Large-scale seasonal forecasts of river discharge by coupling local and global datasets with a stacked neural network: Case for the Loire River system.

Accurate prediction of river discharge is critical for a wide range of sectors, from human activities to environmental hazard management, especially in the face of increasing demand for water resources and climate change. To address this need, a multivariate model that incorporates both local and global data sources, including river and piezometer gauges, sea level, and climate parameters. By employing phase shift analysis, the model optimizes correlations between the target discharge and 12 parameters related to hydrologic and climatic systems, all sampled daily. In addition, a stacked LSTM - a more complex neural network architecture - is used to improve information extraction ability. Exploring river dynamics in the Loire-Bretagne basin and its surroundings, the investigation delves into predictions in daily time steps for one, three, and six months ahead. The resulting forecast features high accuracy and efficiency in predicting river discharge fluctuations, showcasing superior performance in forecasting drought periods over flood peaks. A detailed examination on data used highlights the significance of both local and global datasets in predicting river discharge, where the former dictates short-term predictions, while the latter drives long-range forecasts. Seasonally extended forecasting confirms a strong connection between the forecast leading time and the shift in data correlation, with lower correlation at a lag of 3 months due to seasonal changes affecting forecast quality, compensated by a higher correlation at a longer lag of 6 months. Such mutual effect in this multi-time-step forecasting improves the predictive quality of a six-month horizon, thus encourages progress in long-term prediction to a seasonal scale. The research establishes a practical foundation for effectively utilizing big data to leverage long-term forecasting of environmental dynamics.

Long-run forecasting surface and groundwater dynamics from intermittent observation data: An evaluation for 50 years.

The accurate prediction of water dynamics is critical for operational water resource management. In this study, we propose a novel approach to perform long-term forecasts of daily water dynamics, including river levels, river discharges, and groundwater levels, with a lead time of 7-30 days. The approach is based on the state-of-the-art neural network, bidirectional long short-term memory (BiLSTM), to enhance the accuracy and consistency of dynamic predictions. The operation of this forecasting system relies on an in-situ database observed for over 50 years with records gauging in 19 rivers, the karst aquifer, the English Channel, and the meteorological network in Normandy, France. To address the problem of missing measurements and gauge installations over time, we developed an adaptive scheme in which the neural network is regularly adjusted and re-trained in response to changing inputs during a long operation. Advances in BiLSTM with extensive learning past-to-future and future-to-past further help to avoid time-lag calibration that simplifies data processing. The proposed approach provides high accuracy and consistent prediction for the three water dynamics within a similar accuracy range as an on-site observation, with approximately 3 % error in the measurement range for the 7 day-ahead predictions and 6 % error for the 30 d-ahead predictions. The system also effectively fills the gap in actual measurements and detects anomalies at gauges that can last for years. Working with multiple dynamics not only proves that the data-driven model is a unified approach but also reveals the impact of the physical background of the dynamics on the performance of their predictions. Groundwater undergoes a slow filtration process following a low-frequency fluctuation, favoring long-term prediction, which differs from other higher-frequency river dynamics. The physical nature drives the predictive performance even when using a data-driven model.

How education and GDP drive the COVID-19 vaccination campaign.

BACKGROUND: Since vaccination is the decisive factor for controlling the COVID-19 pandemic, it is important to understand the process of vaccination success which is not well understood on a global level. The study is the first to judge the now completed "first wave" of the vaccination efforts. The analysis is very relevant for the understanding why and where the vaccination process observed got stuck by the end of 2021. METHODS: Using data from 118 countries globally and weighted least squared and survival analysis, we identify a variety of factors playing crucial roles, including the availability of vaccines, pandemic pressures, economic strength measured by Gross Domestic Product (GDP), educational development, and political regimes. RESULTS: Examining the speed of vaccinations across countries until the Fall of 2021 when the global process got stuck, we find that initially authoritarian countries are slow in the vaccination process, while education is most relevant for scaling up the campaign, and the economic strength of the economies drives them to higher vaccination rates. In comparison to North and Middle America, European and Asian countries vaccinated initially fast for 5% and 10% vaccination rate thresholds, but became rather slow reaching the 30% vaccination level and above. The findings are robust to various applied estimation methods and model specifications. CONCLUSIONS: Democratic countries are much faster than authoritarian countries in their vaccination campaigns when controlling for other factors. This finding suggests that the quality of government and the political environment play a key role in popular support for government policies and programs. However, despite the early success of their vaccination campaigns, the democratic country group has been confronted with strong concerns of vaccine reluctance among their vast populations, indicating the two most potent variables explaining the speed of the COVID-19 vaccination campaign are education and economic conditions.

