Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection.

Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, and immunization induces antigen-specific responses that can kill S. Typhi in vitro and control S. Typhi in vivo. Our results indicate that CC003/Unc and CC053/Unc strains can help identify the genetic basis for typhoid susceptibility, S. Typhi virulence mechanism(s) in vivo, and serve as a preclinical mammalian model system to identify effective vaccines and therapeutics strategies.

The Lack of Natural IgM Increases Susceptibility and Impairs Anti-Vi Polysaccharide IgG Responses in a Mouse Model of Typhoid.

Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity of S. Typhimurium infection in mice is dependent on presence of the natural resistance-associated macrophage protein 1 (Nramp1) allele; therefore, we infected mice deficient in secreted form of IgM (sIgM) on either a Nramp1-resistant (129S) or -susceptible (C57BL/6J) background. We found that the lack of natural IgM results in a significantly increased susceptibility and an exaggerated liver pathology regardless of the route of infection or the Nramp1 allele. Reconstitution of sIgM-/- mice with normal mouse serum or purified polyclonal IgM restored the resistance to that of sIgM+/+ mice. Furthermore, immunization of sIgM-/- mice with heat-killed S. Typhi induced a significantly reduced anti-ViPS IgG and complement-dependent bactericidal activity against S. Typhi in vitro, compared with that of sIgM+/+ mice. These findings indicate that natural IgM is an important factor in reducing the typhoid severity and inducing an optimal anti-ViPS IgG response to vaccination.

Anesthetic Considerations for a Novel Method of Surgical Ventricular Remodeling Using the BioVentrix Revivent TC System.

Surgical ventricular remodeling (SVR) is an invasive method of treating patients with heart failure who also have ischemic cardiomyopathy and reduced ejection fraction (EF). Introduced in the mid-1980s, this technique was met with varying success and relatively high morbidity and mortality despite its theoretical benefits. The development of the BioVentrix Revivent TC System (BioVentrix, Inc., San Ramon, CA) as a less-invasive method of surgical ventricular remodeling has created a novel, multidisciplinary approach to heart failure management, which necessitates multiple subspecialties. Currently in the trial phase in the United States and widely used in Europe, the positive results to date appear promising for the rapid adoption of this procedure. For the cardiac anesthesiologist, a thorough understanding of the patient population, procedural goals, and intraoperative management is essential. This overview discusses the advancement in surgical ventricular remodeling, the pertinent surgical steps of the BioVentrix Revivent TC System placement, and specific anesthetic considerations for this novel procedure.

To Clot or Not: HELLP Syndrome and Disseminated Intravascular Coagulation in an Eclamptic Patient with Intrauterine Fetal Demise.

A 39-year-old G2P1001 female presented from an outside hospital following an eclamptic seizure in the setting of HELLP syndrome. This condition was complicated by intrauterine fetal demise and disseminated intravascular coagulation, which required an emergent cesarean section. We report the work-up and intraoperative and postoperative management of this complex patient with multiple medical needs. We focus on the hemostatic abnormalities in this patient and describe how our management would differ from that of a similar, nonpregnant patient.

A stepped-wedge randomized trial protocol of a community intervention for increasing lung screening through engaging primary care providers (I-STEP).

Lung cancer screening with low-dose computed tomography (LDCT) reduces lung cancer mortality, yet few eligible high-risk patients receive it annually. This protocol describes a community-partnered intervention (Toolkit) designed to support primary care practices in making referrals for lung screening and guiding patients into appropriate screening pathways. This study uses a stepped-wedge implementation design. Screening centers are randomized by readiness level to enter the intervention phase in three-month "steps" with pre-intervention data serving as the control. The primary outcome is whether delivery of the Toolkit to primary care practices results in a monthly increase in number of initial LDCT screenings. Six participating centers will identify 10 practices and reach 2-3 providers per practice to train them to use the Toolkit. The Toolkit will address known barriers to screening and referral at the patient and provider levels and provide support for required elements of screening. Toolkit components include adaptable evidence-based interventions to maximize compatibility with workflows. We hypothesize that after nine months of intervention delivery, the number of initial screening per center will double. Involving 60 practices achieves 80% power at 5% level of significance. Implementation outcomes such as adoption, acceptability, feasibility, adaptation, and sustainability will be assessed through field-notes and activity logs. LDCT for lung cancer screening currently reaches a small fraction of eligible adults. To reach the full potential to reduce mortality, primary care practices are an important venue for increasing appropriate referrals. This multidisciplinary trial will encourage acceptability and sustainability by using local knowledge and promoting partnership between providers and patients. Trial registration: ClinicalTrials.gov, NCT03958253.

