Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 4th August 2016 (#54)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
I have included three perspective articles on
open-access data sharing in the final section of this week’s blog. Students
have tended to breeze over these article, but they are important for those students
planning a research career in terms of the development of clinical trials and
the subsequent publication of data from those trials.
Must Read or Save Articles
None
Articles Recommended for Medical Students
ORIGINAL ARTICLE
Innate
Immunity and Asthma Risk in Amish and Hutterite Farm Children
The
Amish and the Hutterites are farming communities with similar gene pools, but
asthma and allergy are more common in Hutterites. The authors provide data that
support the idea that the Amish environment stimulates the innate immune
response and protects the children from asthma.
EDITORIAL
Innate
Immunity in Asthma
This is a landmark article with an excellent
accompanying editorial.
The study is based on the observation that the
prevalence of asthma and allergic disease in children is 4 - 6 times higher in
the Hutterite farming communities than in the Amish farming communities. Both
communities share a common German alpine genetic origin. However, a major
difference exists between the communities related to methods used in dairy
farming which may result in environmental differences in which the children
develop. The Amish practice single-family, non-mechanized dairy farming while
the Hutterites use modern mechanization in their dairies. Dust samples from
Amish farms show increased levels of lipopolysaccharides and a distinct
microbial composition when compared with Hutterite dust samples.
The hypothesis generated is that the dust from Amish farms
induces a low level innate immune response involving transcriptional pathways
and mediators acting via NFkB
and IRF7 preventing asthma and allergic responses. Microbial peptides may also
act via MyD88 and toll-like receptors (TLRs) that activate regulatory T cells
and enhance mucosal tolerance. This type of response contrasts with the more
common adaptive immune response to allergens seen in asthmatics where
allergen-specific type 2 helper T cell and IgE B cell responses are dominant,
producing the acute and delayed allergic responses.
The results of this study on 30 Amish and 30 Hutterite
children aged between 7–14 years indicate that:
1. Endotoxin
in Amish dust were 6.8 times higher than in Hutterite dust (Figure 1B).
2. In
studies of peripheral blood leukocytes comparing both populations, the Amish
group had:
3. Increased
numbers of neutrophils but with reduced cell surface markers for the chemokine
receptor CXCR4,
4. Lower
numbers of eosinophils and with reduced CD11b receptors,
5. No
difference between monocyte numbers or CD11c receptor expression. However,
reduced expression of HLA-DR4 and increased expression of ILT3 suggest an
anti-inflammatory response in the Amish.
In a murine model of experimental allergic asthma, mice
were sensitized to ovalbumin by intraperitoneal injection of the antigen and
subsequently challenged by airway installation of the ovalbumin to produce
acute asthma. Amish or Hutterite dust were then installed a total of 14 times
over 4-6 weeks into the nasal cavities of mice to induce a presumed protection
against asthma as seen in the Amish population.
The dust-exposed BALB/c mice were then challenged with
inhaled ovalbumin followed by increasing doses of nebulized acetylcholine. Both airway’s resistance and cell composition
of the bronchoalveolar lavage (BAL) fluid were studied (Figure 4A). In the mice
previously exposed to Amish dust, airway’s resistance was significantly lower
than in those primed with Hutterite dust.
Further the BAL eosinophil count was significantly lower following Amish
dust exposure. In order to study Myd88 and Myd88-Trif knockout CD57BL6 mice,
mice under similar experimental circumstances, CD57BL6 mice were also required
as controls, with similar results to the BALB/c mice (Figure 4B). The deletion
of the proteins Myd88 and Trif essentially disables the innate immune
response. In both knockout mice groups (Figures 4C and
D), deletion of Myd88 or Myd88 + Trif resulted in abrogation of the protective
effects of Amish dust.
The murine studies indicate that Amish dust exposure
reduced airway’s resistance and BAL eosinophil count and that this effect
required both Myd88 and Trif to be functional. This provided a mechanism for
the protective effect of Amish dust by inhibiting the innate immune response.
Recommended
learning:
1. Review
the pathophysiology of asthma and the clinical presentations and management of
asthma in the paediatric and adult populations.
2. Review
the MED300 medicine clinical case.
REVIEW ARTICLE
Fire-Related
Inhalation Injury
Fire-related
inhalation injury results from a combination of direct exposures, systemic
effects of inhaled toxins, accrual of endobronchial debris, and secondary
infection. This brief review discusses the pathogenesis of and approach to
fire-related inhalation injury.
This is a review that should be read by MED300 and
MED400 during their surgical, ED or ICU rotations.
This article describes fire-related inhalation injury
and also includes an excellent discussion of the pathological processes
involved. Apart from the important clinical examination, the role of
bronchoscopy and imaging in the early management is discussed. The Figure 2 and
Table 1 provide a treatment algorithm and summary of the management, together
with a detailed discussion of the clinical course and time-based management.
