Sunday, 31 July 2016

NEJM Week of 14th July 2016 (#51)

Professor Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week of 14th July 2016 (#51)
University of Notre Dame Australia (Fremantle Campus)



Occasional Editorial Comment


None


Must Read Articles

None


Articles Recommended for Medical Students


Perspective

Beyond Bathrooms — Meeting the Health Needs of Transgender People


Beyond bathroom accessibility, discrimination against transgender people is associated with many adverse health effects. The health care community can help through clinical care, research, and advocacy. But most clinicians lack expertise in transgender health

In my opinion, this is a political wedge issue concocted by right wing Christians in the US to divert attention from truly pressing problems such as wars and climate change. One solution is unisex bathrooms. Transgender rights extend far beyond bathrooms.

There are several points I would like to make:

1.     The fastest growing outpatient clinic at Princess Margaret Hospital is the Gender Diversity Clinic.
2.     With the inclusion of “other” under Gender in the upcoming census, I predict that there will be a larger number of Australians than predicted who will tick this box.
3.     I was discussing transgender issues with one of my MED300 student groups last week when I was told a story. At one of the large GP group practices in the Perth area, a patient with transgender issues asked for an appointment. The front office staff did not know to whom to refer the patient but apparently selected an empathetic physician. This GP has now developed a reputation as the “transgender GP” in the area and their practice is growing rapidly.
4.     Most students and doctors do not have experience interacting and treating transgender patients and may feel awkward in interacting with them.  This includes even such seemingly simple issues as to what pronoun to use when addressing the patient.
5.     It is clearly incumbent upon Australian medical schools to consider the introduction of transgender medicine as another aspect of the medical curriculum.

The final paragraph distills the essence of the article:” Being transgender, like being left-handed, may someday be recognized as merely another inherent human quality, no longer conferring a need for protection. In the meantime, the health care community can better address transgender health needs, help ensure that transgender people feel safe in seeking health care, promote resilience in the face of prejudice, and expand our knowledge of how best to promote transgender health and well-being.”


CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Case 21-2016 — A 32-Year-Old Man in an Unresponsive State


A 32-year-old man was admitted to this hospital after being found in an unresponsive state in his jail cell. He had jaundice and encephalopathy; results of liver-function tests were abnormal, and CT revealed cerebral edema. Diagnostic tests were performed.

This is a very educational CPC involving a patient with acute fulminant liver failure and severe hepatic encephalopathy. A discussion of the causes of acute liver failure are well addressed as is an excellent discussion of acute viral hepatitis. I learnt about subtle aspects of the immune response to hepatitis B including the effects of vaccination. 
 I would also have treated this encephalopathic patient with lactulose rather than focusing on measures to reduce the raised intracranial pressure. Apparently lactulose in this situation is of no proven benefit and, in addition, may worsen dehydration and underlying electrolyte abnormalities exacerbating cerebral oedema.

Recommended learning: Review the pathology, clinical presentations and management of hepatic encephalopathy and portal hypertension.


IMAGES IN CLINICAL MEDICINE

Milk of Urate Bulla


A 71-year-old man with a history of gout and renal transplantation presented with a new blister overlying the second interphalangeal joint just distal to a preexisting tophus on his hand. Examination of the fluid showed sheets of negatively birefringent crystals.

 This is a photograph of a gouty tophus (A) discharging a thick soup of monosodium urate crystals which are demonstrated as negatively birefringent on polarizing microscopy (B).

There are several interesting points which need to be made:

1.     The prevalence of acute gouty arthritis and chronic tophaceous gout has doubled in frequency over the last 20 years. These are now seen regularly on the wards in the Perth area and relate to the obesity epidemic (increased lipids, serum urate and blood sugar and hypertension), an ageing population with more chronic kidney disease and, increased use of thiazide diuretics.
2.     In Australia, the prevalence in the adult non-Aboriginal population is approximately 1.4%, but 4% in Aboriginal Australians.
3.     Acute gouty arthritis is the commonest inflammatory arthritis in males.
4.     The mean time for the development of tophi in untreated gouty patients is 11.5 years and 4-5 years in post-transplantation patients.
5.     Long standing hyperuricemia is an independent risk factor (low OR) for atheromatous cardiovascular disease and chronic kidney disease.

Recommended learning:

1.     Review the causes and significance of hyperuricemia.
2.     Review pathobiology of acute gout, including the role of the inflammasome.
3.     Review the treatment of acute gouty arthritis and chronic gout.
4.     Review the tumour lysis syndrome and its management.

