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A clinical trial is any research on human subjects that involves an investigational medicinal product or device. Investigational medicinal products include unlicensed drugs or drugs used outside the product license (e.g. for a new indication) (ICH-GCP). As per the internationally accepted ICH-GCP guidelines, clinical trials should be conducted strictly per the approved protocol. However, during the lifecycle of a trial, protocol deviations may occur. Under ICH efficacy guidelines, protocol deviations are divided into non-important (minor) or important (major), and the latter can jeopardise the participant’s rights, safety or the quality of data generated by the study. Existing guidelines on protocol deviation management do not detail or standardise actions to be taken for participants, investigational products, data or samples as part of a holistic management of important protocol deviations. Herein, we propose guidelines to address the current literature gap and promote the standardisation of actions to address important protocol deviations in clinical trials. The advised actions should complement the existing local institutional review board and national regulatory authority requirements.

Our goal is to present recent progress in understanding the biological mechanisms underlying anemia from a public health perspective. We describe important advances in understanding common causes of anemia and their interactions, including iron deficiency (ID), lack of other micronutrients, infection, inflammation, and genetic conditions. ID develops if the iron circulating in the blood cannot provide the amounts required for red blood cell production and tissue needs. ID anemia develops as iron-limited red blood cell production fails to maintain the hemoglobin concentration above the threshold used to define anemia. Globally, absolute ID (absent or reduced body iron stores that do not meet the need for iron of an individual but may respond to iron supplementation) contributes to only a limited proportion of anemia. Functional ID (adequate or increased iron stores that cannot meet the need for iron because of the effects of infection or inflammation and does not respond to iron supplementation) is frequently responsible for anemia in low- and middle-income countries. Absolute and functional ID may coexist. We highlight continued improvement in understanding the roles of infections and inflammation in causing a large proportion of anemia. Deficiencies of nutrients other than iron are less common but important in some settings. The importance of genetic conditions as causes of anemia depends upon the specific inherited red blood cell abnormalities and their prevalence in the settings examined. From a public health perspective, each setting has a distinctive composition of components underlying the common causes of anemia. We emphasize the coincidence between regions with a high prevalence of anemia attributed to ID (both absolute and functional), those with endemic infections, and those with widespread genetic conditions affecting red blood cells, especially in sub-Saharan Africa and regions in Asia and Oceania.

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OBJECTIVE--Erythropoietin (EPO) may be protective for early stage diabetic retinopathy, although there are concerns that it could exacerbate retinal angiogenesis and thrombosis. A peptide based on the EPO helix-B domain (helix B-surface peptide [pHBSP]) is nonerythrogenic but retains tissue-protective properties, and this study evaluates its therapeutic potential in diabetic retinopathy. RESEARCH DESIGN AND METHODS--After 6 months of streptozotocin-induced diabetes, rats (n = 12) and age-matched nondiabetic controls (n = 12) were evenly split into pHBSP and scrambled peptide groups and injected daily (10 µg/kg per day) for 1 month. The retina was investigated for glial dysfunction, microglial activation, and neuronal DNA damage. The vasculature was dual stained with isolectin and collagen IV. Retinal cytokine expression was quantified using real-time RT-PCR. In parallel, oxygen-induced retinopathy (OIR) was used to evaluate the effects of pHBSP on retinal ischemia and neovascularization (1-30 µg/kg pHBSP or control peptide). RESULTS--pHBSP or scrambled peptide treatment did not alter hematocrit. In the diabetic retina, Muller glial expression of glial fibrillary acidic protein was increased when compared with nondiabetic controls, but pHBSP significantly reduced this stress-related response (P < 0.001). CD11b+ microglia and proinflammatory cytokines were elevated in diabetic retina responses, and some of these responses were attenuated by pHBSP (P < 0.01-0.001). pHBSP significantly reduced diabetes-linked DNA damage as determined by 8-hydroxydeoxyguanosine and transferase-mediated dUTP nick-end labeling positivity and also prevented acellular capillary formation (P < 0.05). In OIR, pHBSP had no effect on preretinal neovascularization at any dose. CONCLUSIONS Treatment with an EPO-derived peptide after diabetes is fully established can significantly protect against neuroglial and vascular degenerative pathology without altering hematocrit or exacerbating neovascularization. These findings have therapeutic implications for disorders such as diabetic retinopathy. Diabetes 60:2995-3005, 2011, Beyond its established hormonal role in maintaining erythrocyte mass, erythropoietin (EPO) also functions in a paracrine manner to protect tissues during ischemic, toxic, and traumatic instilts (1). EPO is highly [...]

