Diffuse Optical Cerebral Diagnostics For Real-Time Guidance During Pediatric Surgery And Resuscitation

Adequate oxygen and blood flow are vital for the developing pediatric brain. Herein, we apply quantitative diffuse optical techniques, frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS), to non-invasively characterize cerebral oxygenation (StO2), blood flow (CBF), and oxygen metabolism (CMRO2) in pediatric animal models of hypoxic-ischemic injury. In a neonatal swine model (n=8) of congenital cardiac defect repair, we performed a two-part study which validated non-invasive diffuse optical measurements and uncovered significant limitations in the guidance of deep hypothermia using temperature during cardiopulmonary bypass. First, non-invasive CMRO2 was validated against invasive methods over wide temperature ranges (18-37C). Non-invasive measurements of CBF (p\u3c0.001) and CMRO2 (p\u3c0.001) were significantly associated with invasive measurements. Furthermore, a significant hysteresis (p=0.001) of cerebral metabolic temperature-dependence during cooling versus rewarming with respect to NPT is “fixed” with the use of ICT (p\u3e0.5). Second, we compared non-invasively measured cerebral metabolic parameters between cohorts who underwent deep hypothermia with or without circulatory arrest (DHCA; n=8). Cerebral metabolic temperature-dependence with respect to ICT in DHCA animals demonstrated significantly diminished temperature sensitivity during rewarming (p\u3c0.001; i.e., following reperfusion) compared to during cooling. Direct non-invasive CMRO2 measurement is an improved surrogate of cerebral status over temperature and enables individualized management of deep hypothermia and circulatory arrest. In another study of asphyxia-induced pediatric cardiac arrest and cardiopulmonary resuscitation (CPR), non-invasive measures of StO2, oxy-hemoglobin concentration ([HbO2]) and total hemoglobin concentration (THC) at 10-minutes of CPR were significantly associated with return of spontaneous circulation (ROSC). The absolute change in [HbO2] from 1-minute of CPR ([HbO2]CPR) was the optimal predictor of ROSC, with a mean (SD) AUC of 0.91 (0.07) across the first 10 minutes of CPR, evaluated at 1-minute intervals. Furthermore, separate high sensitivity and specificity threshold for ROSC were established. These results show, in several contexts, that non-invasive FD-DOS/DCS neuromonitoring provides unique physiological information about the developing pediatric brain that enables individualized identification of critical neurological risk periods and real-time guidance of clinical care

Berberine Reduces cAMP-Induced Chloride Secretion in T84 Human Colonic Carcinoma Cells through Inhibition of Basolateral KCNQ1 Channels

Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl− secretion in distal colon. The aims of this study were to determine the molecular signaling mechanisms of action of berberine on Cl− secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC50 80 ± 8 μM). In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K+ current by 88%, suggesting inhibition of KCNQ1 K+ channels. Berberine did not affect either apical Cl− conductance or basolateral Na+–K+-ATPase activity. Berberine stimulated p38 MAPK, PKCα and PKA, but had no effect on p42/p44 MAPK and PKCδ. However, berberine pre-treatment prevented stimulation of p42/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl− secretion was partially blocked by HBDDE (∼65%), an inhibitor of PKCα and to a smaller extent by inhibition of p38 MAPK with SB202190 (∼15%). Berberine treatment induced an increase in association between PKCα and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl− secretion through inhibition of basolateral KCNQ1 channels responsible for K+ recycling via a PKCα-dependent pathway

Social media users produce more affect that supports cultural values, but are more influenced by affect that violates cultural values

This is an accepted manuscript of an article published by American Psychological Association in Journal of Personality and Social Psychology, available online at: https://doi.org/10.1037/pspa0000282 The accepted version of the publication may differ from the final published version.Although social media plays an increasingly important role in communication around the world, social media research has primarily focused on Western users. Thus, little is known about how cultural values shape social media behavior. To examine how cultural affective values might influence social media use, we developed a new sentiment analysis tool that allowed us to compare the affective content of Twitter posts in the United States (55,867 tweets, 1888 users) and Japan (63,863 tweets, 1825 users). Consistent with their respective cultural affective values, U.S. users primarily produced positive (vs. negative) posts, while Japanese users primarily produced low (vs. high) arousal posts. Contrary to cultural affective values, however, U.S. users were more influenced by changes in others’ high arousal negative (e.g., angry) posts, whereas Japanese were more influenced by changes in others’ high arousal positive (e.g., excited) posts. These patterns held after controlling for differences in baseline exposure to affective content, and across different topics. Together, these results suggest that across cultures, while social media users primarily produce content that supports their affective values, they are more influenced by content that violates those values. These findings have implications for theories about which affective content spreads on social media, and for applications related to the optimal design and use of social media platforms around the world