                                                                                                                                
IMAGES IN CLINICAL MEDICINE

Jejunal Diverticulosis with Midgut Volvulus and Intestinal Malrotation


A 67-year-old woman with malabsorption and malnourishment was referred for possible intestinal transplantation. CT showed small-bowel dilatation along with a whirl sign and numerous collateral veins, suggestive of a midgut volvulus, shown in a video.

Radiology demonstrates the jejunal diverticula and the operative finding demonstrate the diverticula on the anti-mesenteric border of the jejunum. While the patient exhibited bacterial overgrowth diarrhoea, malabsorption and weight loss, she also developed a midgut volvulus.

 What interested me the most was that after correction of the mechanical volvulus, the jejunum containing diverticula was removed and the malabsorption corrected with evidence of progressive weight gain.



Important Articles Related to Mechanisms of Disease and Translational Research


None


Other Articles which should interest medical students


ORIGINAL ARTICLE

Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs


In patients with ischemic cardiomyopathy and an implantable cardioverter–defibrillator who had ventricular tachycardia, catheter ablation was associated with a lower rate of death, ventricular tachycardia storm, or ICD shock at 28 months than an escalation in antiarrhythmic drugs.

I have found that students will always pick the article related to cardiology! This specific study population are a group of 259 patients with recurrent ventricular tachycardia who have survived an MI with an implantable cardioverter-defibrillator.  The question dealt with is which is more effective, either standard antiarrhythmic drugs + ablation therapy or escalating doses of anti-arrhythmics (amiodarone/mexiletine) over a mean follow up period of 28 months.

The primary end point was a composite of death, three or more documented episodes of VT within 24 hours (VT storm) or ICD activation. The mortality rate was similar in both groups. Thus, the data supporting ablation therapy relates to fewer VT storms and ICD activation.  It must be emphasised that post-MI ablation is an extremely complicated procedure, is very time consuming, and requires skilled expertise and equipment.


ORIGINAL ARTICLE

Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting


The addition of olanzapine to a neurokinin receptor blocker, a serotonin receptor blocker, and dexamethasone markedly improved the control of nausea and vomiting in previously untreated patients receiving highly emetogenic chemotherapy.


CLINICAL DECISIONS

Chemotherapy-Induced Nausea and Vomiting


This interactive feature offers a case vignette accompanied by essays that support either using a standard premedication regimen or adding olanzapine to prevent nausea and vomiting. Share your comments and vote at NEJM.org.

The above include an interesting study and clinical decision making (point-counterpoint) involving the use of olanzapine as an anti-emetic agent. It gives students a chance to review the drugs used to prevent chemotherapy-induced nausea and vomiting produced by very emetogenic chemotherapy (in the study, cisplatin + other drugs or doxorubicin + cyclophosphamide and, in the clinical decision making case, cisplatin + paclitaxel + bevacizumab).

Drugs that can be used to reduce nausea and vomiting include a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist (ondansetron group), dexamethasone, and a neurokinin-1 (NK1) receptor antagonist (aprepitant group). To this mix has been added olanzapine, an atypical antipsychotic drug, which inhibits numerous neurotransmitter receptors.

The authors found that addition of olanzapine significantly improved nausea prevention and complete response rate with few adverse effects, over the group given placebo.

In the clinical decision making, which I believe is much to do about nothing, the discussants indicate:

1.     Weight gain and type 2 diabetes mellitus are not serious considerations with olanzapine in the short term.
2.     Olanzapine produces more drowsiness during the first 24 -48 hours of this very aggressive chemotherapy. To me this is a plus and not a minus. I want to be asleep and not throwing up.
3.     The most important consideration is the patient with extensive cervical cancer who needs specific chemotherapy and is scared of nausea and vomiting. One needs to do everything possible to limit the effects of chemotherapy and allow her to continue this chemotherapy. This is a plus, not a minus, as I would want to be asleep and not vomiting.  In my opinion, this does not even warrant an academic discussion in adding olanzapine to the standard regime.


Sunday, 24 July 2016

NEJM Week of 7th July 2016 (#50)

Professor Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week of 7th July 2016 (#50)
University of Notre Dame Australia (Fremantle Campus)


Occasional Editorial Comment

I was unsure as to where to include the five articles which include the perspective, two on adaptive randomization (AR) in breast cancer trials, the review on adaptive designs for clinical trials and the relevant editorial. While these articles focus on the AR design in breast cancer drug trials, the overall message is that many of the classical phase 2 clinical trials will be modified in the future, using instead AR trials in phase 2 studies.

This is a timely, about time, and refreshing update in clinical trials methodology. It is noteworthy that only three medical students out of 24 found any of these articles or the concept worthy of reading.
I would suggest reading the perspective article thoroughly as this clearly outlines the principles of this new approach, especially in testing oncology drugs.


