Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 31st March 2016 (#36)
University
of Notre Dame Australia
(Fremantle
Campus)
Occasional Editorial Comment
None
Must Read Articles
Perspective
The
Science of Choosing Wisely — Overcoming the Therapeutic Illusion
The
success of efforts to reduce inappropriate use of medical tests and
interventions may be limited by our tendency to overestimate the effect of our
actions. Efforts to promote more rational medical decision making will need to
address this illusion of control.
The premise for this Perspective is to identify a mechanism for reducing the inappropriate
use of medical tests and treatments which could be achieved by changing the way
we think and be applied in a cost-efficient manner.
The author chose to address this process through focusing
on the concept of “therapeutic illusion” which has been defined as “unjustified
enthusiasm for treatment on the part of both patients and doctors.” This
definition has been derived from the concept of “illusion of control,” which is
our tendency to infer causality where none exists.
As practicing physicians, it is essential that we are
aware of these processes and actively work to define the situations in which
they occur.
I quote extracts from the article as I am unable to
improve on the author’s definitions and examples:
Random
chance can encourage physicians to embrace mistaken beliefs about causality.
Knee pain tends to wax and wane, and the example provided is of arthroscopic
joint lavage in osteoarthritis as an example where orthopaedists believe this
to be effective in relieving symptoms, but where evidence has shown this to be
untrue.
The
“therapeutic illusion” is reinforced by a tendency to look selectively for
evidence of impact — one manifestation of the “confirmation bias” that leads us
to seek only evidence that supports what we already believe to be true.
Physicians may be particularly susceptible to that bias when caring for a
patient with a complex illness.
The
illusion of control is deeply ingrained in human psychology in the form of a
“heuristic,” or rule of thumb, that we rely on to interpret events and make
decisions. Many heuristics are subconscious and therefore difficult to avoid or
eradicate, but we can ameliorate their effects by using countervailing,
conscious heuristics.
We
tend to ignore the pretest probability of an illness when making a diagnosis,
which can cause us to overdiagnose rare conditions and underdiagnose common
ones; medical students are therefore taught the rule “When you hear hoof beats,
look for horses, not zebras.”
Two
conscious heuristics can help counteract the therapeutic illusion:
“Before you conclude that a treatment was
effective, look for other explanations.”
“If
you see evidence of success, look for evidence of failure.” In other words,
test assumptions of effectiveness by looking for negative outcomes.
There are many more pearls in this article which should
be read and then reread by all.
Must Save Article
REVIEW ARTICLE
Opioid
Abuse in Chronic Pain — Misconceptions and Mitigation Strategies
The
epidemic of opioid abuse is related in part to incomplete understanding of
pain-relief management, opioid tolerance, and opioid addiction. Among the
prevention strategies are more widespread sharing of data about opioid
neuropharmacology and opioid-use patterns.
This article reviews the use and abuse of opioids in
non-cancer chronic pain in the US. The statistic quoted is that 40% of older US
adults suffer from chronic pain and in the US opioids are the most frequently
prescribed class of medications, though I am sure similar statistics apply to
the Australian population.
The biology of opioid receptors and their distribution
is outlined with an excellent Figure 1. The authors further discuss the
differences between tolerance and physical dependence and addiction (see Table
1), ways to deter opioid abuse, factors associated with the risk of opioid
overdose and addiction and mechanisms that can be used to counteract opioid
diversion and misuse.
Recommended
learning: Opioid pharmacology, in particular mechanisms of
action, opioid overdose and addiction, and ways to deter abuse.
Articles Recommended for Medical Students
IMAGES IN CLINICAL MEDICINE
Paget’s
Disease of Bone
A
57-year-old man with a history of pain in the right knee presented with warmth
and swelling in the right thigh. Examination revealed an asymmetric increase in
right thigh volume. Radiography showed bony enlargement and cortical
thickening.
Most patients with Paget’s disease of bone have
isolated disease and are asymptomatic. They usually present with pain and, less
commonly, deformity. This presentation with pain and increased warmth and size
of the right thigh would be unusual in the Australian population today. The
other unusual feature with the extent of active bone disease in this patient is
a minimally elevated bone alkaline phosphatase in serum.
Recommended
learning: Pathology, clinical presentation and management of
Paget’s disease of bone.
