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Having a common framework for early action to cope with complex disasters can make it easier for authorities and other stakeholders, including populations at risk, to understand the full spectrum of secondary and tertiary effects and thus where to focus preparedness efforts, and how best to provide more targeted warnings and response services. Meteorological and hydrological services world-wide have developed and implemented Multi-Hazard Early Warning Systems (MHEWS) for weather and climate related hazards that are now being expanded and transitioned towards Multi-Hazard Impact-based Early Warning Systems (MHIEWS). While it is still early days it is becoming clear that there are useful lessons from this approach in the COVID-19 global pandemic, and some valuable insight to be gained in risk communication, risk analysis and monitoring methodologies and approaches. The ability to understand and respond effectively to warnings through appropriate behaviours and actions is central to resilient societies and communities. By avoiding physical, societal and economic harm to the greatest extent possible, recovery from a hazard is likely to be faster, less costly and more complete. MHIEWS can be a common approach for all hazards and therefore more likely to become a trusted tool that everyone can understand and use as a basic element of their national disaster risk management system. The interconnectedness of hazards and their impacts is a strong motivator for a common approach. One of the lessons from the COVID-19 pandemic and extreme weather events is the need to understand the vulnerability of individuals, communities and societies so as to provide reliable, targeted guidance and warnings and the willingness and capacity to prepare for a reasonable worst-case scenario based on informed long-term planning. Meteorology and hydrology are making good progress in this direction and the process can be readily applied to health and other sectors. [ABSTRACT FROM AUTHOR]

Background: Recommendations for vitamin D supplementation for preterm infants span a wide range of doses. Response to vitamin D supplementation and impact on outcomes in preterm infants is not well understood. Objective: Evaluate serum 25(OH)D3 concentration changes after 4 weeks in response to two different doses of vitamin D3 supplementation in a population of premature infants and quantify the impact on NICU outcomes. Design: 32 infants born at 24–32 weeks gestation were prospectively randomized to receive 400 or 800 IU/day vitamin D3 supplementation. Serum 25(OH)D3 levels were measured every 4 weeks. The Wilcoxon signed rank test was used to compare serum levels of 25(OH)D3 at 4 weeks and each subsequent time point. A p-value of <0.05 was considered statistically significant. Results: Serum 25(OH)D3 levels at birth were 41.9 and 42.9 nmol/l for infants in the 400 IU group and 800 IU group, respectively (p = 0.86). Cord 25(OH)D3 concentrations significantly correlated with gestational age (r = 0.40, p = 0.04). After 4 weeks of D3 supplementation, median 25(OH)D3 levels increased in both groups (84.6vs. 105.3 nmol/l for 400 vs. 800 IU/day respectively, with significantly more improvement in the higher dose (p = 0.048). Infants in the 400 IU group were significantly more likely to have dual energy x-ray absorptiometry (DEXA) bone density measurements <10 percentile (56% vs 16%, p = 0.04). Conclusions: Improvement in 25(OH)D3 levels at 4 weeks, bone density, and trends towards improvement in linear growth support consideration of a daily dose of 800 IU of vitamin D for infants <32 weeks cared for in the NICU. [ABSTRACT FROM AUTHOR]

Background: Coagulase-negative staphylococci (CoNS) are the most common cause of late-onset sepsis in neonatal intensive care unit settings. Historically, authors have questioned the clinical significance of these bacteremia episodes. Recently, clusters of CoNS bacteremia associated with significant morbidity have been reported. The frequency and importance of these clusters of bacteremia and their associated morbidity remains unclear. Objective: We studied a prolonged cluster of 52 cases of persistent CoNS bacteremia in a level III neonatal intensive care unit to clarify risk factors, morbidity and outcomes associated with persistent CoNS bacteremia. Study Design: A retrospective case-control study of infants with CoNS bacteremia >48 h after initiation of appropriate antibiotics and gestational age-matched control infants was performed. We reviewed patient characteristics prior to and during bacteremia, and outcomes at discharge or death. Results: Persistently infected infants were significantly more likely to have greater duration of exposure to parenteral nutrition, hydrocortisone, antibiotics, and mechanical ventilation prior to infection. Persistently infected infants were significantly more likely than controls to experience feeding intolerance and to require inotropic support, increased respiratory support, and blood product transfusion during bacteremia. Infants with persistent CoNS bacteremia took longer to achieve full enteral feeds, had higher rates of chronic lung disease and increased length of stay compared to controls. No significant difference in mortality was noted. Conclusions: Persistent CoNS bacteremia is associated with clinically significant morbidity including feeding intolerance, respiratory failure, blood transfusion and chronic lung disease in this patient population. This impacts hospital course, increases length of stay and impacts medical needs after discharge. During this study, CoNS bacteremia was difficult to clinically eradicate despite in vitro antibiotic susceptibility. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant depression presents a serious challenge to both patients and clinicians. The anterior and midlateral prefrontal cortices play complementary roles in integrating emotional and cognitive experiences and in modulating subcortical regions. Both regions offer a distinct opportunity for targeted antidepressant treatments. We chose to pilot the safety and therapeutic benefits of chronic and intermittent epidural prefrontal cortical stimulation (EpCS) in patients with treatment-resistant depression. Methods: We enrolled five adults with an average of 5.8 failed antidepressant treatments in their current depressive episode. All subjects underwent comprehensive clinical assessments, detailed neuropsychological testing, and presurgical magnetic resonance imaging. Four cortical stimulation paddle leads were stereotactically placed bilaterally over the anterior frontal poles and midlateral prefrontal cortex. We also acquired a postsurgical computed tomography scan and repeatedly assessed clinical outcomes over time of EpCS as an adjunctive treatment to constant medications. Results: All patients tolerated the therapy. At 7-month follow-up, the average improvement from preimplant baseline on the Hamilton Rating Scale for Depression and the Inventory of Depressive Symptoms—Self-Report were 54.9% (± 37.7) and 60.1% (± 34.1), respectively. Three implanted subjects reached remission. One patient''s left hemisphere leads were explanted 12 weeks postsurgery because of a scalp infection. Conclusions: Bilateral EpCS over anterior and midlateral frontal cortex is a promising new technology for treatment-resistant depression. Future double-blind studies are warranted. [Copyright &y& Elsevier]