Perspective

STATISTICS IN MEDICINE

I-SPY 2 — A Glimpse of the Future of Phase 2 Drug Development?


The I-SPY 2 breast cancer trials assess activity of new agents by adaptive randomization, applying criteria for success on a surrogate end point to predict success in confirmatory trials. Innovative designs may speed progress and eliminate waste in drug development.

I have extracted various sections from the perspective article as these are articulated extremely well:

1.     Traditionally designed phase 2 trials that test treatments one at a time in heterogeneous groups of patients have created a traffic jam: there are too many new drugs, and the signal of a treatment effect can be diluted in these heterogeneous groups.
2.     Adaptive multigroup trials such as I-SPY 2 have the potential to answer several questions simultaneously and more efficiently than traditionally designed trials.
3.     The I-SPY 2 platform will be used to compare up to 12 experimental therapies with a common control in subgroups of breast cancer with 10 distinct biomarker signatures. 
4.     New drugs can enter the platform (see Figure 1 in the Neratinib study) as they emerge from phase 1 testing and exit the platform with an estimate of the chances of future success in a phase 3 trial of prespecified size. This will reduce cost significantly with a greater chance that successful drugs will reach the patient faster.
5.     The platform may be an appealing setting for cooperation among pharmaceutical companies and academic investigators.
6.     The entire process, including design and analysis, is carried out dynamically using Bayesian methods (see Tables 1 and 2).
7.     In the world of trial design, this new platform is still in its adolescence.

 There are many questions that will need to be answered which include:

1.     How robust are the adaptive randomization probabilities and the predictive probabilities of success in a phase 3 trial to misspecifications of the model? 
2.     What are effective ways to communicate to our clinical colleagues the modelling assumptions used, the potential vulnerability of the model to errors, and the best ways to explain these designs to trial participants?
3.     What visual and numerical summaries provide insight into the trial data? Simple summary statistics such as odds ratios or relative risk can be misleading. 
4.     Will the predicted chance of future success (85%) upset equipoise for trial investigators or influence the kinds of patients investigators choose to enrol or not enrol in a future trial? 


ORIGINAL ARTICLE

Adaptive Randomization of Neratinib in Early Breast Cancer


Among patients with HER2-positive, hormone-receptor–negative locally advanced breast cancer, the addition of neratinib to standard therapy resulted in higher rates of pathological complete response, with some higher rates of toxic effects.

This is an important paper (especially Figure 1) which reviews the concept of an AR design and the concept of the platform to which test drugs can be added when they become available after successful phase 1 trials. The analysis of results is based on Bayesian probability which considers multiple variables in each response. Neoadjuvant and adjuvant therapies are also discussed.  

All patients (high risk clinical stage II or III breast cancer) receive the standard of care, namely paclitaxel followed by doxorubicin + cyclophosphamide. The patient then undergoes surgery and the results on the tumour are analysed.  Following these phase 2 studies, various protocols can be established for further phase 3 trials.

EDITORIAL

I-SPY 2 — Toward More Rapid Progress in Breast Cancer Treatment


The editorial reviews the two papers on the AR clinical drug trials in breast cancer and discusses the interpretation and pros and cons of the results.

There have been recent papers published in cardiology in which long-term studies have been carried out on a new device.  By the time the results are presented at meetings and then published, the original device is no longer being used, being supplanted by a newer device. What a waste of time and money! If a platform type study could be utilized to add newer devices (presumed to be more effective, but not proven) where both the new and the newer device could be studied in parallel, then time, money and earlier use by patients will be accomplished.  One wonders how device manufacturers would react to this type of trial design.


Must Read Articles


None


Articles Recommended for Medical Students


Perspective

Zika and the Risk of Microcephaly


An analysis of data from Brazil reveals a strong association between the risk of microcephaly in a newborn and the risk of Zika virus infection during the mother's first trimester of pregnancy. The association in the second and third trimesters was negligible.

In the preceding months the Journal has reviewed data on the pathology of ZIKV on the nervous system, the epidemiology of ZIKV infections and, most recently, has discussed a direct causal association between the virus and clinical disease by fulfilling standard causality criteria.

Today an article provides data from recent ZIKV outbreaks in French Polynesia and Bahia, Brazil.  The greatest chance of developing microcephaly or significant neurological impairment occurs in women who develop a symptomatic infection during the first trimester and who deliver at term.

The article produces more questions than answers.  However, it focuses on our lack of knowledge and data on the outcomes of asymptomatic ZIKV infections during pregnancy and on the other long-term, less severe neurological sequelae not encompassed by microcephaly or marked neurological impairment at birth. The authors indicate that based on the current data available more cases of significant birth defects will occur and that ZIKV infection during pregnancy should be avoided.