Cancer cachexia (CC) is a severe complication during the last stages of the disease, which is characterized by the substantial loss of muscle and fat mass. Currently, there is no effective treatment of CC. Erythropoietin plays tissue‐protective role in different tissues. Based on the structure of erythropoietin, small non‐erythropoietic peptides were synthesized, which activate tissue‐protective signalling pathways. Here, we investigated the influence of the tissue‐protective peptide ARA 284 on CC in rats using the Yoshida hepatoma model. Treatment with ARA 284 (1.7 μg/kg/day) counteracted the loss of body weight (12.46 ± 4.82% ARA 284 vs. 26.85 ± 0.88% placebo, P< 0.01), fat mass (P< 0.01), and lean mass (P< 0.01). It improved spontaneous activity of ARA 284‐treated animals. Further, gastrocnemius mass was increased (13.2% ARA 284 vs. placebo, P< 0.01) in association with induced p‐Akt (P< 0.01) and decreased in p‐p38 MAPK, GSK‐3β, and myostatin (all P< 0.01), suggesting an induction of anabolic pathways. At the same time, we observed the significant increase in the survival of animals by high‐dose ARA 284 treatment (hazard ratio: 0.46, 95% confidence interval: 0.23–0.94, P= 0.0325). Taken together these results suggest that ARA 284 can be considered beneficial in experimental CC and it remains to be seen, if it can have similar beneficial effects in CC patient.

The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard that applies best practices developed for genomics and for other microscopy data to highly multiplexed tissue images and traditional histology.

IN THE OLD but continuing debate about the distribution of human intelligence, I've seen clear and repeated evidence that even the seriously disadvantaged and the least impressive among us can [...]

As the public debate goes on about the two men who are rather foolishly being made to seem the originators of the, Vietnam War, my own unusual experiences with each [...]

Congenital malformations are the leading cause of death in infants of insulin-dependent diabetic mothers. Although there are data to suggest that hyperglycemia itself is teratogenic, few mechanisms have been proposed [...]

When the international trade talks known as the Uruguay Round finally were concluded in April, most of the world breathed a sigh of relief. After eight often-acrimonious years of hashing […]

NOTHING LESS THAN A REVOLUTION in the way Jews and non-Jews think about each other--that is the potential product of a drive, in the making for several decades, under the [...]

Even while parts of the world seem to be taking leave of civilization, far more nations are showing a new zest for free and fair elections. Much of the credit […]

When it was reported earlier this year that fuel rods were being removed from a nuclear reactor near Pyongyang, the North Korean capital, alarms rang in Washington. Since the spent [...]

Something about today's kind of joblessness is different from the brief spasms of unemployment that used to accompany post-Second World War recessions. Economists shudder when they hear that a shortage [...]

The Post-American World. By Fareed Zakaria. New York: W. W. Norton & Company, 2008. 292 pages. $25.95. Since the passing of Walter Lippmann in 1974, no journalist has risen to [...]

