Reaching adults who smoke cigarettes in rural Appalachia: Rationale, design & analysis plan for a mixed-methods study disseminating pharmacy-delivered cessation treatment.

INTRODUCTION: Unlike other U.S. geographical regions, cigarette smoking prevalence remains stagnant in rural Appalachia. One avenue for reaching rural residents with evidence-based smoking cessation treatments could be utilizing community pharmacists. This paper describes the design, rationale, and analysis plan for a mixed-method study that will determine combinations of cessation treatment components that can be integrated within community pharmacies in rural Appalachia. The aim is to quantify the individual and synergistic effects of five highly disseminable and sustainable cessation components in a factorial experiment. METHODS: This sequential, mixed-method research design, based on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework, will use a randomized controlled trial with a 25 fully crossed factorial design (32 treatment combinations) to test, alone and in combination, the most effective evidence-based cessation components: (1) QuitAid (yes vs. no) (2) tobacco quit line (yes vs. no) (3) SmokefreeTXT (yes vs. no) (4) combination NRT lozenge + NRT patch (vs. NRT patch alone), and (5) eight weeks of NRT (vs. standard four weeks). RESULTS: Logistic regression will model abstinence at six-months, including indicators for the five treatment factors and all two-way interactions between the treatment factors. Demographic and smoking history variables will be considered to assess potential effect modification. Poisson regression will model quit attempts and percent of adherence to treatment components as secondary outcomes. CONCLUSION: This study will provide foundational evidence on how community pharmacies in medically underserved, rural regions can be leveraged to increase utilization of existing evidence-based tobacco cessation resources for treating tobacco dependence. CLINICAL TRIALS: NCT05660525.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

An evaluation of the outcome metric 'days alive and at home' in older patients after hip fracture surgery.

'Days alive and at home' is a validated measure that estimates the time spent at home, defined as the place of residence before admission to hospital. We evaluated this metric in older adults after hip fracture surgery and assessed two follow-up durations, 30 and 90 days. Patients aged ≥ 70 years who underwent hip fracture surgery were identified retrospectively via hospital admission and government mortality records. Patients who successfully returned home and were still alive within 90 days of surgery were distinguished from those who were not. Regression models were used to examine which variables were associated with failure to return home and number of days at home among those who did return, within 90 days of surgery. We analysed the records of 825 patients. Median (IQR [range]) number of days at home within 90 days (n = 788) was 54 (0-76 [0-88]) days and within 30 days (n = 797) it was 2 (0-21 [0-28]) days. Out of these, 274 (35%) patients did not return home within 90 days and 374 (47%) within 30 days after surgery. Known peri-operative risk-factors such as older age, pre-operative anaemia and postoperative acute renal impairment were associated with failure to return home. This study supports days alive and at home as a useful patient-centred outcome measure in older adults after hip fracture surgery. We recommend that this metric should be used in clinical trials and measured at 90, rather than 30, postoperative days. As nearly half of this patient population did not return home within 30 days, the shorter time-period catches fewer meaningful events.

Prenatal MR Imaging Phenotype of Fetuses with Tuberous Sclerosis: An Institutional Case Series and Literature Review.

BACKGROUND AND PURPOSE: Most patients with tuberous sclerosis complex (TSC) do not receive prenatal diagnosis. Our aim was to describe MR imaging findings to determine the following: 1. Whether normal fetal MR imaging is more common in fetuses imaged at ≤24 weeks' gestation compared with >24 weeks 2. The frequency of cardiac rhabdomyoma 3. The range of MR imaging phenotypes in fetal tuberous sclerosis complex. MATERIALS AND METHODS: Our institutional fetal MR imaging data base was searched between January 1, 2011 and June 30, 2021, for cases of TSC confirmed either by genetic testing, postnatal imaging, postmortem examination, or composite prenatal imaging findings and family history. A MEDLINE search was performed on June 8, 2021. RESULTS: Forty-seven published cases and 4 of our own cases were identified. Normal findings on fetal MR imaging were seen at a lower gestational age (mean, 24.7 [SD, 4.5 ] weeks) than abnormal findings on MR imaging (mean, 30.0 [SD, 5.3] weeks) (P = .008). Nine of 42 patients with abnormal MR imaging findings were ≤24 weeks' gestation. Subependymal nodules were present in 26/45 cases (57.8%), and cortical/subcortical lesions, in 17/46 (37.0%). A foramen of Monro nodule was present in 15 cases; in 2/7 cases in which this was unilateral, it was the only abnormal cerebral finding. Cardiac rhabdomyoma was absent in 3/48 cases at the time of fetal MR imaging but was discovered later. Megalencephaly or hemimegalencephaly was observed in 3 cases. CONCLUSIONS: Fetuses with abnormal cranial MR imaging findings were older than those with negative findings. Fetal hemimegalencephaly and megalencephaly should prompt fetal echocardiography. Cardiac rhabdomyoma was not always present at the time of fetal MR imaging.