I believe there is also a significant ethical issue raised (the individual versus the society as a whole) with playing “Russian roulette” in endemic areas for sexually active people who avoid responsible birth control and protection.  Education should be provided by the state for women and men. If not, should society then be held responsible for the long-term health care costs in caring for neurologically impaired infants if appropriate care is not taken in prevention?

The knowledge of the ZIKV is still in its infancy, especially in terms of other modes of viral transmission, the genes associated with the expression of disease and other organ systems involved long-term in infants born to infected mothers. Stay tuned and let’s see what the Olympics produces apart from gold medals.


ORIGINAL ARTICLE

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack


In this double-blind, randomized trial involving 13,199 patients with ischemic stroke or transient ischemic attack, ticagrelor was not superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days.

As predicted, a majority of MED300 and MED400 students reviewed this article but frequently did not carefully review the exclusion criteria. The authors note the lower frequency of primary outcome events (stroke, myocardial infarction or death within 90 days - usually stroke within the first two weeks) in this study with aspirin (7.5%) or ticagrelor (6.7%) compared with historical data using aspirin for secondary stroke prevention. Previous studies found a recurrent stroke rate significantly higher at between 10-15%. In previous aspirin studies, patients with surgically amenable carotid artery disease or major intracerebral vessel disease amenable to radiological intervention were not excluded in the analyses although they were in this study.

The data is from an international, randomized, double blind controlled trial comparing either aspirin or ticagrelor in 13,199 patients with a high-risk TIA or non-severe ischaemic stroke (check exclusion criteria) who were started on the drug within 24 hours of initial symptoms. Patients were followed for 90 days with the primary end-point of stroke, MI, or death. The data showed no significant difference in primary outcome with either drug i.e. ticagrelor was not superior to aspirin. The hazard ratios for each treatment should be reviewed to see subtle subgroup differences.

   
CLINICAL PRACTICE

Polycystic Ovary Syndrome


The polycystic ovary syndrome increases the risk of infertility, endometrial cancer, abnormal glucose metabolism, and dyslipidemia. Strategies such as lifestyle modification, hair removal, and combined oral contraceptive therapy and other pharmacotherapies are reviewed.

This is an excellent review on the polycystic ovarian syndrome (PCOS) with key points well summarized in the enclosed box. It should be read by all MED300 before their O&G rotation and the hyperlink stored for the future.
Figure 1 is excellent for demonstrating the basic pathophysiology of the hyperandrogenemia seen in PCOS.
 Specifically review the presented case and the section at the end on conclusions and specific recommendations for this patient. In the section of Diagnosis, there is a detailed discussion of the differential diagnosis and other conditions which need to be excluded before a definitive diagnosis of PCOS can be made.

For those who had forgotten most of what they once knew, this is a valuable review of the basic science, ovarian cholesterol metabolism, mechanisms of hyperandrogenism, and, in particular, a balanced approach to the management of PCOS and the expected outcomes with the therapies available.

Recommended learning:
1.     Review pituitary, ovarian, and adrenal axis in terms of uterine function and the menstrual cycle.
2.     Review the PCOS and other causes of increased androgen levels.


IMAGES IN CLINICAL MEDICINE

Eyelid Melanoma


An 87-year-old man presented with a stye on his left upper eyelid. Despite conservative interventions, the stye had persisted and the skin had become noticeably darker over several weeks. His risk factors included a history of prolonged sun exposure while working as a lifeguard.

This is an interesting clinical picture of an eyelid melanoma in an 87 year old male. Considering the possible complexities of the therapy the patient may have been offered, there is no wonder he decided not to return for follow up.

Recommended learning: Review the clinical presentations of melanoma, prognostic factors, pathology, principles of surgical management and advances in adjuvant and newer therapies.


IMAGES IN CLINICAL MEDICINE

Dubin–Johnson Syndrome


A 48-year-old woman scheduled to receive a laparoscopic cholecystectomy underwent a preoperative evaluation. A laparoscopic exploration, shown in a video, revealed a smooth liver with normal consistency and morphology but with a grossly black appearance.

This is a very interesting and well described case of Dubin-Johnson (autosomal recessive) with excellent clinical pictures, including video, and typical histopathology. The authors demonstrate loss of the MRP2 receptor on the hepatocyte which leads to blockage of the transport of conjugated bilirubin from the canalicular pole of the hepatocyte into the bile canaliculus.

