The splenial angle: a novel radiological index for idiopathic normal pressure hydrocephalus.

OBJECTIVES: To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer's disease (AD), Parkinson's disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans' index and callosal angle. METHODS: Evans' index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. RESULTS: Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. CONCLUSIONS: The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. KEY POINTS: • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans' index and callosal angle in predicting NPH from healthy, Parkinson's disease, and Alzheimer's disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

The topology of ventricle surfaces and its application in the analysis of hydrocephalic ventricles: a proof-of-concept study.

PURPOSE: The cerebral ventricles deform in a non-uniform fashion in response to increased CSF volume and/or pressure in hydrocephalic syndromes. Current research is focused on volumetric analyses, while topological analysis of ventricular surfaces remains understudied. We developed a method of quantitatively modeling the curvature of ventricular surfaces to analyze changes in ventricular surfaces in normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD), using the left frontal horn as an example. METHODS: Twenty-one patients with NPH were recruited from our institution, and 21 healthy controls (HC) and patients with Alzheimer's disease (AD) were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. On T1-weighted fine-cut magnetic resonance sequences, 3D Slicer was used to segment the left frontal horn. Next, the mean curvatures at a set of points on the ventricular surface were determined. The frontal horns were scaled and centered into normalized volumes, allowing for pooling across the study subjects. The frontal horn was divided into superolateral, superomedial, inferolateral, and inferomedial surfaces, and locoregional mean curvatures were analyzed. Statistical comparisons were made between NPH, AD, and HC groups. RESULTS: Significant differences in the mean curvature of lateral surfaces of the ventricles distinguished patterns of distortion between all three cohorts. Significant flattening of the superomedial surface discriminated NPH from HC and AD. However, significant rounding of the inferomedial surface compared to controls was a distinguishing feature of NPH alone. CONCLUSION: NPH ventricles deform non-uniformly. The pattern of surface distortion may be used as an additional tool to differentiate between these hydrocephalic conditions.

Structural volumetric and Periodic Table DTI patterns in Complex Normal Pressure Hydrocephalus-Toward the principles of a translational taxonomy.

Introduction: We previously proposed a novel taxonomic framework to describe the diffusion tensor imaging (DTI) profiles of white matter tracts by their diffusivity and neural properties. We have shown the relevance of this strategy toward interpreting brain tissue signatures in Classic Normal Pressure Hydrocephalus vs. comparator cohorts of mild traumatic brain injury and Alzheimer's disease. In this iteration of the Periodic Table of DTI Elements, we examined patterns of tissue distortion in Complex NPH (CoNPH) and validated the methodology against an open-access dataset of healthy subjects, to expand its accessibility to a larger community. Methods: DTI measures for 12 patients with CoNPH with multiple comorbidities and 45 cognitively normal controls from the ADNI database were derived using the image processing pipeline on the brainlife.io open cloud computing platform. Using the Periodic Table algorithm, DTI profiles for CoNPH vs. controls were mapped according to injury patterns. Results: Structural volumes in most structures tested were significantly lower and the lateral ventricles higher in CoNPH vs. controls. In CoNPH, significantly lower fractional anisotropy (FA) and higher mean, axial, and radial diffusivities (MD, L1, and L2 and 3, respectively) were observed in white matter related to the lateral ventricles. Most diffusivity measures across supratentorial and infratentorial structures were significantly higher in CoNPH, with the largest differences in the cerebellum cortex. In subcortical deep gray matter structures, CoNPH and controls differed most significantly in the hippocampus, with the CoNPH group having a significantly lower FA and higher MD, L1, and L2 and 3. Cerebral and cerebellar white matter demonstrated more potential reversibility of injury compared to cerebral and cerebellar cortices. Discussion: The findings of widespread and significant reductions in subcortical deep gray matter structures, in comparison to healthy controls, support the hypothesis that Complex NPH cohorts retain imaging features associated with Classic NPH. The use of the algorithm of the Periodic Table allowed for greater consistency in the interpretation of DTI results by focusing on patterns of injury rather than an over-reliance on the interrogation of individual measures by statistical significance alone. Our aim is to provide a prototype that could be refined for an approach toward the concept of a "translational taxonomy."

Neuroimaging data repositories and AI-driven healthcare-Global aspirations vs. ethical considerations in machine learning models of neurological disease.

