Comprehensive engineering of the tarantula venom peptide huwentoxin-IV to inhibit the human voltage-gated sodium channel hNav1.7.

Pain is a significant public health burden in the United States, and current treatment approaches rely heavily on opioids, which often have limited efficacy and can lead to addiction. In humans, functional loss of the voltage-gated sodium channel Nav1.7 leads to pain insensitivity without deficits in the central nervous system. Accordingly, discovery of a selective Nav1.7 antagonist should provide an analgesic without abuse liability and an improved side-effect profile. Huwentoxin-IV, a component of tarantula venom, potently blocks sodium channels and is an attractive scaffold for engineering a Nav1.7-selective molecule. To define the functional impact of alterations in huwentoxin-IV sequence, we produced a library of 373 point mutants and tested them for Nav1.7 and Nav1.2 activity. We then combined favorable individual changes to produce combinatorial mutants that showed further improvements in Nav1.7 potency (E1N, E4D, Y33W, Q34S-Nav1.7 pIC50 = 8.1 ± 0.08) and increased selectivity over other Nav isoforms (E1N, R26K, Q34S, G36I, Nav1.7 pIC50 = 7.2 ± 0.1, Nav1.2 pIC50 = 6.1 ± 0.18, Nav1.3 pIC50 = 6.4 ± 1.0), Nav1.4 is inactive at 3 µm, and Nav1.5 is inactive at 10 µm We also substituted noncoded amino acids at select positions in huwentoxin-IV. Based on these results, we identify key determinants of huwentoxin's Nav1.7 inhibition and propose a model for huwentoxin-IV's interaction with Nav1.7. These findings uncover fundamental features of huwentoxin involved in Nav1.7 blockade, provide a foundation for additional optimization of this molecule, and offer a basis for the development of a safe and effective analgesic.

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers.

FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

Recurrent low grade serous ovarian cancer in a 20 year old woman: A case from the Ohio State University College of Medicine.

A 20 year old with recurrent low-grade serous carcinoma (LGSC) is discussed. The differential diagnosis, pathology, epidemiology, treatment options are discussed. Focus on the molecular pathways of LGSC and the implications of the diagnosis on fertility are highlighted.

Perceptions of weight management counseling among gynecologic cancer survivors: opportunities for enhancing survivorship care.

PURPOSE: Oncology practice guidelines recommend incorporating weight management efforts throughout survivorship care; however, some oncologists raise concerns about implementing weight management counseling without damaging patient-provider relationships. This study explores cancer survivors' receptivity to weight management counseling and examines whether views of counseling effectiveness are associated with individual characteristics including health-related perceptions or psychological distress. METHODS: Patients presenting to a NCI Comprehensive Cancer Center gynecologic oncology ambulatory clinic were asked to complete a survey assessing health and weight history, health perceptions, psychological distress, provider preferences, and weight management counseling perceptions. RESULTS: Two hundred forty-four gynecologic cancer patients (38% endometrial, 37% ovarian, 16% cervical, 8% other) completed surveys. Mean participant BMI was 31.6 (SD = 9.6); 69% were overweight/obese. Most survivors (≥85%) agreed that oncologists should discuss healthy eating, exercise, and weight loss; only 14% reported receiving weight management counseling from their oncologist. 79% reported being more likely to attempt weight loss if counseled by a physician; 59% reported counseling would not be offensive. Regression results indicated that viewing weight management counseling as effective was associated with fewer depressive symptoms and greater enjoyment of physical activity, while viewing counseling unfavorably was associated with a history of attempting multiple weight loss strategies and an overall view of healthy behaviors as less beneficial (ps < .05). CONCLUSIONS: Most gynecologic cancer survivors want weight management counseling from oncologists and believe counseling is effective rather than deleterious, yet obesity remains inadequately addressed. Results from this study highlight important topics to be incorporated into weight management counseling.

Bariatric surgery as a means to decrease mortality in women with type I endometrial cancer - An intriguing option in a population at risk for dying of complications of metabolic syndrome.