The result of the laparoscopy and biopsy were predictable based on the clinical history and normal LFTs except for the elevated conjugated bilirubin. This was a well, 48 year old woman who had had intermittent jaundice for at least 20 years associated with conjugated hyperbilirubinemia (not unconjugated as seen in the much more common entity Gilberts’ disease) with no other impairment in liver function.

Recommended learning:
1.     Review the pathophysiology and causes of hyperbilirubinemia.
2.     Review Gilbert’s disease.


CLINICAL PROBLEM-SOLVING

A Bruising Loss


A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention.

This is a very interesting discussion of the differential diagnosis of spontaneous bruising in a 32 year old female which should be read by most medical students during their clinical years. While the cause of this acquired coagulopathy is uncommon (an autoantibody against factor VIII), the principles of management are interesting. Further the authors omitted a rare cause of a factor VIII autoantibody which is primary amyloidosis involving the spleen.

It is interesting that only one of 24 students took the time to review this article. I believe this was due to the inappropriate and “trying too hard” title which turned the students off.

The first words in a paper that the reader sees is the title and thus it is imperative that it capture the interest of the reader to proceed further into the article. The process of title selection takes time and consideration with multiple options considered and shared with co-authors.

It is generally considered that important aspects of a title should include:

1.     Sufficient information about the subsequent work.
2.     A title no more than 12 words in length.
3.     Considering how much information should be in the title? Should it summarize the results of the study? For example in the study on aspirin and ticagrelor for secondary prevention in ischaemic stroke, should the title have been “Ticagrelor and Aspirin are equally effective in preventing a second stoke in patients presenting with an ischaemic stroke?” Apart from exceeding the 12 word limit, does the title provide too much information with the reader then not inclined to read further?
4.     Try breaking the title into two components with the second following the first, but separated by a colon. For example, I wrote a review article many years ago: “Scleroderma: Advances from Osler to the Present.”
5.     Refraining from hyperbole and “attempts to be too cute.” Don’t try too hard like “A Bruising Loss.”


Important Articles Related to Mechanisms of Disease and Translational Research

CLINICAL IMPLICATIONS OF BASIC RESEARCH

Corralling Colonic Flagellated Microbiota


A study of a mouse deficient in the gene Lypd8 showed that the Lypd8 protein prevents flagellated bacteria from invading the inner mucosal lining of colonic epithelium.

This article discusses a role of the mechanical mucous layer in the colon in protecting the host from potentially invasive gut microbiota. There is an excellent Figure 1 which demonstrates the protective role of a protein Lypd8, which is secreted by colonic epithelial cells. This protein binds to the flagellae of motile bacteria at the junction of the loose outer mucous layer with the firm inner mucous layer stopping bacteria entering the inner mucous layer. A  Lypd8 knock-out mouse model resulted in a mouse phenotype which was readily subjected to colitis and patients with inflammatory bowel disease also exhibited reduction in Lypd8 production.

Recommended learning: Review the role of host protective mechanisms within the GI tract, including mechanical barriers, and the role of the innate and adaptive immune systems.

Other Articles which should interest medical students

SPECIAL ARTICLE

State Legal Restrictions and Prescription-Opioid Use among Disabled Adults


In this analysis of Medicare data and a data set of state laws, adoption of legislation to restrict the prescribing and dispensing of opioid medications was not associated with reductions in potentially hazardous use of opioids among disabled Medicare beneficiaries.

This is a timely article on the effect(s) of laws introduced in the US to limit the epidemic of prescription narcotic abuse and to reduce opioid overdose.

In this study, the laws introduced were state specific and varied significantly between states participating from 2006 through 2012. The population studied were disabled Medicare beneficiaries aged from 21 to 64 years. Eight laws that were reviewed in this study and are illustrated best in Figure 1, together with the percentage of beneficiaries subjected to the laws.

 The results to date are disappointing from the legislative point of view. The researchers showed no significant changes in opioid outcomes, such as a decline in the number of prescriptions prescribed for morphine equivalent daily dose of 120 mg, or drug overdosage.

The authors discuss the limitations of the study, and from their findings it becomes apparent that any future similar study should take into consideration the following:

1.     A large number of participants must be included and followed for prolonged periods, possibly up to 10 years (this study was for seven years).
2.     A robust statistical analysis must be carried out.
3.     A nationwide study is more meaningful than individual state studies.
4.     The law(s) must remain stable over the duration of the study without any law changes.
5.     Limiting the amount of opioid in each prescription only appears to lead to more frequent visits to the GP or pain specialist, which significantly increases the total cost to the health care system, and adds more work to overworked GPs in particular without changing the net prescribing habits.
6.     Any laws introduced should be based on evidence and should not be “feel good” or “something needs to be done” laws.