Neuroimaging data repositories are data-rich resources comprising brain imaging with clinical and biomarker data. The potential for such repositories to transform healthcare is tremendous, especially in their capacity to support machine learning (ML) and artificial intelligence (AI) tools. Current discussions about the generalizability of such tools in healthcare provoke concerns of risk of bias-ML models underperform in women and ethnic and racial minorities. The use of ML may exacerbate existing healthcare disparities or cause post-deployment harms. Do neuroimaging data repositories and their capacity to support ML/AI-driven clinical discoveries, have both the potential to accelerate innovative medicine and harden the gaps of social inequities in neuroscience-related healthcare? In this paper, we examined the ethical concerns of ML-driven modeling of global community neuroscience needs arising from the use of data amassed within neuroimaging data repositories. We explored this in two parts; firstly, in a theoretical experiment, we argued for a South East Asian-based repository to redress global imbalances. Within this context, we then considered the ethical framework toward the inclusion vs. exclusion of the migrant worker population, a group subject to healthcare inequities. Secondly, we created a model simulating the impact of global variations in the presentation of anosmia risks in COVID-19 toward altering brain structural findings; we then performed a mini AI ethics experiment. In this experiment, we interrogated an actual pilot dataset (n = 17; 8 non-anosmic (47%) vs. 9 anosmic (53%) using an ML clustering model. To create the COVID-19 simulation model, we bootstrapped to resample and amplify the dataset. This resulted in three hypothetical datasets: (i) matched (n = 68; 47% anosmic), (ii) predominant non-anosmic (n = 66; 73% disproportionate), and (iii) predominant anosmic (n = 66; 76% disproportionate). We found that the differing proportions of the same cohorts represented in each hypothetical dataset altered not only the relative importance of key features distinguishing between them but even the presence or absence of such features. The main objective of our mini experiment was to understand if ML/AI methodologies could be utilized toward modelling disproportionate datasets, in a manner we term "AI ethics." Further work is required to expand the approach proposed here into a reproducible strategy.

Modeling the Properties of White Matter Tracts Using Diffusion Tensor Imaging to Characterize Patterns of Injury in Aging and Neurodegenerative Disease.

Diffusion tensor imaging (DTI) is a relatively novel magnetic resonance-based imaging methodology that can provide valuable insight into the microstructure of white matter tracts of the brain. In this paper, we evaluated the reliability and reproducibility of deriving a semi-automated pseudo-atlas DTI tractography method vs. standard atlas-based analysis alternatives, for use in clinical cohorts with neurodegeneration and ventriculomegaly. We showed that the semi-automated pseudo-atlas DTI tractography method was reliable and reproducible across different cohorts, generating 97.7% of all tracts. However, DTI metrics obtained from both methods were significantly different across the majority of cohorts and white matter tracts (p < 0.001). Despite this, we showed that both methods produced patterns of white matter injury that are consistent with findings reported in the literature and with DTI profiles generated from these methodologies. Scatter plots comparing DTI metrics obtained from each methodology showed that the pseudo-atlas method produced metrics that implied a more preserved neural structure compared to its counterpart. When comparing DTI metrics against a measure of ventriculomegaly (i.e., Evans' Index), we showed that the standard atlas-based method was able to detect decreasing white matter integrity with increasing ventriculomegaly, while in contrast, metrics obtained using the pseudo-atlas method were sensitive for stretch or compression in the posterior limb of the internal capsule. Additionally, both methods were able to show an increase in white matter disruption with increasing ventriculomegaly, with the pseudo-atlas method showing less variability and more specificity to changes in white matter tracts near to the ventricles. In this study, we found that there was no true gold-standard for DTI methodologies or atlases. Whilst there was no congruence between absolute values from DTI metrics, differing DTI methodologies were still valid but must be appreciated to be variably sensitive to different changes within white matter injury occurring concurrently. By combining both atlas and pseudo-atlas based methodologies with DTI profiles, it was possible to navigate past such challenges to describe white matter injury changes in the context of confounders, such as neurodegenerative disease and ventricular enlargement, with transparency and consistency.

Diffusion Tensor Imaging Profiles Can Distinguish Diffusivity and Neural Properties of White Matter Injury in Hydrocephalus vs. Non-hydrocephalus Using a Strategy of a Periodic Table of DTI Elements.