OBJECTIVE: To estimate the cost-effectiveness and utility of a strategy of offering weight loss surgery (WLS) to women with low risk stage I endometrial cancer (EC) and BMI≥40kg/m(2). METHODS: A modified Markov state transition model was designed to compare routine care to WLS for women with low risk stage I endometrioid EC, age<70, with a mean BMI 40. A time horizon of 15years was used to simulate the overall survival (OS) of 96,232 women treated from 1988-2010 from SEER*Stat data. To simulate the effects of WLS on OS, a hazard ratio (0.76, 95% CI 0.59-0.99) representing the OS improvement achieved from this intervention (derived from a prospective trial) was modeled. We assumed that 90% of women undergoing bariatric procedures would experience a reduction in BMI. We assumed that 5% of women not undergoing WLS would achieve weight loss to a BMI of 35. Costs of treatment for obesity-related chronic diseases and quality of life (QOL)-related utilities were modeled from published reports. RESULTS: The mean cost-effectiveness for each strategy was: $69,295 and 8.10 quality-adjusted life years (QALYs) for routine care versus $100,675 and 9.30 QALYs for WLS. WLS had an incremental cost-effectiveness ratio (ICER) of $26,080/QALY compared to routine care. At a willingness to pay threshold of $50,000/QALY, WLS was the strategy of choice in 100% of simulations. CONCLUSIONS: WLS is a potentially cost-effective intervention in women with low risk, early stage EC, at least in part due to improved quality of life with weight reduction.

Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin huwentoxin-IV (µ-TRTX-Hh2a).

Voltage-gated sodium channels (VGSCs) are essential to the normal function of the vertebrate nervous system. Aberrant function of VGSCs underlies a variety of disorders, including epilepsy, arrhythmia, and pain. A large number of animal toxins target these ion channels and may have significant therapeutic potential. Most of these toxins, however, have not been characterized in detail. Here, by combining patch clamp electrophysiology and radioligand binding studies with peptide mutagenesis, NMR structure determination, and molecular modeling, we have revealed key molecular determinants of the interaction between the tarantula toxin huwentoxin-IV and two VGSC isoforms, Nav1.7 and Nav1.2. Nine huwentoxin-IV residues (F6A, P11A, D14A, L22A, S25A, W30A, K32A, Y33A, and I35A) were important for block of Nav1.7 and Nav1.2. Importantly, molecular dynamics simulations and NMR studies indicated that folding was normal for several key mutants, suggesting that these amino acids probably make specific interactions with sodium channel residues. Additionally, we identified several amino acids (F6A, K18A, R26A, and K27A) that are involved in isoform-specific VGSC interactions. Our structural and functional data were used to model the docking of huwentoxin-IV into the domain II voltage sensor of Nav1.7. The model predicts that a hydrophobic patch composed of Trp-30 and Phe-6, along with the basic Lys-32 residue, docks into a groove formed by the Nav1.7 S1-S2 and S3-S4 loops. These results provide new insight into the structural and molecular basis of sodium channel block by huwentoxin-IV and may provide a basis for the rational design of toxin-based peptides with improved VGSC potency and/or selectivity.

Pharmacology of a novel central nervous system-penetrant P2X7 antagonist JNJ-42253432.

In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1ß. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pKi 9.1 ± 0.07) and human (pKi 7.9 ± 0.08) P2X7 channel. The compound blocked the ATP-induced current and Bz-ATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethylammonium)]-induced release of IL-1ß in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1ß induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the α-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

Is bariatric surgery an option for women with gynecologic cancer? Examining weight loss counseling practices and training among gynecologic oncology providers.

OBJECTIVE: The objective of this study was to evaluate gynecologic oncology provider (GOP) practices regarding weight loss (WL) counseling, and to assess their willingness to initiate weight loss interventions, specifically bariatric surgery (WLS). METHODS: Members of the Society of Gynecologic Oncology were invited to complete an online survey of 49 items assessing knowledge, attitudes, and behaviors related to WL counseling. RESULTS: A total of 454 participants initiated the survey, yielding a response rate of 30%. The majority of respondents (85%) were practicing GOP or fellows. A majority of responders reported that >50% of their patient population is clinically obese (BMI ≥ 30). Only 10% reported having any formal training in WL counseling, most often in medical school or residency. Providers who feel adequate about WL counseling were more likely to offer multiple WL options to their patients (p<.05). Over 90% of responders believe that WLS is an effective WL option and is more effective than self-directed diet and medical management of obesity. Providers who were more comfortable with WL counseling were significantly more likely to recommend WLS (p<.01). Approximately 75% of respondents expressed interest in clinical trials evaluating WLS in obese cancer survivors. CONCLUSIONS: The present study suggests that GOP appreciate the importance of WL counseling, but often fail to provide it. Our results demonstrate the paucity of formal obesity training in oncology. Providers seem willing to recommend WLS as an option to their patients but also in clinical trials examining gynecologic cancer outcomes in women treated with BS.