This is an extremely challenging area where changes are probably not likely to be seen in the short-term future.

The only hope I see for future change is early education of medical students and doctors in training. Training should include the ability to make the appropriate diagnosis. This skill should include an understanding of the natural course of the pain syndrome, and learning appropriate scientific, pharmacological, and clinical pain management for both acute and particularly early chronic pain syndromes before inappropriate prescribing habits become established. The future lies in medical student education in alleviating this problem.

Wednesday, 13 July 2016

NEJM Week of 23rd June 2016 (#48)

Professor Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week of 23rd June 2016 (#48)
University of Notre Dame Australia (Fremantle Campus)



Occasional Editorial Comment

None


Must Read Articles

None


Articles Recommended for Medical Students


REVIEW ARTICLE

Crystallopathies


A number of diseases are related to the deposition of crystals, misfolded proteins, or airborne microparticles. These diverse stimuli elicit a host response that is complex but that shows remarkable similarities among diseases, which may offer new therapeutic targets.

This is a novel unifying approach which combines crystals and microparticles into specific groups and coins the new broader term “cystallopathy (Table 1).” 

Crystallopathies are primarily classified into:
1.     intrinsic-organic e.g. bile, cholesterol, amyloid, monosodium urate.
2.     intrinsic-inorganic e.g. calcium pyrophosphate, calcium oxalates, hydroxyapatite.
3.     extrinsic e.g. asbestos, implant debris, tobacco smoke and air pollutants, occupational dusts.

The review then groups the crystallopathies into the predominant pathological process each produces (Figure 1) and into the pathological processes induced, based on their size (Figure 2).

While this may appear somewhat contrived and more complicated than it should, the most important unifying concept is the molecular mechanisms whereby crystals lead to necroinflammation (Figure 3), particularly the NLRP3 inflammasome. The authors then discuss innovative therapies based on molecular targets.

I recommend time reviewing the glossary of terms, especially the types of “-osis” (necrosis, apoptosis, pyproptosis, necroptosis, ferroptosis and NETosis).  Many students will have been introduced to these terms in the pathology lectures on inflammation.  Review the excellent detailed Tables and Figures.

Recommended learning:

1.     Review the pathology of acute inflammation.
2.     Review the clinical types of crystal induced arthropathies (urate, pyrophosphate and hydroxyapatite).
3.     Review the role and structure of the inflammasome.



IMAGES IN CLINICAL MEDICINE

Iododerma from Contrast Material


A 57-year-old man presented with hematuria. Intravenous urography was performed after the administration of iodinated contrast material. Several hours later, generalized pustular eruptions developed, with multiple coalescing vesicles and pus-filled bullae.

This is a very rare cutaneous reaction to iodine-containing contrast material associated with neutrophilia, eosinophilia, and large numbers of neutrophils within the skin.


IMAGES IN CLINICAL MEDICINE

Squamous-Cell Carcinoma of the Tongue


A 73-year-old woman presented with a persistent ulcer and white patch on the right margin of the tongue. Intraoral examination revealed a superficial ulcer with a homogeneous base, an indurated upper border, and an adjacent speckled red and white patch at the lower border.

This is an excellent clinical picture (view at Full screen) of an ulcer on the side of the tongue and histologically confirmed to be a SCC.

Recommended learning:

1.     Review the clinical examination and investigations of a patient presenting with a solitary neck mass.
2.     Review the causes of head and neck cancer (mostly SCC), their associations and, in particular, HPV infection with oropharyngeal cancer.
3.     Review the current status and recommendations for HPV vaccination in Australia.


ORIGINAL ARTICLE

Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood


In this study, a range of values for body-mass index that were well within the accepted normal range in adolescence predicted increased cardiovascular and all-cause mortality during 40 years of follow-up.

This impressive Israeli study required long-term commitment and funding with a relatively simple question asked: what effect does a single BMI reading in adolescence have on the frequency of cardiovascular death 40 years later?

2.3 million Israelis (female and male) with a mean age of 17.3 years (range 16 -19 years) were enrolled in the study, which spanned the period 1967 to 2011. At the onset of the study, the individual BMIs were calculated.  In this adolescent population, the initial BMI range at presentation ranged from 16.7 to 34.1.
The primary outcome was the number of deaths due to cardiovascular causes (coronary artery disease, stroke and sudden death over the duration of the study).
 
2,918 (9.1%) of 32,127 deaths were due to CV disease with the mean age of cardiovascular death being 45.3 years. 90% of deaths occurred in males.

