Primecuts – This Week in the Journals

January 13, 2021

By Keshav Mangalick, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Risk of acute kidney injury and Clostridioides difficile infection with piperacillin/tazobactam, cefepime and meropenem with or without vancomycin [1]

We frequently use broad spectrum antibiotics for hospitalized patients knowing that they may increase risk of acute kidney injury and C. difficile infection, and while there are studies evaluating the risk of AKI and C. difficile infection in isolation, there has not been a large scale study evaluating the risk of both in the same group of patients [2] [3].

This study utilized a retrospective cohort analysis of 789,200 patients at VA medical centers around the country to compare rates of AKI and C difficile infection between patients who received different forms of broad spectrum gram negative rod coverage (piperacillin/tazobactam versus cefepime versus meropenem) +/- vancomycin vs a control group. The study was done in the VA patient population and excluded patients with extreme deviations in creatinine (< 0.6 and > 3.5) as well as patients with hospitalizations > 30 days and/or >20 hospitalizations over the study period, bringing into question the generalizability of the results to women, critically ill patients, and frequently admitted patients.

Patients who had received vancomycin or piperacillin/tazobactam alone had approximately 50% greater risk of experiencing AKI compared to a control population receiving no antimicrobials (adjusted HR 1.49, 95% CI 1.44 – 1.54) and (HR 1.53, 95% CI 1.46 – 1.61) respectively. Risk of AKI with cefepime or meropenem alone was not significantly different than the control population. When vancomycin was added to any of the other studied antibiotics, risk of AKI was increased, most markedly with piperacillin/tazobactam (HR 2.56, 95% CI 2.49 – 2.63). All of the studied antibiotics significantly increased risk of C. difficile infection, with the highest hazard ratio seen in patients who had received cefepime (HR 1.98, 95% CI 1.69 – 2.31) , meropenem (HR 1.93, 95% CI 1.50 – 2.48), vancomycin and cefepime (HR 1.98, 95% CI 1.79 – 2.20) or vancomycin and meropenem (HR 2.09, 95% CI 1.76 – 2.48). This study may be helpful in guiding broad spectrum antibiotic choice, though more generalizable and prospective studies are needed for wider applicability.

Stepped Exercise Program for Patients With Knee Osteoarthritis [4]

Knee pain in the setting of osteoarthritis is an extremely common complaint in the outpatient setting [5]. While we often recommend NSAIDs, exercise, and physical therapy, the nuts and bolts of how to advance patients through this process are less clear.

This study evaluated the efficacy of a stepped exercise program in patients in the VA Health System using a prospective randomized control trial, in which subjects either received arthritis education (control group) via mail every 2 weeks or were enrolled in a stepped exercise program starting for three months. If subjects in the treatment group did not report improvements in pain or function, they were advanced to a coaching call every 2 weeks for 3 months, and if there was still no response to treatment, in-person physical therapy for 3 months. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was measured at baseline and after 9 months for all participants.

The study found that subjects in the treatment group had a significantly lower WOMAC score than those in the control group at 9 months (-6.8 points, 95% CI -10.5 – -3.2 points).

We have all had patients whose referrals to physical therapy were turned down due to limited resources, and a stepped program like this may provide both individual and population benefit by better allocating these resources to those who need it most and are most committed. However, this study may not be generalizable to the general population, given the low percentage of women in the study population, and lack of long-term follow up. In addition, given the nature of the intervention, blinding subjects and their providers was impossible, exposing the study to selection bias.

Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer [6]

While immunotherapy has revolutionized the treatment of cancer over the last decade, only a minority of patients experience durable responses with checkpoint inhibitors, and research continues to examine why and how we can stimulate efficacy in more patients [7]. This study used a murine model to evaluate how blocking PCSK9, a cholesterol-regulating protein, affects tumor growth. There is evidence that lowering cholesterol may reduce tumor growth, and there are currently two PCSK9 blocking antibodies approved for hyperlipidemia [8].

