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1.  Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2012;7(8):e43508.
Background
The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.
Methods
We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1st 1979 through December 31st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.
Results
We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).
Conclusions
Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.
doi:10.1371/journal.pone.0043508
PMCID: PMC3429491  PMID: 22952698
2.  Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study 
Objective To examine the risk of psychosis associated with severe bereavement stress during the antenatal and postnatal period, between conception to adolescence, and with different causes of death.
Design Population based cohort study.
Setting Swedish national registers including births between 1973 and 1985 and followed-up to 2006.
Participants In a cohort of 1 045 336 Swedish births (1973-85), offspring born to mothers exposed to severe maternal bereavement stress six months before conception or during pregnancy, or exposed to loss of a close family member subsequently from birth to 13 years of age were followed until 2006. Admissions were identified by linkage to national patient registers.
Main outcome measures Crude and adjusted odds ratios for all psychosis, non-affective psychosis, and affective psychosis.
Results Maternal bereavement stress occurring preconception or during the prenatal period was not associated with a significant excess risk of psychosis in offspring (adjusted odds ratio, preconception 1.24, 95% confidence interval 0.96 to 1.62; first trimester 0.95, 0.58 to1.56; second trimester 0.79, 0.46 to 1.33; third trimester 1.14, 0.78 to 1.66). Risks increased modestly after exposure to the loss of a close family member from birth to adolescence for all psychoses (adjusted odds ratio 1.17, 1.04 to 1.32). The pattern of risk was generally similar for non-affective and affective psychosis. Thus estimates were higher after death in the nuclear compared with extended family but remained non-significant for prenatal exposure; the earlier the exposure to death in the nuclear family occurred in childhood (all psychoses: adjusted odds ratio, birth to 2.9 years 1.84, 1.41 to 2.41; 3-6.9 years 1.47, 1.16 to 1.85; 7-12.9 years 1.32, 1.10 to 1.58) and after suicide. Following suicide, risks were especially higher for affective psychosis (birth to 2.9 years 3.33, 2.00 to 5.56; 6.9 years 1.84, 1.04 to 3.25; 7-12.9 years 2.68, 1.84 to 3.92). Adjustment for key confounders attenuated but did not explain associations with risk.
Conclusions Postnatal but not prenatal bereavement stress in mothers is associated with an increased risk of psychosis in offspring. Risks are especially high for affective psychosis after suicide in the nuclear family, an effect that is not explained by family psychiatric history. Future studies are needed to understand possible sources of risk and resilience so that structures can be put in place to support vulnerable children and their families.
doi:10.1136/bmj.f7679
PMCID: PMC3898661  PMID: 24449616
3.  In-Utero Exposure to Bereavement and Offspring IQ: A Danish National Cohort Study 
PLoS ONE  2014;9(2):e88477.
Background
Intelligence is a life-long trait that has strong influences on lifestyle, adult morbidity and life expectancy. Hence, lower cognitive abilities are therefore of public health interest. Our primary aim was to examine if prenatal bereavement measured as exposure to death of a close family member is associated with the intelligence quotient (IQ) scores at 18-years of age of adult Danish males completing a military cognitive screening examination.
Methods
We extracted records for the Danish military screening test and found kinship links with biological parents, siblings, and maternal grandparents using the Danish Civil Registration System (N = 167,900). The prenatal exposure period was defined as 12 months before conception until birth of the child. We categorized children as exposed in utero to severe stress (bereavement) during prenatal life if their mothers lost an elder child, husband, parent or sibling during the prenatal period; the remaining children were included in the unexposed cohort. Mean score estimates were adjusted for maternal and paternal age at birth, residence, income, maternal education, gestational age at birth and birth weight.
Results
When exposure was due to death of a father the offsprings' mean IQ scores were lower among men completing the military recruitment exam compared to their unexposed counterparts, adjusted difference of 6.5 standard IQ points (p-value = 0.01). We did not observe a clinically significant association between exposure to prenatal maternal bereavement caused by death of a sibling, maternal uncle/aunt or maternal grandparent even after stratifying deaths only due to traumatic events.
Conclusion
We found maternal bereavement to be adversely associated with IQ in male offspring, which could be related to prenatal stress exposure though more likely is due to changes in family conditions after death of the father. This finding supports other literature on maternal adversity during fetal life and cognitive development in the offspring.
doi:10.1371/journal.pone.0088477
PMCID: PMC3928249  PMID: 24558394
4.  Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight 
PLoS ONE  2010;5(7):e11896.
Background
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
Methodology/Principal Findings
We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).
Conclusions/Significance
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
doi:10.1371/journal.pone.0011896
PMCID: PMC2912844  PMID: 20689593
5.  Severe Maternal Stress Exposure Due to Bereavement before, during and after Pregnancy and Risk of Overweight and Obesity in Young Adult Men: A Danish National Cohort Study 
PLoS ONE  2014;9(5):e97490.
Background
Perinatal stress may programme overweight and obesity. We examined whether maternal pre- and post-natal bereavement was associated with overweight and obesity in young men.
Methods
A cohort study was conducted including 119,908 men born from 1976 to 1993 and examined for military service between 2006 and 2011. Among them, 4,813 conscripts were born to mothers bereaved by death of a close relative from 12 months preconception to birth of the child (exposed group). Median body mass index (BMI) and prevalence of overweight and obesity were estimated. Odds ratio of overweight (BMI≥25 kg/m2) and obesity (BMI≥30 kg/m2) were estimated by logistic regression analysis adjusted for maternal educational level.
Results
Median BMI was similar in the exposed and the unexposed group but the prevalence of overweight (33.3% versus 30.4%, p = 0.02) and obesity (9.8% versus 8.5%, p = 0.06) was higher in the exposed group. Conscripts exposed 6 to 0 months before conception and during pregnancy had a higher risk of overweight (odds ratio 1.15, 95% confidence interval (CI): 1.03; 1.27 and odds ratio 1.13, 95% CI: 1.03; 1.25, respectively). Conscripts born to mothers who experienced death of the child’s biological father before child birth had a two-fold risk of obesity (odds ratio 2.00, 95% CI: 0.93; 4.31). There was no elevated risk in those who experienced maternal bereavement postnatally.
