Primecuts – This Week in the Journals

August 29, 2017

eclipse 2By Scarlett Murphy, MD

Peer Reviewed

American attention shifted away from challenging national conversations in the wake of Charlottesville towards the sky this past Monday, when a total solar eclipse traversed the entire US mainland for the first time since 1918 (1).  Although we missed out on the breath-taking experience of totality, New Yorkers still enjoyed a 72% partial eclipse (2).

President Trump held a special rally in Arizona, where he criticized the media for propagating his comments about Charlottesville that seemed to some to equate terrorist actions wielded by white supremacists with the largely peaceful resistance of counter protestors (3).  At this rally, the president threatened a government shutdown if Congress would not allocate funding for a border-wall with Mexico. Shortly afterwards, Trump pardoned Former Sheriff Joe Arpaio, drawing bipartisan criticism including a public denouncement from Arizona Senator John McCain (4) Arpaio was previously found to be guilty of criminal contempt of court for actively defying a federal district court order to stop detaining immigrants solely on the suspicion that they were undocumented (5).

Just days after Secretary of State Rex Tillerson praised North Korea for holding off on additional nuclear testing since July’s ICBM launch, North Korea fired three short range ballistic missiles off of it’s east coast (6).  Some analysts believe this was in response to Ulchi Freedom Guardian drills, an annual event held between the US and South Korea (6).

While most of the news remains far from uplifting, promising medical developments unfold everyday.  In this week’s Primecuts, we’ll focus on new updates addressing concerns with the 2015 SPRINT trial, examine if continuous glucose monitoring confers benefit in type II diabetes, learn about the role of steroids in acute lower respiratory tract infection, and revisit an affirmed association between HIV and HSV-2. 

SPRINT revisited: Effect of Intensive Blood-Pressure Treatment

on Patient-Reported Outcomes

We are all familiar with the SPRINT trial, the 2015 randomized control trial demonstrating that intensive systolic blood pressure (SBP) control in patients without diabetes lowered overall risk of fatal and non-fatal cardiovascular events as well as all-cause mortality (7).  Initial results were so compelling that the trial was halted after three of the five planned years (7). However, adoption of intensive control in clinical practice has lagged behind the data, with pervasive concerns among providers including increased weakness, impaired cognition, and lower quality of life in patients already burdened by multiple medical comorbidities.

Holding strong to their original thesis, the authors of SPRINT published new findings in the New England Journal this week addressing concerns about how intensive SBP control impacts overall quality of life. As part of the original SPRINT trial design, participants randomly assigned to an SBP target of 120mmHg or 140mmHg also completed multiple surveys at baseline and then at 12 and 24 months. Administered surveys included the physical component summary (PCS) and mental health component summary (MCS) of the Veterans RAND 12-Item Health survey, PHQ-9 surveys, and study-specific surveys regarding overall satisfaction with blood pressure care and medication adherence (8).

No significant differences were found between PCS, MCS and PHQ-9 scores between the two study arms over three years of follow-up.  Patients in the high-intensity arm on average received one additional medication with an overall average SBP reduction of 14.8 mmHg. Medication adherence did not differ between the study arms. Patients even reported slightly higher overall satisfaction with blood pressure care in the high-intensity arm, although the researchers graciously acknowledge the differences’ statistical but not clinical signification (88.6% vs 88.2%) (8).

            While offering reassurance about overall physical and mental well being, this study doesn’t explicitly examine a prominent concern:  possible increased instances of orthostasis or dizziness. However, it’s possible that such episodes implicitly factor into how patients evaluate their overall quality of life. Another possible limitation, acknowledged by the authors, includes a lack of evaluation in the first six months, in which many adverse events or functional status declines may have occurred (8).

Although cognitive function, medication adherence and quality of life were on-average unchanged during the three years of follow-up, I anticipate continued resistance to adding second or third line agents, as many embrace concerns about polypharmacy in the elderly as dogma (9). It will be interesting to see if the dissemination of these findings sways skeptics into intensifying control of their patients with high cardiovascular risk.

No Benefit to Glucocorticoids in Acute Lower Respiratory Tract Infection

In attempt to curtail the rampant misuse of antibiotics in the primary care setting, many providers have been offering oral corticosteroids to patients without asthma who present with acute lower respiratory infections (LRTI).  Acute LRTIs present with the same symptomatology as acute asthma exacerbations, and are associated with similar underlying bronchial epithelial changes (10).  One study reported usage in 15% of LRTI cases, despite a paucity of evidence supporting its use (11).  A new study published in this week’s JAMA examined the efficacy of steroid regimens in symptom reduction of LRTIs in patients without asthma.

In this randomized control trial across 54 family practice locations throughout the UK, 401 adults without a history of asthma presenting with acute LRTI symptoms were randomly assigned to receive a 5-day course of twice daily prednisolone (20 mg) or a placebo pill for the same duration.  Primary outcomes assessed variation between study arms for duration of cough and mean symptom severity scores on days 2-4 (10).

