Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of March 2, 2017 (#84)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
This week there are three articles that reflect the
importance of the title in enticing the readers (medical students) to investigate
the article.
The first is a Perspective article, “The Interpreter,”
which I found to be very informative and which addressed some difficulties interpreters
have in reality dealing with patients with malignancy and severe disease with
whom they empathize. Because of the blandness of the title, students did not
read the article. If it had been titled
e.g. Interpreter’s Challenges, students all agreed that they would have at
least glanced at the article.
The second article “Histology Rings True” under Clinical Problem Solving was read by only
one of 27 students. This is an example of the authors “trying too hard” with
the title which only means something to the readers once they have read the
CPC. The title should be such that it provides the potential reader with some
idea about the contents of the article in order to interest the reader to look
further at the article e.g. hepatic granulomata.
In contrast is a third
article, an editorial, entitled “Ditching the Itch with Anti-Type 2 Cytokine
Therapies for Atopic Dermatitis.” This title is catchy while at the same time
describing the broad contents of the editorial.
Must Read Articles
Perspective
The
Interpreter
When
an interpreter hesitates before translating bad news for a patient, an
oncologist realizes how little consideration most health care professionals
give to these invaluable conduits who are also human beings, emotionally
affected by the news they help to break.
Articles Recommended for Medical Students
Perspective
HISTORY OF MEDICINE
Sickle
Cell Disease — A History of Progress and Peril
Given
sickle cell disease’s prevalence among black Americans, questions of race and
stigma have shadowed the history of its medical treatment. Recent developments
in treating pain crises and gene therapy are part of a history of slow progress
tinged with constant peril.
This Perspective provides the reader with a recent
history of sickle cell disease (SSD) in the US.
The author discusses the racial overtones associated with SSD as well as
current advances in therapy. In 1971,
Richard Nixon introduced his “war on cancer” initiative and in 1972 signed into
law the “Sickle Cell Anemia Control Act” recognising a disease that involved
the African American population and that had been neglected in medical research
until that time.
ORIGINAL ARTICLE
Treatment
of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy
Two
placebo-controlled trials involving pregnant women with subclinical
hypothyroidism or hypothyroxinemia showed that levothyroxine beginning between
8 and 20 weeks of gestation did not significantly improve cognitive outcomes in
children through 5 years of age.
EDITORIAL
Subclinical
Hypothyroidism and Hypothyroxinemia in Pregnancy — Still No Answers
Most students read the article and the editorial
because of both the title and the association with pregnancy. This provides the
student the opportunity to review thyroid function during pregnancy.
The study involved two parallel placebo-controlled
trials which included patients with either i) subclinical hypothyroidism,
defined as a TSH level of 4.0 mU/L or more (the upper limit of normal falls in
pregnancy) together with a normal free T4 level (mean gestational age of 16.7
weeks), or ii) patients with hypothyroxinemia, defined as a low free T4 level
associated with a normal TSH level (mean gestational age of 17.8 weeks). The
question was whether treating these patient groups with levothyroxine to
maintain a TSH level in the former group between 0.1 -2.5 mU/l and a free T4
level in the latter group between 0.86 – 1.9 ng/dl. The results of placebo components
of the trials showed that levothyroxine replacement resulted in no differences
in cognitive function in any of the four groups at five years. Further, the presence or absence of antibodies
against TPO made no difference to the outcomes of the studies.
The editorial indicates however that as the majority of
women in the US and Australia have their first prenatal visit before 12 weeks,
earlier treatment with levothyroxine is more likely if there appears to be any
evidence of thyroid dysfunction. In all
likelihood replacement levothyroxine will be commenced as it is cheap and
unlikely to be harmful.
Recommended
learning: Review the endocrine changes that occur during
pregnancy.
Important Articles Related to Mechanisms of Disease and
Translational Research
ORIGINAL ARTICLE
Anti–Interleukin-31
Receptor A Antibody for Atopic Dermatitis
In a phase 2, placebo-controlled trial, nemolizumab, an
antibody against interleukin-31 receptor A, reduced pruritus in patients with
moderate-to-severe atopic dermatitis. These findings support the role of
interleukin-31 in the pathophysiology of atopic dermatitis.
EDITORIAL
Ditching
the Itch with Anti–Type 2 Cytokine Therapies for Atopic Dermatitis
I found the results of this study very interesting.
Atopic dermatitis is associated with a predominantly Th2 mediated immune
response with local release of TSLP (thymic stromal lymphopoietin, a major
promoter of atopy), 1L-4, IL-13 and IL-31. Both TSLP and IL-31 bind to neuronal
receptors which may explain the role these cytokines play in activating sensory
neurons in the dermis producing the pruritus associated with atopic dermatitis.
This is a 12-week, double-blinded, placebo controlled trial in 264 adult
patients with moderate to severe atopic dermatitis studying the effect of a
monoclonal antibody against the IL-31 receptor A (nemolizumab) on pruritus
control as the primary outcome. Nemolizumab produced a significant improvement
in pruritus in patients compared with controls (63.1% at the highest dose
versus 20.9% in controls).
Recommended learning: Review the diagnosis and management of
atopic dermatitis.
