Randomized trial of three doses of vitamin D to reduce deficiency in pregnant Mongolian women.

BACKGROUND: In winter in Mongolia, 80% of adults have 25-hydroxyvitamin D (25(OH)D) concentrations <25 nmol/l (<10 ng/ml) and 99% have <50 nmol/l (<20 ng/ml). The vitamin D dose to avert deficiency during pregnancy in this population is unknown. METHODS: We conducted a randomized, controlled, double-blind trial of daily 600, 2000, or 4000 IU vitamin D3 for pregnant women in Mongolia (Clinicaltrials.gov #NCT02395081). We examined 25(OH)D concentrations at baseline (12-16 weeks' gestation), 36-40 weeks' gestation and in umbilical cord blood, using enzyme linked fluorescent assay. Sample size was determined to detect 0.4 standard deviation differences in 25(OH)D concentrations with 80% power. FINDINGS: 119 pregnant women were assigned 600 IU, 121 assigned 2000 IU and 120 assigned 4000 IU from February 2015 through December 2016. Eighty-eight percent of participants took ≥80% of assigned supplements. At baseline, 25(OH)D concentrations were similar across arms; overall mean ±â€¯standard deviation concentration was 19 ±â€¯22 nmol/l; 91% were < 50 nmol/l. At 36-40 weeks, 25(OH)D concentrations increased to 46 ±â€¯21, 70 ±â€¯23, and 81 ±â€¯29 nmol/l for women assigned 600, 2000, and 4000 IU, respectively (p < 0.0001 across arms; p = 0.002 for 2000 vs. 4000 IU). Mean umbilical cord 25(OH)D concentrations differed by study arm (p < 0.0001 across arms; p < 0.0001 for 2000 vs. 4000 IU) and were proportional to maternal concentrations. There were no adverse events, including hypercalcemia, attributable to vitamin D supplementation. INTERPRETATION: Daily supplementation of 4000 IU during pregnancy is safe and achieved higher maternal and neonatal 25(OH)D concentrations than 2000 IU. Daily 600 IU supplements are insufficient to prevent vitamin D deficiency in Mongolia. FUND: Anonymous foundation and Brigham and Women's Hospital.

Prenatal protein level impacts homing behavior in Long-Evans rat pups.

OBJECTIVE: This study assessed the effect of varying prenatal protein levels on the development of homing behavior in rat pups. METHODS: Long-Evans rats were fed one of the four isocaloric diets containing 6% (n = 7 litters), 12% (n = 9), 18% (n = 9), or 25% (n = 10) casein prior to mating and throughout pregnancy. At birth, litters were fostered to well-nourished control mothers fed a 25% casein diet during pregnancy, and an adequate protein diet (25% casein) was provided to weaning. On postnatal days 5, 7, 9, 11, and 13, homing behaviors, including activity levels, rate of successful returns to the nest quadrant and latencies to reach the nest over a 3-minute test period were recorded from two starting positions in the home cage. Adult body and brain weights were obtained at sacrifice (postnatal day 130 or 200). RESULTS: Growth was impaired in pups whose mothers were fed a 6% or, to a lesser extent, a 12% casein diet relative to pups whose mothers were fed the 18 and 25% casein diets. The 6 and 12% prenatal protein levels resulted in lower activity levels, with the greatest reduction on postnatal day 13. However, only the 6% pups had reduced success and higher latencies in reaching the nest quadrant when compared with pups from the three other nutrition groups. Latency in reaching the nest quadrant was significantly and negatively associated with adult brain weight. DISCUSSION: Home orientation is a sensitive measure of developmental deficits associated with variations in prenatal protein levels, including levels of protein deficiency that do not lead to overt growth failure.

Prediction of time-to-attainment of recovery for borderline patients followed prospectively for 16 years.

