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Violence against children (VAC) in the home, or by household members, is a human rights and social problem with long-lasting consequences for individuals and society. Global policy instruments like the INSPIRE package have proposed strategies to prevent VAC, including Implementation and enforcement of laws, Norms and values, Safe environments, Parent and caregiver support, Income and economic strengthening, Response and support services, and Education and life skills. This systematic review of reviews aimed to synthesize the recent evidence base (i.e., published since 2000) for each INSPIRE strategy to reduce VAC in the home or by household members. We searched four databases using controlled vocabularies and keywords and searched for additional records in prior reviews of reviews. A total of 67 studies were included in this review, including literature reviews, meta-analyses, systematic reviews, and other types of reviews. We found extensive evidence supporting the effectiveness of parent and caregiver support interventions. However, reviews on other INSPIRE strategies were scarce. We also found a vast underrepresentation of samples from low- and- middle-income countries, children with disabilities, and families affected by forced displacement and conflict. In sum, this systematic review suggests that there are several promising strategies to prevent VAC (e.g., home visiting and parent education), but further research is necessary to strengthen the current body of evidence and effectively inform the implementation and scale-up of evidence-based interventions to protect children from violence globally., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Lesotho's government has shown consistent efforts to implement social protection programmes. However, while recent evidence established a positive causal relationship between some of these programmes and food security there is little evidence on the extent to which these initiatives are associated with better educational and sexual and reproductive health outcomes among vulnerable adolescents in Lesotho., Methods and Findings: The study uses cross-sectional, nationally representative data from the 2018 Lesotho Violence Against Children and Youth Survey. Our research examined the association between social protection receipt and educational and sexual and reproductive health outcomes among adolescents and young people (13-24 years) living in poverty. We employed multivariate logistic regression controlling for age, orphanhood, HIV status and sex. Social protection receipt was defined as household receipt of financial support from a governmental, non-governmental, or community-based program that provides income. Additionally, we fitted a marginal effects model by sex. Among the 3,506 adolescent females and males living in the two lowest poverty quintiles, receipt of social protection was associated with improvements in multiple adolescent outcomes: higher odds of consistent condom use (aOR 1.64, 95% CI 1.17-2.29), educational attainment (aOR 1.79, 95% CI 1.36-2.36), and school enrolment (aOR 2.19, 95% CI 1.44-3.34). Stratified analyses by sex showed that social protection receipt was also associated with reduced likelihood of child marriage among females (aOR 0.59, 95% CI 0.42-0.83) and higher odds of educational attainment and school enrolment among males (aOR 2.53, 95% CI 1.59-4.03 and aOR 3.11, 95% CI 1.56-6.19, respectively)., Conclusions: Our study provides evidence that social protection programs are associated with improved educational, sexual and reproductive health and child marriage prevention outcomes among adolescents living in poverty. Implementing and expanding such social protection initiatives could prove instrumental in improving the well-being of vulnerable adolescents., Contributions: Social protection programs have been increasing in sub-Saharan African countries, playing a pivotal role in poverty reduction, with Lesotho being no exception. Despite the optimistic outlook brought about by the implementation of the National Social Protection Strategy Lesotho I (2014-19) and II (2021-2031), the impact of these programs on some specific outcomes that concern the lives of the most vulnerable adolescents in Lesotho remains to some extent unexplored. Additionally, Lesotho grapples with high rates of HIV, adolescent pregnancy, child marriage and early school dropout, which can further contribute to poor long-term health and social outcomes among adolescents. In this study, we used data from the 2018 Lesotho Violence Against Children and Youth Survey (VACS) to examine the association between receiving social protection and multiple adolescent outcomes: educational, sexual and reproductive. The findings revealed that social protection programs, particularly the existing government-provided cash transfers, are significantly associated with multiple better outcomes among adolescents living in the poorest households in Lesotho. Such cash transfer schemes in Lesotho are associated with improved sexual and reproductive health outcomes for adolescent females, including reduced child marriage rates, and improved educational outcomes for males. These findings indicate that government-led social protection programmes are positively associated with favourable outcomes that can improve the quality of life for adolescents in resource-limited settings., (© 2024. The Author(s).)

