There is little information in the research literature on how parents of children who spend time in a neonatal intensive care unit (NICU) adapt psychologically to the demands of caregiving beyond the initial hospitalization period. Our aim was to compare parents of NICU children with parents of healthy full-term children, looking specifically at the relationship between parental psychosocial health and child characteristics, as well as the relationship between important predictor variables and psychosocial health.A cross-sectional survey was sent to parents as their child turned 3 1/2 years of age. The setting was the province of British Columbia, Canada. The sample included all babies admitted to tertiary level neonatal intensive care units (NICU) at birth over a 16-month period, and a consecutive sample of healthy babies. The main outcome was the SF-36 mental component summary (MCS) score. Predictor variables included caregiver gender; caregiver age; marital status; parental education; annual household income; child health status; child behavior; birth-related risk factors; caregiver strain; and family function.Psychosocial health of NICU parents did not differ from parents of healthy children. Child health status and behavior for NICU and healthy children were strongly related to MCS score in bivariate analysis. In the pooled multivariate model, parental age, low family function, high caregiver strain, and child's internalizing and externalizing behavioral symptoms were independently associated with lower psychosocial health. In addition, female gender was associated with lower psychosocial health in the NICU group, whereas lower education and child's problem with quality of life indicated lower psychosocial health in the healthy baby group.Overall, parental gender, family functioning and caregiver strain played influential roles in parental psychosocial health. Neonatal intensive care is associated with a range of long-term health problems such as cerebral palsy, mental retardation, deafness, blindness and milder but more common problems such as learning disabilities and behavioral problems -13. AlthIn the present study, we sent a questionnaire booklet to mothers of all children admitted to a level III neonatal intensive care unit in the province of British Columbia (Canada) over a 16 month period to collect data on a range of factors in order to examine both neonatal and caregiver outcomes. Our study differs from other NICU follow-up studies in that it is population-based, focuses on preschool aged children and examines the full spectrum of NICU graduates. The aims of this paper are two-fold: (1) to compare psychosocial health of parents of NICU children with parents of healthy full-term children, looking specifically at the relationship between parental psychosocial health and child characteristics ; and (2) to identify predictors of parental psychosocial health .Ethical approval was gained from the University of British Columbia and participating hospitals. Our NICU sample included 2221 surviving babies admitted for more than 24 hours to one of three level III NICUs in British Columbia (BC), Canada over a 16 month period (March 1996 to June 1997). These 3 hospitals  provided 100% of the tertiary care NICU beds in the province. The birth mothers' name and contact details were obtained from the health records department at two hospitals and manually extracted from ledgers of the third hospital. Our list of babies was matched with provincial mortality records to exclude any babies that had died after discharge from the NICU and thereby prevent questionnaires being sent to bereaved parents.A comparison group of 718 healthy singleton full-term babies was recruited from the two hospitals with a hospital-based primary care unit . This sample included all babies delivered over an 11 month period (March 1996 and January 1997) by primary care physicians at these two clinics. Babies with a sibling in the NICU sample and babies subsequently admitted to an NICU for more than 24 hours were excluded. Contact details for the mother were obtained from the health records department at one hospital, and directly from the primary care unit at the other.We excluded from the sample 150 babies  who did not meet our inclusion criteria for the following reasons: parent did not speak English (n = 95); baby died (n = 34); mother died (n = 6); and not applicable (n = 1). In addition, we excluded cases where the questionnaire was completed on the wrong child (n = 7) and where a comparison baby was subsequently admitted to a NICU (n = 7). The overall response rate (after exclusions), was 55% . The response rate for located families (82.8% of the sample was located) was 67.4% (n = 1140) for the NICU group, and 66.4% (n = 393) for the comparison group. Five NICU respondents returned a signed consent form without a completed questionnaire and were dropped from the analysis. Seventy-five percent of parents provided permission for data linkage between the questionnaire data and CNN database. The NICU sample included 181 children that were part of a multiple birth group: 171 twins; and 10 triplets. Table Our main measure of outcome was the SF-36 mental component summary (MCS) score ,26. The Child health status was measured using the Health Status Classification Preschool Version (HSCS-PS) . This meChild behavior was measured with the Child Behavior Checklist 1.5–5 (CBCL/1.5–5) . This quData for birth-related risk data were obtained from the Canadian Neonatal Network Study  for the Caregiver strain was measured using the Parental Impact-Time (PTT) scale from the Infant Toddler Quality of Life Questionnaire . This 7-Family function was measured using the Family Assessment Device (FAD) . Scores A questionnaire booklet, which included the questionnaires described above, was sent to the address of the birth mother as her child turned 3 1/2 years of age. A consent letter was included to obtain permission to link the questionnaire data with hospital birth records. The primary caregiver in our study was defined as the person who, to that point in the child's life, had spent the most amount of time with the child. This could include the mother or father or another parent . We asked the primary caregiver (referred to in this paper as parent) to complete the questionnaire booklet and consent form. Non-respondents were sent a reminder letter, additional copies of the questionnaire booklet and a phone call as necessary. If the telephone number was not in service or reassigned, or a questionnaire booklet was returned to us from the post office, we implemented a comprehensive search strategy that involved searching the Internet and contacting the mothers' primary care physician.T-test. T-test, ANOVA and the equivalent nonparametric tests, and Spearman correlation were used to explore relationships between MCS score and various child characteristics, including health status, behavior and birth-related risk factors. For health status and child behavior, we computed an effect size  or with scores in the normal range (behavior)), to look at the magnitude of the difference in MCS score between subgroups for the NICU and healthy baby samples, and used the Cohen's guidelines for interpretation  [To address the first objective, we compared the psychosocial summary score for the SF-36 questionnaire for parents of NICU children and parents of healthy children using student's s large) .To address the second objective, multiple regression analysis was used to examine the independent effects of, and proportion of variance in MCS scores explained by our predictor variables. For the analysis we examined a pooled model and a model where we stratified by group membership  to separately examine the contribution of each predictor variable for the two samples. Variables with significant (p < .05) or borderline p-values in bivariate analysis were included in the model. Certain birth-related risk factors  were entered into the model on the basis of clinical rather than statistical importance, however, no effects were found. Potential predictor variables include the following: caregiver's gender; caregiver's age (continuous); marital status (married or common-law versus other), caregiver's education (less than high school graduation vs. other); annual household income ; child health status ; child behavior; caregiver strain (continuous); and family function (continuous). For child health status and behavior variables, no problem  and scores in the normal range (behavior) were the reference categories, with mild and moderate/severe  or borderline and clinical range scores (behavior) entered separately, or combined and entered as dichotomous variables. We computed effect sizes to interpret the significance of beta coefficients.The unadjusted mean MCS score for parents of NICU children did not differ from parents of healthy children . We also compared MCS scores after adjusting for the three sample characteristics that differed between the two groups , and no differences were found in the outcome variable.On the HSCS-PS, 55.2% of healthy children had no health problems in any area, compared with 39.8% of NICU children (p < .001 on Chi-square). Table For parents of NICU children, for all 4 health status categories, parental MCS scores decreased as severity of the child health problem increased , with the exception of the presence of a congenital anomaly. For this variable, MCS scores were significantly lower in parents of children with versus without a congenital anomaly . Children with a congenital anomaly (n = 87) had proportionally more mild and moderate/severe health status problems in all 4 categories ; neurosensory problems ; motor development problems ; learning/remembering problems ; poorer quality of life ; more internalizing behaviour symptoms ; more externalizing behavior symptoms ; household income below $30,000 per year ; female gender ;not living as common-law or married ; more caregiver strain ; and lower family function . Borderline significance was also found for less than high school education .We examined a pooled model (both groups together) for a direct comparison of the NICU and healthy groups after adjustment for other variables. Due to the low number of male respondents in the healthy group, we restricted the pooled multivariable analysis to only female respondents. Predictors significantly associated with the outcome were the following: parental age ; internalizing behavior ; externalizing