Research Spotlight

Mereuta, O.M., Abbasi, M., Fitzgerald, S., Dai, D., Kadirvel, R., Hanel, R.A., Yoo, A.J., Almekhlafi, M.A., Layton, K.F., Delgado Almandoz, J.E., Kvamme, P., Mendes Pereira, V., Jahromi, B.S., Nogueira, R.G., Gounis, M.J., Patel, B., Aghaebrahim, A., Sauvageau, E., Bhuva, P., Soomro, J., Demchuk, A.M., Thacker, I.C., Kayan, Y., Copelan, A., Nazari, P., Cantrell, D.R., Haussen, D.C., Al-Bayati, A.R., Mohammaden, M., Pisani, L., Rodrigues, G.M., Puri, A.S., Entwistle, J., Meves, A., Arturo Larco, J.L., Savastano, L., Cloft, H.J., Kallmes, D.F., Doyle, K.M. and Brinjikji, W. (2021). “Histological evaluation of acute ischemic stroke thrombi may indicate the occurrence of vessel wall injury during mechanical thrombectomy.” J Neurointerv Surg May 11;neurintsurg-2021-017310. [Epub ahead of print].

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BACKGROUND: Several animal studies have demonstrated that mechanical thrombectomy (MT) for acute ischemic stroke (AIS) may cause vessel wall injury (VWI). However, the histological changes in human cerebral arteries following MT are difficult to determine. OBJECTIVE: To investigate the occurrence of VWI during MT by histological and immunohistochemical evaluation of AIS clots. METHODS: As part of the multicenter STRIP registry, 277 clots from 237 patients were analyzed using Martius Scarlett Blue stain and immunohistochemistry for CD34 (endothelial cells) and smooth muscle actin (smooth muscle cells). RESULTS: MT devices used were aspiration catheters (100 cases), stentriever (101 cases), and both (36 cases). VWI was found in 33/277 clots (12%). There was no significant correlation between VWI and MT device. The degree of damage varied from grade I (mild intimal damage, 24 clots), to grade II (relevant intimal and subintimal damage, 3 clots), and III (severe injury, 6 clots). VWI clots contained significantly more erythrocytes (p=0.006*) and less platelets/other (p=0.005*) than non-VWI clots suggesting soft thrombus material.Thrombolysis correlated with a lower rate of VWI (p=0.04*). VWI cases showed a significantly higher number of passes (2 [1-4] vs 1 [1-3], p=0.028*) and poorer recanalization outcome (p=0.01*) than cases without VWI. CONCLUSIONS: Histological markers of VWI were present in 12% of AIS thrombi, suggesting that VWI might be related to MT. VWI was associated with soft thrombus consistency, higher number of passes and poorer revascularization outcome. There was no significant correlation between VWI and MT device.

Kirschner, S.K., Deutz, N.E.P., Rijnaarts, I., Smit, T.J., Larsen, D.J. and Engelen, M. (2021). “Impaired intestinal function is associated with lower muscle and cognitive health and well-being in patients with congestive heart failure.” JPEN J Parenter Enteral Nutr May 22. [Epub ahead of print].

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BACKGROUND: Small and large intestinal perturbations have been described as prevalent extracardiac systemic manifestations in Congestive Heart Failure (CHF) but alterations in protein digestion and absorption and plasma short-chain fatty acid concentrations (SCFA), and the potential link with other systemic effects (e.g. lower muscle and cognitive health and well-being) have not been investigated in these patients. METHODS: We analyzed protein digestion and absorption with dual stable tracer method in 14 clinically stable, non-cachectic CHF outpatients (mean left-ventricular ejection fraction: 35.5 (95% CI [30.9, 40.1])% and 15 controls. Small intestinal non-carrier-mediated permeability and active carrier-mediated glucose transport were quantified by sugar permeability test. Plasma SCFA (acetate, propionate, butyrate, isovalerate, valerate) concentrations were measured as intestinal microbial metabolites. Muscle function was assessed by isokinetic dynamometry, cognition by a battery of tests, and well-being by questionnaire. RESULTS: Protein digestion and absorption were impaired by 29.2% (P = 0.001) and active glucose transport by 38.4% (P = 0.010) in CHF. Non-carrier-mediated permeability was not altered. While plasma propionate, butyrate and isovalerate concentrations were lower in CHF (P<0.05), acetate and valerate concentrations did not differ. Overall, intestinal dysfunction was associated with impaired leg muscle quality, emotional distress, and reduced cognitive function (P<0.05). CONCLUSIONS: We identified impaired protein digestion and absorption, and alterations in SCFA concentrations as additional intestinal dysfunctions in CHF that are linked to reduced muscle and cognitive health and well-being. More research is needed to implement strategies to improve intestinal function in CHF and to investigate the mechanisms underlying its link with the other systemic manifestations. This article is protected by copyright. All rights reserved.