OBJECTIVE: The purpose of this study was to determine the most clinically relevant baseline predictors of time-to-recovery from borderline personality disorder. METHOD: Two hundred and ninety in-patients meeting rigorous criteria for borderline personality disorder were assessed during their index admission using a series of semistructured interviews and self-report measures. Recovery status, which was defined as concurrent symptomatic remission and good social and full-time vocational functioning, was reassessed at eight contiguous 2-year time periods. Survival analytic methods (Cox regression), which controlled for overall baseline severity, were used to estimate hazard ratios and their confidence intervals. RESULTS: All told, 60% of the borderline patients studied achieved a 2-year recovery. In bivariate analyses, seventeen variables were found to be significant predictors of earlier time-to-recovery. Six of these predictors remained significant in multivariate analyses: no prior psychiatric hospitalizations, higher IQ, good full-time vocational record in 2 years prior to index admission, absence of an anxious cluster personality disorder, high extraversion, and high agreeableness. CONCLUSION: Taken together, the results of this study suggest that prediction of time-to-recovery for borderline patients is multifactorial in nature, involving factors related to lack of chronicity, competence, and more adaptive aspects of temperament.

Inferior vena cava thrombosis: a review of current practice.

Inferior vena cava (IVC) thrombosis remains under-recognised as it is often not pursued as a primary diagnosis. The aetiology of IVC thrombosis can be divided into congenital versus acquired, with all aetiological factors found among Virchow's triad of stasis, injury and hypercoagulability. Signs and symptoms are related to aetiology and range from no symptoms to cardiovascular collapse. Painful lower limb swelling combined with lower back pain, pyrexia, dilatation of cutaneous abdominal wall veins and a concurrent rise in inflammatory markers are suggestive of IVC thrombosis. Following initial lower limb venous duplex, magnetic resonance imaging (MRI) is the optimal non-invasive imaging tool. Aetiology directs treatment, which ranges from anticoagulation and lower limb compression to open surgery, with endovascular therapies increasingly favoured. The objective of this review is to assess current literature on the aetiology, presentation, investigation, treatment, prognosis and other factors pertaining to IVC thrombosis.

Predictors of suicide attempts in patients with borderline personality disorder over 16 years of prospective follow-up.

BACKGROUND: It is clinically important to understand the factors that increase the likelihood of the frequent and recurrent suicide attempts seen in those with borderline personality disorder (BPD). Although several studies have examined this subject in a cross-sectional manner, the aim of this study was to determine the most clinically relevant baseline and time-varying predictors of suicide attempts over 16 years of prospective follow-up among patients with BPD. METHOD: Two-hundred and ninety in-patients meeting Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD were assessed during their index admission using a series of semistructured interviews and self-report measures. These subjects were then reassessed using the same instruments every 2 years. The generalized estimating equations (GEE) approach was used to model the odds of suicide attempts in longitudinal analyses, controlling for assessment period, yielding an odds ratio (OR) and 95% confidence interval (CI) for each predictor. RESULTS: Nineteen variables were found to be significant bivariate predictors of suicide attempts. Eight of these, seven of which were time-varying, remained significant in multivariate analyses: diagnosis of major depressive disorder (MDD), substance use disorder (SUD), post-traumatic stress disorder (PTSD), presence of self-harm, adult sexual assault, having a caretaker who has completed suicide, affective instability, and more severe dissociation. CONCLUSIONS: The results of this study suggest that prediction of suicide attempts among borderline patients is complex, involving co-occurring disorders, co-occurring symptoms of BPD (self-harm, affective reactivity and dissociation), adult adversity, and a family history of completed suicide.

Assessment of the quality of care and financial impact of a virtual renal clinic compared with the traditional outpatient service model.