Extent of tibiofemoral osteoarthritis before knee arthroplasty: multicenter data from the osteoarthritis initiative.

BACKGROUND: Knee arthroplasty traditionally is recommended for persons with substantial disability and disabling pain attributable to moderate or severe osteoarthritis (OA). Pain and functional status after arthroplasty may be influenced by the extent of knee OA before surgery and recent evidence suggests persons with less severe knee OA before undergoing TKA have greater pain levels and worse function than persons with more severe knee OA. QUESTIONS/PURPOSES: We determined the proportion of patients undergoing knee arthroplasty who had less than moderate knee OA before surgery and who had either a radiographically normal medial or lateral joint space before surgery. METHODS: One hundred sixteen persons in the Osteoarthritis Initiative underwent knee arthroplasty during a 3-year period. Ninety-seven of the 116 patients (84%) had radiographs available less than 1 year before surgery and were included. We used Z-tests to determine whether the proportion of patients with a modified Kellgren-Lawrence (KL) grade of 3 or higher differed from literature-based estimates. In addition, we described the proportion of patients with medial and lateral joint space narrowing. RESULTS: The proportion of patients with a modified KL grade of 3 or higher was 0.81 (95% CI, 0.73-0.89) and was less than the 0.95 estimated population proportion. Of the patients who underwent knee arthroplasty, 85% (82 of 97 knee arthroplasties) had at least one tibiofemoral joint compartment that had no joint space narrowing. One in six patients with OA who underwent knee arthroplasty had a KL grade of 2 or lower. CONCLUSIONS: Variation in the extent of tibiofemoral OA in patients preparing for joint arthroplasty is greater than previously described. A greater percentage of patients undergoing knee arthroplasty may be at risk for increased pain and poorer function than previously assumed after surgery because of less severe knee OA before surgery. LEVEL OF EVIDENCE: Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

A case of Borrelia-associated cutaneous pseudolymphoma in a horse.

This case report describes a 10-year-old horse that developed multiple dermal papules over the right masseter area following removal of a tick from the same site 3 months earlier. Histological examination of a biopsy from a papule was suggestive of either a T-cell-rich B-cell lymphoma or cutaneous lymphoid hyperplasia, a form of pseudolymphoma sometimes associated with a tick bite. Positive serological testing and PCR of the biopsy sample for Borrelia in conjunction with immunohistochemical testing of the skin biopsy, the clinical history and response to treatment with doxycycline strongly supported the diagnosis of Borrelia-associated cutaneous pseudolymphoma.

Association of Physician Densities and Gynecologic Cancer Outcomes in the United States.

OBJECTIVE: To evaluate whether there is an association between county-level obstetrician-gynecologist (ob-gyn) and primary care physician (PCP) densities and gynecologic cancer outcomes in the United States. METHODS: A retrospective cohort study of gynecologic cancers (uterine, ovarian, and cervical) in the Surveillance, Epidemiology, and End Results (SEER) database was performed from 2005 to 2018. County-level demographics were abstracted from the SEER database, population density from the United States Census Bureau, and physician density (ob-gyns and PCPs/100,000 females) from the Area Health Resources File. Backward stepwise regression models were used. RESULTS: Final analysis included 113,938 patients for stage at diagnosis analysis and 98,573 patients for 5-year survival analysis. Uterine, ovarian, and cervical cancers represented 60.0%, 25.0%, and 15.0% of patients, respectively. Most counties (57%) were nonmetropolitan and had a mean ob-gyn density of 8 per 100,000 females and a mean PCP density of 89 per 100,000 females. Multivariate analysis showed that increasing PCP density was associated with earlier stage at diagnosis (95% CI -6.27 to -0.05; P <.05) and increased 5-year survival rates in cervical cancer (95% CI 0.03-0.09; P <.05). Obstetrician-gynecologist density was not found to affect stage or survival outcomes for uterine or ovarian cancer. Analysis of sociodemographic factors for cervical cancer showed that median household income was negatively correlated with stage ( P =.01) and that the percentage of those with bachelor's degrees and metropolitan status were positively correlated with 5-year survival rates ( P <.01). For uterine cancer, the percentage of Black females was positively correlated with stage ( P <.01) and negatively correlated with 5-year survival rates ( P <.01). CONCLUSION: Increasing PCP density, but not ob-gyn density, is associated with earlier stage at diagnosis and improved 5-year survival rates in cervical cancer. County-level sociodemographic factors, including population diversity, metropolitan status, educational attainment, and household income, were also correlated with outcomes across all cancer types. Targeting PCP supply and education in lower density counties may improve population-based care for cervical cancer.