Kelly, R.J., Ansari, A.M., Miyashita, T., Zahurak, M., Lay, F., Ahmed, A.K., Born, L.J., Pezhouh, M.K., Salimian, K.J., Ng, C., Matsangos, A.E., Stricker-Krongrad, A.H., Mukaisho, K.I., Marti, G.P., Chung, C.H., Canto, M.I., Rudek, M.A., Meltzer, S.J. and Harmon, J.W. (2021). “Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett’s Esophagus to Invasive Esophageal Adenocarcinoma.” Ann Surg 273(6): e206-e213.

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OBJECTIVE: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett’s Esophagus (BE) to esophageal adenocarcinoma. BACKGROUND: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. METHODS: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett’s Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. RESULTS: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. CONCLUSION: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.

Budhiraja, P., Kaplan, B., Kalot, M., Alayli, A.E., Dimassi, A., Chakkera, H.A., Heilman, R., Edwards, A.S. and Mustafa, R.A. (2021). “Current State of Evidence on Kidney Transplantation: How Fragile Are the Results?” Transplantation May 6. [Epub ahead of print].

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BACKGROUND: The study aims is to use the fragility index (FI) to examine the strength of evidence of randomized controlled trials (RCTs) published in the last decade on kidney transplantation. METHODS: We searched MEDLINE for studies on kidney transplantation. We included the RCTs that compared 2 groups with 1:1 randomization and reported significant P-values (<0.05) for a dichotomous outcome and were published in the top 10 transplant journals. We calculated the FI; a calculation used to determine the minimum number of subjects needed to change from a nonevent to an event to make the study results nonsignificant (P-value >0.05). RESULTS: 57 RCTs met our inclusion criteria. The median sample size was 100 participants in each arm, the median number of events was 16(IQR 8-30) in the intervention group. Among the included trials, 79% were industry-funded, 93% involved medications, and the majority were open-label. The median FI was 3 (IQR 1-11). In 43% of the trials, the number of patients reported lost to follow-up was higher than or equal to the FI. Only 4% of the RCTs imputed a value for the missing dichotomous outcome. Furthermore, the median number of subjects who discontinued the trial due to adverse effects was 21, which was greater than the FI in 60% of the RCTs. CONCLUSION: The arbitrary classification of results into “significant” and “nonsignificant” based on p-value <0.05 should perhaps be interpreted with the help of other statistical parameters and FI is one of them.

Rosenzweig, M., Wall, A., Spak, C.W., Testa, G. and Johannesson, L. (2021). “Pregnancy after CMV infection following uterus transplantation: A case report from the Dallas Uterus Transplant Study.” Transpl Infect Dis May 26;e13653. [Epub ahead of print].

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Uterus transplantation is a repeatedly proven treatment for women with absolute uterine-factor infertility, which is the congenital or acquired absence of the uterus, who desire to carry, and ultimately deliver, a child. No stranger to the field of transplant or obstetrics is cytomegalovirus. Cytomegalovirus is both a frequent complication after transplant, presenting as an opportunistic infection, as well as a common congenital disease in the newborn child from pregnancy. To date, there have been no reported cases of pregnancy following uterus transplantation from cytomegalovirus-positive donors into cytomegalovirus-negative recipients. We present a case report describing our experience of a cytomegalovirus-negative recipient, transplanted with a uterus from a cytomegalovirus-positive living donor, and subsequently diagnosed with active cytomegalovirus infection despite prophylactic treatment. She was treated for infection prior to embryo transfer and carried a healthy child to term. This case suggests transplanting a cytomegalovirus-positive uterus into a negative donor is possible to do safely.