Conclusion
Maternal bereavement during the prenatal period was associated with increased risk of overweight or obesity in a group of young male conscripts, and this may possibly be reflected to severe stress exposure early in life. However, not all associations were clear, and further studies are warranted.
doi:10.1371/journal.pone.0097490
PMCID: PMC4020839  PMID: 24828434
6.  Psychological Stress and Hospitalization for Childhood Asthma-a Nationwide Cohort Study in Two Nordic Countries 
PLoS ONE  2013;8(10):e78816.
Objective
Exposures to psychological stress in early life may contribute to the development or exacerbation of asthma. We undertook a cohort study based on data from several population-based registers in Denmark and Sweden to examine whether bereavement in childhood led to increased asthma hospitalization.
Methods
All singleton children born in Denmark during 1977-2008 and in Sweden during 1973-2006 were included in the study (N=5,202,576). The children were followed from birth to the date of first asthma hospitalization, emigration, death, their 18th birthday, or the end of study (31 December 2007 in Sweden and 31 December 2008 in Denmark), whichever came first. All the children were assigned to the non-bereaved group until they lost a close relative (mother, father or a sibling), from when they were included in the bereaved group. We evaluated the hazard ratio (HR) of first hospitalization for asthma in bereaved children using Cox proportional hazards regression models, compared to those who were in the non-bereaved group. We also did a sub-analysis on the association between bereavement and first asthma medication.
Results
A total of 147,829 children were hospitalized for asthma. The overall adjusted HR of asthma hospitalization in bereaved children was 1.10 (95% confidence interval (CI): 1.04-1.16), compared to non-bereaved children. The risk of asthma hospitalization was increased in those who lost a close relative at age of 14-17 years (HR=1.54, 95% CI: 1.23-1.92), but not in younger age groups. The association between bereavement and asthma hospitalization did not change over time since bereavement. In the sub-analysis in singleton live births during 1996-2008 recorded in the DMBR, bereavement was associated with a lower use of asthma medication (HR=0.87, 95% CI: 0.80-0.95).
Conclusions
Our data suggests that psychological stress following bereavement in late adolescence is associated with an increased risk of asthma hospitalization or lowers the threshold for asthma hospitalization.
doi:10.1371/journal.pone.0078816
PMCID: PMC3808299  PMID: 24205324
7.  Maternal Use of Antibiotics, Hospitalisation for Infection during Pregnancy, and Risk of Childhood Epilepsy: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e30850.
Background
Maternal infection during pregnancy may be a risk factor for epilepsy in offspring. Use of antibiotics is a valid marker of infection.
Methodology/Principal Findings
To examine the relationship between maternal infection during pregnancy and risk of childhood epilepsy we conducted a historical cohort study of singletons born in northern Denmark from 1998 through 2008 who survived ≥29 days. We used population-based medical databases to ascertain maternal use of antibiotics or hospital contacts with infection during pregnancy, as well as first-time hospital contacts with a diagnosis of epilepsy among offspring. We compared incidence rates (IR) of epilepsy among children of mothers with and without infection during pregnancy. We examined the outcome according to trimester of exposure, type of antibiotic, and total number of prescriptions, using Poisson regression to estimate incidence rate ratios (IRRs) while adjusting for covariates. Among 191 383 children in the cohort, 948 (0.5%) were hospitalised or had an outpatient visit for epilepsy during follow-up, yielding an IR of 91 per 100 000 person-years (PY). The five-year cumulative incidence of epilepsy was 4.5 per 1000 children. Among children exposed prenatally to maternal infection, the IR was 117 per 100 000 PY, with an adjusted IRR of 1.40 (95% confidence interval (CI): 1.22–1.61), compared with unexposed children. The association was unaffected by trimester of exposure, antibiotic type, or prescription count.
Conclusions/Significance
Prenatal exposure to maternal infection is associated with an increased risk of epilepsy in childhood. The similarity of estimates across types of antibiotics suggests that processes common to all infections underlie this outcome, rather than specific pathogens or drugs.
doi:10.1371/journal.pone.0030850
PMCID: PMC3266299  PMID: 22295115
8.  Autism spectrum disorders in children of parents with inflammatory bowel disease – a nationwide cohort study in Denmark 
Purpose
Inflammatory bowel disease (IBD) and autism spectrum disorders (ASD) may share genetic and environmental risk factors. We examined whether parental IBD is associated with an increased risk of ASD in offspring.
Methods
We conducted a registry-based nationwide cohort study including children born alive in Denmark from January 1, 1994 to December 31, 2009, with follow-up throughout 2010. IBD in parents and ASD in offspring were identified using inpatient and outpatient hospital diagnoses. We computed risk of ASD and crude and adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CI) using Cox proportional-hazards regression. We evaluated the risk of ASD according to maternal and paternal IBD, and separately for maternal and paternal Crohn’s disease (CD) and ulcerative colitis (UC). Children with parents free of IBD were the comparison cohort.
Results
We identified 1,005,330 children during the study period. Among them, 11,888 (1.2%) had a parent with IBD and 8,087 (0.8%) had a diagnosis of ASD during up to 17 years of follow-up. The 10-year risks of ASD were 0.7% among children of parents with IBD and 0.9% among children of parents without IBD. The aIRR for ASD among children with parental IBD was 0.8 (95% CI: 0.6–1.0), and results were similar regardless of parent of IBD origin or whether a parent had CD or UC. The estimates were similar for different ASD subtypes.
Conclusion
We found no evidence of an increased risk of ASD among children born to parents with IBD.
doi:10.2147/CEG.S59360
PMCID: PMC4019630  PMID: 24855384
autistic disorder; children; cohort study; epidemiology; inflammatory bowel disease; parents
9.  Parental Inflammatory Bowel Disease and Risk of Asthma in Offspring: A Nationwide Cohort Study in Denmark 
OBJECTIVES:
Common genetic and environmental risk factors may explain the concurrent increase in the incidence of both inflammatory bowel disease (IBD) and asthma. We examined whether IBD in a parent is associated with an increased asthma risk in offspring.