IMAGES IN CLINICAL MEDICINE
Carotid–Cavernous
Sinus Fistula
A
healthy 18-year-old man was in a motor vehicle accident and received a head
injury that resulted in intracranial bleeding at multiple sites, fractures of
facial bones, and immediate traumatic mydriasis and ptosis in the left eye.
This is an extremely rare condition which is usually
described in association with pulsatile exophthalmos, a bruit and pulsatile
tinnitus.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
10-2016 — A 22-Year-Old Man with Sickle Cell Disease, Headache, and Difficulty
Speaking
A
22-year-old man with sickle cell disease presented with headache and difficulty
speaking after smoking marijuana. He had anomia, apraxia, and alexia and was
unable to perform arithmetic. Diagnostic tests were performed, and management
decisions were made.
This CPC describes an acute stroke in a 22-year old
male with a sickle cell disease (SSD) and with obvious sickling on the
peripheral blood smear.
The discussion involves the causes of acute stroke in a
22-year old male, the associations between cannabis use and stroke, and in
particular the vasculopathy associated with SSD and stroke management in SSD.
With international travel, Australian physicians should be aware of the
complications of SSD as these patients do present to EDs in the Perth area. In
this article, there is an excellent CT without contrast demonstrating fresh
clot in the middle cerebral artery and acute dissection of the internal carotid
on MRI.
Recommended
learning: Review the neuroanatomy and function of the cerebral
hemispheres, in particular the classical clinical findings in lesions involving
the dominant and non-dominant hemispheres. Review Gerstmann syndrome.
EDITORIAL
Postmenopausal
Hormone Therapy and Atherosclerosis — Time Is of the Essence
The article (http://www.nejm.org/doi/full/10.1056/NEJMoa1505241)
and the accompanying Editorial in
this week’s Journal are again focused
on postmenopausal HRT (hormone replacement therapy). The Editorial summarizes the article and provides an overview of the
cardiovascular benefit of HRT.
This is a single centre study of 643 postmenopausal
women who were randomly assigned to treatment with estradiol (with or without
progesterone) or placebo. All patients in the study were free of symptoms of
coronary artery disease and were divided into two groups, comprising those that
were < 6 years postmenopause and those that were 10 or more years postmenopause. The aim of this study was to determine if HRT,
initiated in either of these arbitrary time periods, had any effect on coronary
artery disease.
Coronary artery disease was assessed by:
1. the
progression of potentially preventable coronary artery plaque formation using a
surrogate marker, the carotid intimal-medial thickness (CIMT) (data in Table 2),
and
2. coronary
artery calcification score (CAC) and /or cardiac CT angiography (CCTA), which
assessed the extent of irreversible coronary atherosclerosis (Table 3)
Overall, the data indicate that in the early
postmenopausal group, HRT slowed the progression of active plaque (CIMT) but
had no effect on established coronary atherosclerosis (CAC, CCTA). In the late
postmenopausal group, HRT had no effect on slowing plaque formation or on
established coronary atherosclerosis.
As indicated in the Editorial,
the results suggest that the time of initiation of HRT relative to the onset of
menopause may be important but there is clearly much more work to be done in
this area before this can be recommended as the standard of care.
Important Articles Related to Mechanisms of Disease and
Translational Research
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Genetic
Targeting of the Albumin Locus to Treat Hemophilia
Goals
of gene therapy include the integration of the therapeutic gene into the host
genome at expression levels sufficient to ameliorate symptoms. Strategies
involving the transcriptional machinery of albumin in the liver have proved
effective in a mouse model of hemophilia.
This article reviews the frequency of hemophilia A
(factor VIII deficiency) and B (factor IX deficiency, Christmas disease)
worldwide, the treatment and costs, and the lack of availability of this treatment
for most patients worldwide.
In 2004, the
authors transfected the hepatocytes of 10 patients with severe factor IX
deficiency (http://www.nejm.org/doi/full/10.1056/NEJMoa1407309)
with the factor IX genome (F9) incorporated into a recombinant adenovirus 9
vector. In these patients, there was a modest increase in factor IX production
by the host livers. At higher doses of F9 vector, levels of factor IX were sufficient
to reduce bleeding and the frequency of factor IX replacement. However the results
of this type of transfection were short-lived as there is no permanent incorporation
of the transfected F9 into the host liver cell genome (AVV exhibits a tropism
for hepatocytes).
