Histone deacetylase (HDAC) inhibitor specificity determinants are preserved in a class of dual HDAC/non-covalent proteasome inhibitors.

Many disease states require multiple drugs to inhibit multiple targets for their effective treatment/management, i.e. a drug cocktail regimen, or "polypharmacy". Polypharmacology, in contrast, is the development of single agents that can inhibit multiple targets. Each strategy is associated with advantages and disadvantages. Motivated by promising clinical trial data for the treatment of multiple myeloma with the combination of the HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity. In general, previously reported specificity determinants of monovalent HDAC1/6 inhibitors were preserved in our dual HDAC/proteasome inhibitors.

Age-dependent natural killer cell and interferon γ deficits contribute to severe pertussis in infant mice.

Many respiratory infections are selectively injurious to infants, yet the etiology of age-associated susceptibility is unknown. One such bacterial pathogen is Bordetella pertussis. In adult mice, innate interferon γ (IFN-γ) is produced by natural killer (NK) cells and restricts infection to the respiratory tract. In contrast, infant pertussis resembles disease in NK cell- and IFN-γ-deficient adult mice that experience disseminated lethal infection. We hypothesized that infants exhibit age-associated deficits in NK cell frequency, maturation, and responsiveness to B. pertussis, associated with low IFN-γ levels. To delineate mechanisms behind age-dependent susceptibility, we compared infant and adult mouse models of infection. Infection in infant mice resulted in impaired upregulation of IFN-γ and substantial bacterial dissemination. B. pertussis-infected infant mice displayed fewer pulmonary NK cells than adult mice. Furthermore, the NK cells in the infant mouse lungs had an immature phenotype, and the infant lung showed no upregulation of the IFN-γ-inducing cytokine IL-12p70. Adoptive transfer of adult NK cells into infants, or treatment with exogenous IFN-γ, significantly reduced bacterial dissemination. These data indicate that the lack of NK cell-produced IFN-γ significantly contributes to infant fulminant pertussis and could be the basis for other pathogen-induced, age-dependent respiratory diseases.

Factors associated with reintegration trajectory following female genital fistula surgery in Uganda.

BACKGROUND: A female genital fistula, primarily caused by prolonged obstructed labor or after cesarean delivery in resource-limited countries, affects 500,000 to 2,000,000 women worldwide. Fistula is preventable with timely access to high-quality obstetrical care. Access to surgical repair of a female genital fistula has greatly increased over time. However, research surrounding postrepair reintegration, the process of returning to an individual's normal life, remains limited, and further efforts are needed to understand the factors shaping women's ability to rebuild their relationships and lives following repair. OBJECTIVE: This study aimed to characterize the 12-month reintegration trajectory after female genital fistula repair by participant sociodemographic and clinical characteristics. STUDY DESIGN: This study analyzed quantitative survey and medical record data of women (N=60) participating in a longitudinal cohort study assessing recovery after genital fistula repair in Uganda, with baseline and 4 quarterly follow-up assessments in 12 months. The primary outcome of reintegration was assessed using a 19-item postfistula repair reintegration instrument (range, 0-100) where a higher score represents better reintegration. Predictors of interest included parity and living children, quality of life, depressive symptoms at baseline, self-esteem, stigma, trauma, physical symptoms, and social support. We described participant baseline characteristics using means and proportions and estimated a series of mixed-effects linear regression models, including interactions of characteristics with time to understand how these characteristics influence reintegration trajectory in the 12 months after repair. RESULTS: The participants' physical and psychosocial morbidities at baseline were high; more than 80% of participants reported fistula-related physical symptoms, 82% of participants described their general health as poor, and measures of self-esteem, overall social support, and overall quality of life were low. The mean reintegration score at baseline was 33 (standard deviation, 20), which increased to 78 (standard deviation, 19) at 12 months after fistula repair. The participant sociodemographic characteristics statistically associated with reintegration included any living children (ß, 1.08; 95% confidence interval, -0.08 to 2.23). Moreover, psychosocial factors significantly affected reintegration with steeper trajectories for women with depressive symptoms (ß, 0.89; 95% confidence interval, 0.02-1.75) or women experiencing internalized stigma (ß, 0.05; 95% confidence interval, -0.00 to 0.11) and less steep for those with higher self-esteem (ß, -0.11; 95% confidence interval, -0.24 to 0.01), overall social support (ß, -0.06; 95% confidence interval, -0.12 to -0.01), and partner support (ß, -0.21; 95% confidence interval, -0.35 to -0.07). CONCLUSION: Understanding the prominent factors associated with differences in reintegration trajectories across the year after genital fistula surgery has the potential to inform interventions that mitigate challenges and improve women's postrepair recovery experiences.