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Parsing
the Pancreas
High-resolution
analysis of gene expression in individual pancreatic cells is providing new
insights into cell subpopulations and candidate genes relevant to the causes
and progression of pancreatic disorders.
The authors have
reviewed four published studies using isolated single cells from murine and
human pancreas (references 1-4) both from normal patients and from patients
with type 2 diabetes. Single cells were isolated from the pancreas using specific
techniques (Figure 1) and a cDNA library was established for each cell type by
reverse transcription. Using next generation sequencing, the transcriptome was
identified for each islet cell type (a, b, d, e, g) as well as stellate cells, endothelial cells, Schwann cells, immune
cells from diabetic patients, and acinar cells from small and large pancreatic
ducts. Using complex specific computer algorithms on DNA sequences, each cell
type was sorted by a common transcript and studied.
Information such as new cell surface markers, specific
molecular pathways, cell heterogeneity, beta cell genes from diabetic and
normal controls, and studies on “non-malignant” acinar cells from small and
large ducts from patients with adenocarcinoma of the pancreas is now able to be
obtained.
The revolution in
single-cell assays is in the process of incorporating epigenetic and proteomic
analyses. It is allowing
researchers to answer questions that could not hitherto be addressed and raises
prospects for a better understanding of that most complex of organs, the human
brain.
Other Articles which should interest medical students
IMAGES IN CLINICAL MEDICINE
Iodide-Associated
Sialadenitis
A
67-year-old man who had previously had heart transplantation and had chronic
kidney disease underwent coronary angiography. He had received pretreatment
owing to a reported history of iodine allergy but reported neck swelling
several hours later.
This case represents
an unusual, self-limiting, non-allergic complication of iodine contrast
resulting in submandibular gland enlargement without thyroid enlargement in a
patient with chronic kidney disease.
IMAGES IN CLINICAL MEDICINE
Cholesteryl
Ester Crystals in Lysosomal Acid Lipase Deficiency
An
18-year-old woman had elevated aminotransferase levels and a workup negative
for infectious and autoimmune disease. Liver biopsy revealed birefringent
cholesteryl ester crystals consistent with lysosomal acid lipase deficiency.
This patient presented
with massive hepatosplenomegaly with the CT scan demonstrating steatosis. A liver biopsy revealed lipid deposition
predominantly within Kupffer cells. When
frozen tissue was examined by polarizing microscopy, the diagnosis was made.
Recommended learning: Review the causes of hepatosplenomegaly.
CLINICAL PROBLEM-SOLVING
Histology
Rings True
A
58-year-old man with rheumatoid arthritis who was being treated with etanercept
and methotrexate presented to the emergency department with fevers, night
sweats, yellowing of his eyes, and dark urine.
This CPC involves an
immunosuppressed patient presenting with symptoms suggesting infection and
evidence of hepatitis associated with granulomata in the liver. Very interesting differential diagnoses are
provided but with the histopathology suggesting the correct diagnosis.
Recommended learning: Review the causes of hepatic granulomata.
New and Novel Therapies
ORIGINAL ARTICLE
Blinatumomab
versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia
Among
adults with relapsed or refractory B-cell precursor acute lymphoblastic
leukemia, treatment with the bispecific anti-CD19 and anti-CD3 monoclonal
antibody blinatumomab resulted in longer overall survival and higher remission
rates than did chemotherapy.
This study utilizes a monoclonal antibody which binds
to two epitopes. These are CD19 (a B
cell marker) on the surface of leukaemic B lymphocytes and CD3 on the surface
of T lymphocytes. The antibody brings
the cytotoxic T cell in close proximity to the malignant B cell which is then
destroyed.
Patients with
relapsed or refractory B-cell precursor ALL were treated with either the
monoclonal antibody (blinatumomab) or chemotherapy. In those receiving the
monoclonal antibody, the survival rate was extended from 4.0 months to 7.1
months. Another major aim of the study was to improve the overall clinical status
of the patients with the monoclonal antibody thereby allowing 25% of patients
to be eligible for an allogeneic haematopoietic stem cell transplant.
ORIGINAL ARTICLE
BRIEF REPORT
Gene
Therapy in a Patient with Sickle Cell Disease
A
boy with hydroxyurea-refractory sickle cell anemia underwent bone marrow
transplantation with autologous hematopoietic stem cells transduced by a
lentivirus to express an antisickling β-globin variant. No sickle cell crises
occurred in the following 15 months.
This is a single case study of a patient with severe
sickle cell disease who underwent an autologous haematopoietic stem cell
transplant using a lentivirus vector to transfer an anti-sickling b-globin variant.
This is the first of many such studies to come.
Articles Some Medical Students Found Interesting
REVIEW ARTICLE
THE CHANGING FACE OF CLINICAL TRIALS
Informed Consent
An
investigator obtaining informed consent traditionally asks participants to sign
a written consent document — an approach that is becoming outdated. This
multipart review examines electronic and video informed consent and consent in
app-based and Internet-based trials, with videos showing examples.
This review of
informed consent in clinical trials outlines the changes that have occurred in
this area over time. The review involves
such areas as electronic informed consent and internet-based trials, mobile
health research – app-based trials, and video informed consent.