The PRogram In Support of Moms (PRISM): study protocol for a cluster randomized controlled trial of two active interventions addressing perinatal depression in obstetric settings

BACKGROUND: Perinatal depression, the most common pregnancy complication, is associated with negative maternal-offspring outcomes. Despite existence of effective treatments, it is under-recognized and under-treated. Professional organizations recommend universal screening, yet multi-level barriers exist to ensuring effective diagnosis, treatment, and follow-up. Integrating mental health and obstetric care holds significant promise for addressing perinatal depression. The overall study goal is to compare the effectiveness of two active interventions: (1) the Massachusetts Child Psychiatry Access Program (MCPAP) for Moms, a state-wide, population-based program, and (2) the PRogram In Support of Moms (PRISM) which includes MCPAP for Moms plus a proactive, multifaceted, practice-level intervention with intensive implementation support. METHODS: This study is conducted in two phases: (1) a run-in phase which has been completed and involved practice and patient participant recruitment to demonstrate feasibility for the second phase, and (2) a cluster randomized controlled trial (RCT), which is ongoing, and will compare two active interventions 1:1 with ten Ob/Gyn practices as the unit of randomization. In phase 1, rates of depressive symptoms and other demographic and clinical features among patients were examined to inform practice randomization. Patient participants to be recruited in phase 2 will be followed longitudinally until 13 months postpartum; they will have 3-5 total study visits depending on whether their initial recruitment and interview was at 4-24 or 32-40 weeks gestation, or 1-3 months postpartum. Sampling throughout pregnancy and postpartum will ensure participants with different depressive symptom onset times. Differences in depression symptomatology and treatment participation will be compared between patient participants by intervention arm. DISCUSSION: This manuscript describes the full two-phase study protocol. The study design is innovative because it combines effectiveness with implementation research designs and integrates critical components of participatory action research. Our approach assesses the feasibility, acceptance, efficacy, and sustainability of integrating a stepped-care approach to perinatal depression care into ambulatory obstetric settings; an approach that is flexible and can be tailored and adapted to fit unique workflows of real-world practices. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02760004, registered prospectively on May 3, 2016

The Protection of the Rights of Migrant Domestic Workers in a Country of Origin and a Country of Destination: Case Studies of the Philippines and Kuwait

During the spring semester of 2013, the SAIS International Human Rights Clinic researched the protection and promotion of the rights of migrant domestic workers in a country of origin and a country of destination by example of the Philippines and Kuwait. The students embarked on a weeklong fact-finding mission to gain insights into (a) the underlying causes and social consequences of labor migration, (b) the mechanisms to protect migrant domestic workers from abuse and exploitation, and (c) the preventive activities carried out in the two countries. The findings of the two fact-finding missions, supported by academic research and scholarship, policy papers, and press releases, are published in this report. The report describes the situation of migrant domestic workers from the start of their journey in the Philippines, through their arrival and work in Kuwait, and through their repatriation. The report aims (a) to raise public awareness about the rights of migrant domestic workers; (b) to offer practical solutions to policymakers in countries of origin and destination; and (c) to offer practical solutions specifically to the Kuwaiti and Philippine governments to take decisive action to better prevent human rights abuses, punish human rights violators, and protect vulnerable populations. By focusing on Filipino migrant domestic workers, the report aims to facilitate the further development of Kuwait–Philippines intergovernmental cooperation that may serve as a model for labor-receiving and labor-sending countries

Pressure modulation algorithm to separate cerebral hemodynamic signals from extracerebral artifacts

We introduce and validate a pressure measurement paradigm that reduces extracerebral contamination from superficial tissues in optical monitoring of cerebral blood flow with diffuse correlation spectroscopy (DCS). The scheme determines subject-specific contributions of extracerebral and cerebral tissues to the DCS signal by utilizing probe pressure modulation to induce variations in extracerebral blood flow. For analysis, the head is modeled as a two-layer medium and is probed with long and short source-detector separations. Then a combination of pressure modulation and a modified Beer-Lambert law for flow enables experimenters to linearly relate differential DCS signals to cerebral and extracerebral blood flow variation without a priori anatomical information. We demonstrate the algorithm’s ability to isolate cerebral blood flow during a finger-tapping task and during graded scalp ischemia in healthy adults. Finally, we adapt the pressure modulation algorithm to ameliorate extracerebral contamination in monitoring of cerebral blood oxygenation and blood volume by near-infrared spectroscopy.Peer ReviewedPostprint (published version