Longitudinal Analysis of Depressive Symptoms, Perceived Social Support, and Alcohol Use among HIV-Infected Men Who Inject Drugs in Northern Vietnam.

Background: Limited research examines depressive symptoms, alcohol use, and social support among HIV-infected people who inject drugs. Objectives: Using longitudinal data, we investigated whether perceived social support moderates the relationship between depressive symptoms and alcohol use among HIV-infected men who inject drugs in Vietnam. Methods: Data were collected from participants (N = 455; mean age 35 years) in a four-arm randomized controlled trial in Thai Nguyen, Vietnam. Data were collected at baseline, 6, 12, 18, and 24 months with 94% retention excluding dead (N = 103) or incarcerated (N = 37) participants. Multilevel growth models were used to assess whether: (1) depressive symptoms predict when risk of alcohol use is elevated (within-person effects); (2) depressive symptoms predict who is at risk for alcohol use (between-person effects); and (3) within- and between-person perceived social support moderates the depressive symptoms-alcohol relationship. Results: Participants reported high but declining levels of depressive symptoms and alcohol use. Participants with higher depressive symptoms drank less on average (B = -0.0819, 95% CI -0.133, -0.0307), but within-person, a given individual was more likely to drink when they were feeling more depressed than usual (B = 0.136, 95% CI 0.0880, 0.185). The positive relationship between within-person depressive symptoms and alcohol use grew stronger at higher levels of within-person perceived social support. Conclusions: HIV-infected men who inject drugs have increased alcohol use when they are experiencing higher depressive symptoms than usual, while those with higher average depressive symptoms over time report less alcohol use. Social support strengthens the positive relationship between within-person depressive symptoms and alcohol use.

Impact of Abstinence and of Reducing Illicit Drug Use Without Abstinence on Human Immunodeficiency Virus Viral Load.

BACKGROUND: Substance use is common among people living with human immunodeficiency virus (PLWH) and a barrier to achieving viral suppression. Among PLWH who report illicit drug use, we evaluated associations between HIV viral load (VL) and reduced use of illicit opioids, methamphetamine/crystal, cocaine/crack, and marijuana, regardless of whether or not abstinence was achieved. METHODS: This was a longitudinal cohort study of PLWH from 7 HIV clinics or 4 clinical studies. We used joint longitudinal and survival models to examine the impact of decreasing drug use and of abstinence for each drug on viral suppression. We repeated analyses using linear mixed models to examine associations between change in frequency of drug use and VL. RESULTS: The number of PLWH who were using each drug at baseline ranged from n = 568 (illicit opioids) to n = 4272 (marijuana). Abstinence was associated with higher odds of viral suppression (odds ratio [OR], 1.4-2.2) and lower relative VL (ranging from 21% to 42% by drug) for all 4 drug categories. Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with VL suppression (OR, 2.2, 1.6, respectively). Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with lower relative VL (47%, 38%, respectively). CONCLUSIONS: Abstinence was associated with viral suppression. In addition, reducing use of illicit opioids or methamphetamine/crystal, even without abstinence, was also associated with viral suppression. Our findings highlight the impact of reducing substance use, even when abstinence is not achieved, and the potential benefits of medications, behavioral interventions, and harm-reduction interventions.

Approaches for creating comparable measures of alcohol use symptoms: Harmonization with eight studies of criminal justice populations.