BACKGROUND: Patients with chronic kidney disease (CKD) have better outcomes when they have access to specialist nephrology services early in the course of their disease. However, up to 30% of patients with advanced kidney disease face late referral. Virtual clinics represent a potentially innovative mechanism for early assessment of high patient volumes efficiently and cost effectively while maintaining high standards of care. METHODS: A retrospective observational cohort study was completed over a 4-year period from April 2004 to March 2008 at a regional nephrology centre within Northern Ireland. All new patient attendances at the nephrology clinic were identified and those managed via the virtual renal clinic approach were included in this study. A cost comparison of this innovative modality was made with the traditional outpatient service model. RESULTS: There were 427 patients (51.3% female, 48.7% male) managed through the virtual renal clinic. Comorbidities included 180 patients (42.1%) with known CKD and 31 patients (7.3%) with newly identified kidney disease. A total of 118 patients (27.6%) had hypertension while 6 (1.4%) and 57 (13.3%) had type I and II diabetes mellitus (DM) respectively. Referral indications included 211 patients (49.4%) with abnormal renal biochemistry, 35 (8.2%) with proteinuria, 12 (2.8%) with haematuria and 87 patients (20.4%) with a combination of issues. A conservative treatment plan consisting of biochemical surveillance was appropriate for 246 patients (57.6%) while medication review was completed for 113 patients (26.5%) and surgical referral was indicated in 20 patients (4.7%). The virtual renal clinic provided a minimum cost saving of £111.56 per patient attendance compared with traditional outpatient care resulting in 23.3% of patient referrals being managed by the virtual clinic approach in 2009. CONCLUSION: Delayed referral to a renal specialist adversely affects patient outcomes. This study suggests that the implementation of a virtual renal clinic for non-complex renal pathologies can offer a cost-effective, rapid referral mechanism for patient assessment combined with readily available specialist advice.

The 10-year course of PTSD in borderline patients and axis II comparison subjects.

OBJECTIVE: The first objective is to detail the prevalence of post-traumatic stress disorder (PTSD) over a decade of follow-up for those in both study groups. The second is to determine time-to-remission, recurrence, and new onset of PTSD, and the third is to assess the relationship between sexual adversity and the likelihood of remission and recurrence of PTSD. METHOD: The SCID I was administered to 290 borderline in-patients and 72 axis II comparison subjects during their index admission and re-administered at five contiguous 2-year follow-up periods. RESULTS: The prevalence of PTSD declined significantly over time for patients with borderline personality (BPD) (61%). Over 85% of borderline patients meeting criteria for PTSD at baseline experienced a remission by the time of the 10-year follow-up. Recurrences (40%) and new onsets (27%) were less common. A childhood history of sexual abuse significantly decreased the likelihood of remission from PTSD, and an adult history of sexual assault significantly increased the likelihood of a recurrence of PTSD. CONCLUSION: Taken together, the results of this study suggest that PTSD is not a chronic disorder for the majority of borderline patients. They also suggest a strong relationship between sexual adversity and the course of PTSD among patients with BPD.

Sex-specific impact of maternal-fetal risk factors on depression and cardiovascular risk 40 years later.

Major depressive disorder (MDD) and cardiovascular disease (CVD) represent leading causes of morbidity and mortality worldwide. We tested the hypothesis that growth restriction and preeclampsia (referred to as fetal risk) are significant predictors of these conditions, with women at higher risk in adulthood. Adult offspring exposed to fetal risk factors and their discordant siblings were from two prenatal cohorts, whose mothers were followed through pregnancy and whom we recruited as adults 40 years later (n = 538; 250 males and 288 females). Subjects were psychiatrically diagnosed and underwent a stress challenge during which parasympathetic regulation was assessed by electrocardiogram, operationalized as high-frequency R-R interval variability (HF-RRV). Linear mixed models and generalized estimating equations were used to examine the relationship of fetal risk on HF-RRV, MDD and comorbidity of low HF-RRV (lowest 25th percentile) and MDD, including interactions with sex and socioeconomic status (SES). Fetal risk was significantly associated with low HF-RRV response (F = 3.64, P = 0.05), particularly among low SES (interaction: F = 4.31, P < 0.04). When stratified by MDD, the fetal risk impact was three times greater among MDD compared with non-MDD subjects (effect size: 0.21 v. 0.06). Females had a significantly higher risk for the comorbidity of MDD and low HF-RRV than males (relative risk (RR) = 1.36, 95% CI: 1.07-1.73), an association only seen among those exposed to fetal risk (RR = 1.38, 95% CI: 1.04-1.83). Findings suggest that these are shared fetal antecedents to the comorbidity of MDD and CVD risk 40 years later, an association stronger in females than in males.

