Research Spotlight

Artz, J.D. and Bourgeois, J.A. (2021). “Clozapine in geriatric psychiatry: the need for robust contemporary clinical research to ascertain indications, risks, and benefits in vivo.” Int Psychogeriatr June 3;1-3. [Epub ahead of print]. 1-3.

Full text of this article.

The systematic review by Renzenbrink and Wand (2020) in this issue draws attention to a patient population that has been largely ignored within psychiatric research, with treatment of geriatric patients often being guided by studies completed in younger patient populations. Although initially developed in the 1950s, clozapine did not see widespread use until decades later. In the United States, clozapine has been in use for just over thirty years, giving rise to an aging patient population that has either been treated with clozapine for an extended period or may need to initiate treatment with clozapine after failing alternative options.[No abstract; excerpt from article].

Shahim, B., Malaisrie, S.C., George, I., Thourani, V.H., Biviano, A.B., Russo, M.J., Brown, D.L., Babaliaros, V., Guyton, R.A., Kodali, S.K., Nazif, T.M., McCabe, J.M., Williams, M.R., Généreux, P., Lu, M., Yu, X., Alu, M.C., Webb, J.G., Mack, M.J., Leon, M.B. and Kosmidou, I. (2021). “Atrial Fibrillation and Outcomes After Transcatheter or Surgical Aortic Valve Replacement (from the PARTNER 3 Trial).” Am J Cardiol 148: 116-123.

Full text of this article.

The prognostic impact of preexisting atrial fibrillation or flutter (AF) in low-risk patients with severe aortic stenosis treated with transcatheter (TAVR) or surgical aortic valve replacement (SAVR) remains unknown. In this sub-analysis of the PARTNER 3 trial of patients with severe aortic stenosis at low surgical risk randomized 1:1 to TAVR versus SAVR, clinical outcomes were analyzed at 2 years according to AF status. Among 948 patients included in the analysis (452 [47.7%] in the SAVR vs 496 [52.3%] in the TAVR arm), 168 (17.6%) patients had AF [88/452 (19.5%) and 80/496 (16.1%) treated with SAVR and TAVR, respectively]. At 2 years, patients with AF had higher unadjusted rates of the composite outcome of death, stroke or rehospitalization (21.2% vs 12.9%, p = 0.007) and rehospitalization alone (15.3% vs 9.4%, p = 0.03) but not all cause death (3.8% vs 2.6%, p = 0.45) or stroke (4.8% vs 2.6%, p = 0.12). In adjusted analyses, patients with AF had a higher risk for the composite outcome of death, stroke or rehospitalization (hazard ratio [HR] 1.80, 95% confidence interval [CI] 1.20-2.71, p = 0.0046) and rehospitalization alone (HR 1.8, 95% CI 0.12-2.9, p = 0.015), but not death or stroke. There was no interaction between treatment modality and AF on the composite outcome (Pinter = 0.83). In conclusion, preexisting AF in patients with severe AS at low surgical risk was associated with increased risk of the composite outcome of death, stroke or rehospitalization at 2 years, irrespective of treatment modality.

Lansky, A.J., Makkar, R., Nazif, T., Messé, S., Forrest, J., Sharma, R., Schofer, J., Linke, A., Brown, D., Dhoble, A., Horwitz, P., Zang, M., DeMarco, F., Rajagopal, V., Dwyer, M.G., Zivadinov, R., Stella, P., Rovin, J., Parise, H., Kodali, S., Baumbach, A. and Moses, J. (2021). “A randomized evaluation of the TriGuard™ HDH cerebral embolic protection device to Reduce the Impact of Cerebral Embolic LEsions after TransCatheter Aortic Valve ImplanTation: the REFLECT I trial.” Eur Heart J May 17;ehab213. [Epub ahead of print].

Full text of this article.

AIMS : The REFLECT I trial investigated the safety and effectiveness of the TriGuard™ HDH (TG) cerebral embolic deflection device in patients undergoing transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS : This prospective, multicentre, single-blind, 2:1 randomized (TG vs. no TG) study aimed to enrol up to 375 patients, including up to 90 roll-in patients. The primary combined safety endpoint (VARC-2 defined early safety) at 30 days was compared with a performance goal. The primary efficacy endpoint was a hierarchical composite of (i) all-cause mortality or any stroke at 30 days, (ii) National Institutes of Health Stroke Scale (NIHSS) worsening at 2-5 days or Montreal Cognitive Assessment worsening at 30 days, and (iii) total volume of cerebral ischaemic lesions detected by diffusion-weighted magnetic resonance imaging at 2-5 days. Cumulative scores were compared between treatment groups using the Finkelstein-Schoenfeld method. A total of 258 of the planned, 375 patients (68.8%) were enrolled (54 roll-in and 204 randomized). The primary safety outcome was met compared with the performance goal (21.8% vs. 35%, P < 0.0001). The primary hierarchical efficacy endpoint was not met (mean efficacy score, higher is better: -5.3 ± 99.8 TG vs. 11.8 ± 96.4 control, P = 0.31). Covert central nervous system injury was numerically lower with TG both in-hospital (46.1% vs. 60.3%, P = 0.0698) and at 5 days (61.7 vs. 76.2%, P = 0.054) compared with controls. CONCLUSION : REFLECT I demonstrated that TG cerebral protection during TAVR was safe in comparison with historical TAVR data but did not meet the predefined effectiveness endpoint compared with unprotected TAVR controls.

