Acetazolamide Challenge Changes Outer Retina Bioenergy-Linked and Anatomical OCT Biomarkers Depending on Mouse Strain.

Purpose: The purpose of this study was to test the hypothesis that optical coherence tomography (OCT) bioenergy-linked and anatomical biomarkers are responsive to an acetazolamide (ACZ) provocation. Methods: C57BL/6J mice (B6J, a strain with relatively inefficient mitochondria) and 129S6/ev mice (S6, a strain with relatively efficient mitochondria) were given a single IP injection of ACZ (carbonic anhydrase inhibitor) or vehicle. In each mouse, the Mitochondrial Configuration within Photoreceptors based on the profile shape Aspect Ratio (MCP/AR) index was determined from the hyper-reflective band immediately posterior to the external limiting membrane (ELM). In addition, we tested for ACZ-induced acidification by measuring contraction of the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness; the hyporeflective band (HB) signal intensity at the photoreceptor tips was also examined. Finally, the nuclear layer thickness was measured. Results: In response to ACZ, MCP/AR was greater-than-vehicle in B6J mice and lower-than-vehicle in S6 mice. ACZ-treated B6J and S6 mice both showed ELM-RPE contraction compared to vehicle-treated mice, consistent with dehydration in response to subretinal space acidification. The HB intensity at the photoreceptor tips and the outer nuclear layer thickness (B6J and S6), as well as the inner nuclear layer thickness of B6J mice, were all lower than vehicle following ACZ. Conclusions: Photoreceptor respiratory efficacy can be evaluated in vivo based on distinct rod mitochondria responses to subretinal space acidification measured with OCT biomarkers and an ACZ challenge, supporting and extending our previous findings measured with light-dark conditions.

The Be REAL Framework: Enhancing Relationship-Building Skills for Community Health Workers.

Trust plays an integral part in the effective functioning of public health systems. During the COVID-19 pandemic, distrust of public health fueled vaccine hesitancy and created additional barriers to immunization. Although most Americans have received at least one COVID-19 vaccine, the percentage of fully immunized adults remains suboptimal. To reach vaccine-hesitant communities, it is vital that public health be worthy of trust. As trusted members of their communities, community health workers (CHWs) can serve as ideal messengers and conversation partners for vaccination decision-making. We developed the Be REAL framework and training materials to prepare CHWs to work with vaccine-hesitant communities nationwide. Through the four steps of "Relate," "Explore," "Assist," and "Leave (the door open)," CHWs were taught to prioritize relationship building as a primary goal. In this shift from focusing on adherence to public health recommendations (e.g., get vaccinated) to building relationships, the value of vaccine uptake is secondary to the quality of the relationship being formed. The Be REAL framework facilitates CHWs harnessing the power they already possess. The goal of the Be REAL framework is to foster true partnership between CHWs and community members, which in turn can help increase trust in the broader public health system beyond adherence to a specific recommendation.

Do multiple physiological OCT biomarkers indicate age-related decline in rod mitochondrial function in C57BL/6J mice?

Purpose: To test the hypothesis that rod photoreceptor mitochondria function in vivo progressively declines over time. Methods: 2, 12, and 24 month-old dark- and light-adapted C57BL/6J (B6J) mice were examined by OCT. We measured (i) an index of mitochondrial configuration within photoreceptors measured from the profile shape aspect ratio (MCP/AR) of the hyperreflective band posterior to the external limiting membrane (ELM), (ii) a proxy for energy-dependent pH-triggered water removal, the thickness of the ELM-retinal pigment epithelium (ELM-RPE), and its correlate (iii) the hyporeflective band (HB) signal intensity at the photoreceptor tips. Visual performance was assessed by optokinetic tracking. Results: In 2 and 24 month-old mice, MCP/AR in both inferior and superior retina was smaller in light than in dark; no dark-light differences were noted in 12 month-old mice. Dark-adapted inferior and superior, and light-adapted superior, ELM-RPE thickness increased with age. The dark-light difference in ELM-RPE thickness remained constant across all ages. All ages showed a decreased HB signal intensity magnitude in dark relative to light. In 12 month-old mice, the dark-light difference in HB magnitude was greater than in younger and older mice. Anatomically, outer nuclear layer thickness decreased with age. Visual performance indices were reduced at 24 month-old compared to 2 month-old mice. Conclusion: While the working hypothesis was not supported herein, the results raise the possibility of a mid-life adaptation in rod mitochondrial function during healthy aging in B6J mice based on OCT biomarkers, a plasticity that occurred prior to declines in visual performance.