Background: The aim of this study was to create a simplistic taxonomy to improve transparency and consistency in, and reduce complexity of, interpreting diffusion tensor imaging (DTI) profiles in white matter disruption. Using a novel strategy of a periodic table of DTI elements, we examined if DTI profiles could demonstrate neural properties of disruption sufficient to characterize white matter changes specific for hydrocephalus vs. non-hydrocephalus, and to distinguish between cohorts of neural injury by their differing potential for reversibility. Methods: DTI datasets from three clinical cohorts representing pathological milestones from reversible to irreversible brain injury were compared to those of healthy controls at baseline, over time and with interventions. The final dataset comprised patients vs. controls in the following groupings: mild traumatic brain injury (mTBI), n = 24 vs. 27, normal pressure hydrocephalus (NPH), n = 16 vs. 9 and Alzheimer's disease (AD), n = 27 vs. 47. We generated DTI profiles from fractional anisotropy (FA) and mean, axial and radial diffusivity measures (MD, L1 and L2 and 3 respectively), and constructed an algorithm to map changes consistently to a periodic table of elements, which fully described their diffusivity and neural properties. Results: Mapping tissue signatures to a periodic table of DTI elements rapidly characterized cohorts by their differing patterns of injury. At baseline, patients with mTBI displayed the most preserved tracts. In NPH, the magnitude of changes was dependent on "familial" DTI neuroanatomy, i.e., potential for neural distortion from risk of ventriculomegaly. With time, patients with Alzheimer's disease were significantly different to controls across multiple measures. By contrast, patients with mTBI showed both loss of integrity and pathophysiological processes of neural repair. In NPH, some patterns of injury, such as "stretch/compression" and "compression" were more reversible following intervention than others; these neural profile properties suggested "microstructural resilience" to injury. Conclusion: Using the novel strategy of a periodic table of DTI elements, our study has demonstrated it is possible to distinguish between different cohorts along the spectrum of brain injury by describing neural profile properties of white matter disruption. Further work to contribute datasets of disease toward this proposed taxonomic framework would enhance the translatability of DTI profiles to the clinical-research interface.

Clinical Outcomes After Ventriculo-Peritoneal Shunting in Patients With Classic vs. Complex NPH.

Objective: Normal pressure hydrocephalus (NPH) is a neurological condition characterized by a clinical triad of gait disturbance, cognitive impairment, and urinary incontinence in conjunction with ventriculomegaly. Other neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and vascular dementia share some overlapping clinical features. However, there is evidence that patients with comorbid NPH and Alzheimer's or Parkinson's disease may still exhibit good clinical response after CSF diversion. This study aims to evaluate clinical responses after ventriculo-peritoneal shunt (VPS) in a cohort of patients with coexisting NPH and neurodegenerative disease. Methods: The study has two components; (i) a pilot study was performed that specifically focused upon patients with Complex NPH and following the inclusion of the Complex NPH subtype into consideration for the clinical NPH programme, (ii) a retrospective snapshot study was performed to confirm and characterize differences between Classic and Complex NPH patients being seen consecutively over the course of 1 year within a working subspecialist NPH clinic. We studied the characteristics of patients with Complex NPH, utilizing clinical risk stratification and multimodal biomarkers. Results: There was no significant difference between responders and non-responders to CSF diversion on comorbidity scales. After VPS insertion, significantly more Classic NPH patients had improved cognition compared to Complex NPH patients (p = 0.005). Improvement in gait and urinary symptoms did not differ between the groups. 26% of the Classic NPH group showed global improvement of the triad, and 42% improved in two domains. Although only 8% showed global improvement of the triad, all Complex NPH patients improved in gait. Conclusions: Our study has demonstrated that the presence of neurodegenerative disorders co-existing with NPH should not be the sole barrier to the consideration of high-volume tap test or lumbar drainage via a specialist NPH programme. Further characterization of distinct cohorts of NPH with differing degrees of CSF responsiveness due to overlay from neurodegenerative or comorbidity risk burden may aid toward more precise prognostication and treatment strategies. We propose a simplistic conceptual framework to describe NPH by its Classic vs. Complex subtypes to promote the clinical paradigm shift toward subspecialist geriatric neurosurgery by addressing needs for rapid screening tools at the clinical-research interface.

Geographical Variations in Host Predisposition to COVID-19 Related Anosmia, Ageusia, and Neurological Syndromes.