METHODS:
This was a registry-based cohort study of all children born alive in Denmark in 1979–2009, followed through 2010. IBD and asthma were identified using hospital diagnoses; antiasthma medication was also used to identify asthma. We computed risk of asthma and estimated adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CIs) using Cox proportional-hazards regression. We evaluated asthma risk according to maternal and paternal IBD, Crohn's disease (CD), and ulcerative colitis (UC). Children without parental IBD were the comparison cohort for all comparisons.
RESULTS:
We identified 1,845,281 children, of whom 14,952 (0.8%) had a parent with IBD. The 10-year risk of asthma was 6.9% among offspring of parents with CD, 5.6% among offspring of parents with UC, and 5.0% among offspring of parents without IBD. The aIRR for asthma associated with parental IBD was 0.98 (95% CI: 0.91–1.04). The aIRR was 1.09 (95% CI: 0.98–1.22) for parental CD and 0.92 (95% CI: 0.84–1.00) for parental UC. Results were similar regardless of parent of origin or inclusion of antiasthma medication to define asthma.
CONCLUSIONS:
Our data do not provide evidence for an increased risk of asthma in offspring with a parental history of IBD.
doi:10.1038/ctg.2013.12
PMCID: PMC3759218  PMID: 23965919
10.  Long-Term Health Outcomes in Children Born to Mothers with Diabetes: A Population-Based Cohort Study 
PLoS ONE  2012;7(5):e36727.
Background
To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring.
Methods/Principal Findings
We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations.
Conclusions
This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
doi:10.1371/journal.pone.0036727
PMCID: PMC3359312  PMID: 22649497
11.  Prolonged Grief Disorder: Psychometric Validation of Criteria Proposed for DSM-V and ICD-11 
PLoS Medicine  2009;6(8):e1000121.
Holly Prigerson and colleagues tested the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and care of bereaved individuals at heightened risk of persistent distress and dysfunction.
Background
Bereavement is a universal experience, and its association with excess morbidity and mortality is well established. Nevertheless, grief becomes a serious health concern for a relative few. For such individuals, intense grief persists, is distressing and disabling, and may meet criteria as a distinct mental disorder. At present, grief is not recognized as a mental disorder in the DSM-IV or ICD-10. The goal of this study was to determine the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and potential treatment of bereaved individuals at heightened risk of persistent distress and dysfunction.
Methods and Findings
A total of 291 bereaved respondents were interviewed three times, grouped as 0–6, 6–12, and 12–24 mo post-loss. Item response theory (IRT) analyses derived the most informative, unbiased PGD symptoms. Combinatoric analyses identified the most sensitive and specific PGD algorithm that was then tested to evaluate its psychometric validity. Criteria require reactions to a significant loss that involve the experience of yearning (e.g., physical or emotional suffering as a result of the desired, but unfulfilled, reunion with the deceased) and at least five of the following nine symptoms experienced at least daily or to a disabling degree: feeling emotionally numb, stunned, or that life is meaningless; experiencing mistrust; bitterness over the loss; difficulty accepting the loss; identity confusion; avoidance of the reality of the loss; or difficulty moving on with life. Symptoms must be present at sufficiently high levels at least six mo from the death and be associated with functional impairment.
Conclusions
The criteria set for PGD appear able to identify bereaved persons at heightened risk for enduring distress and dysfunction. The results support the psychometric validity of the criteria for PGD that we propose for inclusion in DSM-V and ICD-11.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Virtually everyone loses someone they love during their lifetime. Grief is an unavoidable and normal reaction to this loss. After the death of a loved one, bereaved people may feel sadness, anger, guilt, anxiety, and despair. They may think constantly about the deceased person and about the events that led up to the person's death. They often have physical reactions to their loss—problems sleeping, for example—and they may become ill. Socially, they may find it difficult to return to work or to see friends and family. For most people, these painful emotions and thoughts gradually diminish, usually within 6 months or so of the death. But for a few people, the normal grief reaction lingers and becomes increasingly debilitating. Experts call this complicated grief or prolonged grief disorder (PGD). Characteristically, people with PGD have intrusive thoughts and images of the deceased person and a painful yearning for his or her presence. They may also deny their loss, feel desperately lonely and adrift, and want to die themselves.
Why Was This Study Done?
PGD is not currently recognized as a mental disorder although it meets the requirements for one given in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) and in the World Health Organization's International Statistical Classification of Diseases and Related Health Problems, 10thEdition (ICD-10). Before PGD can be recognized as a mental disorder (and included in DSM-V and ICD-11), bereavement and mental-health experts need to agree on standardized criteria for PGD. Such criteria would be useful because they would allow researchers and clinicians to identify risk factors for PGD and to find ways to prevent PGD. They would also help to ensure that people with PGD get appropriate treatments such as psychotherapy to help them change their way of thinking about their loss and re-engage with the world. Recently, a panel of experts agreed on a consensus list of symptoms for PGD. In this study, the researchers undertake a field trial to develop and evaluate algorithms (sets of rules) for diagnosing PGD based on these symptoms.
What Did the Researchers Do and Find?
The researchers used “item response theory” (IRT) to derive the most informative PGD symptoms from structured interviews of nearly 300 people who had recently lost a close family member. These interviews contained questions about the consensus list of symptoms; each participant was interviewed two or three times during the two years after their spouse's death. The researchers then used “combinatoric” analysis to identify the most sensitive and specific algorithm for the diagnosis of PGD. This algorithm specifies that a bereaved person with PGD must experience yearning (physical or emotional suffering because of an unfulfilled desire for reunion with the deceased) and at least five of nine additional symptoms. These symptoms (which include emotional numbness, feeling that life is meaningless, and avoidance of the reality of the loss) must persist for at least 6 months after the bereavement and must be associated with functional impairment. Finally, the researchers show that individuals given a diagnosis of PGD 6–12 months after a death have a higher subsequent risk of mental health and functional impairment than people not diagnosed with PGD.
What Do These Findings Mean?
