Development of a Small Molecule Downmodulator for the Transcription Factor Brachyury.

Brachyury is an oncogenic transcription factor whose overexpression drives chordoma growth. The downmodulation of brachyury in chordoma cells has demonstrated therapeutic potential, however, as a transcription factor it is classically deemed "undruggable". Given that direct pharmacological intervention against brachyury has proven difficult, attempts at intervention have instead targeted upstream kinases. Recently, afatinib, an FDA-approved kinase inhibitor, has been shown to modulate brachyury levels in multiple chordoma cell lines. Herein, we use afatinib as a lead to undertake a structure-based drug design approach, aided by mass-spectrometry and X-ray crystallography, to develop DHC-156, a small molecule that more selectively binds brachyury and downmodulates it as potently as afatinib. We eliminated kinase-inhibition from this novel scaffold while demonstrating that DHC-156 induces the post-translational downmodulation of brachyury that results in an irreversible impairment of chordoma tumor cell growth. In doing so, we demonstrate the feasibility of direct brachyury modulation, which may further be developed into more potent tool compounds and therapies.

Rare

Potassium-40 is a widespread, naturally occurring isotope whose radioactivity impacts subatomic rare-event searches, nuclear structure theory, and estimated geological ages. A predicted electron-capture decay directly to the ground state of argon-40 has never been observed. The KDK (potassium decay) collaboration reports strong evidence of this rare decay mode. A blinded analysis reveals a nonzero ratio of intensities of ground-state electron-captures (I_{EC^{0}}) over excited-state ones (I_{EC^{*}}) of I_{EC^{0}}/I_{EC^{*}}=0.0095±[over stat]0.0022±[over sys]0.0010 (68% C.L.), with the null hypothesis rejected at 4σ. In terms of branching ratio, this signal yields I_{EC^{0}}=0.098%±[over stat]0.023%±[over sys]0.010%, roughly half of the commonly used prediction, with consequences for various fields [27L. Hariasz et al., companion paper, Phys. Rev. C 108, 014327 (2023)PRVCAN2469-998510.1103/PhysRevC.108.014327].

Ethylcarbene versus Direct Propene Formation in the Near-UV Photodissociation of Ethylketene.

The competing pathways in the photodissociation of gaseous ethylketene at excitation wavelengths of 320.0, 340.0, and 355.1 nm were studied using photofragment translational energy spectroscopy. The primary dissociation channel was C═C bond fission producing ethylcarbene (CH3CH2CH; also known as propylidene) and CO. Product translational energy distributions are consistent with theoretical predictions that ground state ethylcarbene lies ∼34 kJ/mol higher in energy than its isomer dimethylcarbene (CH3CCH3). A second dissociation channel involved direct formation of propene prior to or concurrent with CO elimination. The measured product branching ratios indicate that the effective potential energy barrier for the direct propene channel lies below the energetic threshold for ethylcarbene formation. A minor C-C bond fission channel was also observed, leading to CH3 + CH2CHCO products. Comparisons are made to the results of our recent studies of methylketene and dimethylketene photodissociation.

The fundamentals of laparoscopic surgery in general surgery residency: fundamental for junior residents' self-efficacy.

BACKGROUND: Implementation of the Fundamentals of Laparoscopic Surgery (FLS) by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) has served a need for educational structure for laparoscopic skill within General Surgery training since 2004. This study looks at how FLS affects resident self-efficacy (SE) with laparoscopic procedures. METHODS: We conducted a national survey, linked to the 2020 American Board of Surgery In-Training Examination (ABSITE), in which 9275 residents from 325 US General Surgery Training Programs participated. The online survey included multimodal questions that analyzed whether participants felt they could perform the most commonly-logged laparoscopic operations among residents [Laparoscopic Appendectomy (LA), Laparoscopic Cholecystectomy (LC), Laparoscopic Right Hemicolectomy (LRH), Diagnostic Laparoscopy (DL)] without faculty assistance. This used a 5-point scaled assessment, ranging from "not able to" to "definitely able to." Multivariate analyses determined if completion of FLS made a difference for resident self-efficacy, stratified by post-graduate year (PGY). RESULTS: At the time of the survey, 2300 reported completion of FLS. The percentage of FLS completion increased from PGY1 to PGY5 (4.2% n = 59 vs 85.8% n = 893). PGY1 residents who completed FLS, from 48 diverse institutions, demonstrated the most significant increases in SE (p < 0.05) with significantly higher perceived self-efficacy in LA (p = 0.001) and LRH (p = 0.012). PGY2 and PGY3 residents indicated increased SE in DL (p = 0.037, p = 0.015, respectively), based on FLS completion. These FLS effects were less evident in the more senior classes. CONCLUSIONS: Completion of FLS arguably has the greatest benefits for more junior residents, as it establishes a foundation of laparoscopic knowledge and skill, upon which further residency training can build. Successful completion of the curriculum and assessment offered by the Fundamentals of Laparoscopic Surgery leads to greater sense of ability in early trainees.