Desert crossing strategies of migrant songbirds vary between and within species.

Each year, billions of songbirds cross large ecological barriers during their migration. Understanding how they perform this incredible task is crucial to predict how global change may threaten the safety of such journeys. Earlier studies based on radar suggested that most songbirds cross deserts in intermittent flights at high altitude, stopping in the desert during the day, while recent tracking with light loggers suggested diurnal prolongation of nocturnal flights and common non-stop flights for some species. We analyzed light intensity and temperature data obtained from geolocation loggers deployed on 130 individuals of ten migratory songbird species, and show that a large variety of strategies for crossing deserts exists between, but also sometimes within species. Diurnal stopover in the desert is a common strategy in autumn, while most species prolonged some nocturnal flights into the day. Non-stop flights over the desert occurred more frequently in spring than in autumn, and more frequently in foliage gleaners. Temperature recordings suggest that songbirds crossed deserts with flight bouts performed at various altitudes according to species and season, along a gradient ranging from low above ground in autumn to probably >2000 m above ground level, and possibly at higher altitude in spring. High-altitude flights are therefore not the general rule for crossing deserts in migrant songbirds. We conclude that a diversity of migration strategies exists for desert crossing among songbirds, with variations between but also within species.

Interposition Arthroplasty of the Elbow Utilizing a Lateral Epicondyle Osteotomy.

Management of severe elbow arthritis in young or active patients presents a challenging problem. Interposition arthroplasty is a useful salvage procedure for these patients but has a significant failure rate associated with postoperative instability. Previous studies have sought to preserve the integrity of the medial elbow ligament complex to decrease postoperative instability and the need for external fixation. Our lateral epicondylar osteotomy technique preserves the native lateral elbow ligament complex. Potential advantages include bone-to-bone healing of the osteotomy, decreased postoperative instability, and the decreased need for and associated costs and potential complications of supplemental external fixation.

Rat Bite Fever: A Case Report and Review of the Literature.

Cases of rat-bite fever (RBF) were reported in the literature for more than 2000 years. Not until recently, however, were attempts made to differentiate between RBF and Streptobacillus moniliformis septic arthritis, 2 arguably different clinical entities. There are limited data regarding S moniliformis septic arthritis and the features that distinguish it from RBF, and most conclude that although clinically disparate diseases, it is difficult to differentiate between them. We report a case of a 17-year-old girl who presented with S moniliformis bacteremia and symptoms that spanned both RBF and S moniliformis septic arthritis. This case emphasizes the difficulty in differentiating the 2 clinical entities and the importance of early diagnosis, proper clinical suspicion, and prompt treatment to achieve positive outcomes.

A tissue communication network coordinating innate immune response during muscle stress.

Complex tissue communication networks function throughout an organism's lifespan to maintain tissue homeostasis. Using the genetic model Drosophila melanogaster, we have defined a network of immune responses that are activated following the induction of muscle stresses, including hypercontraction, detachment and oxidative stress. Of these stressors, loss of the genes that cause muscle detachment produced the strongest levels of JAK-STAT activation. In one of these mutants, fondue (fon), we also observe hemocyte recruitment and the accumulation of melanin at muscle attachment sites (MASs), indicating a broad involvement of innate immune responses upon muscle detachment. Loss of fon results in pathogen-independent Toll signaling in the fat body and increased expression of the Toll-dependent antimicrobial peptide Drosomycin. Interestingly, genetic interactions between fon and various Toll pathway components enhance muscle detachment. Finally, we show that JAK-STAT and Toll signaling are capable of reciprocal activation in larval tissues. We propose a model of tissue communication for the integration of immune responses at the local and systemic level in response to altered muscle physiology.

