Research Spotlight

Haque, E.K., Azhar, A., Corbett, J., Frieder, J., Wang, X. and Menter, A. (2020). “A Real-World Evaluation of the Long-Term Safety and Efficacy of Infliximab in the Treatment Moderate-to-Severe Psoriasis.” Dermatol Ther (Heidelb) 10(5): 1121-1135.

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INTRODUCTION: Psoriasis is a chronic immune-mediated inflammatory skin disease that occurs in 2.5-3.5% of the general population. Infliximab (INF), a TNF-α inhibitor biologic agent, is a long-standing efficacious treatment for psoriasis; however, not all patients sustain a long-term response (LTR) because of a number of factors including antibody production. There is a paucity of studies assessing infliximab efficacy over a period ≥ 5 years. METHODS: A retrospective cohort chart review of our clinic patients who had undergone ≥ 5 years of treatment with infliximab for chronic plaque psoriasis was performed. The following variables were recorded and analyzed with the Fisher exact test: age, sex, body mass index ([BMI]; normal weight [NW], overweight [OW], obese [OB]), changes in infliximab strength (dose or frequency), concomitant systemic therapy, and side effects. Clinical improvement was assessed by comparing the total body surface area (tBSA) affected by psoriasis before and after treatment. RESULTS: There was a significant difference in likelihood of achieving LTR between the NW, OW and OB groups (p = 0.044). Non-normal-weight patients (OW + OB) were significantly more likely to achieve and sustain LTR than NW patients (OR 9.07, p = 0.020). There were no other significant associations for the other evaluated variables. LIMITATIONS: Patients who began treatment with infliximab before 2009 (prior to the use of the clinic’s electronic medical record) were excluded. The Psoriasis Area and Severity Index (PASI) was not available for this study. CONCLUSION: Surprisingly, patients who are overweight or obese are more likely to obtain long-term clinical benefit in their psoriasis symptoms with infliximab therapy than patients who are normal weight.

Malek, A.J., Robinson, B.D., Hitt, A.R., Shaver, C.N., Tharakan, B. and Isbell, C.L. (2020). “Doxycycline improves traumatic brain injury outcomes in a murine survival model.” J Trauma Acute Care Surg 89(3): 435-440.

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BACKGROUND: Traumatic brain injury (TBI) has significant morbidity and cost implications. Primary treatment modalities aim to decrease intracranial pressure; however, therapies targeting the underlying pathophysiology of a TBI are limited. The TBI-induced microvascular leak and secondary injury are largely due to proteolysis of the blood-brain barrier (BBB) by matrix metalloproteinase-9. We previously observed doxycycline’s inhibitory affinity on matrix metalloproteinase-9 resulting in preserved BBB integrity in nonsurvival murine studies. This study sought to determine the effect of doxycycline on functional motor and behavioral outcomes in the setting of a TBI murine survival model. METHODS: C57BL/6J mice were assigned to a sham, TBI, or TBI with doxycycline arm. A moderate TBI was induced utilizing a controlled cortical impactor. The TBI with doxycycline cohort received a dose of doxycycline (20 mg/kg) 2 hours after injury and every 12 hours until postoperative day (POD) 6. All mice underwent preoperative testing for weight, modified neurological severity score, wire grip, and ataxia analysis (DigiGait). Postoperative testing was performed on POD 1, POD 3, and POD 6 for the same measures. SAS 9.4 was used for comparative analysis. RESULTS: Fifteen sham mice, 15 TBI mice, and 10 TBI with doxycycline mice were studied. Mice treated with doxycycline had significantly improved modified neurological severity score and wire grip scores at POD 1 (all p < 0.05). Mice treated with doxycycline had significantly improved ataxia scores by POD 3 and POD 6 (all p < 0.05). There was no significant difference in rate of weight change between the three groups. CONCLUSION: Mice treated with doxycycline following TBI demonstrated improved behavioral and motor function suggesting doxycycline's role in preserving murine BBB integrity. Examining the role of doxycycline in human TBIs is warranted given the relative universal accessibility, affordability, and safety profile of doxycycline.

Thai, K.H., Smith, J.C., Stutz, J., Sung, J., Shaver, C. and El Tayeb, M. (2020). “Urethral complications while using 26-French versus 28-French resectoscope sheaths in Holmium Laser Enucleation of the Prostate: A Retrospective Observational Study.” J Endourol Sep 1. [Epub ahead of print.].