The social, economic, emotional, and physical experiences of caregivers for women with female genital fistula in Uganda: A qualitative study.

ABSTRACTThis study aimed to explore the firsthand experiences of informal primary caregivers of women with female genital fistula in Uganda. Caregivers that accompanied women for surgery at Mulago National Teaching and Referral Hospital were recruited between January and September 2015. Caregivers participated in in-depth interviews and focus groups. Data were analysed thematically and informed adaptation of a conceptual framework. Of 43 caregivers, 84% were female, 95% family members, and most married and formally employed. Caregivers engaged in myriad personal care and household responsibilities, and described being on call for an average of 22.5 h per day. Four overlapping themes emerged highlighting social, economic, emotional, and physical experiences/consequences. The caregiving experience was informed by specific caregiver circumstances (e.g. personal characteristics, care needs of their patient) and dynamic stressors/supports within the caregiver's social context. These results demonstrate that caregivers' lived social, economic, emotional, and physical experiences and consequences are influenced by both social factors and individual characteristics of both the caregiver and their patient. This study may inform programmes and policies that increase caregiving supports while mitigating caregiving stressors to enhance the caregiving experience, and ultimately ensure its feasibility, particularly in settings with constrained resources.

Contraceptive access experiences and perspectives of Mexican-origin youth: a binational qualitative study.

Access to comprehensive contraceptive services for youth is essential to improving sexual and reproductive health. However, youth in many countries still face substantial obstacles to contraceptive access and use. The purpose of this study is to compare the contraceptive access experiences and perspectives of pregnant and parenting Mexican-origin youth in Guanajuato, Mexico, and Fresno County, California. Focus groups and in-depth interviews were conducted in Spanish and English among female youth in Mexico (n = 49) and California (n = 25). Participants also completed a brief sociodemographic survey. Using a modified grounded theory approach, qualitative data were coded and thematically analysed based on Penchansky and Thomas's Theory of Access, and results were compared by location. Although knowledge of a service provider was high among youth in both locations, access was affected by social, cultural, and institutional dynamics and contraceptive use was mixed. Across locations, participants described obstacles to accessing their preferred method. Participants worried about parental and peer opinions about their use of contraception (acceptability), and about perceived side effects including infertility and pain (adequacy). Contextual differences included lack of contraceptive choice in Guanajuato (availability) and incomplete knowledge about options in Fresno County (awareness). The power to request and receive their method of choice (agency) emerged as an important dimension that was not part of the original theory. Latina youth living in Mexico and the United States face multiple challenges accessing needed contraceptive options and services. Recognising and reducing these barriers can strengthen the contraceptive care landscape and promote the reproductive health and agency of young people. DOI: 10.1080/26410397.2023.2216527Plain language summary: Although sexually active youth need access to comprehensive sexual and reproductive health services, youth in many countries face substantial barriers to care. This study compares the experiences of pregnant and parenting youth in accessing contraceptive services in Mexico and the United States. We conducted interviews and focus groups with 74 Mexican-origin young women and found that contraceptive use and access was affected by their concerns about parental and peer opinions as well as by provider attitudes. In Mexico, several participants reported being denied their preferred method by their provider. Identifying and addressing barriers to services can improve the quality of care and the reproductive health of young people.

Impact of Sumadhur intervention on fertility and family planning decision-making norms: a mixed methods study.