The novel coronavirus disease (COVID-19), has become the most critical global health challenge in recent history. With SARS-CoV-2 infection, there was an unexpectedly high and specific prevalence of olfactory and taste disorders (OTDs). These high rates of hyposmia and hypogeusia, initially reported as up to 89% in European case series, led to the global inclusion of loss of taste and/or smell as a distinctive feature of COVID-19. However, there is emerging evidence that there are striking differences in the rates of OTDs in East Asian countries where the disease first emerged, as compared to Western countries (15.8 vs. 60.9%, p-value < 0.01). This may be driven by either variations in SARS-CoV-2 subtypes presenting to different global populations or genotypic differences in hosts which alter the predisposition of these different populations to the neuroinvasiveness of SARS-CoV-2. We also found that rates of OTDs were significantly higher in objective testing for OTDs as compared to subjective testing (73.6 vs. 60.8%, p-value = 0.03), which is the methodology employed by most studies. Concurrently, it has also become evident that racial minorities across geographically disparate world populations suffer from disproportionately higher rates of COVID-19 infection and mortality. In this mini review, we aim to delineate and explore the varying rates of olfactory and taste disorders amongst COVID-19 patients, by focusing on their underlying geographical, testing, ethnic and socioeconomic differences. We examine the current literature for evidence of differences in the olfactory and gustatory manifestations of COVID-19 and discuss current pathophysiological hypotheses for such differences.

The Impact of Multimorbidity Burden, Frailty Risk Scoring, and 3-Directional Morphological Indices vs. Testing for CSF Responsiveness in Normal Pressure Hydrocephalus.

Objective: Multimorbidity burden across disease cohorts and variations in clinico-radiographic presentations within normal pressure hydrocephalus (NPH) confound its diagnosis, and the assessment of its amenability to interventions. We hypothesized that novel imaging techniques such as 3-directional linear morphological indices could help in distinguishing between hydrocephalus vs. non-hydrocephalus and correlate with responsiveness to external lumbar drainage (CSF responsiveness) within NPH subtypes. Methodology: Twenty-one participants with NPH were recruited and age-matched to 21 patients with Alzheimer's Disease (AD) and 21 healthy controls (HC) selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Patients with NPH underwent testing via the NPH programme with external lumbar drainage (ELD); pre- and post-ELD MRI scans were obtained. The modified Frailty Index (mFI-11) was used to stratify the NPH cohort, including Classic and Complex subtypes, by their comorbidity and frailty risks. The quantitative imaging network tool 3D Slicer was used to derive traditional 2-dimensional (2d) linear measures; Evans Index (EI), Bicaudate Index (BCI) and Callosal Angle (CA), along with novel 3-directional (3d) linear measures; z-Evans Index and Brain per Ventricle Ratio (BVR). 3-Dimensional (3D) ventricular volumetry was performed as an independent correlate of ventriculomegaly to CSF responsiveness. Results: Mean age for study participants was 71.14 ± 6.3 years (18, 85.7% males). The majority (15/21, 71.4%) of participants with NPH comprised the Complex subtype (overlay from vascular risk burden and AD); 12/21 (57.1%) were Non-Responders to ELD. Frailty alone was insufficient in distinguishing between NPH subtypes. By contrast, 3d linear measures distinguished NPH from both AD and HC cohorts, but also correlated to CSF responsiveness. The z-Evans Index was the most sensitive volumetric measure of CSF responsiveness (p = 0.012). Changes in 3d morphological indices across timepoints distinguished between Responders vs. Non-Responders to lumbar testing. There was a significant reduction of indices, only in Non-Responders and across multiple measures (z-Evans Index; p = 0.001, BVR at PC; p = 0.024). This was due to a significant decrease in ventricular measurement (p = 0.005) that correlated to independent 3D volumetry (p = 0.008). Conclusion. In the context of multimorbidity burden, frailty risks and overlay from neurodegenerative disease, 3d morphological indices demonstrated utility in distinguishing hydrocephalus vs. non-hydrocephalus and degree of CSF responsiveness. Further work may support the characterization of patients with Complex NPH who would best benefit from the risks of interventions.

The National Neuroscience Institute External Ventricular Drain Study: A Pragmatic Multisite Risk-Stratification Pathway to Reduce Ventriculostomy-Related Infection.