Vagus Nerve Stimulation (VNS) is approved by the FDA for treatment of both epilepsy and depression. Recent work has shown that VNS acutely affects pain perception in humans, actually increasing pain sensitivity momentarily while the device is firing. It is unclear how this acutely increased sensitivity might change over time with treatment and how it might relate to longer-term therapeutic effects of VNS on pain. We describe a patient with treatment-resistant depression and a history of severe lumbar degenerative disease with resultant chronic low back pain. His depression and pain symptoms both seemed to respond to VNS. He eventually stopped all medications and remained depression and pain free for 35 months with no change in his device settings. Sixty-six months after VNS implantation and 64 months after his initial clinical antidepressant response, under single-blind conditions, we performed quantitative sensory testing with laboratory thermal pain procedures during acute VNS-on and -off conditions. Interestingly, despite a significant and profound anti-nociceptive clinical response for the previous 35 months, he had significant increases in painfulness ratings while the VNS device was actively firing compared with device-off conditions. This case suggests that VNS-induced acute increases in pain sensitivity can coexist with a clinical anti-nociceptive response. If the acutely increased sensitivity sets the stage for the slower chronic anti-pain effects, the increased acute sensitivity does not disappear. Acute and chronic effects of VNS on pain perception merit further research. [ABSTRACT FROM AUTHOR]

The Sydney 2000 (S2000) Forecast Demonstration Project (FDP) was initiated by the World Meteorological Organization (WMO) World Weather Research Programme (WWRP) to enable the world meteorological community to cooperatively demonstrate advanced technologies and methods for accurate and specific short-term weather forecasting (nowcasting). FDP output was developed in support of the Sydney 2000 Olympics and trialed throughout and beyond the Olympic period. As is the case with all WWRP projects, the WWRP S2000 FDP included an assessment of the social, societal, and economic impacts of the project's forecasts. The Impacts Study considered how Bureau of Meteorology (BoM) forecasters employed the enhanced FDP information to produce more “useful” nowcasts, and how selected end users accessed, utilized, and acted upon these enhanced forecasts. End users included the Sydney Organizing Committee for the Olympic Games (SOCOG) and a small selection of other BoM clients. With few storms or severe weather events during the 2.5-month trial period the opportunity to fully evaluate the impact of the FDP technologies was limited. Nevertheless, positive social, societal, and economic impacts were clearly indicated and additional potential benefits were identified by users. This paper details the WWRP S2000 FDP environment, discusses the processes and outcomes of the WWRP FDP Impacts Study, and outlines the benefits and implications of this type of research to both the producers and users of weather forecast products. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest higher rates of caesarean section among women who identify as racial/ethnic minorities. The objective of this study was to understand factors contributing to differences in caesarean rates across racial and ethnic groups.Methods: Data was collected from 2005 to 2014 Nebraska birth records on nulliparous, singleton births occurring on or after 37 weeks gestation (n = 87,908). Risk ratios (RR) and 95% confidence intervals (CI) for caesarean were calculated for different racial and ethnic categories, adjusting for maternal age, marital status, county of residence, education, insurance status, pre-pregnancy BMI, and smoking status. Fairlie decomposition technique was utilized to quantify the contribution of individual variables to the observed differences in caesarean.Results: In the adjusted analysis, relative to non-Hispanic (NH) White race, both Asian-NH (RR 1.21, 95% CI 1.14, 1.28) and Black-NH races (RR 1.13, 95% CI 1.08, 1.19) were associated with a significantly higher risk for caesarean. The decomposition analysis showed that among the variables assessed, maternal age, education, and pre-pregnancy BMI contributed the most to the observed differences in caesarean rates across racial/ethnic groups.Conclusion: This analysis quantified the effect of social and demographic factors on racial differences in caesarean delivery, which may guide public health interventions aimed towards reducing racial disparities in caesarean rates. Interventions targeted towards modifying maternal characteristics, such as reducing pre-pregnancy BMI or increasing maternal education, may narrow the gap in caesarean rates across racial and ethnic groups. Future studies should determine the contribution of physician characteristics, hospital characteristics, and structural determinants of health towards racial disparities in caesarean rates. [ABSTRACT FROM AUTHOR]