The Fetus with Ganglionic Eminence Abnormality: Head Size and Extracranial Sonographic Findings Predict Genetic Diagnoses and Postnatal Outcomes.

BACKGROUND AND PURPOSE: Ganglionic eminence abnormalities on fetal MR imaging are associated with cerebral malformations. Their presumed genetic basis and associated postnatal outcomes remain largely unknown. We aimed to elucidate these through a multicenter study. MATERIALS AND METHODS: Between January 2010 and June 2020, seven hospitals in 2 countries performing fetal MR imaging examinations identified fetal MR imaging studies demonstrating ganglionic eminence enlargement, cavitation, or both. Cases with no genetic diagnosis, no whole exome sequencing, or no outcome of a liveborn child were excluded. Head size was classified as large (fronto-occipital diameter > 95th centile), small (fronto-occipital diameter <5th centile), or normal. RESULTS: Twenty-two fetuses with ganglionic eminence abnormalities were identified. Of 8 with large heads, 2 were diagnosed with MTOR mutations; 1 with PIK3CA mutation-producing megalencephaly, polymicrogyria, polydactyly, hydrocephalus (MPPH) syndrome; 3 with TSC mutations; 1 with megalencephaly capillary malformation syndrome; and 1 with hemimegalencephaly. Cardiac rhabdomyoma was present prenatally in all cases of TSC; mutation postaxial polydactyly accompanied megalencephaly capillary malformation and MPPH. Of 12 fetuses with small heads, 7 had TUBA1A mutations, 1 had a TUBB3 mutation, 2 had cobblestone lissencephaly postnatally with no genetic diagnosis, 1 had a PDHA1 mutation, and 1 had a fetal akinesia dyskinesia sequence with no pathogenic mutation on trio whole exome sequencing. One of the fetuses with a normal head size had an OPHN1 mutation with postnatal febrile seizures, and the other had peri-Sylvian polymicrogyria, seizures, and severe developmental delay but no explanatory mutation on whole exome sequencing. CONCLUSIONS: Fetal head size and extracranial prenatal sonographic findings can refine the phenotype and facilitate genetic diagnosis when ganglionic eminence abnormality is diagnosed with MR imaging.

Acute disseminated encephalomyelitis and routine childhood vaccinations - a self-controlled case series.

Acute disseminated encephalomyelitis (ADEM) is an autoimmune, central nervous system demyelinating disorder that follows antecedent immunologic challenges, such as infection or vaccination. This study aimed to investigate the potential association between routine childhood vaccinations and ADEM. Children under 7 years of age admitted to the two tertiary level pediatric hospitals in Victoria, Australia with ADEM from 2000-2015 had their clinical information linked to vaccination records from the Australian Childhood Immunization Register. Chart review was undertaken utilizing the Brighton Collaboration ADEM criteria. The self-controlled case-series (SCCS) methodology was employed to determine the relative incidences of ADEM post-vaccination in two risk intervals: 5-28 days and 2-42 days. Forty-six cases were eligible for SCCS analysis with a median age of 3.2 years. Of the forty-six cases, three were vaccine proximate cases and received vaccinations 23, 25 and 28 days before ADEM onset. Two vaccine proximate cases received their 4-year-old scheduled vaccinations (MMR and DTPa-IPV) and one vaccine proximate case the 1-year old scheduled vaccinations (MMR and Hib-MenC). The relative incidence of ADEM during the narrow and broad risk intervals were 1.041 (95% CI 0.323-3.356, p = 0.946) and 0.585 (95% CI 0.182-1.886, p = 0.370) respectively. Sensitivity analyses did not yield any substantial deviations. These results do not provide evidence of an association between vaccinations routinely provided to children aged under 7 years in Australia and the incidence of ADEM. However, these results should be interpreted with caution as the number of ADEM cases identified was limited and further research is warranted.