behavior ; parental strain ; and family function . The pooled model also showed an interaction effect between NICU admission and education (less than high school) , we examined separate models for the NICU and the healthy baby group to further explore the association between gender and MCS score, and to evaluate the potential influence of congenital anomalies in NICU group.Variables that were significantly associated with lower MCS scores at the bivariate level include the following: female caregivers ; household income below $30,000 per year (mean difference = -3.3 and p < .001); not living as common-law or married ; neurosensory problems ; motor development problems ; learning/remembering problems ; poorer quality of life ; more internalizing behaviour symptoms ; more externalizing behavior symptoms ; the presence of a congenital anomaly ; more caregiver strain ; and lower family function .Predictors that were significant in the final regression model appear in Table Variables that were significantly associated with poorer SF-36 MCS scores at the bivariate level include the following: younger parental age ; household income below $30,000 per year ; less than high school education ; not living as common-law or married ; motor development problems ; learning/remembering problems ; poorer quality of life ; more internalizing behavior symptoms ; more externalizing behavior symptoms ; more caregiver strain ; and lower family function .Predictors that were significant in the final regression model appear in Table In the healthy baby sample, younger parental age was related to poorer MCS score, with a one year change in age resulting in a 0.26  change in MCS. A ten year difference in age would correspond to a 2.6 difference in MCS, which would represent a small effect size of 0.27  was used as a denominator). Education was also associated with MCS. Compared with high school graduates, the MCS score for parents with less than a high school education were on average 5.0 lower , which represents a moderate effect size of 0.52, although the effect could range from minimal to large due to lower precision of the beta estimate. Child internalizing symptoms, family function and caregiver strain were associated with parental MCS in a similar way as for NICU parents. However, due to lower numbers and resulting low precision in beta estimates, the effects ranged from minimal to large. Lower parent-reported child quality of life was also associated with a lower parental MCS. Parents who reported a problem with their child's quality of life had MCS scores that were 6.9  lower than parents who reported at least one quality of life problem compared with those who reported at least one problem. Again, due to the small numbers, the effect could range from minimal to large. In the final regression model, the adjusted R2 was .3046 , with 6 out of 16 predictors included in the full model.There is little information in the research literature on how parents of NICU children adapt psychologically to the demands of caregiving beyond the initial hospitalization period. We compared the psychosocial health of parents of NICU children with parents of a group of healthy full-term children using the SF-36, a popular generic measure of psychosocial HRQL. Although children admitted to a NICU at birth are at increased risk of a variety of long-term health problems, we did not find any difference in parental psychosocial health when the two groups were compared. This finding is in agreement with one of the few studies that measured mental health in parents of NICU children at preschool age. Singer et al.  reportedCurrent health status, in bivariate analysis, was strongly related with parental psychosocial health. In both groups of parents, those whose child had a neurosensory, motor development, learning/remembering or quality of life problem had poorer psychosocial health than those with children with no problems in these areas. Child behavior was also strongly related to parental psychosocial health. More specifically, parents of children who scored in the borderline or clinical range for internalizing, externalizing and total behavior problems on the CBCL/1.5–5 reported poorer psychosocial health than parents of children who scored in the normal range. These findings were consistent across both samples of parents. The only birth-related risk factor associated with parental psychosocial health was the presence of a congenital anomaly. Here the effect size was small, but points to the possibility that a congenital anomaly may affect parents mental health adversely. Researchers have reached a consensus that a minimally important difference in HRQL is close to one half of a standard deviation . The difThe factors associated with poorer psychosocial health in the multivariate models provide important information about correlates of adjustment for NICU and healthy baby families. In a more general pooled model, parental age, higher caregiver strain, lower family function, and child's internalizing and externalizing behavior were independently associated with poorer caregiver's mental health score. The effect of lower parental education was modified by NICU status of the child. In the healthy baby group, less than high school education indicated lower MCS score. Child externalizing behavior symptoms and female gender  were associated with lower MCS scores in the NICU group, whereas lower parental age, less education and poorer child quality of life were associated with lower MCS in the healthy baby group. For both samples, as it is also seen in a pooled model results, low family function, high caregiver strain, and child's internalizing behavioral symptoms were independently associated with lower parental psychosocial health. For family function and caregiver strain, only a substantial departure from mean values (at least 2 SDs) would result in a clinically important moderate effect size for the NICU group. Our interpretation for the healthy baby sample is hampered by wide confidence intervals around the beta estimates, resulting in effect sizes that ranged from minimal to large. Internalizing behavior symptoms were associated with only a small effect on caregiver's MCS score, again with wide confidence intervals around the beta coefficients for both samples.A recent publication outlines the integration of a number of theoretical models into one multidimensional model that can be used to describe the caregiving process . This moOur study has several limitations. Because it is not possible to verify cause-effect using a cross-sectional design, we were only able to estimate the direct effect of a limited number of predictor variables on parental psychosocial health. While our study has helped to identify some possibly important caregiving variables, there are other variables important to caregiver health that we did not measure. For example, while it is possible that some parents of children with severe health problems may have received specialized or targeted services  to help them cope with their child's health problems, we did not include measures to determine this. Another limitation concerns our response rate. Although it is within the range often obtained in a postal survey , non-resOur findings would suggest that overall, parental gender, family functioning and caregiver strain played influential roles in parental psychosocial health. For child characteristics, current behavior was more influential than initial birth-related risk factors.MCS – Mental Component ScoreNICU – Neonatal intensive care unitHS – Health statusFAD – Family Assessment DevicePTT – Parental Impact TimeThe author(s) declare that they have no competing interests.Anne Klassen contributed substantially to the study's conception and design, acquisition of data, analysis and interpretation of data; and she drafted and revised and gave final approval of the version to be published.Shoo Lee contributed substantially to the study's conception and design, acquisition of data, analysis and interpretation of data; and revised the article critically for important intellectual content and gave final approval of the version to be published.Parminder Raina contributed substantially to the analysis and interpretation of data; and revised the article critically for important intellectual content and gave final approval of the version to be published.Sarka Lisonkova contributed substantially to the analysis and interpretation of data; and revised the article critically for important intellectual content and gave final approval of the version to be published.The pre-publication history for this paper can be accessed here:


Transitions in the location of care and in who provides such care can be extremely stressful for individuals facing death and for those close to them. The objective of this study was to describe the distribution of transitions in care experienced by palliative care patients following admission to a comprehensive palliative care program (PCP). A better understanding of these transitions may aid in reducing unnecessary change, help predict care needs, enhance transitions that improve quality of life, guide health care system communication links and maximize the cost-effective utilization of different care settings and providers.Transition and demographic information pertaining to all patients registered in the PCP at the Queen Elizabeth II Health Sciences Centre (QEII), Halifax, Nova Scotia, Canada between January 1, 1998 and December 31, 2002 and who died on or prior to December 31, 2002 was extracted from the PCP database and examined. A transition was defined as either: (1) a change in location of where the patient was cared for by the PCP or, (2) a change in which clinical service provided care. Descriptive analysis provided frequencies and locations of transitions experienced from time of PCP admission to death and during the final two and four weeks of life, an examination of patient movement and a summary of the length of stay spent by patients at each care location.Over the five year period, 3974 adults admitted to the QEII PCP experienced a total of 5903 transitions . Patients with no transitions (28%) differed significantly from those who had experienced at least one transition with respect to survival time, age, location of death and diagnosis (p < 0.0001). The majority of patients were admitted to the PCP from various acute care units (66%). Although 54% of all transitions were made to the