In PCSK9-knockout mice, growth of implanted tumors was significantly slowed in comparison to those of control mice, and the treatment group also experienced significantly longer survival. This murine model was then implanted with tumor cells and treated with an anti-PD1 antibody; the PCSK9-knockout mice had minimal tumor growth and 100% survival, a significant difference from the control mice (P = 0.0015 and P = 0.0135, respectively). Mice with intact PCSK9 expression were then treated with either placebo, an anti-PD1 antibody, one of the approved anti-PCSK9 antibodies, or both anti-PD1 and anti-PCSK9 antibodies; despite having intact PSCK9 expression, the mice receiving anti-PCSK9 treatments had significantly reduced tumor growth and increased survival (P < 0.0001 and P < 0.0002, respectively), and those receiving both antibody treatments had significantly reduced tumor growth and increased survival in comparison those just receiving anti-PCSK9 blockade (P < 0.0001 and P < 0.0003, respectively). Using flow cytometry, the authors demonstrated that PCSK9-depleted tumors also had increased infiltration of multiple subtypes of T-cells, suggesting a potential mechanism for the anti-tumor effect.

While this study may not immediately change management, the authors present compelling evidence of synergism between approved agents in a murine model, along with a pathophysiologic basis. Future clinical trials combining these agents would be greatly facilitated by the fact that they are already FDA approved. One limitation of this study was that they authors did not provide a statistical analysis of tumor growth and survival between the mice which received anti-PD1 treatment and those which received both anti-PD1 and anti-PCSK9 treatment, bringing into question the benefit of using both agents versus just anti-PD1 blockade, which is already used in patients.


Reliability of Office, Home, and Ambulatory Blood Pressure Measurements and Correlation With Left Ventricular Mass [9] 

This study compared the statistical reliability of office, home, and 24-hr ambulatory blood pressure measurements using the Spearman-Brown formula, and correlated these modalities with each subject’s respective left ventricular mass index as measured by echocardiogram. Home blood pressure monitoring demonstrated the highest reliability and correlation with LVMI (0.94 for systolic pressure, 0.91 for diastolic pressure, 0.50 correlation with LVMI) vs office (0.89 for SBP, 0.85 for DBP, 0.39 with LVMI) or 24-hr ambulatory measurements (0.85 for SBP, 0.84 for DBP, 0.43 with LVMI).

Association between home insulation and hospital admission rates: retrospective cohort study using linked data from a national intervention programme [11]

This was a retrospective cohort study which studied the effect of a government provided insulation subsidy on cold temperature-related hospital admissions by comparing hospital admissions data between the treatment group and a control group before and after receiving the subsidy. During the study period, hospital admissions increased for both groups, but the increase in overall admissions was significantly lower in the treatment group (RRR 0.89, 95% CI 0.88 to 0.90), reflected specifically in cardiovascular (RRR 0.85, 95% CI 0.81 to 0.90) and respiratory (RRR 0.86, 95% CI 0.82 to 0.90) admissions.

Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells [12]

This study exposed a murine model to hypoxia and demonstrated differentiation of respiratory stem cells into neuroendocrine cells which secrete protective CGRP molecules. When CGRP was exogenously blocked, respiratory epithelial proliferation was reduced, and after destruction of neuroendocrine cells, repletion of intranasal CGRP restored epithelial proliferation. This study provides evidence for a neuroendocrine-mediated response to hypoxia elucidating pathophysiology behind the known proliferation of respiratory neuroendocrine cells in many lung diseases.

Dr. Keshav Mangalick is a 1st year resident at NYU Langone Health

Peer reviewed by Daniel Sartori, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons


  1. Lee, J.D., Heintz, B.H., Mosher, H.J., Livorsi, D.J., Egge, J.A., Lund, B.C., 2020. Risk of acute kidney injury and Clostridioides difficile infection with piperacillin/tazobactam, cefepime and meropenem with or without vancomycin. Clin. Infect. Dis.
  2. Mullins, B.P., Kramer, C.J., Bartel, B.J., Catlin, J.S., Gilder, R.E., 2018. Comparison of the Nephrotoxicity of Vancomycin in Combination With Cefepime, Meropenem, or Piperacillin/Tazobactam: A Prospective, Multicenter Study. Ann. Pharmacother. 52, 639–644.
  3. Stevens, V., Dumyati, G., Fine, L.S., Fisher, S.G., van Wijngaarden, E., 2011. Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection. Clin. Infect. Dis. 53, 42–48.
  4. Allen, K.D., Woolson, S., Hoenig, H.M., Bongiorni, D., Byrd, J., Caves, K., Hall, K.S., Heiderscheit, B., Hodges, N.J., Huffman, K.M., Morey, M.C., Ramasunder, S., Severson, H., Van Houtven, C., Abbate, L.M., Coffman, C.J., 2020. Stepped Exercise Program for Patients With Knee Osteoarthritis. Ann. Intern. Med.
  5. Turkiewicz, A., Petersson, I.F., Björk, J., Hawker, G., Dahlberg, L.E., Lohmander, L.S., Englund, M., 2014. Current and future impact of osteoarthritis on health care: a population-based study with projections to year 2032. Osteoarthr. Cartil. 22, 1826–1832.
  6. Liu, X., Bao, X., Hu, M., Chang, H., Jiao, M., Cheng, J., Xie, L., Huang, Q., Li, F., Li, C.-Y., 2020. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature 588, 693–698.
  7. Topalian, S.L., Hodi, F.S., Brahmer, J.R., Gettinger, S.N., Smith, D.C., McDermott, D.F., Powderly, J.D., Carvajal, R.D., Sosman, J.A., Atkins, M.B., Leming, P.D., Spigel, D.R., Antonia, S.J., Horn, L., Drake, C.G., Pardoll, D.M., Chen, L., Sharfman, W.H., Anders, R.A., Taube, J.M., McMiller, T.L., Xu, H., Korman, A.J., Jure-Kunkel, M., Agrawal, S., McDonald, D., Kollia, G.D., Gupta, A., Wigginton, J.M., Sznol, M., 2012. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. N. Engl. J. Med. 366, 2443–2454.
  8. Ma, X., Bi, E., Huang, C., Lu, Y., Xue, G., Guo, X., Wang, A., Yang, M., Qian, J., Dong, C., Yi, Q., 2018. Cholesterol negatively regulates IL-9–producing CD8+ T cell differentiation and antitumor activity. J. Exp. Med. 215, 1555–1569.
  9. E., S.J., Paul, M., M., K.I., M., B.M., G., P.T., Thomas, B.J., Daichi, S., 2020. Reliability of Office, Home, and Ambulatory Blood Pressure Measurements and Correlation With Left Ventricular Mass. J. Am. Coll. Cardiol. 76, 2911–2922.
  10. Wu, B.G., Kapoor, B., Cummings, K.J., Stanton, M.L., Nett, R.J., Kreiss, K., Abraham, J.L., Colby, T. V, Franko, A.D., Green, F.H.Y., Sanyal, S., Clemente, J.C., Gao, Z., Coffre, M., Meyn, P., Heguy, A., Li, Y., Sulaiman, I., Borbet, T.C., Koralov, S.B., Tallaksen, R.J., Wendland, D., Bachelder, V.D., Boylstein, R.J., Park, J.-H., Cox-Ganser, J.M., Virji, M.A., Crawford, J.A., Edwards, N.T., Veillette, M., Duchaine, C., Warren, K., Lundeen, S., Blaser, M.J., Segal, L.N., 2020. Evidence for Environmental-human Microbiota Transfer at a Manufacturing Facility with Novel Work-related Respiratory Disease. Am. J. Respir. Crit. Care Med.
  11. Fyfe, C., Telfar, L., Barnard, Howden-Chapman, P., Douwes, J., 2020. Association between home insulation and hospital admission rates: retrospective cohort study using linked data from a national intervention programme. BMJ 371, m4571.
  12. Shivaraju, M., Chitta, U.K., Grange, R.M.H., Jain, I.H., Capen, D., Liao, L., Xu, J., Ichinose, F., Zapol, W.M., Mootha, V.K., Rajagopal, J., 2021. Airway stem cells sense hypoxia and differentiate into protective solitary neuroendocrine cells. Science (80-. ). 371, 52 LP – 57.