Australian clinical consensus guideline for the subacute rehabilitation of childhood stroke.

Childhood stroke results in long-term, multifaceted difficulties, affecting motor, cognitive, communication, and behavioral domains of function which impact on participation and quality of life. The Childhood Stroke Consensus Rehabilitation Guideline was developed to improve the care of children with stroke by providing health professionals with recommendations to assist in their rehabilitative treatment. Clinical questions were formulated to inform systematic database searches from 2001 to 2016, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grade of Recommendation, Assessment, Development and Evaluation system was used to grade evidence as strong or weak. Where evidence was inadequate or absent, a modified Delphi consensus process was used to develop consensus-based recommendations. The guideline provides 56 recommendations (1 evidence-based recommendation and 55 consensus recommendations). These relate to the framework of rehabilitation service delivery as well as domain-specific rehabilitation treatment strategies for each domain of function. It is anticipated that this guideline will provide health professions with recommendations to improve the subacute care of children with stroke both in Australia and internationally.

Use of Tobacco for Weight Control across Products among Young Adults in the U.S. Military.

BACKGROUND: Approximately 17% of young adults currently use tobacco, most commonly cigarettes and/or electronic cigarettes (e-cigarettes), followed by other products (i.e., cigarillos, pipe/hookah, smokeless tobacco). Cigarettes have been historically used to control weight. Little is known about use of non-cigarette products for weight control, particularly among non-college young adults. Tobacco use in the military is higher than civilians, and personnel have increased motivation for weight control due to military fitness standards. This population might be vulnerable to use tobacco for this purpose. Purpose: Exploring prevalence, as well as demographic and behavioral correlates, of using tobacco products for weight control, among a large, diverse sample of military young adults. Methods: U.S. Air Force recruits (N = 24,543) completed a questionnaire about tobacco use. Among users of tobacco products, recruits reported if they had ever used that product to maintain their weight. Results: Smokeless tobacco was most commonly used for weight control (12.2%), followed by cigarettes (7.3%), e-cigarettes (5.5%), cigarillos (3.3%), and hookah/pipe (3.2%). Using tobacco for weight control was associated with fewer harm beliefs and more regular use of that product. Among e-cigarette users, having a higher BMI and a lower educational background was associated with ever using this product for weight control. Conclusions: The belief that a tobacco product helps control one's weight might increase the prevalence, and frequency of use, of that product among military young adults. Tobacco cessation programs should assess for this motivation of use and provide education about tobacco harm and alternative strategies for weight maintenance.

Characterization of the colostrum and transition milk proteomes from primiparous and multiparous Holstein dairy cows.

Colostrum plays a vital role in the nutrition, development, and immunity of a newborn calf. This study aimed to characterize the protein profile of colostrum and to identify changes in the colostrum proteome across parity during the transition to mature milk. Colostrum and transition milk samples were collected at milkings 1, 2, 4, and 14 after calving from multiparous (n = 10) and primiparous cows (n = 10). Samples were skimmed, fractionated, and enriched before analysis for low-abundance proteins by liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Changes in protein abundances were analyzed using PROC MIXED in SAS (SAS Institute Inc., Cary, NC) with determination of the adaptive false discovery rate adjustment using a MULTTEST procedure to identify effects of parity (P), milking number (MN), and their interaction (MN×P). We identified 86 proteins through LC-MS/MS, including 3 low-abundance proteins that were affected by P, 78 that were affected by MN, and 36 affected by MN×P. Prominent ontological groupings of proteins affected by MN included defense or immunity proteins, such as immunoglobulins. Proteins involved in the plasminogen activating cascade and more broadly, blood coagulation, were affected by MN×P. The results of this study add to increasing knowledge of the colostrum and transition milk proteomes, and this is the first study to find evidence of different abundances of these proteins when examined across P, MN, and MN×P. These findings aid in the identification of potential milk protein biomarkers for mammary health during the early postpartum period.

A checklist for trauma quality improvement meetings: A process improvement study.

