A Propensity-Matched Cohort Assessing Impact of a Neutralizing Monoclonal Antibody in Mild-to-Moderate Coronavirus Disease 2019.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoaV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. In randomized clinical trials, patients who were treated with the anti-spike monoclonal antibody bamlanivimab had fewer COVID-19-related hospitalizations or emergency department (ED) visits than the control group. Methods: A retrospective cohort was assembled across a multisite healthcare system between November 20, 2020 and March 31, 2021. Ambulatory COVID-19 patients treated with bamlanivimab (n = 209) were propensity score matched without replacement (1:1) to a pool of 1024 eligible control patients who received similar care without bamlanivimab. The primary endpoint was all-cause mortality or admission at 30 days. Secondary endpoints included hospitalization, critical care admission, oxygenation requirements, and infusion-related reactions. Propensity score matching (PSM) analysis was used to assess the effect of bamlanivimab infusion on the composite endpoint and secondary endpoints. Results: A total of n = 209 matched patients were included in each arm of the study. The absolute standardized difference (stddiff) was calculated and indicated a balance between the groups. Almost all variables had a stddiff of less than 0.10, except for respiratory rate (RR) (stddiff = -0.11). For the primary composite endpoint of the matched cohort, 10.1% (n = 21) of patients in the intervention group were hospitalized or deceased within 30-day postbamlanivimab infusion versus 27.8% (n = 58) in the control group (adjusted odds ratio [aOR]: 0.29, 95% confidence interval [CI]: 0.17 to 0.51, P < .001). Conclusion: Patients with ambulatory COVID-19 who received bamlanivimab in the outpatient setting had a statistically significant reduction on the odds of admission postinfusion. Despite bamlanivimab's lack of efficacy on newer SARS-CoV-2 variants, this study demonstrates that neutralizing monoclonal antibodies can be effective against specific variants. If variant identification becomes a more accessible tool in outpatient centers or EDs, more targeted therapeutic options may be considered.

Warthin Tumor of the Caruncle: A Rare Case Report and Review of the Literature.

The authors describe a case of Warthin tumor arising in the caruncle of a 76-year-old man. Clinical examination identified a left medial canthus swelling that was treated by complete local excision. Pathologic examination revealed a benign epithelial tumor with diagnostic features of Warthin tumor. Clinical and histologic features, along with review of the literature, are discussed.

A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity.

AIMS: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group). RESULTS: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. CONCLUSIONS: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents.

Comprehensive medication reviews: Optimal delivery setting and recommendations for quality assessment.

OBJECTIVES: To propose a metric evaluating the quality of comprehensive medication reviews (CMRs), and to discuss the optimal setting for CMR delivery. SUMMARY: First, we provide a current assessment of the quality of CMRs performed in community, payer, and health system/clinic settings, with recommended opportunities for improvement. Thereafter, a companion metric for CMR quality is discussed, because this is critical to ensuring that patients are not just receiving CMR services, but that CMRs reflect evidence-based recommendations supporting optimal patient outcomes. CONCLUSION: Based on the data currently available, accessibility to electronic medical records would enhance patient-specific recommendations to optimize CMR delivery and patient outcomes. Future studies may help to identify additional factors, such as pharmacist-physician collaboration in clinic and use of evidence-based recommendations, that can further enhance CMR quality.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca²âº in adult cardiac myocytes.

Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on nuclear Ca(2+) signaling. Confocal microscopy using fluorescently-labeled endothelin analogs confirmed the presence of ETB at the nuclear membrane of rat cardiomyocytes in skinned-cells and isolated nuclei. Furthermore, in both cardiac myocytes and aortic endothelial cells, endocytosed ET:ETB complexes translocated to lysosomes and not the nuclear envelope. Although ETA and ETB can form heterodimers, the presence or absence of ETA did not alter ETB trafficking. Treatment of isolated nuclei with peptide: N-glycosidase F did not alter the electrophoretic mobility of ETB. The absence of N-glycosylation further indicates that these receptors did not originate at the cell surface. Intracellular photolysis of a caged ET-1 analog ([Trp-ODMNB(21)]ET-1) evoked an increase in nucleoplasmic Ca(2+) ([Ca(2+)]n) that was attenuated by inositol 1,4,5-trisphosphate receptor inhibitor 2-aminoethoxydiphenyl borate and prevented by pre-treatment with ryanodine. A caged cell-permeable analog of the ETB-selective antagonist IRL-2500 blocked the ability of intracellular cET-1 to increase [Ca(2+)]n whereas extracellular application of ETA and ETB receptor antagonists did not. These data suggest that 1) the endothelin receptor in the cardiac nuclear membranes is ETB, 2) ETB traffics directly to the nuclear membrane after biosynthesis, 3) exogenous endothelins are not ligands for ETB on nuclear membranes, and 4) ETB associated with the nuclear membranes regulates nuclear Ca(2+) signaling.