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OBJECTIVE: To determine the rate of the urethral stricture (US) and bladder neck contracture (BNC) between patients who undergo Holmium Laser Enucleation of Prostate (HoLEP) surgery with 26Fr vs. 28Fr resectoscope sheaths (RS). Studies report rates of 2.8-4.4% and 3.6-5.4% for US and BNC, respectively. To date, there are no studies that have shown the difference between resectoscope sheath size and urethral complications. METHODS: We retrospectively reviewed charts of patients who had HoLEP surgery between August 2015 to June 2018, by a single surgeon. Prior history of US or BNC were excluded. The operative set-up for a HoLEP includes Ho:YAG laser, urethral dilation, a 26Fr or 28Fr continuous flow RS, and a tissue morcellator. Primary endpoints include postoperative US or BNC. Secondary endpoints include postoperative catheterization time, success of voiding trial and urinary incontinence. Statistical analysis was performed using appropriate methods. RESULTS: Out of 502 HoLEP patients, 339 consecutive patients had surgery with 28Fr RS (Group A) and 163 consecutive patients had surgery with a 26Fr RS (Group B). Twelve patients (A) and three patients (B) had post-op US (p=0.41). Eight (A) and zero (B) patients had post-op BNC (p=0.0585). SUI at 6 weeks, 3-6 months, and 1 year, was present in 15.9% (both A & B), 6.5% (A) vs 6.1% (B) (p=0.88), and 3.2% (A) vs 1.8% (B) (p=0.564), respectively. Both blood loss and change in hemoglobin were higher in 28Fr group with no significant difference in rate of transfusion. Conclusions Resectoscope sheath size had no impact on the rate of US or BNC, however lower incidence in the 26Fr sheath cohort for both. 28Fr sheath had larger change in hemoglobin levels and estimated blood loss, but the higher rate of transfusion was not statistically significant. No difference in the stress incontinence rates, length of stay, and enucleation rates.

Walejko, J.M., Chelliah, A., Keller-Wood, M., Wasserfall, C., Atkinson, M., Gregg, A. and Edison, A.S. (2020). “Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics.” Metabolites 10(9).

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Women with diabetes during pregnancy are at increased risk of poor maternal and neonatal outcomes. Despite this, the effects of pre-gestational (PGDM) or gestational diabetes (GDM) on metabolism during pregnancy are not well understood. In this study, we utilized metabolomics to identify serum metabolic changes in women with and without diabetes during pregnancy and the cord blood at birth. We observed elevations in tricarboxylic acid (TCA) cycle intermediates, carbohydrates, ketones, and lipids, and a decrease in amino acids across gestation in all individuals. In early gestation, PGDM had elevations in branched-chain amino acids and sugars compared to controls, whereas GDM had increased lipids and decreased amino acids during pregnancy. In both GDM and PGDM, carbohydrate and amino acid pathways were altered, but in PGDM, hemoglobin A1c and isoleucine were significantly increased compared to GDM. Cord blood from GDM and PGDM newborns had similar increases in carbohydrates and choline metabolism compared to controls, and these alterations were not maternal in origin. Our results revealed that PGDM and GDM have distinct metabolic changes during pregnancy. A better understanding of diabetic metabolism during pregnancy can assist in improved management and development of therapeutics and help mitigate poor outcomes in both the mother and newborn.

McCullough, P.A., Kelly, R.J., Ruocco, G., Lerma, E., Tumlin, J., Wheelan, K.R., Katz, N., Lepor, N.E., Vijay, K., Carter, H., Singh, B., McCullough, S.P., Bhambi, B.K., Palazzuoli, A., De Ferrari, G.M., Milligan, G.P., Safder, T., Tecson, K.M., Wang, D.D., McKinnon, J.E., O’Neill, W.W., Zervos, M. and Risch, H.A. (2020). “Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection.” Am J Med Aug 7;S0002-9343(20)30673-2. [Epub ahead of print.].

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Approximately 9 months of the severe acute respiratory syndrome coronavius-2 (SARS-CoV-2 [COVID-19]) spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This article outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy, and 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed will undoubtedly refine and clarify their individual roles; however, we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.