Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

An Exploration of Mineral Density, Elemental and Chemical Composition of Primary Teeth in Relation to Cord-Blood Vitamin D, Using Laboratory Analysis Techniques.

Postnatally, severe vitamin D deficiency commonly results in rickets as well as potential defects in tooth mineralization. The effects of milder deficiency on oral health outcomes later in life are still unclear. This study used micro-computed tomography (µCT), energy dispersive X-ray analysis (EDX), and Raman spectroscopy to investigate mineral density, total density, and elemental composition of enamel and dentine in 63 exfoliated primary incisors from participants with known 25-hydroxyvitamin D levels (25-OHD) at birth. No differences in mineralization and chemical composition using µCT and EDX analysis were observed irrespective of 25-OHD status. Subtle structural differences were observed via Raman spectroscopy, with more crystalline enamel observed in those with sufficient 25-OHD at birth. Although subtle, the differences seen suggest further attention should be given to children with known milder levels of vitamin D deficiency in early life. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Development of a NASA roadmap for planetary protection to prepare for the first human missions to Mars.

As part of planning for future space exploration, COSPAR (The Committee on Space Research) together with participating space agencies, organized and held interdisciplinary meetings to consider next steps in addressing knowledge gaps for planetary protection for future human missions to Mars. Beginning with the results of these meetings and earlier work by NASA, ESA, and COSPAR (e.g., Criswell et al., 2005; Hogan et al., 2006; Rummel et al., 2008) as a base the authors of this paper carried out a follow-on NASA planning activity to identify the necessary steps to be accomplished to close knowledge gaps. We identified significant overlap between the planetary protection needs and other sets of Mars preparation roadmaps (1) microbial monitoring requirements for crew health and medical systems, (2) studies of the microbiome of the built environment, (3) environmental control and life support systems (ECLSS), (4) waste management, and (5) planetary surface operations. In many cases, efforts to mature exploration class systems for Mars that are occurring in other domains can be leveraged with minor changes to address planetary protection gaps as well. In other cases, work planned for testing on the International Space Station (ISS) as an analog for crew Mars transit, or on the lunar surface as an analog for Mars surface operations can be used to close planetary protection technology and knowledge gaps. An overall strategic framework that combines these domains has the advantage of being more comprehensive, efficient, and timely for closing gaps. This approach has led to the development of a NASA roadmap for addressing planetary protection integrated with other related roadmaps. NASA's development and execution of the planetary protection is now viewed in an integrated way with related technology development and testing. Key features of the integrated capabilities roadmap include.

Improving Mobility Practices of Critically Ill Children.

INTRODUCTION: This quality improvement project aimed to improve mobility practices in a pediatric intensive care unit. METHOD: Three interventions were implemented: a staff-developed mobility progression guideline (including patient mobility phase identification using animal images), physical therapy (PT), and occupational therapy (OT) referrals for all patients with expected hospitalizations of more than 3 days, and the use of activity goal posters. The frequency of mobility activities performed, the number of PT and OT referrals and nurses' confidence in mobilizing patients were compared before and after project implementation. RESULTS: Improvements occurred in the median number of daily mobility activities per patient encounter (1.5-4.0), number of PT and OT referrals (43% and 61% increase, respectively), and nurses' confidence in mobilizing patients (69% of clinical nurses agreed their confidence in mobilizing patients improved after protocol implementation). DISCUSSION: Implementation of an interprofessional mobility quality improvement project improved mobility practices in the pediatric intensive care unit.

Dental Consequences of Vitamin D Deficiency during Pregnancy and Early Infancy-An Observational Study.

