Effects of Protein Deficiency on Perinatal and Postnatal Health Outcomes

There are a variety of environmental insults that can occur during pregnancy which cause low birth weight and poor fetal health outcomes. One such insult is maternal malnutrition, which can be further narrowed down to a low protein diet during gestation. Studies show that perinatal protein deficiencies can impair proper organ growth and development, leading to long-term metabolic dysfunction. Understanding the molecular mechanisms that underlie how this deficiency leads to adverse developmental outcomes is essential for establishing better therapeuticstrategies that may alleviate or prevent diseases in later life. This chapter reviews how perinatal protein restriction in humans and animals leads to metabolic disease, and it identifies the mechanisms that have been elucidated, to date. These include alterations in transcriptional and epigenetic mechanisms, as well as indirect means such as endoplasmic reticulum (ER) stress and oxidative stress. Furthermore, nutritional and pharmaceutical interventions are highlighted to illustrate that the plasticity of the underdeveloped organs during perinatal life can be exploited to prevent onset of long-term metabolic disease

Dengue 1 Diversity and Microevolution, French Polynesia 2001–2006: Connection with Epidemiology and Clinics

The molecular characterization of 181 serotype 1 Dengue fever (DENV-1) viruses collected regularly during the 2001–2006 period in French Polynesia (FP) from patients experiencing various clinical presentations revealed that the virus responsible for the severe 2001 outbreak was introduced from South-East Asia, and evolved under an endemic mode until a new epidemic five years later. The dynamics of DENV-1 epidemics in FP did not follow the model of repeated virus introductions described in other South Pacific islands. They were characterized by a long sustained viral circulation and the absence of new viral introduction over a six-year period. Viral genetic variability was not observed only during outbreaks. In contrast with conventional thinking, a significant part of DENV-1 evolution may occur during endemic periods, and may reflect adaptation to the mosquito vector. However, DENV-1 evolution was globally characterized by strong purifying selection pressures leading to genome conservation, like other DENV serotypes and other arboviruses subject to constraints imposed by the host-vector alternating replication of viruses. Severe cases—dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)—may be linked to both viral and host factors. For the first time, we report a significant correlation between intra-host viral genetic variability and clinical outcome. Severe cases were characterized by more homogeneous viral populations with lower intra-host genetic variability

Unexpected decline in tuberculosis cases coincident with economic recession -- United States, 2009

<p>Abstract</p> <p>Background</p> <p>Since 1953, through the cooperation of state and local health departments, the U.S. Centers for Disease Control and Prevention (CDC) has collected information on incident cases of tuberculosis (TB) disease in the United States. In 2009, TB case rates declined -11.4%, compared to an average annual -3.8% decline since 2000. The unexpectedly large decline raised concerns that TB cases may have gone unreported. To address the unexpected decline, we examined trends from multiple sources on TB treatment initiation, medication sales, and laboratory and genotyping data on culture-positive TB.</p> <p>Methods</p> <p>We analyzed 142,174 incident TB cases reported to the U. S. National Tuberculosis Surveillance System (NTSS) during January 1, 2000-December 31, 2009; TB control program data from 59 public health reporting areas; self-reported data from 50 CDC-funded public health laboratories; monthly electronic prescription claims for new TB therapy prescriptions; and complete genotyping results available for NTSS cases. Accounting for prior trends using regression and time-series analyses, we calculated the deviation between observed and expected TB cases in 2009 according to patient and clinical characteristics, and assessed at what point in time the deviation occurred.</p> <p>Results</p> <p>The overall deviation in TB cases in 2009 was -7.9%, with -994 fewer cases reported than expected (<it>P </it>< .001). We ruled out evidence of surveillance underreporting since declines were seen in states that used new software for case reporting in 2009 as well as states that did not, and we found no cases unreported to CDC in our examination of over 5400 individual line-listed reports in 11 areas. TB cases decreased substantially among both foreign-born and U.S.-born persons. The unexpected decline began in late 2008 or early 2009, and may have begun to reverse in late 2009. The decline was greater in terms of case counts among foreign-born than U.S.-born persons; among the foreign-born, the declines were greatest in terms of percentage deviation from expected among persons who had been in the United States less than 2 years. Among U.S.-born persons, the declines in percentage deviation from expected were greatest among homeless persons and substance users. Independent information systems (NTSS, TB prescription claims, and public health laboratories) reported similar patterns of declines. Genotyping data did not suggest sudden decreases in recent transmission.</p> <p>Conclusions</p> <p>Our assessments show that the decline in reported TB was not an artifact of changes in surveillance methods; rather, similar declines were found through multiple data sources. While the steady decline of TB cases before 2009 suggests ongoing improvement in TB control, we were not able to identify any substantial change in TB control activities or TB transmission that would account for the abrupt decline in 2009. It is possible that other multiple causes coincident with economic recession in the United States, including decreased immigration and delayed access to medical care, could be related to TB declines. Our findings underscore important needs in addressing health disparities as we move towards TB elimination in the United States.</p

The Peter Pan paradigm

Genetic and environmental agents that disrupt organogenesis are numerous and well described. Less well established, however, is the role of delay in the developmental processes that yield functionally immature tissues at birth. Evidence is mounting that organs do not continue to develop postnatally in the context of these organogenesis insults, condemning the patient to utilize under-developed tissues for adult processes. These poorly differentiated organs may appear histologically normal at birth but with age may deteriorate revealing progressive or adult-onset pathology. The genetic and molecular underpinning of the proposed paradigm reveals the need for a comprehensive systems biology approach to evaluate the role of maternal-fetal environment on organogenesis

Validation of diffusion tensor MRI measurements of cardiac microstructure with structure tensor synchrotron radiation imaging.