Background: In the current era of evidence-based medicine, scientific publications play a crucial role in guiding patient care. While the lack of diversity among orthopaedic surgeons has been well documented, little is known about the diversity of orthopaedic journal editorial boards. The purpose of this study was to assess the racial/ethnic and gender diversity of U.S. orthopaedic journal editorial boards., Methods: The editorial boards of 13 orthopaedic journals were examined, including 10 subspecialty and 3 general orthopaedic journals. Race/ethnicity and gender were determined for each editorial board member. The representation observed on orthopaedic journal editorial boards was compared with representation at other phases of the orthopaedic pipeline, as well as within the various subspecialty fields of orthopaedics. Logistic regression and t tests were used to evaluate these comparisons., Results: We identified 876 editorial board members of the 13 journals; 14.0% were Asian, 1.9% were Black, 1.9% were Hispanic, 2.4% were multiracial/other, and 79.7% were White. Racial/ethnic representation was similar across the subspecialty fields of orthopaedics (p > 0.05). The representation of women on orthopaedic editorial boards was 7.9%, with differences in gender diversity observed across subspecialty fields (p < 0.05). Among journals in the subspecialty fields of spine and trauma, female editorial board representation was lower than expected, even after taking into account the representation of women in these subspecialty fields (2.0% versus 9.0% [p = 0.002] and 3.8% versus 10.0% [p = 0.03], respectively)., Conclusions: In this study of 13 subspecialty and general orthopaedic journals, the representation of racial/ethnic minorities and women on editorial boards was similar to their representation in academic orthopaedics. However, these values remain low in comparison with the population of patients treated by orthopaedic surgeons. Given the importance of scientific publications in the current era of evidence-based medicine, orthopaedic journals should continue working to diversify the membership of their editorial boards., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H692 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Multiple successful strategies exist for the management of critical-sized bone defects. Depending on the location and etiology of an osseous defect, there are nuances that must be considered by the treating surgeon. The induced membrane technique and various modifications of the Ilizarov method (bone transport by distraction osteogenesis) have been the most common methods for biologic reconstruction. Despite the versatility and high union rates reported, they may not be practical for every patient. The rapid expansion of three-dimensional printing of medical devices has led to an increase in their use within orthopaedic surgery, specifically in the definitive treatment of critical bone defects. This article proposes indications and contraindications for implementation of this technology and reviews the available clinical evidence on the use of custom nonresorbable implants for the treatment of traumatic bone loss. Clinical cases are presented to illustrate the scenarios in which this approach is viable., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

Purpose: We investigated the sensitivity of a screening test for pelvic ring disruption, the AP pelvis radiograph, for clinically serious U-type sacral fractures which merit consultation with an orthopedic trauma specialist and may require transfer to a higher level of care., Methods: Retrospective clinical cohort of 63 consecutive patients presenting with U-type sacral fractures at one level 1 trauma referral center from January 2006 through December 2019. The sensitivity of the first AP pelvis radiograph obtained on admission, interpreted without reference to antecedent or concomitant pelvis computed tomography (CT) by a radiologist and a panel of three blinded orthopedic traumatologists, was determined against a reference diagnosis made from review of all pelvis radiographs, CT images, operative reports, and clinical documentation., Results: Sensitivity of AP pelvis radiograph for U-type sacral fractures was 2% as interpreted by a radiologist and mean 12% (range 5-27%) as interpreted by orthopedic traumatologists with poor inter-rater agreement (Fleiss' κ = 0.11). 94% of sacra were at obscured by radiographic artifact., Conclusion: The sensitivity of an AP pelvis radiograph is poor for U-type sacral fractures, whether interpreted by radiologists or orthopedic traumatologists. Pelvis CT should be considered as a screening test to rule out sacral fracture when the patient reports posterior pelvic pain, even if plain radiography demonstrates no injury or a minimally displaced pelvic ring disruption., Level of Evidence: Diagnostic level III., (© 2021. American Society of Emergency Radiology.)

Background: To strengthen the impact of cash transfers, these interventions have begun to be packaged as cash-plus programmes, combining cash with additional transfers, interventions, or services. The intervention's complementary ("plus") components aim to improve cash transfer effectiveness by targeting mediating outcomes or the availability of supplies or services. This study examined whether cash-plus interventions for infants and children <5 are more effective than cash alone in improving health and well-being., Methods and Findings: Forty-two databases, donor agencies, grey literature sources, and trial registries were systematically searched, yielding 5,097 unique articles (as of 06 April 2021). Randomised and quasi-experimental studies were eligible for inclusion if the intervention package aimed to improve outcomes for children <5 in low- and middle-income countries (LMICs) and combined a cash transfer with an intervention targeted to Sustainable Development Goal (SDG) 2 (No Hunger), SDG3 (Good Health and Well-being), SDG4 (Education), or SDG16 (Violence Prevention), had at least one group receiving cash-only, examined outcomes related to child-focused SDGs, and was published in English. Risk of bias was appraised using Cochrane Risk of Bias and ROBINS-I Tools. Random effects meta-analyses were conducted for a cash-plus intervention category when there were at least 3 trials with the same outcome. The review was preregistered with PROSPERO (CRD42018108017). Seventeen studies were included in the review and 11 meta-analysed. Most interventions operated during the first 1,000 days of the child's life and were conducted in communities facing high rates of poverty and often, food insecurity. Evidence was found for 10 LMICs, where most researchers used randomised, longitudinal study designs (n = 14). Five intervention categories were identified, combining cash with nutrition behaviour change communication (BCC, n = 7), food transfers (n = 3), primary healthcare (n = 2), psychosocial stimulation (n = 7), and child protection (n = 4) interventions. Comparing cash-plus to cash alone, meta-analysis results suggest Cash + Food Transfers are more effective in improving height-for-age (d = 0.08 SD (0.03, 0.14), p = 0.02) with significantly reduced odds of stunting (OR = 0.82 (0.74, 0.92), p = 0.01), but had no added impact in improving weight-for-height (d = -0.13 (-0.42, 0.16), p = 0.24) or weight-for-age z-scores (d = -0.06 (-0.28, 0.15), p = 0.43). There was no added impact above cash alone from Cash + Nutrition BCC on anthropometrics; Cash + Psychosocial Stimulation on cognitive development; or Cash + Child Protection on parental use of violent discipline or exclusive positive parenting. Narrative synthesis evidence suggests that compared to cash alone, Cash + Primary Healthcare may have greater impacts in reducing mortality and Cash + Food Transfers in preventing acute malnutrition in crisis contexts. The main limitations of this review are the few numbers of studies that compared cash-plus interventions against cash alone and the potentially high heterogeneity between study findings., Conclusions: In this study, we observed that few cash-plus combinations were more effective than cash transfers alone. Cash combined with food transfers and primary healthcare show the greatest signs of added effectiveness. More research is needed on when and how cash-plus combinations are more effective than cash alone, and work in this field must ensure that these interventions improve outcomes among the most vulnerable children., Competing Interests: The authors have declared that no competing interests exist.

