Adolescents with type 1 diabetes face demanding challenges due to conflicting priorities between psychosocial needs and diabetes management. This conflict often results in poor glycaemic control and discord between adolescents and parents. Adolescent-parent conflicts are thus a barrier for health care providers (HCPs) to overcome in their attempts to involve both adolescents and parents in improvement of glycaemic control. Evidence-based interventions that involve all three parties  and are integrated into routine outpatient clinic visits are lacking. The Guided Self-Determination method is proven effective in adult care and has been adapted to adolescents and parents (Guided Self-Determination-Young (GSD-Y)) for use in paediatric diabetes outpatient clinics. Our objective is to test whether GSD-Y used in routine paediatric outpatient clinic visits will reduce haemoglobin A1c (HbA1c) concentrations and improve adolescents' life skills compared with a control group.Using a mixed methods design comprising a randomised controlled trial and a nested qualitative evaluation, we will recruit 68 adolescents age 13 - 18 years with type 1 diabetes (HbA1c > 8.0%) and their parents from 2 Danish hospitals and randomise into GSD-Y or control groups. During an 8-12 month period, the GSD-Y group will complete 8 outpatient GSD-Y visits, and the control group will completes an equal number of standard visits. The primary outcome is HbA1c. Secondary outcomes include the following: number of self-monitored blood glucose values and levels of autonomous motivation, involvement and autonomy support from parents, autonomy support from HCPs, perceived competence in managing diabetes, well-being, and diabetes-related problems. Primary and secondary outcomes will be evaluated within and between groups by comparing data from baseline, after completion of the visits, and again after a 6-month follow-up. To illustrate how GSD-Y influences glycaemic control and the development of life skills, 10-12 GSD-Y visits will be recorded during the intervention and analysed qualitatively together with individual interviews carried out after follow-up.This study will provide evidence of the effectiveness of using a GSD-Y intervention with three parties on HbA1c and life skills and the feasibility of integrating the intervention into routine outpatient clinic visits.Danish Data Association ref nr. 2008-41-2322ISRCTN54243636 Type 1 diabetes in adolescents is a challenge for the teenagers, their parents and the diabetes health care providers (HCPs) ,3. The nMost adolescents experience difficulties integrating the diabetes regimen into their lives; they confront significant conflicts between the need for diabetes management and psychosocial developmental needs and challenges ,15. BeloDuring adolescence, the responsibility for the management of diabetes should gradually be transferred from parents to adolescents ,27. SomeHCPs view adolescence as a difficult time in which the processes of managing diabetes, providing guidance and eliciting cooperation from adolescents and their parents are complex -38. AparAccording to Anderson  and DelaIn searching for a method that could be applied by HCPs and adapted to adolescents and their parents, we chose Guided Self-Determination (GSD), which has reduced HbA1c (by 0.4%) and improved life skills in adults with persistently poor glycaemic control of type 1 diabetes . We adjuWe hypothesize that using GSD-Y in routine paediatric outpatient diabetes clinics will reduce HbA1c concentrations and improve adolescents' life skills compared with those in a control group.1) To test whether GSD-Y can be integrated into routine paediatric outpatient diabetes clinics in a collaboration between adolescents, their parents and the interdisciplinary diabetes HCPs.2) To test whether GSD-Y reduces HbA1c and improves life skills in adolescents with type 1 diabetes.3) To illustrate how GSD-Y influences developing life skills in adolescents supported by their parents and their HCPs.The trial will be performed in accordance with the recommendations guiding nurses in clinical research involving human participants (Helsinki Declaration). The project was reviewed by the Danish National Committee on Biomedical Research Ethics on April 17, 2009 as registry- and interview-based research .This study is a life-skills intervention using a mixed methods design comprised of a randomised controlled trial and a nested qualitative evaluation . ObjectiThe protocol is summarised in a flowchart Figure .The study takes place at 2 paediatric outpatient clinics at 2 hospitals in the capital region of Denmark: Glostrup, with the largest diabetes outpatient clinic in Denmark (480 patients) and Hillerød, with the third largest diabetes outpatient clinic in Denmark (171 patients).Two paediatric physicians, 5 paediatric diabetes nurses and 2 dieticians (HCP hereafter), trained and tested in using GSD-Y, will recruit adolescents with type 1 diabetes and conduct the GSD-Y intervention as part of their routine outpatient clinic visits.GSD is a problem-solving and decision-making method designed to overcome barriers to empowerment in adult patient-provider interactions, and these barriers are explained by three grounded theories -51. GSD GSD-Y is aimed at improving glycaemic control and increasing adolescents' life skills. Life skills is defined as "those personal, social, cognitive and physical skills that enable people to control and direct their lives and develop the capacity to live with and produce change in their environment" ,52,57. IBecause part of developing life skills is making self-determined decisions , Self-DeIn our study, the adolescents' need for relatedness is satisfied when they feel a sense of belonging with parents and HCPs because there is an atmosphere where talking openly and honestly about their difficulties living with diabetes is legitimised, and adolescents still feel that they are cared for unconditionally. Satisfaction of the need for autonomy occurs when the adolescents perceive that parents and HCPs try to understand their perspective, acknowledge their feelings, and act in a non-judgmental way by minimizing the use of controlling language and behaviour. This creates an autonomy-supportive environment for decision-making, which helps adolescents act in congruence with their values and interests. Satisfying the need for relatedness and autonomy paves the way for fulfilling the need for competence in diabetes management. Adolescents will believe that they succeed in managing diabetes because parents and HCPs are aware of their current competence and accept their shifting readiness to take responsibility for their diabetes.GSD-Y consists of 18 semi-structured reflection sheets for adolescents Table . In addiBefore each appointment, adolescents and parents complete the reflection sheets Table , 2, 3. TBy filling in reflection sheets with their own words and drawings, adolescents and their parents systematically explore and express their individual and common difficulties and experiences with diabetes in daily life. Thus prepared for appointments in the outpatient clinics, adolescents and their parents are guided by trained GSD-Y HCPs to communicate openly and reflect mutually by sharing and respecting each other's observations, thoughts and feelings as a starting point for a constructive collaboration in a caring relationship. This model adds shared insight to previous patterns of diabetes management, which yields a platform for identifying unknown resources in both adolescents and parents and discovering new strategies for problem-solving between the three parties. This paves the way for agreements and concrete arrangements about how to test new problem-solving strategies in the time between outpatient appointments. At the outpatient appointments, the triad evaluates their experiences with these strategies.The overall aim is for adolescents and parents to identify concrete potential for change  and to aTo use the reflection sheets with adolescents and parents, HCPs must be able to practice advanced communication skills such as mirroring , active To meet Objective 1, HCPs participated in a training programme  Experience of feeling competent in managing diabetes, (ii) experience of HCPs being autonomy-supportive versus controlling, (iii) motivation for diabetes management, (iv) ability to manage diabetes-related distress, (v) involvement and support for autonomy from parents, (vi) well-being.b. Diabetes outcomes directly related to patient management(i) Insulin delivery/number of injections/insulin types, (ii) number of self-monitored blood glucose values, (iii) hypoglycaemic episodes (frequency and severity), (iv) admissions to hospital and reasons for admissions .c. Diabetes outcomes indirectly related to patient management(i) Attendance at intervention or control sessions, (ii) parental participation.The size of the study was based on the primary outcome measure HbA1c. According to a power calculation, an absolute difference of 1.0% in HbA1c between the GSD-Y group and the control group  could be detected with 26 patients in each group. This calculation was based on a standard deviation of the HbA1c value of 1.3% from a study of coping skills training . To compAll adolescents aged 13-18 years who have had type 1 diabetes for more than one year will be invited to participate together with their parents if they meet the following criteria:▪ HbA1c ≥ 8.0% at the last visit before entry into the study and▪ Average HbA1c > 7.5% during the last year before entry into the study.Adolescents will be excluded from