Individual and Institutional Factors Associated with PGY5 General Surgery Resident Self-Efficacy: A National Survey.

BACKGROUND: Variability in post-graduate year 5 (PGY5) residents' operative self-efficacy exists; yet the causes of variability have not been explored. Our study aims to determine resident-related and program-dependent factors associated with residents' perceptions of self-efficacy. STUDY DESIGN: Following the 2020 American Board of Surgery In-Training Examination, a national survey of self-efficacy in 10 of the most commonly performed Accreditation Council for Graduate Medical Education case-log procedures was completed. RESULTS: A total of 1,145 PGY5 residents completed the survey (response rate 83.8%), representing 296 surgical residency programs. Female sex (odds ratio [OR] 0.46 to 0.67; 95% CI 0.30 to 0.95; p < 0.05) was associated with decreased self-efficacy for 6 procedures. Residents from institutions with emphasis on autonomy were more likely to report higher self-efficacy for 8 of 10 procedures (OR 1.39 to 3.03; 95% CI 1.03 to 4.51; p < 0.05). In addition, increased socialization among residents and faculty also correlated with increased self-efficacy in 3 of 10 procedures (OR 1.41 to 2.37; 95% CI 1.03 to 4.69; p < 0.05). Procedures performed with higher levels of resident responsibility, based on Graduated Levels of Resident Responsibility (GLRR) and Teaching Assistant (TA) scores, were correlated with higher self-efficacy (p < 0.001). CONCLUSION: Ensuring that residents receive ample opportunities for GLRR and TA experiences, while implementing programmatic support for resident-dependent factors, may be crucial for building self-efficacy in PGY5 residents. Institutional support of resident "autonomy" and increasing methods of socialization may provide a means of building trust and improving perceptions of self-efficacy. In addition, reevaluating institutional policies that limit opportunities for graduated levels of responsibility, while maintaining patient safety, may lead to increased self-efficacy.

Diversity, Equity, and Inclusion: A Current Analysis of General Surgery Residency Programs.

BACKGROUND: Local, regional, and national diversity, equity, and inclusion (DEI) initiatives have been established to combat barriers to entry and promote retention in surgery residency programs. Our study evaluates changes in diversity in general surgery residency programs. We hypothesize that diversity trends have remained stable nationally and regionally. MATERIALS AND METHODS: General surgery residents in all postgraduate years were queried regarding their self-reported sex, race, and ethnicity following the 2020 ABSITE. Residents were then grouped into geographic regions. Data were analyzed utilizing descriptive statistics, Kruskal-Wallis test, and chi-square analyses. RESULTS: A total of 9276 residents responded. Nationally, increases in female residents were noted from 38.0 to 46.0% (P < .001) and in Hispanic or Latinx residents from 7.3 to 8.3% (P = .031). Across geographic regions, a significant increase in female residents was noted in the Northwest (51.9 to 58.3%, P = .039), Midwest (36.9 to 43.3%, P = .006), and Southwest (35.8 to 47.5%, P = .027). A significant increase in black residents was only noted in the Northwest (0 to 15.8%, P = .031). The proportion of white residents decreased nationally by 8.9% and in the Mid-Atlantic, Southeast, and Southwest between 5.5 and 15.9% (P < .05). DISCUSSION: In an increasingly diverse society, expanding the numbers of underrepresented surgeons in training, and ultimately in practice, is a necessity. This study shows that there are region-specific increases in diversity, despite minimal change on a national level. This finding may suggest the need for region-specific DEI strategies and initiatives. Future studies will seek to evaluate individual programs with DEI plans and determine if there is a correlation to changing demographics.

Site-Specific Carbon-Carbon Bond Fission in Photoexcited Propyl Radicals Leads to Isomer-Selective Carbene and Radical Products.

