formal NNCC training, 81% reported "significant variability" across NNCC training programs, and 88% were both in favor of standardizing training programs and pursuing formal accreditation for NNCC in the next 5 years. CONCLUSIONS: The survey results demonstrate international interest in standardizing NNCC training and development of an accreditation or certification process. We propose consideration of a CBD-type curriculum as a training approach to focus on the development of specific NNCC competencies, rather than assuming the acquisition of these competencies based on time as a surrogate. IMPACT: Continued growth and development in the field of NNCC has led to increasing need for training programs suited to meet the diverse needs of trainees from varied backgrounds. We present the results of an international survey that assessed the structure of existing training programs and the priority areas in which graduates must demonstrate competence, highlighting the combination of CBD and time-based training as one approach to address these recommendations. The survey results support interest in translating published training competencies, existing expertise, and infrastructure across centers into a standardized curriculum for NNCC including certification opportunities.

Predictors of Long-Term Neurodevelopmental Outcome of Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia.

Hypoxic-ischemic encephalopathy (HIE) is a manifestation of perinatal asphyxial insult that continues to evolve over days to weeks following the initial injury. Therapeutic hypothermia has demonstrated that a proportion of this secondary brain injury may indeed be preventable. However, therapeutic hypothermia has also altered the prognostic utility of many bedside tools that are commonly used as predictors of long-term neurodevelopmental outcome in HIE. Clinicians are often confronted with uncertainty when assessing the prognosis of infants with HIE. Improved understanding of the implications and limitations of individual investigations may inform clinical decisions and allow for timely intervention. This review summarizes the predictive value of currently available prognostic markers in HIE infants in the therapeutic hypothermia era, including clinical, biochemical, neurophysiological, physiological, and neuroimaging predictors.

The Response to Stress Questionnaire for Parents Following Neonatal Brain Injury.

OBJECTIVE: The Response to Stress Questionnaire-Brain Injury (RSQ-BI) was adapted utilizing a patient-oriented approach, exploring parental stress, coping, and associated mental health outcomes in parents of children with neonatal brain injury. The contributions of social risk, child adaptive functioning, and brain injury severity were also explored. METHODS: Using a mixed-method design, this study explored adapted stressor items on the RSQ-BI. Parents and clinicians engaged in semistructured interviews to examine key stressors specific to being a parent of a child with neonatal brain injury. The adapted RSQ-BI was piloted in a parent sample (N = 77, child mean age 1 year 7 months) with established questionnaires of social risk, child adaptive functioning, severity of the child's injury, coping style, and parent mental health. Descriptive statistics and correlations examined parent stress, coping, and their association with parent mental health. RESULTS: The final RSQ-BI questionnaire included 15 stressors. Factor analysis showed stressors loaded onto two factors related to (a) daily role stressors and (b) brain injury stressors. Using the RSQ-BI, parents reported brain injury stressors as more stressful than daily role stressors. When faced with these stressors, parents were most likely to engage in acceptance-based coping strategies and demonstrated lower symptoms of parent depression and anxiety. CONCLUSIONS: The RSQ-BI provides a valuable adaptation to understand both stressors and coping specific to being a parent of a child with neonatal brain injury. Relevant interventions that promote similar coping techniques are discussed for future care and research.

A Rapid, Simple, Inexpensive, and Mobile Colorimetric Assay COVID-19-LAMP for Mass On-Site Screening of COVID-19.