These findings validate a set of symptoms and a diagnostic algorithm for PGD. Because most of the study participants were elderly women who had lost their husband, further validation is needed to check that these symptoms and algorithm also apply to other types of bereaved people such as individuals who have lost a child. For now, though, these findings support the inclusion of PGD in DSM-V and ICD-11 as a recognized mental disorder. Furthermore, the availability of a standardized way to diagnose PGD will help clinicians identify the minority of people who fail to adjust successfully to the loss of a loved one. Hopefully, by identifying these people and helping them to avoid the onset of PGD (perhaps by providing psychotherapy soon after a death) and/or providing better treatment for PGD, it should now be possible to reduce the considerable personal and societal costs associated with prolonged grief.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000121.
This study is further discussed in a PLoS Medicine Perspective by Stephen Workman
The Dana Farber Cancer Institute has a page describing its Center for Psycho-oncology and Palliative Care Research
The UK Royal College of Psychiatrists has a leaflet on bereavement (in English, Welsh, Urdu, and Chinese)
The US National Cancer Institute also has information about coping with bereavement for patients and health professionals (in English and Spanish)
MedlinePlus has links to other information about bereavement (in English and Spanish)
The Journal of the American Medical Association has a patient page on abnormal grief
Harvard Medical School provides a short family health guide about complicated grief
Information on DSM-IV and ICD-10 is available
doi:10.1371/journal.pmed.1000121
PMCID: PMC2711304  PMID: 19652695
12.  Maternal Bereavement and Childhood Asthma—Analyses in Two Large Samples of Swedish Children 
PLoS ONE  2011;6(11):e27202.
Background
Prenatal factors such as prenatal psychological stress might influence the development of childhood asthma.
Methodology and Principal Findings
We assessed the association between maternal bereavement shortly before and during pregnancy, as a proxy for prenatal stress, and the risk of childhood asthma in the offspring, based on two samples of children 1–4 (n = 426 334) and 7–12 (n = 493 813) years assembled from the Swedish Medical Birth Register. Exposure was maternal bereavement of a close relative from one year before pregnancy to child birth. Asthma event was defined by a hospital contact for asthma or at least two dispenses of inhaled corticosteroids or montelukast. In the younger sample we calculated hazards ratios (HRs) of a first-ever asthma event using Cox models and in the older sample odds ratio (ORs) of an asthma attack during 12 months using logistic regression. Compared to unexposed boys, exposed boys seemed to have a weakly higher risk of first-ever asthma event at 1–4 years (HR: 1.09; 95% confidence interval [CI]: 0.98, 1.22) as well as an asthma attack during 12 months at 7–12 years (OR: 1.10; 95% CI: 0.96, 1.24). No association was suggested for girls. Boys exposed during the second trimester had a significantly higher risk of asthma event at 1–4 years (HR: 1.55; 95% CI: 1.19, 2.02) and asthma attack at 7–12 years if the bereavement was an older child (OR: 1.58; 95% CI: 1.11, 2.25). The associations tended to be stronger if the bereavement was due to a traumatic death compared to natural death, but the difference was not statistically significant.
Conclusions/Significance
Our results showed some evidence for a positive association between prenatal stress and childhood asthma among boys but not girls.
doi:10.1371/journal.pone.0027202
PMCID: PMC3210147  PMID: 22087265
13.  Prenatal Stress and Risk of Febrile Seizures in Children: A Nationwide Longitudinal Study in Denmark 
We aimed to examine whether exposure to prenatal stress following maternal bereavement is associated with an increased risk of febrile seizures. In a longitudinal population-based cohort study, we followed 1,431,175 children born in Denmark. A total of 34,777 children were born to women who lost a close relative during pregnancy or within 1 year before the pregnancy and they were included in the exposed group. The exposed children had a risk of febrile seizures similar to that of the unexposed children (hazard ratio (HR) 1.00, 95% CI 0.94–1.06). The HRs did not differ according to the nature or timing of bereavement. Our data do not suggest any causal link between exposure to prenatal stress and febrile seizures in childhood.
doi:10.1007/s10803-009-0717-4
PMCID: PMC2694316  PMID: 19291382
Prenatal stress; Bereavement; Febrile seizures; Fetal programming; Longitudinal study
14.  Effects of Prenatal and Perinatal Exposure to Fine Air Pollutants and Maternal Fish Consumption on the Occurrence of Infantile Eczema 
Background
As there is a scarcity of evidence on potential hazards and preventive factors for infantile eczema operating in the prenatal period, the main goal of this study was to assess the role of prenatal exposure to fine particulate matter and environmental tobacco smoke (ETS) in the occurrence of infant eczema jointly with the possible modulating effect of maternal fish consumption.
Methods
The study sample consisted of 469 women enrolled during pregnancy, who gave birth to term babies (>36 weeks of gestation). Among all pregnant women recruited, personal measurements of fine particulate matter (PM2.5) were performed over 48 h in the second trimester of pregnancy. After delivery, every 3 months in the first year of the newborn's life, a detailed, standardized, face-to-face interview was administered to each mother, in the process of which a trained interviewer recorded any history of infantile eczema and data on potential environmental hazards. The estimated risk of eczema related to higher prenatal exposure to fine particulate matter (PM2.5 >53.0 μg/m3) and postnatal ETS as well as the protective effect of maternal fish intake were adjusted for potential confounders in a multivariable logistic regression model.
Results
While the separate effects of higher prenatal PM2.5 and postnatal ETS exposure were not statistically significant, their joint effect appeared to have a significant influence on the occurrence of infantile eczema [odds ratio 2.39, 95% confidence interval (CI) 1.10–5.18]. With maternal fish intake of more than 205 g/week, the risk of eczema decreased by 43% (odds ratio 0.57, 95% CI 0.35–0.93). The incidence rate ratio (IRR) for eczema symptoms, estimated from the Poisson regression model, was increased with both higher exposure to prenatal PM2.5 and postnatal ETS (IRR 1.55, 95% CI 0.99–2.44) and in children of atopic mothers (IRR 1.35, 95% CI 1.04–1.75) but was lower in girls (IRR 0.78, 95% CI 0.61–1.00). The observed preventive effect of fish consumption on the frequency of eczema symptoms was consistent with the results of the logistic analysis (IRR 0.72, 95% CI 0.52–0.99).
