Cerebrospinal fluid protein and glucose examinations and tuberculosis: Will laboratory safety regulations force a change of practice?

Cerebrospinal fluid (CSF) protein and glucose examinations are usually performed in chemical pathology departments on autoanalysers. Tuberculosis (TB) is a group 3 biological agent under Directive 2000/54/EC of the European Parliament but in the biochemistry laboratory, no extra precautions are taken in its analysis in possible TB cases. The issue of laboratory practice and safety in the biochemical analyses of CSF specimens, when tuberculosis infection is in question is addressed in the context of ambiguity in the implementation of current national and international health and safety regulations. Additional protective measures for laboratory staff during the analysis of CSF TB samples should force a change in current laboratory practice and become a regulatory issue under ISO 15189. Annual Mantoux skin test or an interferon-? release assay for TB should be mandatory for relevant staff. This manuscript addresses the issue of biochemistry laboratory practice and safety in the biochemical analyses of CSF specimens when tuberculosis infection is in question in the context of the ambiguity of statutory health and safety regulations

Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency

Summary BACKGROUND Glucocorticoid therapy is associated with potentially serious side-effects, but there is no information available regarding glucocorticoid requirement in adult hypopituitary patients with partial ACTH deficiency

Hospital Outcomes in Patients Hospitalized for COVID-19 Pneumonia: The Effect of SARS-CoV-2 Vaccination and Vitamin D Status

SARS-CoV-2 vaccination promises to improve outcomes for patients with COVID-19 pneumonia (most notably those with advanced age and at high risk for severe disease). Here, we examine serum 25-Hydroxyvitamin D (25(OH)D) status and outcomes in both old (\u3e70 years) and young vaccinated (n = 80) and unvaccinated (n = 91) subjects, who were hospitalized due to COVID- 19 pneumonia in a single center (Connolly Hospital Dublin). Outcomes included ICU admission and mortality. Serum 25(OH)D levels were categorized as D30 (/L), D40 (30–49.99 nmol/L) and D50 (50 nmol/L). In multivariate analyses, D30 was independently associated with ICU admission (OR: 6.87 (95% CI: 1.13–41.85) (p = 0.036)) and mortality (OR: 24.81 (95% CI: 1.57–392.1) (p = 0.023)) in unvaccinated patients, even after adjustment for major confounders including age, sex, obesity and pre-existing diabetes mellitus. While mortality was consistently higher in all categories of patients over 70 years of age, the highest observed mortality rate of 50%, seen in patients over 70 years with a low vitamin D state (D30), appeared to be almost completely corrected by either vaccination, or having a higher vitamin D state, i.e., mortality was 14% for vaccinated patients over 70 years with D30 and 16% for unvaccinated patients over 70 years with a 25(OH)D level greater than 30 nmol/L. We observe that high mortality from COVID-19 pneumonia occurs in older patients, especially those who are unvaccinated or have a low vitamin D state. Recent vaccination or having a high vitamin D status are both associated with reduced mortality, although these effects do not fully mitigate the mortality risk associated with advanced age

MORB generation beneath the ultraslow spreading Southwest Indian Ridge (9–25°E) : major element chemistry and the importance of process versus source

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 9 (2008): Q05004, doi:10.1029/2008GC001959.We report highly variable mid-ocean ridge basalt (MORB) major element and water concentrations from a single 1050-km first-order spreading segment on the ultraslow spreading Southwest Indian Ridge, consisting of two supersegments with strikingly different spreading geometry and ridge morphology. To the east, the 630 km long orthogonal supersegment (<10° obliquity) dominantly erupts normal MORB with progressive K/Ti enrichment from east to west. To the west is the 400 km long oblique supersegment (up to 56° obliquity) with two robust volcanic centers erupting enriched MORB and three intervening amagmatic accretionary segments erupting both N-MORB and E-MORB. The systematic nature of the orthogonal supersegments' ridge morphology and MORB composition ends at 16°E, where ridge physiography, lithologic abundance, crustal structure, and basalt chemistry all change dramatically. We attribute this discontinuity and the contrasting characteristics of the supersegments to localized differences in the upper mantle thermal structure brought on by variable spreading geometry. The influence of these differences on the erupted composition of MORB appears to be more significant at ultraslow spreading rates where the overall degree of melting is lower. In contrast to the moderate and rather constant degrees of partial melting along the orthogonal supersegment, suppression of mantle melting on the oblique supersegment due to thickened lithosphere means that the bulk source is not uniformly sampled, as is the former. On the oblique supersegment, more abundant mafic lithologies melt deeper thereby dominating the more enriched aggregate melt composition. While much of the local major element heterogeneity can be explained by polybaric fractional crystallization with variable H2O contents, elevated K2O and K/Ti cannot. On the basis of the chemical and tectonic relationship of these enriched and depleted basalts, their occurrence requires a multilithology mantle source. The diversity and distribution of MORB compositions, especially here at ultraslow spreading rates, is controlled not only by the heterogeneity of the underlying mantle, but also more directly by the local thermal structure of the lithosphere (i.e., spreading geometry) and its influence on melting processes. Thus at ultraslow spreading rates, process rather than source may be the principle determiner of MORB composition.This work was originally funded in large part by NSF grants OCE-9907630 and OCE-0526905 and more recently by OPP-0425785

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

Expert witnesses in the coronial system.

Letter to the Edito

Cannabis, possible cardiac deaths and the coroner in Ireland.

Background The elevated risk of triggering a myocardial infarction by smoking cannabis is limited to the first 2 h after smoking. Aim To examine the possible role of cannabis in cardiac deaths. Cases and results From 3,193 coroners’ cases over 2 years, there were 13 cases where the clinical information was compatible with a primary cardiac cause of death. An inquest was held in three cases. Myocardial infarction was the primary cause of death in 54%. Other causes were sudden adult death syndrome, sudden death in epilepsy, and poisoning by alcohol and diazepam. Cannabis was mentioned once only on a death certificate, but not as a cause of death. Blood delta9 tetrahydrocannabinolcarboxylic acid was recorded in one case and in no case was plasma tetrahydrocannabinol (THC) measured. Conclusions To attribute sudden cardiac death to cannabis, plasma THC should be measured in the toxicology screen in coroners’ cases where urine cannabinoids are positive. A positive urine cannabinoids immunoassay alone is insufficient evidence in the linkage of acute cardiac death and cannabis

Newspaper reports from the Coroners Court in Ireland are used to reveal the potential complexity and need for reform in forensic toxicology and medicine services.

Newspapers devote regular space to inquests in the public interest. Accuracy in determining the causes of death is important for public health. Expert opinion features prominently in press reports and is an important channel of public education. How expert are the experts and how complex are apparently simple cases? Toxicology cases involving cannabis and stroke, 'junk food' diet, unexplained sudden death, potential drug interactions, allergy during caesarean section, and ecstacy-type drugs are used to illustrate the complexities. A template for reform is suggested to reform the Coroners Laws in Ireland to recognise the complexity of forensic toxicology and medicine