BACKGROUND: With increasing data archives comprised of studies with similar measurement, optimal methods for data harmonization and measurement scoring are a pressing need. We compare three methods for harmonizing and scoring the AUDIT as administered with minimal variation across 11 samples from eight study sites within the STTR (Seek-Test-Treat-Retain) Research Harmonization Initiative. Descriptive statistics and predictive validity results for cut-scores, sum scores, and Moderated Nonlinear Factor Analysis scores (MNLFA; a psychometric harmonization method) are presented. METHODS: Across the eight study sites, sample sizes ranged from 50 to 2405 and target populations varied based on sampling frame, location, and inclusion/exclusion criteria. The pooled sample included 4667 participants (82% male, 52% Black, 24% White, 13% Hispanic, and 8% Asian/ Pacific Islander; mean age of 38.9 years). Participants completed the AUDIT at baseline in all studies. RESULTS: After logical harmonization of items, we scored the AUDIT using three methods: published cut-scores, sum scores, and MNLFA. We found greater variation, fewer floor effects, and the ability to directly address missing data in MNLFA scores as compared to cut-scores and sum scores. MNLFA scores showed stronger associations with binge drinking and clearer study differences than did other scores. CONCLUSIONS: MNLFA scores are a promising tool for data harmonization and scoring in pooled data analysis. Model complexity with large multi-study applications, however, may require new statistical advances to fully realize the benefits of this approach.

A hybrid constructed wetland for organic-material and nutrient removal from sewage: Process performance and multi-kinetic models.

A pilot-scale hybrid constructed wetland with vertical flow and horizontal flow in series was constructed and used to investigate organic material and nutrient removal rate constants for wastewater treatment and establish a practical predictive model for use. For this purpose, the performance of multiple parameters was statistically evaluated during the process and predictive models were suggested. The measurement of the kinetic rate constant was based on the use of the first-order derivation and Monod kinetic derivation (Monod) paired with a plug flow reactor (PFR) and a continuously stirred tank reactor (CSTR). Both the Lindeman, Merenda, and Gold (LMG) analysis and Bayesian model averaging (BMA) method were employed for identifying the relative importance of variables and their optimal multiple regression (MR). The results showed that the first-order-PFR (M2) model did not fit the data (P > 0.05, and R2 < 0.5), whereas the first-order-CSTR (M1) model for the chemical oxygen demand (CODCr) and Monod-CSTR (M3) model for the CODCr and ammonium nitrogen (NH4-N) showed a high correlation with the experimental data (R2 > 0.5). The pollutant removal rates in the case of M1 were 0.19 m/d (CODCr) and those for M3 were 25.2 g/m2∙d for CODCr and 2.63 g/m2∙d for NH4-N. By applying a multi-variable linear regression method, the optimal empirical models were established for predicting the final effluent concentration of five days' biochemical oxygen demand (BOD5) and NH4-N. In general, the hydraulic loading rate was considered an important variable having a high value of relative importance, which appeared in all the optimal predictive models.

Cathelicidin suppresses lipid accumulation and hepatic steatosis by inhibition of the CD36 receptor.

BACKGROUND AND OBJECTIVES: Obesity is a global epidemic which increases the risk of the metabolic syndrome. Cathelicidin (LL-37 and mCRAMP) is an antimicrobial peptide with an unknown role in obesity. We hypothesize that cathelicidin expression correlates with obesity and modulates fat mass and hepatic steatosis. MATERIALS AND METHODS: Male C57BL/6 J mice were fed a high-fat diet. Streptozotocin was injected into mice to induce diabetes. Experimental groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Human mesenteric fat adipocytes, mouse 3T3-L1 differentiated adipocytes and human HepG2 hepatocytes were used in the in vitro experiments. Cathelicidin levels in non-diabetic, prediabetic and type II diabetic patients were measured by enzyme-linked immunosorbent assay. RESULTS: Lentiviral cathelicidin overexpression reduced hepatic steatosis and decreased the fat mass of high-fat diet-treated diabetic mice. Cathelicidin overexpression reduced mesenteric fat and hepatic fatty acid translocase (CD36) expression that was reversed by lentiviral CD36 overexpression. Exposure of adipocytes and hepatocytes to cathelicidin significantly inhibited CD36 expression and reduced lipid accumulation. Serum cathelicidin protein levels were significantly increased in non-diabetic and prediabetic patients with obesity, compared with non-diabetic patients with normal body mass index (BMI) values. Prediabetic patients had lower serum cathelicidin protein levels than non-diabetic subjects. CONCLUSIONS: Cathelicidin inhibits the CD36 fat receptor and lipid accumulation in adipocytes and hepatocytes, leading to a reduction of fat mass and hepatic steatosis in vivo. Circulating cathelicidin levels are associated with increased BMI. Our results demonstrate that cathelicidin modulates the development of obesity.

