Citations

Objective: To report the preliminary safety, tolerability, and cerebral spinal fluid (CSF) sampling utility of serial injections of concentrated intraventricular nicardipine (IVN) in the treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: We report the clinical, radiographic, and laboratory safety and tolerability data of a retrospective case series from a single academic medical center. All patients with aSAH developed vasospasm despite enteral nimodipine and received serial injections of concentrated IVN (2.5 mg/mL). CSF injection safety, tolerability, and utility are defined and reported. Results: A total of 59 doses of concentrated IVN were administered to three patients with poor-grade SAH. In Case 1, a 33-year-old man with modified Fisher scale (mFS) grade 4 and Hunt-Hess scale (HH) score 4 received 26 doses; in Case 2, a 36-year-old woman with mFS grade 4 and HH score 5 received 13 doses; and in Case 3, a 70-year-old woman with mFS grade 3 and HH score 4 received 20 doses. No major safety or tolerability events occurred. Two patients were discharged to a rehabilitation facility, and one died after discharge from the hospital. Conclusions: A concentrated 4 mg IVN dose (2.5 mg/mL) in a 1.6 mL injection appears relatively safe and tolerable and potentially offers a second-line strategy for treating refractory vasospasm in poor-grade SAH without compromising intracranial pressure or cerebral perfusion pressure.

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor–1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

ABSTRACT Introduction Recent military conflicts have resulted in a significant number of lower extremity injuries to U.S. service members that result in amputation or limb preservation (LP) procedures. Service members receiving these procedures report a high prevalence and deleterious consequences of falls. Very little research exists to improve balance and reduce falls, especially among young active populations such as service members with LP or limb loss. To address this research gap, we evaluated the success of a fall prevention training program for service members with lower extremity trauma by (1) measuring fall rates, (2) quantifying improvements in trunk control, and (3) determining skill retention at 3 and 6 months after training. Materials and Methods Forty-five participants (40 males, mean [±SD] age, 34 ± 8 years) with lower extremity trauma (20 with unilateral transtibial amputation, 6 with unilateral transfemoral amputation, 5 with bilateral transtibial amputation, and 14 with unilateral LP procedures) were enrolled. A microprocessor-controlled treadmill was used to produce task-specific postural perturbations which simulated a trip. The training was conducted over a 2-week period and consisted of six 30-minute sessions. The task difficulty was increased as the participant’s ability progressed. The effectiveness of the training program was assessed by collecting data before training (baseline; repeated twice), immediately after training (0 month), and at 3 and 6 months post-training. Training effectiveness was quantified by participant-reported falls in the free-living environment before and after training. Perturbation-induced recovery step trunk flexion angle and velocity was also collected. Results Participants reported reduced falls and improved balance confidence in the free-living environment following the training. Repeated testing before training revealed that there were no pre-training differences in trunk control. The training program improved trunk control following training, and these skills were retained at 3 and 6 months after training. Conclusion This study showed that task-specific fall prevention training reduced falls across a cohort of service members with diverse types of amputations and LP procedures following lower extremity trauma. Importantly, the clinical outcome of this effort (i.e., reduced falls and improved balance confidence) can lead to increased participation in occupational, recreational, and social activities and thus improved quality of life.

Background: Polygenic risk testing examines variation across multiple genes to estimate a risk score for a particular disease, including risk scores for many common, chronic health conditions. Although polygenic risk information (PRI) may be a promising tool for enhancing preventive counseling and facilitating early identification of disease, its potential impact on primary-care encounters and disease prevention efforts has not been well characterized. Methods: We conducted in-depth, semi-structured interviews of patients to assess their understandings of PRI and their beliefs about its relevance to disease prevention. Results: We completed interviews with 19 participants. Participants described enthusiasm for the generation of PRI and recognized its utility for disease prevention. Participants also described the value of PRI as limited if not corroborated by non-genetic risk factors. Finally, participants noted that PRI, by itself, would be insufficient as a trigger for initiating many preventive interventions. Conclusion: PRI has the potential to become an important tool in primary care. However, patient views about PRI as well as the complexities of disease prevention in the primary care context may limit the impact of PRI on disease prevention.

