Correction: A Prospective Cohort Study of Antipsychotic Medications in Pregnancy: The First 147 Pregnancies and 100 One Year Old Babies.

[This corrects the article DOI: 10.1371/journal.pone.0094788.].

The use of first and second-generation antipsychotic drugs and the potential to develop gestational diabetes mellitus among perinatal patients with psychosis.

There is limited knowledge about the effects of antipsychotic exposure on the development of gestational diabetes mellitus (GDM) in women with mental illness. Studies have demonstrated an association between antipsychotic medications and metabolic problems such as weight gain and diabetes mellitus in non-pregnant patients with psychiatric disorders. GDM increases the risk of adverse maternal outcomes, including pregnancy-induced hypertension, antepartum and postpartum haemorrhage, and caesarean delivery. The National Register of Antipsychotic Medication in Pregnancy (NRAMP) is a prospective Australian cohort study that observed women who took antipsychotics during pregnancy. Data from 205 women were extracted for the final analysis and included women who took first or second-generation antipsychotics (FGA,SGA) during the first trimester of pregnancy (at minimum) and had a diagnosis of a psychotic disorder (n = 180). The comparison (non-exposed) group (n = 25) were women with psychosis who chose not to take any antipsychotic during the first trimester (at minimum). The comparison groups were not matched, although groups were homogenous in terms of sex, age range, diagnosis and perinatal status. The results of logistic regression analysis revealed that women who were exposed to FGAs, SGAs were seven and five times, respectively, more likely to develop GDM compared to non-exposed groups. When adjusted for confounding variables such as BMI and family history of diabetes, the potential of developing GDM decreased for women taking SGAs. In conclusion, the risk of developing GDM is lower in women taking SGAs compared with women taking FDAs. In addition, family history of diabetes and BMI adds to the risk.

Differential Effect of Recurrent Concussions on Symptom Clusters in Sport Concussion Assessment Tool.

CONTEXT: Symptom checklist in Sport Concussion Assessment Tool has been widely used in preseason assessment and in concussion diagnosis, but the impact of prior concussions on the graded symptoms after a new concussion has not been evaluated. OBJECTIVE: This study was undertaken to examine reported symptoms associated with recurrent concussions using data of a comprehensive survey among athletes. DESIGN: Retrospective survey and cross-sectional study. SETTING: College athletes. PARTICIPANTS: Student athletes who sustained one or more concussions. MAIN OUTCOME MEASURES: Concussion history and graded symptoms of the most recent concussion at time of the survey were surveyed. The impact of prior concussions was examined over symptoms and aggregated symptoms. RESULTS: Multiple concussions were associated with greater reporting of individual symptoms related to emotion and physical symptoms of sensitivity to light and noise: more emotional (z = 2.3, P = .02); sadness (z = 2.4, P = .02); nervousness (z = 2.4, P = .02); irritability (z = 3.6, P = .01); sensitivity to light (z = 2.6, P = .01); and sensitivity to noise (z = 2.4, P = .04). The composite scores of emotional symptom and sensitivity symptom clusters were significantly higher: t = 2.68 (P < .01) and t = 3.35 (P < .01), respectively. CONCLUSIONS: The significant rises in emotional and sensitivity symptoms may be an important additive effect of concussive injury. Closer attention should be given to these symptom clusters when evaluating concussion injury and recovery.

Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs.

The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy (N = 17) or best supportive care (N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group (P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were $2,720 per week for the targeted treatment group and $3,453 per week for the control group, (P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment (N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs.

A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression-Free Survival Without Increased Health Care Costs.

PURPOSE: The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported. PATIENTS AND METHODS: We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7). RESULTS: The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group ( P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were $4,665 in the precision treatment group and $5,000 in the control group ( P = .126). CONCLUSION: These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.

Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial.

IMPORTANCE: A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects. OBJECTIVE: To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis. INTERVENTIONS: Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed. RESULTS: Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (ß = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (ß = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (ß for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups. CONCLUSIONS AND RELEVANCE: Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00361543.