The North American Free Trade Agreement (NAFTA) is expected to have a significant impact on the business, political, and social life in the US, Canada, and Mexico, and the rest of the world. Unlike the unification of the Europe's closely related markets, NAFTA is considered revolutionary because it will try to unite disparate and distant countries. There is a great possibility that NAFTA will expand to include Central and South American nations in the coming years, leading to the emergence of a new economic bloc . The three-nation free-trade negotiations will end with the signing and ratification of the NAFTA by the US Senate in 1993.

Business enterprises, especially those that trade and invest heavily abroad, should have clear and defined strategies in dealing with the currency markets because currency mismanagement can lead to great financial loss. Corporate financial planners should understand that the value of a currency is governed by constantly changing factors such as interest-rates. To avoid heavy losses,companies should not invest their entire future on any currency market forecast. They should be aware of the direction changes these markets will take, and know the time and the ways to hedge against them. There are several approaches to hedging, including considering options on foreign currency, arranging to buy 'forward ' currency, and using the US Dollar Index.

At the Abyss: An Insider's History of the Cold War. By Thomas C. Reed. New York: Ballantine Books, 2004. 368 pages. $25.95. Reviewed by Joseph R. Cerami, Bush School of [...]

By Fareed Zakaria. New York: W. W. Norton, 2003. 286 pages. $24.95. Fareed Zakaria is an important and usually critical observer of the current Administration's foreign policy. As editor of [...]

PurposeThe safety and efficacy of X-82, an orally administered inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor, was investigated for treatment of wet age-related macular degeneration (AMD) in a phase II clinical trial.MethodsThis phase II, randomised, double-masked, placebo-controlled trial enrolled subjects with a prior diagnosis of exudative AMD having received at least two intravitreal injections of anti-VEGF therapy. Subjects were randomised equally into four groups that received either daily 50mg, 100mg or 200mg dosages of X-82 or a placebo tablet. At each 4-week interval visit for 52 weeks, subjects were to be assessed to determine if rescue treatment was needed with anti-VEGF therapy.Results157 patients were enrolled. Due to gastrointestinal and hepatobiliary adverse events and the fulfilment of the primary endpoint, the trial was stopped prematurely after a second interim analysis. The primary endpoint of non-inferiority of visual acuity compared with placebo was demonstrated in all groups receiving X-82 (p<0.001). There was a dose-dependent trend in the number of injections over a 52-week period, with the 50 mg (n=40), 100 mg (n=39), 200 mg (n=39) and placebo (n=39) group requiring 6.7, 6.0, 4.7 and 8.1 injections, respectively.ConclusionsX-82 oral therapy in combination with pro re nataanti-VEGF injections showed non-inferiority in visual acuity outcomes while achieving a dose-dependent decrease in the number of anti-VEGF injections compared with placebo. Given the limited tolerability and safety issues observed, X-82 does not have a sufficient benefit to risk profile in treatment of patients with AMD.

The new highway bill provides for increased rail-service projects around the country, and transit authorities are touting the advantages of traveling on the fast track. The recently passed highway bill [...]

Background: Alzheimer’s Disease (AD) is a multifactorial disorder driven by genetic and modifiable lifestyle risk factors. Lifestyle primary prevention initiatives may reduce the prevalence and incidence of dementia in older adults. Objectives: The E.Mu.N.I study is a randomized controlled trial investigating the effect of multilevel non-pharmacologic interventions on cognitive performances (primary outcome) and structural and vascular brain MRI markers (secondary outcome), as well as markers of brain functional connectivity change (exploratory outcome), in older adults with subjective memory decline (SMD). Here, we present the study design and the baseline features of the sample. Methods: Cognitively intact older adults with SMD, enrolled between February 2016 and June 2017, were randomly assigned to one of the 3 interventions for 1 year: Active Control Intervention (ACI), i.e., educational lessons; Partial Intervention (PI), i.e., homotaurine administration (100 mg/die) and lessons on the Mediterranean diet; Multilevel Intervention (MI), i.e., PI plus computerized cognitive training and physical exercise training. Results: One-hundred and twenty-eight eligible participants were enrolled (66% female; age: 68?±?5 years). Eighty-two percent of the sample was composed of volunteers with SMD from the community. Participants were randomly allocated to the interventions as follows: ACI (N?=?40), PI (N?=?44), MI (N?=?44). No significant differences among groups emerged on socio-demographic, clinical–neuropsychological variables and MRI markers at baseline. Conclusions: The outcomes obtained from the E.Mu.N.I. study will clarify the efficacy of multilevel non-pharmacologic interventions on cognitive and neuroimaging markers in SMD individuals. This is a crucial step forward for the development of cost-effective non-pharmacologic primary prevention initiatives for AD.

