Citations

AbstractBackgroundP2X purinoceptor 7 (P2RX7), an ATP‐gated cation channel present abundantly in the microglia, induces membrane depolarization and extracellular vesicle (EV) secretion. Previous study demonstrated that administration of GSK1482160, a P2RX7 selective inhibitor, suppressed EVs secretion from murine microglia resulting in accumulation of Tsg101+ intraluminal vesicles (ILVs) in the hippocampus, and restored partial behavioral deficits in P301S tau mice. However, the specificity of GSK1482160 to P2RX7 has never been investigated in P301S tau mice. It is crucial to validate whether P2RX7 is a potential target for alleviating the tauopathy phenotype in P301S tau mice. The purpose of this study is to determine if deletion of P2RX7 is sufficient to recapiturate the therapeutic effect of GSK1482160 in tauopathy mouse model.MethodFours and nine‐months‐old P2RX7‐/‐:P301S and P301S mice were generated for the evaluation of ILV accumulation and tau pathology. Primary microglia and astrocytes from WT (C57BL/6) and P2RX7‐/‐ mice, treated with GSK1482160 and ATP for EV secretion. EVs were isolated from conditioned media via the sequential centrifugation and ultracentrifugation. Finally, EVs were quantified by nanoparticle tracking analysis and exosome specific marker CD9 ELISA. Effects of GSK1482160 on EVs secretion from astrocytes/microglia were also assessed using Western blot with EV specific markers Tsg101 and CD9.ResultExosome specific marker Tsg101, CD9, and tau expression levels were reduced in the hippocampus of nine‐months‐old P2RX7‐/‐:P301S mice compared to P301S mice. No significant difference between the two groups at 4 months of age was observed. Strikingly, primary cultured microglia and astrocytes showed reduction in EV secretion in both ATP stimulated or unstimulated condition from P2RX7‐/‐ group compared to WT group. Additionally, GSK1482160 pretreatment significantly reduced EV secretion from WT astrocytes and microglia, although it had no effects in P2RX7‐/‐ cells. These findings were validated by ELISA of EV marker CD9 and immunoblotting of Tsg101 and flotillin‐1 using isolated EVs.ConclusionResults demonstrate that P2RX7 is primarily responsible for ATP‐induced EV secretion from astrocytes and microglia, and systemic disruption of P2RX7 mimics the effect of GSK1482160 in P301S tau mice, including accumulation of ILVs in microglia and suppression of tau accumulation in the hippocampal regions.

AbstractBackground and ObjectivesSerum tumor markers are widely used for diagnosis, prognosis, treatment response, and surveillance. Our study evaluated cancer embryonic antigen (CEA) in patients with appendiceal adenocarcinoma.MethodsThe National Cancer Database was reviewed (2004–2011) for patients with surgical treatment for appendiceal adenocarcinoma. Patients were stratified into two groups: normal and elevated CEA. Multivariable adjusted Cox proportional hazards regression analyses were used to determine the independent effect of CEA on survival.ResultsOur study consisted of 2867 patients, 54.0% having elevated CEA. Patients with elevated CEA were more likely to have Stage IV disease, be female, and African American; all p < 0.001. Three‐year overall survival (OS) was significantly higher with normal CEA (75.5% vs. 62.8%, p < 0.001). On multivariable analysis, elevated CEA was associated with worse survival (hazard ratio 1.49, 95% confidence interval 1.23–1.80). Patients with elevated CEA had improved 3‐year OS with neo‐adjuvant compared to adjuvant chemotherapy (p = 0.004), while those with normal CEA showed no difference.ConclusionsIn patients with surgically treated appendiceal adenocarcinoma, preoperative elevation in CEA independently predicts decreased 3‐year survival and correlates with improved OS with neo‐adjuvant therapy. CEA levels should be considered in clinical decision‐making regarding neo‐adjuvant therapy in patients with appendiceal adenocarcinoma.