Multiple Bioenergy-Linked OCT Biomarkers Suggest Greater-Than-Normal Rod Mitochondria Activity Early in Experimental Alzheimer's Disease.

Purpose: In Alzheimer's disease, central brain neurons show evidence for early hyperactivity. It is unclear if this occurs in the retina, another disease target. Here, we tested for imaging biomarker manifestation of prodromal hyperactivity in rod mitochondria in vivo in experimental Alzheimer's disease. Methods: Light- and dark-adapted 4-month-old 5xFAD and wild-type (WT) mice, both on a C57BL/6J background, were studied with optical coherence tomography (OCT). We measured the reflectivity profile shape of the inner segment ellipsoid zone (EZ) as a proxy for mitochondria distribution. Two additional indices responsive to mitochondria activity were also measured: the thickness of the external limiting membrane-retinal pigment epithelium (ELM-RPE) region and the signal magnitude of a hyporeflective band (HB) between photoreceptor tips and apical RPE. Retinal laminar thickness and visual performance were evaluated. Results: In response to low energy demand (light), WT mice showed the expected elongation in EZ reflectivity profile shape, relatively thicker ELM-RPE, and greater HB signal. Under high energy demand (dark), the EZ reflectivity profile shape was rounder, the ELM-RPE was thinner, and the HB was reduced. These OCT biomarker patterns for light-adapted 5xFAD mice did not match those of light-adapted WT mice but rather that of dark-adapted WT mice. Dark-adapted 5xFAD and WT mice showed the same biomarker pattern. The 5xFAD mice exhibited modest nuclear layer thinning and lower-than-normal contrast sensitivity. Conclusions: Results from three OCT bioenergy biomarkers raise the novel possibility of early rod hyperactivity in vivo in a common Alzheimer's disease model.

Factors Affecting SARS-CoV-2 Vaccination Intent and Decision Making Among African American, Native American, and Hispanic Participants in a Qualitative Study.

Limited studies are available on how decisions and perceptions on SARS-CoV-2 vaccination have changed since the start of vaccination availability. We performed a qualitative study to identify factors critical to SARS-CoV-2 vaccination decision making and how perspectives evolved among African American/Black, Native American, and Hispanic communities disproportionately affected by COVID-19 and social and economic disadvantage. We conducted 16 virtual meetings, with 232 participants in wave 1 meetings (December 2020) and with 206 returning participants in wave 2 meetings (January and February 2021). Wave 1 vaccine concerns in all communities included information needs, vaccine safety, and speed of vaccine development. Lack of trust in government and the pharmaceutical industry was influential, particularly among African American/Black and Native American participants. Participants showed more willingness to get vaccinated at wave 2 than at wave 1, indicating that many of their information needs had been addressed. Hesitancy remained greater among African American/Black and Native American participants than among Hispanic participants. Participants in all groups indicated that conversations tailored to their community and with those most trustworthy to them would be helpful. To overcome vaccine hesitancy, we propose a model of fully considered SARS-CoV-2 vaccine decision making, whereby public health departments supply information, align with community values and recognize lived experiences, offer support for decision making, and make vaccination easy and convenient.

Transducin-Deficient Rod Photoreceptors Evaluated With Optical Coherence Tomography and Oxygen Consumption Rate Energy Biomarkers.