Vitamin D (25OHD) status during pregnancy is closely correlated with foetal and new-born 25OHD. Calcification for primary teeth begins from the fourth month of intrauterine life and from birth for permanent teeth. Dental consequences of severe 25OHD deficiency are well documented; however, consequences are less documented for milder degrees of 25OHD deficiency. This study examined the dental consequences of vitamin D deficiency/insufficiency during gestation and infancy in a cohort of 81 New Zealand children. Pregnancy and birth data for the children and their mothers and 25OHD status during gestation, birth and at five months were obtained, and dental examinations were conducted. Associations between 25OHD and enamel defects or caries experience were investigated. Of the 81 children, 55% had experienced dental caries and 64% had at least one enamel defect present. Vitamin D insufficiency (25OHD < 50 nmol/L) at all timepoints was not associated with enamel defect prevalence, but during third trimester pregnancy it was associated with an increased caries risk IRR of 3.55 (CI 1.15-10.92) by age 6. In conclusion, maternal 25OHD insufficiency during the third trimester of pregnancy was associated with greater caries experience in primary dentition. No association was found between early life 25OHD and enamel defect prevalence or severity.

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

Associations between childhood cancer treatment and tooth agenesis.

AIM: The aim of this study was to determine the prevalence of dental developmental disturbances in long-term survivors of childhood malignancies in New Zealand children. This study reports associations with potential risk factors to inform oncologists and dentists of the likelihood of dental abnormalities. METHODS: The study population was children aged 14-16 years old who were diagnosed with cancer prior to 10 years of age. A total of 156 children were eligible, of which 59 participated in this study. The indices used in this study were Holtta's Defect Index (HDI), and Oral Health Impact Profile-14 (OHIP-14). RESULTS: The prevalence of agenesis was 15.3%, microdontia 6.8% and root abnormalities 32.2%. Cyclophosphamide equivalent doses above 8,000mg/m2, stem cell therapy (SCT), and head and neck radiation therapy (HNRT) were associated with a higher mean number of teeth missing due to agenesis. SCT and HNRT were associated with a higher total HDI. A binary logistic regression was carried out to determine the odds of agenesis and found that HNRT was the main contributing factor (OR=7.7, p-value=0.04). The linear regression model found that dactinomycin and agenesis correlated with the largest mean OHIP-14. CONCLUSION: This study found that childhood cancer survivors in New Zealand had a high prevalence of developmental dental abnormalities and it identified potential risk factors related to their cancer treatment. Inequitable access to oral rehabilitation for this patient group argues for a mechanism for consistent improved access to publicly funded dental care across district health boards in New Zealand.

A Performance Improvement Initiative for Implementing an Evidence-Based Discharge Bundle for Lung Transplant Recipients.

BACKGROUND: Lung transplant recipients have high hospital readmission rates. Readmissions are costly to institutions and associated with higher mortality among patients within the first year of transplant. Strong evidence indicates that in hospitalized patients, the use of discharge bundles results in lower 30-day hospital readmission rates. LOCAL PROBLEM: A lung transplant team at a Midwest academic medical center performs 40 to 50 lung transplants annually and provides comprehensive, ongoing care for approximately 300 lung transplant recipients. The objective of this quality improvement project was development and implementation of an evidence-based discharge bundle (standardized patient discharge process) to reduce 30-day hospital readmission rates for this patient population. METHODS: A gap analysis was performed using focus groups to identify strategies to reduce readmissions. Using that data, a standardized discharge bundle was developed in collaboration with the transplant team. INTERVENTIONS: The discharge bundle included improvements in discharge planning, scripted communication methods between team members, a standardized medication template for patient education, standardized follow-up appointment process, and increased telephone calls to the patient after discharge. RESULTS: The primary outcome measured was the monthly 30-day hospital readmission rate of facility lung transplant recipients from June through August of 2019 as compared to the same time period in 2018. The readmission rate did not change during the evaluation period. Team members reported improved communication, efficiency, and improved standardization of follow-up care using the discharge bundle. CONCLUSIONS: Implementing a discharge bundle for lung transplant recipients resulted in improved staff satisfaction with the discharge process.

Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer's disease.