BACKGROUND: Each year approximately five million people die from injuries. In countries where systems of trauma care have been introduced, death and disability have decreased. A major component of developed trauma systems is a trauma quality improvement (TQI) program and trauma quality improvement meeting (TQIM). Effective TQIMs improve trauma care by identifying and fixing problems. But globally, TQIMs are absent or unstructured in most hospitals providing trauma care. The aim of this study was to implement and evaluate a checklist for a structured TQIM. METHODS: This project was conducted as a prospective before-and-after study in four major trauma centres in India. The intervention was the introduction of a structured TQIM using a checklist, introduced with a workshop. This workshop was based on the World Health Organization (WHO) TQI Programs short course and resources, plus the developed TQIM checklist. Pre- and post-intervention data collection occurred at all meetings in which cases of trauma death were discussed. The primary outcome was TQIM Checklist compliance, defined by the discussion of, and agreement upon each of the following: preventability of death, identification of opportunities to improve care and corrective actions and a plan for closing the loop. RESULTS: There were 34 meetings in each phase, with 99 cases brought to the pre-intervention phase and 125 cases brought to the post-intervention phase. There was an increase in the proportion of cases brought to the meeting for which preventability of death was discussed (from 94% to 100%, p = 0.007) and agreed (from 7 to 19%, OR 3.7; 95% CI:1.4-9.4, p = 0.004) and for which a plan for closing the loop was discussed (from 2% to 18%, OR 10.9; 95% CI:2.5-47.6, p < 0.001) and agreed (from 2% to 18%, OR 10.9; 95% CI:2.5-47.6, p < 0.001). CONCLUSION: This study developed, implemented and evaluated a TQIM Checklist for improving TQIM processes. The introduction of a TQIM Checklist, with training, into four Indian trauma centres, led to more structured TQIMs, including increased discussion and agreement on preventability of death and plans for loop closure. A TQIM Checklist should be considered for all centres managing trauma patients.

Trabecular bone score in adults with cerebral palsy.

CONTEXT: Bone fragility in cerebral palsy (CP) is secondary to a complex interplay of functional, hormonal, and nutritional factors that affect bone remodelling. A greater understanding of bone microarchitectural changes seen in CP should assist therapeutic decision making. OBJECTIVE: To examine the relationship between trabecular bone score (TBS), BMD and fractures in adults with CP; the influence of clinical factors and body composition on bone microarchitecture were explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: 43 adults (25 male) with CP of median age 25 years (interquartile range 21.4-33.9) who had evaluable dual-energy X-ray absorptiometry imaging of the lumbar spine from a single tertiary hospital between 2005-March 2018. RESULTS: 24/43 (55.8%) of patients had TBS values indicating intermediate or high risk of fracture (<1.31). TBS correlated with areal BMD at the lumbar spine, femoral neck and total body. TBS was significantly associated with arm and leg lean mass, with adjustment for age, gender and height (adjusted R2 = 0.18, p = 0.042 for arm lean mass; adjusted R2 = 0.19, p = 0.036 for leg lean mass). There was no difference in TBS when patients were grouped by fracture status, anticonvulsant use, gonadal status or use of PEG feeding. TBS was lower in non-ambulatory patients compared with ambulatory patients (1.28 vs 1.37, p = 0.019). CONCLUSIONS: Abnormal bone microarchitecture, as measured by TBS, was seen in >50% of young adults with CP. TBS correlated with both areal BMD and appendicular lean mass. Maintaining muscle function is likely to be important for bone health in young adults with CP and needs to be confirmed in further studies.

Onabotulinum toxin-A (Botox) for spastic equinus in cerebral palsy: a prospective kinematic study.