In 2020, Mayo Clinic established an Advanced Care at Home (ACH) program. ACH is a virtual hybrid hospital-at-home (HaH) program that combines telemedicine with in-home care services by utilizing a state that is software-driven, vendor-mediate medical supply chain. The program initially focused on acute medical diagnosis but has expanded to oversee surgical and postsurgical patients with continued inpatient needs. Here, we report the first case of a small bowel obstruction (SBO) managed under a HaH program. A 52-year-old lady presented to the emergency department with symptoms suggestive of mechanical SBO. The diagnosis was confirmed with an abdominopelvic computed tomography (CT) scan, and the patient was admitted to the hospital. Based on the patient’s presentation and laboratory results, the care team proceeded with conservative treatment including nasogastric tube (NG) placement and suctioning, intravenous (IV) fluid replacement, and daily laboratory studies. She spent the first hospital day in the physical hospital ward so that the surgical team could ensure stability clinically and no urgent need for surgical intervention. On hospital day two, she was transferred home with ACH where the NG suctioning and IV replacement therapy could continue, while the medical team conducted daily virtual visits to ensure continued improvement. Additionally, a paramedic and a nurse performed an in-person, head-to-toe assessment and administered medications to the patient twice daily. She spent 5 days in ACH getting acute care and then was discharged into a postacute phase equivalent to outpatient monitoring called the restorative phase. She was monitored remotely for the duration of the restorative phase for 10 more days, and then she recovered fully. This case highlights that high-acuity patients with SBO can receive invasive treatments like NG tube suction as well as be appropriately monitored for clinical decompensation by a virtual hybrid home hospital program which combines virtual care providers with an in-home vendor-mediated supply chain.

Upper and lower limb amputations are frequently associated with phantom limb pain (PLP). Recently, virtual reality (VR) and augmented reality (AR) have been reported as a potential therapy of PLP. We have conducted a systematic review of literature to evaluate the efficacy of VR and AR in managing PLP. Four databases were searched: PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature, and Web of Science. We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for our organization. The initial search resulted in 164 results. After title, abstract, and full-text screening, 9 studies were included. One study was of good quality and 8 studies were of fair to poor quality. Seven studies utilized VR and 2 studies utilized AR. The number of treatment sessions ranged from 1 to 28 and the duration ranged from 10 minutes to 2 hours. Several pain scales were used to evaluate PLP pre- and postintervention including Numeric Rating Scale, Pain Rating Index, McGill Pain Questionnaire, and Visual Analog Scale. All the studies reported improvement of PLP on one or more of pain scales after one or more sessions of VR or AR. Despite the promising results reported by literature, we cannot recommend using VR or AR for PLP. Most of the studies are of poor design and have limited sample size with high bias levels. Therefore, no substantial evidence can be derived from them. However, we do believe further research with high-quality randomized controlled trials should take place to increase the knowledge of the potential advantages.

Abstract Background Atrial fibrillation (AF) pulmonary vein isolation ablation has been utilized increasingly yet variably in the USA. Purpose To identify variations in AF ablation utilization and reimbursement among Medicare beneficiaries (MB). Methodology We used a 100% sample of MB who underwent AF ablation from 2013 to 2019. We stratified data geographically (Northeast, South, West, and Midwest), identified the mean AF prevalence and the number of AF ablations per 100,000 MB, and examined the correlation between AF prevalence and ablation. We also examined the number of cardiologists performing AF ablation per 100,000 MB and the average number of AF ablation per individual cardiologist (ablation/cardiologist), as well as average submitted charge (ASC) for AF ablation. Additionally, we stratified data per urban versus rural areas as well as the gender of performing cardiologists and examined ablation/cardiologist and the ASC. Results Geographic analysis: The mean AF prevalence, the rates AF ablation per 100,000 MB, the number of cardiologists per 100,000 MB, and ablation/cardiologist have shown a steady increase in all regions across years. In all years, the mean AF prevalence was significantly different among regions with the highest prevalence in the Northeast and the lowest in the West (all P&lt;0.001), however, there was no significant difference in the rates of AF ablation per 100,000 MB (all P≥0.056). There was significant correlation between AF prevalence and ablation only in the Midwest and the West, with 46.4% and 43.4% positive correlation respectively (P≤0.0001). The number of cardiologists performing AF ablation per 100,000 MB was not significantly different among regions in all years (All P≥0.48), however, ablation/cardiologist was significantly higher in the West and the South compared to the Northeast and the Midwest (All P&lt;0.0001). On the contrary, the ASC has shown steady decrease in all regions. The ASC was significantly different among regions in all year (all P≤0.003) with higher ASC in the Midwest and the Northeast compared to the south and the West. Urban vs rural analysis: Ablation/cardiologist was not significantly different between urban and rural areas in all years (all P≥0.068) except in 2013 when it was significantly higher in urban areas (P=0.004). The ASC was significantly higher in rural areas only in 2015 and 2019 (P=0.037 and P=0.029 respectively) however, there was no significant difference in the rest of the years (P≥0.07). Gender analysis: Ablation/cardiologist was not significantly different between male and female cardiologists in all years (P≥0.056) except in 2017 when the average was significantly higher per male cardiologists (P=0.007). The ASC was not significantly different in all years (P≥0.362). Conclusion There are variations in AF ablation utilization and reimbursement among MB in the USA according to geographic, urban and rural regions, and the gender of performing cardiologists. Funding Acknowledgement Type of funding sources: None.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (&amp;lt;18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