Characteristics and clinical changes during hospitalization in bipolar and psychotic disorder patients with versus without substance-use disorders.

BACKGROUND: Co-morbid substance-use disorders (SUDs) are prevalent among patients with severe psychiatric disorders, but the characteristics of such patients remain incompletely defined, and their current treatments and responses, poorly documented. METHODS: We evaluated the records of 481 consecutive inpatients diagnosed with DSM-IV bipolar or schizoaffective disorders, or schizophrenia, admitted to McLean Hospital in 2004 or 2009. Demographic and clinical characteristics, and treatments, were extracted from hospital and pharmacy records for bivariate and multivariate analyses. RESULTS: SUD prevalence increased 1.84-times from 2004 (31.3%) to 2009 (57.6%). Patients with (n=204) versus without co-morbid SUDs (n=277) were similar in many respects, but in multivariate modeling, the following factors were more likely with SUD, in rank-order: co-morbid anxiety disorders > men more than women > greater prevalence in 2009 vs. 2004 > younger age > greater doses of mood-stabilizers > shorter hospitalization. CONCLUSIONS: Hospitalized patients with severe primary psychiatric disorders, and comorbid SUD were more likely to be young and have anxiety disorders, to receive more combinations and higher doses of mood-stabilizers, and show more improvement in impulsivity and hostility, but otherwise differed little in treatment-responses. Prevalence of SUD rose substantially in the past five years, with increased but largely unproved use of mood-stabilizers.

Early childhood malnutrition predicts depressive symptoms at ages 11-17.

BACKGROUND: We examined the prevalence of depressive symptoms in Barbadian youth with histories of infantile malnutrition and in a healthy comparison group and the extent to which the effect of malnutrition was mediated/moderated by maternal depression. METHODS: Depressive symptoms were assessed using a 20-item scale administered to youths (11-17 years of age) who had experienced an episode of protein-energy malnutrition (marasmus or kwashiorkor) during the first year of life and in a comparison group of healthy youths without a history of malnutrition. Their mothers completed the same questionnaire on the same test on three occasions when their children were 5-17 years of age at 2-5-year intervals. RESULTS: The prevalence of depressive symptoms was elevated among previously malnourished youth relative to healthy comparison children (p < .001). When youth depression scores were subjected to a longitudinal multiple regression analysis, adjusting for the effect of maternal depressive symptoms, significant effects due to the history of early childhood malnutrition remained and were not discernibly attenuated from an unadjusted analysis. We also found significant independent effects of maternal depressive symptoms on youth depressive symptoms. CONCLUSION: Early childhood malnutrition contributed independently to depressive symptoms in youths who experienced a significant episode of malnutrition in the first year of life. This relationship was not mediated or moderated by the effects of maternal depression. Whether the later vulnerability to depression is a direct effect of the episode of malnutrition and related conditions early in life or whether it is mediated by the more proximal neurobehavioral effects of the malnutrition remains to be determined.

The 10-year course of psychosocial functioning among patients with borderline personality disorder and axis II comparison subjects.

OBJECTIVE: The purpose of this study was to determine the 10-year course of the psychosocial functioning of patients with borderline personality disorder (BPD). METHOD: The social and vocational functioning of 290 inpatients meeting both the Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD and 72 axis II comparison subjects were carefully assessed during their index admission. Psychosocial functioning was reassessed using similar methods at five contiguous 2-year time periods. RESULTS: Borderline patients without good psychosocial functioning at baseline reported difficulty attaining it for the first time. Those who had such functioning at baseline reported difficulty retaining and then regaining it. In addition, over 90% of their poor psychosocial functioning was due to poor vocational but not social performance. CONCLUSION: Good psychosocial functioning that involves both social and vocational competence is difficult for borderline patients to achieve and maintain over time. In addition, their vocational functioning is substantially more compromised than their social functioning.

