Genomic Research and American Indian Tribal Communities in Oklahoma: Learning From Past Research Misconduct and Building Future Trusting Partnerships.

Research misconduct and consequential harms have been inflicted upon American Indian/Alaska Native communities for decades. To protect their people and culture and to retain oversight over research, many Native communities have established tribal health research and institutional review boards. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study showcases a successful, trusting research collaboration with tribal nations and academic investigators in Oklahoma. In 2006, the TODAY Study investigators proposed a modification of the study protocol to collect biological specimens from participants for genomic analyses and indefinite storage. Partnering American Indian tribal nations elected not to participate in the genomics collection and repository proposal. Reasons included 1) protection of cultural values, 2) concerns regarding community anonymity, 3) a potential threat to tribal services eligibility, 4) broad informed consent language, and 5) vague definitions of data access and usage. The nations believed the proposed genomics analyses presented a risk of harm to their people and nations without clear benefit. Since the 2006 proposal and the advancement of genomics research, many tribal communities in Oklahoma, appreciating the potential benefits of genomic research, are developing policies regarding oversight of/access to data and biological specimens to mitigate risks and provide members and communities with opportunities to participate in safe and meaningful genomic research.

Collaborative implementation of a community-based exercise intervention with a partnering rural American Indian community.

BACKGROUND: The prevalence and socioeconomic burden of childhood obesity and diabetes has increased rapidly in the United States in the last 30 years. American Indians have the highest prevalence of type 2 diabetes among newly diagnosed youth in the country. Contributing factors include environmental, behavioral, and genetic components. Some American Indian tribal communities have explored innovative ways to combat this epidemic including collaborations with academic centers on community-based research. METHOD: From 2012 to 2017, the University of Oklahoma Health Science Center and the Choctaw Nation of Oklahoma partnered on a National Institutes of Health-funded project to determine if financial incentives would elicit an increase in physical activity in Native youth. This was a community-based behavioral intervention for overweight or obese American Indian youth ages 11-20 living in a rural community at risk for developing diabetes. RESULTS: Tribal leaders and staff identified culturally appropriate strategies to aid implementation of the trial in their community. Their identified implementation strategies helped standardize the study in order to maintain study integrity. The mutually agreed strategies included co-review of the study by tribal and University research review boards (but designation of the Choctaw Nation review board as the "Board of Record"), training of community-based staff on research ethics and literacy, standardization of the informed consent process by videotaping all study information, creation of a viable and culturally appropriate timeline for study implementation, adapting tribal wellness center operations to accommodate youth, and development of effective two-way communication through training sessions, on-site coordination, and bi-monthly conference calls. CONCLUSION: In an effort to partner collectively on a randomized clinical research trial to combat childhood diabetes, tribal leaders and staff implemented strategies that resulted in a culturally appropriate and organized community-based behavioral intervention research project.

Racial Misclassification in Mortality Records Among American Indians/Alaska Natives in Oklahoma From 1991 to 2015.

OBJECTIVE: The primary purpose of this study was to compare age-adjusted mortality rates before and after linkage with Indian Health Service records, adjusting for racial misclassification. We focused on differences in racial misclassification by gender, age, geographic differences, substate planning districts, and cause of death. Our secondary purpose was to evaluate time trends in misclassification from 1991 to 2015. DESIGN: Retrospective, descriptive study. SETTING: Oklahoma. PARTICIPANTS: Persons contained in the Oklahoma State Health Department Vital Records. MAIN OUTCOME MEASURES: To evaluate the age-adjusted mortality ratio pre- and post-Indian Health Service record linkage (misclassification rate ratio) and to evaluate the overall trend of racial misclassification on mortality records measured through annual percent change (APC) and average annual percent change (AAPC). RESULTS: We identified 2 stable trends of racial misclassification upon death for American Indians/Alaska Natives (AI/ANs) from 1991 to 2001 (APC: -0.2%; 95% confidence interval: -1.4% to 1.0%) and from 2001 to 2005 (APC: -6.9%; 95% confidence interval: -13.7% to 0.4%). However, the trend identified from 2005 to 2015 decreased significantly (APC: -1.4%; 95% confidence interval: -2.5% to -0.2%). For the last 5 years available (2011-2015), the racial misclassification adjustment resulted in higher mortality rates for AI/ANs reflecting an increase from 1008 per 100 000 to 1305 per 100 000 with the linkage process. There were an estimated 3939 AI/ANs in Oklahoma who were misclassified as another race upon death in those 5 years, resulting in an underestimation of actual AI/AN deaths by nearly 29%. CONCLUSIONS: An important result of this study is that misclassification is improving; however, this effort needs to be maintained and further improved. Continued linkage efforts and public access to linked data are essential throughout the United States to better understand the burden of disease in the AI/AN population.

