Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 12th May 2016 (#42)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
EDITORIAL
MAGE-D2
and the Regulation of Renal Salt Transporters
I have not included the article (http://www.nejm.org/doi/full/10.1056/NEJMoa1507629) with
this editorial which discusses the pathophysiology of Bartter’s syndrome with
emphasis on Bartter’s syndrome presenting during pregnancy. For those students
with an interest in renal physiology and the development of the renal function
during embryogenesis or those future obstetricians interested in polyhydramnios,
I recommend the article and the editorial.
The reason I chose this article and editorial in this
week’s review was that, during my internship at Sydney Hospital, Professor
Solomon Posen (my long term mentor who died recently in Sydney on 16/5/2016 http://tributes.smh.com.au/obituaries/smh-au/obituary.aspx?n=solomon-posen-sol&pid=180052181 )
and I looked after a pregnant patient (end of second trimester) who presented
with profound generalised weakness from hypokalaemia due to Bartter’s syndrome.
This was the first detailed case description of Bartter’s syndrome during
pregnancy ( Med J Aust. 1974 Sep
7;2(10):360-5).
Until his recent death, Sol read my weekly reviews and
was never restrained in offering valuable suggestions for improvement. He was a
dedicated academic, who was actively writing until the end. In addition to
multiple publications in the areas of metabolic bone disease, renal
osteodystrophy and hyperparathyroidism, his seminal work was the
differentiation of bone from liver alkaline phosphatase, the basis for his MD
thesis. This formed the foundation for his definite work on “Alkaline
Phosphatase,” published in 1979. Over more recent years he published, “The
Doctor in Literature: Satisfaction or Resentment.” I will very much miss him, not
only for a long friendship, but also for his incisive mind, his generosity, his
loyalty and sense of equity and his witty and insightful personality.
In the future, I plan to discuss medical aspects of the
most important issue of the day, namely Global Warming and Climate Change. As
physicians we can hide in current science which is truly amazing (epidemiology,
public health, surgical techniques, ethics, basic science, new advances in
management of cancer and chronic disease to name just a few) but in fact many
of us are emulating the ostrich. All of
these medical advances pale when compared with how our planet is being
devastated by human activity (anthropogenic climate change – ACC). Climate chaos will have a profound effect on
all life on earth and prominent medical journals need to incorporate this fact
in their articles and editorials.
I call for all medical schools to include within their
curricula a major segment, not only on Medical and Public Health issues, but all
aspects of Global Warming and Climate Change. I would suggest that every medical school
should devote an entire week to this area towards the end of their preclinical
training.
The medical profession, especially the AMA and Colleges,
MUST be much more proactive politically or else the human race will face the inevitable
devastating consequences. The NEJM should also actively pursue all means to
mitigate the effects on human health of Global Warming and Climate Change
because of the Journal’s scientific credibility, its large readership and its
social and scientific responsibility.
Perspective
The
Zika Challenge
At a recent international meeting about the Zika
epidemic, experts exchanged insights, identified knowledge gaps, and agreed on
a plan for accelerating product development and evaluation in the hope of
controlling the spread of the virus in Brazil and elsewhere.
This Perspective is a summary of a recent WHO meeting
convened to discuss the current state of the Zika virus epidemic, particularly
in Brazil. This is a concise summary discussing the biology of the ZIKV and its
relationship with the other flaviviruses, the role of a shared immune response
between flaviviruses, discussions of the current status of ZIKV diagnostic
tools, early data sharing and discussion of management, including vector
control, prophylaxis and the very early stages of vaccine development.
Should the Olympics be held in Summer in the middle of
a ZIKV epidemic when at least 540,000 people from around the globe converge on
Brazil?
I believe that the answer is a resounding NO!! This event will lead to a global pandemic
which does not present with the roar of a lion like Ebola virus but with the
purr of a kitten. In some ways this is reminiscent of the early spread of HIV
infection in the US, when the slow in reporting on the severity of the threat.
Unfortunately, the Olympics will be held due to many
complex globally intertwined interests, which ignore the predictable
consequences.