Bone defects may occur after trauma, infection, or oncologic resection. A critical sized defect is any defect that is unable to spontaneously heal and will require secondary procedure(s) to obtain union. Autologous grafting is widely used, but may be insufficient to obtain union in these situations. Other options include the induced membrane technique, bone transport through distraction osteogenesis, or free vascularized bone transfer. This chapter will review options for obtaining graft, and the aforementioned special techniques for managing these challenging problems.

Objective(s): This study explored the effectiveness of gender-based violence (GBV) interventions on young people living with or affected by HIV in low- and middle-income countries (LMICs)., Design: Systematic review and meta-analysis., Methods: We pre-registered a protocol, then searched 13 databases and grey literature. We screened randomized and quasi-experimental studies (n = 2199) of young people (aged 10-24) living with or affected by HIV in LMICs. Outcomes were GBV and/or GBV-related attitudes. We appraised the data for risk of bias and quality of evidence. Narrative syntheses and multilevel random effects meta-analyses were conducted., Results: We included 18 studies evaluating 21 interventions. Intervention arms were categorized as: sexual health and social empowerment (SHSE; n = 7); SHSE combined with economic strengthening (n = 4); self-defence (n = 3); safer schools (n = 2); economic strengthening only (n = 2); GBV sensitization (n = 2) and safer schools and parenting (n = 1). Risk of bias was moderate/high and quality of evidence low. Narrative syntheses indicated promising effects on GBV exposure, but no or mixed effects on GBV perpetration and attitudes for self-defence and GBV sensitization interventions. Safer school interventions showed no effects. For SHSE interventions and SHSE combined with economic strengthening, meta-analyses showed a small reduction in GBV exposure but not perpetration. Economic-only interventions had no overall effect., Conclusion: SHSE, SHSE plus and self-defence and gender sensitization interventions may be effective for GBV exposure and GBV-related attitudes but not for GBV perpetration. However, the quality of evidence is poor. Future intervention research must include both boys and girls, adolescents living with HIV and key populations.

Background: Ethical and regulatory guidance on the collection and use of human biospecimens (HBS) for research forms an essential component of national health systems in Sub-Saharan Africa (SSA), where rapid advances in genetic- and genomic-based technologies are fueling clinical trials involving HBS and the establishment of large-scale biobanks., Methods: An extensive multi-level search for publicly available ethics regulatory guidance was conducted for each SSA country. A second review documented active trials listed in the WHO International Clinical Trials Registry Platform as of January 2015 in which HBS collection was specified in the protocol. Findings were combined to determine the extent to which countries that are study sites for HBS-related research are supported by regulatory guidance language on the collection, use, ownership and storage of biospecimens., Results: Of the 49 SSA countries, 29 had some form of national ethics guidance, yet only 17 provided language relating to HBS-related research, with specific guidance on consent (14), ownership (6), reuse (10), storage (9), and export/import/transfer (13). Ten countries accounted for 84 % of the active clinical trials involving the collection of HBS in SSA. All except one of these countries were found to have some national guidance in the form of regulations, codes of ethics, and/or standard operating procedures; however, only seven of the ten offered any language specific to HBS., Conclusions: Despite the fact that the bulk of registered clinical trials in SSA involving HBS, as well as existing and proposed sites for biorepositories under the H3Africa Initiative, are currently situated in countries with the most complete ethics and regulatory guidance, variability in the regulations themselves may create challenges for planned and future pan-African collaborations and may require legislative action at the national level to revise. Countries in SSA that still lack regulatory guidance on HBS will require extensive health system strengthening in ethics governance before they can be full participants in the modern research enterprise.