A multi-institutional, propensity-score-matched comparison of post-operative outcomes between general anesthesia and monitored anesthesia care with intravenous sedation in umbilical hernia repair.

PURPOSE: Monitored anesthesia care with intravenous sedation (MAC/IV), recently proposed as a good choice for hernia repair, has faster recovery and better patient satisfaction than general anesthesia; however the possibility of oversedation and respiratory distress is a widespread concern. There is a paucity of the literature examining umbilical hernia repairs (UHR) and optimal anesthesia choice, despite its importance in determining clinical outcomes. METHODS: A retrospective analysis of anesthesia type in UHR was performed in the National Surgical Quality Improvement Program 2005-2013 database. General anesthesia and MAC/IV groups were propensity-score-matched (PSM) to reduce treatment selection bias. Surgical complications, medical complications, and post-operative hospital stays exceeding 1 day were the primary outcomes of interest. Pre-operative characteristics and post-operative outcomes were compared between the two anesthesia groups using univariate and multivariate statistics. RESULTS: PSM removed all observed differences between the two groups (p > 0.05 for all tracked pre-operative characteristics). MAC/IV cases required fewer post-operative hospital stays exceeding 1 day (3.5 vs 6.3 %, p < 0.001). Univariate analysis showed that overall complication rate did not differ (1.7 vs 1.8 %, p = 0.569), however MAC/IV cases resulted in fewer incidences of septic shock (<0.1 vs 0.1 %, p = 0.016). After multivariate logistic regression, MAC/IV was revealed to yield significantly lower chances of overall medical complications (OR = 0.654, p = 0.046). CONCLUSION AND RELEVANCE: UHR under MAC/IV causes fewer medical complications and reduces post-operative hospital stays compared to general anesthesia. The implications for surgeons and patients are broad, including improved surgical safety, cost-effective care, and patient satisfaction.

Clinical and epidemiological characteristics of acute respiratory virus infections in Vietnamese children.

Information about viral acute respiratory infections (ARIs) is essential for prevention, diagnosis and treatment, but it is limited in tropical developing countries. This study described the clinical and epidemiological characteristics of ARIs in children hospitalized in Vietnam. Nasopharyngeal samples were collected from children with ARIs at Ho Chi Minh City Children's Hospital 2 between April 2010 and May 2011 in order to detect respiratory viruses by polymerase chain reaction. Viruses were found in 64% of 1082 patients, with 12% being co-infections. The leading detected viruses were human rhinovirus (HRV; 30%), respiratory syncytial virus (RSV; 23·8%), and human bocavirus (HBoV; 7·2%). HRV was detected all year round, while RSV epidemics occurred mainly in the rainy season. Influenza A (FluA) was found in both seasons. The other viruses were predominant in the dry season. HRV was identified in children of all age groups. RSV, parainfluenza virus (PIV) 1, PIV3 and HBoV, and FluA were detected predominantly in children aged 24 months, respectively. Significant associations were found between PIV1 with croup (P < 0·005) and RSV with bronchiolitis (P < 0·005). HBoV and HRV were associated with hypoxia (P < 0·05) and RSV with retraction (P < 0·05). HRV, RSV, and HBoV were detected most frequently and they may increase the severity of ARIs in children.

Victorian Stroke Telemedicine Project: implementation of a new model of translational stroke care for Australia.