Background. Long-term outcome data by induction type in simultaneous pancreas-kidney (SPK) is limited. Methods. Utilizing the Scientific Registry of Transplant Recipients, we examined all primary SPK transplants between 2000 and 2020, excluding crossmatch-positive recipients. We grouped recipients according to induction regimen into 3 groups: rabbit anti-thymocyte globulin (r-ATG) (n = 5678), alemtuzumab (n = 1199), and interleukin-2 receptor antagonist (IL-2RA; n = 1593). We analyzed the 10-y recipient and composite (kidney and pancreas) graft survival using the Kaplan-Meier survival function. Cox-proportion hazard models were generated to examine the association between induction type, the 10-y recipient, and graft survival. Models were adjusted for recipient age, sex, ethnicity, HLA-mismatch, diabetes type, dialysis dependency, cold-ischemia time, local versus imported organs, panel reactive antibody, steroid maintenance, and Pancreas Donor Risk Index. Results. r-ATG was associated with the lowest 1-y kidney and pancreas rejection rates compared with other agents (P < 0.001). In the univariable analysis, induction type was not associated with recipient (log-rank P = 0.11) or graft survival (log-rank P = 0.36). In the multivariable model for the composite graft survival, alemtuzumab use was associated with 22% increased kidney or pancreas graft loss compared with r-ATG (adjusted hazard ratio, 1.22; 95% confidence interval, 1.05–1.42), whereas IL-2RA use was not a predictor of graft survival. Induction type did not influence recipient survival in the adjusted model. Conclusions. r-ATG use was associated with the lowest SPK rejection rates. Compared with r-ATG, alemtuzumab but not IL-2RA was associated with worse long-term death-censored SPK graft outcome. Our analysis supports the common use of r-ATG for induction in US primary SPK recipients.

AbstractIntroductionThromboembolic events after catheter ablation of ventricular tachycardia (VT) can result in significant morbidity. Thromboembolic prophylaxis after catheter ablation can be achieved by the use of antiplatelet agents, vitamin K antagonists, or direct oral anticoagulants (DOACs). The relative safety and efficacy of these modes of prophylaxis are uncertain. We sought to compare the outcomes of patients who received warfarin or DOACs for thromboembolic prophylaxis after catheter ablation of VT.Methods and ResultsAnticoagulation with DOACS was started after left ventricular VT ablation in a series of 42 consecutive patients with structural heart disease (67 ± 11 years, 3 women, ejection fraction 32 ± 14%). Duration of hospital stay, bleeding episodes, and thromboembolic events were compared to a historic consecutive group of patients (n = 38, 65 ± 13 years, 14 women, ejection fraction 36 ± 13%) in whom anticoagulation with a formerly described protocol of heparin and vitamin K antagonist was used after VT ablation procedures. Hospital stay was significantly shorter in the group where DOACs were used as compared to vitamin K antagonists (3.3 ± 1.8 vs. 5.0 ± 2.5 days postablation; p = 0.001) without an increase of bleeding or thromboembolic events.ConclusionAnticoagulation with DOACs is safe and shortens hospital stay in patients with structural heart disease undergoing left ventricular VT ablation procedures.