home, only 60% of these moves included care provided by PCP staff. During the last four weeks of life, 47% of patients experienced at least one transition; 36% during the final two weeks of life. Shorter stays in each location were evident when care was actively provided by the PCP.A relatively small number of patients under the care of the PCP at the end of life, made several transitions in care setting or service provider. These particular patients need closer scrutiny to understand why such transitions take place so that clinical programs may be designed or modified to minimize the transitions themselves or the impact transitions have on patients and families. For individuals facing death, and for those close to them, transitions in the location of care and in who provides care can be extremely stressful. Such traMuch of the health service research literature in end-of-life care focuses on issues either in hospital or at home. -5 We belThe ultimate goal of understanding these transition issues better is to reduce unnecessary changes, help to predict care needs, enhance transitions that improve patient and caregiver quality of life, guide communication links within the health care system and maximize the cost-effective utilization of different care settings and providers.The primary purpose of this study was to describe the distribution of transitions in care experienced by palliative care patients during the time subsequent to admission to a comprehensive palliative care program. We also report the proportion of transitions as death becomes imminent (the last two and four weeks of life) and describe the length of stay in each location of care or care setting.Subjects included all adult patients registered in the palliative care program (PCP) at the Queen Elizabeth II Health Services Centre (QEII) in Halifax, Nova Scotia, Canada between January 1, 1998 and December 31, 2002 with a recorded date of death on or prior to December 31, 2002. The PCP includes multidisciplinary care for the dying, an in-patient acute care unit, an in-hospital consultation service, a home consultation service and an oncology outpatient clinic consultation service. The team consists of physicians, nurses, social workers, pharmacists, spiritual care and volunteers. There is no free standing hospice facility in Nova Scotia. The PCP has existed since 1988 and, by 1997, had at least one contact with over 62% of those who die annually of cancer in the Halifax Regional Municipality .[Individual level information extracted from the PCP database included demographics , diagnoses, the relationship of the primary caregiver to the patient , reason for referral, location of death and program transition data. The program transition information provided the date of each transition and locations the patient had been moved to or from  as well as the clinical service providing care. For example, for inpatients the service might be the Palliative Care Unit, or a medical or surgical service; for outpatients it might be the Nova Scotia Cancer Centre (NSCC) PCP clinic, the PCP Home Support Service, or the family doctor. The service indicator field also provided a record of whether patients were 'actively' being cared for by PCP staff or whether their care had been transferred to the staff of the NSCC or family doctor .Ethical approval for this research was provided by the Nova Scotia Capital District Health Authority research ethics board.A transition in this study is defined as either: (1) a change in location of where the patient was cared for by the PCP or, (2) a change in which clinical service provided care. For example, a transition might be a move to or from the home, a specific acute care unit or a long-term care facility. A transition would also occur if the patient stayed in a single location, for example at home, but the care being provided was transferred from PCP staff ('actively cared for' by the PCP) to their family physician or home care nurse ('non-active' and no longer 'actively' cared for by PCP staff) or vice versa. This 'transfer of care' transition scenario is illustrated below:Length of stay was calculated as the number of days a patient stayed in a single location while receiving the same form of care. For example, a patient might be admitted to the PCP from home and stay in the home for a total of 86 days at which time the patient was admitted to an acute care inpatient unit. After spending 10 days in acute care the patient was sent home where they died 25 days later.In this scenario the patient experienced two transitions  but had three stay periods (two at home and one in acute care).Survival in this study was defined as the number of days between date of the initial admission to the PCP and death. Cancer is the most prevalent disease among PCP patients, in particular lung cancer. To reflect this we created a diagnostic summary with three categories: lung cancer, all other cancers and other disease only (no cancer). Lung cancer was separated from other cancers as it is the most common cancer affecting both sexes in Nova Scotia, has a short prognosis and often has PCP involvement.The analysis focused on providing a description of the number and location of transitions experienced by patients over the five-year study period. For each patient, the total number of transitions occurring from the date of initial admission to the PCP to the date of death and during the final two and four weeks of life were counted and described. Locations of admission, death, care and service provision are summarized as well as an examination of patient movement from location to location or 'site movements'. Summary statistics are provided to describe the length of stay (LOS) or number of days spent by all patients at each care location.Differences between patients who experienced no transitions versus those who experienced at least one transition were assessed using contingency tables with chi-square techniques and logistic regression.cancer diagnoses. Survival time, the number of days between program admission and death, was highly variable, ranging from 0 days (died same day as admitted to the PCP) to 1688 days, with an average of 100.6 (SD 163.2) and median of 45 days. As recorded in Table In total, 3972 adult patients were admitted to the QEII PCP between January 1, 1998 and December 31, 2002 and had died on or prior to December 31, 2002. There was a slight preponderance of male patients (52%); patients tended to be older  and diagnosed with cancer (90%)  were initially admitted to the PCP as inpatients of various acute care units (n = 2619). Of this inpatient group, only 65 patients (2.5%) were admitted directly into the inpatient unit of the PCP. PCP admissions to care at home accounted for 34% of patients (n = 1335). Care services provided to home patients were provided upon admission by either PCP home care staff (51%) or on an outpatient basis through the NSCC (49%). Very few were admitted to the service from a long-term care facility (n = 17).Overall, 54% of all transitions were made to the home, 27% to other acute care inpatient units within the same hospital, 17.5% to the PCP inpatient unit, and almost 2% to a long-term care facility. PCP staff members, however, were not always actively providing the care provided within each of these locations. For instance, in transitions to home only 60% involved care being 'actively' provided by PCP home care staff or through the NSCC PCP outpatient clinic. The reasons why the PCP was not involved in care provision are varied and include improvements in health status , changes in their personal caregiver situation or movement out of the PCP coverage area etc. In contrast, few transitions involving acute care units were due to a change in care from active care provision by PCP staff to non-active PCP care (4%). Table During the last four weeks of life, 47% of patients experienced at least one transition. The majority of transitions were to an acute care facility , followed by the home (37%) and long-term care (2%). Similar patterns were evident when moves associated with the 2 weeks prior to death were examined. At least one transition was experienced by 36% of patients during these final 2 weeks of life. Moves to an acute care facility accounted for 68% , to the home 30% and 2% to long-term care.The location of death among PCP patients followed a pattern similar to that found at admission. Sixty-seven percent (n = 2644) of deaths occurred within an inpatient acute care unit, 16% of these deaths occurred in the PCP inpatient unit (n = 423). Home deaths were experienced by 31% of all admissions (n = 1218), while 3% (n = 110) of patients died as a long-term care resident.Table Patients followed by the QEII PCP are primarily elderly (75% 60 years of age or older), urban dwellers, with cancer and survive less than six months from time of initial program admission (80%). This age and sex distribution is similar to that experienced among all Nova Scotians who died due to cancer between 1992 and 1998.