BACKGROUND: Stroke telemedicine is widely used to treat patients with acute stroke in Europe and North America but is seldom used in Australia. The Victorian Stroke Telemedicine (VST) programme aims to enhance acute stroke care in regional Australia. METHODS: Twelve-month pilot prospective, historical-controlled, implementation cohort study. Emergency Department (ED) at a large regional hospital in Victoria. Patients ≥ 18 years of age arriving < 4.5 h in the ED with a possible diagnosis of acute stroke. Telemedicine consultation by a Melbourne-based stroke specialist. Stroke thrombolysis rate, timelines for clinical processes, discharge outcomes. RESULTS: In the initial 12 month VST implementation, 62 patients arrived < 4.5 h of stroke onset (60% male; median age 75 years). Compared to pre-VST data (n = 58; 52% male; median age 77 years), stroke thrombolysis use increased from 17% to 26% (P = 0.26). Clinical process timelines improved including door to computed tomography time (reduced by 29 min, P = 0.006), and door to needle time (reduced by 21 min, P = 0.21). There was no significant increase in deaths (pre-VST 7% vs VST 10%), or symptomatic intracerebral haemorrhage (n = 1 tPA patient). More patients who received tPA were discharged to home or rehabilitation (pre-VST 33% vs VST 80%, P = 0.02), with significantly fewer transfers to other acute care services. CONCLUSIONS: The VST pilot implementation provides evidence that telemedicine can enhance the quality of acute stroke care in a regional hospital. Expanding VST to 16 regional hospitals, Australia's largest telestroke programme, will allow for a more comprehensive clinical and economic analysis.

Application of level-set method for deposition in three-dimensional reconstructed porous media.

Three-dimensional (3D) porous structures which are usually discretized by voxels can also be discretized by the level-set method (LSM) and flow, reactive transport, and structure evolution can be modeled. The determination of the solid-liquid interface is detailed as well as the discretization of the governing equations. Comparisons between a one-dimensional analytical solution and LSM are conducted for validation. Deposition in 3D reconstructed media is studied under various flow and reaction conditions. The evolution of the structure is explored locally by means of the pore geometry and globally by means of the permeability and the porosity. The difference between the voxel method and LSM is discussed during the investigations.

A comprehensive profile of the sociodemographic, psychosocial and health characteristics of Ontario home care clients with dementia.

INTRODUCTION: This study provides a comprehensive summary of the sociodemographic, psychosocial and health characteristics of a large population-based cohort of Ontario home care clients (aged 50 years and over) with dementia and examines the variation in these characteristics in those with co-existing neurological conditions. METHODS: Clients were assessed with the Resident Assessment Instrument-Home Care (RAI-HC) between January 2003 and December 2010. Descriptive analyses examined the distribution of these characteristics among clients with dementia relative to several comparison groups, as well as clients with other recorded neurological conditions. RESULTS: Approximately 22% of clients (n=104 802) had a diagnosis of dementia (average age 83 years, 64% female) and about one in four within this group had a co-existing neurological condition (most commonly stroke or Parkinson disease). About 43% of those with dementia did not live with their primary caregiver. Relative to several comparison groups, clients with dementia showed considerably higher levels of cognitive and functional impairment, aggression, anxiety, wandering, hallucinations/delusions, caregiver distress and a greater risk for institutionalization. Conversely, they showed a lower prevalence of several chronic conditions and lower levels of recent health service use. Depressive symptoms were relatively common in the dementia and other neurological groups. CONCLUSION: Clients with co-existing neurological conditions exhibited unique clinical profiles illustrating the need for tailored and flexible home care services and enhanced caregiver assistance programs.

TITRE: Profil complet des caractéristiques sociodémographiques, psychosociales et sanitaires des clients des soins à domicile atteints de démence en Ontario. INTRODUCTION: Cette étude fournit une synthèse des caractéristiques sociodémographiques, psychosociales et sanitaires d'une vaste cohorte représentative des clients des soins à domicile en Ontario (âgés de 50 ans ou plus) atteints de démence et elle examine les variations de ces caractéristiques chez les clients atteints de maladies neurologiques concomitantes. MÉTHODOLOGIE: Les clients ont été évalués à l'aide de l'Instrument d'évaluation des résidents ­ Soins à domicile (RAI-HC) entre janvier 2003 et décembre 2010. Les analyses descriptives fournissent la répartition de ces caractéristiques en comparant les clients atteints de démence et ceux de plusieurs autres groupes ainsi que ceux atteints d'autres maladies neurologiques documentées. RÉSULTATS: Environ 22 % des clients (n = 104 802) avaient reçu un diagnostic de démence (âge moyen de 83 ans, 64 % de femmes) et un sur quatre parmi eux était atteint d'une maladie neurologique concomitante (AVC ou maladie de Parkinson la plupart du temps). Environ 43 % des clients atteints de démence n'habitaient pas avec leur principal aidant. Par rapport aux clients des groupes de comparaison, les clients atteints de démence présentaient des taux considérablement plus élevés de déficit cognitif et fonctionnel, d'agressivité, d'anxiété, d'errance et d'hallucinations ou de délire, avaient plus souvent un aidant en détresse et couraient un plus grand risque de placement en établissement. Par contre, ils étaient moins souvent atteints de diverses maladies chroniques et étaient moins nombreux à avoir eu recours à des services de santé récemment. Les symptômes de dépression étaient relativement fréquents chez les clients atteints de démence et chez ceux atteints d'une autre maladie neurologique. CONCLUSION: Les clients atteints de maladies neurologiques concomitantes présentaient des profils cliniques bien particuliers illustrant la nécessité de personnaliser et d'assouplir les services de soins à domicile et d'améliorer les programmes de soutien pour les aidants.