Conclusions
The findings indicate that higher prenatal exposure to fine particulate matter combined with postnatal exposure to ETS may increase the risk of infant eczema, while maternal fish intake during pregnancy may reduce the risk of infantile eczema.
doi:10.1159/000320376
PMCID: PMC3047761  PMID: 21293147
Fish consumption; Prenatal exposure to fine particles; Cow's milk allergy; Passive tobacco smoke; Cohort study
15.  INTRAUTERINE EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS, FINE PARTICULATE MATTER AND EARLY WHEEZE. PROSPECTIVE BIRTH COHORT STUDY IN 4-YEAR OLDS 
The main goal of the study was to determine the relationship between prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) measured by PAH-DNA adducts in umbilical cord blood and early wheeze. The level of PAH-DNA adducts in the cord blood is assumed to reflect the cumulative dose of PAHs absorbed by the fetus over the prenatal period. The effect of prenatal PAH exposure on respiratory health measured by the incidence rate ratio (IRR) for the number of wheezing days in the subsequent four year follow-up was adjusted for potential confounding factors such as personal prenatal exposure to fine particulate matter (PM2.5), environmental tobacco smoke (ETS), gender of child, maternal characteristics (age, education and atopy), parity, and mold/dampness in the home. The study sample includes 339 newborns of non-smoking mothers 18-35 years of age and free from chronic diseases, who were recruited from ambulatory prenatal clinics in the first or second trimester of pregnancy. The number of wheezing days during the first two years of life was positively associated with prenatal level of PAH-DNA adducts (IRR = 1.69, 95%CI = 1.52 – 1.88), prenatal particulate matter (PM2.5) level dichotomized by the median (IRR = 1.38; 95%CI: 1.25 – 1.51), maternal atopy (IRR = 1.43; 95%CI: 1.29 – 1.58), moldy/damp house (IRR = 1.43; 95%CI: 1.27 – 1.61). The level of maternal education and maternal age at delivery were inversely associated with the IRRs for wheeze. The significant association between frequency of wheeze and the level of prenatal environmental hazards (PAHs and PM2.5) was not observed at ages 3 or 4 years. Although the frequency of wheezing at ages 3 or 4 years was no longer associated with prenatal exposure to PAHs and PM2.5, its occurrence depended on the presence of wheezing in the first two years of life, which nearly tripled the risk of wheezing in later life. In conclusion, the findings may suggest that driving force for early wheezing (<24 months of age) are different to those leading to later onset of wheeze. As we reported no synergistic effects between prenatal PAH (measured by PAH-DNA adducts) and PM2.5 exposures on early wheeze, this suggests the two exposures may exert independent effects via different biological mechanism on wheeze.
doi:10.1111/j.1399-3038.2010.01034.x
PMCID: PMC3683604  PMID: 20444151
prenatal exposure to polycyclic aromatic hydrocarbons; biomarkers of exposure; DNA adducts; early wheeze; 4-year olds; birth cohort study
16.  Racial and Ethnic Disparities in Police-reported Intimate Partner Violence and Risk of Hospitalization among Women 
Objectives
We sought to examine racial and ethnic disparities in police-reported intimate partner violence (IPV) and hospitalization rates and rate ratios among women with police-reported IPV relative to those without such reports.
Methods
This retrospective cohort study linked adult male-to-female IPV police records of non-Hispanic black, Hispanic, and non-Hispanic white women residing in a south central U.S. city with regional hospital discharge data. Rates and incidence rate ratios (IRR) were calculated and age-adjusted where the data allowed.
Results
Police-reported IPV rates were 2 to 3 times higher among black and Hispanic women compared to white women. Overall, hospitalization rates were higher among black and white victims and lower among Hispanic victims than their counterparts in the comparison group (age-adjusted [a] IRR 1.23, 95% confidence interval [CI] 1.08–1.41; aIRR 1.46, CI 1.19–1.79; and aIRR 0.68, CI 0.54–0.86, respectively). Rate ratios were significant for victims among 1) white women for any mental disorder (aIRR 2.02, CI 1.30–3.13) and for episodic mood/depressive disorders in particular (aIRR 2.18, CI 1.33–3.59); 2) black and white women for any injury-related diagnosis (aIRR 2.46, CI 1.48–4.10 and aIRR 3.20, CI 1.65–6.19, respectively); and 3) all women for intentional injury (IRR 10.45, CI 3.56–30.69) and self-inflicted injury (IRR 4.91, 2.12–11.37).
Conclusions
Exposure to IPV as reported to police increases the rate of hospital utilization among Black and white women but lowers the rate for Hispanic women. Screening for IPV in hospitals may identify a substantial number of IPV-exposed women. Primary and secondary prevention efforts related to IPV should be culturally informed and specific.
doi:10.1016/j.whi.2008.09.005
PMCID: PMC2757408  PMID: 19272561
17.  Care-Related Risk Factors for Hospital-Acquired Pressure Ulcers Among Elderly Hip Fracture Patients 
OBJECTIVES
To identify care-related factors associated with increased incidence of hospital-acquired pressure ulcers (HAPU)
DESIGN
Prospective cohort study
SETTING
Nine hospitals in Baltimore Hip Studies network
PARTICIPANTS
658 patients age ≥65 years who underwent surgery for hip fracture
MEASUREMENTS
Skin examinations at baseline and alternating days until hospital discharge. Patients were deemed to have a HAPU if they developed ≥1 new pressure ulcers stage 2 or higher during the hospital stay.
RESULTS
Longer emergency department stays were associated with lower HAPU incidence (>4-6 hours: adjusted incidence rate ratio [aIRR] 0.68, 95% confidence interval [CI] 0.48-0.96; >6 hours: aIRR 0.68, 95% CI 0.46-0.99, both compared to ≤4 hours). Patients with ≥24 hours between admission and surgery had a higher post-surgery HAPU rate than those with <24 hours (aIRR 1.62, 95% CI 1.24-2.11). Surgery with general anesthesia had a lower post-surgery HAPU rate than surgery with other types of anesthesia (aIRR 0.66, 95% CI 0.49-0.88). There was no significant association of HAPU incidence with timing or type of transport to hospital, or surgery duration.