Objectives: This study examined the incidence and risk factors of preoperative deep vein thrombosis (DVT) in patients presenting to an outpatient setting with an isolated calcaneal fracture., Design: Retrospective chart review., Setting: All patients included in the study presented to the treating surgeon at a Level I trauma center with isolated calcaneal fractures as an outpatient between 2005 and 2013., Methods: These patients were either referred from outside hospitals, had been evaluated in the emergency department initially and presented for definitive care, or presented initially to the outpatient clinic. Patients included were over the age of 18, had a preoperative duplex ultrasonography of bilateral lower extremities per the treating surgeon's protocol, and had at minimum 6 weeks follow-up. Patients were excluded if they were a polytrauma, had a documented hypercoagulable state, or were on baseline pharmacologic anticoagulation for another condition. All patients had a preoperative duplex ultrasound of both lower extremities to evaluate for DVT at least 7 days after injury., Main Outcome Measure: Patients found to have a preoperative DVT were compared with those who did not have preoperative DVT for possible risk factors., Results: One hundred fifty-nine patients qualified for our study and of these, 19 (12%) were found to have a DVT preoperatively, almost all of which were in distal veins. All risk factors, including age, sex, and body mass index were analyzed as continuous variables. Older age was found to be a risk factor for DVT (P = 0.009, Odds Ratio = 1.06, 95% CI, 1.01-1.11). All other predictor variables, including body mass index (P = 0.05) and sex (P = 0.08), were not statistically significant predictors in our sample., Conclusions: The incidence of preoperative DVT found here is almost 2 times as high as any previously published examination of lower extremity injuries. Physicians should be aware of this increase so they may counsel patients about the risks of DVTs and the likelihood of any sequelae from developing a DVT that may affect a patient's recovery., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background: Proximal humerus fractures treated in the face of ipsilateral injuries to the shoulder girdle may be predisposed to worse clinical outcomes., Questions/purposes: The purpose of this investigation was to examine outcomes of proximal humerus fractures treated with open reduction internal fixation (ORIF) using an endosteal augment in the presence of a concomitant shoulder girdle injury in comparison to isolated proximal humerus fractures treated with ORIF and endosteal augment., Methods: A prospective database was used to identify proximal humerus fractures with ipsilateral shoulder girdle injuries (glenohumeral and acromioclavicular dislocation, fractures of the acromion, clavicle, scapula, or humeral diaphysis). These were compared to isolated proximal humerus fractures treated in the same fashion (ORIF with endosteal augment). Minimum of 1 year follow-up was required for inclusion. Outcomes assessed included range of motion (ROM), development of avascular necrosis (AVN), hardware-related complications, reoperation, and subjective outcome assessments including the Disabilities of Arm Shoulder and Hand questionnaire (DASH), Constant score, UCLA rating scale, and the Short Form-36 (SF-36)., Results: Fifteen ipsilateral injuries were seen in 14 patients. Seventy-seven isolated proximal humerus fractures were available for comparison. The ipsilateral injury group had significantly worse forward flexion (141 vs 156°, p = 0.02), external rotation (56 vs 64°, p = 0.03), higher rates of avascular necrosis (4 of 14, 28.6% vs 1 of 77, 1.3%, p = 0.002), and inferior SF-36 physical health scores (48.5 vs 63.5; p = .04). Despite these differences, no significant differences were seen with hardware-related complications or DASH, Constant score, or UCLA rating scale results. No patients required secondary reconstructive procedures., Conclusion: Despite a statistically higher rate of AVN and decreased ROM, patient-based outcomes of proximal humerus fractures with ipsilateral shoulder injuries approached those seen in isolated proximal humerus fractures. This suggests that these injuries can achieve similarly good clinical results provided any associated shoulder pathology is identified and treated appropriately.

Background: Convention dictates that an axillary view be obtained when evaluating proximal humerus fractures (PHF). However, the axillary view is frequently omitted because of pain and technical considerations. Furthermore, its diagnostic utility is unclear in this setting., Questions/purposes: The purpose of this study was to (1) determine the rate of obtaining an adequate axillary X-ray and complete shoulder series at a level I trauma center, (2) understand the cost of ordering and attempting an axillary radiograph, and (3) determine if axillary radiographs influence the management of PHF., Patients and Methods: PHF treated between 2009 and 2011 that were ordered for an AP, scapular Y, and axillary view was identified. The types of radiographs actually obtained were recorded. The cost of obtaining three views and a single view of the shoulder with X-ray was determined. Lastly, three surgeons reviewed 42 PHF, both with and without an axillary view (AV), and treatment recommendations were compared., Results: 30% of PHF in this series had an adequate axillary view, and 14% received a complete trauma series. No factors could be identified that were associated with successfully obtaining an axillary view. Reviewers demonstrated substantial intraobserver reliability (κ = 0.759-0.808) regarding treatment recommendations for PHF with and without the axillary view. The addition of the AV had minimal influence on treatment recommendations., Conclusion: Considering that the axillary view for PHF is painful, labor-intensive, costly, and does not appear to provide additional diagnostic value, orthopedic surgeons can consider foregoing the use of the axillary view when evaluating and treating PHF, particularly if other advanced imaging is utilized.

Stress ankle radiographs are routinely performed to determine deep deltoid ligament integrity in supination external rotation (SER) ankle fractures. However, variability is present in the published data regarding what medial clear space (MCS) value constitutes a positive result. The purposes of the present study were to evaluate the diagnostic accuracy of different MCS cutoff values and determine whether this clinical test could accurately discriminate between patients with and without a deep deltoid ligament disruption. MCS measurements were recorded for stress ankle injury radiographs in an SER ankle fracture cohort. Preoperative ankle magnetic resonance imaging studies, obtained for all patients, were then read independently by 2 musculoskeletal attending radiologists to determine deep deltoid ligament integrity. The MCS measurements were compared with the magnetic resonance imaging diagnosis using receiver operating characteristic analyses to determine the sensitivity, specificity, and optimal data-driven cutoff values. SER II-III patients demonstrated a mean stress MCS distance of 4.3 ± 0.98 mm compared with 5.8 ± 1.76 mm in the SER IV cohort (p < .001). An analysis of differing MCS positive cutoff thresholds revealed that a stress MCS of 5.0 mm maximized the combined sensitivity and specificity of the external rotation test: 65.8% sensitive and 76.5% specific. Using the receiver operating characteristic curve analysis of the MCS measurement, the calculated area under the curve was 0.77, indicating inadequate discriminative ability for diagnosing SER pattern fractures with or without a deep deltoid ligament tear. Judicious use of additional diagnostic testing in patients with a stress MCS result between 4.0 mm and 5.5 mm is warranted., (Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The classification systems for fractures of the proximal part of the humerus provide low interobserver and intraobserver reliability when radiographs or two-dimensional computed tomography scans are used. The purpose of this investigation was to determine whether the use of three-dimensional computed tomography scans could improve interobserver and intraobserver reliability of AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) and Neer classifications and treatment recommendations., Methods: Two trauma surgeons, one shoulder surgeon, two senior orthopaedic residents, and two junior orthopaedic residents reviewed the radiographs and two and three-dimensional computed tomography scans of forty fractures of the proximal part of the humerus. Each imaging modality was reviewed in isolation, and fractures were classified according to the Neer and AO/OTA classifications and treatment recommendations were provided. This process was repeated for intraobserver analysis. Interobserver agreement was calculated within and between levels of training for each classification and treatment recommendation with respect to radiographs and two and three-dimensional computed tomography scans., Results: Among attending orthopaedic surgeons and senior residents, the use of three-dimensional computed tomography did not improve agreement compared with the use of two-dimensional computed tomography for the Neer classification based on planes, the AO/OTA classification, or the treatment recommendation, but it did improve agreement among junior residents. Comparing between levels of training, three-dimensional computed tomography increased agreement only between junior residents and more experienced reviewers for the Neer classification based on planes and for the AO/OTA classification but not for the treatment recommendation. Intraobserver agreement for each reviewer for classification and treatment ranged from slight to fair and was not improved through the use of three-dimensional computed tomography., Conclusions: In this investigation, the use of three-dimensional computed tomography imaging did not offer improved interobserver and intraobserver agreement compared with the use of two-dimensional computed tomography imaging with regard to classification and treatment of fractures of the proximal part of the humerus, except among reviewers with limited clinical experience., Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.)