JAK/STAT signaling and cellular iron metabolism in hepatocellular carcinoma: therapeutic implications.

Iron metabolism plays a crucial role in the development and progression of hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Iron is an essential micronutrient that is involved in many physiological processes, including oxygen transport, DNA synthesis, and cellular growth and differentiation. However, excessive iron accumulation in the liver has been linked to oxidative stress, inflammation, and DNA damage, which can increase the risk of HCC. Studies have shown that iron overload is common in patients with HCC and that it is associated with a poor prognosis and reduced survival rates. Various iron metabolism-related proteins and signaling pathways such as the JAK/STAT pathway are dysregulated in HCC. Moreover, reduced hepcidin expression was reported to promote HCC in a JAK/STAT pathway-dependent manner. Therefore, it is important to understand the crosstalk between iron metabolism and the JAK/STAT pathway to prevent or treat iron overload in HCC. Iron chelators can bind to iron and remove it from the body, but its effect on JAK/STAT pathway is unclear. Also, HCC can be targeted by using the JAK/STAT pathway inhibitors, but their effect on hepatic iron metabolism is not known. In this review, for the first time, we focus on the role of the JAK/STAT signaling pathway in regulating cellular iron metabolism and its association with the development of HCC. We also discuss novel pharmacological agents and their therapeutic potential in manipulating iron metabolism and JAK/STAT signaling in HCC.

SCAMP3 promotes breast cancer progression through the c-MYC-ß-Catenin-SQSTM1 growth and stemness axis.

The cellular trafficking protein secretory-carrier-membrane-protein 3 (SCAMP3) has been previously shown to promote hepatocellular carcinoma, melanoma, glioma and pancreatic adenocarcinoma. Moreover, previous work has shown that SCAMP3 regulates the epidermal growth factor receptor (EGFR) in triple negative breast cancer (TNBC). However, the oncogenic role of SCAMP3 in different molecular subtypes of breast cancer (BRCA) remains largely unknown. In this study, the role of SCAMP3 in different molecular subtypes of BRCA was investigated using in silico, in vitro and in vivo approaches. In silico analysis of BRCA patient samples showed that SCAMP3 is highly overexpressed in different BRCA molecular subtypes, advanced disease grades and lymph node metastatic stages. Depletion of SCAMP3 inhibited BRCA cell growth, stemness, clonogenic potential and migration and promoted autophagy and cellular senescence. The expression of stemness markers CD44 and OCT4A was reduced in SCAMP3-silenced MDA-MB-231 cells. SCAMP3 overexpression promoted cell proliferation, clonogenicity, tumor spheroid formation and migration in vitro and tumor growth in vivo. SCAMP3 promoted epithelial-mesenchymal-transition (EMT) by regulating E-cadherin expression. SCAMP3 enhanced in vivo tumor growth in MDA-MB-231 tumor xenograft mouse model. Mechanistically, SCAMP3 depletion inhibited ß-Catenin, c-MYC and SQSTM1 expression, while its overexpression increased the expression of the same oncogenic proteins. Increased SCAMP3 expression associated with increased chemoresistance in BRCA cells while its depletion associated with increased sensitivity to chemotherapy. BRCA patients with high SCAMP3 expression showed poor prognosis, decreased overall survival and relapse free survival relative to counterparts with reduced SCAMP3 expression. These findings suggest that SCAMP3 exerts a wide range of oncogenic effects in different molecular subtypes of BRCA by modulating the c-MYC-ß-Catenin-SQSTM1 axis that targets tumor growth, metastasis, stemness and chemoresistance.