The major messages from the study were:

1.     The cumulative CV mortality for participants with BMIs less than the 50th percentile (BMIs 21 or less) is similar over the 40-year study period (Figure 2, which is the most informative).
2.     For BMIs exceeding the 50th percentile and over, the CV death rate increased progressively with increases in the BMI.
3.     What was unexpected was that for BMIs in the range 21.5 - 23 (50% - 74% percentile), in the accepted normal range, the CV death rate and the all-cause mortality rate began to significantly rise.

There are several factors to consider with this study:

1.     BMI was only measured at the onset.
2.     There was no data on smoking, diabetes mellitus, lipids, fitness or exercise.
3.     Cause-specific data was unavailable for 6.8% of deaths.
4.     The current patient population were not followed into older age, when it would be predicted that the risk of cardiovascular death would significantly increase.
5.     While this data applies to an Israeli population with 85% of participants born in Israel, the countries of origin of the population studied was not too dissimilar from that of most advanced Western societies (demographics in Table 1).
6.     The authors indicate that it is impossible to determine if the BMI in adolescence predetermines the CV mortality or if the initial BMI is a harbinger of a progressive rise in the BMI over time and it is the latter that sets the patient up for risk factors of CV death.  

What advice do you give adolescents whose BMI is in the range 50 -74% percentile? Based on the current data, adolescents should be encouraged to maintain a BMI of less than 23.


ORIGINAL ARTICLE

A Prospective Study of Sudden Cardiac Death among Children and Young Adults


In 490 cases of sudden cardiac death identified over a 3-year period (annual incidence of 1.3 per 100,000), causes were found in 60% through conventional autopsy, and a clinically relevant cardiac gene mutation was found in 27% of the remaining cases in which genetic testing was performed.

This is a large University of Sydney based study of 198 patients, aged 1 to 35 years, with unexplained cardiac death (40%) gathered from a total cohort of 490 patients with sudden cardiac death. Patients were gathered from Australia and New Zealand over 3 years ending in 2012. The most common cause of explained acute sudden cardiac death was coronary artery disease, mostly in the 31 to 35-year-old population (24%) and inherited cardiomyopathies (16%).

Of the 113 patients with unexplained sudden cardiac death, a clinically relevant cardiac gene mutation was identified in 31 (27%). A total of at least 59 cardiac genes were examined (Table 2). In 13% of families, similar abnormal genes were identified therefore allowing genetic counselling. An excellent Nature review on genetics and channelopathies follows (http://www.nature.com/gim/journal/v12/n5/pdf/gim201044a.pdf) .This study reinforces the importance of obtaining a detailed history from any patient with a family history of sudden cardiac death.

Recommended learning: Review the more common diseases associated with hereditary and acquired abnormalities in sodium, potassium, calcium, and chloride channels.


CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL

Case 19-2016 — A 65-Year-Old Man with End-Stage Renal Disease and a Pruritic Rash


A 65-year-old man with end-stage renal disease and a history of syphilis presented with a leg injury and a diffuse pruritic rash. A recent serologic test had been positive for human T-lymphotropic virus type 1. A diagnostic procedure was performed.

This is a patient with end-stage kidney disease who was referred for renal transplant assessment. He was found to be HTLV-1 positive and had developed a new onset skin rash. The differential diagnosis of a pruritic papulo-squamous eruption is discussed in this setting, which included inflammatory diseases, infectious diseases, and malignancy. I recommend that medical students read only the DD unless there is a particular interest in this disorder.


Important Articles Related to Mechanisms of Disease and Translational Research



CLINICAL IMPLICATIONS OF BASIC RESEARCH

A Gut Feeling about Thrombosis


Plasma levels of trimethylamine-N-oxide (TMAO), derived from dietary nutrients, are associated with atherothrombotic disease. Experiments in mice suggest that the mechanism involves platelet activation and show that the gastrointestinal microbiota influence plasma TMAO levels.

This is an interesting and speculative article supports the old adage “you are what you eat.”
The summary of the data (Figure 1) proposes that phosphatidylcholine (PC), choline, and carnitine in the diet are converted by the gut microbiota to trimethylamine (TMA). In the hepatocyte, TMA is converted to TMAO (TMA-N-oxide). In humans, high serum levels of TMAO are associated with diets rich in red meat and eggs. High levels of TMAO are associated with increased cardiovascular events. TMAO modifies cholesterol metabolism and aids in the conversion of macrophages to foam cells. If patients are treated with antibiotics, the TMAO level falls. An excellent more detailed discussion is presented in an earlier editorial from 2013. (http://www.nejm.org/doi/full/10.1056/NEJMe1302154 ).