Purpose: To test the hypothesis that rod energy biomarkers in light and dark are similar in mice without functional rod transducin (Gnat1rd17). Methods: Gnat1rd17 and wildtype (WT) mice were studied in canonically low energy demand (light) and high energy demand (dark) conditions. We measured rod inner segment ellipsoid zone (ISez) profile shape, external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness, and magnitude of a hyporeflective band (HB) intensity dip located between photoreceptor tips and apical RPE; antioxidants were given in a subset of mice. Oxygen consumption rate (OCR) and visual performance indexes were also measured. Results: The lower energy demand expected in light-adapted wildtype retinas was associated with an elongated ISez, thicker ELM-RPE, and higher HB magnitude, and lower OCR compared to high energy demand conditions in the dark. Gnat1rd17 mice showed a wildtype-like ISez profile shape at 20 minutes of light that became rounder at 60 minutes; at both times, ELM-RPE was smaller than wildtype values, and the HB magnitude was unmeasurable. OCR was higher than in the dark. Light-adapted Gnat1rd17 mice biomarkers were unaffected by anti-oxidants. Gnat1rd17 mice showed modest outer nuclear layer thinning and no reduction in visual performance indexes. Conclusions: Light-stimulated changes in all biomarkers in WT mice are consistent with the established light-induced decrease in net energy demand. In contrast, biomarker changes in Gnat1rd17 mice raise the possibility that light increases net energy demand in the absence of rod phototransduction.

IRONMAN: A Novel International Registry of Men With Advanced Prostate Cancer.

PURPOSE: To describe a newly established international registry recruiting diverse patients with advanced prostate cancer across academic and community practices to address unmet needs in this population. PATIENTS AND METHODS: Initiated in 2017, IRONMAN (International Registry for Men with Advanced Prostate Cancer) is a prospective cohort of patients with advanced prostate cancer. The study will enroll 5,000 patients with metastatic hormone-sensitive prostate cancer (mHSPC) or castration-resistant prostate cancer (CRPC), recruited from Australia, the Bahamas, Barbados, Brazil, Canada, Ireland, Jamaica, Kenya, Nigeria, Norway, South Africa, Spain, Sweden, Switzerland, the United Kingdom, and the United States. The study is collecting datatypes to study variation in care and treatment of advanced prostate cancer across countries and across academic, community-based, and government practices with a focus on clinical outcomes, patient-reported outcomes, epidemiologic data, biologic subtypes, and clinician questionnaires. RESULTS: Through July 2022, 2,682 eligible patients were enrolled in 11 of 12 active countries. Sixty-six percent of patients have mHSPC, and 34% have CRPC. On the basis of self-report, 11% of patients are Black and 9% are Hispanic. Five Veterans Affairs Medical Centers are enrolling patients. Globally, 23% of patients report being veterans of military service. CONCLUSION: To our knowledge, this is the first international cohort of people newly diagnosed with advanced prostate cancer designed to describe variations in patient management, experiences, and outcomes. IRONMAN aims to identify optimal treatment sequences to improve survival, understand patient-reported outcomes, and explore novel biomarkers to understand treatment resistance mechanisms. Insights from IRONMAN will inform and guide future clinical management of people with mHSPC and CRPC. This cohort study will provide real-world evidence to facilitate a better understanding of the survivorship of people with advanced prostate cancer.

A New Treatment Protocol of Combined High-Dose Levothyroxine and Repetitive Transcranial Magnetic Stimulation for the Treatment of Rapid-Cycling Bipolar Spectrum Disorders: A Cohort Evaluation of 55 Patients.

Background: Bipolar spectrum disorders (BSD) are highly disabling, with rapid cycling being treatment resistant. High-dose levothyroxine (HDT) has been reported to be effective. Diagnosis is associated with mutations in thyroid-activating enzymes and cerebral transporter protein carrier. Repetitive transcranial magnetic stimulation (rTMS) has neuroplastic effects. Methods: We report data on 55 severely symptomatic patients with rapid-cycling BSD treated with a combination protocol of HDT and rTMS. Of the patients, 31 patients (56.4%) were female and 40 (72.7%) had at least one additional diagnosis. Results: Patients were evaluated at three monthly intervals after acute treatment. Remission was measured using the Sheehan Disability Scale (SDS). The average number of medications prescribed was 1.8, with 32 patients (58.2%) needing only levothyroxine. The average dose of levothyroxine was 303.7 mcg (50 mcg−1000 mcg). A total of 53 patients were in remission (96.4%), with an average duration of 2.0 years. The SDS scores decreased significantly (Cohen's d = 2.61 (95% C.I. 1.81 to 2.83, p < 0.001). One patient had reversible side effects. A total of 52 (94.3%) patients had Deiodinase 1 and 2 (DiO1/DiO2) or SLCO1C1 protein carrier gene mutations. Conclusion: The data support the safety and acceptability of combined HDT/rTMS. Patients achieved long remissions with substantial improvements in quality of life.

