Implementing a Staff-Led Smoking Cessation Intervention in a Diverse Safety-Net Rheumatology Clinic: A Pre-Post Scalability Study in a Low-Resource Setting.

OBJECTIVE: Quit Connect (QC), our specialty clinic smoking cessation intervention, supports clinic staff to check, advise, and connect willing patients to a state quit line or class. QC improved tobacco screening and quit line referrals 26-fold in a predominantly White academic health care system population. Implementing QC includes education, electronic health record (EHR) reminders, and periodic audit feedback. This study tested QC's feasibility and impact in a safety-net rheumatology clinic with a predominantly Black population. METHODS: In this pre-post study, adult rheumatology visits were analyzed 12 months before through 18 months after QC intervention (November 2019 through November 2021, omitting COVID-19 peak April through November 2020). EHR data compared process and clinical outcomes, including offers, referrals to resources, completed referrals, and documented cessation. Clinic staff engaged in pre-post focus groups and questionnaires regarding intervention feasibility and acceptability. Cost-effectiveness was also assessed. RESULTS: Visit-level patients who smoked were 89.8% Black and 69.5% women (n = 550). Before intervention, clinic staff rarely asked patients about readiness to cut back smoking (<10% assessment). After QC intervention, staff assessed quit readiness in 31.8% of visits with patients who smoked (vs 8.1% before); 58.9% of these patients endorsed readiness to cut back or quit. Of 102 accepting cessation services, 37% (n = 17) of those reached set a quit date. Staff found the intervention feasible and acceptable. Each quit attempt cost approximately $4 to $10. CONCLUSION: In a safety-net rheumatology clinic with a predominantly Black population, QC improved tobacco screening, readiness-to-quit assessment, and referrals and was also feasible and cost-effective.

Performance of Modified ALMS and BLISS Criteria with Standard of Care Treatment in Two US Health Care Systems.

OBJECTIVE: A retrospective cohort study was undertaken in a predominantly Black population undergoing standard treatment for lupus nephritis (LN) to estimate the incidence of, and risk factors for, complete response (CR) according to modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Study in Lupus Nephritis (mBLISS) criteria by 12 months. METHODS: Patients with biopsy-proven LN class III or IV ± V, urine protein-to-creatinine ratio of ≥1gm/gm and estimated glomerular filtration rate of >50 ml/minute/1.73 m2 at the time of the incident LN flare were included. The clinical, treatment, and laboratory factors associated with CR were identified using multivariable Cox regression. RESULTS: Of 173 patients, 86.1% were women, 77.5% were Black, and over half (59.5%) had non-commercial insurance. By 12 months, 20.6% (95% confidence interval (95% CI) 14.6-28.6%) achieved mALMS CR and 33.7% (95% CI 26.4-42.4%) achieved mBLISS CR. Factors associated with mBLISS CR were commercial insurance (adjusted CR ratio = 3.5 [95% CI 1.9-6.7]; P < 0.001), albumin (adjusted CR ratio = 1.8 per 1 gm/dl increase in albumin; P = 0.02), and low C4 (adjusted CR ratio = 2.6; P = 0.03). Cumulative incidence of end-stage renal disease (ESRD) at 3 years was 23.1% (95% CI 15.7-31.3%) and 6.1% (95% CI 2.8-11.1%) for death. Patients with non-commercial insurance were more likely to develop ESRD, with cumulative incidence of 30.4% (95% CI 19.6-41.9%) compared to 12.7% (95% CI 5.0-24.2%) for patients with commercial insurance (P = 0.024). CONCLUSION: In a primarily Black, uninsured LN population, despite achieving similar CR rates at 12 months, the incidence of ESRD and death exceeded those observed in controlled clinical trials with placebo arms.

B cell subset composition segments clinically and serologically distinct groups in chronic cutaneous lupus erythematosus.

