Small pelagics in a changing ocean : Biological responses of sardine early stages to warming

Small pelagic fishes are known to respond rapidly to changes in ocean climate. In this study, we evaluate the effects of future environmental warming (+2°C) during the early ontogeny of the European sardine, Sardina pilchardus. Warming reduced the survival of 30-day-old larvae by half. Length at hatching increased with temperature as expected, but no significant effect was observed on the length and growth at 30 days post-hatching. Warming did not significantly affect the thermal tolerance of sardine larvae, even though the mean lethal temperature increased by 1°C. In the warm conditions, sardine larvae showed signs of thermal stress, indicated by a pronounced increase in larval metabolism (Q 10 = 7.9) and a 45% increase in the heat shock response. Lipid peroxidation was not significantly affected by the higher temperature, even though the mean value doubled. Warming did not affect the time larvae spent swimming, but decreased by 36% the frequency of prey attacks. Given the key role of these small pelagics in the trophic dynamics off the Western Iberian upwelling ecosystem, the negative effects of warming on the early stages may have important implications for fish recruitment and ecosystem structure.

Efficacy of early skin-to-skin contact on the rate of exclusive breastfeeding in term neonates: a randomized controlled trial

Background: Despite multiple benefits of breast milk, the rates of exclusive breastfeeding in developing countries are low. Objective: To evaluate the efficacy of early skin -to -skin contact (SSC) on the rate of exclusive breastfeeding (EBF) at 6 weeks of age among term neonates born by vaginal delivery. Methods: Term neonates born by vaginal delivery and did not require any resuscitation were randomized at birth to SSC (n=100) and control (n=100) group. Immediately after clamping the umbilical cord, SSC group neonates were placed on the bare bosom of mother and control group neonates were placed under a radiant warmer for a period of 45 minutes each while mothers underwent management of the third stage of labor and episiotomy repair. Pain experienced by mother during episiotomy repair was recorded using a numerical pain scale The primary outcome evaluated was the rate of exclusive breastfeeding at 6 weeks of postnatal age. Results: A significantly higher proportion of neonates were exclusively breastfeed at 6 weeks of age in the SSC group than in the control group (72% vs. 57.6%, p=0.04, relative risk: 1.3, 95% confidence interval: 1.0 -1.6). The pain score during episiotomy repair in mothers of the SSC group was significantly lower than the control group (4.74±0.85 versus 5.34±0.81; P <0.01). Conclusions: Early SSC significantly improved the rate of exclusively breastfeeding at 6 weeks of age among healthy term neonates. An important additional effect was a decrease in the amount of pain that mothers in the SSC group experienced during episiotomy repair.

Kitāb al-Sukkardān wa-ʻajāʼib al-buldān / taʼlīf al-Shaykh al-Imām al-ʻĀlim al-ʻAllāmah al-ʻUmda Shihāb al-Dīn Abū al-ʻAbbās Aḥmad al-shahīr bi-Ibn Abī Ḥajalah al-Tilimsānī : manuscript, 1567

Title from fol. 1r.

Kitāb Tarjamat thaghr Dimyāṭ al-maḥrūs wa-mā waqaʻa bihā min ʻahd Nūḥ ʻalayhi al-salām ilá ākhir dawlat al-Turk min Kitāb al-ʻAnāṣir li-majālis al-Malik al-Nāṣir : manuscript, [1567]

A history of Damietta, Egypt.

Medicina, y cirugia racional, y espargirica, sin obra manual de hierro, ni fuego, purificada con el de la caridad, en el crisol de la razon, y experiencia, para alivio de los enfermos : con su antidotario de rayzes ... y la farmacopea, donde se explican el modo, y composicion de los remedios, con el uso, dosis, y aplicacion de ellos ... /

Mode of access: Internet.