Recommended
learning: Review the pathophysiology of burns, types of burns
and management of burns and their sequelae at various sites
IMAGES IN CLINICAL MEDICINE
Borrelia recurrentis Infection
After
collapsing in Munich, a 16-year-old male Somalian refugee was brought to a
local hospital with severe headache and abdominal pain. His vital signs were
notable for a temperature of 41°C, a heart rate of 105 bpm, and blood pressure
of 95/50 mm Hg.
This is a very interesting blood smear demonstrating
the causative spirochaete.
This infectious disease is seen most frequently in immigrant
populations usually from Sudan or Ethiopia. Patients frequently present with recurrent
episodes of fever, prominent headache, mental status changes, and nausea. Borrelia recurrentis is a spirochaete that is
present in the body cavity of the louse. The organism is spread when the louse
is crushed. It can be introduced into a break in the skin or into the
conjunctiva when the eyes are rubbed or from the fingers into the mouth. It is
spread when humans are confined to small areas, such as during winter when the
population is indoors or in tents e.g. refugee camps when the infected louse
spreads from clothing, blankets etc.
All other causes of relapsing fever are spread by ticks
who harbour the spirochaete in their saliva.
Recommended
learning: Review the human diseases caused by spirochaetes.
IMAGES IN CLINICAL MEDICINE
Urticaria
Multiforme
A
3-year-old girl presented to the ED on day 1 of a mild pruritic urticarial
rash. The parents described a viral respiratory illness that had occurred a
week earlier. Fever developed on day 2, along with a generalized polycyclic
annular rash with wheals and ecchymotic centers.
This is a classical presentation of a rare paediatric
condition. One feature that
characterises urticarial multiforme is the significant facial and acral oedema
with the urticarial eruption. If you have a particular interest in dermatology
and would like more information and a more in-depth discussion of the
differential diagnoses, this is a good site: (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3613272/ )
CLINICAL PROBLEM-SOLVING
Prevention
as Precipitant
Two days after undergoing uncomplicated bilateral total
knee arthroplasties, a 72-year-old man had a temperature of 101°F and a
pruritic, erythematous rash that originated on his trunk and spread peripherally
to his arms and upper thighs over the course of 24 hours.
As stated above, this is an interesting case of a
patient who had a bilateral total knee arthroplasty and over 24 hours developed
a fever and a rash. Discussion of the differential diagnoses focuses on
cutaneous drug reactions.\
Important Articles Related to Mechanisms of Disease and
Translational Research
ORIGINAL ARTICLE
Inherited
DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer
Inherited
mutations in DNA-repair genes were found in nearly 12% of men with metastatic
prostate cancer, as compared with 2.7% in an unselected general population.
Although the role of PSA determinations is still an
area of controversy, local guidelines have been established. What is clear is
that with the introduction of routine PSA screening, there was a dramatic fall
in the number of patients presenting to physicians with metastatic disease of
the prostate (http://www.nejm.org/doi/full/10.1056/NEJMp1510443
). However, in an individual with an elevated PSA level and microscopic
evidence of prostate cancer, the natural history of the tumour in the
individual patient cannot be predicted (also compare microscopic intraductal
breast cancer and papillary carcinoma of the thyroid).
The answer as to how the tumour will behave in the
short-term in the individual patient will reside in the identification of
specific tumour markers and/or the genetic profile of the tumour.
This multicentre study of 692 men with documented
metastatic prostate cancer is compared with 499 patients with localized
prostate cancer (TCGA cohort) and 53,105 controls without clinical evidence of
cancer (Exome Aggregation Consortium). Germline mutations in genes mediating
DNA-repair processes (Table 2) were identified in 11.8% of patients with
metastatic disease, in 4.6% among patients with localized prostate cancer, and
in 2.7% of the control population. Of the 16 DNA repair genes identified with
mutations (Figure 2), the most common were in BRCA2 (44%), ATM (13%), CHEK2
(12%) and BRCA1 (7%). The 12 remaining ranged from 1-4% of the identified
mutations.
Patient with metastatic prostate cancer who exhibit
these mutations are more likely to respond to inhibitors of PARP1 and to
platinum-based chemotherapy.
The role of screening all men with metastatic prostate
cancer for these genes is as yet undetermined. However, this study and others
involving a variety of tumour types, indicate the future direction of genetic
testing in malignancy in the hope of predicting metastatic potential of
localized tumours and thus the ability to predict responses to chemotherapeutic
agents (pharmacogenetics).
Recommended learning:
1. Review
the epidemiology, genetics, pathology, clinical presentations and the
principles of management of prostate cancer.
2. Review
the current guidelines for PSA screening and indications in clinical practice.
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Modeling
Zika Virus Infection in Pregnancy
This article
reviews the results of four recent murine studies which demonstrate that ZIKR
administered to pregnant mice results in similar changes to those described in
humans. The passage of ZIKR across the placenta and into the developing brain
is well illustrated in Figure 1.
The investigators have found that ZIKR replicates in
maternal and fetal trophoblastic cells, in foetal endothelial cells, and in
macrophages within the placenta. ZIKR appears to bind to a cell-surface
tyrosine kinase called AXL.