Molecular snapshot of an intracellular freezing event in an Antarctic nematode.

The Antarctic nematode, Panagrolaimus sp. DAW1 (formerly called Panagrolaimus davidi), is the best documented example of an organism able to survive intracellular ice formation in all of its compartments. Not only is it able to survive such extreme physiological disruption, but it is able to produce progeny once thawed from such a state. In addition, under slower rates, or less extreme degrees, of cooling, its body remains unfrozen and the vapour pressure difference between the supercooled body fluids and the surrounding ice leads to a process termed cryoprotective dehydration. In contrast to a fairly large body of work in building up our molecular understanding of cryoprotective dehydration, no comparable work has been undertaken on intracellular freezing. This paper describes an experiment subjecting cultures of Panagrolaimus sp. DAW1 to a range of temperatures including a rapid descent to -10 °C, in a medium just prior to, and after, freezing. Through deep sequencing of RNA libraries we have gained a snapshot of which genes are highly abundant when P. sp. DAW1 is undergoing an intracellular freezing event. The onset of freezing correlated with a high production of genes involved in cuticle formation and subsequently, after 24 h in a frozen state, protease production. In addition to the mapping of RNA sequencing, we have focused on a select set of genes arising both from the expression profiles, as well as implicated from other cold tolerance studies, to undertake qPCR. Among the most abundantly represented transcripts in the RNA mapping is the zinc-metalloenzyme, neprilysin, which also shows a particularly strong upregulated signal through qPCR once the nematodes have frozen.

The ability to survive intracellular freezing in nematodes is related to the pattern and distribution of ice formed.

A few species of nematodes can survive extensive intracellular freezing throughout all their tissues, an event that is usually thought to be fatal to cells. How are they able to survive in this remarkable way? The pattern and distribution of ice formed, after freezing at -10°C, can be observed using freeze substitution and transmission electron microscopy, which preserves the former position of ice as white spaces. We compared the pattern and distribution of ice formed in a nematode that survives intracellular freezing well (Panagrolaimus sp. DAW1), one that survives poorly (Panagrellus redivivus) and one with intermediate levels of survival (Plectus murrayi). We also examined Panagrolaimus sp. in which the survival of freezing had been compromised by starvation. Levels of survival were as expected and the use of vital dyes indicated cellular damage in those that survived poorly (starved Panagrolaimus sp. and P. murrayi). In fed Panagrolaimus sp. the intracellular ice spaces were small and uniform, whereas in P. redivivus and starved Panagrolaimus sp. there were some large spaces that may be causing cellular damage. The pattern and distribution of ice formed was different in P. murrayi, with a greater number of individuals having no ice or only small intracellular ice spaces. Control of the size of the ice formed is thus important for the survival of intracellular freezing in nematodes.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.

Partnering in research: a national research trial exemplifying effective collaboration with American Indian Nations and the Indian Health Service.