BACKGROUND: Verubecestat, a BACE1 inhibitor that reduces Aß levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. METHODS: EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. RESULTS: Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. CONCLUSIONS: Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov NCT01739348 , registered on 29 November 2012.

Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease.

BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).

Association between diverticular disease requiring surgical intervention and mortality in the postlung transplant population - a retrospective cohort study.

Lung Transplant recipients are at increased risk of complicated diverticular disease. We aim to assess the rate of diverticular surgery in a postlung transplantation population and identify risk factors for surgery. We performed a retrospective cohort study of lung transplant recipients from 2007 to 2011. Demographic variables were evaluated with the Mann-Whitney U and chi-squared tests. Cox regression was performed to evaluate 1- and 2-year landmark survival, assess predictor variables of diverticular surgery and evaluate impact of surgery on CLAD development. Of 17 of 158 patients (10.7%) underwent diverticular-related surgery. Surgical patients had significantly worse survival than nonsurgical patients at 1 year [aHR 2.93 (1.05-8.21), P = 0.041] and 2 year [aHR 4.17 (1.26-13.84), P = 0.020] landmark analyses. Transplant indication of alpha-1 antitrypsin disease and cystic fibrosis were significantly associated with the need for diverticular surgery. Emergent surgery was associated with poorer survival [aHR 5.12(1.00-26.27), P = 0.050]. Lung transplant patients requiring surgery for complicated diverticular disease have significantly poorer survival than those who do not require surgery. Surgery was more common in patients transplanted for A1AT and CF. Optimal assessment and risk stratification of diverticular disease is necessary to prevent excessive morbidity and mortality following transplantation.

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid-beta (Aß) plaques in the brain. Aß is produced from the sequential cleavage of amyloid precursor protein by ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aß level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia.

BACKGROUND: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. METHODS: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep. RESULTS: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated. CONCLUSIONS: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant.

Community water fluoridation: attitudes and opinions from the New Zealand Oral Health Survey.

OBJECTIVE: To report the responses of adult participants in the 2009 New Zealand Oral Health Survey (NZOHS) to questions about community water fluoridation (CWF). METHODS: The study used quantitative data from the NZOHS. All adult participants aged 18 years and over in the nationally representative NZOHS sample were included in the study (n=3475). Univariate analysis and multinominal logistic regression models were used to examine the associations between variables. RESULTS: Overall, 57.7% of respondents thought that there were dental benefits to adding fluoride to drinking water and 31.7% responded that they did not know. More than 45% of respondents did not know whether there were health risks from adding fluoride to drinking water. Overall, 42.0% of respondents were strongly or somewhat in favour of CWF. CONCLUSION AND IMPLICATIONS: People in the Maori, Pacific and Asian ethnic groups, from the two most deprived quintiles, with no education after high school and who brushed their teeth less than twice a day expressed significantly greater uncertainty about CWF than other population groups. This study suggests further research is required to gain a greater understanding of health literacy about CWF and the cultural appropriateness of CWF in NZ.

The impact of sex and gender on adaptation to space: executive summary.

This review article is a compendium of six individual manuscripts, a Commentary, and an Executive Summary. This body of work is entitled "The Impact of Sex and Gender on Adaptation to Space" and was developed in response to a recommendation from the 2011 National Academy of Sciences Decadal Survey, "Recapturing a Future for Space Exploration: Life and Physical Sciences for a New Era," which emphasized the need to fully understand sex and gender differences in space. To ensure the health and safety of male and female astronauts during long-duration space missions, it is imperative to examine and understand the influences that sex and gender have on physiological and psychological changes that occur during spaceflight. In this collection of manuscripts, six workgroups investigated and summarized the current body of published and unpublished human and animal research performed to date related to sex- and gender-based differences in the areas of cardiovascular, immunological, sensorimotor, musculoskeletal, reproductive, and behavioral adaptations to human spaceflight. Each workgroup consisted of scientists and clinicians from academia, the National Aeronautics and Space Administration (NASA), and other federal agencies and was co-chaired by one representative from NASA and one from the external scientific community. The workgroups met via telephone and e-mail over 6 months to review literature and data from space- and ground-based studies to identify sex and gender factors affecting crew health. In particular, the Life Sciences Data Archive and the Lifetime Surveillance of Astronaut Health were extensively mined. The groups identified certain sex-related differences that impact the risks and the optimal medical care required by space-faring women and men. It represents innovative research in sex and gender-based biology that impacts those individuals that are at the forefront of space exploration.

