Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How HepI glycans impact Ng infectivity and mAb 2C7 function are unknown and form the bases of this dissertation.

Using isogenic mutants, I demonstrate that HepI LOS glycans modulate mAb 2C7 binding. mAb 2C7 causes complement (C’)-dependent bacteriolysis of three (2-Hex/G+, 4-Hex/G+, and 5-Hex/G+) of the HepI mutants in vitro. The 3-Hex/G+ mutant (resistant to C’-dependent bacteriolysis) is killed by neutrophils in the presence of mAb and C’. In mice, 2- and 3-Hex/G+ infections are significantly shorter than 4- and 5-Hex/G+ infections. A chimeric mAb 2C7 that hyperactivates C’, attenuates only 4- and 5-Hex/G+ infections.

This study enhances understanding of the role of HepI LOS pv in gonococcal infections and shows that longer HepI glycans are necessary for prolonged infections in vivo. This is the first study that predicts in vitro efficacy of mAb 2C7 against all four targetable HepI glycans thereby strengthening the rationale for development of 2C7-epitope based vaccines and therapeutics.

Objective: To examine the association of changes in neighborhood-level racial residential segregation with changes in systolic and diastolic blood pressure over a 25-year period.

Design, Setting, and Participants: This observational study examined longitudinal data of 2280 black participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective investigation of adults aged 18 to 30 years who underwent baseline examinations in field centers in 4 US locations from March 25, 1985, to June 7, 1986, and then were re-examined for the next 25 years. Racial residential segregation was assessed using the Getis-Ord Gi* statistic, a measure of SD between the neighborhood's racial composition (ie, percentage of black residents) and the surrounding area's racial composition. Segregation was categorized as high (Gi* > 1.96), medium (Gi* 0-1.96), and low (Gi* < 0). Fixed-effects linear regression modeling was used to estimate the associations of within-person change in exposure to segregation and within-person change in blood pressure while tightly controlling for time-invariant confounders. Data analyses were performed between August 4, 2016, and February 9, 2017.

Main Outcomes and Measures: Within-person changes in systolic and diastolic blood pressure across 6 examinations over 25 years.

Results: Of the 2280 participants at baseline, 974 (42.7%) were men and 1306 (57.3%) were women. Of these, 1861 (81.6%) were living in a high-segregation neighborhood; 278 (12.2%), a medium-segregation neighborhood; and 141 (6.2%), a low-segregation neighborhood. Systolic blood pressure increased by a mean of 0.16 (95% CI, 0.06-0.26) mm Hg with each 1-SD increase in segregation score after adjusting for interactions of time with age, sex, and field center. Of the 1861 participants (81.6%) who lived in high-segregation neighborhoods at baseline, reductions in exposure to segregation were associated with reductions in systolic blood pressure. Mean differences in systolic blood pressure were -1.33 (95% CI, -2.26 to -0.40) mm Hg when comparing high-segregation with medium-segregation neighborhoods and -1.19 (95% CI, -2.08 to -0.31) mm Hg when comparing high-segregation with low-segregation neighborhoods after adjustment for time and interactions of time with baseline age, sex, and field center. Changes in segregation were not associated with changes in diastolic blood pressure.

Conclusions and Relevance: Decreases in exposure to racial residential segregation are associated with reductions in systolic blood pressure. This study adds to the small but growing body of evidence that policies that reduce segregation may have meaningful health benefits.

Objective: To quantify the influence of a large-scale communication training program on NH antipsychotic use called OASIS.

Design, Setting, and Participants: This investigation was a quasi-experimental longitudinal study of NHs in Massachusetts enrolled in the OASIS intervention. Participants were residents living in NHs between March 1, 2011, and August 31, 2013. The data were analyzed from December 2015, to March 2016, and from November through December 2016.

Exposures: The OASIS educational program targets all NH staff (direct care and nondirect care) using a train-the-trainer model. The program goals were to reframe challenging behaviors of residents with cognitive impairment as the communication of unmet needs, to train staff to anticipate resident needs, and to integrate resident strengths into daily care plans.

Main Outcomes and Measures: This study used an interrupted time series model of facility-level prevalence of antipsychotic medication use, other psychotropic medication use (antidepressants, anxiolytics, and hypnotics), and behavioral disturbances to evaluate the intervention's effectiveness in participating facilities compared with control NHs in Massachusetts and New York. The 18-month preintervention (baseline) period was compared with a 3-month training period, a 6-month implementation period, and a 3-month maintenance period.