PURPOSE: Botulinum toxin-A (or Botox) is widely used for the management of equinus gait in children with cerebral palsy but few recent studies have included instrumented gait analysis. METHODS: This was a prospective cohort study. Gait analysis was performed four weeks before and four weeks after Botulinum toxin-A injection for spastic equinus to detect the maximum effects on gait kinematics. Outcome measures included the Gait Profile Score (GPS), the Gait Variable Score (GVS) for the ankle, maximal ankle dorsiflexion and maximal knee extension at midstance. RESULTS: In all, 37 children participated (20 boys); mean age five years seven months (4 years 1 month to 8 years 2 months); 19 with unilateral and 18 bilateral involvement. At a mean four weeks post-injection, the GPS and ankle GVS were unchanged. However maximum ankle dorsiflexion increased for the whole group; median 7.7° (confidence interval (CI) 4° to 10.6°) to 11.5° (CI 7.7° to 12.9°), p = 0.02. Maximum midstance knee extension was unchanged for the whole group, but median knee flexion increased in children with bilateral involvement; 10.9° (CI 7.4° to 20.8°) to 16.5° (CI 8.4° to 19.7°), p = 0.58. CONCLUSION: Injections of the gastrocsoleus for spastic equinus did not result in objective improvements in overall gait. Improvements in ankle dorsiflexion for children with bilateral involvement may be offset by deterioration at the knee. LEVEL OF EVIDENCE: II - prospective cohort study, before and after intervention.

Comparison of preterm and term equivalent age MRI for the evaluation of preterm brain injury.

OBJECTIVE: To compare information obtained from preterm magnetic resonance imaging (MRI; 31-34 weeks) brain scan to that done at term equivalent age. STUDY DESIGN: Prospective observational study of premature infants with evidence or suspicion of parenchymal brain injury on cranial ultrasound. Brain injury on two scans scored using a scoring system and analyzed. RESULTS: Fourteen infants with a median (range) gestation at birth of 28 (25-29) weeks and birth weight of 1254 (680-1557) grams were studied. There was a strong correlation between the brain injury scores for the two scans (Spearman ρ=0.87, P=0.001) with excellent agreement between two radiologists (interclass correlation coefficient 0.9-0.94). There was also a high level of agreement between the preterm and term MRI two scores (Intraclass correlation coefficient, 0.79 (0.53-0.94)). CONCLUSIONS: Preterm MRI is a feasible option for the assessment of preterm brain injury and analysis of data obtained from scan at preterm age is comparable to that obtained at term equivalent age.

Musculoskeletal and Endocrine Health in Adults With Cerebral Palsy: New Opportunities for Intervention.

CONTEXT: Cerebral palsy (CP) increases fracture risk through diminished ambulation, nutritional deficiencies, and anticonvulsant medication use. Studies examining bone mineral density (BMD) in adults with CP are limited. OBJECTIVE: To examine the relationship between body composition, BMD, and fractures in adults with CP. The effect of functional, nutritional, and endocrine factors on BMD and body composition is also explored. DESIGN: Retrospective cross-sectional study. SETTING AND PARTICIPANTS: Forty-five adults with CP (mean age, 28.3 ± 11.0 years) who had dual-energy x-ray absorptiometry imaging at a single tertiary hospital between 2005 and 2015. RESULTS: Seventeen (38%) had a past history of fragility fracture; 43% had a Z-score of ≤ -2.0 at the lumbar spine (LS) and 41% at the femoral neck (FN). In nonambulatory patients, every one unit decrease in FN Z-score increased the risk of fracture 3.2-fold (95% confidence interval, 1.07-9.70; P = .044). Stepwise linear regression revealed that the Gross Motor Function Classification System was the best predictor of LS Z-score (R(2) = 0.550; ß = -0.582; P = .002) and FN Z-score (R(2) = 0.428; ß = -0.494; P = .004); 35.7% of the variance in BMD was accounted for by lean tissue mass. Hypogonadism, present in 20% of patients, was associated with reduced lean tissue mass and reduced LS BMD. Lean tissue mass positively correlated with BMD in eugonadal patients, but not in hypogonadal patients. CONCLUSIONS: Low BMD and fractures are common in adults with CP. This is the first study to document hypogonadism in adults with CP with detrimental changes in body composition and BMD.

Subcortical volumetric reductions in adult Niemann-Pick disease type C: a cross-sectional study.