OBJECTIVE: While the contribution of B-cells to SLE is well established, its role in chronic cutaneous lupus erythematosus (CCLE) remains unclear. Here, we compare B-cell and serum auto-antibody profiles between patients with systemic lupus erythematosus (SLE), CCLE, and overlap conditions. METHODS: B-cells were compared by flow cytometry amongst healthy controls, CCLE without systemic lupus (CCLE+/SLE-) and SLE patients with (SLE+/CCLE+) or without CCLE (SLE+/CCLE-). Serum was analyed for autoreactive 9G4+, anti-double-stranded DNA, anti-chromatin and anti-RNA antibodies by ELISA and for anti-RNA binding proteins (RBP) by luciferase immunoprecipitation. RESULTS: Patients with CCLE+/SLE- share B-cell abnormalities with SLE including decreased unswitched memory and increased effector B-cells albeit at a lower level than SLE patients. Similarly, both SLE and CCLE+/SLE- patients have elevated 9G4+ IgG autoantibodies despite lower levels of anti-nucleic acid and anti-RBP antibodies in CCLE+/SLE-. CCLE+/SLE- patients could be stratified into those with SLE-like B-cell profiles and a separate group with normal B-cell profiles. The former group was more serologically active and more likely to have disseminated skin lesions. CONCLUSION: CCLE displays perturbations in B-cell homeostasis and partial B-cell tolerance breakdown. Our study demonstrates that this entity is immunologically heterogeneous and includes a disease segment whose B-cell compartment resembles SLE and is clinically associated with enhanced serological activity and more extensive skin disease. This picture suggests that SLE-like B-cell changes in primary CCLE may help identify patients at risk for subsequent development of SLE. B-cell profiling in CCLE might also indentify candidates who would benefit from B-cell targeted therapies.

Chronic Cutaneous Lupus Erythematosus: Depression Burden and Associated Factors.

OBJECTIVES: Depression may occur in up to 30% of individuals with cutaneous lupus erythematosus (CLE), many of whom may also have systemic manifestations. Chronic cutaneous lupus erythematosus (CCLE) conditions are less likely to present systemic involvement than acute and subacute conditions but more often cause permanent scarring and dyspigmentation. However, little is known about depression in those who have CCLE confined to the skin (primary CCLE). As African Americans are at high risk for primary CCLE and depression, we aimed to investigate the prevalence of and explore the risk factors for depression in a population-based cohort of predominantly Black patients with primary CCLE. METHODS: This was a cross-sectional analysis of a cohort of individuals with a documented diagnosis of primary CCLE, established in metropolitan Atlanta, GA, USA. Participants were recruited from the Centers for Disease Control and Prevention (CDC) population-based Georgia Lupus Registry, multicenter dermatology clinics, community practices, and self-referrals. The Patient-Reported Outcomes Measurement Information System (PROMIS) was used to measure the primary outcome: depressive symptoms. Stand-alone questions were used to assess sociodemographics and healthcare utilization. Emotional, informational, and instrumental support were measured with PROMIS short forms, interpersonal processes of care with the IPC-29 survey, and skin-related quality of life with the Skindex-29+ tool. RESULTS: Of 106 patients, 92 (86.8%) were female, 91 (85.8%) were Black, 45 (42.9%) were unemployed or disabled, and 28 (26.4%) reported moderate to severe depressive symptoms. Depression severity was lower in patients who were aged ≥ 60 years, were married, or had graduated from college. Univariate analysis showed that being employed (odds ratio [OR] 0.24; 95% confidence interval [CI] 0.10-0.61), insured (OR 0.23; 95% CI 0.09-0.60), reporting higher instrumental, informational, and emotional support (OR 0.75; 95% CI 0.60-0.94; OR 0.62; 95% CI 0.49-0.78; and OR 0.48; 95% CI 0.35-0.65, respectively), visiting a primary care physician in the last year (OR 0.16; 95% CI 0.04-0.61) and reporting better physician-patient interactions (OR 0.56; 95% CI 0.37-0.87) were negatively associated with depression. Patient's perception of staff disrespect (OR 2.30; 95% CI 1.19-4.47) and worse skin-related quality of life (OR 1.04; 95% CI 1.02-1.06) rendered higher risk. In multivariate analysis, only perception of staff disrespect (OR 2.35; 95% CI 1.06-5.17) and lower emotional support (OR 0.48; 95% CI 0.35-0.66) remained associated with depression. CONCLUSION: Over one-quarter of a predominantly Black population-based cohort of individuals with primary CCLE reported moderate to severe depression, a rate three to five times higher than described previously in the general population from the same metropolitan Atlanta area. Our findings suggest that, while patient's perception of discrimination in the healthcare setting may play a role as a determinant of depression, social support may be protective. In addition to routine mental health screening and depression treatment, interventions directed at providing emotional support and improving office staff interpersonal interactions may contribute to reduce the risk of depression in patients with CCLE.

Replicative DNA polymerase δ but not ε proofreads errors in Cis and in Trans.