Evaluation of Prostate Cancer Screening Strategies in a Low-Resource, High-risk Population in the Bahamas.

Importance: The benefit of prostate-specific antigen screening may be greatest in high-risk populations, including men of African descent in the Caribbean. However, organized screening may not be sustainable in low- and middle-income countries. Objective: To evaluate the expected population outcomes and resource use of conservative prostate-specific antigen screening programs in the Bahamas. Design Setting and Participants: Prostate cancer incidence from GLOBOCAN and prostate-specific antigen screening data for 4300 men from the Bahamas were used to recalibrate 2 decision analytical models previously used to study prostate-specific antigen screening for Black men in the United States. Data on age and results obtained from prostate-specific antigen screening tests performed in Nassau from 2004 to 2018 and in Freeport from 2013 to 2018 were used. Data were analyzed from January 15, 2021, to March 23, 2022. Interventions: One or 2 screenings for men aged 45 to 60 years and conservative criteria for biopsy (prostate-specific antigen level >10 ng/mL) and curative treatment (Gleason score ≥8) were modeled. Categories of Gleason scores were 6 or lower, 7, and 8 or higher, with higher scores indicating higher risk of cancer progression and death. Main Outcomes and Measures: Projected numbers of tests and biopsies, prostate cancer (over)diagnoses, lives saved, and life-years gained owing to screening from 2022 to 2040. Results: In this decision analytical modeling study, screening histories from 4300 men (median age, 54 years; range, 13-101 years) tested between 2004 and 2018 at 2 sites in the Bahamas were used to inform the models. Screening once at 60 years of age was projected to involve 40 000 to 42 000 tests (range between models) and prevent 500 to 600 of 10 000 to 14 000 prostate cancer deaths. Screening at 50 and 60 years doubled the number of tests but increased lives saved by only 15% to 16%. Among onetime strategies, screening once at 60 years of age involved the fewest tests per life saved (74-84 tests) and curative treatments per life saved (1.2-2.8 treatments). Conclusions and Relevance: The findings of this decision analytical modeling study of prostate cancer screening in the Bahamas suggest that limited screening offered modest benefits that varied with screening ages and number of tests. The results can be combined with data on capacity constraints and evaluated relative to competing national public health priorities.

Functional Changes Within the Rod Inner Segment Ellipsoid in Wildtype Mice: An Optical Coherence Tomography and Electron Microscopy Study.

Purpose: To test the hypothesis that changing energy needs alter mitochondria distribution within the rod inner segment ellipsoid. Methods: In mice with relatively smaller (C57BL/6J [B6J]) or greater (129S6/ev [S6]) retina mitochondria maximum reserve capacity, the profile shape of the rod inner segment ellipsoid zone (ISez) was measured with optical coherence tomography (OCT) under higher (dark) or lower (light) energy demand conditions. ISez profile shape was characterized using an unbiased ellipse descriptor (minor/major aspect ratio). Other bioenergy indexes evaluated include the external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness and the magnitude of the signal intensity of a hyporeflective band located between the photoreceptor tips and apical RPE. The spatial distribution of rod ellipsoid mitochondria were also examined with electron microscopy. Results: In B6J mice, darkness produced a greater ISez aspect ratio, thinner ELM-RPE, and a smaller hyporeflective band intensity than in light. In S6 mice, dark and light ISez aspect ratio values were not different and were greater than in light-adapted B6J mice; dark-adapted S6 mice showed smaller ELM-RPE thinning versus light, and negligible hyporeflective band intensity in the light. In B6J mice, mitochondria number in light increased in the distal inner segment ellipsoid and decreased proximally. In S6 mice, mitochondria number in the inner segment ellipsoid were not different between light and dark, and were greater than in B6J mice. Conclusions: These data raise the possibility that rod mitochondria activity in mice can be noninvasively evaluated based on the ISez profile shape, a new OCT index that complements OCT energy biomarkers measured outside of the ISez region.