Terminal Deoxynucleotidyl Transferase Is Not Required for Antibody Response to Polysaccharide Vaccines against Streptococcus pneumoniae and Salmonella enterica Serovar Typhi.

B cell antigen receptor (BCR) diversity increases by several orders of magnitude due to the action of terminal deoxynucleotidyl transferase (TdT) during V(D)J recombination. Unlike adults, infants have limited BCR diversity, in part due to reduced expression of TdT. Since human infants and young mice respond poorly to polysaccharide vaccines, such as the pneumococcal polysaccharide vaccine Pneumovax23 and Vi polysaccharide (ViPS) of Salmonella enterica serovar Typhi, we tested the contribution of TdT-mediated BCR diversity in response to these vaccines. We found that TdT+/- and TdT-/- mice generated comparable antibody responses to Pneumovax23 and survived Streptococcus pneumoniae challenge. Moreover, passive immunization of B cell-deficient mice with serum from Pneumovax23-immunized TdT+/- or TdT-/- mice conferred protection. TdT+/- and TdT-/- mice generated comparable levels of anti-ViPS antibodies and antibody-dependent, complement-mediated bactericidal activity against S Typhi in vitro To test the protective immunity conferred by ViPS immunization in vivo, TdT+/- and TdT-/- mice were challenged with a chimeric Salmonella enterica serovar Typhimurium strain expressing ViPS, since mice are nonpermissive hosts for S Typhi infection. Compared to their unimmunized counterparts, immunized TdT+/- and TdT-/- mice challenged with ViPS-expressing S Typhimurium exhibited a significant reduction in the bacterial burden and liver pathology. These data suggest that the impaired antibody response to the Pneumovax23 and ViPS vaccines in the young is not due to limited TdT-mediated BCR diversification.

IL-7 Enables Antibody Responses to Bacterial Polysaccharides by Promoting B Cell Receptor Diversity.

Polysaccharide vaccines such as the Vi polysaccharide (ViPS) of Salmonella enterica serovar Typhi induce efficient Ab responses in adults but not in young children. The reasons for this difference are not understood. IL-7 dependency in B cell development increases progressively with age. IL-7Rα-mediated signals are required for the expression of many VH gene segments that are distal to DH-JH in the IgH locus and for the complete diversification of the BCR repertoire. Therefore, we hypothesized that B cells generated in the absence of IL-7 do not recognize a wide range of Ags because of a restricted BCR repertoire. Compared with adult wildtype mice, young wildtype mice and IL-7-deficient adult mice generated a significantly reduced Ab response to ViPS. Additionally, ViPS-binding B cells in adult wildtype mice predominantly used distal VH gene segments. Transgenic expression of either IL-7 or a BCR encoded by a distal VH gene segment permitted young mice to respond efficiently to bacterial polysaccharides. These results indicate that restricted VH gene usage early in life results in a paucity of Ag-specific B cell precursors, thus limiting antipolysaccharide responses.

An Unmutated IgM Response to the Vi Polysaccharide of Salmonella Typhi Contributes to Protective Immunity in a Murine Model of Typhoid.

T cell-dependent B cell responses typically develop in germinal centers. Abs generated during such responses are isotype switched and have a high affinity to the Ag because of somatic hypermutation of Ab genes. B cell responses to purified polysaccharides are T cell independent and do not result in the formation of bona fide germinal centers, and the dominant Ab isotype produced during such responses is IgM with very few or no somatic mutations. Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation and Ig isotype switching in humans and mice. To test the extent to which unmutated polysaccharide-specific IgM confers protective immunity, we immunized wildtype and AID-/- mice with either heat-killed Salmonella enterica serovar Typhi (S. Typhi) or purified Vi polysaccharide (ViPS). We found that wildtype and AID-/- mice immunized with heat-killed S. Typhi generated similar anti-ViPS IgM responses. As expected, wildtype, but not AID-/- mice generated ViPS-specific IgG. However, the differences in the Ab-dependent killing of S. Typhi mediated by the classical pathway of complement activation were not statistically significant. In ViPS-immunized wildtype and AID-/- mice, the ViPS-specific IgM levels and S. Typhi bactericidal Ab titers at 7 but not at 28 d postimmunization were also comparable. To test the protective immunity conferred by these immunizations, mice were challenged with a chimeric S. Typhimurium strain expressing ViPS. Compared with their naive counterparts, immunized wildtype and AID-/- mice exhibited significantly reduced bacterial burden regardless of the route of infection. These data indicate that an unmutated IgM response to ViPS contributes to protective immunity to S. Typhi.