Background Diffusion tensor imaging (DTI) is widely used to assess tissue microstructure non-invasively. Cardiac DTI enables inference of cell and sheetlet orientations, which are altered under pathological conditions. However, DTI is affected by many factors, therefore robust validation is critical. Existing histological validation is intrinsically flawed, since it requires further tissue processing leading to sample distortion, is routinely limited in field-of-view and requires reconstruction of three-dimensional volumes from two-dimensional images. In contrast, synchrotron radiation imaging (SRI) data enables imaging of the heart in 3D without further preparation following DTI. The objective of the study was to validate DTI measurements based on structure tensor analysis of SRI data. Methods One isolated, fixed rat heart was imaged ex vivo with DTI and X-ray phase contrast SRI, and reconstructed at 100 μm and 3.6 μm isotropic resolution respectively. Structure tensors were determined from the SRI data and registered to the DTI data. Results Excellent agreement in helix angles (HA) and transverse angles (TA) was observed between the DTI and structure tensor synchrotron radiation imaging (STSRI) data, where HADTI-STSRI = −1.4° ± 23.2° and TADTI-STSRI = −1.4° ± 35.0° (mean ± 1.96 standard deviation across all voxels in the left ventricle). STSRI confirmed that the primary eigenvector of the diffusion tensor corresponds with the cardiomyocyte long-axis across the whole myocardium. Conclusions We have used STSRI as a novel and high-resolution gold standard for the validation of DTI, allowing like-with-like comparison of three-dimensional tissue structures in the same intact heart free of distortion. This represents a critical step forward in independently verifying the structural basis and informing the interpretation of cardiac DTI data, thereby supporting the further development and adoption of DTI in structure-based electro-mechanical modelling and routine clinical applications

Global warming and malaria: knowing the horse before hitching the cart

Speculations on the potential impact of climate change on human health frequently focus on malaria. Predictions are common that in the coming decades, tens – even hundreds – of millions more cases will occur in regions where the disease is already present, and that transmission will extend to higher latitudes and altitudes. Such predictions, sometimes supported by simple models, are persuasive because they are intuitive, but they sidestep factors that are key to the transmission and epidemiology of the disease: the ecology and behaviour of both humans and vectors, and the immunity of the human population. A holistic view of the natural history of the disease, in the context of these factors and in the precise setting where it is transmitted, is the only valid starting point for assessing the likely significance of future changes in climate

The search for the 'next' euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

Purpose: A detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presentedMethod: Peer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse.Results: In terms of impact on drug markets, prevalence and harm, the most significant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short-lasting euphoric effects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored.Conclusions: International early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. Pre-emptive research on the most likely compounds to emerge next, so providing drug metabolism and pharmacokinetic data to ensure that new substances are detected early in toxicological samples is recommended. As these compounds are chiral compounds and stereochemistry has a large effect on their potency, it is recommended that detection methods consider the determination of configuration

Predicting the Current and Future Potential Distributions of Lymphatic Filariasis in Africa Using Maximum Entropy Ecological Niche Modelling

Modelling the spatial distributions of human parasite species is crucial to understanding the environmental determinants of infection as well as for guiding the planning of control programmes. Here, we use ecological niche modelling to map the current potential distribution of the macroparasitic disease, lymphatic filariasis (LF), in Africa, and to estimate how future changes in climate and population could affect its spread and burden across the continent. We used 508 community-specific infection presence data collated from the published literature in conjunction with five predictive environmental/climatic and demographic variables, and a maximum entropy niche modelling method to construct the first ecological niche maps describing potential distribution and burden of LF in Africa. We also ran the best-fit model against climate projections made by the HADCM3 and CCCMA models for 2050 under A2a and B2a scenarios to simulate the likely distribution of LF under future climate and population changes. We predict a broad geographic distribution of LF in Africa extending from the west to the east across the middle region of the continent, with high probabilities of occurrence in the Western Africa compared to large areas of medium probability interspersed with smaller areas of high probability in Central and Eastern Africa and in Madagascar. We uncovered complex relationships between predictor ecological niche variables and the probability of LF occurrence. We show for the first time that predicted climate change and population growth will expand both the range and risk of LF infection (and ultimately disease) in an endemic region. We estimate that populations at risk to LF may range from 543 and 804 million currently, and that this could rise to between 1.65 to 1.86 billion in the future depending on the climate scenario used and thresholds applied to signify infection presence

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700