[Patients who had no transitions beyond entry to the PCP appear to be a different population than those with one or more transitions. This group may be a much sicker population since they tended to have much shorter survival times, were older and more likely to die in hospital. They were also more likely to die of disease other than cancer. This population warrants special attention in program planning and service delivery given their potentially higher institutional based needs.The most common transition identified was from an acute care hospital unit "to" the home. This fact, in and of itself, provides evidence for the substantial focus that must take place in hospital on discharge planning for those at the end of life. Attention to the multiple discharge issues for this unique group of patients is likely the single biggest transition issue facing the acute care units and the consulting QEII PCP. Issues of symptom control, drug supplies, home equipment needs, family and professional caregiving needs in the home, advance planning for routine follow up and crisis management as well as the psychological supportive issues all need planning. The acute care teams must do this planning along with the QEII PCP consult team in collaborative fashion. These transitions present challenges in coordination and information transfer in order to facilitate continuity of care for patients and families.The next most common category of transitions was from home "to" the hospital, either to an acute care unit or to the PCP inpatient unit. Just as the previous transition needs to be planned and coordinated so does the home to hospital one. Unfortunately we have no data on how this latter transition occurs. Most often it may be due to a symptom crisis in the home, a lack of caregiver capacity in the home, or a lack of financial resources to bring adequate care to the home. Given thMost patients came to the care of the PCP from within the acute care system. This may be a reflection of the lateness of referral for a substantial number of individuals . These individuals, by the time of referral, may be quite ill in hospital. This initial entry to PCP  may need to be a focus of concern to better understand it. We need to understand the timing of referrals, what can be done to identify and meet patients' needs when required and whether these needs could be met outside of the hospital setting.Once under the care of PCP the most common transitions were "to" home. Only a very small number of patient move "to" or "from" long term care (LTC). The fact that the majority of transitions were to home reflects the goals and expertise of the PCP in emphasizing the home location by coordinating the services needed for care at home. The fact that long term care is a rare transition also needs exploration. Policies may exist or wait times for admission may be such that transition to these facilities for people with short prognosis is difficult to achieve. At the same time, few patients transition "from" long term care. Some local LTC facilities have intramural palliative care programs designed to specifically meet the needs of their residents and their goals of staying in LTC as death approaches, avoiding hospital transfers.The results of this study indicate almost half of patients have a transition in the last month of life and 36% in the last 2 weeks of life. As death approaches these transitions are more likely to be "to" hospital (i.e. 62% of those in the last 4 weeks and 68% of those in the last 2 weeks). Defining the "appropriateness" of these late transitions is difficult. As stated before, they may be due to acute symptom crises or caregiver inability to meet all of the care needs. We have also heard that patients are admitted when they appear in emergency departments with these issues as they have not been able to access professionals to assess and problem solve during nights and weekends. ThereforAs to the generally longer stays for patients when not under "active PCP" care, it may be that they are much less sick with other chronic, non-palliative problems and their prognosis is longer. One might also postulate that for the in-patients, the active involvement of PCP may facilitate shorter stays and transitions to the home. Such facilitation could include more rapid control of symptoms or more expeditions discharge planning. The phenomena may be similar in both the home and long-term care settings.One substantial limitation is the loss of information pertaining to patients who are transitioned to non-active care permanently. Although we do have a record of their death, once a patient is moved to non-active care and ceases further involvement with the PCP, we do not have a record of who has taken responsibility for their care or where this care has been received. Our results and our clinical experience suggest this group may be quite different from those who remain actively cared for by the PCP. We have begun efforts to collect information about this group in order to understand them better.In conclusion, a small number of patients under the care of the PCP very near the end of their lives, make several transitions in care setting or service provider. These particular patients need much closer scrutiny in order to understand why such transitions take place. We will then be able to design or modify clinical programs to minimize the transitions themselves or the impact the transitions have on patients and families. Possible negative impacts of multiple transitions include discontinuity of care, poor coordination of care, financial burden and psychological stress that each move may bring to patients and their families.The author(s) declare that they have no competing interests.FB and BL participated in the conceptualization and design of the project, the analysis and interpretation of the data, first-drafted the majority of the article, and incorporated co-authors' comments into the final draft. PC participated in the conceptualization and design of the project, interpretation of data, and revising of the manuscript. DM participated in the analysis and interpretation of data and revising each draft for critical content. All authors gave approval to the final version.The pre-publication history for this paper can be accessed here:


Survivin and its alternative splice forms are involved in critical cellular processes, including cell division and programmed cell death. Survivin is expressed in the majority of human cancers, but minimally in differentiated normal tissues. Expression levels correlate with tumor aggressiveness and resistance to therapy.In the present study, we identify and characterize a novel survivin isoform that we designate survivin 2α. Structurally, the transcript consists of 2 exons: exon 1 and exon 2, as well as a 3' 197 bp region of intron 2. Acquisition of a new in-frame stop codon within intron 2 results in an open reading frame of 225 nucleotides, predicting a truncated 74 amino acid protein. Survivin 2α is expressed at high levels in several malignant cell lines and primary tumors. Functional assays show that survivin 2α attenuates the anti-apoptotic activity of survivin. Subcellular localization and immunoprecipitation of survivin 2α suggests a physical interaction with survivin.We characterized a novel survivin splice variant that we designated survivin 2α. We hypothesize that survivin 2α can alter the anti-apoptotic functions of survivin in malignant cells. Thus survivin 2α may be useful as a therapeutic tool in sensitizing chemoresistant tumor cells to chemotherapy. Alternative splicing is estimated to occur in 40–60% of all human genes, accounting for some of the discrepancies between the large number of known proteins and the three-fold lower number of human genes in the genome. Alternative splicing generates a multitude of isoforms that have overlapping but distinct functions during embryonic development and that also contribute to maintaining homeostasis in adult differentiated tissues (reviewed in ). AlternSurvivin locus gives rise to alternatively spliced transcripts identified in both human and mice [Survivin was originally identified by structural homology to IAPs in human B-cell lymphoma . It is cand mice -8. To daand mice -8. SurviSurvivin has 2 main functions; one as a chromosomal passenger protein  and the In this report we identify and characterize a novel isoform of survivin, survivin 2α. We show that survivin 2α is expressed at high levels in malignant cells, co-localizes with survivin and has the potential to attenuate the anti-apoptotic effect of survivin.In this work, we characterized a novel isoform of the survivin locus. We surveyed the aligned survivin EST sequences available in the UCSC Human Genome Browser and identified an EST from a human breast tumor cDNA library (I.M.A.G.E. clone 1631662). We sequenced the entire cDNA and designated it Survivin 2α. The complete cDNA sequence is shown in Figure The BIR domain has been shown to be important for homodimerization and coordination of the zinc atom co-factor . In the Survivin is critical for global normal embryonic development, as demonstrated by the early embryonic lethality of mice with homozygous deletions in the survivin gene locus . SurviviTo characterize a function for Survivin 2α, we transfected Daoy cells with Survivin 2α and a combination of Survivin 2α and Survivin. To induce apoptosis in the Daoy cells, we treated them with 2 μM of the chemotherapeutic agent vincristine. Vincristine is a vinca alkaloid that binds to tubulin, inhibiting microtubule polymerization. It kills Daoy cells in culture by PCD. We analyzed early apoptotic events in vincristine-treated transfected cells by Annexin V staining. Survivin 2α antagonized the anti-apoptotic effect of Survivin in co-transfection assays with or without a cell death stimulus , after approval through the Columbus Children's Hospital IRB.IMAGE clone 1631662 (Invitrogen) was sequenced using primers that flanked the multiple-cloning-site.KpnI-BamHI sites of pcDNA4/TO/myc-HisB (Invitrogen) generating an in-frame fusion with the C-terminal myc-tag, or into the KpnI-BamHI sites of pEGFP-N3 generating an in-frame fusion with the C-terminal GFP tag. The start codon in both constructs corresponds to the naturally occurring start codon in the cDNA transcript. The resulting clones were confirmed by sequencing.The cDNA for survivin 2α was amplified from the EST clone (Invitrogen) and cloned into the 2; U2OS osteosarcoma cells (kindly donated by Dr. Greg Otterson) were grown in McCoy's 5A medium supplemented with 10% FBS at 37°C, 5% CO2; RH28  and A549 (lung carcinoma) (ATCC) were grown in RPMI1640 supplemented with 10% FBS at 37°C, 5% CO2. MCF10-A, a non-transformed breast cell line (ATCC) was grown in MEGM, Mammary Epithelial Growth Medium, Serum-free, (Clonetics) supplemented with 100 ng/ml cholera toxin (Sigma Aldrich) at 37°C, 5% CO2.HeLa , Daoy (medulloblastoma), Jurkat (acute lymphoblastic leukemia) and MCF-7 (breast adenocarcinoma) cells (ATCC) were grown in DMEM supplemented with 10% FBS at 37°C, 5% COTransient transfections were performed using Effectene transfection reagent (Qiagen) at a DNA: Effectene ratio of 1:10.Induction of apoptosis by vincristine was done by treatment of cells with complete growth medium supplemented with vincristine sulfate at a final concentration of 2 μM.6 proliferating cells or frozen tumor tissue using TriZol reagent (Invitrogen) as recommended by the supplier. Poly(A) RNA was purified using Oligotex dT kit (Qiagen). 