BACKGROUND AND PURPOSE: Voxel-based analysis has suggested that deep gray matter rather than cortical regions is initially affected in adult Niemann-Pick type C. We sought to examine a range of deep gray matter structures in adults with NPC and relate these to clinical variables. MATERIALS AND METHODS: Ten adult patients with NPC (18-49 years of age) were compared with 27 age- and sex-matched controls, and subcortical structures were automatically segmented from normalized T1-weighted MR images. Absolute volumes (in cubic millimeters) were generated for a range of deep gray matter structures and were compared between groups and correlated with illness variables. RESULTS: Most structures were smaller in patients with NPC compared with controls. The thalamus, hippocampus, and striatum showed the greatest and most significant reductions, and left hippocampal volume correlated with symptom score and cognition. Vertex analysis of the thalamus, hippocampus, and caudate implicated regions involved in memory, executive function, and motor control. CONCLUSIONS: Thalamic and hippocampal reductions may underpin the memory and executive deficits seen in adult NPC. Volume losses in other subcortical regions may also be involved in the characteristic range of motor, psychiatric, and cognitive deficits seen in the disease.

Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C.

OBJECTIVES: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive lysosomal lipid storage disorder that is invariably fatal. NP-C diagnosis can be delayed for years due to heterogeneous presentation; adult-onset NP-C can be particularly difficult to diagnose. We developed a Suspicion Index tool, ranking specific symptoms within and across domains, including family members who have NP-C, to provide a risk prediction score to identify patients who should undergo testing for NP-C. METHODS: A retrospective chart review was performed in 5 centers in Europe and 2 in Australia (n = 216). Three patient types were selected: classic or variant filipin staining NP-C cases (n = 71), NP-C noncases (confirmed negative by filipin staining; n = 64), or controls with at least 1 characteristic symptom of NP-C (n = 81). NP-C signs and symptoms were categorized into visceral, neurologic, or psychiatric domains. Logistic regression was performed on individual signs and symptoms within and across domains, and regression coefficients were used to develop prediction scores for NP-C. Internal validation was performed with the bootstrap resampling method. RESULTS: The Suspicion Index tool has good discriminatory performance with cutpoints for grading suspicion of NP-C. Neonatal jaundice/cholestasis, splenomegaly, vertical supranuclear gaze palsy, cataplexy, and cognitive decline/dementia were strong predictors of NP-C, as well as symptoms occurring in multiple domains in individual patients, and also parents/siblings or cousins with NP-C. CONCLUSIONS: The Suspicion Index tool is a screening tool that can help identify patients who may warrant further investigation for NP-C. A score ≥70 indicates that patients should be referred for testing for NP-C.

Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C.

BACKGROUND AND PURPOSE: Niemann-Pick disease type C (NPC) is a progressive neurovisceral disorder associated with dystonia, ataxia and a characteristic gaze palsy. Neuropathological studies have demonstrated brainstem atrophy associated with neuronal inclusions and loss, and neurofibrillary tangles, although it is not known whether this pathology can be detected in vivo or how these changes relate to illness variables, particularly ocular-motor changes. Our aim was to utilize a method for brainstem atrophy, validated in progressive supranuclear palsy (PSP), in a group of adult patients with NPC, and explore its relationship to illness variables and ocular-motor functioning. METHODS: We calculated the midbrain and pontine area, and pontine-to-midbrain ratio (PMR) from midsagittal images of 10 adult patients with NPC and 27 age- and gender-matched controls. Measures were correlated with illness variables, and measures of horizontal saccadic functioning. RESULTS: Pontine-to-midbrain ratio was 14% higher in the NPC group, but this difference was not significant. However, PMR showed a significant positive correlation with duration of illness and a measure of illness severity. Furthermore, PMR was significantly negatively correlated with saccadic peak velocity and gain, and self-paced saccadic performance. CONCLUSIONS: Pontine-to-midbrain ratio was increased in adult patients with NPC compared to controls, although not to the same degree as previously described in PSP, which also presents with significant gaze palsy. These changes were driven predominantly by progressive midbrain atrophy. The strong correlation with illness and ocular-motor variables suggests that it may be a useful marker for illness progression in NPC.

Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables.