Although there have been many studies of C-H bond fission in the UV photochemistry of alkyl radicals, very little is known about the possible occurrence of C-C bond fission. Here, we report that upon excitation at 248 nm, gaseous 1-propyl radicals primarily undergo C-C bond fission, producing methylene (CH2) and ethyl radicals (C2H5), rather than the more energetically favored methyl (CH3) and ethylene (C2H4). In contrast, the exclusive C-C bond fission products from 2-propyl radicals were ethylidene (CHCH3) plus methyl radicals (CH3). The isomer-selective formation of high-energy carbene + radical products involves excited-state site-specific C-C bond fission at the radical carbon, with quantum yields comparable to those for C-H bond fission. Our observations suggest that a general feature of alkyl radical photochemistry is predissociation of the initially formed Rydberg states by high-lying valence states, yielding high-energy carbene plus alkyl radical products.

American Board of Surgery Entrustable Professional Activities (EPAs): Assessing Graduating Residents' Perception of Preoperative Entrustment.

OBJECTIVE: To determine if graduating surgical residents are achieving entrustment of surgical entrustable professional activities (EPAs). We hypothesize that postgraduate year 5 (PGY5) residents are achieving evaluation and management entrustment in the selected EPAs. DESIGN: In January 2020, surgical residents completed a survey following the American Board of Surgery In-Training Examination (ABSITE) to measure their levels of entrustment in 4 of the 5 ABS-selected EPAs. A Resident Entrustability Index (REI) score was developed to ascertain PGY5 residents' levels of entrustment (range 1-5). Residents indicated how often their assessments and operative plans were modified in the prior 6 months for each EPA (1=Always, 2=Frequently, 3=Occasionally, 4=Rarely, 5=Never). An independent clinical decision-making score (ICDM) was developed with subsequent evaluation of its relationships to intrinsic, resident-related and extrinsic, program-dependent factors. SETTING: A national post-ABSITE survey. PARTICIPANTS: All general surgery residents participating in ABSITE were invited to participate. Of the 1367 PGY5 residents that completed the survey, 1049 residents (76.7%) responded to the surgical EPA items. RESULTS: Residents achieved an average REI of 4, indicating rare modification of assessments and operative plans for the 4 EPAs assessed. Complete entrustment was reported for inguinal hernias and penetrating abdominal trauma (Median REI = 5, IQR 4, 5) indicating assessments and operative plans were never modified. Lack of entrustment (REI ≤3) was reported by a minority of residents (ranging from 8.6% for operative plan of right lower quadrant pathology to 12.8% for operative plan of blunt abdominal trauma). Significant resident-related and program-dependent factors associated with achievement of expected ICDM was socializing with a co-resident (p = 0.001), while training in one's hometown (p < 0.001) and policies that mandate attendings be scrubbed in (p = 0.022) were associated with decreased achievement of expected ICDM. Overall, 89.2% and 90.3% of PGY5 residents are attaining appropriate levels of entrustment and ICDM abilities, respectively, within 6 months of graduating. CONCLUSIONS: Of the EPAs evaluated, PGY5 residents are achieving appropriate levels of entrustment in evaluation and management. Although this is the case for a vast majority of PGY5 residents, there is still work to be done to ensure that all PGY5 residents are attaining entrustment prior to graduation. Our study also provides content validity for the surgical EPAs in assessing levels of entrustment in PGY5 residents.

Dimethylcarbene versus Direct Propene Formation in Dimethylketene Photodissociation.

Highly reactive carbenes are usually produced by photolysis of ketenes, diazoalkanes, or diazirines. Sequential kinetic pathways for deactivation of nascent carbenes usually involve bimolecular reactions in competition with isomerization producing stable products such as alkenes. However, the direct photolytic production of stable products, effectively bypassing formation of free carbenes, has been postulated for over 50 years but remains very poorly understood. Often termed "rearrangement in the excited state" (RIES), examples include 1,2-hydrogen migration within photoexcited carbene precursors yielding alkenes and the Wolff rearrangement in photogenerated carbonyl-substituted carbenes producing ketenes. In this study, the two competing CO elimination channels from photoexcited gaseous dimethylketene, producing dimethylcarbene and propene, were studied as a function of electronic excitation energy, under collision-free conditions, by using photofragment translational energy spectroscopy with vacuum ultraviolet photoionization of the products. A significant fraction of the dimethylcarbene → propene isomerization exothermicity (∼300 kJ/mol) was released as propene + CO translational energy, indicating that propene is formed prior to or concurrent with CO elimination. An increase in the propene yield with increasing excitation energy suggests that the effective potential energy barrier for this channel lies ∼24 kJ/mol above the energetic threshold for dimethylcarbene formation via C═C bond fission. Possible mechanisms for direct propene elimination are discussed in light of the observed energy dependence for the competing pathways.

Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work in everybody. The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level. Early pilot studies by us to discover blood biomarkers for mood state were promising [1], and validated by others [2]. Recent work by us has identified blood gene expression biomarkers that track suicidality, a tragic behavioral outcome of mood disorders, using powerful longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality) [3-6]. These studies showed good reproducibility with subsequent independent genetic studies [7]. More recently, we have conducted such studies also for pain [8], for stress disorders [9], and for memory/Alzheimer's Disease [10]. We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients. First, we used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a simple visual analog scale that we had previously developed (SMS-7). Second, we prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, we validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, we tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last 3 had also been identified by our previous suicidality studies. Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.

Defining the Deficit in US Surgical Training: The Trainee's Perspective.

BACKGROUND: Self-efficacy is the personal judgment of how well one can successfully complete a task. The goal of this study was to assess self-efficacy of PGY5 residents for common general surgery operations. We hypothesized there are deficits in self-efficacy of PGY5 residents, and self-efficacy of a given operation correlates with experience performing the operation without attending assistance (independently) and teaching the operation from start to finish. METHODS: A survey was linked to the 2020 American Board of Surgery In-Training Examination. From the ACGME case log's 15 most commonly performed surgeon-chief operations and AHRQ's 15 most common operations, 10 operations were selected. Residents evaluated their ability to perform these operations independently using a 5-point self-efficacy scale. Residents were asked whether they had experience performing these operations independently or teaching the operation from start to finish. Descriptive statistics and Pearson correlation were used to examine the relationship between self-efficacy and operative experience. RESULTS: In all, 1,145 of 1,367 PGY5 residents (84%) responded. Highest self-efficacy was in performing wide-local excision (90.24%) and lowest was in performing open thyroidectomy (19.58%). Eighty-eight (7.7%) reported self-efficacy in all procedures. Statistically significant positive correlations were identified between experience and self-efficacy for cases performed without assistance (r = 0.98, p < 0.01) and cases taught (r = 0.91, p < 0.01). CONCLUSIONS: With 5 months left in training, 92.3% of residents report deficits in preparation for practice, as defined by self-efficacy to complete common procedures independently. Resident self-efficacy increased in direct relation to performed cases and cases taught.

Direct Observation of Ethylidene (CH3CH), the Elusive High-Energy Isomer of Ethylene.

Despite experimental efforts spanning more than 80 years, there has been no direct observation of free ethylidene (CH3CH), the simplest alkyl-substituted carbene. Here, we report that ethylidene is indefinitely stable in the absence of collisions if produced in the triplet ground state at energies below the threshold for intersystem crossing. Near-UV photolysis of gaseous methylketene, or propenal (followed by isomerization to methylketene), leads to CO loss producing triplet ethylidene, which is detected by photoionization mass spectrometry. Electronically excited singlet ethylidene is also produced, rapidly undergoing isomerization by a 1,2-hydrogen atom shift, producing highly vibrationally excited ethylene. The measured product translational energy distributions verify the theoretically calculated enthalpy of formation of triplet ethylidene and are consistent with a singlet-triplet energy gap of approximately 12.5 kJ/mol.

Subpicosecond HI elimination in the 266 nm photodissociation of branched iodoalkanes.

The 266 nm photodissociation dynamics of 1-iodopropane and 2-iodopropane were studied using photofragment translational energy spectroscopy using vacuum ultraviolet (VUV) photoionization and electron impact ionization detection of products. The photochemistry of 1-iodopropane was found to be similar to that of iodomethane and iodoethane, with dominant production of I*(2P1/2), and no evidence (<0.21%) for HI + alkene formation. Significantly different behavior was observed for 2-iodopropane, with dominant production of ground state I(2P3/2), and a HI yield >10.5%. The anisotropy (ß) parameters for all channels approached the limiting value of 2.0, indicating that 1,2-HI elimination occurs on subpicosecond timescales, like direct C-I bond fission, following excitation to 3Q0. The HI translational energy and angular distributions were similar to those for I(2P3/2), suggesting that motion of the heavy I atom in HI is largely derived from the repulsive nature of the 1Q1 surface correlating to R + I with the light H atom picked up by ground state I late in the exit channel producing highly vibrationally excited HI.

Creutzfeldt-Jakob Disease: In-hospital demographics report of national data in the United States from 2016 and review of a rapidly-progressive case.