100 ng of poly(A) purified RNA was used as a template in a reverse transcription reaction using random hexamers and Omniscript Reverse transcriptase (Qiagen) and performed according to manufacturer's instructions. Quantitative real-time PCR reactions using Taqman probes (FAM/TAMRA) were run in triplicate on an ABI Prism 7700 Real-time PCR machine (Applied Biosystems). Control GAPDH reactions (Applied Biosystems) were run to normalize ΔCt values. Relative change was calculated by the comparative CT method, 2(-ΔΔCt). The survivin 2α specific primers consist of: Forward 5'GCTTTGTTTTGAACTGAGTTGTCAA; Reverse 5'GCAATGAGGGTGGAAAGCA; and Probe: 6FAM AGATTTGAGTTGCAAAGACACTTAGTATGGGAGGG TAMRARNA was isolated from 10Two apoptosis assays were performed: Caspase-3 assay and Annexin-V FLUOS. For caspase assays 2,000 cells from each experimental condition were subjected to the caspase-3 assay, Caspase 3/7 GLO (Promega) and analyzed on a Victor3 plate reader (Applied Biosystems). Experiments were performed in triplicate.Annexin V/propidium iodide staining was carried out using the Roche Annexin-V-Fluos Staining Kit following the manufacturer's instructions. Fluorescein and propidium iodide fluorescence measured with a Coulter EPICS XL flow cytometer. Experiments were performed in triplicate.6 cells for each condition were fixed in 2.5% gluteraldehyde for 24 hours and processed for EM. For cell analysis, 10 to 12 fields containing 8–10 cells per field at a magnification of 3500× were used. At least 100 cells were counted for each experimental condition and assigned to categories of healthy or dying based on their morphological appearance, including nuclear integrity. Image collection was performed on a Hitachi H-600 transmission electron microscope equipped with a GATAN image acquisition system.Proliferating HeLa cells, grown on glass coverslips, were transiently transfected with a GFP-tagged survivin 2α expression construct or co-transfected with GFP-tagged survivin 2α and HcRed-tagged survivin. 24 hours post-transfection the cells were fixed in 4% paraformaldehyde and stained with 50 μg/ml Hoechst dye. Cells were analyzed on a Zeiss LSM510 META confocal microscope, using a 63x PlanApochromat objective. For electron microscopy analysis, proliferating HeLa cells were transfected with GFP-tagged survivin 2α construct for 12 hours. The cells were aseptically sorted by FACS based on green fluorescence from GFP-survivin 2α for positive and negative populations. This was done in order to separate an enriched population that consisted of >90% GFP expressing cells. 10HeLa cells transfected with Flag-survivin and survivin-2α myc were collected in Cell Lysis Buffer  and incubated at 4°C for 30 min. The cell lysate was clarified by centrifugation and the clarified supernatant dissolved 1:5 in Co-IP buffer . The equivalent of 400 μg of lysate total protein was incubated with 2 μg of anti-Flag M2 antibody at 4°C for 1 h with constant rotation. As a control the same amount of lysate protein was incubated in the absence of antibody. Fifty microliters of agarose-conjugated protein A (Invitrogen) were added and the mixture incubated for a further hour in the same conditions. The protein-antibody-protein A complexes were pulled down by centrifugation and subjected to 3 washes with co-IP buffer. The proteins were analyzed through electrophoretic separation in a 20% SDS-PAGE, electroblotted onto nitrocellulose and immunoprobed with an antibody against myc-tag. Detection was performed using the ECL kit (Amersham). Protein standards were used for size determination.Subcellular localization predicted by PSORTII program. Coiled-Coil domain predicted by Coils and PairCoil programsHC performed bioinformatic analysis, subcellular localization, functional studies, co-immunoprecipitation and drafted the manuscript. LH performed quantitative real time PCR in cell lines and primary tumors. RA conceived the study and participated in its design and coordination, and was responsible for overseeing the final version of the manuscript. All authors have read and approved the final manuscript.


Scalp-recorded electroencephalographic (EEG) signals produced by partial synchronization of cortical field activity mix locally synchronous electrical activities of many cortical areas. Analysis of event-related EEG signals typically assumes that poststimulus potentials emerge out of a flat baseline. Signals associated with a particular type of cognitive event are then assessed by averaging data from each scalp channel across trials, producing averaged event-related potentials (ERPs). ERP averaging, however, filters out much of the information about cortical dynamics available in the unaveraged data trials. Here, we studied the dynamics of cortical electrical activity while subjects detected and manually responded to visual targets, viewing signals retained in ERP averages not as responses of an otherwise silent system but as resulting from event-related alterations in ongoing EEG processes. We applied infomax independent component analysis to parse the dynamics of the unaveraged 31-channel EEG signals into maximally independent processes, then clustered the resulting processes across subjects by similarities in their scalp maps and activity power spectra, identifying nine classes of EEG processes with distinct spatial distributions and event-related dynamics. Coupled two-cycle postmotor theta bursts followed button presses in frontal midline and somatomotor clusters, while the broad postmotor “P300” positivity summed distinct contributions from several classes of frontal, parietal, and occipital processes. The observed event-related changes in local field activities, within and between cortical areas, may serve to modulate the strength of spike-based communication between cortical areas to update attention, expectancy, memory, and motor preparation during and after target recognition and speeded responding. A new analysis considers EEG signals, not as average responses, but as individual event-related perturbations in ongoing dynamical brain processes The waking brain updates and fulfills intentions through brain processes that operate within and across multiple brain areas to integrate perception, association, and action. Fulfillment of intentions is facilitated by features of these and other processes that support informed anticipation of and selective attention to events and their probable consequences. The dynamics of ongoing electroencephalographic (EEG) activity recorded from the human scalp differ markedly with state of attention and intention , yet mosThe adequacy of time-domain ERP averaging for modeling macroscopic brain dynamics also depends on the assumption that the cortical sources of EEG activity contributing to and not contributing to average ERP waveforms are somehow distinct. The scalp topographies of unaveraged EEG and averaged ERP data may, however, be quite similar , stronglThe above considerations suggest that event-related EEG dynamics may be better modeled as coordinated event-related perturbations in the statistics of multiple, intermittently active local field processes. Since the volume-conducted scalp projections of such processes generally overlap, they cannot be separately identified in the scalp-recorded data. An alternate approach we adopt here is to separate the contributions of local field processes by using distinct differences in their time courses .Following stimuli belonging to an anticipated but infrequently presented category, the averaged ERP is dominated by a broad vertex-positive peak often called P300 after its earliest appearance in auditory responses . ResultsThe independent component analysis (ICA) method provides a complete decomposition of single-trial (or continuous) EEG data, separating the data into distinct information sources. As the results presented below show, the amount of information about cortical dynamics provided by this method is large. Here, we detail for the first time dynamics occurring within single trials of the classes of maximally independent EEG processes whose event-related activities contribute to 31-channel visual target responses recorded during a test of spatial selective visual attention .To orient readers used to analyses of the raw scalp-channel data, we first present conventional ERP results at selected channels. As we previously reported, in these experiments performance level was high; more than 95% of targets were followed by a button press within the allotted response window (150–1000 ms). Mean subject-median reaction time (RT) was 352 ms. The average ERP time locked to onset of the target stimulus followed by a subject button press contained the expected late positive complex or P300 positivity following early stimulus-locked peaks conventionally termed P1, N1, P2, and N2 A. The scIn the grand average of the same epochs, each time-locked to the subject response B, the eaAt frontocentral channel Fz, however, the late positivity in the stimulus-locked grand average C, bottomp < 0.01) for 14 of the 15 subjects even after the subject-mean ERP was subtracted from each trial (data not shown).A concurrent but weaker theta power increase near 6 Hz B was maxConventionally, characterizing the sources of ERP  or eventWhile component IC1 accounted for the largest part of the P300 peak in the upper trial, in the lower trial the same IC1 process showed mixed low alpha and beta activity with a smaller postmotor response positivity. Note that the positive postresponse contribution of IC1 in this trial (thin blue trace) was sometimes larger than the observed positivity in the whole-channel data (thick black trace). At these times, some of the other 24 components contributed negative potentials to the signal at this scalp channel, partially canceling the IC1 positivity in the recorded data. Thus ICA, applied to the continuous or concatenated single-trial data, may actually recover more of the actual projected signals than are available in the single-channel data.Cluster analysis, applied to the normalized scalp topographies and power spectra of all 465 components from the 15 subjects see , identifThe location of the equivalent dipole for a radially oriented cortical source patch  is typically deeper than the cortical patch itself . The equThe spatial standard deviations of the other component cluster dipoles were smaller. Their equivalent dipoles indicate the respective dominant cortical regions of their source domains. Though the mean cluster scalp map for the central occipital alpha cluster (Cα) could be fit satisfactorily by a single equivalent dipole located in the central occiput, for several of the cluster components a better model of the component scalp map was obtained from a symmetric dipole pair in left and right pericalcarine cortex (data not shown).Mean dynamics properties of nine nonartifact component clusters are summarized in Two