BACKGROUND: Mindful of social norms shaping health among women pressured to prove early fertility in Nepal, a bi-national research team developed and piloted a 4-month intervention engaging household triads (newly married women, their husbands, and mothers-in-law) toward advancing gender equity, personal agency, and reproductive health. This study evaluates the impact on family planning and fertility decision-making. METHODS: In 2021, Sumadhur was piloted in six villages with 30 household triads (90 participants). Pre/post surveys of all participants were analyzed using paired sample nonparametric tests and in-depth interviews with a subset of 45 participants were transcribed and analyzed thematically. RESULTS: Sumadhur significantly impacted (p < .05) norms related to pregnancy spacing and timing, and sex preference of children, as well as knowledge about family planning benefits, pregnancy prevention methods, and abortion legality. Family planning intent also increased among newly married women. Qualitative findings revealed improved family dynamics and gender equity, and shed light on remaining challenges. CONCLUSIONS: Entrenched social norms surrounding fertility and family planning contrasted with participants' personal beliefs, highlighting needed community-level shifts to improve reproductive health in Nepal. Engagement of influential community- and family-members is key to improving norms and reproductive health. Additionally, promising interventions such as Sumadhur should be scaled up and reassessed.

Societal norms are among the key influencers that shape the decisions that people make about their desired family size and the methods they will apply to achieve it. To support women in Nepal, where norms are often layered upon the expectation that women will prove their fertility soon after marriage, a bi-national research team developed and piloted a 4-month intervention, Sumadhur, engaging newly married women, their husbands, and mothers-in-law. This study evaluated the impact the Sumadhur had on norms, knowledge, and intent related to family planning. From pre- and post-questionnaires, we found norms significantly shifted and knowledge significantly improved among all participant groups as a result of participating in Sumadhur. From interviews following the intervention, we found that family dynamics and gender equity also improved despite lingering challenges including unchanged norms about the expected timing of a couple's first child. Our results confirmed that it is critical to engage influential community and family members in improving norms and supporting women to make decisions about their reproduction. Additionally, promising interventions like Sumadhur should be scaled up and re-evaluated.

Determination of the Re-188 Calibration Number for the Capintec CRC- 25PET Dose Calibrator.

BACKGROUND: During the development of novel Re-188 radiopharmaceuticals, it was discovered that no calibration settings were published to calibrate Re-188 on the Capintec CRC-25PET dose calibrator. METHODS: Sodium [188Re]perrhenate was eluted from an OncoBeta 188W/188Re generator to measure activity on a Capintec CRC-25R dose calibrator using established dose calibrator settings provided by the manufacturer. The eluent was then used to tune the calibra on settings on a Capintec CRC-25PET dose calibrator, accounting for geometry. Radionuclidic purity of the [188Re]perrhenate source was verified via gamma spectroscopy. RESULTS: The calibrator number for Re-188 was determined to be 469 x 10 for the Capintec CRC-25PET dose calibrator, which differed from the manufacturer provided calibra on number of 496 x 10 for the Capintec CRC-25R dose calibra on model. W-188 breakthrough was characterised as < 0.01%. CONCLUSION: This previously unreported calibration number can be used to determine the activity of Re- 188 labelled radiopharmaceuticals using the Capintec CRC-25PET dose calibrator model.

Moving Morehouse School of Medicine Translation Tx Research through MDTTs-Multidisciplinary Translational Teams.

Morehouse School of Medicine (SOM) works to achieve its vision of advancing health equity through conducting transformational, translation science (Tx). Tx describes our translational research continuum, symbolizing a method and scientific philosophy that intentionally promotes and supports convergence of interdisciplinary approaches and scientists to stimulate exponential advances for the health of diverse communities. Morehouse SOM actualizes Tx through multidisciplinary translational teams (MDTTs). We chronicle the identification of MDTTs by documenting formation, composition, functioning, successes, failures, and sustainability. Data and information were collected through key informant interviews, review of research documents, workshops, and community events. Our scan identified 16 teams that meet our Morehouse SOM definition of an MDTT. These team science workgroups cross basic science, clinical, and public health academic departments, and include community partners and student learners. We present four MDTTs, in various stages of progress, at Morehouse SOM and how they are advancing translational research.

The COVID-19 Pandemic in the Nawalparasi District of Nepal: a mixed methods assessment of increased alcohol use and violence against women.