Despite the fact that numerous major public health problems have plagued American Indian communities for generations, American Indian participation in health research traditionally has been sporadic in many parts of the United States. In 2002, the University of Oklahoma Health Sciences Center (Oklahoma City, Oklahoma) and 5 Oklahoma American Indian research review boards (Oklahoma City Area Indian Health Service, Absentee Shawnee Tribe, Cherokee Nation, Chickasaw Nation, and Choctaw Nation) agreed to participate collectively in a national research trial, the Treatment Options for Type 2 Diabetes in Adolescence and Youth (TODAY) Study. During that process, numerous lessons were learned and processes developed that strengthened the partnerships and facilitated the research. Formal Memoranda of Agreement addressed issues related to community collaboration, venue, tribal authority, preferential hiring of American Indians, and indemnification. The agreements aided in uniting sovereign nations, the Indian Health Service, academics, and public health officials to conduct responsible and ethical research. For more than 10 years, this unique partnership has functioned effectively in recruiting and retaining American Indian participants, respecting cultural differences, and maintaining tribal autonomy through prereview of all study publications and local institutional review board review of all processes. The lessons learned may be of value to investigators conducting future research with American Indian communities.

Cancer incidence and staging among American Indians in Oklahoma.

BACKGROUND: This study describes overall and site specific cancer incidence among AI/ANs compared to whites in Oklahoma and differences in cancer staging. METHODS: Age-adjusted incidence rates obtained from the Oklahoma Central Cancer Registry are presented for all cancer sites combined and for the most common cancer sites among AI/ANs with comparisons to whites. Percentages of late stage cancers for breast, colorectal, and melanoma cancers are also presented. RESULTS: AI/ANs had a significantly higher overall cancer incidence rate compared to whites (629.8/100,000 vs. 503.3/100,000), with a rate ratio of 1.25 (95% CI: 1.22, 1.28). There was a significant disparity in the percentage of late stage melanoma cancers between 2005 and 2009, with 14.0% late stage melanoma for whites and 20.0% for AI/ANs (p-value:0.03). CONCLUSIONS: Overall, there were cancer disparities between AI/ANs and whites in Oklahoma. Incidence rates were higher among AI/ANs for all cancers and many site specific cancers.

Cold tolerance abilities of two entomopathogenic nematodes, Steinernema feltiae and Heterorhabditis bacteriophora.

Entomopathogenic nematodes are effective biological control agents against insect pests but their commercial application is restricted by their limited shelf life. This study applies our knowledge of the cold tolerance of nematodes to this problem and investigates further the cold tolerance mechanisms of Steinernema feltiae and Heterorhabditis bacteriophora infective juveniles. When frozen using a fast freezing regime these nematodes are moderately freezing tolerant, with a lower lethal temperature of -5°C. Survival is significantly enhanced by slow freezing overnight (at -1°C), with a decrease in the lower lethal temperature to -14°C. This may indicate that these nematodes are capable of cryoprotective dehydration. Acclimation at 5°C further enhanced freezing survival in S. feltiae but only by a small amount. Nematodes that had survived freezing to -13°C retained their pathogenicity to an insect host. Rapid cold hardening or exposure to a cold shock had no significant effect on freezing survival. The further development of methods based on cryoprotective dehydration may result in a method for the commercial storage of these nematodes.

Surgical cricothyrotomy in the wilderness: a case report.

Although the surgical cricothyrotomy procedure is used on combat casualties in the most challenging environments, we are unaware of any published report in the United States of surgical cricothyrotomy performed in a wilderness recreational setting. We describe a 31-year-old male rock climber who fell 24.4 m (80 feet), sustaining serious injuries and requiring rescue from the base of the cliff by a cave/cliff rescue team. Ultimately, a surgical cricothyrotomy proved necessary because of ongoing oropharyngeal bleeding, facial fractures creating an unstable airway, and the need to place the patient in the litter. The patient survived a prolonged and arduous evacuation. This report presents the management of the patient during the rescue and the challenges faced by the rescue team physician and others that led to the decision to perform an improvised surgical cricothyrotomy.

Rhabdomyolysis after prolonged suspension in a cave.