Mössbauer spectroscopy of europium-containing glasses: Optical activator study for x-ray image plates.

A fluorozirconate glass (ZBLAN) containing BaCl2 nanocrystals doped with divalent Eu is a promising material for x-ray image plates for medical diagnosis. Since it is known that Eu2+ readily oxidizes to Eu3+, which reduces fluorescence efficiency of the image plates, 151Eu Mössbauer spectroscopy was used in this work to monitor the Eu oxidation state of the samples during degradation over time in the presence of ambient humidity. In addition, Mössbauer spectroscopic experiments show that the oxidation state has already changed during the glass melt: The sample made from 5 mol% EuCl2 contained 78% EuCl2 + 22% EuCl3 deduced from the relative areas of the absorption lines. The sample made from 2.5 mol% EuCl2 + 2.5 mol% EuCl2 contained 37% EuCl2 + 63% EuCl3, i.e. 26% of the original EuCl2 was oxidized to EuCl3.

Cannabinoid CB2 receptor activation attenuates cytokine-evoked mucosal damage in a human colonic explant model without changing epithelial permeability.

Cannabinoid receptor activation is protective in animal colitis models. We sought to investigate if cannabinoids attenuated colitis-like tissue damage in human colonic specimens, with the hypothesis that cannabinoids would be protective in a cytokine-driven model of human colonic mucosal damage. Healthy human colonic mucosa was incubated with pro-inflammatory cytokines TNF-α and IL-1ß to elicit colitis-like tissue damage. The cytokine-driven increase in scored crypt and mucosal damage and lymphocyte density was attenuated with concomitant hydrocortisone pretreatment. The cannabinoid receptor 2 (CB2) receptor-selective agonist JWH-015 significantly reduced colitis scores following cytokine incubation, as evidenced by a reduction in mucosal crypt and luminal epithelial damage and lymphocyte density in the lamina propria. The effect of JWH-015 was reversed in the presence of the CB2 receptor inverse agonist JTE-907. Anandamide was also protective in the cytokine-incubated explant colitis model in a manner reversible with JTE-907, while CB1 receptor agonism with ACEA was without effect. TNF-α and IL-1ß together evoked an increase in paracellular epithelial permeability in Caco-2 cell monolayers over 48h of incubation. However, neither CB2 nor CB1 receptor activation altered the cytokine-evoked increase in permeability. These findings support a discrete role for CB2 receptors in the attenuation of detrimental pro-inflammatory cytokine-mediated mucosal damage in the human colon without directly affecting mucosal epithelial barrier function.

CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC.

The aim of this study was to evaluate the efficacy of the chemokine CCL19 (ELC) as an adjuvant for intradermal gene gun delivery of Her2/neu DNA and to investigate the role of B cells in CCL19-mediated enhancement of immune responses. Balb/c mice were immunized intramuscularly (i.m.) on days 1 and 15 with plasmid DNA (pDNA) (100 µg DNA) or intradermally (i.d.) by gene gun delivery (1-2 µg DNA). Administration of pDNA encoding Her2/neu (pDNA(Her2/neu) was compared with pDNA(Her2/neu) plus pDNA(CCL19), pDNA(CCL19), mock vector or uncoated gold particles/phosphate-buffered saline (PBS). Tumor challenge was performed subcutaneously on day 25 with syngeneic Her2/neu(+) tumor cells (D2F2/E2). Intradermal immunization by gene gun led to an enhancement of tumor protection by the DNA vaccine as compared with i.m. immunization. The protective effect of the vaccine was further enhanced by coadministration of pDNA(CCL19) both after i.m. and i.d. immunization. Tumor protection was associated with Her2/neu-specific T cell and humoral immune responses. Experiments in B-cell-deficient µMT mice showed that B cells are crucial for CCL19-mediated enhancement of tumor rejection, most likely as antigen-presenting B cells. DNA vaccines against Her2/neu may play a future role in the treatment of Her2/neu-positive breast cancer patients in a clinical situation of minimal residual disease.