No difference was observed between the prednisolone and placebo arms for median cough duration (5 days in both arms). There was a non-statistically significant reduction in symptom severity scores (adjusted difference -0.2, relative reduction 9.3%) for the prednisolone group. No significant effects were observed for secondary outcomes including duration of non-cough symptoms, duration of abnormal peak flow, antibiotic use, or other adverse events (10).

This study addressed a novel question, as previous trials have evaluated inhaled but not oral corticosteroids for this condition. Limitations include a low recruitment rate (possibly signifying biased patient selection), and the potential to have unwittingly included patients with chronic or post-infectious cough who may have responded more favorably to steroids. The scope of the study did not address the efficacy of steroids in patients presenting with an infection severe enough to warrant initial antibiotics (10).

Acute LRTIs cause significant distress to patients. Exploring pharmacologic options that have shown efficacy in similar conditions is tempting given the dire need to curb inappropriate antibiotic use. However, oral corticosteroids don’t affect cough duration or severity in LRTIs, and this study’s authors actively recommend against their usage in patients who don’t have asthma or COPD (10).  For now, patients should be advised to stick to their grandma’s chicken soup.

Continuous Glucose Monitoring in Type II diabetes

The use of continuous blood glucose monitors (CGM) has provided individuals with type 1 diabetes (T1DM) more robust data for optimized glycemic control, with randomized trials showing significant reductions in HbA1c and reduced blood glucose variability. Previous trials on whether CGM could offer similar benefit in individuals with type II diabetes (T2DM) have shown mixed results.  In this week’s Annals of Internal Medicine, a new study demonstrated improved glycemic control with CGM in individuals with T2DM receiving multiple daily insulin (MDI) injections (12).

In this randomized clinical trial, 158 patients who met selection criteria throughout 25 endocrinology clinics were randomized either to the CGM experimental arm or the control arm, in which they monitored blood glucose four times daily using a traditional monitor (12).

Patients were assessed at follow-up visits at 4, 12 and 24 weeks.  Adjustments were made to insulin regimen based on the provider’s clinical judgment rather than a specific protocol.  Primary outcome was HbA1c reduction at 24 weeks (12).

At the end of the 24-week period, HbA1c reduction in the CGM arm was significantly greater than in the control group, although both groups attained HbA1c reduction (8.5% to 7.5% vs. 8.5% to 7.9%). Individuals in the CGM arm gained 1.3 kg over the 24-week period, whereas individuals in the control arm on average did not gain weight.  Episodes of severe hypoglycemia, DKA or HHS were not observed in either arm (12).

Acknowledged limitations to this study include the fact that follow-up was limited to six months, although the authors were optimistic about the high level of participation throughout the trial duration. The study was funded through the CGM device manufacturer, although they did not have approval authority over the final manuscript (12).

The reduction of HbA1c in both arms without significant pharmacologic adjustments may indicate that more frequent glucose monitoring alone improves glycemic control.  It is also worthwhile to note that reductions in HbA1c in CGM arm, while statistically significant, were also moderate at best (0.4% difference).  Weight gain experienced in the CGM arm is consistent with developments in other studies aiming for tighter glycemic control, and is an unfortunate complication that may limit overall macrovascular benefit to intensive treatment (12). A study of another CGM device that required patients to actively scan the system did not exhibit beneficial reduction in HbA1c, supporting both the idea that processes that require less patient input are more likely to aid in patient success but also muddling our ability to draw solid conclusions about the potential benefits of CGM in this population (13).  In a world with ever-advancing technology, it is essential to continually evaluate new developments, including CGM, that may benefit management of a highly prevalent illness associated with devastating morbidity when poorly managed.

HSV-2 incidence increases the likelihood of HIV acquisition

Herpes simplex 2 (HSV-2) and HIV infections are associated with major morbidity and mortality worldwide, with the burden of disease falling predominately on lower-income nations. A co-infection syndrome between HSV-2 and HIV has been previously described in literature, however, supporting data stems from small meta-analyses now over a decade old. A new WHO-funded meta-analysis of over 57 longitudinal studies published this week in the Lancet examined whether this purported association remained strong after considering a substantial amount of new research (14).

Researchers comprehensively reviewed available literature to identify appropriate cohort studies, case-controlled studies and controlled trials that assess the effect of pre-existing HSV-2 infection on HIV acquisition. Using data from these studies and previous meta-analyses, they estimated the association between HIV seroconversion with HSV-2 infection incidence or prevalence. They examined whether sex or membership in a general risk or higher risk pool (female sex workers, men who have sex with men, serodiscordant couples, and STD clinic patients) affected this relationship (14).

In this study, the incidence of new HIV was triple the baseline rate in general populations with high HSV-2 prevalence, and double the baseline in higher risk populations with similarly elevated HSV-2 prevalence. High incidence of new HSV-2 infections in general populations conferred an even higher risk than HSV-2 prevalence for new HIV acquisition (adjusted RR 2.7, 95% CI 2.2–3.4 vs RR 4.7, 95% CI 2.2–10.1) (14).

Because both infections are associated with the same body of risk factors, multiple opportunities for confounding are present, although the researchers believe they controlled for most instances.  Most of the populations categorized as general were African, which may have affected the generalizability of results to other world regions. As with all meta-analysis, publication bias may underlie many conclusions, although effects were believed to be minimal in this study (14).