Objective: The gastrointestinal microbiome in preterm infants exhibits significant influence on optimal outcomes–with dysbiosis shown to substantially increase the risk of the life-threatening necrotizing enterocolitis. Iron is a vital nutrient especially during the perinatal window of rapid hemoglobin production, tissue growth, and foundational neurodevelopment. However, excess colonic iron exhibits potent oxidation capacity and alters the gut microbiome–potentially facilitating the proliferation of pathological bacterial strains. Breastfed preterm infants routinely receive iron supplementation starting 14 days after delivery and are highly vulnerable to morbidities associated with gastrointestinal dysbiosis. Therefore, we set out to determine if routine iron supplementation alters the preterm gut microbiome. Methods: After IRB approval, we collected stool specimens from 14 infants born <34 weeks gestation in the first, second, and fourth week of life to assess gut microbiome composition via 16S rRNA sequencing. Results: We observed no significant differences in either phyla or key genera relative abundance between pre- and post-iron timepoints. We observed notable shifts in infant microbiome composition based on season of delivery. Conclusion: Though no obvious indication of iron-induced dysbiosis was observed in this unique study in the setting of prematurity, further investigation in a larger sample is warranted to fully understand iron's impact on the gastrointestinal milieu. [ABSTRACT FROM AUTHOR]

Background: The role of oxidative stress remains unclear in the multifactorial pathophysiologic mechanism of lung disease in preterm infants. Aims: The aim of this study was to examine the associations among chronic lung disease (CLD), oxidative stress, and oxygen requirements in preterm infants. Design: Prospective, longitudinal, and correlational design. Subjects: Preterm infants born at <32 weeks’ gestation (N = 31), median gestation of 29.0 weeks (range 24.9–31.7). Measurements: The diagnosis of CLD was obtained from the medical record. Oxidative stress was measured using 8-hydroxydeoxyguanosine (8-OHdG) in the cord blood at birth and urine on Days 1 and 7. Oxygen requirements were measured using fraction of inspired oxygen (FIO2) recorded in the first hour after birth/admission and the average FIO2 during the first 12 hr and 7 days after birth. Descriptive statistics are presented. Comparison analyses were performed using Kruskal–Wallis and Fisher’s exact tests. Results: Infants with CLD (n = 12) had lower gestational age (p = .04) and weight (p = .04) at birth, more days on the ventilator (p = .004), and longer neonatal intensive care unit stay (p = .04) compared to infants without CLD (n = 19). CLD was associated with lower oxidative stress levels (p = .03) and higher oxygen requirements during the first 12 hr (p = .025) and on Day 7 (p = .001). Lower oxidative stress levels on Day 7 were associated with higher oxygen requirements in the first 12 hr (p = .01) and on Day 7 (p = .03). Conclusion: Our results linking CLD and higher oxygen requirements with low oxidative stress contradict previous reports. Findings identify a gap in knowledge for postresuscitation oxygen therapy in preterm infants and expose the role of oxidative stress from inflammation and intermittent hypoxia in the etiology of CLD. [ABSTRACT FROM AUTHOR]

Abstract: Transcranial magnetic stimulation (TMS) of the prefrontal cortex can cause changes in acute pain perception. Several weeks of daily left prefrontal TMS has been shown to treat depression. We recruited 20 patients with fibromyalgia, defined by American College of Rheumatology criteria, and randomized them to receive 4000 pulses at 10Hz TMS (n =10), or sham TMS (n =10) treatment for 10 sessions over 2weeks along with their standard medications, which were fixed and stable for at least 4weeks before starting sessions. Subjects recorded daily pain, mood, and activity. Blinded raters assessed pain, mood, functional status, and tender points weekly with the Brief Pain Inventory, Hamilton Depression Rating Scale, and Fibromyalgia Impact Questionnaire. No statistically significant differences between groups were observed. Patients who received active TMS had a mean 29% (statistically significant) reduction in pain symptoms in comparison to their baseline pain. Sham TMS participants had a 4% nonsignificant change in daily pain from their baseline pain. At 2weeks after treatment, there was a significant improvement in depression symptoms in the active group compared to baseline. Pain reduction preceded antidepressant effects. TMS was well tolerated, with few side effects. Further studies that address study limitations are needed to determine whether daily prefrontal TMS may be an effective, durable, and clinically useful treatment for fibromyalgia symptoms. [Copyright &y& Elsevier]