A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury.

Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30 % of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the "miserable minority," the cognitive and physical symptoms do not resolve following the first 3 months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both posttraumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI. The challenge is thus to use neuroimaging tools that are sensitive to DAI/TAI, such as diffusion tensor imaging (DTI), in order to detect brain injuries in mTBI. Of note here, recent advances in neuroimaging techniques, such as DTI, make it possible to characterize better extant brain abnormalities in mTBI. These advances may lead to the development of biomarkers of injury, as well as to staging of reorganization and reversal of white matter changes following injury, and to the ability to track and to characterize changes in brain injury over time. Such tools will likely be used in future research to evaluate treatment efficacy, given their enhanced sensitivity to alterations in the brain. In this article we review the incidence of mTBI and the importance of characterizing this patient population using objective radiological measures. Evidence is presented for detecting brain abnormalities in mTBI based on studies that use advanced neuroimaging techniques. Taken together, these findings suggest that more sensitive neuroimaging tools improve the detection of brain abnormalities (i.e., diagnosis) in mTBI. These tools will likely also provide important information relevant to outcome (prognosis), as well as play an important role in longitudinal studies that are needed to understand the dynamic nature of brain injury in mTBI. Additionally, summary tables of MRI and DTI findings are included. We believe that the enhanced sensitivity of newer and more advanced neuroimaging techniques for identifying areas of brain damage in mTBI will be important for documenting the biological basis of postconcussive symptoms, which are likely associated with subtle brain alterations, alterations that have heretofore gone undetected due to the lack of sensitivity of earlier neuroimaging techniques. Nonetheless, it is noteworthy to point out that detecting brain abnormalities in mTBI does not mean that other disorders of a more psychogenic origin are not co-morbid with mTBI and equally important to treat. They arguably are. The controversy of psychogenic versus physiogenic, however, is not productive because the psychogenic view does not carefully consider the limitations of conventional neuroimaging techniques in detecting subtle brain injuries in mTBI, and the physiogenic view does not carefully consider the fact that PTSD and depression, and other co-morbid conditions, may be present in those suffering from mTBI. Finally, we end with a discussion of future directions in research that will lead to the improved care of patients diagnosed with mTBI.

CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model.

Secondary lymphoid-tissue chemokine (SLC/CCL21) is a CC chemokine that is constitutively expressed in various lymphoid tissues and binds to chemokine receptor CCR7 on mature dendritic cells (DCs) and distinct T-and B-cell sub-populations. In vivo, CCL21 regulates the encounters between DC and T cells and thus is a key regulator of adaptive immune responses. We asked whether CCL21 is able to augment immunogenicity of a DNA-based vaccine against Her2/neu in a Balb/c mouse model with syngeneic Her2/neu+ tumor cells (D2F2/E2). Mice were vaccinated intramuscularly with plasmid DNA (pDNA) on day 1 and boosted on day 15; tumor challenge was performed subcutaneously on day 25. Coexpression of CCL21 and Her-2/neu resulted in induction of a TH1-polarized immune response and substantial improvement of the protective effect of the DNA vaccine. Coexpression of tumor antigen pDNA(Her2/neu) with both pDNA(GM-CSF) and pDNA(CCL21) as adjuvants led to further improvement of protection by the vaccine (70% tumor-free mice on day 35 vs 40% with either adjuvant alone vs 5-10% with tumor antigen alone). Our results show that CCL21 is a potent adjuvant for DNA vaccination, particularly in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Clinical use of a pDNA(Her2/neu/CCL21/GM-CSF) vaccine might be particularly promising in minimal residual Her2/neu+ breast cancer.