Milvexian for the Prevention of Venous Thromboembolism.

BACKGROUND: Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor. METHODS: In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding. RESULTS: Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively. CONCLUSIONS: Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).

Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants.

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Correcting QUEST Magnetic Resonance Imaging-Sensitive Free Radical Production in the Outer Retina In Vivo Does Not Correct Reduced Visual Performance in 24-Month-Old C57BL/6J Mice.

Purpose: To test the hypothesis that acutely correcting a sustained presence of outer retina free radicals measured in vivo in 24-month-old mice corrects their reduced visual performance. Methods: Male C57BL/6J mice two and 24 months old were noninvasively evaluated for unremitted production of paramagnetic free radicals based on whether 1/T1 in retinal laminae are reduced after acute antioxidant administration (QUEnch-assiSTed [QUEST] magnetic resonance imaging [MRI]). Superoxide production was measured in freshly excised retina (lucigenin assay). Combining acute antioxidant administration with optical coherence tomography (i.e., QUEST OCT) tested for excessive free radical-induced shrinkage of the subretinal space volume. Combining antioxidant administration with optokinetic tracking tested for a contribution of uncontrolled free radical production to cone-based visual performance declines. Results: At two months, antioxidants had no effect on 1/T1 in vivo in any retinal layer. At 24 months, antioxidants reduced 1/T1 only in superior outer retina. No age-related change in retinal superoxide production was measured ex vivo, suggesting that free radical species other than superoxide contributed to the positive QUEST MRI signal at 24 months. Also, subretinal space volume did not show evidence for age-related shrinkage and was unresponsive to antioxidants. Finally, visual performance declined with age and was not restored by antioxidants that were effective per QUEST MRI. Conclusions: An ongoing uncontrolled production of outer retina free radicals as measured in vivo in 24 mo C57BL/6J mice appears to be insufficient to explain reductions in visual performance.

Sildenafil-evoked photoreceptor oxidative stress in vivo is unrelated to impaired visual performance in mice.

PURPOSE: The phosphodiesterase inhibitor sildenafil is a promising treatment for neurodegenerative disease, but it can cause oxidative stress in photoreceptors ex vivo and degrade visual performance in humans. Here, we test the hypotheses that in wildtype mice sildenafil causes i) wide-spread photoreceptor oxidative stress in vivo that is linked with ii) impaired vision. METHODS: In dark or light-adapted C57BL/6 mice ± sildenafil treatment, the presence of oxidative stress was evaluated in retina laminae in vivo by QUEnch-assiSTed (QUEST) magnetic resonance imaging, in the subretinal space in vivo by QUEST optical coherence tomography, and in freshly excised retina by a dichlorofluorescein assay. Visual performance indices were also evaluated by QUEST optokinetic tracking. RESULTS: In light-adapted mice, 1 hr post-sildenafil administration, oxidative stress was most evident in the superior peripheral outer retina on both in vivo and ex vivo examinations; little evidence was noted for central retina oxidative stress in vivo and ex vivo. In dark-adapted mice 1 hr after sildenafil, no evidence for outer retina oxidative stress was found in vivo. Evidence for sildenafil-induced central retina rod cGMP accumulation was suggested as a panretinally thinner, dark-like subretinal space thickness in light-adapted mice at 1 hr but not 5 hr post-sildenafil. Cone-based visual performance was impaired by 5 hr post-sildenafil and not corrected with anti-oxidants; vision was normal at 1 hr and 24 hr post-sildenafil. CONCLUSIONS: The sildenafil-induced spatiotemporal pattern of oxidative stress in photoreceptors dominated by rods was unrelated to impairment of cone-based visual performance in wildtype mice.

The Cancer Prevention Project of Philadelphia: preliminary findings examining diversity among the African diaspora.