Chronically ill patients with superimposed acute illness requiring hospitalization are more likely to develop an extended length of stay, hospital-acquired infections, and adverse events throughout their hospitalization. An excellent alternative to managing this population of patients in the traditional bricks-and-mortal (BAM) hospital is the hospital-at-home (HaH) model. The Advanced Care at Home (ACH) program is Mayo Clinic’s HaH model that provides acute and postacute care to high-acuity patients in their homes rather than in the traditional hospital and skilled nursing facility. We report a case of postoperative care through the ACH program of a patient suffering from short gut syndrome, high-output ileostomy, and severe protein-calorie malnutrition in the setting of previously diagnosed triple-negative invasive ductal carcinoma (IDC) of the right breast complicated by lung and brain metastasis. The patient had multiple complications that required repeated scare escalations directed by a multidisciplinary virtual care. Despite these complications, the ACH model of care was able to keep the patient in the home setting the majority of the time, limiting BAM hospital days, and eliminating the need to use the emergency department for acute escalation for 3 months. The patient was able to recover during this time period and proceed to successful take-down of the ileostomy. This case highlights the benefits of the ACH program by offering high-acuity hospital-level care to severely ill patients in the comfort of their homes. Highly qualified providers paired with curated technology in the home allowed for prompt identification of patient decompensation and timely initiation of treatment while avoiding institutionalization.

Maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma (MM) is the standard treatment and recommended to be continued until disease progression. However, in the real world, patients discontinue treatment due to various reasons. We sought to determine the effect of early versus late discontinuation on survival outcomes in MM patients who underwent ASCT at The Ohio State University. We retrospectively reviewed 340 patients who underwent ASCT from 2005 to 2016 and received maintenance therapy for at least six months without progression. We compared the outcomes of patients who received maintenance for three years or less (early group) to the patients who continued maintenance beyond three years (late group). Lenalidomide (89%) and bortezomib (10%) were the most common agents used for maintenance chemotherapy. In Kaplan–Meier analysis, patients in the late group had prolonged progression-free (PFS) (p < 0.001) and overall survival (OS) (p < 0.001). The 5-year estimated OS in late group was 96% vs. 79% in the early group and 5-year PFS was 80% in late group vs. 50% in the early group. The most common reasons for discontinuation of maintenance in early group were adverse events (55.9%) and patient preference (22.5%). For the late group, it was disease progression (23.9%) and adverse events (14.3%). Fifty-five percent of patients in the late group were still on maintenance treatment at the last follow-up. Continuation of maintenance therapy was thus associated with improved outcomes, while adverse events prevented most patients from continuing treatment.

BACKGROUND: Current literature has identified textbook outcome (TO) as a quality metric after cancer surgery. We studied whether TO after pancreatic resection has a stronger association with long-term survival than individual hospital case volume. STUDY DESIGN: Patients undergoing surgery for pancreatic adenocarcinoma from 2010 to 2015 were identified from the National Cancer Database. Hospitals were stratified by volume (low less than 6, medium 6 to 19, and high 20 cases or more per year), and overall survival data were abstracted. We defined TO as adequate lymph node count, negative margins, length of stay less than the 75th percentile, appropriate systemic therapy, timely systemic therapy, and without a mortality event or readmission within 30 days. The association of TO and case volume was assessed using a multivariable Cox regression model for survival. RESULTS: Overall, 7270 patients underwent surgery, with 30.7%, 48.7%, and 20.6% performed at low-, medium-, and high-volume hospitals, respectively. Patients treated at low-volume hospitals were more likely to be Black, be uninsured or on Medicaid, have higher Charlson comorbidity scores, and be less likely to achieve TO (23.4% TO achievement vs 37.5% achievement at high-volume hospitals). However, high hospital volume was no longer associated with overall survival once TO was added to the multivariable model stratified by volume status. Achievement of TO corresponded to a 31% decrease in mortality (hazard ratio 0.69; p < 0.001), independent of hospital volume. CONCLUSIONS: Improved long-term survival after pancreatic resection was associated with TO rather than high hospital volume. Quality improvement efforts focused on TO criteria have the potential to improve outcomes irrespective of case volume.