participating in the study if they meet any of the following criteria:▪ Diagnosed with a psychiatric disease▪ Consulting a psychologist at the time of recruitment▪ Unable to understand, talk or read Danish.Adolescents and parents willing to participate and fulfilling the inclusion criteria will be randomised to either an intervention group (n = 34) (GSD-Y) or a control group (n = 34) (standard care), using stratified randomisation by the adolescent's usual HCP. Randomisation will be performed using sealed envelopes. Neither adolescents nor the HCPs can possibly be blinded to the study. The adolescents in the control group will be offered the GSD-Y intervention after the study has concluded (14-18 month wait-list design).Consent to participate in the study will be obtained by the adolescents' usual HCP. After informed written consent is obtained from the adolescent and at least one parent, adolescents will be randomised into either the intervention or the control group. The adolescent or their parents remain free to withdraw at any time during the study without giving reasons and without prejudicing further treatment. If a participant withdraws consent from further study participation, their data will remain on file and will be included in the final study analysis if the consent for use of the data is not withdrawn; if consent for use of data is also withdrawn, data will be destroyed immediately.The GSD-Y intervention will be delivered by the adolescent's usual HCP in individual settings for a total of 8 visits during an 8- to 12 month period. Each of the 8 visits will last for 1 hour and will include specific reflection sheets, and each visit will cover a specific topic .Danish versions of 6 scales were compiled in one questionnaire Table . The queThe scales included the following:▪ Perceived competence for diabetes management (PCD), assessing patients' experiences of feeling able to manage their diabetes successfully ▪ Health Care Climate Questionnaire (HCCQ) assessing the degree to which patients believed their HCPs to be autonomy-supportive versus controlling in providing general treatment ▪ Treatment Self-Regulation Questionnaire (TSRQ) assessing the motivation for diabetes management and the degree to which behaviours tended to be self-determined. The TRSQ consists of three subscales; (I) Autonomous, (II) Controlled, (III) A-motivated ▪ Problem Areas In Diabetes (PAID) assessing diabetes-related distress including a wide range of feelings related to living with diabetes and its treatment, including guilt, anger, depressed mood and fear ▪ The Perception of Parents Scale (POPS)  assessin▪ WHO-5 Well-being Index capturing emotional well-being in the last two weeks (WHO-5) .The scales were translated and harmonised in accordance with recommended guidelines . InternaRegarding secondary outcomes b and c, a case report form will be completed at every outpatient visit by the adolescents' HCPs. Furthermore, demographic data will be collected at baseline, after the intervention/control period and at the 6-month follow-up.To meet Objective 2 and test if GSD-Y effectively reduces HbA1c and improves life skills in adolescents with type 1 diabetes, we will analyse HbA1c and quantitative data from the questionnaires using PAWS Statistics18 for Windows . Statistical analyses will include frequency, mean, standard deviation and confidence intervals. Comparisons of primary and secondary outcomes for the two groups will be conducted comparing data at baseline, at the end of the study, and after a 6-month follow-up period using appropriate parametric tests for variables fulfilling the normal distribution criteria or appropriate non-parametric tests for variables not fulfilling the normal distribution criteria. A Bonferroni correction for multiple testing will be performed.Improvement of life skills will be defined as increases in HCCQ-scores, TSRQ-scores on autonomy or in relative autonomy index (formed by subtracting TSRQ-scores on control from TSRQ-scores on autonomy), PCD, POPS, WHO-5 and frequency of SMBG per week, and decreases in TSRQ-scores on amotivation, PAID scores and HbA1c. Differences within the GSD-Y group and between the GSD-Y group and the control group will be calculated at the end of the intervention (8-12 months) and after a 6-month follow-up period.Ten to twelve adolescents from the intervention group and their parents and HCPs will be followed during the intervention period. To ensure that we follow triads who face significant challenges, we will select them on the basis of high PAID scores and low WHO-5 scores at baseline, which indicate difficulties with life skills.Data will be collected during the intervention period by recording two or three outpatient appointments between 1) adolescent, parent and HCP, 2) adolescent and HCP, and 3) parent and HCP.Individual interviews will be carried out and recorded with the above-mentioned triads after the intervention's endpoint measures at a 6-month follow-up visit using a semi-structured interview guide  preparedTo meet Objective 1, the analysis of the recorded outpatient visits and the individual interviews will explore how adolescents, parents and HCPs experience the following:▪ the implementation of GSD-Y in routine clinics ▪ usefulness of components of GSD-Y and additional support required for sustained uptake▪ sustainability of GSD-Y and issues to consider in extending the model to adolescents in general with diabetes or other chronic disordersTo meet Objective 3, the analysis will also explore and illustrate how GSD-Y influences the process of adolescents developing life skills supported by their parents and their HCPs. Because the intervention is theory-driven , the anaData from the recorded outpatient clinics and the individual interviews will be transcribed verbatim. NVivo 8 software will be used to facilitate the analysis. To maximise the validity of our findings, at least two researchers will participate in the analysis.Improvement of life skills after participating in the intervention group will be defined if we recognize that the adolescents have met the following benchmarks:- start to integrate the disease into their lives .- develop autonomously based motivation for blood glucose measurement, registration and regulation, because they think it is important and not because it is either imposed by parents/HCPs or driven by an "I should do" feeling.- express their own goals for blood glucose and HbA1c regulation, and there is consistency between their objectives, values and behaviours.- are conscious about what they want to talk about at the outpatient clinics.- have insight into new ways to handle situations and relate constructively to the disease and their own reactions  four times each year until the study is finished. The meetings will provide an opportunity to discuss the research design, methods for data collection, schedules, data analyses, outcomes and statistical challenges.The day-to-day management of the study will be led by the project leader. Every week the project leader will meet with the involved HCPs who are running the intervention. These meetings will provide the opportunity to discuss current challenges regarding using the GSD-Y in routine outpatient clinical care.HCP: health care providers; GSD-Y: guided self-determination - young; HbA1c: glycosylated haemoglobinThe authors declare that they have no competing interests.All authors have read and approved the final manuscript. VZ is involved in the conception of the study and its implementation. VZ and BT have contributed to the design of the study and VZ, BT and BAE to development of the protocol. GRH drafted the manuscript with all authors providing critical review and final approval.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/11/55/prepubAppendix 1. Content of GSD-Y training of paediatric diabetes HCPs.Click here for file


This infection requires the binding of factor X to the capsid of this adenovirus. Another organ, the adrenal gland is also infected upon systemic administration of Ad, however, whether this infection is dependent on the cocksackie adenovirus receptor (CAR) or depends on the binding of factor X to the viral capsid remained to be determined. In the present work, we have used a pharmacological agent (warfarin) as well as recombinant adenoviruses lacking the binding site of Factor X to elucidate this mechanism in mice. We demonstrate that, as observed in the liver, adenovirus infection of the adrenal glands in vivo requires Factor X. Considering that the level of transduction of the adrenal glands is well-below that of the liver and that capsid-modified adenoviruses are unlikely to selectively infect the adrenal glands, we have used single-photon emission computed tomography (SPECT) imaging of gene expression to determine whether local virus administration (direct injection in the kidney) could increase gene transfer to the adrenal glands. We demonstrate that direct injection of the virus in the kidney increases gene transfer in the adrenal gland but liver transduction remains important. These observations strongly suggest that serotype 5 adenovirus uses a similar mechanism to infect liver and adrenal gland and that selective transgene expression in the latter is more likely to be achieved through transcriptional targeting.Recombinant, replication-deficient serotype 5 adenovirus infects the liver upon  In vitro and in vivo upon local injection, they can infect a wide range of cell types such as epithelial cells In vivo, systemic injection of recombinant adenovirus is followed by a rapid disappearance of the virus from the