Early gene expression analysis in 9L orthotopic tumor-bearing rats identifies immune modulation in molecular response to synchrotron microbeam radiation therapy

Synchrotron Microbeam Radiation Therapy (MRT) relies on the spatial fractionation of the synchrotron photon beam into parallel micro-beams applying several hundred of grays in their paths. Several works have reported the therapeutic interest of the radiotherapy modality at preclinical level, but biological mechanisms responsible for the described efficacy are not fully understood to date. The aim of this study was to identify the early transcriptomic responses of normal brain and glioma tissue in rats after MRT irradiation (400Gy). The transcriptomic analysis of similarly irradiated normal brain and tumor tissues was performed 6 hours after irradiation of 9 L orthotopically tumor-bearing rats. Pangenomic analysis revealed 1012 overexpressed and 497 repressed genes in the irradiated contralateral normal tissue and 344 induced and 210 repressed genes in tumor tissue. These genes were grouped in a total of 135 canonical pathways. More than half were common to both tissues with a predominance for immunity or inflammation (64 and 67% of genes for normal and tumor tissues, respectively). Several pathways involving HMGB1, toll-like receptors, C-type lectins and CD36 may serve as a link between biochemical changes triggered by irradiation and inflammation and immunological challenge. Most immune cell populations were involved: macrophages, dendritic cells, natural killer, T and B lymphocytes. Among them, our results highlighted the involvement of Th17 cell population, recently described in tumor. The immune response was regulated by a large network of mediators comprising growth factors, cytokines, lymphokines. In conclusion, early response to MRT is mainly based on inflammation and immunity which appear therefore as major contributors to MRT efficacy.

Initiation and continuation of randomized trials after the publication of a trial stopped early for benefit asking the same study question: STOPIT-3 study design

BACKGROUND Randomized control trials (RCTs) stopped early for benefit (truncated RCTs) are increasingly common and, on average, overestimate the relative magnitude of benefit by approximately 30%. Investigators stop trials early when they consider it is no longer ethical to enroll patients in a control group. The goal of this systematic review is to determine how investigators of ongoing or planned RCTs respond to the publication of a truncated RCT addressing a similar question. METHODS/DESIGN We will conduct systematic reviews to update the searches of 210 truncated RCTs to identify similar trials ongoing at the time of publication, or started subsequently, to the truncated trials ('subsequent RCTs'). Reviewers will determine in duplicate the similarity between the truncated and subsequent trials. We will analyze the epidemiology, distribution, and predictors of subsequent RCTs. We will also contact authors of subsequent trials to determine reasons for beginning, continuing, or prematurely discontinuing their own trials, and the extent to which they rely on the estimates from truncated trials. DISCUSSION To the extent that investigators begin or continue subsequent trials they implicitly disagree with the decision to stop the truncated RCT because of an ethical mandate to administer the experimental treatment. The results of this study will help guide future decisions about when to stop RCTs early for benefit.

Bayesian Adaptive Designs for Early Phase Clinical Trials

My dissertation focuses mainly on Bayesian adaptive designs for phase I and phase II clinical trials. It includes three specific topics: (1) proposing a novel two-dimensional dose-finding algorithm for biological agents, (2) developing Bayesian adaptive screening designs to provide more efficient and ethical clinical trials, and (3) incorporating missing late-onset responses to make an early stopping decision. Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which toxicity and efficacy monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a phase I/II trial design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. Trials of combination therapies for the treatment of cancer are playing an increasingly important role in the battle against this disease. To more efficiently handle the large number of combination therapies that must be tested, we propose a novel Bayesian phase II adaptive screening design to simultaneously select among possible treatment combinations involving multiple agents. Our design is based on formulating the selection procedure as a Bayesian hypothesis testing problem in which the superiority of each treatment combination is equated to a single hypothesis. During the trial conduct, we use the current values of the posterior probabilities of all hypotheses to adaptively allocate patients to treatment combinations. Simulation studies show that the proposed design substantially outperforms the conventional multi-arm balanced factorial trial design. The proposed design yields a significantly higher probability for selecting the best treatment while at the same time allocating substantially more patients to efficacious treatments. The proposed design is most appropriate for the trials combining multiple agents and screening out the efficacious combination to be further investigated. The proposed Bayesian adaptive phase II screening design substantially outperformed the conventional complete factorial design. Our design allocates more patients to better treatments while at the same time providing higher power to identify the best treatment at the end of the trial. Phase II trial studies usually are single-arm trials which are conducted to test the efficacy of experimental agents and decide whether agents are promising to be sent to phase III trials. Interim monitoring is employed to stop the trial early for futility to avoid assigning unacceptable number of patients to inferior treatments. We propose a Bayesian single-arm phase II design with continuous monitoring for estimating the response rate of the experimental drug. To address the issue of late-onset responses, we use a piece-wise exponential model to estimate the hazard function of time to response data and handle the missing responses using the multiple imputation approach. We evaluate the operating characteristics of the proposed method through extensive simulation studies. We show that the proposed method reduces the total length of the trial duration and yields desirable operating characteristics for different physician-specified lower bounds of response rate with different true response rates.