Expanding the spectrum of thyroid carcinoma with somatic DICER1 mutation: a survey of 829 thyroid carcinomas using MSK-IMPACT next-generation sequencing platform.

DICER1 gene encodes an RNaseIII endoribonuclease essential for the cleavage of pre-microRNA to mature microRNA. Germline DICER1 mutation results in DICER syndrome, a cancer predisposition syndrome which manifests in the thyroid gland as early-onset multinodular goiter and increased risk for differentiated thyroid carcinoma. Recently, somatic DICER1 mutations were described in various thyroid neoplasms, including follicular adenoma, papillary thyroid carcinoma, follicular carcinoma, and poorly differentiated thyroid carcinoma. In this study, we identified and described 14 cases (1.7%) with somatic DICER1 mutations from a cohort of 829 patients with thyroid follicular cell-derived thyroid carcinomas which were sequenced using MSK-IMPACT targeted next-generation sequencing platform. We expanded the histologic spectrum of thyroid carcinomas with somatic DICER1 mutations to include Hurthle cell carcinoma, high-grade differentiated thyroid carcinoma, and anaplastic thyroid carcinoma. All patients were adults with a median age of diagnosis of 59 years (range: 22-82). Although rare, a subset of thyroid cancers, including the aggressive subtypes, display somatic DICER1 mutations, some of which have oncogenic potential.

Real-world evaluation of insulin requirements after GLP1 agonist or SGLT2 inhibitor initiation and titration.

PURPOSE: To describe insulin adjustments made following initiation of glucagon-like peptide 1 agonist (GLP1a) or sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy in patients within a primary care setting. METHODS: This was a multicenter, retrospective cohort study conducted at an academic health system. Adults with type 2 diabetes mellitus initiated on a GLP1a or SGLT2i while on insulin and managed by an ambulatory care pharmacist were included. The primary endpoint was the percent change in total daily insulin dose at specified time points (2 weeks, 4 weeks, 6 weeks, 3 months, and 6 months) after agent initiation. The secondary endpoints included a glycosylated hemoglobin (HbA1c) value of less than 8%, change from baseline HbA1c, and safety profiles of GLP1a therapy and SGLT2i therapy. RESULTS: Of the 150 patients included, 123 were initiated on a GLP1a and 27 on an SGLT2i. After 6 months, GLP1a initiation had resulted in a mean 23.5% decrease (P < 0.001) in insulin dosage and SGLT2i resulted in a mean 0.2% increase (P = 0.20). Insulin dosage reduction with GLP1a use was significantly different between baseline and each time point (P < 0.001). About 72% of patients initiated on a GLP1a and 59% of those initiated on an SGLT2i achieved an HbA1c value of less than 8%. The mean absolute change from baseline in HbA1c concentration was -1.7% with GLP1a use and -1.5% with SGLT2i use (P < 0.001 for both comparisons with baseline values). Hypoglycemia occurred in 21% of patients on a GLP1a and 11% of those on an SGLT2i. CONCLUSION: After GLP1a initiation, the mean total daily insulin dose decreased by 23.5%; after SGLT2i initiation, insulin requirements increased by a mean of 0.2%. These results will help guide insulin adjustments after initiation of these medications.

Pharmacist hypertension management using an electronic health record-based approach.

OBJECTIVES: To evaluate the impact of the chronic medication optimization pharmacist (CMOP) program on blood pressure (BP) control and time to goal compared with usual care in the ambulatory care setting. STUDY DESIGN: This was a retrospective cohort study that included patients from June 2018 to June 2020 who were seen in an ambulatory care clinic for hypertension management. METHODS: Patients aged 18 to 80 years were divided into 2 cohorts based on hypertension management by usual care or the CMOP program. Patients were enrolled in the CMOP program either by referral or identification via a data analytics tool. The primary outcome assessed the proportion of patients within BP goal (< 140/90 mm Hg) at 3 months. Secondary outcomes assessed the proportion of patients within goal at 6 months, time and number of visits to goal, and adherence (CMOP cohort only). RESULTS: The primary end point demonstrated a greater proportion of patients within goal in the CMOP cohort compared with usual care (69.4% vs 42.3%; P < .001). The CMOP cohort also displayed a greater proportion of patients achieving goal within 6 months (75.7% vs 60.4%; P = .014) and faster time to goal (42.99 vs 63.12 days; P = .002), but more visits (1.67 vs 1.18; P = .001). Lastly, adherence improved from 50.4% to 72.1% in the patients with a documented adherence assessment in the pharmacist group (P = .03). CONCLUSIONS: The pharmacist intervention improved BP control in a primarily African American patient population compared with usual care. Future studies should assess the sustainability of this intervention.