Objective: Cancer mortality inequity among persons of African Ancestry is remarkable. Yet, Black inclusion in cancer biology research is sorely lacking and warrants urgent attention. Epidemiologic research linking African Ancestry and the African Diaspora to disease susceptibility and outcomes is critical for understanding the significant and troubling health disparities among Blacks. Therefore, in a cohort of diverse Blacks, this study examined differences in genetic ancestry informative markers (AIMs) in the DNA repair pathway and the cancer related biomarker 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL).Methods: Participants completed a questionnaire and provided bio-specimens. AIMs in or around DNA repair pathway genes were analyzed to assess differences in minor allele frequency (MAF) across the 3 ethnic subgroups. NNAL concentration in urine was measured among current smokers.Results: To date the cohort includes 852 participants, 88.3% being Black. Of the 752 Blacks, 51.3% were US-born, 27.8% were Caribbean-born, and 19.6% were Africa-born. Current and former smokers represented 14.9% and 10.0%, respectively. US-born Blacks were more likely to be smokers and poor metabolizers of NNAL. Two-way hierarchical clustering revealed MAF of AIMs differed across the 3 ethnic subgroups.Conclusion: Our findings are consistent with the emerging literature demonstrating Black heterogeneity underscoring African Ancestry genetic subgroup differences - specifically relevant to cancer. Further investigations, with data harmonization and sharing, are urgently needed to begin to map African Ancestry cancer biomarkers as well as race, and race by place\region comparative biomarkers to inform cancer prevention and treatment in the era of precision medicine.

Rod Photoreceptor Neuroprotection in Dark-Reared Pde6brd10 Mice.

Purpose: The purpose of this study was to test the hypothesis that anti-oxidant and / or anti-inflammation drugs that suppress rod death in cyclic light-reared Pde6brd10 mice are also effective in dark-reared Pde6brd10 mice. Methods: In untreated dark-reared Pde6brd10 mice at post-natal (P) days 23 to 24, we measured the outer nuclear layer (ONL) thickness (histology) and dark-light thickness difference in external limiting membrane-retinal pigment epithelium (ELM-RPE) (optical coherence tomography [OCT]), retina layer oxidative stress (QUEnch-assiSTed [QUEST] magnetic resonance imaging [MRI]); and microglia/macrophage-driven inflammation (immunohistology). In dark-reared P50 Pde6brd10 mice, ONL thickness was measured (OCT) in groups given normal chow or chow admixed with methylene blue (MB) + Norgestrel (anti-oxidant, anti-inflammatory), or MB or Norgestrel separately. Results: P24 Pde6brd10 mice showed no significant dark-light ELM-RPE response in superior and inferior retina consistent with high cGMP levels. Norgestrel did not significantly suppress the oxidative stress of Pde6brd10 mice that is only found in superior central outer retina of males at P23. Overt rod degeneration with microglia/macrophage activation was observed but only in the far peripheral superior retina in male and female P23 Pde6brd10 mice. Significant rod protection was measured in female P50 Pde6brd10 mice given 5 mg/kg/day MB + Norgestrel diet; no significant benefit was seen with MB chow or Norgestrel chow alone, nor in similarly treated male mice. Conclusions: In early rod degeneration in dark-reared Pde6brd10 mice, little evidence is found in central retina for spatial associations among biomarkers of the PDE6B mutation, oxidative stress, and rod death; neuroprotection at P50 was limited to a combination of anti-oxidant/anti-inflammation treatment in a sex-specific manner.

Potential Risk Factors Contributing to Development of Venous Thromboembolism for Total Knee Replacements Patients Prophylaxed With Rivaroxaban: A Retrospective Case-Control Study.

