Idiopathic pulmonary fibrosis is a restrictive lung disease with high mortality and severe debilitation.  Progressive destruction of the gas-exchanging regions of the lungs results in symptoms of cough and dyspnoea, limited physical activity, and reduced quality of life and independence.  Abnormal wound-healing involving multiple signalling pathways with tyrosine kinase receptors has been shown to be involved in the pathogenesis of lung fibrosis; therefore, inhibition of these pathways is a potential target for therapy of pulmonary fibrosis.

In a 12-month randomized controlled trial involving 432 patients with idiopathic pulmonary fibrosis, the efficacy and safety of 4 different oral doses of the tyrosine kinase inhibitor BIBF 1120 was compared to placebo.  It was concluded that BIBF 1120, at a dose of 150 mg twice daily, was associated with a trend toward a reduction in the decline of forced vital capacity, with fewer acute exacerbations and preserved quality of life as compared to placebo. 

Although this study failed, by a very small margin, to show statistically significant results, the evidence of safety and a trend towards improvement in the treatment of idiopathic pulmonary fibrosis warrants further investigation of the tyrosine kinase inhibitor BIBF 1120. 

Full article: http://www.nejm.org/doi/full/10.1056/NEJMoa1103690#t=article
Summary: http://www.nejm.org/doi/full/10.1056/NEJMoa1103690#t=abstract

Title: Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis
Authors: Richeldi L, Costabei U, Selman M, Kim DS, Hansell DM, Nicholson Age et al
Journal Title: The New England Journal of Medicine

The use of unfractionated or low-molecular weight heparin is common in the in-patient setting as a means of prophylaxis against stasis-induced thromboembolic events.  A possible and very serious complication of heparin use is the development of herparin-induced thrombocytopenia (HIT). This condition involves the development of a paradoxical prothrombotic and thrombocytopenic state after the host immune system develops a humoral response to a new antigen exposed during a confirmational shift in the protein platelet factor 4 (PF4) formed when bound by heparin.  Confirmation of this suspected complication depends on clinical history and the demonstration of antibody versus the heparin:PF4 complex using enzyme-linked immunosorbant assay (ELISA). Lifesaving treatment in this condition consists of discontinuation of all forms of heparin thearpy and the commencement of novel direct anti-thrombin (factor II) medications. Agatroban is a direct thrombin inhibitor that has been adapted for use in this manner.

This recent retrospective study has evaluated the usefulness of Argatroban in the treatment of patients in the ICU who have developed multi-organ failure due to a diagnosis of HIT. The findings support the usage and efficacy of Agatroban as anti-thrombotic agent in the treatment of HIT.

Full article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911727/?tool=pubmed
Summary: http://www.ncbi.nlm.nih.gov/pubmed/20487559
PMID: 20487559

Title: Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study
Authors: Saugel B, Phillip V, Moessmer G, Schmid RM, Huber W.
Journal Title: Critical Care

The ‘triad of death’ consists of the presence of acidosis, coagulopathy and hypothermia in an injured patient. It is very difficult to reverse and is consequently associated with a high fatality, making it a dreaded presentation which requires high vigilance and swift action. This article aimed to look closer at these presentations, their outcomes and management.

It was found that the mortality rates for this presentation are still high, despite a general decrease in patient fatality following major trauma. All three components appear to increase the likelihood of death individually. However, when all three occur together, one can additionally worsen the effect of the others causing what is referred to as a “vicious cycle resulting in death”. Nevertheless, the presence of severe coagulopathy is linked with higher risk than the extremes of the other two in a “triad of death” presentation. New agents targeting this are therefore suggested.

Full article:
http://emj.bmj.com.proxy.library.rcsi.ie/content/early/2011/07/23/emj.2011.113167.full?sid=8a94e5f8-d4c3-44b8-bdf8-2f343cea2593
Summary: http://emj.bmj.com/content/early/2011/07/23/emj.2011.113167.abstract
PMID: 21785151

Title: Trauma patients with the ‘triad of death’
Authors: Mitra B, Tullio F, Cameron PA, Fitzgerald M
Journal: Emergency Medicine Journal

The estimated prevalence of atrial fibrillation (AF) is 0.4%-1% in the general population and increases to 10% in those above 80 years of age (Go, 2001). AF accounts for 15% of strokes in persons of all ages and 30% in persons over the age of 80 years. All patients with nonvalvular atrial fibrillation are evaluated for oral antithrombotic therapy to prevent thromboembolism using the CHADS2 score. Those with a score above 2 are considered moderate or high risk and started on warfarin anticoagulation therapy, unless contraindicated. Warfarin is highly effective for reducing the rate of ischemic strokes but is limited by a narrow therapeutic range, drug and food interactions and frequent INR monitoring and dose adjustments.