Humoral Immunity in Mice Transplanted with Hematopoietic Stem Cells Derived from Human Umbilical Cord Blood Recapitulates That of Human Infants.

Immunodeficient mice transplanted with human hematopoietic stem cells (HSCs) have been referred to as "Human Immune System" (HIS) mice and are a translational platform for studying human immune responses in vivo. Human HSC sources used in generating HIS mice include fetal liver (FL), umbilical cord blood (CB), and adult bone marrow (BM). Since HSCs from FL, CB, and BM are produced at various stages of human development, we tested whether mice transplanted with these three HSCs differ in their immune responses. We found that compared with CB HSCs or FL HSCs, adult BM HSCs reconstitute the immune system poorly. The resulting HIS mice do not mount an antibody response to Borrelia hermsii infection and as a consequence suffer persistently high levels of bacteremia. While both CB and FL HSCs yield comparable levels of immune reconstitution of HIS mice resulting in robust anti-B. hermsii immune responses, FL HSC-transplanted mice exhibited a discernable difference in their human B cell maturity as identified by an increased frequency of CD10+ immature B cells and relatively smaller lymphoid follicles compared with CB HSC-transplanted mice. Although CB HSC-transplanted mice generated robust antibody responses to B. hermsii and specific protein antigens of B. hermsii, they failed to respond to Salmonella typhi Vi polysaccharide, a classical T cell-independent antigen. This situation resembles that seen in human infants and young children. Therefore, CB HSC-transplanted mice may serve as a translation platform to explore approaches to overcome the impaired antipolysaccharide responses characteristic of human infants.

Surgeon Attitudes Regarding the Use of Generic Implants: An OTA Survey Study.

OBJECTIVES: To determine the role of generic orthopaedic trauma implants in the current orthopaedic trauma market, as perceived by OTA members, and investigate potential hurdles to the use of generic implants and other cost-containment measures. DESIGN: Survey study. SETTING: Not applicable. PARTICIPANTS: All active OTA members with valid e-mail addresses were invited to participate. INTERVENTION: Participants completed a brief online survey with questions regarding participation in cost-containment and incentive programs, industry relationships, generic implant use, and the role of surgeons in cost containment. MAIN OUTCOME MEASURES: Survey data. RESULTS: Participation in cost-containment programs (comanagement agreements, bundled payment for care improvement, and gainsharing) was found to be very low among participants (17%, 36.5%, 17%, respectively). Industry sales representatives were present in a majority of participants' cases (76.9%) the majority of time, but relatively a few surgeons (21.2%) felt their presence was necessary. Most surgeons were aware of the availability of generic implants (72.6%), but a few had adopted the use of such implants (25.5%), despite 50/52 (96.2%) prescribing generic drugs and 45/52 (86.5%) using generic products in their own households. CONCLUSIONS: Most participants agreed that generic orthopaedic implants have a role in cost containment, but a few have adopted these implants. The presence of sales representatives does not seem to be necessary for most surgeons, and minimizing or eliminating their presence may result in substantial savings for health care institutions. Increased education and the use of financial incentive programs may encourage improved surgeon participation in cost containment and adoption of generic implants and may help reduce health care spending. LEVEL OF EVIDENCE: Level 4. See Instructions for Authors for a complete description of levels of evidence.

Septic Arthritis of the Pediatric Shoulder: From Infancy to Adolescence.