Rivaroxaban after total knee arthroplasty (TKA) is used to prevent postoperative venous thromboembolism (VTE); however, despite thromboprophylaxis, some patients still develop postoperative VTE. To determine whether tourniquet time, time to initiate rivaroxaban (TTIRIV), or Body Mass Index (BMI) was associated with postoperative VTE. A retrospective case-control study was conducted. Those patients that developed VTE despite prophylaxis (cases) were compared to controls (no VTE). A univariate analysis was conducted (p < 0.05 statistically significant). Seven VTE cases were identified from 234 TKA-patients. Patients with and without VTE had BMI of 40.1 ± 9.1 and 32.8 ± 7.5, respectively (p = 0.064). TTIRIV in VTE and control group was 28.2 ± 4.7 hours and 26.4 ± 4.2 hours, respectively (p = 0.39). Mean tourniquet time in VTE and control group was 65.0 ± 8.7 minutes and 49 ± 8.8 minutes, respectively (p = 0.0007). Statistically significant differences in tourniquet times were noted between VTE and non-VTE group but not for TTIRIV and BMI. Prolonged tourniquet use could pose a potential risk factor for postoperative VTE. Thromboprophylaxis management may need to be adjusted, based on patient-specific factors that could include increasing doses of oral anticoagulants and/or mechanical prophylaxis. However, further large-scale studies are required to establish pathophysiology.

Drugs to Prevent Bronchopulmonary Dysplasia: Effect of Baseline Risk on the Number Needed to Treat.

Infants born very preterm have a variable baseline risk of bronchopulmonary dysplasia (BPD). Using the example of evidence-based drug therapies to prevent BPD, we designed a visual aid that displays the "number needed to treat" with CIs for caffeine, vitamin A, and hydrocortisone over a range of baseline risks.

Age-related murine hippocampal CA1 laminae oxidative stress measured in vivo by QUEnch-assiSTed (QUEST) MRI: impact of isoflurane anesthesia.

Age-related impairments in spatial learning and memory often precede non-familial neurodegenerative disease. Ex vivo studies suggest that physiologic age-related oxidative stress in hippocampus area CA1 may contribute to prodromal spatial disorientation and to morbidity. Yet, conventional blood or cerebrospinal fluid assays appear insufficient for early detection or management of oxidative stress within CA1 sub-regions in vivo. Here, we address this biomarker problem using a non-invasive MRI index of CA1 laminae oxidative stress based on reduction in R1 (= 1/T1) after anti-oxidant administration. An R1 reduction reflects quenching of continuous and excessive production of endogenous paramagnetic free radicals. Careful motion-correction image acquisition, and avoiding repeated exposure to isoflurane, facilitates detection of hippocampus CA1 laminae oxidative stress with QUEnch-assiSTed (QUEST) MRI. Intriguingly, age- and isoflurane-related oxidative stress is localized to the stratum lacunosum of the CA1 region. Our data raise the possibility of using QUEST MRI and FDA-approved anti-oxidants to remediate spatial disorientation and later neurodegeneration with age in animals and humans.

Novel imaging biomarkers for mapping the impact of mild mitochondrial uncoupling in the outer retina in vivo.

PURPOSE: To test the hypothesis that imaging biomarkers are useful for evaluating in vivo rod photoreceptor cell responses to a mitochondrial protonophore. METHODS: Intraperitoneal injections of either the mitochondrial uncoupler 2,4 dinitrophenol (DNP) or saline were given to mice with either higher [129S6/eVTac (S6)] or lower [C57BL/6J (B6)] mitochondrial reserve capacities and were studied in dark or light. We measured: (i) the external limiting membrane-retinal pigment epithelium region thickness (ELM-RPE; OCT), which decreases substantially with upregulation of a pH-sensitive water removal co-transporter on the apical portion of the RPE, and (ii) the outer retina R1 (= 1/(spin lattice relaxation time (T1), an MRI parameter proportional to oxygen / free radical content. RESULTS: In darkness, baseline rod energy production and consumption are relatively high compared to that in light, and additional metabolic stimulation with DNP provoked thinning of the ELM-RPE region compared to saline injection in S6 mice; ELM-RPE thickness was unresponsive to DNP in B6 mice. Also, dark-adapted S6 mice given DNP showed a decrease in outer retina R1 values compared to saline injection in the inferior retina. In dark-adapted B6 mice, transretinal R1 values were unresponsive to DNP in superior and inferior regions. In light, with its relatively lower basal rod energy production and consumption, DNP caused ELM-RPE thinning in both S6 and B6 mice. CONCLUSIONS: The present results raise the possibility of non-invasively evaluating the mouse rod mitochondrial energy ecosystem using new DNP-assisted OCT and MRI in vivo assays.