Seguridad de los antipsicóticos atípicos en el embarazo / Safety of atypical antipsychotic drugs during pregnancy

Introducción. Desde la introducción de los antipsicóticos de segunda generación (ASG), su prescripción ha incrementado notablemente en mujeres con enfermedad mental, y cada vez son más las mujeres embarazadas expuestas. Sin embargo, la información disponible con respecto a la seguridad de estos fármacos en gestantes es todavía limitada. Objetivos. Aclarar el impacto de los ASG durante el embarazo a partir de la literatura disponible para ofrecer una herramienta clínica de apoyo. Metodología. Se ha llevado a cabo una revisión exhaustiva de la literatura disponible. Siguiendo los criterios PRISMA para la búsqueda, se ha identificado literatura publicada desde mayo de 1995 hasta octubre de 2015 en: PUBMED (Medline), SCOPUS, LILACS y MEDES. Resultados. La búsqueda arrojó un total de 192 estudios tras descartarse duplicados, y 47 artículos fueron incluidos en la revisión de acuerdo con los criterios de inclusión establecidos. Conclusiones. Aunque se necesitan más estudios, no parece existir un daño consistente congénito en el feto con el uso de ASG. Según la literatura disponible, la exposición intrauterina a ASG se ha asociado con algunas complicaciones neonatales y obstétricas. Hay alguna evidencia que relaciona olanzapina y clozapina con un mayor riesgo de diabetes gestacional y macrosomía en el neonato, pero es evidente que el tratamiento de la enfermedad mental durante el embarazo es vital y promueve mejores resultados para la madre y el infante. Actualmente, olanzapina y quetiapina son los ASG más frecuentemente usados durante el embarazo y, a pesar de algunos riesgos observados, parecen seguros en general (AU)

Introduction. Since the introduction of second generation antipsychotics (SGAs), prescribing has increased considerably in women with a range of mental illnesses, and now increasingly used by women during pregnancy. However, information regarding the safety of SGAs during pregnancy is limited. Objectives. To clarify the impact of SGAs during pregnancy from the available literature, and to provide a clinical support tool. Methodology. An exhaustive review of the available literature was conducted. Following the PRISMA criteria, literature published from May 1995 to October 2015 was identified from PubMed (Medline), SCOPUS, LILACS and MEDES databases. Results. The search yielded a total of 192 studies after duplicates were excluded, and 47 articles were included in the review in accordance with the inclusion criteria. Conclusions. While more research is needed, SGAs do not appear to cause marked congenital foetal harm. According to the available literature, in utero exposure to SGAs is associated with some neonatal and obstetric complications. While olanzapine, and clozapine in particular, is associated with increased risk of gestational diabetes and large for gestational age newborns, from this review of the literature it is clear that treating mental illness during pregnancy is vital and promotes better outcomes for both mother and infant. Currently olanzapine and quetiapine are the most frequently used SGAs during pregnancy, and despite some risks observed, overall safety is reported (AU)

Antipsychotic use in pregnancy.

INTRODUCTION: Antipsychotic medications are being prescribed for a growing number of women with mental illnesses. However, evidence regarding their safety in pregnancy is still insufficient to provide adequate support for clinical practice, creating increasing concern among pregnant women and clinicians. AREAS COVERED: The aim of this article is to review published data regarding the safety of antipsychotic medications in pregnancy with a focus on the most commonly used atypical antipsychotics. EXPERT OPINION: Given the potential harm of not treating severe psychiatric illnesses during pregnancy, careful administration of antipsychotics is recommended for pregnant women who suffer from severe mental disorders. The most frequently used antipsychotics in pregnancy are olanzapine, risperidone and quetiapine, and do not appear to cause consistent, congenital harm to the fetus. No specific patterns of fetal limb or organ malformation related to these drugs have been reported. There is some evidence suggesting an association between antipsychotic use in pregnancy and the development of gestational diabetes. Also there appears to be an association between antipsychotic medication use in pregnancy and increased neonatal respiratory distress and withdrawal symptoms. Further studies are needed for clinicians to balance good maternal mental health, healthy pregnancies and good infant health outcomes.

The neural substrate for binaural masking level differences in the auditory cortex.