Results: This study included 93 NHs enrolled in the OASIS intervention (27 of which had a high prevalence of antipsychotic use) compared with 831 nonintervention NHs. Among OASIS facilities, prevalences of atypical antipsychotic prescribing were 34.1% at baseline and 26.5% at the study end (absolute reduction of 7.6% and relative reduction of 22.3%) compared with a drop of 22.7% to 18.8% in the comparison facilities (absolute reduction of 3.9% and relative reduction of 17.2%). In the OASIS implementation phase, NHs experienced a reduction in antipsychotic use prevalence among OASIS facilities (-1.20%; 95% CI, -1.85% to -0.09% per quarter) greater than that among non-OASIS facilities (-0.23%; 95% CI, -0.47% to 0.01% per quarter), resulting in a net OASIS influence of -0.97% (95% CI, -1.85% to -0.09%; P = .03). A difference in trend was not sustained in the maintenance phase (difference of 0.93%; 95% CI, -0.66% to 2.54%; P = .48). No increases in other psychotropic medication use or behavioral disturbances were observed.

Conclusions and Relevance: Antipsychotic use prevalence declined during OASIS implementation of the intervention, but the decreases did not continue in the maintenance phase. Other psychotropic medication use and behavioral disturbances did not increase. This study adds evidence for nonpharmacological programs to treat behavioral and psychological symptoms of dementia.

IMPORTANCE: Viruses of the flaviviral family, including DENV and Zika virus transmitted by Aedes aegypti, continue to be a threat to global health by causing major outbreaks in tropical and subtropical regions, with no available direct-acting antivirals for treatment. A better understanding of the molecular requirements for the design of potent and specific inhibitors against flaviviral proteins will contribute to the development of targeted therapies for infections by these viruses. The cyclic peptides reported here as DENV protease inhibitors provide novel scaffolds that enable exploiting the prime side of the protease active site, with the aim of achieving better specificity and lower hydrophilicity than those of current scaffolds in the design of antiflaviviral inhibitors.

IMPORTANCE: The correlates analysis of the RV144 HIV-1 vaccine trial suggested that the presence of antibodies to the V1V2 region of HIV-1 gp120 was responsible for the modest protection observed in the trial. In addition, V1V2 harbors one of the key vulnerable sites of HIV-1 Env recognized by a family of broadly neutralizing MAbs such as PG9. Thus, V1V2 is a key target for vaccine development. However, this vulnerable site is structurally polymorphic, and designing immunogens that present different conformations is crucial for targeting this site. We show here that such immunogens can be designed and that they induced conformation-specific antibody responses in rabbits. Our immunogens are therefore prototypes of vaccine candidates targeting the V1V2 region of HIV-1 Env.

IMPORTANCE: Novel immunogens were designed to focus the antibody response of rabbits on the V1V2 epitopes of HIV-1 gp120 since such antibodies were associated with reduced infection rates of HIV, SIV, and SHIV. The vaccine-induced antibodies were broadly cross-reactive with the V1V2 regions of HIV subtypes B, C and E and, importantly, facilitated Fc-mediated phagocytosis, an activity not induced upon immunization of rabbits with gp120. This is the first immunogenicity study of vaccine constructs that focuses the antibody response on V1V2 and induces V2-specific antibodies with the ability to mediate phagocytosis, an activity that has been associated with protection from infection with HIV, SIV, and SHIV.

METHODS: Deidentified datasets containing numbers of physicians trained, orders by physicians and hospitals, and designs (fenestration/scallop configuration) was provided for U.S. ZFEN devices ordered (April 2012-August 2015). We evaluated the number of physicians trained, the number of devices ordered, hospital characteristics, and fenestration/scallop design configurations. Cook Medical assembled the datasets but played no role in study design, analysis, or interpretation of data.