The use of novel diffuse optical spectroscopies for improved neuromonitoring during neonatal cardiac surgery requiring antegrade cerebral perfusion

BackgroundSurgical procedures involving the aortic arch present unique challenges to maintaining cerebral perfusion, and optimal neuroprotective strategies to prevent neurological injury during such high-risk procedures are not completely understood. The use of antegrade cerebral perfusion (ACP) has gained favor as a neuroprotective strategy over deep hypothermic circulatory arrest (DHCA) due to the ability to selectively perfuse the brain. Despite this theoretical advantage over DHCA, there has not been conclusive evidence that ACP is superior to DHCA. One potential reason for this is the incomplete understanding of ideal ACP flow rates to prevent both ischemia from underflowing and hyperemia and cerebral edema from overflowing. Critically, there are no continuous, noninvasive measurements of cerebral blood flow (CBF) and cerebral oxygenation (StO2) to guide ACP flow rates and help develop standard clinical practices. The purpose of this study is to demonstrate the feasibility of using noninvasive, diffuse optical spectroscopy measurements of CBF and cerebral oxygenation during the conduct of ACP in human neonates undergoing the Norwood procedure.MethodsFour neonates prenatally diagnosed with hypoplastic left heart syndrome (HLHS) or a similar variant underwent the Norwood procedure with continuous intraoperative monitoring of CBF and cerebral oxygen saturation (StO2) using two non-invasive optical techniques, namely diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy (FD-DOS). Changes in CBF and StO2 due to ACP were calculated by comparing these parameters during a stable 5 min period of ACP to the last 5 min of full-body CPB immediately prior to ACP initiation. Flow rates for ACP were left to the discretion of the surgeon and ranged from 30 to 50 ml/kg/min, and all subjects were cooled to 18°C prior to initiation of ACP.ResultsDuring ACP, the continuous optical monitoring demonstrated a median (IQR) percent change in CBF of −43.4% (38.6) and a median (IQR) absolute change in StO2 of −3.6% (12.3) compared to a baseline period during full-body cardiopulmonary bypass (CPB). The four subjects demonstrated varying responses in StO2 due to ACP. ACP flow rates of 30 and 40 ml/kg/min (n = 3) were associated with decreased CBF during ACP compared to full-body CPB. Conversely, one subject with a higher flow6Di rate of 50 ml/kg/min demonstrated increased CBF and StO2 during ACP.ConclusionsThis feasibility study demonstrates that novel diffuse optical technologies can be utilized for improved neuromonitoring in neonates undergoing cardiac surgery where ACP is utilized. Future studies are needed to correlate these findings with neurological outcomes to inform best practices during ACP in these high-risk neonates

Premature Senescence and Increased TGFβ Signaling in the Absence of Tgif1

Transforming growth factor β (TGFβ) signaling regulates cell cycle progression in several cell types, primarily by inducing a G1 cell cycle arrest. Tgif1 is a transcriptional corepressor that limits TGFβ responsive gene expression. Here we demonstrate that primary mouse embryo fibroblasts (MEFs) lacking Tgif1 proliferate slowly, accumulate increased levels of DNA damage, and senesce prematurely. We also provide evidence that the effects of loss of Tgif1 on proliferation and senescence are not limited to primary cells. The increased DNA damage in Tgif1 null MEFs can be partially reversed by culturing cells at physiological oxygen levels, and growth in normoxic conditions also partially rescues the proliferation defect, suggesting that in the absence of Tgif1 primary MEFs are less able to cope with elevated levels of oxidative stress. Additionally, we show that Tgif1 null MEFs are more sensitive to TGFβ-mediated growth inhibition, and that treatment with a TGFβ receptor kinase inhibitor increases proliferation of Tgif1 null MEFs. Conversely, persistent treatment of wild type cells with low levels of TGFβ slows proliferation and induces senescence, suggesting that TGFβ signaling also contributes to cellular senescence. We suggest that in the absence of Tgif1, a persistent increase in TGFβ responsive transcription and a reduced ability to deal with hyperoxic stress result in premature senescence in primary MEFs