Life's Essential 8 Cardiovascular Health Score and Cardiorespiratory Fitness in the Community.

BACKGROUND: The relation of cardiorespiratory fitness (CRF) to lifestyle behaviors and factors linked with cardiovascular health remains unclear. We aimed to understand how the American Heart Association's Life's Essential 8 (LE8) score (and its changes over time) relate to CRF and complementary exercise measures in community-dwelling adults. METHODS AND RESULTS: Framingham Heart Study (FHS) participants underwent maximum effort cardiopulmonary exercise testing for direct quantification of peak oxygen uptake (V̇O2). A 100-point LE8 score was constructed as the average across 8 factors: diet, physical activity, nicotine exposure, sleep, body mass index, lipids, blood glucose, and blood pressure. We related total LE8 score, score components, and change in LE8 score over 8 years with peak V̇O2 (log-transformed) and complementary CRF measures. In age- and sex-adjusted linear models (N=1838, age 54±9 years, 54% women, LE8 score 76±12), a higher LE8 score was associated favorably with peak V̇O2, ventilatory efficiency, resting heart rate, and blood pressure response to exercise (all P<0.0001). A clinically meaningful 5-point higher LE8 score was associated with a 6.0% greater peak V̇O2 (≈1.4 mL/kg per minute at sample mean). All LE8 components were significantly associated with peak V̇O2 in models adjusted for age and sex, but blood lipids, diet, and sleep health were no longer statistically significant after adjustment for all LE8 components. Over an ≈8-year interval, a 5-unit increase in LE8 score was associated with a 3.7% higher peak V̇O2 (P<0.0001). CONCLUSIONS: Higher LE8 score and improvement in LE8 over time was associated with greater CRF, highlighting the importance of the LE8 factors in maintaining CRF.

Initial Experience with Apixaban for Extended Venous Thromboembolism Prophylaxis After Radical Cystectomy.

Patients who undergo radical cystectomy (RC) are at elevated risk of venous thromboembolism and associated morbidity and mortality. Guidelines recommend extended thromboprophylaxis (ETP), typically with heparins, but adherence is low. Outside urology, low-dose apixaban has been used for postoperative ETP with success. We describe our first experiences with low-dose apixaban for ETP after RC for bladder cancer. In our sample of 72 patients who underwent RC for cancer and subsequently received apixaban 2.5 mg twice daily for ETP, there were no symptomatic thromboembolic events and no major bleeding events. Other complication rates were in line with historical reports. Our experience with apixaban 2.5 mg twice daily for ETP after RC demonstrates safety and potential efficacy. A transition from injectable to oral thromboprophylaxis has the potential to improve adherence and patient satisfaction, while allowing the possibility of further extending prophylaxis beyond 28 d, which may be beneficial in selected patients. Further evaluation of apixaban for thromboprophylaxis in urologic cancer surgery is warranted. PATIENT SUMMARY: Home injectable heparin is used for 4 weeks after bladder removal surgery to prevent blood clots. We evaluated our use of the oral medication apixaban for prevention of blood clots after bladder removal surgery and found that none of our patients had major bleeding events or symptomatic blood clots. We conclude that there should be further evaluation of the use of oral instead of injectable medication to prevent blood clots after urology surgery.

Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder.

Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8 years (range 1-14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% versus 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20 years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous TINF2 variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7 years (range 0.7-12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non-TINF2 pathogenic variants was 70% by age 60 years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs.

A Multicomponent Library Resource Model to Enhance Academic Global Health Education Among Residency Programs.

Global health is becoming an increasingly important component of medical education. Medical libraries have an opportunity to assist global health residents with their information needs, but first it is important to identify what those needs are and how best they can be addressed. This article reports a collaboration between global health faculty and an academic medical librarian to assess the information needs of global health pathway residents and how assessment data are used to create a multicomponent program designed to enhance global health education.

Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB.

We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKß) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB.

p16 Protein and gigaxonin are associated with the ubiquitination of NFκB in cisplatin-induced senescence of cancer cells.

The molecular mechanism of p16-mediated senescence in cisplatin-treated cancer cells is not fully understood. Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFκB. Chromatin immunoprecipitation assays show that this modification is associated with the inhibition of NFκB interacting with its DNA binding sequences, leading to decreased expression of NFκB-transcribed proteins. LCMS proteomic analysis of LAP-TAP-purified proteins from HeLa cells containing a tetracycline-inducible GFP-S peptide-NFκB expression system identified gigaxonin, an ubiquitin E3 ligase adaptor, as an NFκB-interacting protein. Immunoblotting and siRNA studies confirmed the NFκB-gigaxonin interaction and the dependence of this binding on p16-NFκB binding. Using gel shift assays, we have confirmed p16-NFκB and gigaxonin-NFκB interactions. Furthermore, we have observed increased NFκB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression. Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0.0000542), indicating the importance of nuclear p16 expression in prognosis. Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors. However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors. These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFκB.