Achieving Digestive Autonomy and Gastrointestinal Continuity in a Patient with Short Bowel Syndrome Secondary to Concomitant Jejunal Atresia and Small Intestinal Hirschsprung's Disease.

Concomitant presentation of jejunal atresia and Hirschsprung's disease is rare and places children at high risk for developing short bowel syndrome and parenteral nutrition dependence, which can affect the feasibility/timing of pull-through. A patient was born with jejunal atresia with a delayed diagnosis of Hirschsprung's disease. After several procedures and bowel resections, the patient was ultimately left with an end jejunostomy and long Hartman's pouch with short bowel syndrome, dependent on parenteral nutrition. The patient initially presented to our institution at age 2 with failure to thrive secondary to an obstructed/dilated jejunostomy and mild enterocolitis of their defunctionalized segment. The patient subsequently underwent completion of subtotal colectomy and revision of jejunostomy utilizing a serial transverse enteroplasty to manage the dilated bowel and gain length. The patient was able to wean off parenteral nutrition and achieve nutritional autonomy by age 5. Following this, the patient was able to undergo an ileoanal pull-through. After the pull-through, the patient was able to pass stool independently and suffered no major complications to date. Serial transverse enteroplasty can be successfully utilized in patients with a history of Hirschsprung's disease and jejunal atresia to achieve nutritional autonomy and ultimately reestablish gastrointestinal continuity with pull-through.

Colonic Resection in an 8-Year-Old Girl with Intractable Functional Constipation and Diffuse Colonic Dysmotility and Failed Antegrade Flushes.

Optimal surgical management of patients with intractable constipation and diffuse colonic motility is not well defined. We present a patient with such a history, who ultimately achieved successful surgical management of constipation through a stepwise approach. An 8-year-old female presents with longstanding constipation and diffuse colonic dysmotility demonstrated with colonic manometry. She initially underwent sigmoid resection and cecostomy which failed and required diverting ileostomy. We initially proceeded with an extended resection, colonic derotation (Deloyers procedure), and neo-appendicostomy (neo-Malone) which resulted in successful spontaneous stooling for 1 year. Her constipation recurred and she subsequently underwent completion colectomy with ileorectal anastomosis given that she previously demonstrated ability to stool independently. Six months from surgery the patient continues to stool daily with assistance of fiber and loperamide. This case highlights a stepwise surgical approach to managing constipation due to diffuse colonic dysmotility and demonstrates that diffuse dysmotility may benefit from an upfront subtotal resection; however, it is crucial to assess a patient's ability to empty their rectum prior.

The impact of frailty on outcomes following laparoscopic repair of 'giant' paraesophageal hernias.

BACKGROUND: Frailty is a measure of physiologic reserve and correlates with surgical outcomes in the elderly. Patients who present with giant paraesophageal hernias (PEH) are typically older than 65. We defined 'giant' as a PEH with 50% or more of the stomach in the chest. We hypothesized that frailty correlates with 30-day complications, length of stay, and discharge destination following laparoscopic giant PEH repair. METHODS: Patients older than 65 to undergo primary laparoscopic repair of a giant PEH at a single academic medical center between 2015 and 2022 were included. Hernia size was determined by preoperative imaging. Frailty was assessed clinically prior to surgery using the modified Frailty Index (mFI), an 11-item instrument that counts clinical deficits associated with frailty. A score ≥ 3 was considered frail. A major complication was a Clavien grade IIIB or higher. RESULTS: Of the 162 patients included in the study, mean age was 74.4 ± 7.2, and 66% of patients were female (n = 128). The mFI was ≥ 3 in 37 patients (22.8%). Frail patients were older (78 ± 7.9 vs. 73 ± 6.6 years, p = 0.02). There was no difference in overall complication rate (40.5% vs. 29.6%, p = 0.22) or major complication rate (8.1% vs. 4.8%, p = 0.20) between frail and non-frail patients. Functionally impaired patients (METS < 4) were more likely to develop a major complication (17.9% vs. 3.0%, p < 0.01). Average length of stay was 2.4 days, and frail patients experienced a longer mean hospital stay (2.5 ± 0.2 vs. 2.3 ± 1.8, p = 0.03). Frail patients were more likely to be discharged to a destination other than home. CONCLUSION: Increased frailty as assessed by the mFI is correlated with length of stay and discharge destination following laparoscopic repair of giant PEH in patients > 65. Complication rates were comparable for both frail and non-frail cohorts.