Abstract Context Metformin is the first-line drug for treating diabetes but has a high failure rate. Objective To identify demographic and clinical factors available in the electronic health record (EHR) that predict metformin failure. Methods A cohort of patients with at least 1 abnormal diabetes screening test that initiated metformin was identified at 3 sites (Arizona, Mississippi, and Minnesota). We identified 22 047 metformin initiators (48% female, mean age of 57 ± 14 years) including 2141 African Americans, 440 Asians, 962 Other/Multiracial, 1539 Hispanics, and 16 764 non-Hispanic White people. We defined metformin failure as either the lack of a target glycated hemoglobin (HbA1c) (&lt;7%) within 18 months of index or the start of dual therapy. We used tree-based extreme gradient boosting (XGBoost) models to assess overall risk prediction performance and relative contribution of individual factors when using EHR data for risk of metformin failure. Results In this large diverse population, we observed a high rate of metformin failure (43%). The XGBoost model that included baseline HbA1c, age, sex, and race/ethnicity corresponded to high discrimination performance (C-index of 0.731; 95% CI 0.722, 0.740) for risk of metformin failure. Baseline HbA1c corresponded to the largest feature performance with higher levels associated with metformin failure. The addition of other clinical factors improved model performance (0.745; 95% CI 0.737, 0.754, P &lt; .0001). Conclusion Baseline HbA1c was the strongest predictor of metformin failure and additional factors substantially improved performance suggesting that routinely available clinical data could be used to identify patients at high risk of metformin failure who might benefit from closer monitoring and earlier treatment intensification.

Abstract Systemic lupus erythematosus (SLE) inflicts damage via autoantibody complexes that result in multiorgan damage and renal failure. The BXSB.Yaa mouse is a well-established model of SLE. We show that genetic disruption of multiple components of the MHC I axis greatly accelerates autoimmune disease in this model. Mice lacking both CD8 and IL15 succumb to SLE-like disease earliest (mean age 14 wks), implying a protective role for CD8 T cells and potentially natural killer cells dependent on IL15. BXSB.Yaa mice develop an expanded population of CD8 T cells with increased expression of both CD122 and IL15Rα, which we propose is due to increased expression of IL15R on these cells. Neither Foxp3 nor CD25 are elevated, and IL10 deficient BXSB.Yaa mice fail to show accelerated disease. However, lytic function appears significant as BXSB.Yaa mice deficient in perforin show decreased survival. TCR analysis failed to suggest a biased CD8 T cell repertoire, suggesting that the cellular targets of suppression are not antigenically discrete. Overall, the results suggest the existence of potent MHC I-dependent suppressor cell population(s) that normally protect BXSB.Yaa mice from an even more aggressive form of SLE-like disease. Moreover, the results support a model in which suppression is unlikely to be mediated by cytokine regulation but instead by lytic mechanisms. Harnessing this inherent regulatory cell population could provide a novel strategy to treat SLE and related syndromes.

Background: Prior studies have reported conflicting results of persistent iatrogenic atrial septal defect (iASD) and its impact following a transcatheter edge-to-edge repair (TEER) procedure. This study aims to evaluate the incidence of iASD and its clinical and hemodynamic impact after a TEER. Methods: Consecutive patients who underwent a TEER procedure from June 2014 to September 2020 at the Mayo Clinic were identified. The presence of iASD was retrospectively identified on post-procedure transthoracic echocardiography (TTE) to group patients into an iASD+ group and an iASD− group for comparison of prognosis and cardiac function. Results: A total of 316 patients were included; the mean age was 79.1 ± 9.1 years, and 67.7% were male. Persistent iASD was diagnosed in 108 (34.2%) patients. There was no difference concerning all-cause mortality, heart failure hospitalization, and stroke/TIA between groups at follow-up (median follow-up of 9 months). Post-procedure TTE demonstrated no differences regarding right ventricle (RV) and left ventricle (LV) dimensions and function, including TAPSE (15.2 ± 4.6 vs. 15.4 ± 5.5 mm, p = 0.875), and LV ejection fraction (51.1 ± 14.0% vs. 51.3 ± 13.9%, p = 0.933). However, patients with iASD had higher RV systolic pressure (48.7 ± 14.4 vs. 45.5 ± 14.5 mmHg, p = 0.042) compared with patients without iASD. Conclusion: Notwithstanding higher RV pressures, patients with persistent iASD had no hemodynamic compromise and an equal prognosis compared with those without a residual atrial defect after a TEER procedure. These findings support the mid-term safety of procedures in which an interatrial defect needs to be created and would argue against the need for interventional closure.