Two recent quoted publications focus on mechanisms to
incorporate F9 permanently into the host hepatocyte genome without producing
untoward side effects. In vitro and in vivo studies in murine models have achieved
acceptable, though low factor IX protein production. This was achieved using,
in one example, the AVV DNA construct containing promoterless human F9
downstream from active targeted murine albumin DNA. Murine cells produced both
mouse albumin and human factor IX. However, the murine hepatocytes exhibited a
low long-term vector incorporation rate of 0.5%.
This exciting area of gene transfer represents the
future for the replacement of deficient proteins, particularly where the
deficient protein can be secreted by hepatocytes, in association with a
commonly produced protein such as albumin (represents > 25% of all proteins
produced by the liver). Challenges that remain are experiments in non-human
primates with production of adequate levels of the deficient secreted protein,
without producing transaminitis or other potential complications such as
insertional oncogenesis or alteration in endogenous gene expression, particularly
oncogenes or an immunogenic protein such as albumin.
Other articles which should be of interest to medical students
Perspective
Immersion
Day — Transforming Governance and Policy by Putting on Scrubs
The
disconnect between real-world health care and the information delivered in
boardrooms or policy discussions is a barrier to responsive governance and
policymaking. So Mission Health immerses board members, journalists,
legislators, and regulators in its daily work
This is an interesting Perspective that demonstrates the effectiveness of immersing
inexperienced bureaucrats involved in formulating health care policy in the day
to day operations within the hospital. This was not a hospital tour, but a true
immersion experience which took both time and commitment of the bureaucrats.
After this immersion experience at Mission Health in Asheville, NC, subsequent
appropriate requests for hospital funding were reviewed as being favourable.
Such a simple, obvious step can transform governance and policy! Every bureaucrat involved enjoyed the experience
which opened their eyes to the reality of medical practice in the trenches.
ORIGINAL ARTICLE
Randomized
Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease
In
this randomized, controlled trial from Europe involving patients with
persistent symptoms attributed to Lyme disease, there was no benefit associated
with 12 additional weeks of treatment with either doxycycline or
clarithromycin–hydroxychloroquine.
EDITORIAL
Time for a Different Approach to Lyme Disease and Long-Term
Symptoms
These are somewhat predictable European results for the
management of patients with long-term symptoms attributable to presumed chronic
Lyme disease using either doxycycline or clarithromycin-hydroxychloroquine. The
cause of this abundance of symptoms is unclear but frequently manifests as
fibromyalgia or prolonged fatigue.
As the author of the Editorial indicates, it is important
to consider alternative diagnoses, such as sleep apnoea in patients without the
classical phenotype, and to keep an open mind, although management of these
patients can be extremely challenging, time consuming, and long-term.
SPECIAL REPORT
The
Neglected Dimension of Global Security — A Framework for Countering
Infectious-Disease Crises
The
Ebola epidemic demonstrated how ill-prepared the global community is for major
infectious disease crises. Now an international expert group has outlined a
framework for preparedness, detection, and response to future
infectious-disease threats.
This Special Report highlights the area of global
security particularly as it relates to the recent infectious disease epidemics
of Ebola and Zika virus infections. Figure 1 demonstrates the chronology and
sites of origins of recent infectious disease outbreaks worldwide.
The recommendations of the Commission on a Global
Health Risk Framework for the Future are illustrated and frankly obvious. The
bottom line with any proactive international preparedness is that in order to
identify a potential outbreak/epidemic/pandemic early and manage it requires
both international sharing and cooperation and adequate independent funding in
advance – proactive, not reactive.
It sickens me when I see the major roadblock is the
lack of predictable and sustainable funding for public world health. Surely all
affluent Western societies should contribute a sum which a fixed proportion of
their GDP. The sums indicated are paltry ($1.9 - $3.4 billion) when in 2011 the
US annual military budget was $600 – 700 billion with up to $ 22 billion documented
wasted dollars. If the US claims to be the world policeman, surely it can
afford this sum for policing world health. You can prepare as much as you like,
but if the money is not there, then all of the Commissions and their erudite
recommendations represent only posturing and is for naught.
Recently President Obama
requested that the Congress appropriate $1.6 – 1.9 billion for Zika virus research
and public health (not a new funding request but a transfer from the requested Ebola
virus funding which is now no longer newsworthy, but still omnipresent. By the
way, in spite of pressure by the administration, the Congress has yet to appropriate any of these funds).
As they say, it
will “take an act of Congress” but when? Probably when the Zika virus infects a
billionaire or their family. Mosquitoes are equal opportunity vectors.