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases.

Motor neuron dysfunctions (MNDys) in Frontotemporal Lobar Degeneration (FTLD) have been consistently reported. Clinical and neurophysiological findings proved a variable range of pathological changes, also affecting the corticospinal tract (CST).

What's in store for the U.S. currency that has been the standard of the world? Bankers and economists describe the real value of an inflated Yankee dollar. It sounds like [...]

The purpose of this article is to define how the selection of HVAC equipment and layout impact the achievable noise criteria (NC) levels in occupied spaces. It will focus on [...]

HUMANISTS EXPECT their heroes to be positive. That's what humanism is, after all--a positive morality that launches off the negation of belief; an actively asserted moral framework that hinges on [...]

The calm period in the Middle East following the conclusion of the Persian Gulf War could result in a long-anticipated economic boom that would encourage an inflow of industrial investment. The investment could include such agro-industrial projects as food packaging and processing, as well as water conservation and fish farming, turnkey factory projects, and the development of local markets. Although the first companies doing business in the Middle East will be those with previous ties there, subsequent diversification could occur in the communications, medical supplies, and hospital management industries. In addition to Kuwait and Saudi Arabia, the United Arab Emirates, Oman, Bahrain, and Israel could provide investment opportunities for US firms. The negative elements of Middle East investment that should be kept in mind are the obstacles to marketing caused by bitterness among Palestinians and other Arabs, the weak home market, and the close relationship between the Soviet Union and Iraq.

Brain connectivity measures represent candidate biomarkers of neuronal dysfunction in neurodegenerative diseases. Previous findings suggest that the behavioural variant of frontotemporal dementia (bvFTD) and its variants (i.e., frontal and temporo-limbic) may be related to the vulnerability of distinct functional connectivity networks. In this study, 82 bvFTD patients were included, and two patient groups were identified as frontal and temporo-limbic bvFTD variants. Two advanced multivariate analytical approaches were applied to FDG-PET data, i.e., sparse inverse covariance estimation (SICE) method and seed-based interregional correlation analysis (IRCA). These advanced methods allowed the assessment of (i) the whole-brain metabolic connectivity, without any a prioriassumption, and (ii) the main brain resting-state networks of crucial relevance for cognitive and behavioural functions.

Discusses the contribution of blood glucose to age-associated declines in the functioning of cells and tissues. Chemical attachment of glucose to proteins; Nonenzymatic glycosylation of proteins in the body; Formation of cross-links between adjacent protein molecules; Role of protein crosslinking on the stiffening and loss of elasticity of aging tissues.

The article discusses the prevention of sickle-cell anemia through the use of chemical sodium cyanate. Sickle-cell anemia is a hereditary disorder caused by the presence of abnormal hemoglobin, the iron-containing protein in red blood cells that carries oxygen from the lungs to other tissues. Based on chemical analysis of the cyanate-treated cells, the compound has reacted with the terminal amino group of the hemoglobin molecule. Once the reaction occurs it is irreversible that the cyanate stays on the hemoglobin for the lifetime of the molecule.

