Primecuts – This Week in the Journals

May 17, 2017

Electronic_medical_recordBy Maxine W Stachel, MD

Peer Reviewed

The past week saw a massive worldwide cyber-hacking attack that affected many well-known brands and, disturbingly, at least a dozen hospitals in Britain’s National Health Service. Using a program allegedly stolen from the US National Security Administration, hackers were able to freeze NHS electronic medical records, which left doctors unable to access patient files and patients unable to access care. Outpatient appointments and elective surgeries were cancelled. Some emergency departments were even forced to divert patients needing urgent care to other institutions until the ransomed computers were unlocked.

As anyone who routinely uses Quadramed or CPRS can avow, our hospital electronic medical records are woefully out-of-date. And given the enormous amount of sensitive information contained on hospital servers, EMRs make especially attractive targets for ransomware. While some of the systems-wide problems will take significant investments of time and money to address, you can do your part by updating your computer regularly and not clicking on dodgy email links at work. And if that doesn’t alleviate your anxiety, you can always take solace in the steady progress of evidence-based medicine, as outlined in this week’s Primecuts: 


Thiazolidinediones and Advanced Liver Fibrosis in Nonalcoholic Steatohepatits: A Meta-analysis[1]

Nonalcoholic steatohepatitis is a leading cause of liver disease in the US, and is expected to become the primary indication for liver transplantation by 2020. While there are no drugs currently approved for the treatment of NASH, there is a growing body of literature to support the use of thiazolidinediones (TZDs) in patients with the condition.

In a new meta-analysis on the subject, investigators examined eight RCTs using TZDs (five using pioglitazone and three using rosiglitazone) in a combined 516 patients with biopsy-proven NASH. Patients were followed for 6-24 months, The researchers found that TZDs were associated with improvement in advanced fibrosis (OR 3.15; 95% CI, 1.25-7.93; p=0.01), improvement in fibrosis of any stage (OR 1.66; 95% CI, 1.12-2.47; p=0.01) and resolution of NASH (OR 3.22; 95% CI, 2.17-4.79, p<0.001). Impressively the results remained significant even when diabetic patients were excluded from the analysis. All of these effects were attributed to pioglitazone use; rosiglitazone produced no statistically significant effects. Side effects of TZDs included weight gain and lower extremity edema.

This study suggests that TZDs (specifically pioglitazone) might be used to reverse advanced fibrosis in NASH and thereby improve the prognosis of patients at highest risk for poor outcomes. The fact that the effect extended to non-diabetics suggests that it might be reasonable to expand the approved indications for pioglitazone use. Although the study failed to show improvement in NASH with rosiglitazone use, it seems possible that the effect seen with pioglitazone is indeed a class-wide effect of TZDs and that an insufficient number of rosiglitazone RCTs were included to make it apparent. Likewise, while the meta-analysis demonstrated only mild adverse effects of weight gain and pedal edema, it was not powered to uncover more serious effects such as the development of congestive heart failure. The short duration of the trials may also have limited the number of adverse outcomes seen in the study population.

The results of the trial are encouraging overall, but further and more longitudinal studies will be necessary to demonstrate that improvements in a surrogate endpoint will translate into clinical recovery of patients with NASH. 

Cancer-Associated Mutations in Endometriosis without Cancer[2]

Endometriosis affects approximately 10% of women of child-bearing age, and commonly presents with dysmenorrhea, pelvic pain and infertility. While ectopic endometrial tissue is usually considered benign, it can bear some of the hallmarks of cancer, including local invasiveness and resistance to apoptosis. In particular, the deep infiltrating subtype of endometriosis manifests with nodules that locally invade pelvic structures, causing patients to suffer deep dyspareunia and dyschezia. Medical therapy with progestins or gonadotropin-releasing hormone analogues often produces unacceptable side effects or insufficient efficacy. The genetic basis and pathogenesis of deep infiltrating endometriosis remain unclear, encumbering efforts to produce novel therapies to address the condition.

In a study published this week in NEJM, researchers analyzed deeply infiltrating endometriotic lesions from 39 women with a mean age of 37 years. Three types of independent molecular genetic analyses were conducted simultaneously: exome-wide sequencing with confirmation of cancer-driver mutations by Safe-SeqS and immunohistochemical stains in one sample set; panel-based sequencing validated by droplet digital PCR in another set of samples; and droplet PCR alone in a third set. Through the combination of these “next-generation” sequencing and validation tools, the researchers discovered that most of the lesions contained somatic mutations.