The role of weight control in the management of type 2 diabetes mellitus: Bariatric surgery.

Diabetes mellitus is one of the major epidemics in the United States. It is heavily associated with obesity and multiple metabolic derangements that lead to long term morbidity, mortality as well as financial burden. Although medical therapy has been the mainstay in the management of diabetes mellitus, there remains a large portion of this patient population which struggles to obtain adequate glycemic control and long-term weight control with medical management alone. Bariatric surgery is a powerful tool in combating diabetes mellitus and affects glucose homeostasis through a variety of pathways. While it does provide a durable pathway for weight loss, improvement in glucose homeostasis is not only affected by the weight loss seen after bariatric surgery. Changes in gut hormone secretion, insulin regulation, and gut microbial composition also affect how these operations improve glucose homeostasis. Through improvement in the management of diabetes mellitus, comorbidities including cardiovascular disease, in turn demonstrate improvement. In this article, we will discuss the role of bariatric (metabolic) surgery as it relates to long term weight loss and the impact that weight loss has on improvement in diabetes mellitus.

Nationwide Bibliometric Analysis of Integrated Plastic Surgery Program Directors.

Studies have linked bibliometric indices with the academic level of plastic surgeons, but this relationship has not been explored with residency program directors (PDs). As teachers of the next generation, PDs' academic performance is an important component of residency program success. We sought to identify distinguishing characteristics of integrated plastic surgery programs, focusing on their PD bibliometric indices. Methods: We identified plastic surgery programs based on 2021 Doximity reputation and research output rankings, respectively, and then divided them into four quartiles (Q1-Q4). PD academic history and bibliometric indices (h-index, the number of publications, and citations) were collected through Doximity profiles and program websites: PubMed, Scopus, Google Scholar, American Society of Plastic Surgeons, and Accreditation Council for Graduate Medical Education. Results: Eighty-four programs were identified. There was a significant positive relationship between h-index, the number of publications, and type of research with reputation ranking (P < 0.05). After adjusting for years of experience post-training, h-index (OR = 1.24; P < 0.001) and the number of publications (OR = 1.05, P < 0.001) were significantly associated with reputation ranking. There was a statistically significant relationship between PD research fellowship completion and research output ranking (P < 0.01). After adjusting for years of experience post-training, h-index (OR = 1.05; P = 0.047) and the number of publications (OR = 1.01; P = 0.04) were significantly associated with research output ranking. Conclusion: Higher ranked programs tend to have PDs who have a strong record of scholarly activity, as evidenced by certain bibliometric indices.

Understanding Opioid Prescribing Practices of Resident Physicians.

BACKGROUND: To compare opioid prescribing practices of resident physicians across a variety of surgical and nonsurgical specialties; to identify factors which influence prescribing practices; and to examine resident utilization of best practice supplemental resources. METHODS: An anonymous survey which assessed prescribing practices was completed by residents from one of several different subspecialties, including internal medicine, obstetrics and gynecology, general surgery, neurosurgery, orthopedic surgery, and urology. Fisher's exact test assessed differences in prescribing practices between specialties. RESULTS: Only 35% of residents reported receiving formal training in safe opioid prescribing. Overall, the most frequently reported influences on prescribing practices were the use of standardized order sets for specific procedures, attending preference, and patient's history of prescribed opioids. Resident physicians significantly underutilize best practice supplemental resources, such as counseling patients on pain expectations prior to prescribing opioid medication; contacting established pain specialists; screening patients for opioid abuse; referring to the Prescription Monitoring Program; and counseling patients on safe disposal of unused pills (P < .001). DISCUSSION: The incorporation of comprehensive prescribing education into resident training and the utilization of standardized order sets can promote safe opioid prescribing.

Incidence and Characterization of Rectal Complications From Fecal Management Systems.