Heavy alcohol use in lung donors increases the risk for primary graft dysfunction.

BACKGROUND: Heavy alcohol use is known to increase the risk of acute lung injury and the acute respiratory distress syndrome. This is in part due to increased production of reactive oxygen species. We hypothesized that recipients of lungs from heavy drinkers would be more susceptible to lung injury following transplantation. METHODS: In this retrospective cohort study, donor histories and transplant outcomes were reviewed in 192 consecutive lung transplant recipients. Donors were classified as No Alcohol Use, Moderate Alcohol Use, or Heavy Alcohol Use based on documented donor histories. RESULTS: Freedom from mechanical ventilation took longer in the lung transplant recipients whose donors had Heavy Alcohol Use, compared with those whose donors had No Alcohol Use or Moderate Alcohol Use (p = 0.01). At admission to the intensive care unit, the Heavy Alcohol Use group had median PaO2 /FiO2 ratio 219 (interquartile range [IQR]: 162 to 382), compared with 305 (IQR: 232 to 400) in the Moderate Alcohol Use group and 314 (IQR: 249 to 418) in the No Alcohol Use group (p = 0.005). The odds of developing severe primary graft dysfunction (PGD) in the Heavy Alcohol Use group versus the No Alcohol Use group were 8.7 times greater (95% confidence interval 1.427 to 53.404, p = 0.019) after controlling for factors known to be associated with PGD. CONCLUSIONS: Recipients of donors with a heavy alcohol use history had an over 8 times greater risk of developing severe PGD following lung transplant. The increase in PGD resulted in poorer gas exchange in the recipients of donor lungs from heavy alcohol users, and these recipients subsequently required mechanical ventilation for a longer time following transplant. Further investigation into lung donors with heavy alcohol use histories is necessary to determine those at highest risk for PGD following transplant.

A qualitative assessment of program characteristics for preventing secondary conditions in individuals with fetal alcohol spectrum disorders.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) are a major public health problem that affects 2 to 5 percent of the population. Individuals with FASD are at high risk for secondary conditions, such as mental health problems, school disruptions, and trouble with the law. Evidence-based intervention programs are needed to prevent and treat secondary conditions in this population. OBJECTIVES: The purpose of this study was to identify intervention program characteristics for preventing secondary conditions in individuals with FASD from the perspectives of parents and service providers. METHODS: This qualitative study utilized a phenomenological approach to identify program characteristics for preventing secondary conditions. Twenty-five parents of children (ages 3 to 33) with FASD and 18 service providers participated in focus groups or individual interviews. Data was systematically analyzed using a framework approach. Themes did not differ by participant type. RESULTS: Participants emphasized five primary characteristics of intervention programs for individuals with FASD. Programs need to 1) be available to individuals across the lifespan, 2) have a prevention focus, 3) be individualized, 4) be comprehensive, and 5) be coordinated across systems and developmental stages. Participants discussed a variety of specific intervention strategies for each developmental stage and setting. CONCLUSIONS: Program characteristics identified in this study are consistent with a positive behavior support framework. This framework is discussed in the context of research on existing interventions for individuals with FASD, and recommendations for future intervention development and evaluation are highlighted.

Potentially preventable admissions to New Zealand public hospitals for dental care: a 20-year review.