CONCLUSION
Most of the factors hypothesized to be associated with higher pressure ulcer incidence were either associated with lower incidence or were not significantly associated, suggesting that HAPU development may not be as sensitive to care-related factors as commonly believed. Rigorous studies of innovative preventive interventions are needed to inform policy and practice.
doi:10.1111/j.1532-5415.2011.03849.x
PMCID: PMC3532032  PMID: 22332674
Pressure ulcers; Hospitals; Hip fracture; Risk factors
18.  Increased Risk of Acute Pancreatitis and Biliary Disease Observed in Patients With Type 2 Diabetes 
Diabetes Care  2009;32(5):834-838.
OBJECTIVE
The objective of this study was to assess the risk of acute pancreatitis in patients with type 2 diabetes compared with that in patients without diabetes. We also examined the risk of biliary disease (defined as occurrence of cholelithiasis, acute cholecystitis, or cholecystectomy), which is a major cause of pancreatitis.
RESEARCH DESIGN AND METHODS
We conducted a retrospective cohort study using a large, geographically diverse U.S. health care claims database. Eligible patients (≥18 years) were enrolled for at least 12 continuous months (1999–2005), with no incident events of pancreatitis or biliary disease during that 1 year baseline period. ICD-9 codes and prescription data were used to identify patients with type 2 diabetes; ICD-9 codes were also used to identify cases of pancreatitis and biliary disease. Overall, 337,067 patients with type 2 diabetes were matched on age and sex with 337,067 patients without diabetes. Incidence rates of disease and 95% CI were calculated per 100,000 person-years of exposure.
RESULTS
The type 2 diabetic cohort had a 2.83-fold (95% CI 2.61–3.06) greater risk of pancreatitis and 1.91-fold (1.84–1.99) greater risk of biliary disease compared with the nondiabetic cohort. Relative to patients of corresponding age without diabetes, younger type 2 diabetic patients had the highest risk of pancreatitis (<45 years: incidence rate ratio [IRR] 5.26 [95% CI 4.31–6.42]; ≥45 years: 2.44 [2.23–2.66]).
CONCLUSIONS
These data suggest that patients with type 2 diabetes may have an increased risk of acute pancreatitis and biliary disease.
doi:10.2337/dc08-1755
PMCID: PMC2671118  PMID: 19208917
19.  Preconception Predictors of Birth Outcomes: Prospective Findings from the Central Pennsylvania Women's Health Study 
Maternal and child health journal  2009;15(7):829-835.
Objective
To examine maternal pre-pregnancy (preconception) predictors of birthweight and fetal growth for singleton live births occurring over a 2-year period in a prospective study.
Methods
Data are from a population-based cohort study of 1,420 women who were interviewed at baseline and 2-years later; self-report data and birth records were obtained for incident live births during the followup period. The analytic sample includes 116 singleton births. Baseline preconception maternal health status and health-related behaviors were examined as predictors of birthweight and fetal growth, controlling for prenatal and sociodemographic variables, using multiple regression analysis.
Results
Preconception BMI (overweight or obese) and vegetable consumption (at least one serving per day) had statistically significant independent and positive effects on birthweight and fetal growth. Maternal weight gain during pregnancy, a prenatal variable, was an additional independent predictor of birthweight and fetal growth. Sociodemographic variables were not significant predictors after controlling for preconception and prenatal maternal characteristics.
Conclusions
Findings confirm that preconception maternal health status and health-related behaviors can affect birthweight and fetal growth independent of prenatal and socioeconomic variables. Implications for preconception care are discussed.
doi:10.1007/s10995-009-0473-2
PMCID: PMC2939188  PMID: 19472041
Preconception health; Birthweight; Body mass index; Nutrition; Cohort study
20.  The Relationship Between Maternal Depression, In-Home Violence, And Use Of Physical Punishment: What Is The Role Of Child Behavior? 
Archives of disease in childhood  2008;94(2):138-143.
Context
Maternal depression and in-home violence are independently associated with the use of physical punishment on children; however, the combined impact of these factors on the practice of physical punishment is unknown, as is the extent to which their relationship to physical punishment varies with child behavior.
Objectives
1) Determine the combined impact of maternal depression and violence exposure on one physical punishment practice, smacking; 2) Explore the role of child behaviors in this relationship.
Methods
Multivariable regression analysis of a nationally representative sample of US kindergarten children. Maternal depressive symptoms, violence exposure, and use of smacking as a discipline technique were measured by parent interview. Child behaviors were reported by teachers.
Results
12,764 mother-child dyads were included in the analysis. The adjusted odds ratio (aOR) for smacking among mothers with depressive symptoms was 1.59 (95% CI 1.40, 1.80); among mothers exposed to in-home violence, 1.48 (95% CI 1.18, 1.85); among dually exposed mothers, 2.51 (95% CI 1.87, 3.37). Adjusting these models for child self-control or externalizing behavior yielded no change in these associations, and no effect modification by child behavior was detected. Among mothers reporting to smack their children, depression was associated with an increased smacking frequency (aIRR 1.12; 95% CI 1.01, 1.24); however, this association was reduced to borderline significance when adjusting the models for child self-control or externalizing behavior (aIRRs 1.10; 95% CI 1.00, 1.21). Depressed mothers who were also exposed to violence demonstrated higher rates of smacking (aIRR 1.29; 95% CI 1.09, 1.53); this remained stable when adjusting for child behaviors.
Conclusion
Maternal depression and violence exposure are associated with smacking as a means of punishment. The magnitude of this association is increased when depression and violence occur together. When coexistent, they also appear associated with the frequency of smacking. Child self-control and externalizing behavior do not appear to impact substantially the association between maternal depressive symptoms, violence exposure, and smacking.
doi:10.1136/adc.2007.128595
PMCID: PMC2829298  PMID: 18786952
Maternal Depression; Violence; Corporal Punishment; Spanking; Smacking; Child Behavior
21.  Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study 
PLoS Medicine  2010;7(10):e1000351.
An observational study by Ruth Gilbert and colleagues finds that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop serious neurological sequelae.