blood stream zona fasciculata, has been shown to be particularly prone to infection Recombinant, serotype 5 adenoviruses are probably the most widely used delivery vectors in gene therapy. in vitro infection of an adenovirus serotype 5 is thought to involve the binding of the viral fiber to the coxsackie adenovirus receptor (CAR), followed by internalization mediated by cellular αv-integrins in vivo infection was initially thought to be similar to the in vitro one, recent data have changed the overall consensus: Despite a strong expression of CAR in the liver in vivo. Since then, different studies have demonstrated a role of vitamin K-dependent blood factors in liver transduction Classically, the sequence of Although adrenal glands can be infected through systemic administration of the virus, the level of transgene expression achieved remains low. This modest level of transgene expression is illustrated by the fact that gene transfer in the adrenal glands cannot be visualized by sensitive, whole-body imaging techniques such as PET or even SPECT using the Na/I symporter (NIS) as a reporter gene, while transgene expression in the liver can easily be detected and quantified using either of these methodologies In this context, the aim of the present study is to gain a better understanding of the transduction of the adrenal glands by type 5 adenovirus and to assess a new administration routes to improve adrenal gland transduction by this vector.The replication-incompetent adenovirus, Ad-CMV-rNIS, in which the immediate-early promoter of CMV drives the expression of rat NIS, has been described previously 8 or 1×109 PFU/mouse) in sterile saline buffer  was administered intravenously. For the intra-renal injections, Ad-CMV-rNIS (5×108 PFU/mouse) were injected into the parenchyma of the left kidney of anaesthetised, 7-week-old Balb/c mice. For biodistribution studies, mice were also injected subcutaneously (s.c.) with 133 µg of warfarin/mouse 3 and 1 day prior to Ad vector injections as previously described Animal housing and procedures were conducted according to the guidelines of the French Agriculture Ministry and were approved by the institutional review board  (Permit number # A06-088-14). Gene-transfer studies were performed on female Balb/c mice obtained at 8 weeks of age from Janvier . Ad-CMV-rNIS (5×1099mTc pertechnetate (99mTcO4−) obtained from a freshly eluted 99Mo/99mTc generator. Precisely 20 min later, mice were imaged under Isofluran anaesthesia . Localization of the kidney was performed using 99mTc-Dimercaptosuccinic acid (99mTc-DMSA) as a probe. Briefly, DMSA (TechneScan DMAS) was labelled using a standard procedure 99mTc pertechnetate and 99mTc-DMSA) SPECT/CT scans were performed using a micro-SPECT-CT , using a previously published protocol Forty eight hours after adenovirus administration, mice were injected intraperitoneally with 100 MBq β-galactosidase activity was measured as previously described We first assessed whether the CAR receptor is expressed in the adrenal glands. For that purpose, mRNA was extracted from dissected adrenal glands or a liver biopsy (as a positive control) and subjected to reverse-transcription and PCR amplification. As expected, CAR is indeed expressed in the liver . By cont9 PFU) and a replication-deficient adenovirus in which the hexon hypervariable region 5 had been modified . Both viruses encode the LacZ gene driven by the same promoter and both are equally able to infect CAR-positive cells in vivo. In the adrenal glands, systemic administration of AdHwt resulted in a very significant increase in β-galactosidase expression compared to untreated controls, while systemic injection of AdH[GA]24 resulted in levels of β-galactosidase transcripts fifty times lower than those obtained with AdHwt  was used. Warfarin inhibits the vitamin K-dependent γ carboxylation of the glutamic acid residues in the N-termini of Factor II, VII, IX and X as well as protein C and results in reduced functional, circulating levels of these coagulation factors. To compare the effect of warfarin on adenovirus-mediated gene transfer in the liver and the adrenal glands, warfarin was administered three and one days before virus administration. Twenty-four hours after the last injection of warfarin, the animals were administered intravenously with 6×10he liver . Pre-trehe liver . In the he liver . RT-qPCRhe liver . In bothhe liver . These r8 PFU of Ad-CMV-nls-LacZ were injected systemically in warfarin-treated mice or warfarin-treated mice supplemented with 33 µg of recombinant factor X  (intravenous injection) prior to adenovirus administration. Forty-eight hours later, experimental animals were culled and livers and adrenal glands were collected. To determine whether factor X can restore gene transfer abolished by warfarin, 6×1099mTc-dimercaptosuccinic acid (99mTc-DMSA) is used in nuclear medicine to visualize the renal cortex 99mTc-DMSA in the kidneys. A three-dimensional reconstruction of the images is also presented  To investigate whether intra-renal administration of adenovirus could lead to improved transduction, mice were injected with 5×1099mTc-DMSA  and this complex is taken up by cells in a CAR-independent mechanism. This concept has been elucidated in the liver but has also been demonstrated in the spleen Although adenovirus infection has been thought, for more than a decade, to require the binding of the virus to the cellular CAR, recent data have demonstrated that, in vivo as well as transduction of the adrenal glands by any gene delivery vector was demonstrated using imaging of gene expression. In this context, monitoring of gene transfer using NIS as a reporter gene by SPECT/CT offers many advantage. This methodology allows repetitive, longitudinal studies of transgene expression 99mTc-DMSA to help to locate transgene expression.To our knowledge, this is the first time that the warfarin-sensitive nature of adenovirus infection Local delivery of adenovector, through intra-renal injection, results in an increased transduction of the adrenal gland. SPECT/CT imaging of gene expression using this route to administer a replication-deficient adenovirus encoding the Na/I symporter led to a clear, discrete signal in the kidney area. The transduction of the adrenal glands was verified by RT-PCR on biopsies and RT-PCR on mRNAs extracted from the kidneys failed to provide any signal. Quantitative analysis of the images suggested that transgene expression was increased by a factor varying from two to five with the intra-renal route of administration. Considering the short half-life of adenoviruses in the circulation Adenoviral infection of the adrenal glands has been exploited in pre-clinical gene therapy protocols for diseases related to adrenal dysfunctions


Rwanda's National PMTCT program aims to achieve elimination of new HIV infections in children by 2015. In November 2010, Rwanda adopted the WHO 2010 ARV guidelines for PMTCT recommending Option B (HAART) for all HIV-positive pregnant women extended throughout breastfeeding and discontinued (short course-HAART) only for those not eligible for life treatment. The current study aims to assess the cost-effectiveness of this policy choice.Based on a cohort of HIV-infected pregnant women in Rwanda, we modelled the cost-effectiveness of six regimens: dual ARV prophylaxis with either 12 months breastfeeding or replacement feeding; short course HAART (Sc-HAART) prophylaxis with either 6 months breastfeeding, 12 months breastfeeding, or 18 months breastfeeding; and Sc-HAART prophylaxis with replacement feeding. Direct costs were modelled based on all inputs in each scenario and related unit costs. Effectiveness was evaluated by measuring HIV-free survival at 18 months. Savings correspond to the lifetime costs of HIV treatment and care avoided as a result of all vertical HIV infections averted.All PMTCT scenarios considered are cost saving compared to “no intervention.” Sc-HAART with 12 months breastfeeding or 6 months breastfeeding dominate all other scenarios. Sc-HAART with 12 months breastfeeding allows for more children to be alive and HIV-uninfected by 18 months than Sc-HAART with 6 months breastfeeding for an incremental cost per child alive and uninfected of 11,882 USD. This conclusion is sensitive to changes in the relative risk of mortality by 18 months for exposed HIV-uninfected children on replacement feeding from birth and those who were breastfed for only 6 months compared to those breastfeeding for 12 months or more.Our findings support the earlier decision by Rwanda to adopt WHO Option B and could inform alternatives for breastfeeding duration. Local contexts and existing care delivery models should be part of national policy decisions. In 2009, an estimated 370,000 children were newly infected with human immunodeficiency virus (HIV) globally, primarily due to mother-to-child transmission (MTCT) Compared to previously recommended regimens for the prevention of mother-to-child transmission (PMTCT) of HIV in resource-limited settings Against this context of evolving evidence and recommendations, countries are revising national PMTCT guidelines and are called to make informed policy choices based on local context, balancing the effectiveness, cost, feasibility and sustainability of various PMTCT regimens options. However, previous PMTCT cost-effectiveness studies have not included the range of PMTCT regimen options currently available and often did not adequately account for the cost of treating HIV-infected infants, given that many HIV-infected children now survive into adolescence and adulthood In Rwanda, the