The ROCKET AF trial has evaluated a new agent called rivaroxaban, an oral Factor Xa inhibitor that promises to provide more consistent and predictable anticoagulation than warfarin. Patel et al have shown that a once-daily fixed dose of rivaroxaban was non-inferior to dose-adjusted warfarin for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation.

Dabigatrin (direct thrombin inhibitor), Apixaban (a Factor Xa inhibitor) and now, Rivaroxaban are alternative oral anticoagulants that are at least as effective as warfarin, without the need for regular anticoagulation monitoring.

Full article: http://www.nejm.org/doi/full/10.1056/NEJMoa1009638#t=article
Summary: http://www.ncbi.nlm.nih.gov/pubmed/21830957
PMID: 21830957

Title: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
Authors: Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al
Journal Title: New England Journal of Medicine

Vitamin D deficiency is an exciting new topic of research as it has been linked to not only bone health, but also to cancer, hypertension, diabetes and autoimmune disorders such as multiple sclerosis.  Northern latitude regions, such as Ireland, are considered high risk for Vitamin D deficient patients.

Much to the joy of researchers in this field, the Endocrine Society has reviewed current research and established Clinical Practice Guidelines for “evaluation, treatment and prevention of vitamin D deficiency”, thus recognizing the importance of this topic. Vitamin D deficiency is defined as serum 25-hydroxyvitamin D  levels below 20 ng/mL. Recommended values are now set between 40-60 ng/mL. Some high risk groups include pregnant women, African-Americans, obese individuals and individuals with malabsorption conditions. This publication outlines specific serum targets and daily intake levels to achieve this based on age. Prevention and treatment can be achieved by Vitamin D2 or D3 supplementation and by fortified food intake. 

Be on the lookout for Vitamin D in the literature as we learn more about its integral role in human health.

Full article (requires access to RCSI Library):
http://jcem.endojournals.org.proxy.library.rcsi.ie/content/96/7/1911.full?sid=64de8de5-24f1-483d-90f9-24427cd429cd
Summary: http://www.ncbi.nlm.nih.gov/pubmed/21646368
PMID: 21646368

Title: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
Authors: Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al
Journal Title: The Journal of Clinical Endocrinology and Metabolism

Medication and pregnancy has always been a risky combination with ambiguous effects on both mother and foetus. Since the discovery of the teratogenic properties of thalidomide, drug trials have become much more stringent in order to validate the efficacy of a medication while limiting its harmful effects. Recently, a cohort study was carried out in Denmark over a 12-year period to determine the risk of orofacial clefts and the use of corticosteroids in pregnancy. There were 832,636 live births documented during this time, of which 1,232 births were diagnosed with orofacial clefts. Of these, 84 were linked to corticosteroid use during the first trimester. The results found no increase in risk of orofacial clefts with the use of most types of corticosteroids. Yet it was highlighted that the use of dermatologic corticosteroids may have a causal association with orofacial clefts; further studies are needed in order to clarify this relationship.

Full article: http://www.cmaj.ca/content/early/2011/04/11/cmaj.101063.full.pdf+html
Summary: http://www.ncbi.nlm.nih.gov/pubmed/21482652
PMID: 21482652

Title: Corticosteroid use during pregnancy and risk of orofacial clefts
Authors: Hviid A, Mølgaard-Nielsen D
Journal Title: Canadian Medical Association Journal (CMAJ)

As medical students and future medical practitioners, we spend a lot of time differentiating between possible conditions, treatment options, etc. This approach is used not only in our practice but also in our career decisions. Medical students choose their future specialties sometimes with very little exposure or knowledge. There seems to be an increasing sense of urgency in beginning to invest in a particular specialty from earlier on, and the rewards of early exploration are clear as the demands to gain a competitive edge are high and the applicant pool continues to increase. However, pre-clinical exploration remains a self directed learning process, with lack of true institutional guidance for the most part. This leaves room for biases and poorly-informed decisions. More structured guidance is needed as regards decision-making and information-gathering to enable medical students to make informed decisions while benefiting from the advantages of self-directed exploration.

Full article: http://www.nejm.org/doi/full/10.1056/NEJMp1105004#t=article
PMID: 21812670

Title: A Differentiation Diagnosis — Specialization and the Medical Student
Authors: Xu R
Journal Title: New England Journal of Medicine