Introduction: Obesity during pregnancy increases the risk for maternal complications like gestational diabetes, preeclampsia, and maternal inflammation. Maternal obesity also increases the risk of childhood obesity, intrauterine growth restriction (IUGR) and diabetes to the offspring. Increased circulating free fatty acids (FFAs) in obesity due to adipose tissue lipolysis induces lipoapoptosis to hepatocytes, cholangiocytes, and pancreatic-β-cells. During the third trimester of human pregnancy, there is an increase in maternal lipolysis and release of FFAs into the circulation. It is currently unknown if increased FFAs during gestation as a result of maternal obesity cause placental cell lipoapoptosis. Increased exposure of FFAs during maternal obesity has been shown to result in placental lipotoxicity. The objective of the present study is to determine saturated FFA-induced trophoblast lipoapoptosis and also to test the protective role of monounsaturated fatty acids against FFA-induced trophoblast lipoapoptosis using in vitro cell culture model. Here, we hypothesize that saturated FFAs induce placental trophoblast lipoapoptosis, which was prevented by monounsaturated fatty acids. Methods: Biochemical and structural markers of apoptosis by characteristic nuclear morphological changes with DAPI staining, and caspase 3/7 activity was assessed. Cleaved PARP and cleaved caspase 3 were examined by western blot analysis. Results: Treatment of trophoblast cell lines, JEG-3 and JAR cells with palmitate (PA) or stearate (SA) induces trophoblast lipoapoptosis as evidenced by a significant increase in apoptotic nuclear morphological changes and caspase 3/7 activity. We observed that saturated FFAs caused a concentration-dependent increase in placental trophoblast lipoapoptosis. We also observed that monounsaturated fatty acids like palmitoleate and oleate mitigates placental trophoblast lipoapoptosis caused due to PA exposure. Conclusion: We show that saturated FFAs induce trophoblast lipoapoptosis. Co-treatment of monounsaturated fatty acids like palmitoleate and oleate protects against FFA-induced trophoblast lipoapoptosis. [ABSTRACT FROM AUTHOR]

Numerous studies have examined the acute antidepressant effects of prefrontal transcranial magnetic stimulation (TMS). However, there is little information on whether TMS can be used as a maintenance treatment to maintain normal mood once subjects have responded. We describe seven adults with bipolar depression who responded acutely to TMS and were then treated with TMS weekly for up to 1 year. TMS was carried out over the left prefrontal cortex at 110% motor threshold, 5 Hz for 8 s for 40 trains. Three subjects completed 1 full year of weekly TMS with an average Hamilton Rating Scale for Depression of 13 (sd=5.9) over the year. These data suggest but do not prove that TMS might eventually be used as an adjunctive maintenance treatment for at least some patients with bipolar depression. Much work remains. Depression and Anxiety 00:000–000, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Key Clinical Message: First‐line therapy for congenital chylothorax is conservative treatment. However, surgical intervention or chemical pleurodesis is required for refractory cases. With all the concerns regarding its complications, povidone–iodin provided a successful management for a high‐output congenital chylothorax. However, renal and thyroid function must be monitored during treatment. [ABSTRACT FROM AUTHOR]

The objective of the present study was to evaluate intakes and serum levels of vitamin A, vitamin E, and related compounds in a cohort of maternal-infant pairs in the Midwestern USA in relation to measures of health disparities. Concentrations of carotenoids and tocopherols in maternal serum were measured using HPLC and measures of socio-economic status, including food security and food desert residence, were obtained in 180 mothers upon admission to a Midwestern Academic Medical Center labour and delivery unit. The Kruskal-Wallis and independent-samples t tests were used to compare measures between groups; logistic regression models were used to adjust for relevant confounders. P < 0·05 was considered statistically significant. The odds of vitamin A insufficiency/deficiency were 2·17 times higher for non-whites when compared with whites (95% CI 1·16, 4·05; P = 0·01) after adjustment for relevant confounders. Similarly, the odds of being vitamin E deficient were 3·52 times higher for non-whites (95% CI 1·51, 8·10; P = 0·003). Those with public health insurance had lower serum lutein concentrations compared with those with private health insurance (P = 0·05), and living in a food desert was associated with lower serum concentrations of β-carotene (P = 0·02), after adjustment for confounders. Subjects with low/marginal food security had higher serum levels of lutein and β-cryptoxanthin compared with those with high food security (P = 0·004 and 0·02 for lutein and β-cryptoxanthin). Diet quality may be a public health concern in economically disadvantaged populations of industrialised societies leading to nutritional disadvantages as well. [ABSTRACT FROM AUTHOR]