A 29-year-old man was caving and could not ascend his rope. He was rescued after 4+ hours of hanging after which he could not feel his legs and could not move one of them. He was shivering but still alert. In the field, he received calcium chloride, normal saline, and bicarbonate. At the hospital, he was found to have elevated creatine phosphokinase levels that resolved after continued intravenous fluid. Suspension trauma can include early syncope and late rhabdomyolysis. Persons suspended passively must be rescued immediately and given intravenous fluid to prevent rhabdomyolysis and renal failure.

Pododermatitis in captive-reared black stilts (Himantopus novaezelandiae).

A potential cause of pododermatitis ("bumblefoot") was investigated in captive-reared juvenile black stilts at the Department of Conservation "Kaki Recovery Program" at Twizel, New Zealand. To address the importance of substrate, the development of clinical signs in individuals was compared among aviaries that contained rubber matting and/or salt footbaths, and controls. No effect of either experimental manipulation of the environment was apparent on pododermatitis development. With the substrate appearing not to be an initiating factor, and a previous study that indicated that the birds' diet fulfills the nutritional requirements for rearing black stilts in captivity, results of this study suggest that insufficient space for exercise may instead be the cause.

Osmoregulation in the Antarctic nematode Panagrolaimus davidi.

A technique for determining the internal osmotic concentration of a small nematode using a modified nanolitre osmometer is described and used to investigate osmoregulation in the Antarctic nematode Panagrolaimus davidi. This technique enables the osmotic concentration to the measured with an accuracy of +/-12 mmol kg(-1). The pattern of melting in the nematode's different body compartments suggests that it is the osmolality of its pseudocoelomic fluid that is being measured. Panagrolaimus davidi maintains its internal osmotic concentration above that of the external medium and is thus an hyperosmotic regulator. The nematode achieves regulation under hyposmotic stress more rapidly than under hyperosmotic stress.

Patterns of Care and Outcomes for Small Cell Carcinoma of the Cervix: A National Retrospective Analysis of 542 Cases.

PURPOSE: Small cell carcinoma of the cervix (SCCC) represents 1% to 5% of cervical cancers, with limited data on management and outcomes. We evaluated patterns of care and outcomes for SCCC using the National Cancer Database. METHODS AND MATERIALS: This retrospective cohort study of SCCC (2004-2011) included 542 cases. Patient demographic, diagnosis, treatment information, and overall survival (OS) were compared with descriptive statistics, logistic regression, Kaplan-Meier, and Cox models. Clinical reasoning was used to select variables for multivariable models to avoid overfitting. RESULTS: SCCC had more comorbidities, higher grade, and advanced stage than other histologies. SCCC received neoadjuvant chemotherapy (36%) more often than squamous cell carcinoma (23%) and adenocarcinoma (13%, P < .001). SCCC had worse OS across all stages (P < .001). Looking at SCCC alone, patients who received chemoradiation (CRT) (with external beam and brachytherapy) and those who received chemotherapy and surgery (without RT) had similar OS (median OS 44 vs 47 months; P = .7) on Kaplan-Meier. Patients receiving CRT were more likely to have stage II or III and N+ disease (P < .001). When evaluating chemoradiation, the addition of brachytherapy resulted in improved median OS (35 vs 19 months; P = .001) regardless of surgical resection status and controlling for age and stage. Even after controlling for stage, age, and comorbidities, the addition of brachytherapy was associated with a 40% improvement in OS (hazard ratio 1.4, 95% confidence interval 1.0-2.0). CONCLUSIONS: SCCC patients benefit from chemotherapy with aggressive local treatment. Patients who receive CRT that included brachytherapy did as well as patients who received chemotherapy followed by surgery. Brachytherapy remains an essential component in the treatment of SCCC with CRT.

Current Volumetric Models Overestimate Vestibular Schwannoma Size Following Stereotactic Radiosurgery.