Background. Septic arthritis of the glenohumeral joint in the pediatric population (<18 yo) is not commonly described in the literature. There is a corresponding paucity of information regarding its presentation and treatment. Methods. An IRB approved review of patients treated with irrigation and debridement by the Orthopaedic Department was completed. This retrospective study includes four patients, presenting from 2005 to 2015, with septic arthritis of the shoulder. Results. The mean age (M age) at presentation was 5 years, with a range of 1 month to 15 years. Patients presented on average after 7 days with pain and a mean temperature of 39°C, erythrocyte sedimentation rate of 66 mm/hr, a C-reactive protein level of 11.17 g/dL, and a white blood cell count of 20.2 × 10(3)/mcL. Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa were cultured from the wounds. All cases were treated operatively with irrigation and debridement and with antimicrobial therapy. Patients received antibiotics for an average of 6 weeks. Conclusion. Septic arthritis of the shoulder occurs in all pediatric ages. Successful treatment of septic arthritis of the shoulder was accomplished in four cases without division of the biceps sheath, with an average follow-up of 8 months.

Safety of Intra-Articular Implantation of Oligo[Poly(ethylene glycol) Fumarate] Scaffolds into the Rabbit Knee.

Implantable biomaterials supporting extended release of pharmacologic agents may permit localized intra-articular delivery of drugs that modulate the fibrotic response to injuries and surgery. Oligo[poly (ethylene glycol)] fumarate (OPF) is an attractive organic carrier, but its safety profile within synovial joints remains unclear. Here, we assessed the safety of OPF sponges using a validated in vivo model of knee arthrofibrosis. A cohort of 102 rabbits was divided into five groups: arthrotomy only (24), arthrotomy with OPF scaffold placement (24), surgically induced contracture (24), surgically induced contracture with OPF scaffold placement (24), and control without any surgical intervention (6). Six rabbits per surgical group were sacrificed at 72 h, 2, 8, and 24 weeks. Outcomes included biomechanical testing of range of motion, histologic analysis of synovial and cartilage tissues, and scaffold degradation. Cartilage histology and biomechanical measurements were comparable between groups with and without OPF. Synovial inflammation scores were similar among most groups with a minimally elevated score in the rabbits with arthrotomy and OPF versus those with arthrotomy alone. Scores for synovial tissues in rabbits with contracture and OPF were clinically equivalent to those with contractures alone. Most animals (92%) retained scaffold fragments at 24 weeks. Thus, OPF scaffolds implanted into native or arthrofibrotic rabbit knees neither induce nor aggravate cartilage damage, synovial inflammation, or contractures. The apparent safety of OPF scaffolds suggests that they are suitable carriers for the controlled delivery of reagents into the intra-articular joint space to treat arthrofibrosis.

Orthopaedic fellowship selection criteria: a survey of fellowship directors.

BACKGROUND: The pursuit of a fellowship has become increasingly popular over the past several years, with >90% of graduating orthopaedic residents applying for a fellowship position. Despite the ample literature available pertaining to the selection of orthopaedic residents, there is no similar research for the selection of fellows. METHODS: Four hundred and fifteen of 475 orthopaedic fellowship program directors in the United States were surveyed on selection criteria used to choose fellows. The survey asked fellowship directors to rank the importance of various criteria on a Likert scale of 1 through 5 points (with 1 point denoting most important and 5 points denoting least important). RESULTS: The overall response rate was 193 (46.5%) of 415 orthopaedic fellowship program directors. The most important criteria in selecting an applicant for an interview were a letter of recommendation from subspecialty faculty (1.38 points), quality of residency program (2.02 points), and a letter of recommendation from the residency program director (2.12 points). The most important criteria in completing the rank order list following the interview were the interview (1.17 points), a letter of recommendation from subspecialty faculty (1.46 points), a letter of recommendation from the residency program director (2.16 points), and expressed interest in program (2.16 points).

Surgical technique for symmetric patellar resurfacing during total knee arthroplasty.

Patellar resurfacing is a commonly performed procedure during total knee arthroplasty (TKA). Common goals of patellar resurfacing are to obtain a stable, functional, patellofemoral joint with minimal pain. This is typically accomplished by resecting the patella in a symmetric fashion while attempting to restore native patellar thickness. Several cutting guides have been developed to assist with patellar resurfacing during TKA; however, we feel that the patella can be resected in a predictably symmetric fashion without the use of cutting guides or other specialized equipment. The following is a description of a novel patellar resurfacing technique that reproducibly results in a smoothly resected patella that is free of asymmetry and obliquity without the use of cutting guides. It can reliably be performed in an efficient manner that reduces equipment needs without prolonging operative time.