In the US, the Congress has gone into recess without
approving additional funding for ZIKV research. I recommend you read the
article from the Washington Post and listen to the excellent video clip on ZIKV.
Republicans indicated there “was no urgency” in extending the funding ( https://www.washingtonpost.com/news/powerpost/wp/2016/05/27/congress-leaves-town-with-no-zika-resolution-lengthy-negotiations-ahead/ ).
Within the next month, most conservative Republican
Southern states, which have rejected Obamacare for partisan reasons, will be in
the middle of a ZIKV epidemic and will be screaming for the Congress to
appropriate more funding.
Must Read Articles
Perspective
Health
as a Family Affair
Despite the substantial burden borne by informal caregivers,
our society has only recently recognized that our conception of illness as
solely an individual experience is too narrow. Acknowledgment of illness’s
effects on families suggests a better approach to care.
ORIGINAL ARTICLE
One-Year
Outcomes in Caregivers of Critically Ill Patients
Investigators
evaluated the caregivers of patients who had received mechanical ventilation
for at least 7 days in an ICU. Although there was a large burden of depressive
symptoms soon after discharge, the burden diminished in magnitude, in most
caregivers, during the subsequent year.
While the article focuses on the symptoms of depression
over a twelve-month period in caregivers of patients who had been treated in an
ICU on a ventilator for at least 7 days, the Perspective article deals with the
general area of the burden borne by caretakers of patients with major illness, particularly
those with chronic disease (cardiac, pulmonary, rheumatic, malignancy) and
those in palliative care. It is interesting that in palliative care the
physician’s responsibility extends not only to the patient but also to the
caregiver(s), including after death of the patient.
Concern for the caretaker should include such areas as
individual health (physical, emotional, social), financial health, loss of
work, respite care, and psychiatric support. Medical students need to be
reminded that there is more to caregiver illness than Takotsubo’s
cardiomyopathy.
Caretaker health is clearly an area in which a major
component of the patient’s health care cost is borne by the caregiver and should
be considered within the financial equation of total health care costs.
Must Save Articles
REVIEW ARTICLE
Clinical
Implications of Genomic Discoveries in Lung Cancer
Many
genetic lesions have been identified in lung cancers. The findings shed light
on molecular pathogenesis and have led to the definition of abnormalities that
can be targeted by therapeutic agents that occasionally elicit dramatic
responses.
This is an article that should be saved, although at
first glance it may not appear relevant to medical students. For those
interested in the genetic basis of lung cancer, this is a must read review. However,
for most readers, I would suggest focusing on Figures 2 and 3 and Table 1. This
article demonstrates the complexities of genes and cancer. There is slow but definitive progress and
awareness of the more common mutations particularly in adenocarcinoma of the
lung, where research in these areas will eventually lead to significant changes
in prevention and targeted gene-based therapies.
Articles Recommended for Medical Students
ORIGINAL ARTICLE
Serious
Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone
Among
more than 11,000 patients with moderate-to-severe asthma,
fluticasone–salmeterol was noninferior to fluticasone alone with respect to
severe asthma events.
EDITORIAL
Safety
of Fluticasone plus Salmeterol in Asthma — Reassuring Data, but No Final Answer
As indicated in the editorial comments, the article
does not answer all of the questions but it does answer many in patients with
“serious asthma.” There was no increase in adverse drug-related events in those
patients with “serious asthma” treated with the combination of fluticasone and
salmeterol (a long-acting beta agonist – LABA) over those treated with
fluticasone alone, suggesting the long-term (26-week study) safety use of LABAs
in this patient population. Another important aspect of the combined drug usage
was that fewer severe asthma exacerbations occurred in this group.
There are several aspects of the study that need
discussion:
1. The
population of patients with “serious asthma,” including age and
inclusion/exclusion criteria, must be noted.
2. There
is an assumption that the effects (positive and negative) of LABAs (salmeterol
versus formoterol) are similar, which may not be true. Unfortunately, a side to
side comparison between these drugs would never be funded.