To control the COVID-19 pandemic and prevent its resurgence in areas preparing for a return of economic activities, a method for a rapid, simple, and inexpensive point-of-care diagnosis and mass screening is urgently needed. We developed and evaluated a one-step colorimetric reverse-transcriptional loop-mediated isothermal amplification assay (COVID-19-LAMP) for detection of SARS-CoV-2, using SARS-CoV-2 isolate and respiratory samples from patients with COVID-19 (n = 223) and other respiratory virus infections (n = 143). The assay involves simple equipment and techniques and low cost, without the need for expensive qPCR machines, and the result, indicated by color change, is easily interpreted by naked eyes. COVID-19-LAMP can detect SARS-CoV-2 RNA with detection limit of 42 copies/reaction. Of 223 respiratory samples positive for SARS-CoV-2 by qRT-PCR, 212 and 219 were positive by COVID-19-LAMP at 60 and 90 min (sensitivities of 95.07% and 98.21%) respectively, with the highest sensitivities among nasopharyngeal swabs (96.88% and 98.96%), compared to sputum/deep throat saliva samples (94.03% and 97.02%), and throat swab samples (93.33% and 98.33%). None of the 143 samples with other respiratory viruses were positive by COVID-19-LAMP, showing 100% specificity. Samples with higher viral load showed shorter detection time, some as early as 30 min. This inexpensive, highly sensitive and specific COVID-19-LAMP assay can be useful for rapid deployment as mobile diagnostic units to resource-limiting areas for point-of-care diagnosis, and for unlimited high-throughput mass screening at borders to reduce cross-regional transmission.

The Impact of Brain Metastases and Associated Neurocognitive Aspects on Health Utility Scores in EGFR Mutated and ALK Rearranged NSCLC: A Real World Evidence Analysis.

BACKGROUND: In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health-related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. MATERIALS AND METHODS: In a prospective observational cohort study (2014-2016), outpatients with stage IV lung cancer completed demographic and EQ-5D-3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT-brain (FACT-Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). RESULTS: Of 519 patients with 1,686 EQ-5D-3L-derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT-Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK-rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT-Br and tests of NCF. CONCLUSION: Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene-addicted tumors have superior HUS. IMPLICATIONS FOR PRACTICE: In the setting of EGFR mutations or ALK rearrangement non-small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ-5D questionnaire is associated with measures of health-related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.

Hyperglycemia and Glucose Variability Are Associated with Worse Brain Function and Seizures in Neonatal Encephalopathy: A Prospective Cohort Study.

OBJECTIVES: To investigate how glucose abnormalities correlate with brain function on amplitude-integrated electroencephalography (aEEG) in infants with neonatal encephalopathy. STUDY DESIGN: Neonates born at full term with encephalopathy were enrolled within 6 hours of birth in a prospective cohort study at a pediatric academic referral hospital. Continuous interstitial glucose monitors and aEEG were placed soon after birth and continued for 3 days. Episodes of hypoglycemia (≤50 mg/dL; ≤2.8 mmol/L) and hyperglycemia (>144 mg/dL; >8.0 mmol/L) were identified. aEEG was classified in 6-hour epochs for 3 domains (background, sleep-wake cycling, electrographic seizures). Generalized estimating equations assessed the relationship of hypo- or hyperglycemia with aEEG findings, adjusting for clinical markers of hypoxia-ischemia (Apgar scores, umbilical artery pH, and base deficit). RESULTS: Forty-five infants (gestational age 39.5 ± 1.4 weeks) were included (24 males). During aEEG monitoring, 16 episodes of hypoglycemia were detected (9 infants, median duration 77.5, maximum 220 minutes) and 18 episodes of hyperglycemia (13 infants, median duration 237.5, maximum 3125 minutes). Epochs of hypoglycemia were not associated with aEEG changes. Compared with epochs of normoglycemia, epochs of hyperglycemia were associated with worse aEEG background scores (B 1.120, 95% CI 0.501-1.738, P < .001), less sleep-wake cycling (B 0.587, 95% CI 0.417-0.757, P < .001) and more electrographic seizures (B 0.433, 95% CI 0.185-0.681, P = .001), after adjusting for hypoxia-ischemia severity. CONCLUSIONS: In neonates with encephalopathy, epochs of hyperglycemia were temporally associated with worse global brain function and seizures, even after we adjusted for hypoxia-ischemia severity. Whether hyperglycemia causes neuronal injury or is simply a marker of severe brain injury requires further study.