component clusters made distinct contributions to the late positive complex of the target ERP. After subtracting the larger back-projected scalp-data contributions of components accounting for blinks and saccadic eye movements, the response-locked ERP at both periocular channels contained a broad, approximately 2-μV positive-going scalp potential peaking on average 39 ms before the recorded button press. The P3f cluster-mean response-locked positivity began near 150 ms, consistent with direct neurophysiological evidence that by 150 ms after stimulus onset, visual information is spread throughout the brain by a complex web of afferent and efferent connections . SubtracThe far-frontal (P3f) component cluster response appears similar to the 280-ms “P2a” peak noted in responses to  visual “oddball” stimuli by The significance of the stimulus-locked P300 (or P3b) peak over central parietal cortex has long been debated. Our results clearly show E that inIn the RT-sorted FM cluster ERP image C, the twThough the equivalent dipole locations of components in the two midline clusters were somewhat overlapping see , their mThe theta burst appears to resemble other reported FM EEG activity patterns: theta bursts or trains (fmθ) appearing during mental concentration  and brieThe scalp map of the CM cluster E resemblThe left and right mu rhythm component clusters . Onset of the stimulus-locked ERP of the P3b cluster at about the same time was soon followed by the far-frontal P3f cluster onset  poststimulus time windows following nontarget and target stimuli in these experiments . The majThe group mean equivalent dipole locations shown in Production of scalp EEG signals requires partial synchronies in local field activity extending across the relatively large (2-cm or more) domains of neuropile . These mTraditionally, averaging event-locked EEG data from single scalp channels to form an ERP is assumed to reject, by random phase cancellation, “background” EEG rhythms whose statistics are tacitly assumed to be unaffected by experimental events. To test the effect of the average ERP on the observed spectral perturbations, we computed the cluster ERSPs again after removing the component mean ERP from each trial (data not shown). All the effects shown in Note that many of the cluster ERSPs –9 share At and after the button press, a mean frontocentral theta power increase appeared in all 15 subjects' data. It was partially phase coherent in four of the component clusters and was not eliminated by removing the subject-mean ERP from each trial. Local bursts of theta-band activity are widely distributed on the human cortex  and assoFollowing nontarget stimuli in this experiment, FM components exhibited weak “theta ringing”  not accompanied by increased theta power . Here, fThe postmotor theta bursts seen here following correct speeded responses very likely are tightly linked to the ERP feature with strong theta-band energy that follows highly speeded manual (or foot) responses in the Erickson flanker task . Luu andIn this speeded response paradigm at least, the ERP P300 positivity was nearly strictly time-locked to and predominantly followed the motor response. The P300 positivity was, here, indeed a late positive complex of potentials generated in several brain areas, confirming results of invasive recording  and clinAs in our previous single-trial analysis of some of these data , partialThe central posterior alpha-ringing feature of the stimulus-locked ERP can be parsimoniously described as arising through alpha phase resetting. The P300/P3b feature, on the other hand, might better conform to the usual conception of an ERP as measuring evoked response activity added to ongoing EEG activity. Note in both induced and evoked aspects.The variety of these ERP features suggests that assuming a strict dichotomy between evoked and phase-reset activities is unproductive. Rather, each ERP feature may be usefully and better characterized as summing event-related perturbations of various sorts in the ongoing activities of one or more localized cortical EEG processes. To produce a reproducible peak or peaks in the average ERP, these perturbations should involve some degree of  phase locking of the contributing process activities to the time-locking events in one or more frequency regions. At very low (near-DC) frequencies, event-related “phase locking” implies event-related “sign locking.” For example, the P300 would never appear in ERP averages at all if it were negative-going in half the trials. Similarly, there need be no strong dichotomy between evoked phenomena that involve partial phase locking and so contribute to average ERPs, and induced phenomena that may involve changes in spectral amplitudes but do not show phase locking and thus do not contribute to average ERPs. Rather, it is important to realize that most event-related EEG dynamics have The results presented here confirm that extensive, complex, and flexible information concerning links between cognitive processes and macroscopic brain dynamics are available in noninvasive high-density EEG data. Availability of more comprehensive analysis techniques, such as that introduced here, should make EEG  data analysis of increasing interest both to cognitive neuroscientists and to neurophysiologists, as event-related EEG dynamic models complement observations of slow-changing hemodynamics while greatly expanding the restricted spatial information available from single- and multineuron spike recordings.ERPs were recorded from subjects who attended to randomized sequences of filled disks appearing briefly inside one of five empty squares that were constantly displayed 0.8 cm above a central fixation cross see  followinFifteen right-handed volunteers  with normal or corrected-to-normal vision participated in the experiment. Subjects were instructed to maintain fixation on the central cross while responding only to stimuli presented in the green-colored (attended) square. Subjects were required to press a thumb button held in their right hand as quickly as possible following stimuli presented in the attended location see . Thirty EEG data were collected from 29 scalp electrodes mounted in a standard electrode cap  at locations based on a modified International 10–20 System, and from two periocular electrodes placed below the right eye and at the left outer canthus. All channels were referenced to the right mastoid with input impedance less than 5kΩ. Data were sampled at 512 Hz with an analog pass band of 0.01–50 Hz. To further minimize line noise artifacts, responses were digitally low-pass filtered below 40 Hz prior to analysis. Trials containing electrooculographic potentials larger than 70 μV or amplifier blocking were rejected, and brain responses to stimuli presented at each location in each attention condition were stored separately. Responses to target stimuli were analyzed only when  subjects responded 150–1000 ms after target onset. The few targets followed by no such button press were not considered in the present analysis.unaveraged data. Systematic application of ICA to unaveraged data from these experiments was first demonstrated for non-target stimulus trials  ICA models of EEG activity are possible e.g., . It remaAs first demonstrated by simulations , when trhttp://sccn.ucsd.edu/eeglab) was applied to sets of 400 to 600 1-s trials  time-locked from −200 ms before to +800 ms after onsets of target stimuli presented at any of the five stimulus locations  component maps and mean activity log spectra from the 15 subjects were clustered by applying a modified Mahalanobis distance measure  to vectoTo examine stimulus- and response-induced changes in the EEG spectrum, we computed ERSP transforms  for eachp < 0.01. To construct between-subject mean ERSPs, we used binomial statistics to select a significance cutoff based on the minimum number of subjects required to have significant differences (in the same direction) from baseline at a given time/frequency point (p < 0.0001). ERSP transforms of the data were computed at each channel and then for each clustered data component. To test for partial phase locking  between EEG processes and the occurrence of experimental events across trials, we used intertrial phase coherence  of oherence .p < 0.01 (uncorrected) between pairs of independent components (from the same subject) included in each pair of independent component clusters (defined below). To exclude the possibility that the observed phase linkages arose only from common phase locking of the portion of the single-trial data constituting the ERP, we also subtracted the concurrent mean ERP from each trial before computing phase coherence. Functions to compute and plot the time/frequency measures used here are also available in the EEGLAB toolbox.To test the presence of nonrandom phase relationships (possibly including fixed delays) between activities in different  independent components, we performed event-related phase coherence analysis , again wBoth simple anatomic considerations and observed results of ICA decomposition suggest that cortical EEG sources may be usefully modeled as patches of cortex with partially synchronous local field activities. In brief, the high local coupling density of both excitatory and, particularly, inhibitory neurons in cortex means that local field potentials sufficiently synchronous to create measurable EEG signals should tend to extend through a compact spatial domain—roughly speaking, a patch of cortex of unspecified extent. Through volume conduction, partially synchronous activities within cortical source patches produce far-field potentials throughout the brain and on the scalp. The distribution of the scalp electrical field produced by such a source patch is nearly identical to that of a small dipolar potential element whose geometry is like a tiny flashlight battery oriented perpendicular to the cortical surface. This “battery” is termed the equivalent dipole for the cortical source.http://sccn.ucsd.edu/eeglab/dipfit.html). Some bilaterally symmetric component maps were better fit with symmetric dual-dipole models. The successful fits of single-dipole models for many of the clustered components is compatible with their generation within a single, compact patch of cortex, while bilateral dual-dipole models are compatible with tightly coupled oscillatory activity (without net phase delay) in two bilaterally symmetric cortical patches densely connected via corpus callosum or common subcortical drive.Here, we used a relatively simple and well-known method for fitting the positions and orientations of equivalent dipoles in a four-shell spherical head model for each component . To reduce the time required to process the 485 component maps, we used a version (3.0) of the BESA software that allowed batch processing to fit single-dipole models to each component scalp map. , normalized, and averaged. These cluster mean maps were then fit with single-dipole models to roughly illustrate the regional distinctions between the sources of the component clusters. Finally, the cluster-mean dipoles and event-related time/frequency information measured by ERSP, intertrial phase coherence,and event-related phase coherence analysis of all the single trials were visualized together in three dimensions using an animated display developed by