Video engagement to improve handwashing duration: A longitudinal study assessing creative and messaging fatigue.

BACKGROUND: Poor hand hygiene can contribute to increased rates of health care and community-acquired infections. Effective hand hygiene involves both a washer's technique and the duration of their wash. METHODS: The purpose of this longitudinal study was 2-fold: to improve the ability of hand-washers to meet the recommended handwashing duration of ≥20 seconds and to assess the effect of washer fatigue with the intervention. An innovative system of smart connected soap and towel dispensers synchronized to engaging video content was implemented to meet this objective. RESULTS: The intervention increased mean handwashing duration by 7.5 seconds (95% CI: 6.6, 8.4) and improved handwashing duration ≥20 seconds by 39.3% (P < .001). Using a similar cohort of hand-washers over 26 months, the video content had peak effect in month 1, and declined to a new steady state at month 11. DISCUSSION: Handwashing for the recommended time can be difficult to achieve. Most hand hygiene studies examine the rate of completion without measuring duration. CONCLUSIONS: Video engagement can improve and sustain handwashing duration. To mitigate creative and messaging fatigue, video content refresh for this intervention should be considered at 3 months for optimal effect or at 11 months prior to full decline to new steady state.

Patient perspectives of telemedicine in gynecologic oncology during COVID.

Objectives: Healthcare rapidly expanded the use of telemedicine during the COVID- 19 pandemic. Research regarding telemedicine benefits and patient perspectives during COVID are limited. The aim of this study was to determine how the pandemic impacted patient perspectives and value of telemedicine in gynecologic oncology. Methods: A cross-sectional survey was distributed to patients presenting for an appointment to the gynecologic oncology ambulatory clinic. The survey assessed patient demographics, frequency of technology use, and preferences of telemedicine use in their care. Descriptive statistics were generated and Pearson's chi square and analysis of variance (ANOVA) were used for statistical analysis. Results: 116 patients completed the survey. Respondent age range was 20-70 years old. Most respondents (80 %) had a cancer diagnosis. Nearly all (91 %) patients had access to online medical records via an online portal. Increased use of technology was not associated with agreeing to a telemedicine visit. Only 36 % stated they would feel comfortable with a telemedicine visit with a gynecologic oncologist. Patients were more willing to agree to video rather than telephone visits (41.8 % vs 24.5 %). The pandemic did not affect patient comfort level with telemedicine. Conclusions: Despite increased use and overall favorable impression, patients were not more eager to participate in telemedicine during the pandemic. Patients are open to incorporating telemedicine more often in follow up settings.

Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides.

A fundamental mechanism that drives the propagation of electrical signals in the nervous system is the activation of voltage-gated sodium channels. The sodium channel subtype Nav1.7 is critical for the transmission of pain-related signaling, with gain-of-function mutations in Nav1.7 resulting in various painful pathologies. Loss-of-function mutations cause complete insensitivity to pain and anosmia in humans that otherwise have normal nervous system function, rendering Nav1.7 an attractive target for the treatment of pain. Despite this, no Nav1.7 selective therapeutic has been approved for use as an analgesic to date. Here we present a summary of research that has focused on engineering peptides found in spider venoms to produce Nav1.7 selective antagonists. We discuss the progress that has been made on various scaffolds from different venom families and highlight the challenges that remain in the effort to produce a Nav1.7 selective, venom-based analgesic.

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study.

PURPOSE: Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS: Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS: Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION: This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

Synchronous and asynchronous transmitter release at nicotinic synapses are differentially regulated by postsynaptic PSD-95 proteins.

The rate and timing of information transfer at neuronal synapses are critical for determining synaptic efficacy and higher network function. Both synchronous and asynchronous neurotransmitter release shape the pattern of synaptic influences on a neuron. The PSD-95 family of postsynaptic scaffolding proteins, in addition to organizing postsynaptic components at glutamate synapses, acts transcellularly to regulate synchronous glutamate release. Here we show that PSD-95 family members at nicotinic synapses on chick ciliary ganglion neurons in culture execute multiple functions to enhance transmission. Together, endogenous PSD-95 and SAP102 in the postsynaptic cell appear to regulate transcellularly the synchronous release of transmitter from presynaptic terminals onto the neuron while stabilizing postsynaptic nicotinic receptor clusters under the release sites. Endogenous SAP97, in contrast, has no effect on receptor clusters but acts transcellularly from the postsynaptic cell through N-cadherin to enhance asynchronous release. These separate and parallel regulatory pathways allow postsynaptic scaffold proteins to dictate the pattern of cholinergic input a neuron receives; they also require balancing of PSD-95 protein levels to avoid disruptive competition that can occur through common binding domains.

Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center.

The incidence of acute renal failure, defined by the risk, injury, or failure criteria of the RIFLE criteria (risk, injury, failure, loss, and end-stage kidney disease), in 66 patients who received colistimethate sodium was 45%, and 21% of patients stopped therapy because of nephrotoxicity. The RIFLE criteria should be used in the future to allow for comparison of nephrotoxicity among studies.

Influence of race on kidney transplantation in the Department of Defense healthcare system.

BACKGROUND: We report the influence of race on transplant outcomes in the Department of Defense (DOD) system. METHODS: Retrospective cohort analysis of all kidney transplants performed at WRAMC from 1996 to 2005. Kaplan-Meier analysis was used to assess for differences in graft survival, and Cox regression was used to calculate adjusted hazard ratios for graft loss. For our analyses, we used the cutoff of 6 years (year 2000) when we introduced thymoglobulin induction; maintenance immunosuppression consisted of mycophenolate mofetil and tacrolimus, and rapid steroid taper (completed withdrawal at 6 weeks) was used for all patients. RESULTS: There were 220 transplants (91 Blacks, 107 Caucasians and 22 Asians). Because the curve for graft survival for Blacks over time violated the proportional hazards assumption (at 6 years post-transplant), analysis was segregated into two segments. Through 6 years of follow-up, graft survival was 77% for Blacks and 81% for non-Blacks (p = 0.74 by log rank). Through 9 potential years of follow-up, graft survival for Blacks was 56% and 78% for Whites (p = 0.005). In Cox regression analysis, Black race, compared with non-Black race, was not significantly associated with graft loss at 6 years, but was significantly associated with graft loss occurring after 6 years. CONCLUSIONS: In the DOD health system, no significant differences were seen in graft survival among recipients of different races at 6 years. Black recipients who received a kidney transplant before the year 2000 showed decreased graft survival compared to non-Blacks. This was consistent with change in immunosuppressive regimen in our institution with the introduction of thymoglobulin induction and maintenance therapy with tacrolimus, mycophenolate mofetil and withdrawal of prednisone at 6 weeks.

Outcomes in African-Americans vs. Caucasians using thymoglobulin or interleukin-2 receptor inhibitor induction: analysis of USRDS database.

AIM: We used the USRDS database to test the hypothesis that graft survival was similar using either rabbit antithymocyte globulin (rATG) vs. interleukin-2 receptor inhibitor (IL2i) in the Prograf era. We further explored the variable of race in the two groups of patients. METHODS: We conducted a retrospective cohort study of kidney transplant patients in the USRDS from 2000 through 2005 to compare graft survival (including death) using rATG vs. IL2i with particular reference to outcomes between African-Americans vs. Caucasians. Kaplan-Meier analysis was performed to assess patient and graft survival after transplantation, stratified by recipient induction with rATG versus IL2i. Cox regression analysis was performed to assess adjusted survival after transplantation, assessing whether induction rATG (vs. IL2i) was significant as an interaction term (i.e. an effect modifier) with black race for graft survival. Propensity score analysis was used to address potential confounding by indication. RESULTS: In stratified Cox Regression analysis limited to IL2i, black race was significantly associated with graft loss (adjusted hazard ratio (AHR) 1.17, 95% CI, 1.09-1.26). In analysis limited to rATG induction, black race was not significant (AHR 1.00, 95% CI, 0.92-1.10). We detected a significant interaction between rATG and black race (in comparison with non-black race) for the development of graft loss (AHR, 0.86, 95% CI, 0.76-0.97). Analysis limited to black recipients showed that while use of rATG was not significantly different from IL2i (AHR 0.95, 95% CI 0.87-1.04), the direction of this association was in the opposite direction of non-blacks. CONCLUSIONS: Patient and graft survival were similar in African-American and Caucasian recipients of kidney transplantation using either rATG or IL2i. Limitations of the study are the retrospective nature of USRDS data, center-bias in using rATG vs. IL2i and lack of data on steroid dosage. Results of the present study call for a critical review of induction practices.