Plasma cholesterol levels and brain development in preterm newborns.

BACKGROUND: To assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns. METHODS: Sixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition. RESULTS: Early plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years. CONCLUSIONS: Higher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes.

Understanding Early Childhood Resilience Following Neonatal Brain Injury From Parents' Perspectives Using a Mixed-Method Design.

OBJECTIVES: The current study used a mixed-method design to qualitatively examine parents' definitions of resilience and factors they believed optimized their child's early outcome following neonatal brain injury. This was followed by quantitative analyses of early developmental and mental health outcomes and their relation to salient biopsychosocial factors. METHODS: Participants were parents of children diagnosed with neonatal brain injury due to stroke or hypoxic-ischemic encephalopathy (N=51; age range of children 18 months to 8 years). The Parent Experiences Questionnaire (PEQ) was used to qualitatively analyze parents' open-ended responses about their child's early experiences and outcome. The Child Behavior Checklist (CBCL) and Scales of Independent Behaviour Early Developmental Form (SIB-ED) parent ratings were used to measure child resilience from a quantitative perspective, identifying "at-risk" and "resilient" children using standard cutoffs. "Resilient" and "at-risk" children were compared on biopsychosocial variables using univariate t tests and chi-square analyses. RESULTS: Parents provided five unique definitions of their child's positive outcomes, and many children demonstrated resilience based on parent perspectives and quantitative definitions. Supporting factors included close medical follow-up, early intervention, and intrinsic factors within the child and parent. Group comparisons of "resilient" and "at-risk" children highlighted the importance of parent mental health across these early developmental and mental health outcomes. CONCLUSIONS: Many children were described as resilient during the early years by parents using qualitative and quantitative approaches. Findings highlighted the importance of parent well-being in promoting optimal early outcomes. (JINS, 2019, 25, 390-402.).

Spontaneous cerebrospinal fluid leak and idiopathic intracranial hypertension.

PURPOSE OF REVIEW: To review the most recent literature on the relationship of spontaneous cerebrospinal fluid (CSF) leak with idiopathic intracranial hypertension (IIH) and considerations in management of these conditions. RECENT FINDINGS: A link has been proposed between spontaneous CSF leak and IIH based on similar demographics, radiologic, and clinical findings in these patients, and on a plausible mechanism of skull base erosion in the setting of high CSF pressure over time. IIH patients with CSF leak may not present with classic IIH signs and symptoms as the leak can alleviate excess pressure; however, they may develop these after a leak is repaired. There may also be a higher risk of leak recurrence if intracranial hypertension is not treated postoperatively. SUMMARY: A growing body of evidence supports an association between IIH and spontaneous CSF leak. However, this relationship is still not fully elucidated, and there is no current agreement on how to incorporate screening, management, or counseling guidelines for CSF leak into the care of IIH patients. There are also no specific guidelines for evaluation/management of IIH in patients with spontaneous CSF leak. Further interdisciplinary research is needed to explore this connection and to establish screening, evaluation, and management guidelines.

Development and prospective evaluation of CAPLET, a cancer ambulatory patient physical function longitudinal evaluation tool for routine clinical practice.