Staphylococcus aureus (S. aureus)- colonized cracked nipples. We aimed to replicate the study with a more rigorous design and adequate sample size.A small, non-blinded, RCT  had reported that oral antibiotics reduced the incidence of mastitis in lactating women with S. aureus-colonized cracked nipples. We planned to recruit two groups of 133 women with S. aureus-colonized cracked nipples.Our intention was to conduct a double-blind placebo-controlled trial to determine if an antibiotic (flucloxacillin) could prevent mastitis in lactating women with We spent over twelve months submitting applications to five hospital ethics committees and seven funding bodies, before commencing the trial. Recruitment to the trial was very slow and only ten women were randomized to the trial after twelve months, and therefore the trial was stopped early.In retrospect we should have conducted a feasibility study, which would have revealed the low number of women in these Melbourne hospitals (maternity wards and breastfeeding clinics) with damaged nipples. The appropriate use of antibiotics for breastfeeding women with cracked nipples still needs to be tested. Mastitis is a common problem for breastfeeding women ,2. BeforStaphylococcus aureus (S. aureus), in Canada[S. aureus should be "treated aggressively with systemic antibiotics". However, the chi-square test used by the authors is inappropriate because one cell contains an expected value less than 5. Using Fisher's exact test, the p value is 0.10 [The authors of one trial were convinced that their intervention was effective, despite methodological difficulties ,14. Liviin Canada. They co is 0.10 .As the Livingstone and Stringer trial had been published in a major lactation journal and was likely to be very influential in practice , it needS. aureus. A randomised controlled trial was conducted: participating women were randomized to receive a seven day course of either an oral antibiotic (flucloxacillin) or identical placebo capsules. A follow-up visit was arranged one week after recruitment for women with positive nipple culture for S. aureus. Women with negative nipple culture were followed up by telephone at one week. All women received a final telephone interview at six weeks.The aim of our study was to prevent mastitis in breastfeeding women with cracked nipples colonized with S. aureus-colonized cracked nipples who received only breastfeeding advice developed mastitis within one week. In order to detect a 50% decrease in incidence, ie mastitis occurring in 15% of women receiving oral antibiotics, a sample size of 133 women in each group is required, with 95% confidence and 80% power. Sample size was calculated using Epi-Info 6.The primary outcome was the incidence of mastitis in each group in the week following recruitment. In the study by Livingstone and Stringer  30% of wS. aureus [S. aureus (27/50) [S. aureus, we would need 133 × 2 × 2 = 532 women with cracked nipples, to recruit two groups of 133 women with S. aureus-colonized cracked nipples. To allow for loss to follow-up, it was planned to recruit 570 women.A previous study in Australia found that 62% (13/21) of cultures from breastfeeding women with cracked nipples were positive for . aureus . An earl (27/50) . AssuminA review of the literature on the topic of nipple damage found a lack of consistency in assessment of nipple damage . Many reOur definitions of nipple damage are as follows: mild 1 or 2 mm wide; moderate 3–9 mm wide; severe: greater than 10 mm wide and / or yellow colour visible in crack. In addition to a clinical assessment, a more permanent record of nipple damage was created using digital photography. It was planned for the photographs to be reviewed independently by three lactation consultants, in order to allow a thorough assessment of nipple damage and changes over time, rather than relying on the clinical assessment alone. .Furthermore, although the WHO defines mastitis as an inflammation of the breast , there i• at least two breast symptoms  and• at least one of fever or 'flu-like symptoms.As we intended to recruit over 500 women we planned a multi-centred trial, involving a number of public and private maternity hospitals in inner Melbourne. All hospitals provide a breastfeeding clinic staffed with International Board Certified Lactation Consultants for women having breastfeeding difficulties following hospital discharge. The public hospitals, where women tend to have shorter hospital stays, also provide home visits by domiciliary midwives post discharge. It was foreseen that there would be replication in the requirements of the hospital ethics committees and logistical difficulties for one researcher (LA) to conduct the study on multiple sites.Each hospital had its own research ethics committee (or committees) and different forms to submit (at the time of this study). Approval was obtained from the Ethics Committees at La Trobe University (20/11/2000), Royal Women's Hospital (6/9/2000), Mercy Hospital for Women (12/2/2001), Frances Perry House (23/8/2001), Freemasons Maternity Hospital (15/3/2001) and Cabrini Private Hospital (24/04/02). One private hospital did not appear to have a procedure in place to deal with a research proposal. Negotiations continued with this hospital from late 2000 until mid-2002 when the hospital insisted that we sign a Sponsor Indemnity Form, which the university advised us against.The researcher visited the postnatal wards and breastfeeding clinics of these hospitals each day or second day and asked a senior member of the nursing staff if there were any breastfeeding women with damaged nipples in the ward. The staff member introduced the researcher to the woman in order to inform the woman about the study and invite her to participate in the trial. Also, the researcher asked the domiciliary midwives to inform women at home with a cracked nipple about the trial. If the woman were interested in the study, the midwife gave the researcher the woman's name and phone number. After a telephone discussion, the researcher would visit her at home to assess her eligibility.Thus, the researcher was visiting a number of hospitals on a daily basis and making home visits to potential participants and follow-up visits to participants one week after recruitment. Therefore, if the researcher was going to be unavailable one week, she could not recruit women the week prior (as she would not be able to follow them up).All potential participants had a specimen collected from their nipple crack for culture and sensitivity. As this was collected for the purpose of research rather than clinical practice, it was necessary to seek funding for the cost of the microbiological assessment. We intended to recruit 570 women, therefore substantial funds were required. A number of applications (seven) were submitted to local, national and international funding bodies in 2001. A funding application to the Medical Research Foundation for Women and Babies for 2002 was successful .S. aureus and up to 6 days in one instance (mean 3.6).We recognized that there would be a delay between recruitment  and randomization (when the result was available). The Microbiology laboratory faxed the result to the researcher (or the researcher contacted the laboratory on weekends). However, the minimum time was 2 days for the laboratory to identify The delay meant that women would be at home when the results were available and the researcher was required to visit the participant at her home to deliver the capsules. In addition to the inconvenience, a small number of women had already developed mastitis by the time the researcher contacted her with the result.It was expected that a local company specializing in the preparation of placebos for drug trials would prepare the identical capsules. A common practice is to cover the active capsule with a larger capsule; participants are unaware if their capsule contains the active capsule or an inert substance. However, when the company realized that the active capsule contained a penicillin-like drug they were unable to participate, as they do not have a license for penicillin. Finally, the pharmaceutical company, CSL Ltd, provided us with identical empty capsules as well as active flucloxacillin capsules. A pharmacy technician at the pharmacy department at the Royal Women's Hospital opened each capsule manually and inserted glucose powder. Randomisation was conducted in blocks of ten, stratified according to hospital. Ten bottles were prepared for each hospital prior to the trial commencing (further capsules were not needed).Not all the women who were eligible for the trial were interested in taking part , 80% would be eligible and 95% would agree to participate, thus there would be 537 eligible women per year. We anticipated that we would recruit approximately ten women with cracked nipples per week. It would therefore take 57 weeks (57 × 10) to recruit the total sample.However, recruitment was slow, as very few women were identified with damaged nipples. Hospital staff made unsolicited remarks that nipple damage was seen much less frequently than in the past. Midwives have been trained to help women position the baby and attach the baby at the breast; women are reporting the presence of nipple pain and any nipple damage is usually identified at an early stage. In the past, women may have continued to breastfeed with poor attachment of the baby to the breast, resulting in more severe damage, whereas at the time of the study maternity staff were likely to suggest "resting" the damaged nipple and expressing the milk by hand or electric pump until the damage