RESULTS: Between April 2012 and August 2015, 553 physicians attended formal ZFEN training sessions, 388 (70%) of whom ordered a total of 2669 devices. An increase in orders per month (nine in June 2012 and 91 in August 2015, 911% growth; P < .001) and in number of physicians ordering per month (eight in June 2012 and 62 in August 2015, 675% growth; P < .001) was observed. Teaching hospitals, representing all U.S. regions (Midwest 927, 35%; South 799, 30%; Northeast 547, 20%; West 396, 15%), accounted for 1703 (64%) ZFEN orders. Of 553 trained physicians, 165 (30%) ordered no devices, 116 (21%) ordered 1 device, 144 (26%) ordered 2-5 devices, 61 (11%) ordered 6-10 devices, 39 (7%) ordered 11-20, and 28 (5%) ordered > 20 devices. For physicians contributing > 6 months of data (n = 336), the average number of devices ordered per year was three (standard deviation, 4); 272 (81%) ordered < /= 5 devices/year, 15 (4.5%) ordered 11-20 devices/year, and 3 (0.9%) ordered > 20 devices/year. Of devices with design details available (2618 of 2669; 98%), most common designs were 2 small fenestrations/1 scallop (1443; 55%), 2 small fenestrations/1 large fenestration (568; 22%), 1 small fenestration/1 scallop (173, 6.6%), and 2 small fenestrations (169; 6.5%). The average number of target vessels incorporated in each design was 2.7/device; 2071 (79%) incorporated three, 398 (15%) incorporated two.

CONCLUSIONS: Since 2012, ZFEN has demonstrated a ninefold increase in monthly orders, with 553 physicians trained. Unlike the experience of rapid dissemination seen with infrarenal endografts, only 28 (5%) physicians have ordered > 20, whereas 165 (30%) have ordered none, and 272 (81%) ordered < /= 5 devices/year. Assuming that volume, in general, correlates with outcomes, this adoption pattern raises questions whether fenestrated technology should be regionalized to high-volume centers.

METHODS: Participants underwent a 1.5-day course covering open and endovascular procedures on high-fidelity simulators and cadavers. Before and after the course, participants completed a written test that assessed procedural knowledge concerning index open vascular and endovascular procedures. Participants also assessed their own procedural competence in open and endovascular procedures on a 5-point Likert scale (1: no ability to perform, 5: performs independently). Scores before and after the course were compared among postgraduate year (PGY) 1-2 and PGY 3-7 trainees. Participants completed a survey to rate the relevance and realism of open and endovascular simulations.

RESULTS: Fifty-eight vascular integrated residents and vascular fellows (PGY 1-7) completed the course and all assessments. After course participation, procedural knowledge scores were significantly improved among PGY 1-2 residents (50% correct before vs 59% after; P < .0001) and PGY 3-7 residents (52% correct before vs 63% after; P = .003). Self-rated procedural competence was significantly improved among PGY 1-2 (2.2 +/- 0.1 before vs 3.1 +/- 0.1 after; P < .0001) and PGY 3-7 (3.0 +/- 0.1 before vs 3.7 +/- 0.1 after; P < /= .0001). Self-rated procedural competence significantly improved for both endovascular (2.4 +/- 0.1 before vs 3.3 +/- 0.1 after; P < .0001) and open procedures (2.7 +/- 0.1 before vs 3.5 +/- 0.1 after; P < .0001). More than 93% of participants reported they were "satisfied" or "very satisfied" with the relevance and realism of the open and endovascular simulations. All participants reported they would recommend the course to other trainees.

CONCLUSIONS: This intensive vascular surgical skills and simulation course improved procedural knowledge concerning index open vascular and endovascular procedures among PGY 1-2 and PGY 3-7 trainees. The course also improved self-rated procedural competence across all levels of training for open and endovascular procedures. Trainees rated the value of a surgical skills and simulation course highly. These results support strong consideration for the implementation of similar intensive simulation and surgical skills courses with ongoing objective assessment of their educational effect.

METHODS: This is a single-center, prospective, observational cohort study evaluating 30-day and 1-year outcomes in all consecutive patients who underwent fenestrated and branched endovascular repair of complex aortic aneurysms (definition: requiring one or more fenestrations or branches). Data were collected prospectively through an Institutional Review Board-approved registry and a physician-sponsored investigational device exemption clinical trial (G130210).