Associations between Weber C ankle fractures and pronation external rotation (PER) injuries of the Lauge-Hansen classification have often been incorrectly correlated. The purpose of the present study was to evaluate the Lauge-Hansen designation of Weber C fractures by establishing the proportion of Weber C fractures that are supination external rotation (SER), supination adduction (SA), pronation abduction (PA), PER, and hyperplantarflexion variant fractures. A clinical database of operative ankle fractures treated by the senior author (D.G.L.) was reviewed. The inclusion criteria were patient age older than 16 years, preoperative ankle radiographs, and Weber C fracture designation. A total of 132 patients met the inclusion criteria, and the proportion of PA, PER, SER, SA, and variant fractures among the Weber C fractures was analyzed. PA fractures accounted for 0.8% (n = 1), PER fractures 56.8% (n = 75), SER fractures 35.6% (n = 47), and hyperplantarflexion variant fractures 6.8% (n = 9) of the 132 Weber C fractures. Patients with Weber C-PER fractures were more commonly male (p = .005) and younger (p = .003) and demonstrated a greater fibular fracture height (p < .001) than those with Weber C-SER and Weber C-variant fractures. Our study quantitatively demonstrated that not all Weber C fractures occur secondary to pronation injuries. This distinction is important, because all pronation injuries will demonstrate medial ankle injury, but SER and variant fractures might not. We therefore recommend careful evaluation of the fibular fracture characteristics, including the direction of fracture propagation and the distance from the tibial plafond, when classifying Weber C fractures using the Lauge-Hansen system, because correct classification is vital in preparation for appropriate operative treatment., (Copyright © 2014 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the impact of preoperative coronal plane deformity on functional and radiographic outcomes on endosteal strut augmentation of proximal humerus fracture fixation., Design: Single surgeon, retrospective analysis of a prospective database. Case series., Setting: Academic level 1 trauma center., Patients/participants: Seventy-two patients with isolated proximal humerus fractures fulfilled all inclusion/exclusion criteria with a minimum follow-up of 12 months., Intervention: Proximal humerus open reduction internal fixation with a laterally placed proximal humeral locking plate and endosteal placement of an allograft fibula treated through the anterolateral approach., Main Outcome Measurements: Global functional outcome as determined by the Disabilities of the Arm, Shoulder and Hand (DASH) score and Short Form 36 physical function. Shoulder-specific functional outcome as determined by the Constant-Murley and the University of California Los Angeles shoulder scores., Results: The mean age was 62 years old (range, 26-90 years). There were 32 varus fractures (neck-shaft angle, 110.8 degrees) and 40 valgus fractures (neck-shaft angle, 168.9 degrees). There was no significant difference in the initial postoperative (varus: 132.5 degrees, valgus: 135.5 degrees) and final (varus: 129.9 degrees, valgus: 132.2 degrees) neck-shaft angles or change in humeral height (varus: 0.94 mm, valgus: 1.48 mm). There were no significant differences in functional outcomes [Constant (varus: 85.2, valgus: 88.7) DASH (varus: 21.4, valgus: 13.9), University of California Los Angeles (28.6, varus 30.4), and Short Form 36 (varus: 66.8, valgus: 59.1)]. There were 2 patients in the valgus group and 3 patients in the varus group with an asymptomatic humeral head screw penetration (mean Constant 84.5, DASH 9.5). There was 1 deep infection in the varus group and 2 in the valgus group necessitating implant removal after fracture union. There was 1 case of avascular necrosis in the valgus group (DASH 19.4, Constant 73)., Conclusions: There were no significant differences in complication rates, radiographic, or clinical outcomes between fractures presenting with preoperative varus coronal displacement compared with those presenting with valgus coronal displacement. The equivalent outcomes may be attributed to the uniform operative technique and fibular strut augmentation used by the primary surgeon., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: A pronation external rotation (PER) ankle fracture is a relatively uncommon injury. The purpose of this study was to examine the immediate and short-term clinical outcomes of operatively treated PER IV ankle fractures and compare them with a similarly treated cohort of supination external rotation IV (SER IV) fractures., Methods: 22 PER IV and 108 SER IV fractures were identified from a single surgeon's prospectively collected database from 2004 to 2010. All patients were treated with fracture fragment and ligament specific fixation during the same time period by the same surgeon. Postoperative radiographs and bilateral ankle computed tomography (CT) scans were reviewed for articular incongruity, syndesmotic malreduction, and loss of reduction. Clinical outcome measures, including the Foot and Ankle Outcome Score (FAOS) and ankle range of motion (ROM), were collected at latest follow-up visit., Results: There was no difference in the rate of wound complications, fracture nonunion, or loss of reduction between the PER IV and SER IV groups. There was no significant difference in the incidence of postoperative articular incongruity (19% vs 8%, P = .23); however, the PER IV cohort was found to have a significantly higher rate of syndesmotic malreduction (40% vs 18%, P = .04). No clinically or statistically significant differences were detected between the 2 groups in regard to all FAOS domains., Conclusion: In a cohort of operatively treated PER IV fractures, fracture fragment and ligament specific fixation resulted in good short-term outcomes that were comparable to those seen in similarly treated patients with an SER IV fracture pattern. However, a notably greater number of syndesmotic malreductions were noted in the PER IV cohort, and therefore heightened scrutiny is recommended in treating this particular injury pattern., Level of Evidence: Level III, retrospective comparative study.

Summary: In this study, we present a novel technique for reduction and fixation of complex, unstable proximal humerus fractures with diaphyseal extension with the assistance of fibula allograft. We treated 14 patients using this technique since 2009 and found that it improves the reduction and enhances fixation while making the surgical procedure technically more manageable, and allows for early postoperative motion. In the first part of this study, we describe in detail the indications and surgical technique applied to these fractures. In the second part, we review the clinical and radiographic outcomes of these patients. Using this new technique, we have achieved an excellent union rate with minimal incidence of complications when treating these challenging fractures.

Objectives: To quantify the radiographic tibia and fibula shaft fracture characteristics that are associated with a concomitant ipsilateral ankle injury., Design: Retrospective case-control study., Setting: Academic level I trauma center., Patients: Seventy-one adult patients with an operatively treated tibial shaft fracture met the inclusion/exclusion criteria., Intervention: Preoperative radiographs were categorized according to tibia and fibula fracture pattern, location and spatial relationship to each other. Preoperative computed tomographic scans were then evaluated to assess for the presence of an articular ankle injury., Main Outcome Measurements: (1) incidence of concomitant tibial shaft fracture and ipsilateral ankle injury; and (2) statistical association between tibia and fibula fracture characteristics in patients with and without an ipsilateral ankle fracture., Results: Thirty-five of 71 (49.3%) tibial shaft fracture patients had a concomitant ipsilateral ankle injury. Of these, 31 (88.6%) ankle injuries occurred in patients with a spiral pattern tibia fracture of the distal third diaphysis (P < 0.001). A spiral pattern tibia fracture, a distal one-third tibial shaft fracture location, or a spiral pattern fibula fracture all were significantly associated with the presence of an ipsilateral ankle injury (P ≤ 0.001; P = 0.001; and P = 0.002, respectively). Patients with either a transverse pattern or absent fibula fracture, a nonspiral pattern tibia fracture, or a midshaft diaphyseal tibia fracture location were significantly less likely to have an associated ankle injury (P ≤ 0.001; P ≤ 0.001; and P = 0.012, respectively)., Conclusions: Ipsilateral ankle fractures are commonly associated with tibial shaft fractures, specifically distal one-third spiral type injuries. Recognition of an associated ankle injury is important as it can alter operative and postoperative management. Clinical studies are needed to examine patient outcomes with or without ipsilateral ankle injury to determine the clinical significance of this entity., Level of Evidence: Prognostic level IV. See instructions for authors for a complete description of levels of evidence.