BACKGROUND: Fecal management systems have become ubiquitous in hospitalized patients with fecal incontinence or severe diarrhea, especially in the setting of perianal wounds. Although fecal management system use has been shown to be safe and effective in initial series, case reports of rectal ulceration and severe bleeding have been reported, with a relative paucity of clinical safety data in the literature. OBJECTIVE: The purpose of this study was to determine the rate of rectal complications attributable to fecal management systems, as well as to characterize possible risk factors and appropriate management strategies for such complications. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a large academic medical center. PATIENTS: All medical and surgical patients who underwent fecal management system placement from December 2014 to March 2017 were included. MAIN OUTCOME MEASURES: We measured any rectal complication associated with fecal management system use, defined as any rectal injury identified after fecal management system use confirmed by lower endoscopy. RESULTS: A total of 629 patients were captured, with a median duration of fecal management system use of 4 days. Overall, 8 patients (1.3%) experienced a rectal injury associated with fecal management system use. All of the patients who experienced a rectal complication had severe underlying comorbidities, including 2 patients on dialysis, 1 patient with cirrhosis, and 3 patients with a recent history of emergent cardiac surgery. In 3 patients the bleeding resolved spontaneously, whereas the remaining 5 patients required intervention: transanal suture ligation (n = 2), endoscopic clip placement (n = 1), rectal packing (n = 1), and proctectomy in 1 patient with a history of pelvic radiotherapy. LIMITATIONS: The study was limited by its retrospective design and single institution. CONCLUSIONS: This is the largest study to date evaluating rectal complications from fecal management system use. Although rectal injury rates are low, they can lead to serious morbidity. Advanced age, severe comorbidities, pelvic radiotherapy, and anticoagulation status or coagulopathy are important factors to consider before fecal management system placement. See Video Abstract at http://links.lww.com/DCR/B698. INCIDENCIA Y CARACTERIZACIN DE LAS COMPLICACIONES RECTALES DE LOS SISTEMAS DE MANEJO FECAL: ANTECEDENTES:Los sistemas de manejo fecal se han vuelto omnipresentes en pacientes hospitalizados con incontinencia fecal o diarrea severa, especialmente en el contexto de heridas perianales. Aunque se ha demostrado que el uso del sistema de tratamiento fecal es seguro y eficaz en la serie inicial, se han notificado casos de ulceración rectal y hemorragia grave, con una relativa escasez de datos de seguridad clínica en la literatura.OBJETIVO:Determinar la tasa de complicaciones rectales atribuibles a los sistemas de manejo fecal. Caracterizar los posibles factores de riesgo y las estrategias de manejo adecuadas para tales complicaciones.DISEÑO:Estudio de cohorte retrospectivo.ENTORNO CLINICO:Centro médico académico de mayor volumen.PACIENTES:Todos los pacientes médicos y quirúrgicos que se sometieron a la colocación del sistema de manejo fecal desde diciembre de 2014 hasta marzo de 2017.PRINCIPALES MEDIDAS DE VALORACION:Cualquier complicación rectal asociada con el uso del sistema de manejo fecal, definida como cualquier lesión rectal identificada después del uso del sistema de manejo fecal confirmada por endoscopia baja.RESULTADOS:Se identificaron un total de 629 pacientes, con una duración media del uso del sistema de manejo fecal de 4,0 días. En general, 8 (1,3%) pacientes desarrollaron una lesión rectal asociada con el uso del sistema de manejo fecal. Todos los pacientes que mostraron una complicación rectal tenían comorbilidades subyacentes graves, incluidos dos pacientes en diálisis, un paciente con cirrosis y tres pacientes con antecedentes recientes de cirugía cardíaca emergente. En tres pacientes el sangrado se resolvió espontáneamente, mientras que los cinco pacientes restantes requirieron intervención: ligadura de sutura transanal (2), colocación de clip endoscópico (1), taponamiento rectal (1) y proctectomía en un paciente con antecedentes de radioterapia pélvica.LIMITACIONES:Diseño retrospectivo, institución única.CONCLUSIONES:Este es el estudio más grande hasta la fecha que evalúa las complicaciones rectales del uso del sistema de manejo fecal. Si bien las tasas de lesión rectal son bajas, pueden provocar una morbilidad grave. La edad avanzada, las comorbilidades graves, la radioterapia pélvica y el estado de anticoagulación o coagulopatía son factores importantes a considerar antes de la colocación del sistema de manejo fecal. Consulte Video Resumen en http://links.lww.com/DCR/B698.

Lung surgery in children and their post-operative risk of respiratory infection.