The binaural masking level difference (BMLD) is a phenomenon whereby a signal that is identical at each ear (S0), masked by a noise that is identical at each ear (N0), can be made 12-15 dB more detectable by inverting the waveform of either the tone or noise at one ear (Sπ, Nπ). Single-cell responses to BMLD stimuli were measured in the primary auditory cortex of urethane-anesthetized guinea pigs. Firing rate was measured as a function of signal level of a 500 Hz pure tone masked by low-passed white noise. Responses were similar to those reported in the inferior colliculus. At low signal levels, the response was dominated by the masker. At higher signal levels, firing rate either increased or decreased. Detection thresholds for each neuron were determined using signal detection theory. Few neurons yielded measurable detection thresholds for all stimulus conditions, with a wide range in thresholds. However, across the entire population, the lowest thresholds were consistent with human psychophysical BMLDs. As in the inferior colliculus, the shape of the firing-rate versus signal-level functions depended on the neurons' selectivity for interaural time difference. Our results suggest that, in cortex, BMLD signals are detected from increases or decreases in the firing rate, consistent with predictions of cross-correlation models of binaural processing and that the psychophysical detection threshold is based on the lowest neural thresholds across the population.

A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies.

BACKGROUND: Many women diagnosed with varying psychiatric disorders take antipsychotic medications during pregnancy. The safety of antipsychotic medications in pregnancy is largely unknown. METHODS: We established the National Register of Antipsychotic Medications in Pregnancy in 2005. Women who are pregnant and taking an antipsychotic medication are interviewed every 6 weeks during pregnancy and then followed until their babies are one year old. The baby's progress is closely followed for the first year of life. FINDINGS: As of April 18 2012, 147 pregnancies had been followed through to completion. There were 142 live births and data is available for 100 one year old babies. 18% of babies were born preterm, with a higher dose of antipsychotic medication correlating to an increased likelihood of premature delivery; 43% of babies required special care nursery or intensive care after birth; 37% had any degree of respiratory distress and 15% of babies developed withdrawal symptoms. Congenital anomalies were seen in eight babies. Most pregnancies resulted in the birth of live, healthy babies. The use of mood stabilisers or higher doses of antipsychotics during pregnancy increased the likelihood of babies experiencing respiratory distress or admission to Special Care Nursery or Neonatal Intensive Care Units. CONCLUSION: There is a great need for safety and efficacy information about the use of antipsychotic medications in pregnancy. Live, healthy babies are the most common outcome following the use of antipsychotic medication in pregnancy, but clinicians should be particularly mindful of neonatal problems such as respiratory distress.

Diffuse large B cell lymphoma in hyper-IgE syndrome due to STAT3 mutation.

The Job or hyper-immunoglobulinemia E syndrome is a primary immunodeficiency that is usually inherited in an autosomal dominant fashion. With the discovery of mutations in the STAT3 gene in the majority of autosomal dominant cases, it is now possible to make a molecular diagnosis of hyper-IgE syndrome. Both primary and secondary immunodeficiencies, including hyper-IgE syndrome, may predispose for malignancies, especially lymphomas, mainly mature B cell lymphomas, and classical Hodgkin lymphoma. Here, we report of a 48-year-old male with hyper-IgE syndrome who developed a primary parotid gland diffuse large B cell lymphoma. Analysis for STAT3 mutations demonstrated that the causal mutation of hyper-IgE syndrome, R382Q, arose de novo in the patient and it was transmitted to three of his five children, all three of whom are clinically affected. We review the literature regarding lymphoma in hyper-IgE syndrome and the possible etiologic relationship with STAT3 mutations.

Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia.

Estrogen treatment may enhance the recovery of schizophrenia in women. However, adverse effects on uterine and breast tissue and other physical side effects may limit the long-term therapeutic use of estrogen. Raloxifene hydrochloride is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects. To provide an indication of the potential therapeutic dose for raloxifene hydrochloride in postmenopausal women with schizophrenia, this study pools data from an ongoing randomized controlled trial of adjunctive 120 mg/day oral raloxifene hydrochloride (n=13) versus oral placebo (n=13), with data from a previous pilot study administering 60 mg/day raloxifene hydrochloride (n=9). Analysis of variance found significant interaction effects for total (p=.01) and general (p=.02) Positive and Negative Syndrome Scale (PANSS) symptomatology. Participants randomized to receive 120 mg/day raloxifene hydrochloride experienced a significantly more rapid recovery of total and general psychotic symptoms compared to both 60 mg/day raloxifene hydrochloride and placebo. The demonstrated benefit of adjunctive treatment with 120 mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia.