Objectives: The purpose of this study is to report the rate of anatomic reduction, articular subsidence, and clinical outcomes for Schatzker II tibial plateau fractures treated with structural bone allografts., Design: This is a retrospective case series., Setting: Academic Level I Trauma Center., Patients/participants: A trauma registry was used to identify 77 Schatzker II tibial plateau fractures., Intervention: Schatzker II tibial plateau fracture open reduction internal fixation and structural bone graft using either Plexur P (N = 29) or fibular allograft (N = 48)., Main Outcome Measurement: The primary outcome was articular subsidence. Secondary outcomes included fracture malreduction and clinical outcomes including the Knee Outcome Survey Activities of Daily Living Scale, the Lower Extremity Functional Scale, and the Short Form (SF)-36., Results: No patients experienced subsidence > 2mm. This rate is significantly lower than published rates for autogenous iliac crest (30.3%, P < 0.0001) and calcium phosphate cement (8.7%, P = 0.0099). The rate of fracture malreduction was 11.7% (9/77); only 4 had more than 3 mm of residual incongruity. Average outcome scores were the following: Knee Outcome Survey Activities of Daily Living Scale, 81.7; Lower Extremity Functional Scale, 78.5; SF-36 physical component, 48.3; and SF-36 mental component, 53.1. There was no difference between patients treated with Plexur P or fibula with regard to the primary or secondary outcomes., Conclusions: The use of structural allograft resulted in a high rate of anatomic reduction and negligible rate of articular subsidence and good clinical outcomes in the treatment of this population of Schatzker II tibial plateau fractures. This compares favorably with historical results using nonstructural grafts., Level of Evidence: Therapeutic level IV. See instructions for authors for a complete description of levels of evidence.

Objective: The majority of orthopaedic surgeons rely on a lateral fluoroscopic image to assess reduction during patella fracture osteosynthesis. However, a comprehensive radiographic description of the lateral view of the patella has not been performed previously, and no accessory views to better visualize specific anatomic features have been developed. The purpose of this study was to provide a detailed anatomic description of all radiographic features of the true lateral of the patella, describe reproducible accessory views for assessing specific features of the patella, and demonstrate their utility in a fracture model., Methods: Twelve cadaver knee specimens free of patellofemoral pathology were used, and imaging was performed using standard C-arm fluoroscopy. For each specimen, a true lateral radiographic projection of the patella was obtained and distinct features were noted. Next, an arthrotomy was made and steel wire was contoured and fixed to various anatomic regions of the patella so as to obliterate the radiographic densities on the true lateral projection, thus confirming their anatomic correlation. Ideal views of the lateral and medial facets themselves were determined using radiographic markers and varying amounts of internal or external rotation of the specimen. Last, a transverse osteotomy was created in each patella and the ability of the true lateral and accessory views to detect malreduction was assessed., Results: The true lateral projection of the patella was obtained with the limb in neutral alignment. Constant radiographic features of the lateral view of the patella include the articular tangent, a secondary articular density of variable length, and a dorsal cortical density. The articular tangent was produced by the central ridge between the medial and lateral facets in all specimens. The secondary articular density was created by a confluence of the edge of the lateral and edge of the medial facets in 5 patellas, a confluence of the edge of the lateral facet and the intersection of the odd and medial facets in 6 patellas, and the edge of the lateral facet alone in 1 patella. The edge of the lateral facet gave a constant contribution to the appearance of the secondary articular density in all cases. A distinct accessory view of the tangent of the lateral facet could be seen with an average of 17 degrees of patella external rotation (range, 12-35 degrees), and the tangent of the medial facet with an average of 26.5 degrees of internal rotation (range, 15-45 degrees). These accessory views were better able to visualize malreduction than the single lateral projection in a fracture model in all specimens., Conclusions: Described here is a comprehensive description of the true lateral radiographic view of the patella and accessory views. These views can be used in the evaluation of minimally displaced patella fractures if a computerized tomography is not desired to better assess the true amount of displacement and when assessing intraoperative reduction during patella fracture osteosynthesis.