prevalence of HIV among pregnant women is 4.3% In 2010, authors calculated the cost and effects of different PMTCT scenarios for a cohort comprising the estimated 10,300 HIV-infected pregnant women needing PMTCT in Rwanda in 2009 We compared PMTCT regimen options  for HIV-For Dual ARV prophylaxis, two infant feeding options were considered: 1) exclusive breastfeeding (BF) during 6 months and continuation of BF for the first 12 months (Option-A), and 2) replacement feeding from birth. For Sc-HAART, the infant feeding options were: 1) breastfeeding for 6, 12, or 18 months (Option-B), and 2) replacement feeding from birth. While 6 months of exclusive breastfeeding is currently recommended in Rwanda, recent data suggest that rate of exclusive breastfeeding in the general population is only 38% The replacement feeding component was modeled on the Partners In Health (PIH) delivery model, operating in 2 rural districts in Rwanda since 2005. The model includes provision of 9 months of formula and related supplies, community health workers conducting home visits for direct observed ARV therapy, social worker home visits, regular support for formula preparation and active follow up of defaulters Under each scenario, all HIV-positive pregnant women eligible (CD4 count <500) for HAART treatment receive long course (Lc) HAART, initiated at time of diagnosis, for life. First-line regimen is tenofovir, lamivudine, and nevirapine (TDF+3TC+NVP). If CD4 is above 350, NVP is replaced by EFV after the first trimester. The infant ARV regimen includes Sd-NVP at birth, followed by once daily NVP for 6 weeks. In the absence of data for Rwanda, we considered 73% of HIV-infected pregnant women in PMTCT programs to be eligible for ART – as reported in the literature For the purposes of modeling and comparison across options, we included a scenario in which the mother-baby pair receive no intervention and assumed that in each scenario all women non-eligible for Lc-HAART were covered with the chosen option . We also assumed that the entire cohort of HIV-infected pregnant women discovers their HIV status when tested during antenatal care visits. Pregnant women who did not come for antenatal visits, who came late, who were identified during labor, or who had suboptimal regimens for any other reason such as low adherence were not considered in the base case model. Also, in Rwanda, where there is very high coverage of HIV counselling and testing services and of ART programs, some HIV-infected pregnant women are already aware of their HIV status when initiating PMTCT services and are enrolled in ART programs. Given that these women were eligible for treatment and were already receiving lifelong ART prior to ANC and PMTCT, we did not attribute additional ART costs to the PMTCT program for the purposes of the cost-effectiveness calculations .One-way sensitivity analysis was performed for the main inputs of the model: breastfeeding practices; cost of ART, laboratory tests, and replacement feeding; the proportion of eligible women; HIV transmission rates and HIV-free survival rates.Direct costs were modeled based on all inputs in each PMTCT option (including staff time and consumables) and related cost components. Since PMTCT in Rwanda is horizontally integrated with other services, we included only the extra cost of adding PMTCT services to existing activities and attributed a percentage of the indirect costs . We assume that if PMTCT services were to be established in new sites, infrastructure and other capital costs would be similar across PMTCT treatment options and, therefore, the ranking across options would not change. Using an exchange rate of 570 Rwandan Francs per USD For HIV-positive pregnant women (identified through PMTCT) eligible to ART, we calculated the cost of treatment for 18 months only, as this would contribute to 18 month HIV-free survival in breastfed children.The replacement feeding component includes counseling for replacement feeding in the maternity ward after delivery (staff time of feeding assistants and midwives); follow-up home visits by community midwives with related staff time and transport costs (1 visit per week during first 2 months of enrolment and 1 visit per month during months 3–18); education at health centers by social workers ; time spent by health staff in administrative issues and meetings related to milk distribution; material provided to mothers ; the cost of formula from birth until 9 months of age, using the least expensive bulk formula pricing available in Rwanda  and the cost of training staff (5 days on average per staff).Two outcomes of interest were considered to evaluate PMTCT regimen effectiveness: the number of children HIV infections averted against “no intervention”, and 18-month HIV-free survival . The transmission probabilities used to estimate the numbers of HIV infections in children born to HIV-positive mothers and the relative risks of mortality for HIV exposed uninfected children used to calculate 18-month HIV-free survival rates were extracted from the literature, including from two large reviews et al., which reported the longest follow-up period, we assumed a survival rate of 15.1 years from the date of diagnosis Savings correspond to the lifetime costs of HIV treatment and care  for the HIV infections averted among children or the average number of years of survival under treatment multiplied by the annual cost of treatment and care, adjusted for the rate of access to treatment and adherence. Costs were discounted using a 3% rate, as per common practice in cost-effectiveness analysis Children antiretroviral treatment (ART) costs apply to 90% of the cohort of HIV-infected children. This percentage was obtained assuming 95% access to ART . The highest number of new HIV infections in children takes place when mothers receive Dual ARV and breastfeed for 12 months (865 new infections).Across all Sc-HAART options throughout the breastfeeding period, the shortest breastfeeding period (6 months) averted the most HIV infections (286 new infections versus 488 in the case of 18 months breastfeeding). Dual therapy with replacement feeding is associated with 76 fewer vertical HIV infections than Sc-HAART during 18 months of breastfeeding (412 versus 488), but remains inferior to Sc-HAART during 12 months breastfeeding (387 new infections). Infections through long-term breastfeeding overcome the effects of a more effective regime of ARV prophylaxis.Analysis of HIV-free survival, within the assumptions of the base case, changes the ranking across options. The highest numbers of HIV-uninfected children still alive at 18 months are found with Sc-HAART with 12 months breastfeeding  followed by Sc-HAART with 18 months breastfeeding . The other Sc-HAART scenarios (Sc-HAART with 6 months breastfeeding and with replacement feeding) still rank higher than Option A.The annual cost of treatment and care per child, according to age range, is provided in When ranking scenarios based on the number of HIV infections, the analysis showed two alternatives averting more HIV infections and saving more money than all the other scenarios : Sc-HAARWhen ordering scenarios based on the number of children alive and uninfected, ICER analysis shows that there are only two alternatives that are not dominated : Sc-HAARGiven the uncertainty embedded in the input values of the base case scenario, we conducted a one-way sensitivity analyses for key variables of the model.To investigate the sensitivity of findings to breastfeeding practices, ranges were used for both breastfeeding duration and for the percentage of exclusive breastfeeding. As per recommendations, the base case uses 6 months as actual duration of breastfeeding (for options other than Sc-HAART for 12 and 18 months). However, anecdotal reports from health providers in Rwanda suggest that breastfeeding duration for HIV-infected women may be higher than the recommended 6 months due to lack of financial means. Therefore, we took 18 months as the low range (or worst scenario) in terms of actual breastfeeding duration in cases when health providers recommend 6 months to the mothers. For the percentage of women practicing exclusive breastfeeding during the first 6 months, the base case uses 38% as per the rate in the general population Even in the most favorable of the breastfeeding scenarios (with 92% of mothers exclusively breastfeeding for the recommended 6 months), the highest number of HIV infections are averted by Sc-HAART with replacement feeding. The second best option in terms of number of infections averted remains Sc-HAART with 6 months breastfeeding. As expected, an extra infection averted through Sc-HAART with replacement feeding against Sc-HAART with 6 months' breastfeeding would cost more . In the worst case scenario for breastfeeding practices, when the percentage of mixed feeding and the actual breastfeeding duration increase to 18 months (independently of the duration of HAART), the number of HIV infections averted with the breastfeeding options (other than Sc-HAART for 18 months) decreases substantially. Therefore, Sc-HAART with replacement feeding becomes even more favorable and this scenario dominates all the others .When looking at HIV-free survival as an outcome of interest, we find that across the range of values for breastfeeding practices, Sc-HAART with 12 months breastfeeding still allows more HIV uninfected children alive at 18 months than Sc-HAART with 6 months breastfeeding and all other scenarios are dominated, The extra cost per child alive and uninfected is of 11,780 USD in the worst case scenario