Secondary structure forming sequences drive SD-MMEJ repair of DNA double-strand breaks.

Alternative end-joining (alt-EJ) repair of DNA double-strand breaks is associated with deletions, chromosome translocations, and genome instability. Alt-EJ frequently uses annealing of microhomologous sequences to tether broken ends. When accessible pre-existing microhomologies do not exist, we have postulated that new microhomologies can be created via limited DNA synthesis at secondary-structure forming sequences. This model, called synthesis-dependent microhomology-mediated end joining (SD-MMEJ), predicts that differences between DNA sequences near double-strand breaks should alter repair outcomes in predictable ways. To test this hypothesis, we injected plasmids with sequence variations flanking an I-SceI endonuclease recognition site into I-SceI expressing Drosophila embryos and used Illumina amplicon sequencing to compare repair junctions. As predicted by the model, we found that small changes in sequences near the I-SceI site had major impacts on the spectrum of repair junctions. Bioinformatic analyses suggest that these repair differences arise from transiently forming loops and hairpins within 30 nucleotides of the break. We also obtained evidence for 'trans SD-MMEJ,' involving at least two consecutive rounds of microhomology annealing and synthesis across the break site. These results highlight the importance of sequence context for alt-EJ repair and have important implications for genome editing and genome evolution.

Gout in Native Hawaiian Patients in Hawai'i: Clinical Characteristics and Disparities.

OBJECTIVE: The purpose of this study was to investigate differences in clinical characteristics and health care use of Native Hawaiian and White patients with gout. METHODS: We performed a retrospective chart review of Native Hawaiian and White patients with gout treated from 2011 to 2017 within a large health care system in Hawai'i. We compared demographic characteristics, clinical outcomes, and risk factors for gout. We used multivariable logistic regression to identify predictive factors of emergency department visits. RESULTS: We identified 270 Native Hawaiian patients with gout and 239 White patients with gout. The Native Hawaiian patients were younger on average (54.0 vs 64.0 years; P < 0.0001) and had an earlier onset of disease (50.0 vs 57.0 years; P < 0.0001). Native Hawaiian patients with gout had higher mean (7.58 vs 6.87 mg/dL; P < 0.0001) and maximum (10.30 vs 9.50 mg/dL; P < 0.0001) serum urate levels compared to White patients with gout. Native Hawaiian patients with gout also had a greater number of tophi (median 2.00 vs 1.00; P < 0.0001). Native Hawaiians patients with gout were 2.7 times more likely to have frequent (≥1) emergency department visits than White patients with gout. Native Hawaiian patients with gout were less likely to have a therapeutic serum urate ≤6.0 mg/dL and had lower rates of rheumatology specialty care. CONCLUSION: Native Hawaiian patients have a higher disease burden of gout, with earlier disease onset and more tophi. Native Hawaiian patients with gout are more likely to use emergency services for gout and have lower rates of rheumatology specialty care compared to White patients. Future studies are needed to promote culturally appropriate preventive care and management of gout in Native Hawaiians.

The impact of COVID-19 on cancer screening and treatment in older adults: The Multiethnic Cohort Study.

Background: The Coronavirus Disease of 2019 (COVID-19) has impacted the health and day-to-day life of individuals, especially the elderly and people with certain pre-existing medical conditions, including cancer. The purpose of this study was to investigate how COVID-19 impacted access to cancer screenings and treatment, by studying the participants in the Multiethnic Cohort (MEC) study. Methods: The MEC has been following over 215,000 residents of Hawai'i and Los Angeles for the development of cancer and other chronic diseases since 1993-1996. It includes men and women of five racial and ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and White. In 2020, surviving participants were sent an invitation to complete an online survey on the impact of COVID-19 on their daily life activities, including adherence to cancer screening and treatment. Approximately 7,000 MEC participants responded. A cross-sectional analysis was performed to investigate the relationships between the postponement of regular health care visits and cancer screening procedures or treatment with race and ethnicity, age, education, and comorbidity. Results: Women with more education, women with lung disease, COPD, or asthma, and women and men diagnosed with cancer in the past 5 years were more likely to postpone any cancer screening test/procedure due to the COVID-19 pandemic. Groups less likely to postpone cancer screening included older women compared to younger women and Japanese American men and women compared to White men and women. Conclusions: This study revealed specific associations of race/ethnicity, age, education level, and comorbidities with the cancer-related screening and healthcare of MEC participants during the COVID-19 pandemic. Increased monitoring of patients in high-risk groups for cancer and other diseases is of the utmost importance as the chance of undiagnosed cases or poor prognosis is increased as a result of delayed screening and treatment. Funding: This research was partially supported by the Omidyar 'Ohana Foundation and grant U01 CA164973 from the National Cancer Institute.