OBJECTIVE: Accurate volume assessment is essential for the management of vestibular schwannoma after stereotactic radiosurgery (SRS). A cuboidal approximation for volume is the standard surveillance method; however, this may overestimate tumor volume. We sought to evaluate several volumetric models and their suitability for post-SRS surveillance. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: We evaluated 54 patients with vestibular schwannoma before and after SRS. INTERVENTION(S): Gold-standard volumes were obtained by a radiation oncologist using contouring software. Volume was also calculated by cuboidal, ellipsoidal, and spherical formulae using tumor diameters obtained by a neuroradiologist. MAIN OUTCOME MEASURE(S): Percent error (PE) and absolute percent error (APE) were calculated. Paired t test evaluated bias, and the Bland-Altman method evaluated reproducibility. Linear regression evaluated predictors of model error. RESULTS: All models overestimated volume compared with the gold standard. The cuboidal model was not reproducible before SRS (p < 0.001), and no model was reproducible after SRS (cuboidal p < 0.001; ellipsoidal p = 0.02; spherical p = 0.02). Significant bias was present before SRS for the cuboidal model (p < 0.001), and post-SRS for all models [cuboidal (p < 0.001), ellipsoidal (p < 0.02), and spherical (p = 0.005)]. Model error was negatively associated with pretreatment volume for the cuboidal (PE p = 0.03; APE p = 0.03), ellipsoidal (PE p = 0.03; APE p = 0.04), and spherical (PE p = 0.02; APE p = 0.03) methods and lost linearity post-SRS. CONCLUSIONS: The standard cuboidal practice for following vestibular schwannoma tumor volume after SRS overestimates size. Ellipsoidal and spherical estimations have improved performance but also overestimate volume and lack reliability post-SRS. The development of other volumetric models or application of contouring software should be investigated.

Longitudinal Radiographic Outcomes of Vestibular Schwannoma in Single and Fractionated Stereotactic Radiosurgery: A Retrospective Cohort Study.

Management of vestibular schwannoma (VS) includes stereotactic radiosurgery (SRS) in single or fractionated treatments. There is a paucity of literature on the three-dimensional (3D) volumetric kinetics and radiological changes following SRS and no consensus on appropriate post-SRS surveillance imaging timeline. This is a retrospective cohort study with institutional review board approval. A total of 55 patients met study criteria. We collected volumetric kinetic data in VS treated with SRS over time using a target volume contouring software. We also tracked radiographic phenomena such as pseudoprogression and necrosis. A secondary objective was to describe our overall treatment success rate and any failures. For all treatments groups, pseudoprogression most typically occurred within 12 months post-SRS, after which tumor volumes on average normalized and then decreased from pretreatment size at the last follow-up. Only two patients required salvage therapy post-SRS and were considered SRS treatment failures. Both patients were in the five-fraction cohort but with a lower biologically equivalent dose. Our study is first to collect 3D volumetric kinetics of VS following single and fractionated SRS in contrast to extrapolations from single and two-dimensional measurements. Our longitudinal data also show initial increases in volume in the first 12 months post-SRS followed by later declines, setting up interesting questions regarding the utility of early posttreatment surveillance imaging in the asymptomatic patient. Finally, we show low rates of treatment failure (3.6%) and show in our cohort that SRS dose de-escalation posed a risk of treatment failure.

Correction: Using financial incentives to promote physical activity in American Indian adolescents: A randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0198390.].

Adapting CAHPS for an American Indian population.

OBJECTIVE: Develop a culturally appropriate, reliable, and valid survey that can be used by the Choctaw Nation Health Services (CNHS) to compare patients' health care experiences across CNHS clinics, and to support quality improvement efforts. METHODS: We worked with CNHS staff to adapt the CAHPS Clinician and Group Survey for this purpose. We conducted cognitive interviews and a field-test to evaluate the survey. RESULTS: Cognitive testing yielded a survey that covered issues relevant to CNHS patients. Field testing yielded 696 surveys, (58% response rate). Analyses provided support for internal consistency of multi-item scales. Correlations among scales indicate the scales were related to one another but not redundant. DISCUSSION: The CAHPS American Indian Survey is useful for assessing perceptions of care at the clinic level and across different clinics. The close partnership with CNHS helped yield a survey that is scientifically sound, reflects how services are organized and delivered locally, and meets CNHS information needs.