for breastfeeding practices and 10,774 USD in the most favorable breastfeeding scenario.We conclude that our ranking across PMTCT scenarios is robust, or not sensitive, to breastfeeding practices.Acknowledging that the cost of inputs may vary over time, we explored the variability of our results for potential 50% cost increases or decreases in the inputs that account for the highest proportion of cost, namely: ARV cost, laboratory costs and the cost of replacement feeding. As expected, if prices of ARV and laboratory tests increase, the replacement feeding options become more favourable. If prices of ARV and laboratory tests decrease, Sc-HAART scenarios become more cost-effective since they become cheaper. The opposite occurs when cost of replacement feeding increases. When ARV costs increase, savings also increase.When looking at HIV infections averted, we found that even with varying input costs, Sc-HAART with replacement feeding and Sc-HAART with 6 months breastfeeding remain highest in the ranking across PMTCT options. When all costs increase by 50%, Sc-HAART with 6 months breastfeeding still dominates all scenarios, with the exception of Sc-HAART and replacement feeding, which allows more HIV infections averted for an extra cost of 11,643 USD per extra HIV infection averted. When all costs decrease by 50%, the same is true and the extra cost per extra HIV infection averted becomes as low as 2,995 USD.When looking at HIV-free survival as an outcome of interest, Sc-HAART with 12 months breastfeeding and Sc-HAART with 6 months breastfeeding remain the dominant scenarios across the range of cost variations (+/−50%). The ICER for Sc-HAART with 12 months breastfeeding versus Sc-HAART with 6 months breastfeeding increases to 16,590 USD when costs increase and it decreases to 7,175 USD when costs decrease.Our findings are therefore not sensitive to potential variations (estimated at a maximum of ±50%) in input costs.With respect to the new eligibility criteria of a CD4 threshold of 500, data concerning the proportion of eligible women in Rwanda were not available. Thus we assumed that 73% of women in PMTCT programs may be eligible for ART, as reported in the literature With 36% of women eligible to ART, we found that when looking at HIV infections averted as an outcome of interest, Sc-HAART with 6 months breastfeeding still dominates all scenarios, with the exception of Sc-HAART and replacement feeding, which allows more HIV infections averted for an extra cost of 3,415 USD per extra HIV infection averted. When looking at HIV-free survival as an outcome of interest, Sc-HAART with 12 months breastfeeding and Sc-HAART with 6 months breastfeeding remain the dominant scenarios. Sc-HAART with 12 months breastfeeding allows more HIV uninfected children alive at 18 months for an increased extra cost of 15,639 USD per uninfected child alive at 18 months. Our results are thus not sensitive to plausible changes in the proportion of eligible women in the cohort of HIV-positive pregnant women.Ranges for the HIV transmission rates, as per the most recent data available in the literature, are provided in For HIV infections averted as an outcome of interest, when the low transmission rates are used, Sc-HAART with 6 months breastfeeding dominates all options with the exception of Sc-HAART with replacement feeding. However, the extra cost for an extra infection averted with Sc-HAART and replacement feeding versus Sc-HAART with 6 months breastfeeding increases to 38,712 USD. When the high transmission rates are used, the extra cost for an extra infection averted with Sc-HAART with replacement feeding versus Sc-HAART with 6 months breastfeeding decreases to 2,951 USD.For HIV-free survival as an outcome of interest, Sc-HAART with 12 months breastfeeding and Sc-HAART with 6 months breastfeeding still dominate all other scenarios across the ranges of HIV transmission rates. The ICER for Sc-HAART with 12 months breastfeeding versus 6 months breastfeeding decreases to 7,542 USD when low HIV transmission rates are used and it increases to 94,544 USD when high transmission rates are used.In the absence of national data for Rwanda, the Relative Risks (RR) of mortality rates for children breastfeeding for only 6 months or being formula fed were drawn from the literature see . HoweverWhen redoing the analysis with this lower range (RR = 1), Sc-HAART with replacement feeding allows the highest number of children alive and uninfected at 18 months, for an extra cost per child of 7,745 USD compared to Sc-HAART with 6 months breastfeeding. All other options are dominated see .When looking at the threshold at which the rankings of scenarios change, we found that Sc-HAART with replacement feeding becomes the scenario with highest HIV-free survival attainments if RR is 1.4 or lower. This would require a setting where replacement feeding with an available, nutritionally adequate and safe diet could be provided, such as in the model described in our study. For Sc-HAART with 6 months breastfeeding to become the favourite option in terms of HIV-free survival attainments, RR should be of 1.1 or below. This RR of mortality rate at 18 months might be the actual rate in some context, depending from the conditions of mothers/infants (and the support provided to them) during the weaning period and in the months that follow. When the analysis is re-done using the higher RR ranges , Sc-HAARWe conclude that when using HIV-free survival as an outcome of interest, our results are sensitive to the assumptions used for the mortality rates among HIV exposed uninfected children, and therefore to the conditions  in which early weaning (after 6 months breastfeeding) or replacement feeding would take place.This study modelled cost-effectiveness of various PMTCT ARV regimens and infant feeding options in the Rwandan context to inform policy dialogue at a time of increasing need for more value for money in global health interventions, and a global commitment to the virtual elimination of MTCT by 2015 This study shows that all PMTCT regimens under analysis are cost saving compared to “no intervention”. This indicates that investing in PMTCT services does bring future savings when taking into account the reduced needs for treatment and care services for children in whom infection is averted. As such, it is a moral and practical imperative for governments to aim for the highest number of children alive and HIV-uninfected  within an affordable PMTCT program.Sc-HAART with 12 months breastfeeding and Sc-HAART with 6 months breastfeeding dominate all other scenarios when considering 18-months HIV-free survival. Sc-HAART with 12 months breastfeeding allows the highest number of children alive and HIV uninfected at 18 months, for an incremental cost per extra child of USD 11,882. However, this finding is very sensitive to the values used for the relative risk of mortality comparing children who are breastfed for 12 months or longer to exposed but HIV-uninfected children who are breastfed for 6 months or those who are formula fed from birth. Given the uncertainty embedded in these mortality assumptions, it is difficult to draw unidirectional conclusions. Cost-effectiveness findings for HIV-free survival are sensitive to the actual feasibility of providing nutritionally adequate and safe replacement feeding. WHO has recently issued programme guidance supporting the non-discontinuation of HAART after initiation among all HIV positive pregnant women (Option B+) When considering HIV infections averted, the most cost-effective PMTCT regimens are Sc-HAART for 6 months post-partum with exclusive breastfeeding and Sc-HAART with replacement feeding. A recent analysis from Malawi also suggested that Sc-HAART with 6 months breastfeeding was cost effective for PMTCT An important limitation of our study is that the theoretical model excludes the possible impact of suboptimal treatment delivery resulting from poor adherence rates, losses to follow up, and suboptimal timing of ARV initiation. In addition, non-adherence to the different interventions considered would each have distinct impacts on our study's endpoints. Results are based on the ideal manifestation of the data, without taking into account possible deviations, for the main purpose of ranking options for decision making. Since fewer than 100% of women enroll and completely adhere to PMTCT In Rwanda, the national ART policy states that all persons living with HIV should have universal access to care and treatment for HIV. Therefore, the additional cost for each child who becomes infected is an increased – and lifelong – cost for the Government of Rwanda as the health care payer. Although our model uses the longest surviving paediatric cohort currently available in the literature Our analysis demonstrates that all PMTCT regimen options under analysis are cost saving relative to no PMTCT intervention. Failure to intervene to prevent MTCT is therefore unacceptable from an ethical, financial and public health perspective. Still, the quest for an HIV free generation should be considered within the broader maternal health, and child survival and development contexts.Our findings support the earlier decision the Government of Rwanda made to adopt Option B (Sc-HAART) of the WHO 2010 ARV guidelines for PMTCT. Sc-HAART with 12 months breastfeeding bears the most benefit for HIV-free child survival from a public health perspective. Resource-constrained countries must consider their local context and health care delivery framework to weigh the risks and benefits of each option when setting national PMTCT policies.