BACKGROUND: This report highlights a rapidly progressive case of Creutzfeldt-Jakob Disease (CJD) whose time from symptom onset to death spanned less than two months. We also explore the most recently available in-patient demographics data for discharges with CJD in the United States. METHODS: We reviewed a CJD case and systematically analyzed a retrospective cohort of CJD discharges using the Healthcare Cost and Utilization Project (HCUP) to evaluate the existing national data on the status of CJD demographics and dispositions in the United States in 2016. RESULTS: An estimated total of 710 hospital discharges with a diagnosis of CJD were seen across the United States in 2016. According to HCUP, the average age of patients was 66.15 ±â€¯11.54 years with 48.6 % female. Average time to intubation from admission to hospital was 4.71 ±â€¯7.32 days with a rate of intubation of 6.34 %. The mean hospital cost was $19,901.25 ± $18,743.48. The rate of in-hospital mortality was 8.45 %. No significant geographical differences were noted (p = 0.49). No significant differences were seen among incidence in specific ethnic groups (p = 0.33) or income quartiles (p = 0.90). CONCLUSIONS: Our data shows that the incidence of CJD in 2016 appears to be equally distributed among individuals in the United States by demographic categories. Additionally, our case-study from 2019 illustrates an important example for diagnosing a rapidly-progressing case of CJD.

High activation and skewed T cell differentiation are associated with low IL-17A levels in a hu-PBL-NSG-SGM3 mouse model of HIV infection.

The humanized NOD/SCID/IL-2 receptor γ-chainnull (NSG) mouse model has been widely used for the study of HIV pathogenesis. Here, NSG mice with transgenic expression of human stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 (NSG-SGM3) were injected with peripheral blood leukocytes (PBL mice) from two HIV-infected (HIV+ ) patients who were under anti-retroviral therapy (ART; referred as HIV+ mice) or one HIV-seronegative healthy volunteer (HIV- ). Such mice are either hu-PBL-NSG-SGM3 HIV+ or HIV- mice, depending on the source of PBL. The kinetics of HIV replication and T cell responses following engraftment were evaluated in peripheral blood and secondary lymphoid tissues. High HIV replication and low CD4 : CD8 ratios were observed in HIV+ mice in the absence of anti-retroviral therapy (ART). Consistent with high activation and skewed differentiation of T cells from the HIV-infected donor, HIV+ mice exhibited a higher T cell co-expression of human leukocyte antigen D-related (HLA-DR) and CD38 than HIV- mice, as well as a shifted differentiation to a CCR7- CD45RA+ terminal effector profile, even in the presence of ART. In addition, HIV replication and the activation/differentiation disturbances of T cells were associated with decreased plasma levels of IL-17A. Thus, this hu-PBL-NSG-SGM3 mouse model recapitulates some immune disturbances occurring in HIV-infected patients, underlying its potential use for studying pathogenic events during this infection.

Blood lead levels in children in urban and rural areas: Using multilevel modeling to investigate impacts of gender, race, poverty, and the environment.

Many studies of children's exposure to lead (Pb) are carried out in urban and industrialized environments. This study analyzed blood lead level (BLL) data collected from 2011 to 2016 from approximately 140,000 children ages <1 to 6 years across South Carolina (SC), including urban and rural areas. Individual-level characteristics included children's age, and race/ethnicity. Block group variables examined included population by race and ethnicity, households below the poverty level, median year homes built, urban/rural classification, and percent road coverage. BLL were higher in urban compared to rural children but increased to a greater extent in rural children from age < 1 year to 2 years. Road coverage was strongly associated with higher BLL in urban areas, and with home age more weakly, but neither road coverage nor home age was associated with BLL in rural areas. Young urban children may receive greater exposure to Pb from house dust and outdoor legacy Pb contamination, and young rural children through diet and drinking water. Black children had higher BLL in urban areas than white children, and the converse was true in rural areas. Population data indicated that rural areas had more poverty than urban areas, but strong associations between increased children's BLL and either ethnicity or socio-economic status (SES) at the block group level was not observed, likely due to distinct characteristics of poverty and geographic distribution by ethnicity in urban as compared to rural areas of SC. Individual demographics and environmental characteristics may be more closely associated with BLL than geographically aggregated SES and race/ethnicity characteristics. Interventions to reduce children's exposure to Pb should occur at as early an age as possible, and differences between rural and urban areas should be considered as interventions are developed to reduce children's BLL.