O’Toole, R.V., Joshi, M., Carlini, A.R., Murray, C.K., Allen, L.E., Huang, Y., Scharfstein, D.O., O’Hara, N.N., Gary, J.L., Bosse, M.J., Castillo, R.C., Bishop, J.A., Weaver, M.J., Firoozabadi, R., Hsu, J.R., Karunakar, M.A., Seymour, R.B., Sims, S.H., Churchill, C., Brennan, M.L., Gonzales, G., Reilly, R.M., Zura, R.D., Howes, C.R., Mir, H.R., Wagstrom, E.A., Westberg, J., Gaski, G.E., Kempton, L.B., Natoli, R.M., Sorkin, A.T., Virkus, W.W., Hill, L.C., Hymes, R.A., Holzman, M., Malekzadeh, A.S., Schulman, J.E., Ramsey, L., Cuff, J.A.N., Haaser, S., Osgood, G.M., Shafiq, B., Laljani, V., Lee, O.C., Krause, P.C., Rowe, C.J., Hilliard, C.L., Morandi, M.M., Mullins, A., Achor, T.S., Choo, A.M., Munz, J.W., Boutte, S.J., Vallier, H.A., Breslin, M.A., Frisch, H.M., Kaufman, A.M., Large, T.M., LeCroy, C.M., Riggsbee, C., Smith, C.S., Crickard, C.V., Phieffer, L.S., Sheridan, E., Jones, C.B., Sietsema, D.L., Reid, J.S., Ringenbach, K., Hayda, R., Evans, A.R., Crisco, M.J., Rivera, J.C., Osborn, P.M., Kimmel, J., Stawicki, S.P., Nwachuku, C.O., Wojda, T.R., Rehman, S., Donnelly, J.M., Caroom, C., Jenkins, M.D., Boulton, C.L., Costales, T.G., LeBrun, C.T., Manson, T.T., Mascarenhas, D.C., Nascone, J.W., Pollak, A.N., Sciadini, M.F., Slobogean, G.P., Berger, P.Z., Connelly, D.W., Degani, Y., Howe, A.L., Marinos, D.P., Montalvo, R.N., Reahl, G.B., Schoonover, C.D., Schroder, L.K., Vang, S., Bergin, P.F., Graves, M.L., Russell, G.V., Spitler, C.A., Hydrick, J.M., Teague, D., Ertl, W., Hickerson, L.E., Moloney, G.B., Weinlein, J.C., Zelle, B.A., Agarwal, A., Karia, R.A., Sathy, A.K., Au, B., Maroto, M., Sanders, D., Higgins, T.F., Haller, J.M., Rothberg, D.L., Weiss, D.B., Yarboro, S.R., McVey, E.D., Lester-Ballard, V., Goodspeed, D., Lang, G.J., Whiting, P.S., Siy, A.B., Obremskey, W.T., Jahangir, A.A., Attum, B., Burgos, E.J., Molina, C.S., Rodriguez-Buitrago, A., Gajari, V., Trochez, K.M., Halvorson, J.J., Miller, A.N., Goodman, J.B., Holden, M.B., McAndrew, C.M., Gardner, M.J., Ricci, W.M., Spraggs-Hughes, A., Collins, S.C., Taylor, T.J. and Zadnik, M. (2021). “Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial.” JAMA Surg 156(5): e207259.

Full text of this article.

IMPORTANCE: Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist. OBJECTIVE: To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections. DESIGN, SETTING, AND PARTICIPANTS: This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers. INTERVENTIONS: A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder. MAIN OUTCOMES AND MEASURES: The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence. RESULTS: The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, -3.4%; 95% CI, -6.9% to 0.1%; P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, -3.7%; 95% CI, -6.7% to -0.8%; P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, -1.6% to 2.1%; P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections. CONCLUSIONS AND RELEVANCE: Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02227446.

Luan, Y., Leclerc, D., Cosín-Tomás, M., Malysheva, O.V., Wasek, B., Bottiglieri, T., Caudill, M.A. and Rozen, R. (2021). “Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex-specific Placental Transcription Changes.” Mol Nutr Food Res May 19;e2100197. [Epub ahead of print]. e2100197.

Full text of this article.

SCOPE: Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. We reported that diets containing 5-fold higher FA than recommended for mice (5xFASD) during pregnancy, resulted in methylenetetrahydrofolate reductase (MTHFR) deficiency and altered choline/methyl metabolism, with neurobehavioral abnormalities in newborns. Our goal was to determine whether these changes had their origins in the placenta during embryonic development. METHODS AND RESULTS: Female mice were fed control diet (CD) or 5xFASD for a month before mating and maintained on these diets until embryonic day 17.5. 5xFASD led to pseudo-MTHFR deficiency in maternal liver and altered choline/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S-adenosylmethionine: S-adenosylhomocysteine ratio) and glycerophosphocholine were decreased in placenta and embryonic liver. FASD resulted in sex-specific transcriptome profiles in placenta, with validation of dietary expression changes of 29 genes involved in angiogenesis, receptor biology or neurodevelopment, and altered methylation of the serotonin receptor 2A gene. CONCLUSION: Moderate increases in folate intake during pregnancy result in placental metabolic and gene expression changes, particularly in angiogenesis, which may contribute to abnormal behavior in pups. These results are relevant for determining a safe upper limit for folate intake during pregnancy.