PURPOSE: A patient's physical function is a critical outcome variable for measuring and improving chronic care management. However, patient-reported outcome measures of physical function are not routinely assessed in cancer outpatients, in part due to limitations of tools available. This study presents the development and evaluation of the Cancer Ambulatory Patient Physical Function Longitudinal Evaluation Tool (CAPLET) as an adaptive response tool for routinely screening for physical dysfunction in oncology clinical practice. METHODS: In phase 1, 407 adult outpatients at Princess Margaret Cancer Centre completed the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, Health Assessment Questionnaire Disability Index (HAQ-DI), EuroQuol-5D-3L ( EQ-5D-3L), and patient-reported outcome (PRO)-Eastern Cooperative Oncology Group (ECOG). CAPLET was developed based on a branching logic algorithm navigating patients to appropriate domains of HAQ-DI/WHOAS using their responses to the PRO-ECOG/EQ-5D-3L as screeners. Sensitivity/specificity of CAPLET screeners for HAQ-DI/WHODAS items were reported. In phase 2, CAPLET vs the WHODAS/HAQ-DI were alternatively administrated to 318 adult outpatients in a two-arm trial comparing time to completion and acceptability between the tools. RESULTS: Using a patient's ECOG status and the sum of the mobility, self-care, and usual activity dimensions of the EQ-5D-3L to dichotomize patients as with or without difficulty, CAPLET achieved a sensitivity > 90% against recommended WHODAS and HAQ-DI cutoffs for significant dysfunction. Sensitivity of screeners for capturing dysfunction in individual WHODAS/HAQ-DI items ranged from 85 to 100%. Compared to the HAQ-DI/WHODAS, CAPLET was associated with a 50% reduction in administration times and improved patient acceptability, while reducing question burden by 84% for half the sample population. CONCLUSIONS: CAPLET improves the feasibility of capturing detailed assessments of patient-reported physical function in cancer outpatients.

Multiple-micronutrient supplementation for women during pregnancy.

BACKGROUND: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- and middle-income countries. They are exacerbated in pregnancy due to the increased demands of the developing fetus, leading to potentially adverse effects on the mother and baby. A consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane Review in 2017, evidence from several trials has become available. The findings of this review will be critical to inform policy on micronutrient supplementation in pregnancy. OBJECTIVES: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes. SEARCH METHODS: For this 2018 update, on 23 February 2018 we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. We also contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: All prospective randomised controlled trials evaluating MMN supplementation with iron and folic acid during pregnancy and its effects on pregnancy outcomes were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but excluded quasi-randomised trials. Trial reports that were published as abstracts were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified 21 trials (involving 142,496 women) as eligible for inclusion in this review, but only 20 trials (involving 141,849 women) contributed data. Of these 20 trials, 19 were conducted in low- and middle-income countries and compared MMN supplements with iron and folic acid to iron, with or without folic acid. One trial conducted in the UK compared MMN supplementation with placebo. In total, eight trials were cluster-randomised.MMN with iron and folic acid versus iron, with or without folic acid (19 trials)MMN supplementation probably led to a slight reduction in preterm births (average risk ratio (RR) 0.95, 95% confidence interval (CI) 0.90 to 1.01; 18 trials, 91,425 participants; moderate-quality evidence), and babies considered small-for-gestational age (SGA) (average RR 0.92, 95% CI 0.88 to 0.97; 17 trials; 57,348 participants; moderate-quality evidence), though the CI for the pooled effect for preterm births just crossed the line of no effect. MMN reduced the number of newborn infants identified as low birthweight (LBW) (average RR 0.88, 95% CI 0.85 to 0.91; 18 trials, 68,801 participants; high-quality evidence). We did not observe any differences between groups for perinatal mortality (average RR 1.00, 95% CI 0.90 to 1.11; 15 trials, 63,922 participants; high-quality evidence). MMN supplementation led to slightly fewer stillbirths (average RR 0.95, 95% CI 0.86 to 1.04; 17 trials, 97,927 participants; high-quality evidence) but, again, the CI for the pooled effect just crossed the line of no effect. MMN supplementation did not have an important effect on neonatal mortality (average RR 1.00, 95% CI 0.89 to 1.12; 14 trials, 80,964 participants; high-quality evidence). We observed little or no difference between groups for the other maternal and pregnancy outcomes: maternal anaemia in the third trimester (average RR 1.04, 95% CI 0.94 to 1.15; 9 trials, 5912 participants), maternal mortality (average RR 1.06, 95% CI 0.72 to 1.54; 6 trials, 106,275 participants), miscarriage (average RR 0.99, 95% CI 0.94 to 1.04; 12 trials, 100,565 participants), delivery via a caesarean section (average RR 1.13, 95% CI 0.99 to 1.29; 5 trials, 12,836 participants), and congenital anomalies (average RR 1.34, 95% CI 0.25 to 7.12; 2 trials, 1958 participants). However, MMN supplementation probably led to a reduction in very preterm births (average RR 0.81, 95% CI 0.71 to 0.93; 4 trials, 37,701 participants). We were unable to assess a number of prespecified, clinically important outcomes due to insufficient or non-available data.When we assessed primary outcomes according to GRADE criteria, the quality of evidence for the review overall was moderate to high. We graded the following outcomes as high quality: LBW, perinatal mortality, stillbirth, and neonatal mortality. The outcomes of preterm birth and SGA we graded as moderate quality; both were downgraded for funnel plot asymmetry, indicating possible publication bias.We carried out sensitivity analyses excluding trials with high levels of sample attrition (> 20%). We found that results were consistent with the main analyses for all outcomes. We explored heterogeneity through subgroup analyses by maternal height, maternal body mass index (BMI), timing of supplementation, dose of iron, and MMN supplement formulation (UNIMMAP versus non-UNIMMAP). There was a greater reduction in preterm births for women with low BMI and among those who took non-UNIMMAP supplements. We also observed subgroup differences for maternal BMI and maternal height for SGA, indicating greater impact among women with greater BMI and height. Though we found that MMN supplementation made little or no difference to perinatal mortality, the analysis demonstrated substantial statistical heterogeneity. We explored this heterogeneity using subgroup analysis and found differences for timing of supplementation, whereby higher impact was observed with later initiation of supplementation. For all other subgroup analyses, the findings were inconclusive.MMN versus placebo (1 trial)A single trial in the UK found little or no important effect of MMN supplementation on preterm births, SGA, or LBW but did find a reduction in maternal anaemia in the third trimester (RR 0.66, 95% CI 0.51 to 0.85), when compared to placebo. This trial did not measure our other outcomes. AUTHORS' CONCLUSIONS: Our findings suggest a positive impact of MMN supplementation with iron and folic acid on several birth outcomes. MMN supplementation in pregnancy led to a reduction in babies considered LBW, and probably led to a reduction in babies considered SGA. In addition, MMN probably reduced preterm births. No important benefits or harms of MMN supplementation were found for mortality outcomes (stillbirths, perinatal and neonatal mortality). These findings may provide some basis to guide the replacement of iron and folic acid supplements with MMN supplements for pregnant women residing in low- and middle-income countries.