BACKGROUND: In Nepal and across the globe, the COVID-19 pandemic has primed an environment for increased rates of violence against women (VAW). This paper explores pandemic-driven economic insecurity and increased alcohol use as instigators of VAW and Intimate Partner Violence (IPV) within newly married households in the rural, Nawalparasi region of Nepal. METHODS: This study is a secondary analysis of data obtained from the Sumadhur Intervention pilot study that has been previously described and demonstrates successful implementation of group-based, household-level intervention for women's empowerment and sexual and reproductive health education (1). Our three sets of data were collected before and during the COVID-19 pandemic. The first set is from a Longitudinal Cohort of 200 newly married women who were surveyed twice a year from February 2017 through July 2020. The second data set is a subset cohort of newly married women, their husbands, and their mothers-in-law (31 women, 31 husbands and 31 mothers-in-law) who participated in Sumadhur in January 2021. The third data set was obtained through in-depth interviews in July 2021 from 15 households following Sumadhur. The interviews were thematically coded, and subthemes were identified. A t-test of the January 2021 survey data set was run to look at correlations between income loss, alcohol consumption and experience of IPV among newly married women. All other survey data was analyzed for change over time. RESULTS: At three months after the onset of the pandemic (July 2020), the Longitudinal Cohort survey data from newly married women reported increased rates of husbands' alcohol use as well as personal experiences of IPV as compared to pre-pandemic averages. There was a statistically significant difference (p < 0.001) in the effects of income loss on increased alcohol use and experience of IPV. Qualitative results iterated the common theme of alcohol use and economic insecurity as upstream instigators of VAW in the community. CONCLUSIONS: In the Nawalparasi district of Nepal, the pandemic has led to unstable economic situations that have instigated alcohol use among men, and increased rates of IPV among young, newly married women, and reports of VAW in the community. We have demonstrated a need for urgent programmatic and policy responses aimed at reducing VAW and IPV and protecting women during times of uncertainty and crisis.

Women's sexual activity and experiences following female genital fistula surgery.

BACKGROUND: Surgical repair has a transformative impact on the lives of women affected by female genital fistula; however, various physical, social, and economic challenges may persist postrepair and prevent complete reengagement in relationships and communities. Nuanced investigation of these experiences is needed to inform programming that aligns with women's reintegration needs. AIM: We investigated the sexual activity resumption, experiences, and concerns of women in Uganda during the year following genital fistula repair surgery. METHODS: Women were recruited from Mulago Hospital between December 2014 and June 2015. We collected data at baseline and 4 times postsurgery about sociodemographic characteristics and physical/psychosocial status; we also assessed sexual interest and satisfaction twice. We performed in-depth interviews with a subset of participants. We analyzed quantitative findings via univariate analyses, and qualitative findings were coded and analyzed thematically. OUTCOMES: We assessed sexual readiness, fears, and challenges following surgical repair of female genital fistula using quantitative and qualitative measures of sexual activity, pain with sex, sexual interest/disinterest, and sexual satisfaction/dissatisfaction. RESULTS: Among the 60 participants, 18% were sexually active at baseline, which decreased to 7% postsurgery and increased to 55% at 1 year after repair. Dyspareunia was reported by 27% at baseline and 10% at 1 year; few described leakage during sex or vaginal dryness. Qualitative findings showed wide variance of sexual experiences. Some reported sexual readiness quickly after surgery, and some were not ready after 1 year. For all, fears included fistula recurrence and unwanted pregnancy. CONCLUSION: These findings suggest that postrepair sexual experiences vary widely and intersect meaningfully with marital and social roles following fistula and repair. In addition to physical repair, ongoing psychosocial support is needed for comprehensive reintegration and the restoration of desired sexuality.

The COVID-19 Pandemic in the Nawalparasi District of Nepal: A Mixed Methods Assessment of Increased Alcohol Use and Intimate Partner Violence.

