Current Insights Into K-associated Fetal Anemia and Potential Treatment Strategies for Sensitized Pregnancies.

K-associated anemic disease of the fetus and newborn (K-ADFN) is a rare but life-threatening disease in which maternal alloantibodies cross the placenta and can mediate an immune attack on fetal red blood cells expressing the K antigen. A considerably more common disease, D-associated hemolytic disease of the fetus and newborn (D-HDFN), can be prophylactically treated using polyclonal α-D antibody preparations. Currently, no such prophylactic treatment exists for K-associated fetal anemia, and disease is usually treated with intrauterine blood transfusions. Here we review current understanding of the biology of K-associated fetal anemia, how the maternal immune system is sensitized to fetal red blood cells, and what is understood about potential mechanisms of prophylactic HDFN interventions. Given the apparent challenges associated with preventing alloimmunization, we highlight novel strategies for treating sensitized mothers to prevent fetal anemia that may hold promise not only for K-mediated disease, but also for other pathogenic alloantibody responses.

Sacubitril/valsartan vs ACEi/ARB at hospital discharge and 5-year survival in older patients with heart failure with reduced ejection fraction: A decision analysis approach.

BACKGROUND: In clinical trials, sacubitril/valsartan has demonstrated significant survival benefits compared to angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB). Whether older patients with heart failure with reduced ejection fraction (HFrEF) benefit as much, due to higher rates of comorbidities, frailty and drug discontinuation, is unknown. METHODS AND RESULTS: Using a cohort of Medicare beneficiaries hospitalized with HFrEF between 2016 and 2018, we determined all-cause mortality and HF-readmission rates among patients not given ACEi/ARB or sacubitril/valsartan at hospital discharge, by age. We then used risk reductions from the SOLVD, PARADIGM-HF and PIONEER-HF trials to estimate the benefits of ACEi/ARB and sacubitril/valsartan. We then incorporated age-specific estimates of drug discontinuation from Medicare. A Markov decision process model was used to simulate 5-year survival and estimate number needed to treat, comparing discharge on ACEi/ARB vs sacubitril/valsartan by age. After accounting for drug discontinuation rates, which were surprisingly slightly higher among those discharged on ACEi/ARB (2.3%/month vs 1.9%/month), there was a small but significant survival advantage to discharge on sacubitril/valsartan over 5 years (+0.81 months [95% CI 0.80, 0.81]). The benefit of sacubitril/valsartan over ACEi/ARB did not decrease with increasing age - the number needed to treat among 66 to 74-year-old patients was 84 and among 85+ year-old patients was 67. CONCLUSIONS: Even after accounting for "real world" rates of drug discontinuation, discharge on sacubitril/valsartan after conferred a small, but significant, survival advantage which does not appear to wane with increasing age.

Rural-Urban Differences in Breast Cancer Surgical Delays in Medicare Beneficiaries.

BACKGROUND: Delays between breast cancer diagnosis and surgery are associated with worsened survival. Delays are more common in urban-residing patients, although factors specific to surgical delays among rural and urban patients are not well understood. METHODS: We used a 100% sample of fee-for-service Medicare claims during 2007-2014 to identify 238,491 women diagnosed with early-stage breast cancer undergoing initial surgery and assessed whether they experienced biopsy-to-surgery intervals > 90 days. We employed multilevel regression to identify associations between delays and patient, regional, and surgeon characteristics, both in combined analyses and stratified by rurality of patient residence. RESULTS: Delays were more prevalent among urban patients (2.5%) than rural patients (1.9%). Rural patients with medium- or high-volume surgeons had lower odds of delay than patients with low-volume surgeons (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.58-0.88; OR = 0.74, 95% CI = 0.61-0.90). Rural patients whose surgeon operated at ≥ 3 hospitals were more likely to experience delays (OR = 1.29, 95% CI = 1.01-1.64, Ref: 1 hospital). Patient driving times ≥ 1 h were associated with delays among urban patients only. Age, black race, Hispanic ethnicity, multimorbidity, and academic/specialty hospital status were associated with delays. CONCLUSIONS: Sociodemographic, geographic, surgeon, and facility factors have distinct associations with > 90-day delays to initial breast cancer surgery. Interventions to improve timeliness of breast cancer surgery may have disparate impacts on vulnerable populations by rural-urban status.

Surgeon and medical oncologist peer network effects on the uptake of the 21-gene breast cancer recurrence score assay.