Background
The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known.
Methods and Findings
Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07–0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2–15) after maternal seroconversion at 10 weeks, and 18 (9–75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21–2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%–38.1%).
Conclusion
The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Toxoplasmosis is a very common parasitic infection. People usually become infected with Toxoplasma gondii, the parasite that causes toxoplasmosis, by eating raw or undercooked meat that contains the parasite, but it can also be contracted by drinking unfiltered water or by handling cat litter. Most people with toxoplasmosis never know they have the disease. However, if a pregnant woman becomes infected with T. gondii, she can transmit the parasite to her unborn baby (fetus). Overall, about a quarter of women who catch toxoplasmosis during pregnancy transmit the parasite to their fetus. If transmission occurs early during pregnancy, the resultant “congenital toxoplasmosis” increases the risk of miscarriage and the risk of the baby being born with brain damage, epilepsy, deafness, blindness, or developmental problems (“serious neurological sequelae”). In the worst cases, babies may be born dead or die soon after birth. Congenital toxoplasmosis caught during the final third of pregnancy may not initially cause any health problems but eyesight problems often develop later in life.
Why Was This Study Done?
Clinicians can find out if a woman has been infected with T. gondii during pregnancy by looking for parasite-specific antibodies (proteins made by the immune system that fight infections) in her blood. If the pattern of antibodies suggests a recent infection, the woman can be given spiramycin or pyrimethamine-sulfonamide, antibiotics that are thought to reduce the risk of transmission to the fetus and the severity of toxoplasmosis in infected fetuses. In some countries where toxoplasmosis is particularly common (for example, France), pregnant women are routinely screened for toxoplasmosis and treated with antibiotics if there are signs of recent infection. But is prenatal treatment an effective way to prevent the serious neurological sequelae or postnatal death (SNSD) associated with congenital toxoplasmosis? In this observational study, the researchers examine this question by studying a group of children identified as having congenital toxoplasmosis by prenatal or neonatal screening in six European countries. An observational study measures outcomes in a group of patients without trying to influence those outcomes by providing a specific treatment.
What Did the Researchers Do and Find?
The researchers followed 293 children in whom congenital toxoplasmosis had been identified by prenatal screening (in France, Austria, and Italy) or by neonatal screening (in Denmark, Sweden, and Poland) for an average 4 years. Two-thirds of the children received prenatal treatment for toxoplasmosis and 23 fetuses (8% of the fetuses) developed SNSD; nine of these cases of SNSD were terminated during pregnancy. By comparing the number of cases of SNSD among children who received prenatal treatment with the number among children who did not receive prenatal treatment, the researchers estimate that prenatal treatment reduced the risk of SNSD by three-quarters. They also estimate that to prevent one case of SNSD after maternal infection at 10 weeks of pregnancy, it would be necessary to treat three fetuses with confirmed infection. To prevent one case of SNSD after maternal infection at 30 weeks of pregnancy, 18 fetuses would need to be treated. Finally, the researchers report that the effectiveness of pyrimethamine-sulfonamide and spiramycin (which is less toxic) was similar, and that a third of live-born infants with brain damage that was detected after birth subsequently developed SNSD.
What Do These Findings Mean?
These findings suggest that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop SNDS and would be particularly effective in fetuses whose mothers acquired T. gondii during the first third of pregnancy. These findings should be interpreted with caution, however, because of the small number of affected fetuses in the study and because of uncertainty about the timing of maternal infection. Furthermore, these findings only relate to the relatively benign strain of T. gondii that predominates in Europe and North America; further studies are needed to test whether prenatal treatment is effective against the more virulent strains of the parasite that occur in South America. Finally, because this study is an observational study, its findings might reflect differences between the study participants other than whether or not they received prenatal treatment. These findings need to be confirmed in randomized controlled trials of prenatal screening, therefore, before any policy decisions are made about routine prenatal screening and treatment for congenital toxoplasmosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000351.
The US Centers for Disease Control and Prevention provides detailed information about all aspects of toxoplasmosis, including toxoplasmosis in pregnant women (in English and Spanish)
The UK National Health Services Choices website has information for patients about toxoplasmosis and about the risks of toxoplasmosis during pregnancy
KidsHealth, a resource maintained by the Nemours Foundation (a not-for-profit organization for children's health), provides information for parents about toxoplasmosis (in English and Spanish)
Tommy's, a nonprofit organization that funds research on the health of babies, also has information on toxoplasmosis
MedlinePlus provides links to other information on toxoplasmosis (in English and Spanish)
EUROTOXO contains reports generated by a European consensus development project
Uptodate provides information about toxoplasmosis and pregnancy
doi:10.1371/journal.pmed.1000351
PMCID: PMC2953528  PMID: 20967235
22.  Early life bereavement and childhood cancer: a nationwide follow-up study in two countries 
BMJ Open  2013;3(5):e002864.
Objective
Childhood cancer is a leading cause of child deaths in affluent countries, but little is known about its aetiology. Psychological stress has been suggested to be associated with cancer in adults; whether this is also seen in childhood cancer is largely unknown. We investigated the association between bereavement as an indicator of severe childhood stress exposure and childhood cancer, using data from Danish and Swedish national registers.
Design
Population-based cohort study.
Setting
Denmark and Sweden.
Participants
All live-born children born in Denmark between 1968 and 2007 (n=2 729 308) and in Sweden between 1973 and 2006 (n=3 395 166) were included in this study. Exposure was bereavement by the death of a close relative before 15 years of age. Follow-up started from birth and ended at the first of the following: date of a cancer diagnosis, death, emigration, day before their 15th birthday or end of follow-up (2007 in Denmark, 2006 in Sweden).
Outcome measures
Rates and HRs for all childhood cancers and specific childhood cancers.
Results
A total of 1 505 938 (24.5%) children experienced bereavement at some point during their childhood and 9823 were diagnosed with cancer before the age of 15 years. The exposed children had a small (10%) increased risk of childhood cancer (HR 1.10; 95% CI 1.04 to 1.17). For specific cancers, a significant association was seen only for central nervous system tumours (HR 1.14; 95% CI 1.02 to 1.28).
