Objective To evaluate seroreactivity and disease flares after COVID‐19 vaccination in a multi‐ethnic/racial cohort of patients with systemic lupus erythematosus (SLE). Methods 90 SLE patients and 20 healthy controls receiving a complete COVID‐19 vaccine regimen were included. IgG seroreactivity to the SARS‐CoV‐2 spike receptor‐binding domain (RBD) and SARS‐CoV‐2 microneutralization were used to evaluate B cell responses; IFN‐γ production to assess T cell responses was measured by ELISpot. Disease activity was measured by the hybrid SLE disease activity index (SLEDAI) and flares were assigned by the SELENA/SLEDAI flare index. Results Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS‐CoV‐2 spike RBD than controls. Twenty‐six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti‐dsDNA level prior to vaccination associated with decreased vaccine responses. IgG seroreactivity to the SARS‐CoV‐2 Spike RBD strongly correlated with the SARS‐CoV‐2 microneutralization titers and antigen‐specific IFN‐γ production determined by ELISpot. In a subset of patients with poor antibody responses, IFN‐γ production was likewise diminished. Pre‐/post‐vaccination SLEDAI scores were similar. Only 11.4% of patients had a post‐vaccination flare; 1.3% were severe. Conclusion In a multi‐ethnic/racial study of SLE patients 29% had a low response to the COVID‐19 vaccine which was associated with being on immunosuppression. Reassuringly, disease flares were rare. While minimal protective levels remain unknown, these data suggest protocol development is needed to assess efficacy of booster vaccination.

Adiposity is an established risk factor for postmenopausal breast cancer. Recent data suggest that high insulin levels in overweight women may play a major role in this relationship, due to insulin’s mitogenic/anti-apoptotic activity. However, whether overweight women who are metabolically healthy (i.e. normal insulin sensitivity) have elevated risk of breast cancer is unknown. We investigated whether overweight women with normal insulin sensitivity (i.e., homeostasis model assessment of insulin resistance [HOMA-IR] index, or fasting insulin level, within the lowest quartile [q1]) have increased breast cancer risk. Subjects were incident breast cancer cases (N=497) and a subcohort (N=2,830) of Women’s Health Initiative (WHI) participants with available fasting insulin and glucose levels. In multivariate Cox models, metabolically healthy overweight women, defined using HOMA-IR, were not at elevated risk of breast cancer compared to metabolically healthy normal weight women (hazard ratio [HR]HOMA-IR=0.96; 95% confidence interval [CI],0.64-1.42). In contrast, the risk among women with high (q3-4) HOMA-IRs was elevated whether they were overweight (HRHOMA-IR=1.76; 95% CI,1.19-2.60) or normal weight (HRHOMA-IR=1.80; 95% CI,0.88-3.70). Similarly, using fasting insulin to define metabolic health, metabolically unhealthy women (insulin q3-4) were at higher risk of breast cancer regardless of whether they were normal weight (HRinsulin=2.06; 95% CI,1.01-4.22) or overweight (HRinsulin=2.01; 95% CI,1.35-2.99), whereas metabolically healthy overweight women did not have significantly increased risk of breast cancer (HRinsulin=0.96; 95% CI,0.64-1.42) relative to metabolically healthy normal weight women. Metabolic health (e.g., HOMA-IR or fasting insulin) may be more biologically relevant and more useful for breast cancer risk stratification, than adiposity per se.

Objective To estimate the impact of HIV infection on the incidence of high grade cervical intraepithelial neoplasia (CIN). Study Design HIV seropositive and comparison seronegative women enrolled in a prospective U.S. cohort study were followed with semiannual Pap testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using Cox analysis. Median follow-up (IQR) was 11.0 (5.4–17.2) years for HIV seronegative and 9.9 (2.5–16.0) for HIV seropositive women. Results CIN3+ was diagnosed in 139 (5%) HIV seropositive and 19 (2%) seronegative women (P < 0.0001), with CIN2+ in 316 (12%) and 34 (4%) (P < 0.0001). The annual CIN3+ detection rate was 0.6/100 person-years in HIV seropositive women and 0.2/100 person years in seronegative women (P < 0.0001). The CIN3+ detection rate fell after the first two years of study, from 0.9/100 person-years among HIV seropositive women to 0.4/100 person-years during subsequent follow-up (P < 0.0001). CIN2+ incidence among these women fell similarly with time, from 2.5/100 person-years during the first two years after enrollment to 0.9/100 person-years subsequently (p < 0.0001). In Cox analyses controlling for age, the hazard ratio for HIV seropositive women with CD4 counts <200/cmm compared to HIV seronegative women was 8.1 (95% C.I. 4.8, 13.8) for CIN3+ and 9.3 (95% C.I. 6.3, 13.7) for CIN2+ (P < 0.0001). Conclusion Although HIV seropositive women have more CIN3+ than seronegative women, CIN3+ is uncommon and becomes even less frequent after initiation of regular cervical screening.

BackgroundCase-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess the assumption of proportional hazards of case-cohort Cox models have been proposed.MethodsWe extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define “case-cohort Schoenfeld residuals”, and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer.ResultsSimulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches.ConclusionsThe proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.

L. crispatus may have a beneficial effect on the burden of HPV in both HIV-infected and HIV-uninfected women (independent of pH).