Postnatal polyunsaturated fatty acids associated with larger preterm brain tissue volumes and better outcomes.

BackgroundHuman studies investigating the link between postnatal polyunsaturated fatty acids and preterm brain growth are limited, despite emerging evidence of potential effects on outcomes.MethodsSixty preterm neonates <32 weeks gestational age with magnetic resonance imaging (MRI) scanning at near-birth and near-term age were assessed for brain tissue volumes, including cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and ventricular cerebrospinal fluid. Red blood cell fatty acid content was evaluated within 1 week of each MRI scan. Neurodevelopmental outcome at 30-36 months corrected age was assessed.ResultsAdjusting for potential confounders, higher near-birth docosahexaenoic acid levels are associated with larger cortical gray matter, deep gray matter, and brainstem volumes and higher near-term levels with larger deep gray matter, cerebellar, and brainstem volumes at near-term age; lower near-birth linoleic acid levels are correlated with larger white matter volume at near-term age. By 30-36 months corrected age, larger cortical and deep gray matter, cerebellar, and brainstem volumes by term age are associated with improved language scores and larger cerebellar and brainstem volumes with improved motor scores.ConclusionSpecific polyunsaturated fatty acid levels have differential and time-dependent associations with brain region growth. Larger brain volumes are associated with improved outcomes at preschool age.

Maternal or neonatal infection: association with neonatal encephalopathy outcomes.

This corrects the article DOI: 10.1038/pr.2014.47.