Surgery Program Director Turnover Correlates With Residency Graduate Failure on American Board of Surgery Examinations in Civilian Residency Programs.

PURPOSE: The Review Committee for Surgery requires a minimum program director (PD) tenure of 6 years. The impact of PD turnover on the performance of program graduates is unknown. We hypothesize that (1) the majority of PDs step down before 6-year tenure and (2) higher PD turnover is associated with higher failure rate on American Board of Surgery (ABS) examinations. METHODS: Start and stop dates of all surgery PDs between January 1, 2000 and December 31, 2017 were obtained for civilian surgery programs. A Kaplan-Meier curve of PD "survival" was constructed. Programs were divided into High Turnover (HT; ≥4 PD changes, n = 33) and Low Turnover (LT; ≤3 PD changes, n = 191) groups. Five-year (2013-2017) ABS pass rates were also obtained. Pass rates and compliance with current standards were compared between groups. RESULTS: Kaplan-Meier analysis revealed that 40% of PDs do not comply with ACGME policy and serve <6 years. HT programs had lower mean pass rates on ABS certifying exam than LT programs (76% vs 83%, p < 0.01), but not qualifying exam (88% vs 88%). HT programs are less likely to meet the current 65% pass rate standard (82% vs 93%, p < 0.05). CONCLUSIONS: (1) An estimated 40% of general surgery PDs had tenures of <6 years. (2) Greater PD turnover is associated with lower ABS pass rates among general surgery graduates.

Sagittal plane walking biomechanics in individuals with knee osteoarthritis after quadriceps strengthening.

OBJECTIVE: To compare sagittal walking gait biomechanics between participants with knee osteoarthritis (KOA) who increased quadriceps strength following a lower-extremity strengthening intervention (responders) and those who did not increase strength following the same strengthening protocol (non-responders) both at baseline and following the lower extremity strengthening protocol. DESIGN: Fifty-three participants with radiographic KOA (47% female, 62.3 ± 7.1 years, BMI = 28.5 ± 3.9 kg/m2) were enrolled in 10 sessions of lower extremity strengthening over a 28-day period. Maximum isometric quadriceps strength and walking gait biomechanics were collected on the involved limb at baseline and 4-weeks following the strengthening intervention. Responders were classified as individuals who increased quadriceps strength greater than the upper limit of the 95% confidence interval (CI) for the minimal detectable change (MDC) in quadriceps strength (29 Nm) determined in a previous study. 2 × 2 functional analyses of variance were used to evaluate the effects of group (responders and non-responders) and time (baseline and 4-weeks) on time-normalized waveforms for knee flexion angle (KFA), vertical ground reaction force (vGRF), and internal knee extension moment (KEM). RESULTS: A significant group x time interaction for KFA demonstrated greater KFA in the first half of stance at baseline and greater knee extension in the second half of stance at 4-weeks in responders compared to non-responders. There was no significant group x time interaction for vGRF or internal KEM. CONCLUSIONS: Quadriceps strengthening may be used to stimulate small changes in KFA in individuals with KOA.

The molecular basis for the neofunctionalization of the juvenile hormone esterase duplication in Drosophila.

The Drosophila melanogaster enzymes juvenile hormone esterase (DmJHE) and its duplicate, DmJHEdup, present ideal examples for studying the structural changes involved in the neofunctionalization of enzyme duplicates. DmJHE is a hormone esterase with precise regulation and highly specific activity for its substrate, juvenile hormone. DmJHEdup is an odorant degrading esterase (ODE) responsible for processing various kairomones in antennae. Our phylogenetic analysis shows that the JHE lineage predates the hemi/holometabolan split and that several duplications of JHEs have been templates for the evolution of secreted ß-esterases such as ODEs through the course of insect evolution. Our biochemical comparisons further show that DmJHE has sufficient substrate promiscuity and activity against odorant esters for a duplicate to evolve a general ODE function against a range of mid-long chain food esters, as is shown in DmJHEdup. This substrate range complements that of the only other general ODE known in this species, Esterase 6. Homology models of DmJHE and DmJHEdup enabled comparisons between each enzyme and the known structures of a lepidopteran JHE and Esterase 6. Both JHEs showed very similar active sites despite low sequence identity (30%). Both ODEs differed drastically from the JHEs and each other, explaining their complementary substrate ranges. A small number of amino acid changes are identified that may have been involved in the early stages of the neofunctionalization of DmJHEdup. Our results provide key insights into the process of neofunctionalization and the structural changes that can be involved.