OBJECTIVE: Ventriculostomy-related infection (VRI) is associated with potential serious morbidity, extended hospitalization duration, increased health care costs, and mortality. We assessed the effectiveness of a pragmatic risk-stratification pathway for external ventricular drain (EVD) management, allowing for surgical decision making, in reducing the rate of VRIs. METHODS: Two studies were performed concurrently. A retrospective audit of EVD infection rates and outcomes in our unit across 3 hospitals was conducted from January to December 2014. The second prospective study compared the same variables during the implementation of the EVD pathway across the 3 sites from January 2015 to December 2016. RESULTS: The number of patients requiring EVDs increased from 2014 to 2016 (165 vs. 189 vs. 197 patients, respectively), with a significant increase in patients with intraventricular hemorrhage (P = 0.009). Despite increasing risk, overall EVD infections decreased during the implementation period, from 4.8% (8/165) in 2014 to 3.7% in 2015 (7/189) and 2.0% in 2016 (4/197, P = 0.33). In 2 sites (site 1, 2.0% vs. 2.1% vs. 1.9%, and site 2, 4.7% vs. 5.0% vs. 5.3%), transition to the EVD risk-stratification pathway maintained already low infection rates; in site 3, EVD infections decreased from 6.8% (5/73) to 3.9% (4/102) and 0% (0/86, P = 0.06). CONCLUSIONS: The introduction of a pragmatic evidence-based risk-stratification pathway, in which different options for EVD management are incorporated, results in low EVD infection rates across a multisite institutional practice. Our results are comparable to published protocols involving the implementation of standard care bundles and/or antibacterial EVDs alone, in reducing VRIs.

DTI Profiles for Rapid Description of Cohorts at the Clinical-Research Interface.

Normal pressure hydrocephalus (NPH) is a syndrome comprising gait disturbance, cognitive decline and urinary incontinence that is an unique model of reversible brain injury, but it presents as a challenging spectrum of disease cohorts. Diffusion Tensor Imaging (DTI), with its ability to interrogate structural white matter patterns at a microarchitectural level, is a potentially useful tool for the confirmation and characterization of disease cohorts at the clinical-research interface. However, obstacles to its widespread use involve the need for consistent DTI analysis and interpretation tools across collaborator sites. We present the use of DTI profiles, a simplistic methodology to interpret white matter injury patterns based on the morphology of diffusivity parameters. We examined 13 patients with complex NPH, i.e., patients with NPH and overlay from multiple comorbidities, including vascular risk burden and neurodegenerative disease, undergoing extended CSF drainage, clinical assessments, and multi-modal MR imaging. Following appropriate exclusions, we compared the morphology of DTI profiles in such complex NPH patients (n = 12, comprising 4 responders and 8 non-responders) to exemplar DTI profiles from a cohort of classic NPH patients (n = 16) demonstrating responsiveness of white matter injury to ventriculo-peritoneal shunting. In the cohort of complex NPH patients, mean age was 71.3 ± 7.6 years (10 males, 2 females) with a mean MMSE score of 21.1. There were 5 age-matched healthy controls, mean age was 73.4 ± 7.2 years (1 male, 4 females) and mean MMSE score was 26.8. In the exemplar cohort of classic NPH patients, mean age was 74.7 ± 5.9 years (10 males, 6 females) and mean MMSE score was 24.1. There were 9 age-matched healthy controls, mean age was 69.4 ± 9.7 years (4 males, 5 females) and mean MMSE score was 28.6. We found that, despite the challenges of acquiring DTI metrics from differing scanners across collaborator sites and NPH patients presenting as differing cohorts along the spectrum of disease, DTI profiles for responsiveness to interventions were comparable. Distinct DTI characteristics were demonstrated for complex NPH responders vs. non-responders. The morphology of DTI profiles for complex NPH responders mimicked DTI patterns found in predominantly shunt-responsive patients undergoing intervention for classic NPH. However, DTI profiles for complex NPH non-responders was suggestive of atrophy. Our findings suggest that it is possible to use DTI profiles to provide a methodology for rapid description of differing cohorts of disease at the clinical-research interface. By describing DTI measures morphologically, it was possible to consistently compare white matter injury patterns across international collaborator datasets.

Association between pacifier use and breast-feeding, sudden infant death syndrome, infection and dental malocclusion.