RESULTS: We performed 100 consecutive complex endovascular aortic aneurysm repairs (November 2010 to March 2016) using 58 (58%) commercially manufactured custom-made devices and 42 (42%) physician-modified devices to treat 4 (4%) common iliac, 42 (42%) juxtarenal, 18 (18%) pararenal, and 36 (36%) thoracoabdominal aneurysms (type I, n = 1; type II, n = 4; type III, n = 12; type IV, n = 18; arch, n = 1). The repairs included 309 fenestrations, branches, and scallops (average of 3.1 branch arteries/case). All patients had 30-day follow-up for 30-day event rates: three (3%) deaths; six (6%) target artery occlusions; five (5%) progressions to dialysis; eight (8%) access complications; one (1%) paraparesis; one (1%) bowel ischemia; and no instances of myocardial infarction, paralysis, or stroke. Of 10 type I or type III endoleaks, 8 resolved (7 with secondary intervention, 1 without intervention). Mean follow-up time was 563 days (interquartile range, 156-862), with three (3%) patients lost to follow-up. On 1-year Kaplan-Meier analysis, survival was 87%, freedom from type I or type III endoleak was 97%, target vessel patency was 92%, and freedom from aortic rupture was 100%. Average lengths of intensive care unit stay and inpatient stay were 1.4 days (standard deviation, 3.3) and 3.6 days (standard deviation, 3.6), respectively.

CONCLUSIONS: These results show that complex aortic aneurysms can now be treated with minimally invasive fenestrated and branched endovascular repair. Endovascular technologies will likely continue to play an increasingly important role in the management of patients with complex aortic aneurysm disease.

METHODS: We performed a cluster-randomized trial of current adult smokers referred to eight vascular surgery practices from September 1, 2014, to July 31, 2015. A three-component smoking cessation intervention (physician advice, nicotine replacement therapy, and telephone-based quitline referral) was compared with usual care. The primary outcome was smoking cessation for 7 days, assessed 3 months after the intervention. Secondary outcomes were patients' nicotine dependence and health expectancies of smoking assessed using Patient Reported Outcomes Measurement Information System (PROMIS; RAND Corporation, Santa Monica, Calif).

RESULTS: We enrolled 156 patients (65 in four intervention practices, 91 in four control practices), and 141 (90.3%) completed follow-up. Patients in the intervention and control practices were similar in age (mean, 61 years), sex (68% male), cigarettes per day (mean, 14), and prior quit attempts (77%). All three components of the intervention were delivered to 75% of patients in intervention practices vs to 7% of patients at control practices (P < .001). At 3 months, 23 of 57 patients (40.3%) in the intervention group quit smoking (23 of 56 patients quit who completed follow-up, plus 1 death included in the analysis in the denominator as a smoker), and 26 of 84 patients (30.9%) In the control group quit smoking (26 patients of 84 who completed follow-up, including 2 deaths included in the denominator as smokers). This difference (40.3% quit rate in intervention, 31% quit rate in control; P = .250) was not statistically significant in crude analyses (P = .250) or analyses adjusted for clustering (P = .470). Multivariable analysis showed factors associated with smoking cessation were receipt of physician advice (odds ratio for cessation, 1.96; 95% confidence interval, 1.28-3.02; P < .002) and nicotine replacement therapy (odds ratio, 1.92; 95% confidence interval, 1.43-2.56; P < .001).

CONCLUSIONS: Implementation of a brief, surgeon-delivered smoking cessation intervention is feasible for patients with peripheral arterial disease. A larger trial will be necessary to determine whether this is effective for smoking cessation.

METHODS: At the UMass Memorial Center for Complex Aortic Disease, a vascular surgeon with experience in medical finances is supported to manage the billing and coding of FEVAR procedures for medical center and physician reimbursement. A comprehensive financial analysis was performed for all FEVAR procedures (2011-2015), independent of insurance status, patient presentation, or type of device used. Medical center CM (actual reimbursement minus direct costs) was determined for each index FEVAR procedure and for all related subsequent procedures, inpatient or outpatient, 3 months before and 1 year subsequent to the index FEVAR procedure. Medical center CM for outpatient clinic visits, radiology examinations, vascular laboratory studies, and cardiology and pulmonary evaluations related to FEVAR were also determined. Surgeon reimbursement for index FEVAR procedure, related adjunct procedures, and assistant surgeon reimbursement were also calculated. All financial analyses were performed and adjudicated by the UMass Department of Finance.