OBJECTIVE: To describe the prevalence of admissions to New Zealand public hospitals for dental care and associated time trends for people of all ages during the 20-year period 1990-2009. METHODS: The New Zealand Ministry of Health National Minimum Data Set (NMDS), a collection that covers all publicly funded hospital discharges, was the primary data source for this study. Data over a 20-year period from 1 January 1990 to 31 December 2009 were included, and a subset of ICD 10 codes (K02-K09 and K12 and K13) were selected to identify potentially preventable or ambulatory care sensitive conditions (ACSC) leading to admission to hospital. Volumes, proportions and rates of admission are presented to describe the patterns of admission to hospital. RESULTS: There were 120,046 admissions to public hospitals in New Zealand between 1990 and 2009 for which the provision of dental care was the primary reason for admission. The rate of admission to hospital for dental care increased from 0.92 per 1000 population in the period 1990-1994 to 2.15 per 1000 population in 2005-2009. Dental admission rates were greatest in the 3- to 4-year-old age group, for Maori and Pacific people and for people in the most deprived quintile of the NZDep 2006 index. Almost one-third of people aged 18-34 years who were admitted to hospital primarily for dental care were acute admissions. CONCLUSION: Both the volume and the rate of admission to New Zealand public hospitals for dental care have increased over the period of this study. A continued focus on strategies to reduce the impact of dental disease, particularly in the early childhood population and on ensuring accessible primary dental care for the adult population, is required.

Prevention of secondary conditions in fetal alcohol spectrum disorders: identification of systems-level barriers.

Fetal alcohol spectrum disorders (FASD) impact 2-5% of the US population and are associated with life-long cognitive and behavioral impairments. Individuals with FASD have high rates of secondary conditions, including mental health problems, school disruptions, and trouble with the law. This study focuses on systems-level barriers that contribute to secondary conditions and interfere with prevention and treatment. Using a phenomenological methodology, semi-structured interviews and focus groups were conducted with parents of children with FASD and service providers. Data were analyzed using a framework approach. Participants emphasized the pervasive lack of knowledge of FASD throughout multiple systems. This lack of knowledge contributes to multi-system barriers including delayed diagnosis, unavailability of services, and difficulty qualifying for, implementing, and maintaining services. FASD is a major public health problem. Broad system changes using a public health approach are needed to increase awareness and understanding of FASD, improve access to diagnostic and therapeutic services, and create responsive institutional policies to prevent secondary conditions. These changes are essential to improve outcomes for individuals with FASD and their families and facilitate dissemination of empirically supported interventions.

Teething signs and symptoms: persisting misconceptions among health professionals in New Zealand.

OBJECTIVES: To investigate current beliefs and treatment recommendations for teething symptoms among health professionals in New Zealand. DESIGN: Cross-sectional survey of seven groups of health professionals. METHOD: A written questionnaire was mailed in March 2011 to 336 health professionals practising in Wellington City, Hutt Valley and Kapiti Coast, in New Zealand. The self-administered questionnaire sought information on how many children are perceived to experience teething symptoms, what symptoms are attributed to teething, suggested treatments for teething symptoms, and how distressing teething is to children and parents. RESULTS: The response rate to the single-wave survey was 41%. Although the beliefs varied widely across the groups, almost half (48%) of health professionals believed that some children have teething-associated problems, and 32% believed that most children do. Just over one-third of participants incorrectly attributed fever to teething. Health professionals also incorrectly chose nappy rash (31%), loose stools (27%), runny nose (19%) and mouth ulcers (15%) as teething signs or symptoms. Most participants (65%) suggested paracetamol as a treatment for teething; 60% chose teething gels and 48% suggested teething toys or rings. Most respondents believed that teething is moderately distressing to both the child and parent. CONCLUSIONS: The findings show that misconceptions about the symptoms of teething are held by some health professionals. Many believe that teething causes a variety of serious and systemic symptoms. The study has also shown that teething beliefs vary greatly across the different health professions.