Ten of 39 lesions (26%) carried mutations in well-documented cancer driver genes ARID1A, PIK3CA, KRAS and PPP2R1A.

These findings have several important implications for research into both cancer and endometriosis. First, given the benign nature of most endometriotic lesions, these findings call into question the reliability of testing for genetic mutations to predict or monitor cancer risk. Epigenetics play an increasingly recognized role in the development of cancer, and this study highlights the caution with which doctors and patients should interpret the results of genetic cancer screens. In addition, the findings of this study begin to answer some of the long-standing questions about the phenotypic heterogeneity of endometriosis and variability in its pathogenesis. Such detailed genetic analysis may ultimately enlighten diagnosis of the disease and speed development of targeted treatments.

The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study[3] 

Gout is the most common inflammatory arthritis, and its prevalence in the US has steadily increased to 3.9% (over 8 million adults).[4] More than half of patients suffer comorbid hypertension and metabolic syndrome. The traditional dietary recommendation for patients at risk of gout has been a diet low in purines, which often results in increased consumption of refined carbohydrates and unhealthy fats, leading to increased insulin resistance and a worsened cardiovascular risk profile. Affected patients would benefit from a more comprehensive dietary strategy.

In a prospective cohort study published in BMJ, researchers enrolled 44,444 men with no history of gout and used validated food frequency surveys to assign each participant a DASH dietary pattern score (high intake of fruits, vegetables, legumes, low fat dairy, whole grains, and low intake of sodium, sweet drinks, and red and processed meats) and a Western dietary pattern score (high intake of red and processed meats, fried foods, refined grains, desserts). Dietary pattern scores were re-calculated every four years, and non-dietary factors (BMI, medications, medical conditions, gout incidence) were assessed biennially.

Over 26 years of follow-up, the researchers documented 1731 confirmed cases of gout meeting American College of Rheumatology criteria. The DASH dietary pattern was associated with significantly reduced risk of gout (adjusted relative risk for extreme fifths 0.68, 95% CI 0.57-0.80, p<0.001) while a higher Western dietary pattern score was associated with elevated risk (1.42, CI 1.16-1.74, p=0.005). The relationship remained after adjusting for age, BMI, diuretics use, history of HTN and renal failure, and coffee and alcohol intake.

The most important limitation of this study is its observational design, which is not powered to prove causation. RCTs that assign patients to various diets will be necessary to definitively determine whether a specific diet might prevent gout. It should also be noted that the demographics of the current study skew very heavily toward white men, which could limit generalizability to more diverse populations. However, given higher prevalence and incidence of gout in the African American community, the present study likely underestimates the effect in this group. With further study and reinforced patient compliance, the DASH diet might well offer a new tool for preventing gout and its comorbidities in motivated, high-risk patients.

Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians[5]

More than half of Americans over 50 years old are at risk for osteoporotic fracture, and over 50 million already carry a diagnosis of osteoporosis or osteopenia. Last revised in 2008, this updated guideline compares risks and benefits of treatment options for low bone density in men and women. In the development of the new guidelines, the ACP performed a systematic analysis of RCTs, review articles, large observational studies and case reports published between 2005-2011. As in other ACP guidelines, the evidence was graded according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

The first and strongest recommendation, based on highest-quality evidence, is that clinicians offer treatment with alendronate, risedronate, zoledronic acid or denosumab to reduce the risk for hip and vertebral fractures in women with known osteoporosis. Weaker recommendations suggest that clinicians avoid estrogen and raloxifene therapies in menopausal women with osteoporosis, as these therapies do not reduce most fractures in this population. (This is a significant change from the 2008 guideline, which reported that estrogens could reduce fractures in the broader categories of postmenopausal women or women with low bone density). Estrogens and raloxifene were also noted to increase risk for CVAs and VTEs. The overall effect of calcium, vitamin D or physical activity alone was unclear.

Other relatively weak recommendations (supported by low quality evidence) are to [1] treat osteoporosis in women for 5 years (very few studies evaluated longer treatment, and one RCT of bisphosphonates found no difference in outcomes at 10 years vs. 5 years), [2] avoid bone density monitoring during the 5-year treatment period (it has not been shown to change management), [3] offer bisphosphonate therapy to men with osteoporosis to reduce risk of vertebral fracture (seems reasonable, but very few RCTs studied men specifically), [4] treat osteopenia in women over 65 on a case-by case basis (depending on individual patient preference and risk profile). The guidelines also recommend prescription of generic drugs wherever possible, to reduce costs and help improve compliance.