ORIGINAL ARTICLE
Clinical
Significance of Symptoms in Smokers with Preserved Pulmonary Function
Chronic
obstructive pulmonary disease diagnosis rests on chronic pulmonary symptoms and
airflow obstruction. This study showed that people may have chronic COPD
symptoms but no airflow obstruction. Such patients have more COPD exacerbations
than those without chronic symptoms.
EDITORIAL
Smoking,
Not COPD, as the Disease
The article and editorial are very enlightening,
particularly the latter which should be read by all medical students along with
the introduction to the article. The major discussion focuses on the definition
of COPD, defined as persistent airflow obstruction in smokers.
A group of present or past smokers with symptoms (cough
and sputum, and less commonly SOB, wheeze and reduced energy), in whom there is
no spirometric evidence of airway obstruction (thus they do not fulfil the
international definition of COPD), were studied. The message is that for
smokers with symptoms, irrespective of normal or abnormal spirometric tests, it
is the presence of respiratory symptoms that determines the number of future acute
exacerbations of pulmonary disease.
Smokers with symptoms are more likely to exhibit a
decrease in exercise activity and greater airway thickening without emphysema
on HRCT. Further there is a slight reduction overall in FEV1, FVC and IC. All
smokers with symptoms are treated similarly with inhaled corticosteroids and
bronchodilators, irrespective of the lack of evidence in those patients without
evidence of airway obstruction.
Recommended
learning:
1. Review
the pathology, definitions and evidenced-based therapy for patients with COPD,
emphysema and chronic bronchitis.
2. Review
the types of ILD directly caused by smoking.
ORIGINAL ARTICLE
Patterns
of Growth and Decline in Lung Function in Persistent Childhood Asthma
Data
from a controlled trial of asthma treatment that enrolled patients in the first
decade of life were combined with follow-up data to provide novel information
on the growth and decline in lung function in the first three decades of life
in patients with asthma.
This is a very important and interesting article on
patients with persistent childhood asthma who had their FEV1 levels measured
over a prolonged period of time. The
statistical analyses were complicated. When I saw the possible lung function
trajectories (ratios of FEV1/normal control age related FEV1) projected through
the age of 30 years (review Fig. 1 carefully), I was impressed with the
similarities with bone mineral densities, particularly in females where optimal
achieved bone mass could be reduced by early use of corticosteroid or reduced
oestrogen levels.
The methods section should be carefully reviewed. This is a subset analysis of the original
CAMP cohort (Childhood Asthma Management Program) in which four possible lung
function trajectories (approximately 25% of the patients are in each group) are
arbitrarily chosen and the study participants ultimately allocated into each
group.
The data suggest that “childhood impairment of lung
function and male sex were the most significant predictors of abnormal
longitudinal patterns of lung-function growth and decline. Children with persistent
asthma and reduced growth of lung function are at increased risk for fixed
airflow obstruction and possibly COPD in early adulthood.” It will be very
important to follow this cohort over time to determine if the two groups who
never obtain optimal lung growth develop early onset COPD and whether they have
persistent symptoms.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
14-2016 — A 37-Year-Old Woman with Adult-Onset Psychosis
Examination
of a 37-year-old woman with adult-onset psychosis revealed weight loss, a
thyroid nodule, anemia, and micronutrient deficiencies. Diagnostic tests were
performed.
This is an interesting CPC of a 37-year-old female
presenting with difficult to manage psychosis who was subsequently found to
have coeliac disease. The treating doctors fulfilled Koch’s postulates,
demonstrating the very uncommon associated between these two entities in this
patient.
What amazes me is the continual references to the
“astute endocrinologist” who suggested an association between iron deficiency
anaemia and coeliac disease in a patient with a strong family history of
autoimmune disease. It should be noted throughout the CPC that there was no
mention of obtaining a faecal blood test or taking a menstrual history in the
patient by the “astute endocrinologist”, although the latter was mentioned in
passing at the end of the discussion. There was no discussion of the low serum
vitamin B12 (predominantly absorbed in the terminal ileum) level which was
assumed to be due to malabsorption from coeliac disease. The patient could well
have also had autoimmune pernicious anaemia accounting for the low vitamin B12
level with antibodies demonstrated against intrinsic factor and parietal cells.