Background: Vitamin A is an essential nutrient for pregnant women, and other vitamin A-related compounds, including lutein and lycopene, have been associated with maternalinfant outcomes. The objective of this study was to quantify the status of vitamin A and related compounds in maternalinfant pairs at the time of delivery, and to determine its impact on clinical outcomes. Methods: Maternal and cord blood samples were collected in 189 mother-infant pairs. Concentrations of lutein + zeaxanthin, β-cryptoxanthin, lycopene, carotenes, and retinol were measured using highperformance liquid chromatography. Descriptive statistics was calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements. Kruskal-Wallis and independent samples t test were used to compare measures between retinol groups. Linear and logistic regression models were used to adjust for relevant confounders. p < 0.05 was considered statistically significant. Results: Ten percent of mothers had serum retinol concentrations ≤ 0.70 μmol/L; 80% of infants had serum retinol concentrations ≤ 0.70 μmol/L. Low maternal retinol con- centrations were associated with maternal anemia ( p = 0.04) and a trend toward low birth weight ( p = 0.06). Maternal and infant concentrations of vitamin A compounds were highly correlated. After adjustment for confounders, maternal lutein was associated with a C-section ( p = 0.03) and a diagnosis of respiratory distress syndrome in the infant ( p = 0.02). Maternal lycopene was associated with growth parameters in the infant. Conclusions: As vitamin A-related compounds are modifiable by diet, future research determining the clinical impact of these compounds is warranted. [ABSTRACT FROM AUTHOR]

Abstract: Background: Evidence suggests that adequate vitamin D status in infancy plays a role in improving bone health and preventing disease, including type 1 diabetes, infections, and asthma. The objective of this study was to provide newborn hospitalized infants with American Academy of Pediatrics recommendations of 400 IU/day vitamin D-3 and measure the effect on serum 25(OH)D levels. Design: This trial was conducted August 2009 to June 2010. Infants were randomized to a control were measured from cord blood, every 7 days, and at discharge. Intact parathyroid hormone was measured at discharge. Participants/setting: Fifty-two infants <32 weeks gestational age who received formula feedings during their neonatal intensive care unit hospitalization. Statistical analysis: Patient characteristics for each treatment group were summarized using descriptive statistics. The Mann-Whitney test was used to compare continuous variables, and categorical variables were compared using the χ2 test or Fisher''s exact test. The Pearson correlation coefficient was used to look at associations between continuous variables. Results: The mean cord blood level for all participants was 17.6±7.0 ng/mL. White infants had significantly higher 25(OH)D levels than non-white infants (P=0.0003). The mean 25(OH)D level at discharge of the supplemented group was 23.1±7.0 ng/mL (57.66±17.47 nmol/L), the mean 25(OH)D level of the unsupplemented group was 17.8±4.7 ng/mL (44.43±11.3 nmol/L), (P=0.007). Serum 25(OH)D showed a positive correlation with serum calcium in the first week of life (r=0.44, P=0.003) and negative correlation with parathyroid hormone levels at discharge (r=−0.35, P=0.02). Conclusions: In newborn hospitalized infants, vitamin D-3 supplementation of 400 IU/day increased mean 25(OH)D levels from 17 ng/mL at birth to 23.1 ng/mL at discharge. Lower 25(OH)D levels were correlated with hypocalcemia during the first week of life, and elevated parathyroid hormone levels at discharge. [Copyright &y& Elsevier]

Combined transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) can be used to study anticonvulsant drugs. A previous study showed that lamotrigine (LTG) inhibited brain activation induced when TMS was applied over motor cortex, whereas it increased activation induced by TMS applied over prefrontal cortex. The present double-blind, placebo-controlled, crossover study in 30 healthy subjects again combined TMS and fMRI to test whether the effects seen previously with LTG would be confirmed and to compare these with a second anticonvulsant drug, valproic acid (VPA). Statistical parametric mapping analysis showed that both LTG and VPA, compared to placebo, inhibited TMS-induced activation of the motor cortex. In contrast, when TMS was applied over prefrontal cortex, LTG increased the activation of limbic regions, confirming previous results; VPA had no effect. We conclude that LTG and VPA have similar inhibitory effects on motor circuits, but differing effects on the prefrontal corticolimbic system. The study demonstrates that a combination of TMS and fMRI techniques may be useful in the study of the effects of neuroactive drugs on specific brain circuits. [ABSTRACT FROM AUTHOR]

To investigate different cortical effects of lamotrigine and valproic acid, 30 paid healthy adult men were given, in a randomized/blinded fashion on three separate days (separated by a week), either a single dose of lamotrigine 325 mg, or a single dose of valproic acid 1,250 mg, or placebo. Resting motor threshold (RMT), cortical silent period (CSP) and motor evoked potential recruitment curves (RC) were assessed at baseline and 3 h after administration of each medication (or placebo). Lamotrigine caused a significant increase (63.32 vs. 69.25) in the RMT, compared with an insignificant increase following valproic acid (62.50 vs. 63.35), and a decrease (62.60 vs. 62.36) following placebo ( F2,26 = 18.58, P < 0.0001). No significant difference in CSP was found between placebo and drugs ( F2,26 = 0.119, P > 0.05). RCs were significantly suppressed by lamotrigine ( t = 2.07, P < 0.05) and enhanced by valproic acid ( t = 2.39, P < 0.05). Lamotrigine and valproic acid have different effects on cortical neuronal excitability as demonstrated by TMS. [ABSTRACT FROM AUTHOR]