Background: We previously reported that treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) in combination with the checkpoint inhibitors targeting CTLA-4 and/or PD-1 (ipilimumab (I) and nivolumab (N)) led to high overall response rates (ORR) and complete response (CR) rates in relapsed/refractory (R/R) Hodgkin's lymphoma patients in a Phase 1 ECOG-ACRIN sponsored clinical trial. As previously presented in the Phase 1 component of NCT01896999 (E4412), the ORR for the treatment arms were: BV+I 76%, BV+N 89%, and BV+I+N 82%, with CR rates of 57%, 61%, and 73% across the groups, respectively. This suggested that not all patients who responded derived equal benefit. Moreover, with a median follow-up of 2.24 years, the PFS of 1.1 year, NR, and 2.49 years across the groups suggest that even some patients who achieved CR progressed on or subsequent to treatment. Currently biomarkers have no ability to predict which patients will maximally benefit from these therapies. We investigated blood-based immune biomarkers mechanistically across all cohorts which may explain differential responses and guide future treatment decisions for R/R HL patients.

Truth as Propaganda Arch Puddington offers up a clearheaded look at the controversial Radio Free Europe and Radio Liberty broadcasts that shook communism's hold on Eastern Europe and Russia. It [...]

Marxism stole years from Poland's youth, but some young people trumped the system -- or so author Antoni Libera suggests in a delightful novel, Madame, set in Warsaw during the [...]

The Argentine dance sweeping the world is easy to learn -- if you're something of a Fred Astaire with a year to spare and access to the masters. Hardly any [...]

Despite a booming economy and recent fluctuations in the price of the precious metal, financial analysts, fund managers and brokers still regard it as a sound investment. When its price [...]

As big corporations continue the trend of massive mergers, they may be imperiling the U.S. economy. The billowing size of each new merger or takeover gives the impression that corporate [...]

An art museum that looks like a voluptuous metal flower has riveted the world of art and architecture and is turning the once-drab city of Bilbao into a world-class tourist [...]

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In the proliferation of art museum, the ruggedly industrial Massachusetts Museum of Contemporary Art seems particular well-suited to display its cache of modern art. To speak frankly, I've long considered [...]

The U.S. military has been stretched to the breaking point. For the U.S. to have a 21st-century fighting force will call for new spending of a magnitude that will stun [...]

After 65 years of plains based on the views of ardent, internationalist traders, the sealing trade deficit threatens to undermine the prosperity of United States. Treasury Secretary Robert Rubin, in [...]

Epidemiological studies suggest that there exists a beneficial effect on low to moderate alcohol consumption on the incidence of cardiovascular disease. Once ingested, alcohol is metabolized to acetaldehyde, a two-carbon, [...]

Congress failed to pass `the worst trade bill ever,' but the legislation could have made Africa into a transshipment point for goods made in China. Clinton may bring it back. [...]

The president wants to enter into foreign-trade agreements with limited congressional oversight. But opponents fear such authority will further erode protection of U.S. workers. A big part of U.S. foreign [...]

Power Rules: How Common Sense Can Rescue American Foreign Policy by Leslie H. Gelb New York: HarperCollins Publishers, 2009 352 pages $27.99 In Power Rules, Leslie Gelb, President Emeritus and [...]

In this paper we study the relationships between a family of ALC -like fuzzy description logics (FDLs) defined over left-continuous t-norms and some many-valued multi-modal logics (MMLs). We analyze these relationships in both directions, that is, how to merge FDLs into MMLs and vice-versa. The analysis starts from the relationships between the languages to reach systematically the deeper level of reasoning tasks. At this level we are able to truly investigate both formalisms from each other point of view. Finally, the results concerning translations between reasoning tasks are applied in order to get decidability and complexity bounds. [ABSTRACT FROM AUTHOR]

Cognitive reserve may delay disease onset and mitigate symptoms presentation in neurodegenerative dementias. Although high occupation levels can be associated with higher cognitive reserve in the behavioural variant of frontotemporal dementia (bvFTD), it was never addressed how specific occupation profiles involving social interaction, executive and attention abilities can modulate neural reserve in bvFTD.