Up-regulation of thromboxane A2 impairs cerebrovascular eNOS function in aging atherosclerotic mice.

We previously reported that in healthy mouse cerebral arteries, endothelial nitric oxide synthase (eNOS) produces H2O2, leading to endothelium-dependent dilation. In contrast, thromboxane A2 (TXA2), a potent pro-oxidant and pro-inflammatory endogenous vasoconstrictor, is associated with eNOS dysfunction. Our objectives were to elucidate whether (1) the cerebrovascular eNOS-H2O2 pathway was sensitive to oxidative stress associated with aging and dyslipidemia and (2) TXA2 contributed to cerebral eNOS dysfunction. Atherosclerotic (ATX = LDLR(-/-); hApoB(+/+)) and wild-type (WT) control mice were used at 3 and 12 months old (m/o). Three-m/o ATX mice were treated with the cardio-protective polyphenol catechin for 9 months. Dilations to ACh and the simultaneous eNOS-derived H2O2 production were recorded in isolated pressurized cerebral arteries. The age-associated decrease in cerebral eNOS-H2O2 pathway observed in WT was premature in ATX mice, decreasing at 3 m/o and abolished at 12 m/o. Thromboxane synthase inhibition by furegrelate increased dilations at 12 months in WT and at 3 and 12 months in ATX mice, suggesting an anti-dilatory role of TXA2 with age hastened by dyslipidemia. In addition, the non-selective NADP(H) oxidase inhibitor apocynin improved the eNOS-H2O2 pathway only in 12-m/o ATX mice. Catechin normalized the function of this pathway, which became sensitive to L-NNA and insensitive to furegrelate or apocynin; catechin also prevented the rise in TXA2 synthase expression. In conclusion, the age-dependent cerebral endothelial dysfunction is precocious in dyslipidemia and involves TXA2 production that limits eNOS activity. Preventive catechin treatment reduced the impact of endogenous TXA2 on the control of cerebral tone and maintained eNOS function.

Chlamydia trachomatis Mimicking COVID-19 Chronic Follicular Conjunctivitis.

PURPOSE: To characterize the clinical presentation and report lab findings of Chlamydia trachomatis follicular conjunctivitis in two patients with a positive history of active COVID-19 infection. Participants. Two patients with follicular conjunctivitis with a recent history of COVID-19 infection. DESIGN: Retrospective, noncomparative, case report. METHODS: Demographic data including age, gender, and place of residence were recorded. A full exam with an emphasis on inflammatory characteristics and systematic workup. Sample follicles were surgically excised in selected cases, and molecular and histopathological analyses were performed. RESULTS: Both patients were initially treated for viral conjunctivitis. After symptoms failed to resolve, biopsy results indicated that both patients were positive for chlamydia conjunctivitis and treated accordingly. CONCLUSIONS: These cases illustrate the role of biopsy as an investigative tool in chronic conjunctivitis and the importance of having a broad differential when treating patients with acute conjunctivitis.

Biphenotypic sinonasal sarcoma: Report of 3 cases with a review of literature.