Abstract: Rationale: Cognitive deficits are of particular importance in schizophrenia since they are strongly associated with poor prognosis. We investigated the relationship between prefrontal cortical atrophy as measured by MRI and the neuropsychological performance of participants diagnosed with DSM-IV-TR schizophrenia. Methods: Fourteen unmedicated adult patients and thirteen matched controls were studied. Subjects underwent MRI yielding 1 mm isotropic T1-weighted images. Voxel based morphometry was applied to all images using SPM5. The mean gray level of Brodmann area (BA) 9 was also extracted and evaluated using simple regression along with relative score differences on patients neuropsychological tests compared to controls. Results: Patients exhibited a poorer performance on the Controlled Word Association Task (COWAT), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Patients also presented a greater level of apathy as indexed by the Apathy Evaluation Scale (AES). There was a significant decrease in gray matter volume in patients with schizophrenia in left supplementary motor area, bilateral superior frontal gyrus, left middle frontal gyrus, right opercular area, left angular gyrus, left superior temporal gyrus and left cerebellar hemisphere. Within the schizophrenia group, decreased BA9 gray matter volume was correlated with poorer performance on the WCST and TMT-B. Conclusion: Prefrontal gray matter abnormalities in schizophrenia patients may be associated with some symptoms including difficulties with set-shifting and decreased mental flexibility. Further studies evaluating prefrontal connectivity may clarify if such impairment results from abnormalities of the frontal area alone, or are a result of altered networks involving the frontal and extra-frontal areas. [Copyright &y& Elsevier]

Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, double-blind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS.Neuropsychopharmacology (2007) 32, 1649–1660; doi:10.1038/sj.npp.1301288; published online 3 January 2007 [ABSTRACT FROM AUTHOR]

Abstract: Dopamine D1 receptors play an important role in memory and cognition in non-human primates. Dopamine D1 agonists have been shown to reverse performance deficits in both aged non-human primates and in primates with lesions to dopamine systems. This study explored whether a single dose of the first full D1 agonist dihydrexidine (DAR-0100) would cause changes in brain activity (perfusion) in dopamine-rich brain regions. We used a new gadolinium-contrast magnetic resonance perfusion scanning technique to measure brain activity. A within-subject cross-over double-blind randomized design was used in 20 adults with SCID-diagnosed schizophrenia. Each morning at 0800 h, they were scanned on a 3.0 T MRI scanner for perfusion. They then received either 20 mg of dihydrexidine, or placebo, subcutaneously over 15 min. Over the next 45 min, they had intermittent MRI scans. Two days later, they had a repeat of the Day 1 schedule, but received the opposite treatment from that given on the first day. Within-day, as well as between-day, comparisons were made to test for perfusion effects of dihydrexidine. Analysis revealed that dihydrexidine induced a significant increase in both prefrontal and non-prefrontal perfusion compared to placebo. The greatest increases occurred approximately 20 min after dihydrexidine infusion, consistent with the short pharmacokinetic half-life of dihydrexidine. These data are consistent with the hypothesis formulated from studies of non-human primates that dihydrexidine and other D1 agonists may be able to modulate prefrontal dopaminergic function. [Copyright &y& Elsevier]

Abstract: The potential of dopamine D1 receptor agonists to have beneficial effects on cognitive function has been suggested by a body of preclinical evidence. We now report the use of dihydrexidine (DAR-0100), the first full D1 agonist, in a pilot study assessing single low dose safety and tolerability in patients with schizophrenia. A within-subject cross-over design was used in 20 adults (18–65 years) with SCID-IV diagnosed schizophrenia. Subjects were outpatients with a moderate level of residual negative symptoms, and were on stable dosing of non-D1-blocking antipsychotic drugs. Following screening, subjects were hospitalized for 48 h, and at 0800 h each morning scanned on a 3 T MRI scanner for resting brain perfusion, followed by a Blood Oxygen Level Dependent (BOLD) fMRI scan during an N-Back working memory task. They then received 20 mg subcutaneously (SC) of dihydrexidine or placebo over 15 min, followed by 45 min of intermittent MRI scans of perfusion and BOLD activity during the working memory task. Blood was drawn for serum drug levels and subjects were evaluated for clinical and cognitive changes. The procedure was repeated using the opposite challenge 2 days later. Dihydrexidine was well tolerated with no serious adverse events although three subjects had mild dizziness and five subjects experienced nausea. There was no significant effect of drug on clinical interview ratings or delayed (afternoon) neuropsychological performance. No medication interactions were seen. Thus, a single subcutaneous dose of dihydrexidine is tolerated and safe in patients with schizophrenia and does not produce delayed clinical or neuropsychological improvements. [Copyright &y& Elsevier]