PURPOSE: Pediatric surgeons at our institution are often asked by families about a theoretical increased risk of severe common upper respiratory infections in children status post lung resection. No data exist on this topic. We, therefore, aimed to examine the risk of severe respiratory infection in children after pulmonary resection. METHODS: A chart review was conducted on all pediatric patients who underwent pulmonary resection between August 1st, 2009 and January 31st, 2019. Collected data included patient characteristics, operation, complications and any admission for respiratory infection. RESULTS: Fifty-seven patients met inclusion criteria. Resections included lobectomy (45.6%), segmentectomy (14.0%), and wedge resection (40.4%). Twelve (21.1%) were immunocompromised and 6 (10.5%) had post-operative complications. Within 1 year of surgery, 2 (3.5%) patients were hospitalized for a viral upper respiratory illness (URI), 1 (1.8%) for bacterial pneumonia, and none due to influenza. CONCLUSION: In the general pediatric population, the risk of admission for respiratory illness is 3-21%. At this institution, overall risk of respiratory infection after lung resection appears comparable to baseline community risk. Our findings could aid counseling pediatric patients and their families regarding the 1-year risk of infection after lung resection.

Trends in Antibiotic Duration for Complicated Intra-Abdominal Infections : Adaptation to Current Guidelines.

INTRODUCTION: The 2017 surgical infection society (SIS) guidelines recommend 4 days of antibiotic therapy after source control for complicated intra-abdominal infections (cIAIs). Inappropriate exposure to antibiotics has a negative impact on outcomes in individual patients and populations. The goal of this study was to evaluate our institution's practice patterns and adherence to current antibiotic guidelines. METHODS: Medical records from 2010 to 2018 for cIAIs were examined. Complicated appendicitis and complicated diverticulitis cases were included. Exclusion criteria included other etiologies of IAIs, pediatric cases, and cancer operations. RESULTS: Fifty-nine complicated appendicitis cases and 96 complicated diverticulitis cases were identified. For all cases, antibiotic duration prior to publication of the SIS guidelines was significantly longer than post-SIS duration (appendicitis: 12.6 ± 1.1 days pre-SIS [n = 37] vs 9.0 ± 1.1 days post-SIS [n = 22], P = .01; diverticulitis: 15.1 ± 0.8 days pre-SIS [n = 49] vs 11.2 ± 0.5 post-SIS [n = 47], P = .04). Surgical management (SM) was associated with shorter duration of postsource control antibiotic exposure compared with percutaneous drainage (PD) for both appendicitis (SM 10.0 ± 1.2 days vs PD 13.4 ± 1.0 days, P = .02) and diverticulitis (SM 12.8 ± 1.5 days vs PD 16.0 ± 1.5, P = .07). Patients with complicated appendicitis received shorter duration of antibiotics when managed by acute care surgeons compared to general surgeons (8.4 ± 1.1 vs 11.9 ± 0.8, P = .02). CONCLUSION: Despite improvements after the SIS guidelines' publication, the antibiotic duration is still longer than recommended. Surgical intervention and management by acute care specialists were associated with a shorter duration of antibiotic exposure.

Global Contributions and Trends in Research within the Top-ranked Plastic Surgery Journal.

BACKGROUND: We aimed to longitudinally study the relative research contributions of US and international plastic surgeons by evaluating publications within the premier plastic surgery journal over the last 2 decades. We hypothesized that even with an increased pressure to publish in this journal, the relative research contributions from American plastic surgeons will continue to be the largest overall and in all subspecialties. METHODS: Data for the surgical subspecialty, corresponding author's country of origin, and region were extracted from all original articles in 2 randomly selected monthly issues of Plastic & Reconstructive Surgery (PRS) from the last 2 decades to evaluate longitudinal trends. Data were also extracted from all of the original articles published in PRS for the last 3 years to analyze the recent distribution of research output. RESULTS: During the last 2 decades, the relative proportion of total original articles written by US authors has increased. They have published proportionally more articles in the Reconstructive and Breast field while publishing relatively less in the hand/peripheral nerve field. From the first decade of analysis, US authors wrote relatively fewer articles in the hand/peripheral nerve field, whereas in the second decade, the US authors wrote relatively fewer articles in the Experimental field. In the last 3 years, US authors published relatively fewer articles in the Experimental and Cosmetic fields. CONCLUSIONS: Each country's scientific productivity in PRS is related to funding, interest, patients' demand, and healthcare market pressure. In this study, we see that these factors influence trends within research publications over the last 2 decades.

Evaluating the July Effect in Oral and Maxillofacial Surgery: Part I-Mandibular Fractures.