had healed.th November 2002.Recruitment began at two hospitals in November 2001, two others in February 2002 and a fifth hospital in June 2002. Recruitment was slow as few women had damaged nipples. During the months of the trial, the rate of recruitment decreased rather than increased. Additionally, the flucloxacillin supplied by CSL were labeled to use before the end of November 2002. Therefore it was decided to stop recruiting, once a twelve-month recruiting period had elapsed. The trial stopped recruiting on the 14S. aureus. Thirteen of the nipple cultures were positive and ten women were randomized to receive flucloxacillin (n = 5) or placebo capsules (n = 5). Two women had already developed mastitis prior to receiving the results and the third woman had developed a rash and did not want to take the capsules. All women were followed-up at one week and six weeks. Of the ten women in the RCT, one woman in the placebo group developed mastitis . Three women reported that they had not taken the capsules. When the study was unblinded it showed that all three were in the placebo group.Of the 158 women referred to the study as possible participants, 48 women were eligible . Twenty-six of these women refused . Therefore, 22 were potentially eligible in that they had at least one cracked nipple and consented to take part in the trial if the results of the nipple swab confirmed This trial experienced a number of problems, both foreseen and unforeseen. In the trial conducted by Livingstone and Stringer, there is no mention of women refusing to participate in the study or not taking the treatment they were allocated . It is nWe thought the estimate of 5% of breastfeeding women developing a cracked nipple was a conservative estimate. For example, in Western Australia, Duffy et al had found that 6% of women in their intervention group had cracked nipples, compared to 69% in their control group . HoweverIn retrospect, we should have conducted a pilot or feasibility study before commencing the trial. The appropriate use of antibiotics for breastfeeding women with cracked nipples still needs to be tested. We hope our experience will be useful for others planning trials of mastitis or nipple damage.None declared.All authors contributed to the design of the trial, LA reviewed the literature, conducted the trial, and wrote the first draft of the paper. All authors approved the final draft of the paper.The pre-publication history for this paper can be accessed here:


Most hospitals keep and update their paper-based medical records after introducing an electronic medical record or a hospital information system (HIS). This case report describes a HIS in a hospital where the paper-based medical records are scanned and eliminated. To evaluate the HIS comprehensively, the perspectives of medical secretaries and nurses are described as well as that of physicians.We have used questionnaires and interviews to assess and compare frequency of use of the HIS for essential tasks, task performance and user satisfaction among medical secretaries, nurses and physicians.The medical secretaries use the HIS much more than the nurses and the physicians, and they consider that the electronic HIS greatly has simplified their work. The work of nurses and physicians has also become simplified, but they find less satisfaction with the system, particularly with the use of scanned document images.Although the basis for reference is limited, the results support the assertion that replacing the paper-based medical record primarily benefits the medical secretaries, and to a lesser degree the nurses and the physicians. The varying results in the different employee groups emphasize the need for a multidisciplinary approach when evaluating a HIS. Hospital information systems (HIS) and Electronic Medical Records (EMRs) are considered prerequisites for the efficient delivery of high quality health care in hospitals. However, a large number of legal and practical constraints influence on the design and introduction of such systems . Hence, Aust-Agder Hospital is the first hospital in Norway to eliminate the paper-based medical record, using a widespread  and comm® , a commercially available combined EMR and hospital administrative system in March 2000. In April 2001, all except the psychiatric department started to scan documents. From this date, all new patient data was channeled into the EMR in these departments, either as electronic text and data or as scanned documents. The HIS was available in 1100 terminals throughout the hospital, except for the inpatients' rooms. The transition to HIS was administered by a project group, which had been recruited from the hospital staff. The group worked in conjunction with the IT department and the HIS vendor, and was also responsible for communicating with and training the users. The group regularly held series of mandatory hands-on training classes adapted to each profession . However, a substantial proportion of the users never attended the classes, particularly the physicians. To reach these users, a task force of medical secretaries was trained and employed during the first month after implementation of the HIS for ambulant training in the wards. Further support was provided by a network of super users (the most experienced users) among the ward staff.The investigation was performed in a 410-bed community hospital in Aust-Agder county, Norway. The hospital serves a population of 102,000, caring for 18,600 inpatients and 74,000 outpatients per year (1998). The patients are admitted by primary care physicians external to the hospital and followed up by the hospital physicians. The hospital comprises of departments for psychiatry, general surgery, internal medicine, orthopaedics, gynecology, ear, nose and throat and ophthalmology. Well funded, and with a strong commitment by the hospital administration, the hospital staff began implementation of DIPS 2000The patient data in the EMR part of the HIS is either stored as searchable text and numbers or as document images. The former, called "regular electronic data", essentially consists of the chronological, text-based medical record integrated with lab data in numerical form and textual radiology reports fig . The latA questionnaire previously used in a national survey of hospital physicians  was modiThe survey was conducted during February–April 2002, and 85 medical secretaries, 235 nurses and 80 physicians in the medical, surgical and other somatic wards received the questionnaire. Of these, 79 medical secretaries (93%), 172 nurses (73%) and 70 physicians (88%) responded, giving a total response rate of 81% (321/400). We used Teleform™ for data acquisition and SPSS 11.0 for Windows™ for statistical analysis.In addition to the survey, one of the authors interviewed 8–12 representatives of each profession for 0.5–2 hours. Comments on advantages and disadvantages of the system in all relevant work tasks were noted and summarizedThe medical secretaries used the HIS routinely for most of their tasks defined in the questionnaire. This stands in contrast to the nurses and the physicians fig . The numThe medical secretaries reported that all of the defined tasks were performed more easily than before the HIS was introduced . The disadvantages of the document images, for instance that they can not be searched, therefore seem to affect the user satisfaction of nurses and physicians to a stronger degree than that of the medical secretaries.Not surprisingly, the medical secretaries were more satisfied with the system than the nurses and the physicians figs  and 4. TThe use of the HIS by medical secretaries, nurses and physicians may to some degree be compared at a task-by-task level when the tasks are equally worded. In these tasks, work roles seem to explain the differences. For instance, the tasks "Reviewing the patient's problems" (tasks 1) and "Seek out specific information from patient records" (task 2) appeared in all questionnaires. Of all the respondents, only the physicians had a significant proportion finding that these tasks were more difficult to perform than before figure . A possiA secondary finding in this study was that the physicians reported frequent computer-related problems, much more frequent than that of medical secretaries and nurses fig . This maIn the questionnaire, we do not know how often each task is carried out (using the HIS or not) or how long it takes, which means that demanding tasks might be outnumbered by the less demanding ones. Furthermore, the list of tasks supported in some way by the system may not be complete, and the list does not cover the full range of conceivable tasks suited for support by any given HIS. However, given that the tasks defined for each group cover important parts of their information-related work, a cautious comparison of general patterns of use between groups of hospital employees is possible.Evaluation of a HIS in a hospital that has eliminated the paper-based medical record reveals considerable differences in user satisfaction and reported use of the system among medical secretaries, nurses and physicians. Although the basis for reference is limited, the results seem to support the claim that replacing the paper-based medical record primarily benefits the medical secretaries, and to a lesser degree the nurses and the physicians. Inspired by Aust-Agder Hospital, two of 22 other Norwegian hospitals using the same system (as of Aug 2002) are about to eliminate the paper-based medical record, making a future comparison between hospitals possible. When assessing the effects of a HIS on a hospital organization by asking users, the multidisciplinary nature of health care provision should be reflected in the selection of hospital employees that participate in the evaluation.The authors declare that they have no competing interests.HL, THK and AF planned the investigation. HL and THK developed the questionnaires for the medical secretaries and nurses. THK organized the administration of the questionnaires, and HL scanned and analysed the data. HL, THK and AF wrote the manuscript jointly.The pre-publication history for this paper can be accessed here:Appendix A: Task lists The three lists of tasks as they appear in the questionnaire developed for the medical secretaries, nurses and physicians, respectively.Click here for fileAn English translation of the questionnaire used for the physicians in the survey. It is meant for review purposes.Click here for file