Conclusions
Our data suggest that psychological stress in early life is associated with a small increased risk of childhood cancer.
doi:10.1136/bmjopen-2013-002864
PMCID: PMC3664350  PMID: 23793702
Childhood cancer; bereavement; psychological stress; risk factor; follow up
23.  Task-Sharing of HIV Care and ART Initiation: Evaluation of a Mixed-Care Non-Physician Provider Model for ART Delivery in Rural Malawi 
PLoS ONE  2013;8(9):e74090.
Background
Expanding access to antiretroviral therapy (ART) in sub-Saharan Africa requires implementation of alternative care delivery models to traditional physician-centered approaches. This longitudinal analysis compares outcomes of patients initiated on antiretroviral therapy (ART) by non-physician and physician providers.
Methods
Adults (≥15 years) initiating ART between September 2007 and March 2010, and with >1 follow-up visit were included and classified according to the proportion of clinical visits performed by nurses or by clinical officers (≥80% of visits). Multivariable Poisson models were used to compare 2-year program attrition (mortality and lost to follow-up) and mortality by type of provider. In sensitivity analyses only patients with less severe disease were included.
Results
A total of 10,112 patients contributed 14,012 person-years to the analysis: 3386 (33.5%) in the clinical officer group, 1901 (18.8%) in the nurse care group and 4825 (47.7%) in the mixed care group. Overall 2-year program retention was 81.8%. Attrition was lower in the mixed care and higher in the clinical officer group, compared to the nurse group (adjusted incidence rate ratio [aIRR]=0.54, 95%CI 0.45-0.65; and aIRR=3.03, 95%CI 2.56-3.59, respectively). While patients initiated on ART by clinical officers in the mixed care group had lower attrition (aIRR=0.36, 95%CI 0.29-0.44) than those in the overall nurse care group; no differences in attrition were found between patients initiated on ART by nurses in the mixed care group and those included in the nurse group (aIRR=1.18, 95%CI 0.95-1.47). Two-year mortality estimates were aIRR=0.72, 95%CI 0.49-1.09 and aIRR=5.04, 95%CI 3.56-7.15, respectively. Slightly higher estimates were observed when analyses were restricted to patients with less severe disease.
Conclusion
The findings of this study support the use of a mixed care model with well trained and regularly supervised nurses and medical assistants to provide HIV care in countries with high HIV prevalence.
doi:10.1371/journal.pone.0074090
PMCID: PMC3774791  PMID: 24066099
24.  Comorbid Diabetes and End-of-Life Expenditures among Medicare Beneficiaries with Heart Failure 
Journal of Cardiac Failure  2011;18(1):41-46.
Background
Diabetes is associated with increased risk of mortality in heart failure. We examined the association of diabetes with expenditures, hospitalizations, and procedures among Medicare beneficiaries with heart failure during the last six months of life.
Methods and Results
In a 5% national Medicare sample, the prevalence of diabetes was 41.7% among 16,613 beneficiaries who died in 2007 with a diagnosis of heart failure. Diabetes was associated with higher expenditures during the last six months of life (mean $39,042 vs $29,003, p<0.001), even after adjusting for covariates, including age, gender, race, geographic location, comorbidities, and prior hospitalizations (cost ratio 1.08, 95% CI 1.05–1.12). For both diabetic and non-diabetic adults, over half of Medicare expenditures were related to hospitalization costs (mean $22,516 vs $15,721, p<0.001). When compared to their counterparts without diabetes, beneficiaries with diabetes had higher rates of hospitalization (adjusted incidence rate ratio (aIRR) 1.09, 95% CI 1.05–1.12) and days spent in the ICU.
Conclusions
Comorbid diabetes was common in heart failure and associated with higher expenditures, much of which was driven by increased rates of hospitalizations. Programs that focus on prevention of hospitalizations may reduce the substantial costs associated with heart failure near the end of life.
doi:10.1016/j.cardfail.2011.09.011
PMCID: PMC3285442  PMID: 22196840
25.  Evidence for a contribution of the community response to HIV decline in eastern Zimbabwe? 
AIDS Care  2013;25(Suppl 1):S88-S96.
Membership of indigenous local community groups was protective against HIV for women, but not for men, in eastern Zimbabwe during the period of greatest risk reduction (1999–2004). We use four rounds of data from a population cohort to investigate: (1) the effects of membership of multiple community groups during this period; (2) the effects of group membership in the following five years; and (3) the effects of characteristics of groups hypothesised to determine their effect on HIV risk. HIV incidence from 1998 to 2003 was 1.18% (95% CI: 0.78–1.79%), 0.48% (0.20–1.16%) and 1.13% (0.57–2.27%), in women participating in one, two and three or more community groups at baseline versus 2.19% (1.75–2.75%) in other women. In 2003–2005, 36.5% (versus 43% in 1998–2000) of women were members of community groups, 50% and 56% of which discussed HIV prevention and met with other groups, respectively; the corresponding figures for men were 24% (versus 28% in 1998–2000), 51% and 58%. From 2003 to 2008, prior membership of community groups was no longer protective against HIV for women (1.13% versus 1.29%, aIRR = 1.25;p = 0.23). However, membership of groups that provided social spaces for dialogue about HIV prevention (0.62% versus 1.01%, aIRR = 0.54; p = 0.28) and groups that interacted with other groups (0.65% versus 1.01%, aIRR = 0.51; p = 0.19) showed non-significant protective effects. For women, membership of a group with external sponsorship showed a non-significant increase in HIV risk compared to membership of unsponsored groups (adjusted odds ratio = 1.63, p = 0.48). Between 2003 and 2008, membership of community groups showed a non-significant tendency towards higher HIV risk for men (1.47% versus 0.94%, p = 0.23). Community responses contributed to HIV decline in eastern Zimbabwe. Sensitive engagement and support for local groups (including non-AIDS groups) to encourage dialogue on positive local responses to HIV and to challenge harmful social norms and incorrect information could enhance HIV prevention.
doi:10.1080/09540121.2012.748171
PMCID: PMC3687248  PMID: 23745635
community response; social capital; community groups; HIV decline; Zimbabwe

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