OBJECTIVE: To critically review all literature related to pacifier use for full-term healthy infants and young children.The specific review questions addressed are:What is the evidence of adverse and/or positive outcomes of pacifier use in infancy and childhood in relation to each of the following subtopics: INCLUSION CRITERIA: Specific criteria were used to determine which studies would be included in the review: (i) the types of participants; (ii) the types of research design; and (iii) the types of outcome measures. To be included a study has to meet all criteria.The participants included in the review were healthy term infants and healthy children up to the age of 16 years. Studies that focused on preterm infants, and infants and young children with serious illness or congenital malformations were excluded. However, some total population studies did include these children.It became evident early in the review process that very few randomised controlled trials had been conducted. A decision was made to include observational epidemiological designs, specifically prospective cohort studies and, in the case of sudden infant death syndrome research, case-control studies. Purely descriptive and cross-sectional studies were excluded, as were qualitative studies and all other forms of evidence.A number of criteria have been proposed to establish causation in the scientific and medical literature. These key criteria were applied in the review process and are described as follows: (i) consistency and unbiasedness of findings; (ii) strength of association; (iii) temporal sequence; (iv) dose-response relationship; (v) specificity; (vi) coherence with biological background and previous knowledge; (vii) biological plausibility; and (viii) experimental evidence.Studies that did not meet the requirement of appropriate temporal sequencing of events and studies that did not present an estimate of the strength of association were not included in the final review.Our specific interest was pacifier use related to:Studies that examined pacifier use related to procedural pain relief were excluded. Studies that examined the relationship between pacifier use and gastro-oesophageal reflux were also excluded as this information has been recently presented as a systematic review. SEARCH STRATEGY: The review comprised published and unpublished research literature. The search was restricted to reports published in English, Spanish and German. The time period covered research published from January 1960 to October 2003. A protocol developed by New Zealand Health Technology Assessment was used to guide the search process. The search comprised bibliographic databases, citation searching, other evidence-based and guidelines sites, government documents, books and reports, professional websites, national associations, hand search, contacting national/international experts and general internet searching. ASSESSMENT OF QUALITY: All studies identified during the database search were assessed for relevance to the review based on the information provided in the title, abstract and descriptor/MeSH terms, and a full report was retrieved for all studies that met the inclusion criteria. Studies identified from reference list searches were assessed for relevance based on the study title. Keywords included: dummy, dummies, pacifier(s), soother(s), comforter(s), non-nutritive sucking, infant, child, infant care.Initially, studies were reviewed for inclusion by pairs of principal investigators. Authorship of articles was not concealed from the reviewers. Next, the methodological quality of included articles was assessed independently by groups of three or more principal investigators and clinicians using a checklist. All 20 studies that were accepted met minimum set criteria, but few passed without some methodological concern. DATA EXTRACTION: To meet the requirements of the Joanna Briggs Institute, reasons for acceptance and non-acceptance at each phase were clearly documented. An assessment protocol and report form was developed for each of the three phases of review. The first form was created to record investigators' evaluations of studies included in the initial review. Those studies that failed to meet strict inclusion criteria were excluded at this point. A second form was designed to facilitate an in-depth critique of epidemiological study methodology. The checklist was pilot tested and adjustments were made before reviewers were trained in its use. When reviewers could not agree on an assessment, it was passed to additional reviewers and discussed until a consensus was reached. At this stage, studies other than cohort, case-control and randomised controlled trials were excluded. Issues of clarification were also addressed at this point. The final phase was that of integration. This phase, undertaken by the principal investigators, was assisted by the production of data extraction tables. Through a process of trial and error, a framework was formulated that adequately summarised the key elements of the studies. This information was tabulated under the following headings: authors/setting, design, exposure/outcome, confounders controlled, analysis and main findings. RESULTS: With regard to the breast-feeding outcome, 10 studies met the inclusion criteria, comprising two randomised controlled trials and