PURPOSE: The purpose of this study was to determine whether the timing of mandibular fracture repair within the academic year affects the complication rate using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. MATERIALS AND METHODS: The ACS-NSQIP database was accessed and queried from 2008 to 2017 for all Current Procedural Terminology codes pertaining to open treatment of mandibular fractures. The cases were stratified into 2 groups based on academic quarter: the quarter 1 (Q1) group (July-September) and the remaining-quarters group. The inclusion criteria encompassed all Current Procedural Terminology codes in the ACS-NSQIP registry that defined mandibular fractures and age greater than 18 years. Demographic characteristics, as well as medical and surgical complications, were compared between the 2 cohorts. Descriptive statistics were calculated to characterize and compare patient cohorts, and Fisher exact test and χ2 analyses were performed to compare complication rates between groups. RESULTS: The Q1 group included 614 cases, and the remaining-quarters group included 1,454. The most common individual complications included wound dehiscence (1.6% overall; 2.1% in Q1 group vs 1.4% in remaining-quarters group, P = .22), combined superficial and deep-space infection (4.9% overall; 4.4% in Q1 group vs 3.3% in remaining-quarters group; P = .91 and P = .21, respectively), and reoperation (3.9% overall; 4.6% in Q1 group vs 3.6% in remaining-quarters group, P = .29). Medical complications including acute kidney injury, venous thromboembolism, urinary tract infection, and sepsis or septic shock were rare (<1%). Complication rates did not significantly differ between the third quarter and the remainder of the year on bivariate analysis. CONCLUSIONS: Our results do not support the idea of a "July effect" regarding postoperative outcomes after mandibular fracture repair. Further studies are needed to elucidate this phenomenon within all procedures under the wide umbrella of the specialty.

Antithrombotic prescriptions for many general surgery patients significantly increases the likelihood of post-operative bleeding complications.

BACKGROUND: The investigators hypothesized that despite cessation recommendations for peri-operative antithrombotic management in the elective setting, the use of these drugs is likely associated with increased odds for bleeding complications. METHODS: Humana® insurance claims (22 million covered lives) from 2007 through 2017 were analyzed. Only patients undergoing elective general surgery procedures were included. Patient Safety Indicator 09 (PSI-09) coding for post-operative hemorrhage and hematoma were analyzed. RESULTS: Despite the existence of peri-operative management guidelines, patients prescribed antithrombotic agents were 2.3 times more likely to develop post-operative bleeding complications (OR: 2.3436, 95% CI: 2.2155-2.4792, P < 0.0001). Nearly all antithrombotics prescribed in the pre-operative period led to a two-fold increased likelihood of post-operative bleeding-the odds ratios of enoxaparin and rivaroxaban approached seven. CONCLUSION: The data should remind surgeons to closely monitor the peri-operative management and post-operative course of patients pre-operatively prescribed antithrombotics-especially enoxaparin and rivaroxaban given the high risk of postoperative bleeding complications.

Evaluating the July Effect in Oral and Maxillofacial Surgery: Part II-Orthognathic Surgery.

PURPOSE: The purpose of this study was to determine if there is an increased postoperative complication rate in orthognathic surgery during the first academic quarter (Q1) (July to September). MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was accessed to identify cases with Current Procedural Terminology codes pertaining to orthognathic procedures from 2008 to 2017. Procedures were separated into 2 groups based on time in the academic year: Q1 (July to September) versus remaining quarters (RQ). The inclusion criteria were Current Procedural Terminology codes representing operations resulting in movement of the dentate portion of the jaws and age of 18 years or older. Patient demographic characteristics and perioperative complications were compared between the groups. Descriptive statistics, Fisher exact tests, and χ2 tests were executed. RESULTS: The Q1 cohort included 877 cases, and the RQ cohort included 2,062 cases. The average age of patients was 47.0 ± 19.5 years in Q1 versus 47.2 ± 19.4 years in RQ. The most frequent complications were blood transfusion (11.97% in Q1 vs 12.57% in RQ, P = .64), reoperation (8.67% in Q1 vs 8.84% in RQ, P = .87), and combined superficial and deep-space infection (5.02% in Q1 vs 5.76% in RQ, P = .51). Medical complications involving other organ systems were rare (<1%). Analyses showed no significance between complication rate and time of year. CONCLUSIONS: The results of this study indicate that there is no association between time of year and complication rates after orthognathic surgery. Additional investigations could be useful in shining light on this topic as it pertains to the training of future surgeons.