Lynn to Halibut Point, Rockport, Massachusetts, Atlantic Coast, 1873 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Eldridge's new chart from Lynn to Halibut Point : with the harbors of Salem, Beverly, Marblehead, Manchester, Gloucester & Rockport, compiled from the latest surveys, [by George Eldridge] ; G.W. Boynton, sc. It was published by S. Thaxter & Son, 1873. Scale [ca. 1:58,370]. This map is a nautical chart covering the Atlantic Coast of Massachusetts from Lynn to Halibut Point, Rockport, Massachusetts. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Massachusetts State Plane Coordinate System, Mainland Zone (in Feet) (Fipszone 2001). All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, or other information associated with the principal map. This map shows coastal features such as lighthouses, buoys, beacons, rocks, channels, points, coves, islands, and more. Depths are shown by soundings and shading. Includes sailing directions and table of tides. This layer is part of a selection of digitally scanned and georeferenced historic maps of Massachusetts from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of regions, originators, ground condition dates (1755-1922), scales, and purposes. The digitized selection includes maps of: the state, Massachusetts counties, town surveys, coastal features, real property, parks, cemeteries, railroads, roads, public works projects, etc.

Barnstable, Massachusetts 15 Minute Digital Raster Graphic

This layer is a digital raster graphic of the historic 15-minute USGS topographic quadrangle map of Barnstable, Massachusetts. The edition date is 1893 and the map was reprinted in 1907. A digital raster graphic (DRG) is a scanned image of a U.S. Geological Survey (USGS) standard series topographic map, including all map collar information. The image inside the map neatline is geo-referenced to the surface of the earth and fit to the Universal Transverse Mercator projection. The horizontal positional accuracy and datum of the DRG matches the accuracy and datum of the source map. The names of quadrangles which border this one appear on the map collar in their respective positions (N,S,E,W) in relation to this map.

Barre, Massachusetts 15 Minute Digital Raster Graphic

This layer is a digital raster graphic of the historic 15-minute USGS topographic quadrangle map of Barre, Massachusetts. The suvery (ground condition) date is 1887, the edition date is March, 1894 and the map was reprinted in 1942. A digital raster graphic (DRG) is a scanned image of a U.S. Geological Survey (USGS) standard series topographic map, including all map collar information. The image inside the map neatline is geo-referenced to the surface of the earth and fit to the Universal Transverse Mercator projection. The horizontal positional accuracy and datum of the DRG matches the accuracy and datum of the source map. The names of quadrangles which border this one appear on the map collar in their respective positions (N,S,E,W) in relation to this map.

Becket, Massachusetts 15 Minute Digital Raster Graphic

This layer is a digital raster graphic of the historic 15-minute USGS topographic quadrangle map of Becket, Massachusetts. The survey (ground condition) date is 1886. A digital raster graphic (DRG) is a scanned image of a U.S. Geological Survey (USGS) standard series topographic map, including all map collar information. The image inside the map neatline is geo-referenced to the surface of the earth and fit to the Universal Transverse Mercator projection. The horizontal positional accuracy and datum of the DRG matches the accuracy and datum of the source map. The names of quadrangles which border this one appear on the map collar in their respective positions (N,S,E,W) in relation to this map.

Belchertown, Massachusetts 15 Minute Digital Raster Graphic

This layer is a digital raster graphic of the historic 15-minute USGS topographic map of the Belchertown, Massachusetts quadrangle. The suvey (ground condition) dates are 1885 and 1887; the edition date is November, 1893. A digital raster graphic (DRG) is a scanned image of a U.S. Geological Survey (USGS) standard series topographic map, including all map collar information. The image inside the map neatline is geo-referenced to the surface of the earth and fit to the Universal Transverse Mercator projection. The horizontal positional accuracy and datum of the DRG matches the accuracy and datum of the source map. The names of quadrangles which border this one appear on the map collar in their respective positions (N,S,E,W) in relation to this map.