Patients who require prolonged mechanical ventilation (PMV) are increasing and producing financial burdens worldwide. This study determines the cost per QALY , out-of-pocket expenses, and lifetime costs for PMV patients stratified by underlying diseases and cognition levels.A nationwide sample of 50,481 patients with continual mechanical ventilation for more than 21 days was collected during 1997–2007. After stratifying the patients according to specific diagnoses, a latent class analysis (LCA) was performed to categorise PMV patients with multiple co-morbidities into several homogeneous groups. The survival functions were estimated for individual groups using the Kaplan-Meier method and extrapolated to 300 months through a semi-parametric method. The survival functions were adjusted using an EQ-5D utility value derived from a convenience sample of 142 PMV patients to estimate quality-adjusted life expectancies (QALE). Another convenience sample of 165 patients was used to estimate the out-of-pocket expenses. The lifetime expenditures paid by the single-payer National Health Insurance (NHI) system and patients' families were estimated by multiplying average monthly expenditures by the survival probabilities and summing the values over lifetime.PMV therapy costs more than 100,000 U.S. dollars (USD) per QALY for all patients with poor cognition. For patients with partial cognition, PMV therapy costs less than 56,000 USD per QALY for those with liver cirrhosis, intracranial or spinal cord injuries, and 57,000–69,000 USD for patients with multiple co-morbidities under age of 65. The average lifetime cost of PMV was usually below 56,000 USD. The out-of-pocket expenses were often more than one-third of the total cost of treatment.PMV treatment for patients with poor cognition would cost more than 5 times Taiwan's GDP (gross domestic products), or less cost-effective. The out-of-pocket expenses for PMV provision should also be considered in policy decision. The number of patients who require prolonged mechanical ventilation (PMV) is rapidly increasing worldwide, which is likely due to an aging population with multiple co-morbidities and to the increasing availability and effectiveness of life-sustaining technologies Most countries with national health insurance systems have employed various economic analyses to improve overall cost-effectiveness and to control both costs and expenditures Based on the results of our previous study of the life expectancy and quality of life in PMV patients The current study was approved by the Institutional Review Board of the National Taiwan University Hospital (IRB number: 200912072R). A nationwide sample of 50,481 patients who were over the age of 17 who had received continual mechanical ventilation for more than 21 days during 1998–2007 was collected Each new patient who fulfilled the criteria for PMV was followed starting on day 21 of PMV treatment and continuing until he/she was deceased or censored on 31 December 2007. The lifetime survival of PMV patients (up to 300 months) was obtained via linear extrapolation of a logit-transformed curve of the survival ratio between the study population and an age- and gender-matched reference population. Background population measures were generated by the Monte Carlo method using life tables of the general population of Taiwan.R statistical package for QALE estimation and can be downloaded for free The full methods and mathematical proof assuming a constant excess hazard, have been described in our previous reports st day after PMV initiation to the time of EQ-5D assessment. A cross-sectional sample of PMV patients was obtained, and a kernel-type smoothing method  was performed to estimate the mean QOL throughout the follow-up time period of 9 years To estimate the quality of life (QOL) utility function for PMV patients, we recruited a convenient, cross-sectional sample of 142 PMV subjects The lifetime survival probabilities along the duration-to-dates were multiplied (or adjusted) with the EQ-5D-measured QOL values to obtain a quality-adjusted survival curve. The total area under this curve was the QALE with QALY as the unit We calculated the lifetime healthcare expenditures by the NHI for the 50,481 PMV patients from the 21st day of PMV treatment to the end of life and including the cost of both inpatient and outpatient care. The calculation process was as follows: for each diagnosis-specific group, we summed the average monthly expenditures for each patient and divided the aggregate by the number of PMV patients who were still alive during each month to estimate the average monthly costs to the NHI. Annual NHI expenditures were adjusted to the 2010 Consumer Price Index (CPI). We did not discount after 2010, because PMV patients rarely survive for more than 2–3 years. The total average monthly expenditures were multiplied by the monthly survival probabilities for each diagnosis-specific group over the course of a lifetime, and all values were summed to obtain the lifetime healthcare expenditure within each disease category. In Taiwan, no specific price index has been constructed for calibrating NHI expenditures on health services. Nevertheless, the Taiwanese government occasionally adjusts NHI payment schemes based on the consumer price index and the prices of selected services.t (duration-to-date) and then multiplied by monthly survival probabilities. The sum of these values represented the average lifetime out-of-pocket expenses for each diagnosis-specific group.This survey was approved by the Institutional Review Board of the Chia-Yi Christian Hospital (IRB number: 098050). To estimate the out-of-pocket money paid by patients and their families, we recruited convenient, cross-sectional 165 PMV subjects during 2009–2010 who received long-term care (>21 days) at eight institutions throughout Taiwan. A written informed consent was obtained from every patient or his/her family caregiver. We asked family caregivers to estimate their relevant expenses over the last month, including the use of supplementary healthcare-related resources not covered by the NHI, non-healthcare related resources, and any loss of salary associated their caregiving responsibilities. The sum of these expenses was calculated by a kernel smoothing method to obtain average monthly expenses along time The CER of PMV treatment for each diagnosis group was calculated using the following formula: Estimated total lifetime cost of PMV treatment per patient/Estimated QALE with PMV treatment per patient = cost-per-QALY. It is practically impossible to find a reference group for PMV patients, because these patients require ventilator everyday for at least 6 hours to sustain their lives and such a ventilation support has continued for more than 21 days. In general, such patients would have died within the same day, had they not been on ventilator.ex post approach instead of the conventional ex ante approach. Our survival data were real follow-up for 10 years and the healthcare expenditures were retrieved from the reimbursement data files of the NHI plus adjustment for the 2010 CPI. We also calculated the standard errors of the means by the bootstrap method for 100 repeated samples in these parameters, including life expectancy, quality of life, quality adjusted life expectancy (QALE) and lifetime cost. However, uncertainties still exist on the different quality of life and extrapolation method, as we have reclassified the PMV patients according to different underlying diseases and/or co-morbidities. In general, the uncertainty on the utility value of QOL depends heavily on the level of patient's cognition We used We selected subcohorts of patients received PMV between 1998 and 2001, and assumed that these cohorts were only followed until the end of 2001 and then extrapolated these results to the end of 2007. Then, we compared the semiparametric predictions with the Kaplan-Meier (K-M) estimates of the follow-ups from 1998 to 2007. Assuming that the K-M estimates are the gold standard, we calculated the relative biases for subcohorts stratified by different underlying diseases and co-morbidities.A total of 50,481 new patients receiving PMV were included during the 10-year study period, with a mean age of 72±14.5 years. The demographic and clinical characteristics of the study population were relatively similar to those of the two convenience sample populations that were assessed to measure quality of life and to determine out-of-pocket expenses, as summarised in After stratification by different underlying causes, we found that most lifetime costs for PMV were below 56,000 USD except for patients who survived for more than 3–4 years, which often included patients with degenerative neurological diseases, stroke, intracranial or spinal cord injuries or multiple co-morbidities who were younger than 65 years old  and 3. TThe QALE of PMV patients with partial cognition was generally 2 times greater than that of patients with poor cognition. The QALE of patients with injuries or liver cirrhosis was generally better than that of patients with chronic renal failure or cancer. When a patient suffered from both cancer and chronic renal failure, the QALE was the lowest, with a QALY of 0.16 and 0.36 for patients with poor and partial cognition, respectively . For patOf the 23,697 PMV patients with multiple co-morbidities, the latent class model typically yielded 3–4 clusters within each age stratum, including heart disease, septicaemia/shock, chronic obstructive pulmonary disease (COPD) and/or others  . The QALth year to that of the 10th year were all below 20%. Among them, the relative biases of most PMV patients with a specific diagnosis ranged between 0.9% and 5.5%, or, are more accurate as they were generally more homogeneous  after implementation of PMV are summarized in the upper panel, while that of out-of pocket expenses (estimated by kernel smoothing method on a convenient sample of 165 patients) are summarized in the lower panel with the original surveyed data and depicted.(TIFF)Click here for additional data file.Table S1Validation of extrapolation method by comparing the Kaplan-Meier (K–M) estimates of 10-year follow-up of PMV patients and those based on the survival of first 4-year and extrapolated to 10-year.(DOCX)Click here for additional data file.


