Research Spotlight

McLaughlin, C. M., N. Channabasappa, J. Pace, H. Nguyen and H. G. Piper (2017). “Growth trajectory in children with short bowel syndrome during the first two years of life.” J Pediatr Gastroenterol Nutr: 2017 Sep [Epub ahead of print].

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OBJECTIVES: Infants with short bowel syndrome (SBS) require diligent nutritional support for adequate growth. Enteral independence is a primary goal, but must be balanced with ensuring sufficient nutrition. We aimed to describe growth trajectory in infants with SBS as function of nutritional intake during first two years of life. METHODS: Infants with SBS were reviewed (2008-2016). Z-scores for weight, height, and head circumference (HC), were recorded at birth, 3, 6, 12, 18, and 24 months. Nutritional intake, serum liver enzyme, and bilirubin levels were assessed at all time points. Pearson correlation coefficients were used to measure association with p < 0.05 considered significant. RESULTS: Forty-one infants were included, with median gestational age of 34 weeks (IQR 29-36 weeks). Median small bowel length was 36 cm (IQR 26-52 cm) and median % expected small bowel length was 28% (IQR 20-42%). Mean Z-scores for weight and length were > 0 at birth, but < 0 from 3 months to 2 years. HC remained < 0 throughout the study. Mean Z-scores at 2 years for weight, length, HC and weight-for-length were -0.90 (SD 1.1), -1.33 (SD 1.4), -0.67 (SD 1.2), and -0.12 (SD 1.2) respectively. Percentage calories from PN was positively correlated with weight in the first 3 months of life (p = 0.01). CONCLUSION: Babies with SBS are high risk for poor growth during the first 2 years of life. Although weaning PN is important for these patients, doing so too quickly in infancy may contribute to compromised growth. The long-term impact on overall development is not known.

Wu, N., F. Meng, T. Zhou, Y. Han, L. Kennedy, J. Venter, H. Francis, S. DeMorrow, P. Onori, P. Invernizzi, F. Bernuzzi, R. Mancinelli, E. Gaudio, A. Franchitto, S. Glaser and G. Alpini (2017). “Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by mir-200b down-regulation.” Faseb j 31(10): 4305-4324.

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Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct-ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2-knockout (Mdr2-/-) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2-/- mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2-/- mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine N-acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells in vitro, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2-/- mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2-/- mice and patients with PSC compared with controls and decreased in Mdr2-/- mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2-/- ablates biliary proliferation, liver fibrosis, and angiogenesis. In vitro, overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.-Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.

Aguilar, P. R., B. C. Bemiss, C. Witt, D. E. Byers, D. Kreisel, V. Puri, B. Meyers, G. A. Patterson, A. S. Krupnick, R. D. Yusen, E. P. Trulock and R. R. Hachem (2017). “Impact of delayed chest closure on surgical site infection after lung transplantation.” Ann Thorac Surg 104(4): 1208-1214.

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BACKGROUND: Delayed chest closure is an increasingly used approach in the management of bleeding and hemodynamic instability after lung transplantation. We sought to evaluate the impact of delayed chest closure on surgical site infection. METHODS: We performed a single-center retrospective cohort study and included adult patients who received a lung transplant at our center between January 1, 2010, and July 31, 2014. We defined surgical site infection as a thoracotomy incision wound or pleural space infection. Follow-up was complete through 6 months after transplantation. We used logistic regression models to examine the impact of delayed chest closure on surgical site infection and to identify other potential risk factors. RESULTS: During the study period, 67 of the 232 transplant procedures (29%) required delayed chest closure, and surgical site infection developed in 22 recipients (9%). Among the patients with surgical site infection, 18 experienced a wound infection, and 8 experienced a pleural space infection; 4 experienced concomitant wound and pleural space infection. Among the 67 who underwent delayed chest closure, 13 patients (19%) experienced a surgical site infection compared with 9 of the 165 patients (5%) who underwent primary closure (p = 0.001). In multivariate analysis, delayed chest closure was an independent risk factor for surgical site infection. CONCLUSIONS: Although delayed chest closure may have an important role in the immediate management of recipients of a lung transplant, it is an independent risk factor for surgical site infection, and this is associated with increased morbidity.

Alter, H., T. M. Block, N. Brown, A. Brownstein, C. Brosgart, K. M. Chang, P. J. Chen, F. V. Chisari, C. Cohen, H. El-Serag, J. Feld, R. Gish, J. Glenn, T. Greten, H. Guo, J. T. Guo, Y. Hoshida, J. Hu, K. V. Kowdley, W. Li, J. Liang, S. Locarnini, A. S. Lok, W. Mason, B. McMahon, A. Mehta, R. Perrillo, P. Revill, C. M. Rice, J. Rinaudo, R. Schinazi, C. Seeger, K. Shetty, J. Tavis and F. Zoulim (2017 ). “A research agenda for curing chronic hepatitis b virus infection.” Hepatology 2017 Sep [Epub ahead of print].

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There is a growing interest in discovery and development of new therapeutics that will cure chronic hepatitis B virus (HBV) infection, due to the recent establishment of new cell culture-based and small animal-based models. These new systems create unprecedented opportunities to study the entire viral life cycle and to search for vulnerabilities that can be exploited for curative purposes. Here we propose a scientific pathway that we believe will lead to the development of curative therapies for chronic HBV infection and its associated diseases.

Bagel, J., K. C. Duffin, A. Moore, L. K. Ferris, K. Siu, J. Steadman, F. Kianifard, J. Nyirady and M. Lebwohl (2017). “The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study.” J Am Acad Dermatol 77(4): 667-674.

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BACKGROUND: Moderate-to-severe scalp psoriasis has not been evaluated in prospective trials of patients without moderate-to-severe body psoriasis. OBJECTIVE: Evaluate the efficacy and safety of secukinumab in moderate-to-severe scalp psoriasis. METHODS: In this 24-week, double-blind, phase 3b study, 102 patients were randomized 1:1 to subcutaneous secukinumab 300 mg or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4 to 20. The primary efficacy variable was 90% improvement of Psoriasis Scalp Severity Index (PSSI 90) score from baseline to week 12. RESULTS: At week 12, PSSI 90 (secukinumab 300 mg vs placebo, 52.9% vs 2.0%) and Investigator’s Global Assessment modified 2011 scalp responses of 0 or 1 (secukinumab 300 mg vs placebo, 56.9% vs 5.9%) were significantly greater with secukinumab 300 mg than placebo (P < .001 for both). In addition, significantly more patients achieved complete clearance of scalp psoriasis at week 12 with secukinumab 300 mg than placebo (35.3% vs 0%; P < .001). The median time to 50% reduction in PSSI score was 3.29 weeks with secukinumab 300 mg. The safety profile of secukinumab was consistent with previous phase 3 studies. LIMITATIONS: There was no active comparator arm. CONCLUSION: Secukinumab is efficacious and well-tolerated for patients with extensive moderate-to-severe scalp psoriasis.