Cancer Health Disparities Research Training: A Qualitative Report.

The Research Education Core of the Pacific Islands Partnership for Cancer Health Equity (PIPCHE) conducted a systematic review of participant learning. All students from both the University of Guam and the University of Hawai'i who have completed the program were asked two open-ended questions, which were then thematically analyzed. (1) What impact did the training have on your career? (2) What did you learn about cancer health disparities? Findings include themes such as expanding social networks, building professional skills, providing opportunities and funding, inspiring a future career in research, and giving back to the community. The results also indicate that students learned that cancer disparities research was complex and diverse, required cultural sensitivity, different areas of cancer research and education, the importance of mentor and peer relationships. Trainees spoke very favorably about the weekly seminar format. These findings are consistent with studies in other similar programs. The authors recommend future educational outcome research.

Subcutaneous immunoglobulin therapy in statin-induced necrotizing autoimmune myopathy.

We report a case of statin-associated necrotising autoimmune myopathy successfully treated with subcutaneous immunoglobulin therapy (SCIG) monotherapy without corticosteroids. This is a 51-year old female with seronegative rheumatoid arthritis, who had been on statins for several years, who developed proximal muscle weakness and elevated creatine kinase after resuming her statin post sleeve gastrectomy for weight loss. Our patient had a history of severe side effects to prednisone. She did not respond to mycophenolate, cyclophosphamide, and rituximab treatment. She had responded to partial treatment with intravenous immunoglobulin (IVIG) but had a severe headache after IVIG infusion. IVIG treatment was discontinued. We tried SCIG treatment, and she was able to tolerate the SCIG treatment with intermittent headaches that were less intense. After treatment with SCIG, creatine kinase levels decreased significantly, with an improvement of muscle strength. She continues to do well on SCIG treatment. To our knowledge, no other cases of statin-associated necrotising autoimmune myopathy treated with SCIG have been reported in the literature. More studies and reports are needed to confirm the utility and efficacy of SCIG in statin-associated necrotising autoimmune myopathy, as well as to provide information about dosing, tolerability, and durability of SCIG in the treatment of statin-associated necrotising autoimmune myopathy.

Patterns of health care utilization of gout patients in Hawai'i-high rates of emergency department utilization as compared to rheumatoid arthritis.

Recent and comprehensive research of gout in the Pacific region and Hawai'i is significantly lacking. This study was conducted to improve the understanding of the healthcare utilization of gout patients within a single health care system in Hawai'i. The objective was to examine gout inpatient, outpatient and emergency department care within a single health care system in Hawai'i. This study was a retrospective chart review of patients, ≥ 18 years admitted to three Hawai'i Pacific Health facilities for a primary diagnosis of gout or rheumatoid arthritis (RA) from 2011 to 2017. Population data for the State of Hawai'i was used to calculate visit rates per 1,000 Hawai'i adults. Trend analysis was performed to compare changes over time. We studied gout health care utilization concurrently with RA to provide an internal comparison group for the healthcare utilization patterns of interest. Gout patients were primarily managed in the outpatient setting with high rates of emergency department visits. In contrast, RA patients were primarily managed in the outpatient setting, with low rates of emergency department visits. Both gout and RA patients had low rates of inpatient admissions. The cost of gout emergency department visits was approximately 3.4 times higher than gout outpatient visits. The rates for gout emergency department visits, outpatient visits, inpatients visits, and RA outpatient visits in 2017 were trending downward and significantly changed from 2011 (p <0.05). The rates for RA emergency department visits and inpatient visits were not significantly changed from 2011-2017. Gout care in Hawai'i remains suboptimal with higher rates of emergency department visits, as compared to RA. Because emergency department visits are associated with higher cost, efforts should be made to reduce these emergency department visits to improve the quality of care.