BACKGROUND AND PURPOSE: Variable alterations to the structure of the corpus callosum have been described in adults with NPC, a neurometabolic disorder known to result in both white and gray matter pathology. This study sought to examine the structure of the callosum in a group of adult patients with NPC and compared callosal structure with a group of matched controls, and to relate callosal structure with state and trait illness variables. MATERIALS AND METHODS: Nine adult patients with NPC were matched to control subjects (n = 26) on age and sex. The corpus callosum was segmented from the midsagittal section of T1-weighted images on all subjects, and total area, length, bending angle, and mean thickness were calculated. In addition, 39 regional thickness measures were derived by using a previously published method. All measures were compared between groups, and analyzed alongside symptom measures, biochemical parameters, and ocular-motor measures. RESULTS: The callosal area and mean thickness were significantly reduced in the patient group, and regional thickness differences were greatest in the genu, posterior body, isthmus, and anterior splenium. Global callosal measures correlated significantly with duration of illness and symptom score, and at trend level with degree of filipin staining. Measures of reflexive saccadic peak velocity and gain, and self-paced saccades, correlated strongly with total callosal area. CONCLUSIONS: Callosal structure and size reflect both state and trait markers in adult NPC, and they may be useful biomarkers to index both white and gray matter changes that reflect illness severity and progression.

White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study.

OBJECTIVE: Niemann-Pick disease type C (NPC) is a progressive neurovisceral disorder with disrupted intracellular cholesterol metabolism that results in significant alterations to neuronal and axonal structure. Adult patients present with ataxia, gaze palsy, impaired cognition, and neuropsychiatric illness, but the neural substrate has not been well-characterized in vivo. Our aim was to investigate a well-characterized sample of adults with confirmed NPC for gray and white matter abnormalities. METHODS: We utilized a combination of optimized voxel-based morphometry of T1-weighted images and tract-based spatial statistics of diffusion tensor images to examine gray matter volume and white matter structural differences in 6 adult patients with NPC and 18 gender- and age-matched controls. RESULTS: Patients with NPC demonstrated bilateral gray matter reductions in large clusters in bilateral hippocampus, thalamus, superior cerebellum, and insula, in addition to smaller regions of inferoposterior cortex. Patients demonstrated widespread reductions in fractional anisotropy in major white matter tracts. Subsequent analysis of measures of axial and radial diffusivity suggest that these changes are contributed to by both impaired myelination and altered axonal structure. CONCLUSIONS: Findings in gray matter areas are broadly consistent with human and animal studies of selective vulnerability of neuronal populations to the neuropathology of NPC, whereas more widespread white matter changes are consistent with the hypothesis that disrupted myelination and axonal structure predate changes to the neuronal cell body. These findings suggest that volumetric analysis of gray matter and diffusion tensor imaging may be useful modalities for indexing illness stage and monitoring response to emerging treatment.

A bivariate measurement error model for nitrogen and potassium intakes to evaluate the performance of regression calibration in the European Prospective Investigation into Cancer and Nutrition study.

OBJECTIVES: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, the performance of 24-h dietary recall (24-HDR) measurements as reference measurements in a linear regression calibration model is evaluated critically at the individual (within-centre) and aggregate (between-centre) levels by using unbiased estimates of urinary measurements of nitrogen and potassium intakes. METHODS: Between 1995 and 1999, 1072 study subjects (59% women) from 12 EPIC centres volunteered to collect 24-h urine samples. Log-transformed questionnaire, 24-HDR and urinary measurements of nitrogen and potassium intakes were analysed in a multivariate measurement error model to estimate the validity of coefficients and error correlations in self-reported dietary measurements. In parallel, correlations between means of 24-HDR and urinary measurements were computed. Linear regression calibration models were used to estimate the regression dilution (attenuation) factors. RESULTS: After adjustment for sex, centre, age, body mass index and height, the validity coefficients for 24-HDRs were 0.285 (95% confidence interval: 0.194, 0.367) and 0.371 (0.291, 0.446) for nitrogen and potassium intakes, respectively. The attenuation factors estimated in a linear regression calibration model were 0.368 (0.228, 0.508) for nitrogen and 0.500 (0.361, 0.639) for potassium intakes; only the former was different from the estimate obtained using urinary measurements in the measurement error model. The aggregate-level correlation coefficients between means of urinary and 24-HDR measurements were 0.838 (0.637, 0.932) and 0.756 (0.481, 0.895) for nitrogen and potassium intakes, respectively. CONCLUSIONS: This study suggests that 24-HDRs can be used as reference measurements at the individual and aggregate levels for potassium intake, whereas, for nitrogen intake, good performance is observed for between-centre calibration, but some limitations are apparent at the individual level.