As more families participate expanded newborn screening for metabolic disorders in China, the overall number of false positives increases. Our goal was to assess the potential impact on parental stress, perceptions of the child's health, and family relationships.Parents of 49 infants with false-positive screening results for metabolic disorders in the expanded newborn screening panel were compared with parents of 42 children with normal screening results. Parents first completed structured interview using likert scales, closed and open questions. Parents also completed the parenting stress index.A total of 88 mothers and 41 fathers were interviewed. More mothers in the false-positive group reported that their children required extra parental care (21%), compared with 5% of mothers in the normal-screened group (P<0.001). 39% of mothers in the false-positive group reported that they worry about their child's future development, compared with 10% of mothers in the normal-screened group (P<0.001). Fathers in the false-positive group did not differ from fathers in the normal-screened group in reporting worry about their child's extra care requirements, and their child's future development. Children with false-positive results compared with children with normal results were triple as likely to experience hospitalization .The results showing false-positive screening results may affect parental stress and the parent-child relationship. Parental stress and anxiety can be reduced with improved education and communication to parents about false-positive results. Expanded newborn screening (NBS) using tandem mass spectrometry (MS/MS) to identify more than 30 biochemical genetic disorders is an important advance in early disease detection. It has greater sensitivity than past screening methods and allows for presymptomatic detection and identification of metabolic disorders This report firstly describes china parents' responses to false-positive newborn screening results among a cohort of children born after January 1, 2008, when voluntary expanded newborn screening began in Beijing. The psychological effects of false-positive have not been studied in Chinese population before.Mothers and fathers of children with false-positive newborn screen results, defined as the initial result being abnormal or inconclusive for any of 35 biochemical disorders, were invited to participate after a referral was made for additional confirmatory testing. The authors contracted with a screening center, Center for Clinical Laboratory Development, Chinese Academy of Medical Science, which conducts newborn screening for more than 80% of birthing hospitals in Beijing, to recruit and interview parents of infants with false-positive newborn screen results. This was a comparative cross sectional study. Participants were enrolled by this laboratory between 2008 and 2009. Parents of children with false-positive results were sent a recruitment letter with a reply paid envelope more than 6 months after the diagnosis of a metabolic disorder had been ruled out. This inviting letter included, a short questionnaire (2 copies), two written informed consent  Parents of twins and triplets were sent a single letter. Parents who did not “opt out” by returning a response card indicating a preference not to be contacted were called to participate in a telephone interview The comparison group for the false-positive cohort consisted of parents of 6- to 12-month-old children with normal screening results, selected randomly from the screening center database.The storage NBS card contain the date of birth, birth weight, parents' names, birth hospital, and address. All recruitment occurred between January 1, 2008, and December 31, 2009. All participants completed the study questionnaire once. Additional follow-up interviews were not included in the study design.Exclusions included parents of children who had died and parents of newborns whose birth weight was 2500 g. or gestation less than 32 weeks Complete details of data collection have been reported previously a coefficient in this study was 0.92.Parents next completed the parenting stress index (PSI), short form Statistical Package for Social Science, SPSS version 15.0  was used for data entry and analysis. Descriptive statistics such as means and standard deviation (SD) for age of mothers and frequency and percentages for categorical variables  were determined. The characteristics of children, parents, and families in the false-positive group were compared with those in the normal-screened group by using the student's unpaired t-test for continuous and scale variables and fisher' exact test for dichotomous variables. Student's unpaired t-test was also used to compare the PSI scores between different groups. The number of hospitalizations occurring before 6 months of age was compared for the 2 groups by using Poisson regression. For the PSI, subjects who failed the defensive responding index (scores of 10) were dropped from the analyses. The result of open ended questionnaire was analysis by frequency and percentages. All P values were2-sided, and values of <0.05 were considered significant The sample included parents of 49 children with false-positive newborn screen and 42 children with normal newborn screen results. A total of 88 mothers  and 41 fathers  were interviewed. For 38 infants , both parents responded. The number of enrolled families divided by the number of families contacted determined the participation rates, which were 48% for the false-positive group and 42% for the normal-screened group.As noted in Although parents in the 2 groups reported both worry about their child's health, more mothers in the false-positive group reported that their children required extra parental care (21%), compared with 5% of mothers in the normal-screened group (P<0.001). Thirty-nine percent of mothers in the false-positive group reported that they worry about their child's future development, compared with 10% of mothers in the normal-screened group (P<0.001). Fathers in the false-positive group did not differ from fathers in the normal-screened group in reporting worry about their child's extra care requirements, and their child's future development. In additional, thirty-seven percent of parents in the false-positive group reported that they child have visited a primary care physician in the first 6 months of life, while 15% parents in the normal-screened group (P<0.001). The child hospitalizations during the first 6 months of life among false-positive group was 0.27, compared with 0.09 in the normal- screened group (P<0.001).As shown in As shown in Parents in the false-positive group reported a lower tolerance of false-positive results. Ten (14%) parents in the false-positive group reported that they would not have the test performed again for another child, while no parents in the normal-screened group. 28% parents  reported that they didn't know false-positive when they began participate in screening. In the last open-ended question: “what change can be made in the expanded screening process”, fifty-six percent (n = 72) of parents expressed a need for more information about newborn screening and false-positive results, 16% (n = 21) of parents voiced that providers should provide clearer explanations of the reasons of repeat screening.Expanded newborn screening programs have expanded dramatically in the past decade. The main risks are related to false positive results and results with ambiguous implications for treatment-risks. Our results indicate that a false-positive result from an expanded newborn screening test can induce some parents to experience stress and affect parents' perceptions of their child's health, and the parent-child relationship. This finding is expressed by parents' higher overall stress on the PSI, more than four times required extra parental care, 3 times the number of children hospitalized, longer hospital stays in the false-positive group compared with the normal screen group.False-positive screening results have been associated with increased anxiety and stress in parents of infants who require follow-up testing, even after the infant's good health is confirmed. The true impact of false-positive newborn screening tests is just beginning to be well described. Early screening programs for phenylketonuria (PKU) showed poor parental understanding of false-positive results and a tendency for parents of such children to perceive their children as medically vulnerable More recent research has demonstrated associations between false positive results and mothers' perceptions that their children with false positive results require increased parental care, and a trend towards increased hospitalization Studies have demonstrated that education of parents about false-positive results is lacking Hewlett's review suggest that parental stress and anxiety can be reduced with improved education and communication to parents, specifically at the time of follow-up screening The results of This study has a number of limitations. The disparity in the children's ages between the false-positive and normal-screened groups could have biased results. However, the PSI used to measure parental stress, is considered age independent for small increments of age. It is possible that our study design, in which participants were interviewed 6 months after the resolution of the false-positive screening result, may not have fully captured the stress and anxiety experienced during the waiting period. In additional, sample sizes were small for both respondent groups. The samples were also geographically limited, potentially limiting the generalizability of our results. In the process of our study, the response rate was 45%, lower than other reported This study suggests that false-positive screening results may affect parental stress. This is especially true for parents who have not received adequate information about newborn screening. Therefore, Parental stress and anxiety can be reduced with improved education and communication to parents about false-positive results.