eight cohort studies. The research was conducted between 1995 and 2003 in a wide variety of settings involving research participants from diverse socioeconomic and cultural backgrounds. Information regarding exposure and outcome status, and potential confounding factors was obtained from: antenatal and postnatal records; interviews before discharge from obstetric/midwifery care; post-discharge interviews; and post-discharge postal and telephone surveys. Both the level of contact and the frequency of contact with the informant, the child's mother, differed widely. Pacifier use was defined and measured inconsistently, possibly because few studies were initiated expressly to investigate its relationship with breast-feeding. Completeness of follow-up was addressed, but missing data were not uniformly identified and explained. When comparisons were made between participants and non-participants there was some evidence of differential loss and a bias towards families in higher socioeconomic groups. Multivariate analysis was undertaken in the majority of studies, with some including a large number of sociodemographic, obstetric and infant covariates and others including just maternal age and education.As might be expected given the inconsistency of definition and measurement, the relationship between pacifier use and breast-feeding was expressed in many different ways and a meta-analysis was not appropriate. In summary, only one study did not report a negative association between pacifier use and breast-feeding duration or exclusivity. Results indicate an increase in risk for a reduced overall duration of breast-feeding from 20% to almost threefold. The data suggest that very infrequent use may not have any overall negative impact on breast-feeding outcomes.Six sudden infant death syndrome case-control studies met the criteria for inclusion. The research was conducted with information gathered between 1984 and 1999 in Norway, UK, New Zealand, the Netherlands and USA. Exposure information was obtained from a variety of sources including: hospital and antenatal records, death scene investigation, and interview and questionnaire. Information for cases was sought within 2 days after death, within 2-4 weeks after death and in one study between 3 and 11 years after death. Information for controls was sought from as early as 4 days of a nominated sudden infant death syndrome case, to between 1 and 7 weeks from the case date, and again in one study some 3-11 years later. In the majority of the studies case ascertainment was determined by post-mortem. Pacifier use was again defined and measured somewhat inconsistently. All studies controlled for confounding factors by matching and/or using multivariate analysis. Generally, antenatal and postnatal factors, as well as infant care practices, and maternal, family and socioeconomic issues were considered.All five studies reporting multivariate results found significantly fewer sudden infant death syndrome cases used a pacifier compared with controls. That is, pacifier use was associated with a reduced incidence of sudden infant death syndrome. These results indicate that the risk of sudden infant death syndrome for infants who did not use a pacifier in the last or reference sleep was at least twice, and possibly five times, that of infants who did use a pacifier.Three studies reported a moderately sized positive association between pacifier use and a variety of infections. Conversely, one study found no positive association between pacifier use at 15 months of age and a range of infections experienced between the ages of 6 and 18 months. Given the limited number of studies available and the variability of results, no meaningful conclusions could be drawn.Five cohort studies and one case-control study focused on the relationship between pacifier use and dental malocclusion. Not one of these studies reported a measure of association, such as an estimate of relative risk. It was therefore not possible to include these studies in the final review.Implications for practice It is intended that this review be used as the basis of a 'best practice guideline', to make health professionals aware of the research evidence concerning these health and developmental consequences of pacifier use, because parents need clear information on which they can base child care decisions. With regard to the association between pacifier use and infection and dental malocclusion it was found that, due to the paucity of epidemiological studies, no meaningful conclusion can be drawn. There is clearly a need for moreepidemiological research with regard to these two outcomes. The evidence for a relationship between pacifier use and sudden infant death syndrome is consistent, while the exact mechanism of the effect is not well understood. As to breast-feeding, research evidence shows that pacifier use in infancy is associated with a shorter duration and non-exclusivity. It is plausible that pacifier use causes babies to breast-feed less, but a causal relationship has not been irrefutably proven.Because breast-feeding confers an important advantage on all children and the incidence of sudden infant death syndrome is very low, it is recommended that health professionals generally advise parents against pacifier use, while taking into account individual circumstances.