RESULTS: The index hospitalization for 63 FEVAR procedures incurred $2,776,726 of direct costs and generated $3,027,887 in reimbursement, resulting in a positive CM of $251,160. Subsequent related hospital procedures (n = 26) generated a CM of $144,473. Outpatient clinic visits, radiologic examinations, and vascular laboratory studies generated an additional CM of $96,888. Direct cost analysis revealed that grafts accounted for the largest proportion of costs (55%), followed by supplies (12%), bed (12%), and operating room (10%). Total medical center CM for all FEVAR services was $492,521. Average surgeon reimbursements per FEVAR from 2011 to 2015 increased from $1601 to $2480 while the surgeon payment denial rate declined from 50% to 0%. Surgeon-led negotiations with the Centers for Medicare and Medicaid Services during 2015 resulted in a 27% increase in physician reimbursement for the remainder of 2015 ($2480 vs $3068/case) and a 91% increase in reimbursement from 2011 ($1601 vs $3068). Assistant surgeon reimbursement also increased ($266 vs $764). Concomitant FEVAR-related procedures generated an additional $27,347 in surgeon reimbursement.

CONCLUSIONS: Physician leadership in the coding, billing, and contractual negotiations for FEVAR results in a positive medical center CM and increased physician reimbursement.

METHODS: We stratified limbs from a prospectively maintained database of consecutive patients referred to a limb preservation center according to WIfI stage (October 2013-May 2015). Comorbidities, multimodal limb treatment, including foot operations and revascularization, and patient-centered outcomes (wound healing, limb salvage, amputation-free survival, maintenance of ambulatory and independent living status, and mortality) were compared among WIfI stages. Multivariate analysis was performed to identify predictors of wound healing and limb salvage.

RESULTS: We identified 280 threatened limbs encompassing all WIfI stages in 257 consecutive patients: stage 1, 48 (17%); stage 2, 67 (24%); stage 3, 64 (23%); stage 4, 83 (30%); and stage 5 (unsalvageable), 18 (6%). Operative foot debridement, minor amputation, and use of revascularization increased with increasing WIfI stage (P

CONCLUSIONS: In patients treated aggressively for limb salvage, WIfI stage correlated with intensity of multimodal limb treatment and with limb salvage and patient-centered outcomes at 1 year. Revascularization improved limb salvage in severe ischemia. These data support the Society for Vascular Surgery WIfI system as a powerful tool to risk-stratify patients with threatened limbs and guide treatment.

METHODS: A pair-matched cluster-randomized controlled school-based trial was conducted in which 8 public high schools were randomized to either a 12-session school nurse-delivered cognitive-behavioral counseling intervention plus school-based after school exercise program, or 12-session nurse contact with weight management information (control). Overweight or obese adolescents (N = 126) completed anthropometric and behavioral assessments at baseline and 8-month follow-up. Main outcome measures included diet, activity, and BMI. Mixed effects regression models were conducted to examine differences at follow-up.

RESULTS: At follow-up, students in intervention compared with control schools were not different in BMI, percent body fat, and waist circumference. Students reported eating breakfast (adjusted mean difference 0.81 days; 95% confidence interval [CI] 0.11-1.52) on more days/week; there were no differences in other behaviors targeted by the intervention.

CONCLUSIONS: While a school-based intervention including counseling and access to an after-school exercise program is theoretically promising with public health potential, it was not effective in reducing BMI or key obesogenic behaviors. Our findings are important in highlighting that interventions targeted at the individual level are not likely to be sufficient in addressing the adolescent obesity epidemic without changes in social norms and the environment.

Methods and Materials: Imaging the World Africa (ITWA) is the registered non-governmental organization division of Imaging the World (ITW), a not-for-profit organization whose primary aim is the integration of affordable high-quality ultrasound into rural health centers. In 2013, ITWA began the pilot phase of an IRB-approved breast care protocol at a rural health center in Uganda. As part of the protocol’s diagnostic arm, an ultrasound-guided percutaneous breast core biopsy training curriculum was implemented in tandem with creation of regionally supplied biopsy kits.

Results: A surgeon at a rural regional referral hospital was successfully trained and certified to perform ultrasound-guided percutaneous breast core biopsies. Affordable and safe biopsy kits were created using locally available medical supplies with the cost of each kit totaling $10.62 USD.

Conclusion: Successful implementation of an ultrasound-guided percutaneous breast core biopsy program in the resource-limited setting is possible and can be made sustainable through incorporation of local health care personnel and regionally supplied biopsy materials. Our hope is that ITWA’s initial experience in rural Uganda can serve as a model for similar programs in the future.

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