Results from this study were largely consistent with previously published data, but novel in that they highlight a relationship between incident exposure and subsequent HIV acquisition (prior studies have only been able to link HSV-2 prevalence with HIV). Efforts are underway to develop an HSV-2 vaccine, and these results strengthen the idea that funding targeting HSV-2 reduction could have a beneficial effect on reducing not only HSV-2 but also HIV burden globally (14). 


Global Burden of Rheumatic Heart Disease

In the 2015 Global Burden of Disease Study, researchers examined worldwide prevalence and associated mortality of rheumatic heart disease over the past 25 years.  Results published in this week in the New England Journal cited an overall decline in global prevalence and mortality, but noted that rates remain high in vulnerable-low income countries, including South Asia, central sub-Saharan Africa and Oceania where an estimated 10-15 per 1000 persons are living with rheumatic heart disease (15).

Vitamin C and Leukemia in Murine Models

Researchers working with hematopoetic stem cells (HSC) in vivo in mice models discovered a relationship between systemic vitamin C depletion and reduced Tet2 tumor suppressor function, leading to increased HSC frequency and function and accelerated leukaemogenesis.  Increased dietary vitamin C consumption subsequently reversed this process, suggesting that accumulated ascorbate in cells leads to increased tumor suppressor gene expression, in turn suppressing HSC frequency, myelopoesis and leukamogenesis (16).

Older adults “on the move”

Older adults living in independent living facilities who participated in the “On the Move” exercise program as part of a randomized single intervention trial showed greater overall improvement in walking ability than those who participated in conventional senior exercise programs.  The “On the Move” program focuses on timing and movement coordination, whereas “usual care” exercise programs typically focus on seated strength, endurance and flexibility (17).

Dr. Scarlett Murphy is a 1st year resident at NYU Langone Health

Peer reviewed by David Kudlowitz, MD, NYU Internal Medicine Associates, NYU Langone Health

Image courtesy of Wikimedia Commons


1. Fountain H. A Total Solar Eclipse Leaves  a Nation in Awe. The New York Times. August 21 2017

2. Wolfe J. New York Today: How to Watch the Solar Eclipse. The New York Times. August 21 2017

3. Wagner J, Johnson J, Paquette D. Trump threatens shutdown, suggests controversial pardon at Arizona rally.  The Washington Post. August 23rd 2017.

4.  Davis JH, Haberman M. Trump Pardons Joe Arpaio, Who Became Face of Crackdown on Illegal Immigration. The New York Times. August 25 2017.

5. Perez-Pena R. Former Arizona Sheriff Joe Arpaio Is Convicted of Criminal Contempt.  The New York Times. July 31 2017.

6. Kim J, Stewart P. North Korea tests short-range missiles as South Korea, U.S. conduct drills.  Reuters. August 25 2017. 

7. Original Sprint Trial

8. Berlowitz DR, Foy CG, Kazis LE, et al. Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. N Engl J Med 2017; 377:733-744. Published online August 24, 2017. DOI: 10.1056/NEJMoa1611179

9. Maher RL, Hanlon JT, Hajjar ER. Clinical Consequences of Polypharmacy in Elderly. Expert opinion on drug safety. 2014;13(1):10.1517/14740338.2013.827660. doi:10.1517/14740338.2013.827660.

10. Hay AD, Little P, Harnden A, Thompson M, Wang K, Kendrick D, Orton E, Brookes ST, Young GJ, May M, Hollinghurst S, Carroll FE, Downing H, Timmins D, Lafond N, El-Gohary M, Moore M. Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract InfectionA Randomized Clinical Trial. JAMA. 2017;318(8):721–730.

11. Ebell MHR, Radke T. Antibiotic use for viral acute respiratory tract infections remains common. Am J Manag Care. 2015;21(10):e567-e575.

12.  Schwartz SS. Optimizing glycemic control and minimizing the risk of hypoglycemia in patients with type 2 diabetes. Drugs in Context. 2013;2013:212255. doi:10.7573/dic.212255.

13. Beck RW, Riddlesworth TD, Ruedy K, Ahman A, et al. Continuous Glucose Monitoring Versus Usual Care in Patients with Type 2 Diabetes Receiving Multiplde Daily Insulin Injections. Ann Intern Med. Published online Ausgust 22, 2017. doi:10.7326/M16-2855

14. Looker KJ, Elmes JAR, Gottleib SL, et al. Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. Lancet Infect Dis. Published online August 23, 2017.

15. Watkins DA, Johnson CO, Colquhoun SM, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med 2017;377:713-722.

16. Agathacleous M, Meacham CE, Burgess RJ, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. Published online August 21, 2017. doi: 10.1038/nature23876

17. Brach JS, Perera S, Gilmore S, VanSwearingen JM, Brodine D, Nadkarni NK, Ricci E. Effectiveness of a Timing and Coordination Group Exercise Program to Improve Mobility in Community-Dwelling Older AdultsA Randomized Clinical Trial. JAMA Intern Med. Published online August 14, 2017. doi:10.1001/jamainternmed.2017.3609