Management of Teeth in the Line of Mandibular Angle Fractures Treated with Open Reduction and Internal Fixation: A Systematic Review and Meta-Analysis.

BACKGROUND: Mandibular angle fractures are common and frequently involve a tooth in the fracture line. Despite trends toward more conservative indications for tooth extraction during open repair, the literature remains heterogeneous. This review aims to ascertain the effect of tooth extraction/retention on patient outcomes following mandible open reduction and internal fixation and to evaluate the evidence surrounding indications for extraction. METHODS: PubMed, EMBASE, the Cochrane Library, Elsevier text mining tool database, and clinicaltrials.gov were queried through March of 2018 for English language publication on adults with traumatic mandibular fractures. The review protocol was not registered online. Quality of evidence was assigned using the Grading of Recommendations Assessment, Development and Evaluation methodology. Meta-analyses were performed when definitions of outcomes were deemed similar. RESULTS: Overall, 26 of 1212 identified studies met inclusion criteria. Indications for tooth extraction and rates of extraction varied considerably across studies. The quality of evidence was low or very low for all outcomes. Tooth retention was associated with lower overall complications (OR, 0.54; 95 percent CI, 0.37 to 0.79), major complications requiring readmission or reoperation (OR, 0.47; 95 percent CI, 0.24 to 0.92), and malocclusion (OR, 0.56; 95 percent CI, 0.32 to 0.97); there was no difference in wound issues or nonunion. Removal of asymptomatic teeth was associated with inferior alveolar nerve injury (39.4 percent versus 16.1 percent). CONCLUSIONS: The literature is limited by retrospective study deign and poor follow-up; however, when indicated, tooth extraction is not associated with an increased risk of infection or nonunion. Removal of asymptomatic teeth was associated with a risk of inferior alveolar nerve injury. Additional high-quality studies are needed to evaluate potentially expanded indications for tooth extraction.

Small-Molecule Positive Allosteric Modulators of the ß2-Adrenoceptor Isolated from DNA-Encoded Libraries.

Conventional drug discovery efforts at the ß2-adrenoceptor (ß2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first ß2AR small-molecule positive allosteric modulators (PAMs)-compound (Cmpd)-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs. We used purified human ß2ARs, occupied by a high-affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded Cmpd-6. It exhibits a low micro-molar affinity for the agonist-occupied ß2AR and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Cmpd-6 is cooperative with G protein and ß-arrestin1 (a.k.a. arrestin2) to stabilize high-affinity, agonist-bound active states of the ß2AR and potentiates downstream cAMP production and receptor recruitment of ß-arrestin2 (a.k.a. arrestin3). Cmpd-6 is specific for the ß2AR compared with the closely related ß1AR. Structure-activity studies of select Cmpd-6 analogs defined the chemical groups that are critical for its biologic activity. We thus introduce the first small-molecule PAMs for the ß2AR, which may serve as a lead molecule for the development of novel therapeutics. The approach described in this work establishes a broadly applicable proof-of-concept strategy for affinity-based discovery of small-molecule allosteric compounds targeting unique conformational states of GPCRs.

Detection of Lung Contour with Closed Principal Curve and Machine Learning.

Radiation therapy plays an essential role in the treatment of cancer. In radiation therapy, the ideal radiation doses are delivered to the observed tumor while not affecting neighboring normal tissues. In three-dimensional computed tomography (3D-CT) scans, the contours of tumors and organs-at-risk (OARs) are often manually delineated by radiologists. The task is complicated and time-consuming, and the manually delineated results will be variable from different radiologists. We propose a semi-supervised contour detection algorithm, which firstly uses a few points of region of interest (ROI) as an approximate initialization. Then the data sequences are achieved by the closed polygonal line (CPL) algorithm, where the data sequences consist of the ordered projection indexes and the corresponding initial points. Finally, the smooth lung contour can be obtained, when the data sequences are trained by the backpropagation neural network model (BNNM). We use the private clinical dataset and the public Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) dataset to measure the accuracy of the presented method, respectively. To the private dataset, experimental results on the initial points which are as low as 15% of the manually delineated points show that the Dice coefficient reaches up to 0.95 and the global error is as low as 1.47 × 10-2. The performance of the proposed algorithm is also better than the cubic spline interpolation (CSI) algorithm. While on the public LIDC-IDRI dataset, our method achieves superior segmentation performance with average Dice of 0.83.