This process can either lead to damage of placental
vessels, decreased fetal blood flow and increased fetal death. Moreover, the
virus may spread to cortical neural progenitor cells and radial glial cells
resulting in cortical atrophy and subsequent microcephaly.
These murine models will help to define ZIKR induced
pathology and hopefully can be used to define ZIKR human immunopathogenesis due
to similarities between murine and human trophoblast function and placental
development and also parallel developments in the nervous systems.
Other Articles which should interest medical students
REVIEW ARTICLE
THE
CHANGING FACE OF CLINICAL TRIALS
Pragmatic
Trials
In
pragmatic trials, participants are broadly representative of people who will
receive a treatment or diagnostic strategy, and the outcomes affect day-to-day
care. The authors review the unique features of pragmatic trials through a
wide-ranging series of exemplar trials.
This is another review article in the Clinical Trial Series
which addresses the area of pragmatic trials. The authors attempt to contrast
explanatory trials with pragmatic trials.
Nine levels for assessing the level of pragmatism in a
trial are outlined in Table 1 and each level is individually addressed
throughout the article. In Table 2, examples of specific trials and their
pragmatic attributes are described. At the end of the article the message I got
was that most trials exhibit varying degrees of pragmatism, none are completely
pragmatic, and none are capable of answering all of the potential questions
about the value of any health care intervention. The authors suggest that with
any trial, it should be as pragmatic as possible except when the quality of the
trial is compromised or clinical questions of interest are not able to be
addressed.
Perspective
Strengthening
Research through Data Sharing (1)
Data
sharing can strengthen academic research, the practice of medicine, and the
integrity of the clinical trial system. Many policy, privacy, and practical
issues need to be addressed, but the stakes are too high to step back in the
face of that challenge.
Perspective
The
Yale Open Data Access (YODA) Project — A Mechanism for Data Sharing (2)
As
medical research moves toward the more open approach to data sharing from which
physics, astronomy, and genetics currently benefit, the YODA Project offers one
of several pioneering data-sharing mechanisms that are already in use.
Perspective
Toward
Fairness in Data Sharing (3)
A
new consortium, ACCESS CV, aims to provide avenues for data sharing while
minimizing risks and unintended consequences. It has identified challenges
including data complexity, publication and selection bias, increased risk of
type I errors, and patient privacy.
I will attempt to summarize the above three
perspectives in the following statements:
In January 2016, a proposal from the International
Committee of Medical Journal Editors (ICMJE) regarding data-sharing from
clinical trials was published in the Journal http://www.nejm.org/doi/full/10.1056/NEJMe1515172 .
In this, the authors outlined reasons for sharing data from clinical trials
whether they be publicly funded (NIH) or funded by pharmaceutical
companies. They suggested that the
investigators agree to data sharing at the time of the clinical trial
registration and that the investigators agree to sharing the data from deidentified
patients within six months of publication as a requirement for publishing their
data in a specific journal.
In Editorial 1
of this week’s Journal, the editors, who strongly favour the recommendations of
the ICMJE, recruited Senator Elizabeth Warren to comment on the proposal. As a
JD and a faculty member of Harvard, a member of the ICMJE, a Senator from
Massachusetts, and a powerful national liberal political force, she provided an
eloquent endorsement of the recommendations. In addition to an inability to
publish in specific journals, she also suggested that those federally funded
who elect not to share their data may find themselves ineligible for future
federal funding.
In Editorial 2,
the Yale Open Data Access (YODA) Project is described. The discussion focuses
on the need to ensure participants’ privacy, the role of an independent funded arbiter
who would provide for accountability, transparency, and arranging for the
sharing of the data. Who would fund this individual, the journal in which the
results are published or the provider of the study funds? The final area
involves appropriate academic recognition of the original investigators if the
data they generated are then mined and analysed by another party. I consider this
is a major area of concern.
In Editorial 3,
opposite points of view are expressed with regard to fairness in data
sharing. The authors summarize their
recommendations as follows:
1.
that the
ICMJE come together with trialists and other stakeholders to discuss the
potential benefits, risks, burdens, and opportunity costs of its proposal and
explore alternatives that will achieve the same goals efficiently
2.
that
the timeline for providing deidentified individual patient data should allow a
minimum of 2 years after the first publication of the results and an additional
6 months for every year required to complete the study, up to a maximum of 5
years (the authors provide a justification for this suggestion)
3.
that
an independent statistician should have the opportunity to conduct confirmatory
analyses before publication of an article, thereby advancing the ICMJE’s stated
goal of increasing “confidence and trust in the conclusions drawn from clinical
trials,” and
4.
that persons
who were not involved in an investigator-initiated trial but want access to the
data should financially compensate the original investigators for their efforts
and investments in the trial and the costs of making the data available
Clearly there is a long way to go to resolve these
issues. I would hope that there is
significant compromise on the timeline and appropriate academic recognition by
the investigators’ institution.