The course of dissociation for patients with borderline personality disorder and axis II comparison subjects: a 10-year follow-up study.

OBJECTIVE: The purpose of this study was to assess the severity of dissociation reported by borderline patients and axis II comparison subjects over 10 years of prospective follow-up. METHOD: The Dissociative Experiences Scale (DES) - a 28-item self-report measure - was administered to 290 borderline in-patients and 72 axis II comparison subjects during their index admission. It was also re-administered at five contiguous 2-year follow-up periods. RESULTS: The overall severity of dissociative experiences of those in both study groups decreased significantly over time but was discernibly greater in borderline patients (61% vs. 43%). The same pattern emerged for the subtypes of dissociation that were studied: absorption, depersonalization and amnesia. CONCLUSION: The severity of dissociation declines significantly over time for even severely ill borderline patients. However, it remains as a recurring problem for over a third of those with DES scores that initially were in the range associated with trauma-spectrum disorders.

The 10-year course of physically self-destructive acts reported by borderline patients and axis II comparison subjects.

OBJECTIVE: The purpose of this paper was to determine the frequency and methods of two forms of physically self-destructive acts (i.e. self-mutilation and suicide attempts) reported by borderline patients and axis II comparison subjects over 10 years of prospective follow-up. METHOD: Two hundred and ninety borderline patients and 72 axis II comparison subjects were interviewed about their physically self-destructive acts during their index admission and at five contiguous 2-year follow-up periods. RESULTS: It was found that a high percentage of borderline patients reported multiple acts and methods of each of these two forms of physically self-destructive behavior prior to their index admission. It was also found that the percentage of borderline patients reporting multiple acts and methods declined significantly over time. However, these acts remained significantly more common among borderline patients than axis II comparison subjects. CONCLUSION: The course of self-mutilation and suicide attempts among borderline patients is initially more serious and ultimately more benign than previously recognized.

Specificity in the familial aggregation of overt and covert conduct disorder symptoms in a referred attention-deficit hyperactivity disorder sample.

BACKGROUND: To examine the familial associations of overt and covert antisocial behavior within the diagnosis of conduct disorder (CD) in families ascertained by referred children with attention-deficit hyperactivity disorder (ADHD), and to test if these familial associations differed between male and female probands. METHOD: Subjects were clinically-referred male and female ADHD children (n = 273) and their first-degree biological relatives (n = 807). Scores for overt and covert conduct problems were calculated by summing the DSM-III-R conduct disorder symptoms, as derived from structured diagnostic interviews. Familial aggregation analyses were conducted with multivariate regression modeling methodology. RESULTS: Proband overt scores significantly predicted the overt scores of their relatives, and proband covert scores significantly predicted the covert scores of their relatives. There was no evidence of covert symptom scores predicting overt scores or vice versa. There was some evidence that the aggregation of covert symptoms was stronger in the families of female probands. CONCLUSIONS: These results provide preliminary evidence that overt and covert conduct disorder symptoms are independently transmitted through families and may represent distinct familial syndromes.

Socio-economic status, family disruption and residential stability in childhood: relation to onset, recurrence and remission of major depression.

BACKGROUND: Childhood adversity significantly increases the risk of depression, but it is unclear whether this risk is most pronounced for depression occurring early in life. In the present study, we examine whether three aspects of childhood adversity--low socio-economic status (SES), family disruption, and residential instability--are related to increased risk of depression during specific stages of the life course. We also examine whether these aspects of childhood adversity are related to the severity of depression. METHOD: A sample of 1089 of the 4140 births enrolled in the Providence, Rhode Island cohort of the National Collaborative Perinatal Project was interviewed between the ages of 18 and 39. Measures of parental SES, childhood family disruption and residential instability were obtained upon mother's enrolment and at age 7. Age at onset of major depressive episode, lifetime number of depressive episodes, and age at last episode were ascertained via structured diagnostic interviews. Survival analysis was used to identify risk factors for depression onset and remission and Poisson regression was used to model the recurrence rate of depressive episodes. RESULTS: Low parental SES, family disruption and a high level of residential instability, defined as three or more family moves, were related to elevated lifetime risks of depression; the effects of family disruption and residential instability were most pronounced on depression onset by age 14. Childhood adversity was also related to increased risk of recurrence and reduced likelihood of remission. CONCLUSIONS: Childhood social disadvantage significantly influences risk of depression onset both in childhood and in adulthood. Early childhood adversity is also related to poor prognosis.