Background In Nepal and across the globe, the COVID-19 pandemic has primed an environment for increased rates of intimate partner violence (IPV). This paper examines how the upstream factors of alcohol use and economic insecurity in the Nawalparasi district of Nepal has brought about higher rates of IPV among newly married women. Methods This study is a secondary analysis of data obtained from the Sumadhur Intervention pilot study that has been previously described and demonstrates successful implementation of group-based, household-level intervention for women's empowerment and sexual and reproductive health education (1). Our three sets of data were collected before and during the COVID-19 pandemic. The first set is from a longitudinal cohort of 200 newly married women who were surveyed twice a year from February 2017 through July 2020. The second data set is from a cohort of newly married women, their husbands, and their mothers-in-law (31 women, 31 husbands and 31 mothers-in-law) who participated in Sumadhur in January 2021. The third data set was obtained through in-depth interviews in July 2021 from 15 households following Sumadhur . The interviews were thematically coded, and subthemes were identified. The survey data was analyzed for change over time. Results In households in the Nawalparasi district of Nepal, between 2019 and 2020 there was an increase in alcohol consumption with reports of drinking every day increasing from 9.2% to 13.6%. In July 2020, 30% (N=31/102) of newly married women said their husbands' alcohol consumption had increased since the pandemic. In 2019, 47.06% (N=88/187) of participants reported that they had experienced any form of IPV. In July 2021, 74% (N=23/31) of women reported being physically forced to have sexual intercourse with their husband when they did not want to and in the past four months, 68% (N=21/31) reported being forced to perform sexual acts against their will. The interviews highlighted the presence of alcohol use in the community as well as increased concerns over economic insecurity. Mothers-in-law consistently described increased rates of IPV and community violence since the pandemic. Conclusions The pandemic has led to precarious economic situations that have influenced alcohol use among men, and instances of IPV among young, newly married women. We have demonstrated a need for urgent programmatic and policy responses aimed at reducing IPV, which has increased during the pandemic. Family interventions centering on women, such as Sumadhur , are critical to implement along with community-wide emergency preparedness to ensure autonomy, safety, and wellbeing now and in future times of uncertainty.

Examining Factors Associated With Minority Turnover Intention in State and Local Public Health Organizations: The Moderating Role of Race in the Relationship Among Supervisory Support, Job Satisfaction, and Turnover Intention.

CONTEXT: There is a need to understand minority governmental public health workforce turnover to ensure the retention of public health minority workers, capitalize on diversity benefits, and enhance public health's capacity to serve diverse populations. OBJECTIVE: This study assesses the moderating effect of minority health workers' race on (1) the relationship between the workforce environment, particularly employees' perceptions of their pay and supervisory support on job satisfaction, and (2) the relationship between job satisfaction and turnover intentions. DESIGN: Using the 2017 Public Health Workforce Interests and Needs Survey (PH WINS), a cross-sectional survey of the public health workforce, a hierarchical logistic regression modeling technique was used to assess the moderating role of race on the relationship between supervisory support, pay and job satisfaction, and turnover intentions. SETTING AND PARTICIPANTS: The PH WINS survey data from state and local health department employees. MAIN OUTCOME MEASURE: Job satisfaction, pay, supervisory support, and turnover intention. RESULTS: Job satisfaction was found to mediate the relationship between the work environment factors of pay satisfaction and supervisory support and turnover. Our findings also suggest that while race moderates the influence of compensation and supervisory support on job satisfaction, race has no moderating effect on the job satisfaction-turnover intentions relationship. CONCLUSIONS: A focus on boosting job satisfaction, particularly through pay equity and perceived support, may reduce turnover among minority public health personnel.

The development and feasibility of a group-based household-level intervention to improve preconception nutrition in Nawalparasi district of Nepal.

BACKGROUND: In a setting such as Nepal with malnutrition and persistent poor maternal and infant health outcomes, developing interventions to improve the nutrition of preconception and pregnant women is essential. OBJECTIVE: The objectives of this paper are to describe the full design process of an intervention for newly married women, their husbands, and mothers-in-law to improve maternal nutrition and gender norms, and findings from the feasibility and acceptability pilot. METHODS: In this paper we describe the three phases of the design of an intervention in rural Nepal. We first conducted a mixed methods formative phase which included in depth interviews with newly married women, their husbands and mothers-in-law (N=60) and a longitudinal study for 18 months with 200 newly married women. We then designed of a household level, group, intervention, in close partnership with community members. Finally, we conducted a pilot intervention with 90 participants and collected both pre/post survey data and in-depth qualitative interviews with a subset (N= 30). All participants from all phases of the study lived in Nawalparasi district of Nepal. Qualitative data was analyzed using a thematic analysis, with inductive and deductive themes and quantitative data was analyzed using descriptive statistics. RESULTS: Our formative work highlighted lack of awareness about nutrition, and how women eating last, limited mobility, household and community inequitable gender norms and poor household-level communication contributed to low quality diets. Thus we designed Sumadhur, an intervention that brought groups of households (newly married wife, husband, and mother-in-law) together weekly for four months to strengthen relationships and gain knowledge through interactive content. We found Sumadhur to be highly feasible and acceptable by all respondents, with most (83%) attending 80% of sessions or more and 99% reporting that they would like it to continue. Pre/post surveys showed a decrease in the proportion of women eating last and increase in knowledge about nutrition in preconception and pregnancy. Qualitative interviews suggested that respondents felt it made large impacts on their lives, in terms of strengthening relationships and trust, understanding each other, and changing behaviors. CONCLUSIONS: We show how a designing an intervention in close partnership with the target recipients and local stakeholders can lead to an intervention that is able to target complicated and culturally held practices and beliefs, positively benefit health and wellbeing, and that is very well received. TRIAL REGISTRATION: ClinicalTrials.gov NCT04383847 , registered 05/12/2020.