Association between pacifier use and breast-feeding, sudden infant death syndrome, infection and dental malocclusion.

OBJECTIVE: To critically review all literature related to pacifier use for full-term healthy infants and young children. The specific review questions addressed are: What is the evidence of adverse and/or positive outcomes of pacifier use in infancy and childhood in relation to each of the following subtopics: • breast-feeding; • sudden infant death syndrome; • infection; • dental malocclusion. INCLUSION CRITERIA: Specific criteria were used to determine which studies would be included in the review: (i) the types of participants; (ii) the types of research design; and (iii) the types of outcome measures. To be included a study has to meet all criteria. TYPES OF PARTICIPANTS: The participants included in the review were healthy term infants and healthy children up to the age of 16 years. Studies that focused on preterm infants, and infants and young children with serious illness or congenital malformations were excluded. However, some total population studies did include these children. Types of research design: It became evident early in the review process that very few randomised controlled trials had been conducted. A decision was made to include observational epidemiological designs, specifically prospective cohort studies and, in the case of sudden infant death syndrome research, case-control studies. Purely descriptive and cross-sectional studies were excluded, as were qualitative studies and all other forms of evidence. A number of criteria have been proposed to establish causation in the scientific and medical literature. These key criteria were applied in the review process and are described as follows: (i) consistency and unbiasedness of findings; (ii) strength of association; (iii) temporal sequence; (iv) dose-response relationship; (v) specificity; (vi) coherence with biological background and previous knowledge; (vii) biological plausibility; and (viii) experimental evidence. Studies that did not meet the requirement of appropriate temporal sequencing of events and studies that did not present an estimate of the strength of association were not included in the final review. Types of outcome measures: Our specific interest was pacifier use related to: • breast-feeding; • sudden infant death syndrome; • infection; • dental malocclusion. Studies that examined pacifier use related to procedural pain relief were excluded. Studies that examined the relationship between pacifier use and gastro-oesophageal reflux were also excluded as this information has been recently presented as a systematic review. SEARCH STRATEGY: The review comprised published and unpublished research literature. The search was restricted to reports published in English, Spanish and German. The time period covered research published from January 1960 to October 2003. A protocol developed by New Zealand Health Technology Assessment was used to guide the search process. The search comprised bibliographic databases, citation searching, other evidence-based and guidelines sites, government documents, books and reports, professional websites, national associations, hand search, contacting national/international experts and general internet searching. ASSESSMENT OF QUALITY: All studies identified during the database search were assessed for relevance to the review based on the information provided in the title, abstract and descriptor/MeSH terms, and a full report was retrieved for all studies that met the inclusion criteria. Studies identified from reference list searches were assessed for relevance based on the study title. Keywords included: dummy, dummies, pacifier(s), soother(s), comforter(s), non-nutritive sucking, infant, child, infant care. Initially, studies were reviewed for inclusion by pairs of principal investigators. Authorship of articles was not concealed from the reviewers. Next, the methodological quality of included articles was assessed independently by groups of three or more principal investigators and clinicians using a checklist. All 20 studies that were accepted met minimum set criteria, but few passed without some methodological concern. DATA EXTRACTION: To meet the requirements of the Joanna Briggs Institute, reasons for acceptance and non-acceptance at each phase were clearly documented. An assessment protocol and report form was developed for each of the three phases of review. The first form was created to record investigators' evaluations of studies included in the initial review. Those studies that failed to meet strict inclusion criteria were excluded at this point. A second form was designed to facilitate an in-depth critique of epidemiological study methodology. The checklist was pilot tested and adjustments were made before reviewers were trained in its use. When reviewers could not agree on an assessment, it was passed to additional reviewers and discussed until a consensus was reached. At this stage, studies other than cohort, case-control and randomised controlled trials were excluded. Issues of clarification were also addressed at this point. The final phase was that of integration. This phase, undertaken by the principal investigators, was assisted by the production of data extraction tables. Through a process of trial and error, a framework was formulated that adequately summarised the key elements of the studies. This information was tabulated under the following headings: authors/setting, design, exposure/outcome, confounders controlled, analysis and main findings. RESULTS: With regard to the breast-feeding outcome, 10 studies met the inclusion criteria, comprising two randomised controlled trials and eight cohort studies. The research was conducted between 1995 and 2003 in a wide variety of settings involving research participants from diverse socioeconomic and cultural backgrounds. Information regarding exposure and outcome status, and potential confounding factors was obtained from: antenatal and postnatal records; interviews before discharge from obstetric/midwifery care; post-discharge interviews; and post-discharge postal and telephone surveys. Both the level of contact and the frequency of contact with the informant, the child's mother, differed widely. Pacifier use was defined and measured inconsistently, possibly because few studies were initiated expressly to investigate its relationship with breast-feeding. Completeness of follow-up was addressed, but missing data were not uniformly identified and explained. When comparisons were made between participants and non-participants there was some evidence of differential loss and a bias towards families in higher socioeconomic groups. Multivariate analysis was undertaken in the majority of studies, with some including a large number of sociodemographic, obstetric and infant covariates and others including just maternal age and education. As might be expected given the inconsistency of definition and measurement, the relationship between pacifier use and breast-feeding was expressed in many different ways and a meta-analysis was not appropriate. In summary, only one study did not report a negative association between pacifier use and breast-feeding duration or exclusivity. Results indicate an increase in risk for a reduced overall duration of breast-feeding from 20% to almost threefold. The data suggest that very infrequent use may not have any overall negative impact on breast-feeding outcomes. Six sudden infant death syndrome case-control studies met the criteria for inclusion. The research was conducted with information gathered between 1984 and 1999 in Norway, UK, New Zealand, the Netherlands and USA. Exposure information was obtained from a variety of sources including: hospital and antenatal records, death scene investigation, and interview and questionnaire. Information for cases was sought within 2 days after death, within 2-4 weeks after death and in one study between 3 and 11 years after death. Information for controls was sought from as early as 4 days of a nominated sudden infant death syndrome case, to between 1 and 7 weeks from the case date, and again in one study some 3-11 years later. In the majority of the studies case ascertainment was determined by post-mortem. Pacifier use was again defined and measured somewhat inconsistently. All studies controlled for confounding factors by matching and/or using multivariate analysis. Generally, antenatal and postnatal factors, as well as infant care practices, and maternal, family and socioeconomic issues were considered. (ABSTRACT TRUNCATED)