Overall, the study by Zhu et al Cell, 2016 provides more evidence that gut microbiota production of TMA and then TMAO by the hepatocyte leads to increased platelet hypersensitivity by releasing intracellular calcium, increasing the risk of platelet aggregation and progression of the atherosclerotic vascular disease.


Other Articles which should interest medical students



Perspective

A Global, Neutral Platform for Sharing Trial Data


Brigham and Women's Hospital–Harvard University's Multi-Regional Clinical Trials Center, along with partners, is designing a platform to link existing data-sharing platforms and communities and host data from investigators who want to share data but lack the resources to do so.

The four perspective articles involve handling of data obtained from clinical trials. They involve collection of data, analysis, platforms, sharing of data, and patient confidentially. Several initiatives have been undertaken to enable sharing of clinical trial data to benefit patients, researchers and funding agencies. Shared data will lead to an increase in specific data, aid in standardizing protocols and limit unnecessary duplicative research endeavours.

Two paragraphs from the perspective articles summarize the relevant information:

 “Moral arguments strongly favor data sharing, especially for data generated using philanthropic or public resources. But the practical benefits of data sharing are also compelling. If biomedical researchers continue to share data, the HBGDki (The Healthy Birth, Growth, and Development Knowledge Integration) and other knowledge bases can become living repositories that advance the field, fulfill the goals of the taxpayers and private funders who enabled the work, and honor the wishes of the participants in the studies. The end result of data sharing, done properly, will be more knowledge that will help all people lead healthy and productive lives.” (http://www.nejm.org/doi/full/10.1056/NEJMp1605441).

“Despite emerging requirements that clinical trial data be made available, as yet there has been no organized effort to coordinate existing platforms and servers and provide a basic platform to enable most data generators to share their trial data simply, efficiently, and appropriately and to enable discovery of patient-level data wherever they reside. Now such an entity is being created, sponsored by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard University (MRCT Center). We are working with institutional and individual partners to design a data-sharing platform that we call “Vivli” — meant to recall the Greek “vivlithĂ­ki,” or library, and the Latin “viv,” or life. Vivli will link existing data-sharing platforms and communities, while hosting data from investigators who aspire to share data but lack the resources to do so. To establish a platform expeditiously, we plan to launch Vivli in partnership with existing data-sharing systems.” (http://www.nejm.org/doi/full/10.1056/NEJMp1605348)



ORIGINAL ARTICLE

Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma


A randomized trial suggests that patients with negative PET-CT findings after two cycles of ABVD may have the bleomycin dropped from the regimen for the final four cycles. The omission of bleomycin reduced pulmonary toxic effects without reducing overall survival.



EDITORIAL

Fine-Tuning the Treatment of Hodgkin’s Lymphoma


This study raises the question: how aggressive does therapy need to be to cure advanced Hodgkin’s lymphoma particularly if the side effects of therapy are significant? The main therapeutic area of concern in the standard treatment protocols was bleomycin which can result in acute and progressive pulmonary injury.

After two cycles of standard ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), 1135 patients underwent a PET-CT to ascertain if residual disease was present. 937 had negative PET-CT scans. Of these 470 continued on the standard ABVD for a further 4 cycles, while 465 had four cycles of AVD excluding the bleomycin (Figure 1). In summary, the primary outcome (3-year progression-free survival) was similar in both groups with less pulmonary toxicity in the group not receiving bleomycin.
The remaining 172 patients, with a positive PET-CT after two rounds of ABVD, received more complex chemotherapy with or without radiation depending on the oncologist’s choice. Of these, the 3-year progression-free survival was similar to the above groups.

In summary, the use of PET-CT after two cycles of standard chemotherapy for advanced Hodgkin’s lymphoma was useful in determining the subsequent treatment protocols which all resulted in similar primary outcomes.

Recommended learning: Review the biology, pathology, clinical presentations, principles of therapy, and overall outcomes in patients with Hodgkin’s lymphoma.


EDITORIAL

K13-Propeller Mutations and Malaria Resistance


Currently the major concern in treating falciparum malaria is the developing drug resistance to artemisinin which is the major and most effective drug. This drug, isolated from the sweet wormwood plant, had been used by the Chinese for over 4000 years to treat malaria. It is now synthesised in yeast.

The mechanism for this drug resistance is the development of the K13-propeller mutation in the malarial parasite. Patient samples from 59 countries with endemic falciparum malaria were studied for the K-13 mutation.  Fortunately, this was found only in Plasmodium falciparum in South-East Asia and China, not sub-Saharan Africa. Artemisinin not only clears the disease forming asexual blood stages, but also kills the gametocytes which are responsible for disease transmission. Thus, it is an extremely valuable drug and the development of drug resistance in sub-Saharan Africa would be a public health disaster.