In contrast to the effects seen in younger adults, depressed elderly subjects have shown more modest antidepressant responses to transcranial magnetic stimulation (TMS). We theorized that higher stimulation intensities in older depressed subjects with prefrontal atrophy might be needed to stimulate underlying cortex. In an open design with patients on stable baseline medications, we treated 18 treatment-resistant elderly depressed subjects (mean age 61.2±7.3) with 15 rTMS sessions over 3 weeks. We adjusted the delivered TMS intensity to account for MRI measured prefrontal atrophy. The skull to prefrontal cortex distance increased with age, whereas the skull to motor cortex distance did not. All subjects tolerated the higher doses well. The average intensity used was 114% of motor threshold (MT) with a range from 103–141% MT. There was an average 35% decline over the 3 weeks in HRSD scores. After 3 weeks of treatment, 27% (5/18) met response criteria (>50% improvement), with four of these five also meeting criteria for remission (exit Hamilton Depression Score <8). These initial pilot findings support the need for blinded studies using prefrontal TMS in an elderly population, testing whether TMS, delivered at stimulation intensities calculated to overcome atrophy, is more effective than TMS without adjusting for atrophy. Depression and Anxiety 19:249–256, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

: BackgroundFocal prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) was originally investigated as a potential antidepressant under the assumption that in depressed patients, prefrontal cortex stimulation would produce changes in connected limbic regions involved in mood regulation.: MethodsFourteen adult patients with depression were scanned in a 1.5-T scanner using interleaved rTMS (1 Hz) applied on the left prefrontal cortex over 7.35 min. Images were analyzed with Statistical Parametric Mapping 2b and principal component analysis.: ResultsOver the left prefrontal cortex, 1-Hz TMS was associated with increased activity at the site of stimulation as well as in connected limbic regions: bilateral middle prefrontal cortex, right orbital frontal cortex, left hippocampus, mediodorsal nucleus of the thalamus, bilateral putamen, pulvinar, and insula (t = 3.85, p < .001). Significant deactivation was found in the right ventromedial frontal cortex.: ConclusionsIn depressed patients, 1-Hz TMS at 100% motor threshold over the left prefrontal cortex induces activation underneath the coil, activates frontal–subcortical neuronal circuits, and decreases activity in the right ventromedial cortex. Further work is needed to understand whether these immediate changes vary as a function of TMS use parameters (intensity, frequency, location) and whether they relate to neurobiologic effects and antidepressant mechanisms of TMS. [Copyright &y& Elsevier]

: BackgroundVagus nerve stimulation (VNS) is an approved treatment for epilepsy and has been investigated in clinical trials of depression. Little is known about the relationship of VNS parameters to brain function. Using the interleaved VNS /functional magnetic resonance imaging (fMRI) technique, we tested whether variations of VNS pulse width (PW) would produce different immediate brain activation in a manner consistent with single neuron PW studies.: MethodsTwelve adult patients with major depression, treated with VNS, underwent three consecutive VNS/fMRI scans, each randomly using one of three PWs (130 μs, 250 μs, or 500 μs). The data were analyzed with SPM2.: ResultsGlobal activations induced by PWs 250 and 500 were both significantly greater than that induced by PW 130 but not significantly different from each other. For global deactivation, PWs 130 and 250 were both significantly greater than PW 500 but not significantly different from each other. Regional similarities and differences were also seen with the various PWs.: ConclusionsThe data confirm our hypothesis that VNS at PW 500 globally produces no more activation than does PW 250, and PW 130 is insufficient for activation of some regions. These data suggest that PW is an important variable in producing VNS brain effects. [Copyright &y& Elsevier]

Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been shown to improve depressive symptoms. We designed and carried out the following left prefrontal rTMS study to determine the safety, feasibility, and potential efficacy of using TMS to treat the depressive symptoms of bipolar affective disorder (BPAD). Methods: We recruited and enrolled 23 depressed BPAD patients (12 BPI depressed state, nine BPII depressed state, two BPI mixed state). Patients were randomly assigned to receive either daily left prefrontal rTMS (5 Hz, 110% motor threshold, 8 sec on, 22 sec off, over 20 min) or placebo each weekday morning for 2 weeks. Motor threshold and subjective rating scales were obtained daily, and blinded Hamilton Rating Scale for Depression (HRSD) and Young Mania Rating Scales (YMRS) were obtained weekly. Results: Stimulation was well tolerated with no significant adverse events and with no induction of mania. We failed to find a statistically significant difference between the two groups in the number of antidepressant responders (>50% decline in HRSD or HRSD <10 – 4 active and 4 sham) or the mean HRSD change from baseline over the 2 weeks (t =-0.22, p=0.83). Active rTMS, compared with sham rTMS, produced a trend but not statistically significant greater improvement in daily subjective mood ratings post-treatment ( t =1.58, p=0.13). The motor threshold did not significantly change after 2 weeks of active treatment ( t =1.11, p=0.28). Conclusions: Daily left prefrontal rTMS appears safe in depressed BPAD subjects, and the risk of inducing mania in BPAD subjects on medications is small. We failed to find statistically significant TMS clinical antidepressant effects greater than sham. Further studies are needed to fully investigate the potential role, if any, of TMS in BPAD depression. [ABSTRACT FROM AUTHOR]