Water and sanitation associated with improved child growth.

OBJECTIVE: To examine the relation between household water and sanitation, and the risk of stunting and reversal of stunting in Khartoum and Crezira regions, Sudan. DESIGN: Prospective cohort study. SETTING: A total of 25 483 children aged 6-72 months from rural Sudan enrolled in an 18-month field trial in 1988 to study the effect of vitamin A supplementation on child health and survival. RESULTS: The mean height-for-age z-scores at baseline and the end of study were -1.66 and -1.55, respectively, for the group with water and sanitation facilities, and -2.03 and -1.94 for the group without water and sanitation, after adjustment for age, region, gender, mother's literacy, intervention group (vitamin A vs placebo), family wealth, breastfeeding and cleanliness. Among children of normal height-for-age at baseline, the risk of stunting (<-2 height-for-age z-score) was lowest in the group that came from homes that had both water and sanitation compared to children from homes without these facilities (multivariate RR=0.79, 95% CI 0.69-0.90). Among children stunted at baseline, those coming from homes with water and sanitation had a 17% greater chance of reversing stunting than those coming from homes without either facility (adjusted RR=1.17, 95% CI 0.99-1.38). We did not detect a synergistic association between access to water and sanitation. CONCLUSIONS: Water and sanitation are independently associated with improved growth of children. SPONSORSHIP: None.

Effects of inhaled glucocorticoids on bone density in premenopausal women.

BACKGROUND: Inhaled glucocorticoids are the most commonly used medications for the long-term treatment of patients with asthma. Whether long-term therapy with inhaled glucocorticoids reduces bone mass, as oral glucocorticoid therapy does, is controversial. In a three-year prospective study, we examined the relation between the dose of inhaled glucocorticoids and the rate of bone loss in premenopausal women with asthma. METHODS: We studied 109 premenopausal women, 18 to 45 years of age, who had asthma and no known conditions that cause bone loss and who were treated with inhaled triamcinolone acetonide (100 microg per puff). We measured bone density by dual-photon absorptiometry at base line, at six months, and at one, two, and three years. Serum osteocalcin and parathyroid hormone and urinary N-telopeptide, cortisol, and calcium excretion were measured serially. We measured inhaled glucocorticoid use by means of monthly diaries, supported by the use of an automated actuator-monitoring device. RESULTS: Inhaled glucocorticoid therapy was associated with a dose-related decline in bone density at both the total hip and the trochanter of 0.00044 g per square centimeter per puff per year of treatment (P= 0.01 and P=0.005, respectively). No dose-related effect was noted at the femoral neck or the spine. Even after the exclusion of all women who received oral or parenteral glucocorticoids at any time during the study, there was still an association between the decline in bone density and the number of puffs per year of use. Serum and urinary markers of bone turnover or adrenal function did not predict the degree of bone loss. CONCLUSIONS: Inhaled glucocorticoids lead to a dose-related loss of bone at the hip in premenopausal women.

Bias in estimating association parameters for longitudinal binary responses with drop-outs.

This paper considers the impact of bias in the estimation of the association parameters for longitudinal binary responses when there are drop-outs. A number of different estimating equation approaches are considered for the case where drop-out cannot be assumed to be a completely random process. In particular, standard generalized estimating equations (GEE), GEE based on conditional residuals, GEE based on multivariate normal estimating equations for the covariance matrix, and second-order estimating equations (GEE2) are examined. These different GEE estimators are compared in terms of finite sample and asymptotic bias under a variety of drop-out processes. Finally, the relationship between bias in the estimation of the association parameters and bias in the estimation of the mean parameters is explored.