Clinical characteristics and prognostic analysis of Chinese patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in adults. As it is a highly heterogenous disease, many studies have focused on finding useful prognostic factors to help guide therapy. In this report, we examine several biological markers in 83 patients with DLBCL enrolled in our hospital, including cell origin, serum lactate dehydrogenase (LDH) levels, and international prognostic index (IPI), in order to find the best combination of prognostic factors. We also examined whether DLBCL has a significant geographic difference, since several studies have suggested that the prevalence and potential etiological factors of lymphomas in China may be different from those in other countries. Our results demonstrate that: (1) patients in China have higher extranodal tissue involvement and different extranodal organ distribution than patients reported from other countries; (2) Chinese patients have higher rates of germinal center (GC) cell origin; and (3) among nine prognostic variables, lower IPI scores, GC cell origin determined by immunohistochemical staining, and no more than 1.5 times of normal levels of LDH are statistically significant good prognostic factors in Chinese patients with DLBCL, whereas age at the time of diagnosis, clinical stage, beta(2)-microglobulin levels, extranodal tissue involvement, and expression levels of Bcl-6 protein were not useful in determining prognosis.

Preliminary findings from the National Register of Antipsychotic Medication in Pregnancy.

OBJECTIVE: Following the presentation of a case study and an overview of current data highlighting the need for further research into the use of antipsychotic medication during pregnancy, the aim of the present paper was to outline the establishment of, and present preliminary data from, the National Register of Antipsychotic Medication in Pregnancy (NRAMP). METHOD: Australian women with a history of psychosis, including schizophrenia, bipolar affective disorder with psychosis, schizoaffective disorder and first-episode psychosis, who are pregnant, are currently being invited to participate. The confluence of speculated national pregnancy rates and epidemiological data regarding child-bearing-age women with psychosis suggested an enrollment target of 100 women over a 24 month period. Details of antipsychotic medication are recorded throughout the pregnancy and for 1 year postnatally. Interviews with the mother are conducted 6 weekly antenatally, and then at 6 and 12 weeks, and 6 and 12 months postnatally, to assess symptoms of psychosis and depression, and attitudes towards parenting. In addition, consultations are conducted with the women's health-care providers to collate information regarding pharmacology and related side-effects, obstetric outcomes, psychiatric diagnoses and symptoms during pregnancy and for 1 year after delivery, and the provision of details on the baby's health and well-being. RESULTS: NRAMP was launched in 2005. Ethics approvals have been gained at 14 sites nationally. Thirty women have consented, and 11 have completed. Data including demographics, health-care provision and medication for the first 30 participants are presented. CONCLUSIONS: The establishment of NRAMP is an important strategy in improving the management of serious mental illness such as schizophrenia and related disorders, in women who are pregnant. This project involves extensive collaboration between many different clinical groups and industry, and shall culminate in an important resource to improve the quality of life for both patients and future generations.

Hormone modulation: a novel therapeutic approach for women with severe mental illness.

OBJECTIVES: Accumulating evidence describes the effects of oestrogen and other gonadal hormones on the central nervous system and, in particular, on the mental state of women. Evidence supporting the psychotherapeutic effects of exogenous oestrogen has started to emerge only over the past two decades. The purpose of the present paper was to provide an overview of different applications of adjunctive hormones, as treatments for symptoms of severe mental illness in women. METHODS: Three case reports are presented: in each case the woman selected had participated in large, double-blind, randomized controlled trials exploring hormone modulation. Case study 1 presents a premenopausal woman with schizophrenia, who received an 8 week trial of daily adjunctive 200 microg transdermal oestradiol. Case study 2 presents a postmenopausal woman with schizophrenia on a 12 week trial of adjunctive raloxifene hydrochloride 120 mg per day. Case study 3 presents a woman with schizoaffective disorder, in the manic phase, who received tamoxifen 40 mg per day for 28 days. RESULTS: Adjunctive oestradiol was associated with an improvement in symptoms of psychosis in a premenopausal woman with schizophrenia; adjunctive raloxifene was associated with an improvement in cognitive functioning in a postmenopausal woman with schizophrenia; and adjunctive tamoxifen was associated with an improvement in symptoms of mania in a woman with schizoaffective disorder. CONCLUSIONS: These findings are consistent with preliminary research trials suggesting that adjunctive hormone modulation is a promising area of gender-specific treatment for serious mental illness.