A parental/family history of poor oral health may influence the oral-health-related quality of life (OHRQOL) of adults.To determine whether the oral health of mothers of young children can predict the OHRQOL of those same children when they reach adulthood.Oral examination and interview data from the Dunedin Study's age-32 assessment, as well as maternal self-rated oral health data from the age-5 assessment were used. The main outcome measure was study members' short-form Oral Health Impact Profile (OHIP-14) at age 32. Analyses involved 827 individuals (81.5% of the surviving cohort) dentally examined at both ages, who also completed the OHIP-14 questionnaire at age 32, and whose mothers were interviewed at the age-5 assessment.There was a consistent gradient of relative risk across the categories of maternal self-rated oral health status at the age-5 assessment for having one or more impacts in the overall OHIP-14 scale, whereby risk was greatest among the study members whose mothers rated their oral health as "poor/edentulous", and lowest among those with an "excellent/fairly good" rating. In addition, there was a gradient in the age-32 mean OHIP-14 score, and in the mean number of OHIP-14 impacts at age 32 across the categories of maternal self-rated oral health status. The higher risk of having one or more impacts in the psychological discomfort subscale, when mother rated her oral health as "poor/edentulous", was statistically significant.These data suggest that maternal self-rated oral health when a child is young has a bearing on that child's OHRQOL almost three decades later. The adult offspring of mothers with poor self-rated oral health had poorer OHRQOL outcomes, particularly in the psychological discomfort subscale. Oral-health-related quality of life (OHRQOL) measures examine the extent to which oral disease affects an individual's well-being. They aim to determine the subjective functional and psycho-social impacts of oral disease, and complement traditional objective clinical indicators to facilitate a more holistic approach to oral health . ResearcA potential impact on OHRQOL that remains unexamined is the effect of parental/family history of poor oral health. It is likely that intergenerational processes link maternal oral health  to oral health and disease risk in offspring -28. If mPopulation oral health and population OHRQOL, while inextricably linked, are not the same. While it can be debated whether the primary objective of public health measures should be the improvement of oral health or OHRQOL, it is likely that the burden of impaired OHRQOL is substantial. For this reason, putative predisposing factors for poor OHRQOL require careful and comprehensive examination. This will allow the identification of those who are at greatest risk of suffering poor OHRQOL due to poor oral health, but also independently of clinical oral health factors. Thus, the current study sought to determine whether the oral health of mothers of young children can predict the OHRQOL of those same children when they reach adulthood. It tested the hypothesis that mothers' self-rated oral health when children are young can predict her offspring's OHRQOL many years later.This study uses oral examination and interview data collected from study members during the age-32 assessment of the Dunedin Multidisciplinary Health and Development Study (DMHDS), and interview data obtained from their mothers at the age-5 assessment (in 1977/78). The DMHDS is a prospective cohort study of 1,037 children born at Queen Mary Hospital, Dunedin, New Zealand between 1 April 1972 and 31 March 1973. These 1037 children represent 91% of the 1139 eligible children born between these dates, and 972 (96% of the surviving 1015) were assessed at age 32. Ethics approval was granted by the Otago Research Ethics Committee; participants gave informed consent.Some 922 children (88.9%) were orally examined at age 5. The accompanying parent  was asked about dentate status and (if dentate) to rate their own oral health . The three fathers were excluded from further analysis, as were six mothers who rated their oral health as "don't know". These five responses, combined with the edentulous responses, were grouped into three categories: "excellent/fairly good", "average", and "poor/edentulous", corresponding to the "excellent" or "fairly good" response; "average" response; and" fairly poor", "very poor" or "edentulous" responses respectively.every surface of a missing tooth was decayed prior to extraction [Calibrated examiners carried out dental examinations for caries and missing teeth on 932 of the 972 study members who attended the age-32 assessment (conducted November 2003-June 2005). The intraclass correlation coefficient for intraexaminer reliability was 0.99 for both examiners, and also 0.99 for interexaminer reliability; WHO examination criteria were used . Tooth straction .Socioeconomic status (SES) at age 32 was determined using standard NZ indices which apply a six-interval classification according to occupation; for example, a doctor scores 1 and a labourer scores 6 . Those sThe short-form Oral Health Impact Profile (OHIP-14) was used to assess oral health-related quality of life . This haPost hoc comparisons (using the LSD test) were conducted to determine which groups differed. Statistical tests were two-tailed . Multivariate analysis used the generalized linear model (GLM) command with modified Poisson regression analysis (using a robust error variance procedure) to estimate the relative risk of having one or more impacts on the OHIP-14 subscales and overall scale at age 32, and to model the age-32 mean OHIP-14 score and the mean count of total number of impacts at age 32.Descriptive and bivariate analyses used SPSS version 16.0 . Multivariate analyses used Stata version 11.0 . Chi-square tests examined the statistical significance of associations observed between categorical variables. Kruskal-Wallis tests were used for continuous dependent variables. Of the original 1037 children, 919 (88.6%) had an oral examination at age 5, with their mother reporting on her own oral health at this assessment, and 972 (95.8% of surviving cohort) were assessed at age 32. The analysis was limited to the 827 (81.5% of surviving cohort) study members who were dentally examined at both ages, who completed the OHIP-14 at the age-32 assessment, and whose mothers had been interviewed  at the age-5 assessment. An attrition analysis found statistically significant differences between those who were examined at both ages, and those who were examined at age 5 only  among study members at age 32 (Table Multivariate modelling was used to determine the relative risk (RR) of having one or more impacts on the OHIP-14 scale, and on each of the subscales, at age 32, for each of the categories of maternal self-rated oral health at the age-5 assessment (using the "excellent/fairly good" category as a referent), while controlling for low SES, high caries trajectory, and having one or more missing teeth. There was a consistent gradient of RR across the categories of maternal self-rated oral health status at the age-5 assessment for having one or more impacts in the overall OHIP-14 scale, whereby risk was greatest among the study members whose mothers rated their oral health as "poor/edentulous", and lowest among those with an "excellent/fairly good" rating  than those whose mothers self-rated their oral health as "excellent/fairly good" . More of the latter were low SES, and had a mother who was edentulous or had poor oral health in 1977/78. This may have led to an under-estimation of the strength of the observed associations. Although data were available for a wide range of potential confounders, it was not practical to control for all of these in the models. Those which were included were chosen on the basis of biological plausibility, and guided by previous research. We relied on maternal self-report data at the age-5 assessment, and on study members' self-report data on SES at the age-32 assessment. The reliability and validity of self-report data has been addressed elsewhere . In the While these findings are unique, they are moderately consistent with data on adults that are available from other studies, thus increasing confidence in the validity of the longitudinal and intergenerational findings ,12,14,16The longitudinal associations found between maternal self-rated oral health at the age-5 assessment and study members' OHRQOL at age 32 were noteworthy, with clear gradients in the mean OHIP-14 score, the mean total number of impacts, and the prevalence of one or more impacts overall. Findings from a recent study provide evidence of a strong association between maternal self-rated oral health when children are young, and caries risk among those children many years later . Childrepsychosocial impact, orofacial pain, oral functions and social impact [oral functions dimension; the physical pain dimension to the orofacial pain dimension; the psychological discomfort dimension to the social impact dimension; and the physical disability, psychological disability, social disability, and handicap dimensions to the psychosocial impact dimension [There has been some interesting debate in recent years on the dimensional structure of the OHIP-14 scale, with the suggestion of the existence of a more parsimonious set of OHIP dimensions comprising l impact ,47,48. Iimension . Factor social impact" scale according to a reduced set of subscales) gradient showed an association which was independent of confounders. Is there a reason why this one subscale should be the only one independently associated with maternal self-rated oral health from 27 years earlier? While it is unclear exactly how mothers' self-rated oral health impacts on their adult offspring's OHRQOL 27 years later, it is likely there are complex psychological, socioeconomic and socio-cultural factors processes at play, as well as the more direct diffusion of oral health status  between the generations. The psychological discomfort subscale asks two questions of study members: how often in the previous four weeks they had (a) been self-conscious, or (b) had felt tense, because of trouble with their teeth, mouth or dentures, responding on the five-point Likert scale. While mothers' response to the self-reported oral health question asked at the age-5 assessment undoubtedly reflected their physical oral health at that time, it is possible that it also captures another domain involving psychosocial factors--one similar to that captured by the psychological discomfort subscale--in effect, "negative emotionality". Negative emotionality is one of the three superfactors of the Multidimensional Personality Questionnaire; it comprises aggression, alienation and stress reaction subscales, and a high score is related to anger, depression, neuroticism, anxiety, and poor reaction to stress [Of the prevalence of impacts within the individual subscales, only the psychological discomfort subscale  rate their own oral health unfavourably must be considered to be at greater risk than most.Severe oral disease is now concentrated among a relatively small group of individuals. The targeting of those most at risk of both oral disease, and the subjective impact of oral disease, will ensure the most efficient use of scarce resources. This evidence suggesting that OHRQOL can be influenced by circumstances early in the life course means the The authors declare that they have no competing interests.DMS participated in the data analysis and interpretation, and in drafting the manuscript. WMT participated in the conception and design of the study, and in drafting the manuscript. JMB made critical comments on the manuscript, and participated in drafting the manuscript. RP made critical comments on the manuscript, and helped to draft the manuscript. All authors read and approved the final manuscript.