Antibody-Mediated Internalization of Infectious HIV-1 Virions Differs among Antibody Isotypes and Subclasses.

Emerging data support a role for antibody Fc-mediated antiviral activity in vaccine efficacy and in the control of HIV-1 replication by broadly neutralizing antibodies. Antibody-mediated virus internalization is an Fc-mediated function that may act at the portal of entry whereby effector cells may be triggered by pre-existing antibodies to prevent HIV-1 acquisition. Understanding the capacity of HIV-1 antibodies in mediating internalization of HIV-1 virions by primary monocytes is critical to understanding their full antiviral potency. Antibody isotypes/subclasses differ in functional profile, with consequences for their antiviral activity. For instance, in the RV144 vaccine trial that achieved partial efficacy, Env IgA correlated with increased risk of HIV-1 infection (i.e. decreased vaccine efficacy), whereas V1-V2 IgG3 correlated with decreased risk of HIV-1 infection (i.e. increased vaccine efficacy). Thus, understanding the different functional attributes of HIV-1 specific IgG1, IgG3 and IgA antibodies will help define the mechanisms of immune protection. Here, we utilized an in vitro flow cytometric method utilizing primary monocytes as phagocytes and infectious HIV-1 virions as targets to determine the capacity of Env IgA (IgA1, IgA2), IgG1 and IgG3 antibodies to mediate HIV-1 infectious virion internalization. Importantly, both broadly neutralizing antibodies (i.e. PG9, 2G12, CH31, VRC01 IgG) and non-broadly neutralizing antibodies (i.e. 7B2 mAb, mucosal HIV-1+ IgG) mediated internalization of HIV-1 virions. Furthermore, we found that Env IgG3 of multiple specificities (i.e. CD4bs, V1-V2 and gp41) mediated increased infectious virion internalization over Env IgG1 of the same specificity, while Env IgA mediated decreased infectious virion internalization compared to IgG1. These data demonstrate that antibody-mediated internalization of HIV-1 virions depends on antibody specificity and isotype. Evaluation of the phagocytic potency of vaccine-induced antibodies and therapeutic antibodies will enable a better understanding of their capacity to prevent and/or control HIV-1 infection in vivo.

Oxygen Tension-Controlled Matrices with Osteogenic and Vasculogenic Cells for Vascularized Bone Regeneration In Vivo.

Despite recent progress, segmental bone defect repair is still a significant challenge in orthopedic surgery. While bone tissue engineering approaches using biodegradable matrices along with bone/blood vessel forming cells offered improved possibilities, current regenerative strategies lack the ability to achieve vascularized bone regeneration in critical-sized/segmental bone defects. In this study, we introduced and evaluated a two-pronged approach for vascularized bone regeneration in vivo. The goal was to demonstrate vascularized bone formation using oxygen tension-controlled (OTC) matrices seeded with bone and blood vessel forming cells. OTC matrices were coimplanted with rabbit mesenchymal stem cells (MSCs) and peripheral blood-derived endothelial progenitor cells (PB-EPCs) to demonstrate the osteogenic and vasculogenic differentiation of these cells, postseeding on a matrix, especially deep inside the matrix pore structure. Matrices coimplanted with varied rabbit MSC and PB-EPC ratios (1:4, 1:1, and 4:1) were assessed in a nude mouse subcutaneous implantation model to determine a coimplantation ratio with superior osteogenic as well as vasculogenic properties. The implants were analyzed, at week 8, for endothelial (CD31 and Von Willebrand factor [vWF]) and osteogenic marker (RunX2 and Col I) staining qualitatively and collagen deposition and number of vessel formation quantitatively. Results from these experiments established MSC-to-PB-EPC ratio 1:1 as the best coimplantation ratio. OTC matrix with 1:1 coimplantation ratio was assessed for segmental bone defect repair in a rabbit critical-sized bone defect model. The group under investigation was OTC matrix, and the matrix was seeded with MSCs, EPCs, or MSCs:EPCs in a 1:1 ratio. Explants at week 12 were evaluated for bone defect repair via micro-CT and histology. Results from rabbit in vivo experiments show enhanced mineralization and vascularization for the 1:1 coimplantation group. Overall, the study establishes a two-pronged approach involving OTC matrix and effective progenitors for large-area and vascularized bone regeneration.