It is now well established that in yeast, and likely most eukaryotic organisms, initial DNA replication of the leading strand is by DNA polymerase ε and of the lagging strand by DNA polymerase δ. However, the role of Pol δ in replication of the leading strand is uncertain. In this work, we use a reporter system in Saccharomyces cerevisiae to measure mutation rates at specific base pairs in order to determine the effect of heterozygous or homozygous proofreading-defective mutants of either Pol ε or Pol δ in diploid strains. We find that wild-type Pol ε molecules cannot proofread errors created by proofreading-defective Pol ε molecules, whereas Pol δ can not only proofread errors created by proofreading-defective Pol δ molecules, but can also proofread errors created by Pol ε-defective molecules. These results suggest that any interruption in DNA synthesis on the leading strand is likely to result in completion by Pol δ and also explain the higher mutation rates observed in Pol δ-proofreading mutants compared to Pol ε-proofreading defective mutants. For strains reverting via AT→GC, TA→GC, CG→AT, and GC→AT mutations, we find in addition a strong effect of gene orientation on mutation rate in proofreading-defective strains and demonstrate that much of this orientation dependence is due to differential efficiencies of mispair elongation. We also find that a 3'-terminal 8 oxoG, unlike a 3'-terminal G, is efficiently extended opposite an A and is not subject to proofreading. Proofreading mutations have been shown to result in tumor formation in both mice and humans; the results presented here can help explain the properties exhibited by those proofreading mutants.

Primary preventive services in patients with systemic lupus erythematosus: study from a population-based sample in Southeast U.S.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients are at risk for complications that can be mitigated by appropriate preventive care. We examined the receipt of immunizations, cancer screening, and cardiovascular risk preventive services in a predominantly Black cohort of SLE patients from the Southeast U.S. To identify gaps in primary preventive services (PPS) that might be specific to SLE as opposed to local health system factors, we used as reference a population-based sample from the same area. METHODS: A cross-sectional design was used to characterize the percentage of PPS received by 751 SLE patients from Atlanta, GA, and 9040 subjects from the same community, of whom 938 had diabetes. Factors associated with the receipt of PPS were examined with multivariable analysis of variance. RESULTS: Approximately 65% of recommended PPS were provided to the SLE, overall community (OC), and diabetes samples. However, only 22.5%, 45.7%, and 27.6% of SLE, OC, and diabetes subjects, respectively, received all recommended services. Factors associated with a higher percentage of PPS received by SLE patients included older age (63.6% if age ≥65 years, 45.8% if age between 18 and 35 years), having medical insurance (61.1% for insured, 49.7% for uninsured), having a primary care physician (PCP) (59.0% if patient had PCP, 51.8% if patient did not have PCP), and being a non-smoker (61.9% for non-smokers, 49.9% for smokers). CONCLUSIONS: Less than one-quarter of SLE patients from a southeast U.S. community received all the recommended services that were studied. Further research is warranted to unravel the barriers that prevent SLE patients from reaching appropriate standards of preventive care.

Mismatch repair-dependent mutagenesis in nondividing cells.

Mismatch repair (MMR) is a major DNA repair pathway in cells from all branches of life that removes replication errors in a strand-specific manner, such that mismatched nucleotides are preferentially removed from the newly replicated strand of DNA. Here we demonstrate a role for MMR in helping create new phenotypes in nondividing cells. We show that mispairs in yeast that escape MMR during replication can later be subject to MMR activity in a replication strand-independent manner in nondividing cells, resulting in either fully wild-type or mutant DNA sequence. In one case, this activity is responsible for what appears to be adaptive mutation. This replication strand-independent MMR activity could contribute to the formation of tumors arising in nondividing cells and could also contribute to mutagenesis observed during somatic hypermutation of Ig genes.

Cigarette smoke induces DNA damage and alters base-excision repair and tau levels in the brain of neonatal mice.

The prenatal and perinatal periods of brain development are especially vulnerable to insults by environmental agents. Early life exposure to cigarette smoke (CS), which contains both genotoxicants and oxidants, is considered an important risk factor for both neurodevelopmental and neurodegenerative disorders. Yet, little is known regarding the underlying pathogenetic mechanisms. In the present study, neonatal Swiss ICR (CD-1) albino mice were exposed to various concentrations of CS for 4 weeks and the brain examined for lipid peroxides, DNA damage, base-excision repair (BER) enzymes, apoptosis, and levels of the microtubule protein tau. CS induced a dose-dependent increase in both malondialdehyde and various types of DNA damage, including single-strand breaks, double-strand breaks, and DNA-protein cross-links. However, the CS-induced DNA damage in the brain returned to basal levels 1 week after smoking cessation. CS also modulated the activity and distribution of the BER enzymes 8-oxoguanine-DNA-glycosylase (OGG1) and apyrimidinic/apurinic endonuclease (APE1) in several brain regions. Normal tau (i.e., three-repeat tau, 3R tau) and various pathological forms of tau were also measured in the brain of CS-exposed neonatal mice, but only 3R tau and tau phosphorylated at serine 199 were significantly elevated. The oxidative stress, genomic dysregulation, and alterations in tau metabolism caused by CS during a critical period of brain development could explain why CS is an important risk factor for both neurodevelopmental and neurodegenerative disorders appearing in later life.