BACKGROUND: Drivers behind the adoption of gene expression profiling in breast cancer oncology have been shown to include exposure to physician colleagues' use of a given genomic test. We examined adoption of the Oncotype DX 21-gene breast cancer recurrence score assay (ODX) in the United States after its incorporation into clinical guidelines. The influence of patient-sharing ties and co-location with prior adopters and the role of these potential exposures across medical specialties on peers' adoption of the test were examined. METHODS: We conducted a retrospective cohort study of women with incident breast cancer using a 100% sample of fee-for-service Medicare enrollee claims over 2008-2011. Peer networks connecting medical oncologists and surgeons treating these patients were constructed using patient-sharing and geographic co-location. The impact of peer connections on the adoption of ODX by physicians and testing of patients was modeled with multivariable hierarchical regression. RESULTS: Altogether, 156,229 women identified with incident breast cancer met criteria for cohort inclusion. A total of 7689 ODX prescribing physicians were identified. Co-location with medical oncologists who adopted the test in the early period (2008-2009) was associated with a 1.38-fold increase in the odds of a medical oncologist adopting ODX in 2010-2011 (95% CI = 1.04-1.83), as was co-location with early-adopting surgeons (odds ratio [OR] = 1.25, 95% CI = 1.00-1.58). Patients whose primary medical oncologist was linked to an early-adopting surgeon through co-location (OR = 1.17, 95% CI = 1.04-1.32) or both patient-sharing and co-location (OR = 1.17, 95% CI = 1.03-1.34) were more likely to receive ODX. CONCLUSIONS: Exposure to surgeon early adopters through peer networks and co-location was predictive of ODX uptake by medical oncologists and testing of patients. Interventions focused on the role of surgeons in molecular testing may improve the implementation of best practices in breast cancer care.

Patient and physician factors associated with Oncotype DX and adjuvant chemotherapy utilization for breast cancer patients in New Hampshire, 2010-2016.

BACKGROUND: Oncotype DX® (ODX) is used to assess risk of disease recurrence in hormone receptor positive, HER2-negative breast cancer and to guide decisions regarding adjuvant chemotherapy. Little is known about how physician factors impact treatment decisions. The purpose of this study was to examine patient and physician factors associated with ODX testing and adjuvant chemotherapy for breast cancer patients in New Hampshire. METHODS: We examined New Hampshire State Cancer Registry data on 5630 female breast cancer patients diagnosed from 2010 to 2016. We performed unadjusted and adjusted hierarchical logistic regression to identify factors associated with a patient's receipt of ODX, being recommended and receiving chemotherapy, and refusing chemotherapy. We calculated intraclass correlation coefficients (ICCs) to examine the proportion of variance in clinical decisions explained by between-physician and between-hospital variation. RESULTS: Over the study period, 1512 breast cancer patients received ODX. After adjustment for patient and tumor characteristics, we found that patients seen by a male medical oncologist were less likely to be recommended chemotherapy following ODX (OR = 0.50 (95% CI = 0.34-0.74), p < 0.01). Medical oncologists with more clinical experience (reference: less than 10 years) were more likely to recommend chemotherapy (20-29 years: OR = 4.05 (95% CI = 1.57-10.43), p < 0.01; > 29 years: OR = 4.48 (95% CI = 1.68-11.95), p < 0.01). A substantial amount of the variation in receiving chemotherapy was due to variation between physicians, particularly among low risk patients (ICC = 0.33). CONCLUSIONS: In addition to patient clinicopathologic characteristics, physician gender and clinical experience were associated with chemotherapy treatment following ODX testing. The significant variation between physicians indicates the potential for interventions to reduce variation in care.

Inducible Germline IgMs Bridge Trypanosome Lytic Factor Assembly and Parasite Recognition.

Trypanosomiasis is a devastating neglected tropical disease affecting livestock and humans. Humans are susceptible to two Trypanosoma brucei subspecies but protected from other trypanosomes by circulating high-density lipoprotein (HDL) complexes called trypanosome lytic factors (TLFs) 1 and 2. TLFs contain apolipoprotein L-1 contributing to lysis and haptoglobin-related protein (HPR), which can function as a ligand for a parasite receptor. TLF2 also uniquely contains non-covalently associated immunoglobin M (IgM) antibodies, the role and origin of which remain unclear. Here, we show that these TLF2-associated IgMs interact with both HPR and alternate trypanosome surface proteins, including variant surface glycoprotein, likely facilitating complex biogenesis and TLF uptake into parasites. TLF2-IgMs are germline antibodies that, while present at basal concentrations in healthy individuals, are elicited by trypanosome infection in both murine models and human sleeping sickness patients. These data suggest that poly- and self-reactive germline antibodies such as TLF2-associated IgMs play a role in antimicrobial immunity.