The advances in understanding the functional and structural anatomy of bipolar affective disorder (BPAD) outlined in the rest of this volume provide the background and rationale for attempting to manipulate these regions as potential antidepressant and anti-manic therapies. The idea of using circuit and device based approaches to regulating mood follows in the tradition of electroconvulsive therapy (ECT). In marked contrast to ECT, however, these new stimulation techniques represent an important new paradigm shift, with treatments that neither produce seizures nor require general anesthesia. The new techniques are safer, with fewer side effects, and are more focal than ECT in their entry into the brain. Transcranial magnetic stimulation (TMS) produces direct cortical brain stimulation by creating a powerful transient magnetic field. Five published randomized controlled trials suggest it has clinically significant acute antidepressant effects. One controlled study suggests that it may have antimanic effects as well. Vagus nerve stimulation (VNS) involves direct electrical stimulation of the vagus nerve in the neck, with propagation of the signal to the brainstem. One controlled and one open study in epilepsy patients with depression found antidepressant effects of VNS. An open study of VNS in treatment resistant unipolar and bipolar depression found acute antidepressant effects. These two device-based approaches to stimulating the brain offer promise as potential acute and even long-term treatments. Imaging studies suggest that TMS likely causes changes in mood regulating regions by stimulating limbic regions from the cortex down, while VNS influences this same circuit from the brainstem up. These two approaches are not yet approved by the Food and Drug Administration (FDA) for use in the US, although pivotal trials geared for eventual FDA approval are underway. Finally, the research determining whether and how these devices work to influence mood also promises to help unravel the pathophysiology of BPAD. [Copyright &y& Elsevier]

Omega-3 and omega-6 fatty acids are important for neonatal development and health. One mechanism by which omega-3 and omega-6 fatty acids exert their effects is through their metabolism into oxylipins and specialized pro-resolving mediators. However, the influence of oxylipins on fetal growth is not well understood. Therefore, the objective of this study was to identify oxylipins present in maternal and umbilical cord plasma and investigate their relationship with infant growth. Liquid chromatography–tandem mass spectrometry was used to quantify oxylipin levels in plasma collected at the time of delivery. Spearman's correlations highlighted significant correlations between metabolite levels and infant growth. They were then adjusted for maternal obesity (normal body mass index (BMI: ≤30 kg/m2) vs. obese BMI (>30 kg/m2) and smoking status (never vs. current/former smoker) using linear regression modeling. A p-value < 0.05 was considered statistically significant. Our study demonstrated a diverse panel of oxylipins from the lipoxygenase pathway present at the time of delivery. In addition, both omega-3 and omega-6 oxylipins demonstrated potential influences on the birth length and weight percentiles. The oxylipins present during pregnancy may influence fetal growth and development, suggesting potential metabolites to be used as biomarkers for infant outcomes. [ABSTRACT FROM AUTHOR]

Background: QuPath is an open-source digital image analyzer notable for its user-friendly design, cross-platform compatibility, and customizable functionality. Since it was first released in 2016, at least 624 publications have reported its use, and it has been applied in a wide spectrum of settings. However, there are currently limited reports of its use in placental tissue. Here, we present the use of QuPath to quantify staining of G-protein coupled receptor 18 (GPR18), the receptor for the pro-resolving lipid mediator Resolvin D2, in placental tissue. Methods: Whole slide images of vascular smooth muscle (VSM) and extravillous trophoblast (EVT) cells stained for GPR18 were annotated for areas of interest. Visual scoring was performed on these images by trained and in-training pathologists, while QuPath scoring was performed with the methodology described herein. Results: Bland–Altman analyses showed that, for the VSM category, the two methods were comparable across all staining levels. For EVT cells, the high-intensity staining level was comparable across methods, but the medium and low staining levels were not comparable. Conclusions: Digital image analysis programs offer great potential to revolutionize pathology practice and research by increasing accuracy and decreasing the time and cost of analysis. Careful study is needed to optimize this methodology further. [ABSTRACT FROM AUTHOR]

Background: QuPath is an open-source digital image analyzer notable for its user-friendly design, cross-platform compatibility, and customizable functionality. Since it was first released in 2016, at least 624 publications have reported its use, and it has been applied in a wide spectrum of settings. However, there are currently limited reports of its use in placental tissue. Here, we present the use of QuPath to quantify staining of G-protein coupled receptor 18 (GPR18), the receptor for the pro-resolving lipid mediator Resolvin D2, in placental tissue. Methods: Whole slide images of vascular smooth muscle (VSM) and extravillous trophoblast (EVT) cells stained for GPR18 were annotated for areas of interest. Visual scoring was performed on these images by trained and in-training pathologists, while QuPath scoring was performed with the methodology described herein. Results: Bland–Altman analyses showed that, for the VSM category, the two methods were comparable across all staining levels. For EVT cells, the high-intensity staining level was comparable across methods, but the medium and low staining levels were not comparable. Conclusions: Digital image analysis programs offer great potential to revolutionize pathology practice and research by increasing accuracy and decreasing the time and cost of analysis. Careful study is needed to optimize this methodology further. [ABSTRACT FROM AUTHOR]

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). Method: Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10. Results: Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment. Conclusion: The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]