Brain-Derived Neurotrophic Factor and Nerve Growth Factor Therapeutics for Brain Injury: The Current Translational Challenges in Preclinical and Clinical Research.

Ischemic stroke and traumatic brain injury (TBI) are among the leading causes of death and disability worldwide with impairments ranging from mild to severe. Many therapies are aimed at improving functional and cognitive recovery by targeting neural repair but have encountered issues involving efficacy and drug delivery. As a result, therapeutic options for patients are sparse. Neurotrophic factors are one of the key mediators of neural plasticity and functional recovery. Neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as potential therapeutic options to increase neural repair and recovery as they promote neuroprotection and regeneration. BDNF and NGF have demonstrated the ability to improve functional recovery in preclinical and to a lesser extent clinical studies. Direct and indirect methods to increase levels of neurotrophic factors in animal models have been successful in improving postinjury outcome measures. However, the translation of these studies into clinical trials has been limited. Preclinical experiments have largely failed to result in significant impacts in clinical research. This review will focus on the administration of these neurotrophic factors in preclinical and clinical stroke and TBI and the challenges in translating these therapies from the bench to the clinic.

Lactate supports a metabolic-epigenetic link in macrophage polarization.

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)­induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate­citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage­dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)­driven metabolic-epigenetic link in M2 macrophages.

ECO-CollecTF: A Corpus of Annotated Evidence-Based Assertions in Biomedical Manuscripts.

Analysis of high-throughput experiments in the life sciences frequently relies upon standardized information about genes, gene products, and other biological entities. To provide this information, expert curators are increasingly relying on text mining tools to identify, extract and harmonize statements from biomedical journal articles that discuss findings of interest. For determining reliability of the statements, curators need the evidence used by the authors to support their assertions. It is important to annotate the evidence directly used by authors to qualify their findings rather than simply annotating mentions of experimental methods without the context of what findings they support. Text mining tools require tuning and adaptation to achieve accurate performance. Many annotated corpora exist to enable developing and tuning text mining tools; however, none currently provides annotations of evidence based on the extensive and widely used Evidence and Conclusion Ontology. We present the ECO-CollecTF corpus, a novel, freely available, biomedical corpus of 84 documents that captures high-quality, evidence-based statements annotated with the Evidence and Conclusion Ontology.

Local insulin application has a dose-dependent effect on lumbar fusion in a rabbit model.

The purpose of this study was to determine if locally applied insulin has a dose-responsive effect on posterolateral lumbar fusion. Adult male New Zealand White rabbits underwent posterolateral intertransverse spinal fusions (PLFs) at L5-L6 using suboptimal amounts of autograft. Fusion sites were treated with collagen sponge soaked in saline (control, n = 11), or with insulin at low (5 or 10 units, n = 13), mid (20 units, n = 11), and high (40 units, n = 11) doses. Rabbits were euthanized at 6 weeks. The L5-L6 spine segment underwent manual palpation and radiographic evaluation performed by two fellowship trained spine surgeons blinded to treatment. Differences between groups were evaluated by analysis of variance on ranks followed by post-hoc Dunn's tests. Forty-three rabbits were euthanized at the planned 6 weeks endpoint, while three died or were euthanized prior to the endpoint. Radiographic evaluation found bilateral solid fusion in 10%, 31%, 60%, and 60% of the rabbits from the control and low, mid, and high-dose insulin-treated groups, respectively (p < 0.05). As per manual palpation, 7 of 10 rabbits in the mid-dose insulin group were fused as compared to 1 of 10 rabbits in the control group (p < 0.05). This study demonstrates that insulin enhanced the effectiveness of autograft to increase fusion success in the rabbit PLF model. The study indicates that insulin or insulin-mimetic compounds can be used to promote bone regeneration.