Biphenotypic sinonasal sarcoma (BSNS) is a rare recently described distinct spindle cell sarcoma which arises exclusively in the sinonasal region and is characterized by concomitant neural and myogenic differentiation. Before this neoplasm was characterized, most were classified as other entities including adult fibrosarcoma, monophasic synovial sarcoma and malignant peripheral nerve sheath tumor. By immunohistochemistry, these tumors characteristically express S100 and smooth muscle actin (SMA) and/or muscle specific actin (MSA). Most cases harbor rearrangements of PAX3 (paired box gene 3), and the most frequent translocation partner is MAML3 (mastermind like transcriptional coactivator 3). Herein, we described three cases of BSNS involving the nasal cavity with or without paranasal sinus involvement. We also did a literature review of the clinical features, histologic and immunophenotypic findings, cytogenetics, pathogenesis and behavior of this rare entity.

p16 Immunoreactivity Correlates With Morphologic Diagnosis of HPV-associated Anal Intraepithelial Neoplasia: A Study of 1000 Biopsies.

p16 is the most useful diagnostic marker for human papillomavirus (HPV)-associated anogenital lesions. In the cervix, the pattern of p16 immunoreactivity generally correlates with lesion severity. p16 expression in anal intraepithelial neoplasia (AIN) is far less studied. Whether such correlation holds true has to be determined. We correlated the degree and pattern of p16 immunohistochemistry (IHC) results with morphologic diagnoses of 1000 anal squamous and transitional zone biopsy specimens. Using the Lower Anogenital Squamous Terminology criteria, p16 IHC results were classified as block staining, partial staining, or negative. Among 150 samples without morphologic evidence of AIN, p16 was negative in 85% and partial staining in 15%. AIN 1 (n=400) revealed diverse results: 28% negative, 35% partial, and 37% block staining. Among AIN 2 (n=298), 89% were block, 9% partial staining, and 2% negative. AIN 3 (n=152) revealed block (95%) or partial staining (5%). For the detection of AIN 2/3, p16 block staining yielded 91% sensitivity, 73% specificity, 80% positive predictive value, 91% negative predictive value, and a Youden Index of 0.64. Combining block staining and partial staining slightly increased sensitivity (99%) and negative predictive value (98%), but significantly decreased specificity (43%), positive predictive value (59%) and Youden Index (0.42, P<0.001). As with the cervix, p16 immunoreactivity correlates with morphologic diagnoses of AIN. Block staining offers the optimal diagnostic value for AIN 2/3. Caution is required since AIN 1 frequently exhibits block staining; the prognostic value of p16 warrants further investigation.

[Age-dependent oxidative stress: toward an irreversible failure in endothelial maintenance]. / Âge et stress oxydant : vers un déséquilibre irréversible de l'homéostasie endothéliale.

In order to maintain cellular homeostasis against endogenous and exogenous aggressions, different cellular mechanisms of defence, maintenance and repair are continuously activated throughout life. Hormesis, a concept based on the fact that mild stresses protect cells against subsequent stresses, amplifies the efficacy of the cellular mechanisms of defence and repair. Ageing, senescence and ultimately death, result from the exhaustion of these mechanisms maintaining cellular functions. One of the major sources of vascular endothelial damage is oxidative stress. The age-dependent shift in the redox environment towards pro-oxidation contributes to a progressive compensatory remodelling of the endothelium, an accumulation of damages, and its dysfunction, the premises for atherosclerosis. We propose that in agreement with the concept of hormesis, a moderate exposure during endothelial maturation to mild physiological oxidative stressors determines -vascular longevity.

Potent in vivo antiangiogenic effects of GS-101 (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), an antisense oligonucleotide preventing the expression of insulin receptor substrate-1.