Overall these recommendations emphasize the growing importance of osteoporosis diagnosis and treatment to our aging population. They also highlight areas still lacking for high quality research data, and encourage clinicians to make informed treatment decisions on a patient-specific basis.


Bioengineering of an Intraabdominal Endocrine Pancreas[6]

As part of an ongoing study ( number NCT02213003), deceased donor islet cells were successfully transplanted onto the omentum of a 43 year old woman with a 25-year history of Type I diabetes. The patient was maintained on immunosuppressive agents and a low carbohydrate diet and exercised regularly. She was successfully weaned from 33 U daily exogenous insulin regimen, and at 1 year remained euglycemic with an HbA1c level of 6.0%. Studies of long-term safety and feasibility are ongoing.

Leukotriene B4 antagonism ameliorates experimental lymphedema[7]

Lymphedema is a common, debilitating, and often iatrogenic condition with no pharmacologic treatment options. Stanford scientists have shown that the development of lymphedema is an inflammatory phenomenon marked by LTB4 elevation in animal models and humans. Clinical tests of an LTB4 inhibtor (bestatin) already used as a cancer drug in Japan are raising hopes for patients with secondary lymphedema (caused by radiation, surgery or trauma).

Use of the National Heart, Lung, and Blood Institute Data Repository[8]

NHLBI instituted a formal data repository (BioLINCC) in 2000, requiring that all investigators receiving NHLBI funding for observational studies or clinical trials make their de-identified data available to the scientific community within two years of study completion. In this review of the repository use, it was found that from 2000-2016, 370 investigators requested clinical trial data, resulting in over 200 additional publications. Most the data (72%) were used for post-hoc secondary analysis of new questions, and 7-9% were used for new statistical analyses and meta-analyses; only twice were primary studies repeated by subsequent investigators. 

Subjective Crepitus as a Risk Factor for Incident Symptomatic Knee Osteoarthritis: Data from the Osteoarthritis Initiative[9]

In one of the first long-term studies on the relationship between crepitus and joint disease, researchers at Baylor University followed thousands of patients at high risk for osteoarthritis for at least 4 years, and assessed them annually using surveys and X-rays. Researchers found that crepitus without pain was associated with the presence of joint deformity and the development of arthritis within one year.

Dr. Maxine W Stachel is an intern, internal medicine at  NYU Langone Medical Center

Peer reviewed by Neha Jindal, MD, department of medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


[1] Musso G, et al. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: A meta-analysis. JAMA Int Med. 2017 May 15.

[2] Anglesio MS, et al. Cancer-associated mutations in endometriosis without cancer. N Engl J Med. 2017 May 11; 376:1835-1848. DOI: 10.1056/NEJMoa1614814. Accessed May 14, 2017.

[3] Rai SK, et al. The Dietary Approaches to Stop Hypertension (DASH) diet, Western diet, and risk of gout in men: prospective cohort study. BMJ. 2017 May 9;357:j1794. DOI: 10.1136/bmj.j1794. Accessed May 14, 2017.

[4] Zhu Y, et al. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011 Oct;63(10):3136-41. doi: 10.1002/art.30520.. Accessed May 15, 2017.

[5] Qaseem A, et al. Treatment of low bone density or osteoporosis to prevent fractures in men and women: A clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017 May 9. DOI: 10.7326/M15-1361. Accessed May 14, 2017.

[6] Baidal DA, et al. Correspondence: Bioengineering of an Intraabdominal Endocrine Pancreas. N Engl J Med. 2017 May 11; 376:1887-1889. DOI: 10.1056/NEJMc1613959. Accessed May 14, 2017.

[7] Tian W, et al. Leukotriene B4 antagonism ameliorates experimental lymphedema. Science Transl. Med. 2017 May 10;6(389). DOI:10.1126/scitranslmed.aal3920. Accessed May 14, 2017.

[8] Coady SA, et al. Use of the National Heart, Lung, and Blood Institute Data Repository.

N Engl J Med. 2017 May 11;376:1849-1858. DOI: 10.1056/NEJMsa1603542. Accessed May 14, 2017.

[9] Lo GH, et al. Subjective crepitus as a risk factor for incident symptomatic knee osteoarthritis: data from the osteoarthritis initiative. Arthritis Care & Research. 2017 May 4. DOI: 10.1002/acr.23246. Accessed May 14, 2017.