Another consideration for management not discussed, when
the patient was readmitted for psychosis and a flare in her coeliac disease,
would have been a course of corticosteroids. This would have controlled the disease
process, reversed her psychosis and her denial of the disease, thus allowing
her to recommence her gluten-free diet. This would have been a pragmatic
approach to health care cost containment.
The strong points of the CPC are a very good discussion
of psychosis in a 37-year-old patient and an excellent discussion of the histo-
and immunopathology of coeliac disease.
Recommended
learning:
1. For
MED400 students, review the different presentations of psychosis, their peak
ages of presentation and their management.
2. Review
the pathology, diagnosis, presentations, and management of coeliac disease.
Important Articles Related to Mechanisms of Disease and
Translational Research
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Blood
and Bone
Hematopoietic
stem-cell transplantation has come a long way in 60 years, but substantive
clinical challenges remain. Hoxb5, a marker for long-term HSCs, has been
used to better understand their niche.
This is a fascinating article describing the work of
Chen et al in Nature 2016 in which long-lived haematopoietic stem cells (HSCs) in
bone marrow could be identified in mice using a specific cell marker (Hoxb5).
They used this technique to demonstrate that the majority of HSCs reside in
close proximity to marrow endothelial cells. It raises the consideration that
when autologous HSCs are transplanted, maybe they should also be infused with autologous
bone marrow endothelial progenitor cells.
Recommended
learning: Review the area of stem cell biology, in particular
the role of HSCs, their future differentiation and the factors necessary for
differentiation.
Other Articles which should interest medical students
Perspective
Drug
Regulation and Pricing — Can Regulators Influence Affordability?
Regulation
may contribute to high drug costs, but there are several ways in which
regulators at the European Medicines Agency believe they can contribute to
keeping drug spending sustainable, beginning with approving genetics and
biosimilars more rapidly.
This article is for those students interested in public
health policy and the role regulators should play (four examples are provided)
in maintaining a rational and practical price for new pharmaceuticals. This is
a balancing act between the pharmaceutical companies who claim they need more
profit in order to recoup R&D costs while on the other hand to increase
shareholder profit. Take the recent example of sofosbuvir, an RNA polymerase
inhibitor, used to treat hepatitis C where R&D costs were recouped within
the first three months of its use in the US market!
What Australians need to be aware of is that the
majority of the R&D costs of new drugs are borne by US patients and US
citizens who pay exorbitant prices for health insurance. The most frequent reason that Americans
declare bankruptcy is their inability to pay for their health care costs.
IMAGES IN CLINICAL MEDICINE
Diaphragmatic
Hernia Causing Lung Collapse
A
54-year-old man with a history of cerebral palsy and mental impairment
presented with acute respiratory distress. He was afebrile and had a
nonproductive cough. Examination revealed an absence of air sounds in the right
hemithorax, with audible bowel sounds.
As an intern in Sydney in 1969 it was common practice,
for even interns, to place suprapubic peritoneal catheters for acute peritoneal
dialysis, unlike today where acute haemodialysis is performed through central
venous access. Following the introduction of several litres of dialysis fluid
through the peritoneal catheter, the patient developed acute respiratory
distress, tachypnoea, cyanosis, tachycardia and hypotension and was found to
have stony dull percussion note on the right and tracheal deviation to the
left. CXR confirmed a massive right pleural effusion with mediastinal shift to
the left. I was almost as distressed as the patient. Before the patient coded,
the head of the bed was elevated and the pleural and peritoneal fluid was
quickly withdrawn. The patient then
improved dramatically. Addition of Trypan blue to the remaining peritoneal
fluid and its demonstration in the remaining pleural fluid confirmed the
presence of a previously asymptomatic diaphragmatic hernia.
MAGES IN CLINICAL MEDICINE
Hair-on-End
Sign
A
35-year-old man with a history of sickle cell disease presented with a sickle
cell crisis and headaches. CT of the head revealed a thickened calvarium with
perpendicular proliferation of the trabeculae, a finding termed the hair-on-end
sign.
This is an interesting CT demonstrating excessive
medullary haematopoiesis in the diploic space of the calvarium most commonly seen
in thalassemia major.