Angiogenesis is a complex phenomenon regulated by both pro- and antiangiogenic factors such as the vascular endothelial growth factor (VEGF), and inflammation may be involved in the process. Although antagonizing VEGF has been proposed as a therapeutic approach to limit corneal angiogenesis, alternative targets are needed. In this study, we demonstrate that, under proangiogenic experimental conditions, human endothelial cells (hECs) express more insulin receptor substrate (IRS)-1 proteins relative to quiescent cells. The antisense oligonucleotide, GS-101 (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), targeting IRS-1 mRNA, dose-dependently inhibited (p < 0.01) both IRS-1 expression and in vitro angiogenesis (hEC tube-like structure formation) with IC(50) of 8.51 +/- 3.01 microM (mean +/- S.E.M.) and 2.47 +/- 0.56 microM, respectively, demonstrating that partial IRS-1 down-regulation interferes with angiogenesis. The antiangiogenic effects of GS-101 were associated with a decrease in protein kinase B (Akt) activation but not mitogen-activated protein kinase-1/2 and a dose-dependent reduction in vascular endothelial growth factor-A (IC(50) = 5.59 +/- 2.76 microM) and the proinflammatory cytokine interleukin-1beta (IC(50) = 2.19 +/- 1.07 microM) mRNA expression. In accordance, once daily topical application of GS-101 dose-dependently inhibited injury-dependent corneal angiogenesis in vivo (p < 0.05). GS-101 in vivo efficacy was achieved at final tissue concentrations within in vitro EC(50) for IRS-1 down-regulation. In conclusion, these results suggest that IRS-1 is important for angiogenesis and that GS-101 could become a novel therapeutic tool against corneal angiogenesis.

A Previously Unrecognized Monocytic Component of Pheochromocytoma and Paraganglioma.

We describe a consistently present, previously unrecognized, population of monocytes in pheochromocytomas and paragangliomas. Although sustentacular cells are generally recognized as a common component of these tumors, differential immunohistochemical staining for CD163 and S100 shows that monocytes can in fact be more numerous. These cells frequently resemble sustentacular cells topographically and cytologically, possibly explaining why they have not been previously noticed. They contribute to the tumor proteome and may have implications for tumor biology. No correlations were identifiable between the presence of these cells and any clinical characteristics of the tumors in the present study. A possible association with genotype is suggested by immunoblot showing high expression of CD163 protein in tumors with succinate dehydrogenase mutations.

Evolution of interdisciplinary geriatric transitions of care on readmission rates.

OBJECTIVES: To evaluate the effect of an interdisciplinary transitions of care (TOC) service on readmission rates in a geriatric population. STUDY DESIGN: Single-center retrospective cohort study of adults 60 years or older discharged from an academic medical center. METHODS: From July 1, 2013, to February 21, 2016, a total of 4626 patients discharged from 1 hospital, including inpatient, emergency department, observation, and short-stay units, were included. Cases were scheduled for a TOC service with the interdisciplinary team. Controls received usual care at other sites. All-cause 14-, 30-, and 90-day readmission rates between propensity score-matched study groups were evaluated by intention-to-treat (ITT), per-protocol (PP), and as-treated methods. RESULTS: During the study period, 513 patients were scheduled for at least 1 component of the TOC intervention (ITT group). Of those patients, 215 completed all scheduled visits (PP group). Readmission rate after 30 days demonstrated no difference in the ITT group compared with the control group (12.8% vs 10.7%; P = .215), although it was significantly lower in the PP group in comparison with the control group (12.8% vs 7.9%; P = .042). CONCLUSIONS: An interdisciplinary team based in a patient-centered medical home improved readmission rates for all patients who completed the intervention (PP group).

Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients.

Endothelial senescence may contribute to the pathogenesis of age-related vascular disorders. Furthermore, chronic exposure to risk factors for cardiovascular disease (CVD) accelerates the effects of chronological aging by generating stress-dependent damages, including oxidative stress, therefore promoting stress-induced premature senescence. Our objective was to determine whether a chronic treatment with an antioxidant (N-acetyl-cystein, NAC) could delay senescence of endothelial cells (EC) isolated and cultured from arterial segments of patients with severe coronary artery disease. If EC were considered as one population (n=26), chronic NAC treatment slightly shortened telomere attrition rate associated with senescence but did not significantly delay the onset of endothelial senescence. However, in a subgroup of NAC-treated EC (n=15) cellular senescence was significantly delayed, NAC decreased lipid peroxidation (HNE), activated the catalytic subunit of telomerase (hTERT) and inhibited telomere attrition. In contrast, in another subgroup of EC (n=11) characterized by initial short telomeres, no effect of NAC on HNE and high levels of DNA damages, the antioxidant was not beneficial on senescence, suggesting an irreversible stress-dependent damage. In conclusion, chronic exposure to NAC can delay senescence of diseased EC via hTERT activation and transient telomere stabilization, unless oxidative stress-associated cell damage has become irreversible.