Background: With regard to supination-external rotation type-IV (SER IV) ankle fractures, there is no consensus regarding which patient, injury, and treatment variables most strongly influence clinical outcome. The purpose of this investigation was to examine the impact of articular surface congruity on the functional outcomes of operatively treatment of SER IV ankle fractures., Methods: A prospectively generated database consisting of operatively treated SER IV ankle fractures was reviewed. Postoperative computed tomography (CT) scans were used to assess ankle joint congruity. Ankles were considered incongruent in the presence of &gt;2 mm of articular step-off, intra-articular loose bodies, or an articular surface gap of &gt;2 mm (despite an otherwise anatomic reduction) due to joint impaction and comminution. Patients with at least one year of clinical follow-up were eligible for analysis. The primary and secondary outcome measures were the Foot and Ankle Outcome Score (FAOS) and ankle motion., Results: One hundred and eight SER IV fractures met our inclusion criteria. The average duration of follow-up was twenty-one months. Seventy-two patients (67%) had a congruent ankle joint, and thirty-six (33%) had elements of articular surface incongruity on postoperative CT scanning. These two groups were similar with regard to comorbidities and injury and treatment variables. At the time of the final follow-up, the group with articular incongruity had a significantly worse FAOS with regard to symptoms (p = 0.012), pain (p = 0.004), and activities of daily living (p = 0.038). Those with articular incongruity had worse average scores in the FAOS sport domain as well. No significant differences in ankle motion were found between the two groups., Conclusions: In this population of patients with an operatively treated SER IV ankle fracture, the presence of postoperative articular incongruity correlated with inferior early clinical outcomes. Orthopaedic surgeons should scrutinize ankle fracture reductions and strive for perfection to allow for the best possible clinical outcome., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Background: Patellar fractures are debilitating injuries that compromise the knee extensor mechanism and are frequently associated with poor outcomes. The purpose of this study was to quantify the functional outcomes of operative treatment of patellar fractures., Methods: Functional outcome data on thirty patients with an isolated unilateral patellar fracture were prospectively obtained at three, six, and twelve months postoperatively., Results: All fractures healed. There were two complications (7%) related to the surgery (wound dehiscence and refracture), and eleven patients (37%) underwent removal of symptomatic implants. The tibial plateau-patella angle demonstrated patella baja in seventeen (57%) of the patients. Anterior knee pain during activities of daily living was experienced by twenty-four (80%) of the patients. Clinical improvement occurred over the first six months. However, functional impairment persisted at twelve months, with objective testing demonstrating that the knee extensor mechanism on the injured side had deficits in strength (-41%), power (-47%), and endurance (-34%) as compared with the uninjured side., Conclusions: Despite advances in surgical protocols and acceptable radiographic outcomes, functional impairment remains common after treatment of patellar fractures. Rehabilitation strategies following surgical stabilization of these injuries will be a fruitful area for future clinical research.

Background: The posterolateral approach to the ankle is a valuable approach for the treatment of ankle fractures (SER) ankle fractures. The purpose of this study was to determine the complication rate for ankle fractures treated through the posterolateral approach. We hypothesized that this approach would be associated with a low incidence of complications and good clinical outcomes., Methods: A total of 112 patients with SER ankle fractures treated through a posterolateral approach met inclusion criteria. Prospectively collected data were examined retrospectively from chart review, preoperative plain radiographs, and MRI as well as postoperative radiographs. The mean age was 51.5 (range, 18 to 86) years. The primary outcome of the study was major (surgical debridement, flap, or split thickness skin graft) and minor (epidermolysis requiring local wound care) wound complications. The secondary outcomes included infection, symptomatic hardware, reoperation, loss of reduction, malreduction, nonunion, Foot and Ankle Outcome Scores, range of motion, and other perioperative complications., Results: There were 11 minor wound related complications (9.8%) and 3 major wound complications (2.7%), 1 of which required a split thickness skin graft. The overall postoperative wound infection rate was 4.4% (5 of 112); 2 patients required hardware removal due to deep infection. Of patients, 7% (8 of 112) reported symptomatic lateral sided hardware and thus underwent removal of implants. The overall reoperation rate was 12.5%. The complication rate was 23%. No patients experienced loss of reduction., Conclusions: The posterolateral approach to the ankle was a valuable approach for SER ankle fractures. This series demonstrated many key aspects of this approach including access to the apex of the fibula fracture for posterior antiglide plating, access to the posterior malleolus for fixation, access to the posterior inferior tibiofibular ligament for repair, minimal major wound complications, good functional outcomes, and minimal need for reoperation.

Background: Geriatric patients' (defined as those older than 65 years old) inherent comorbidities, functional limitations, and bone quality present obstacles to successful clinical outcomes for operatively treated supination external rotation (SER) ankle fractures. We retrospectively reviewed a prospectively collected series of SER injuries between 2004 and 2010. This is a comparison of the radiographic and clinical outcomes of our geriatric (27 patients) and nongeriatric (81 patients) populations. We hypothesized that geriatric patients would have worse outcomes when compared to nongeriatric patients., Methods: All SER ankle fractures (176) treated by a single surgeon were enrolled in a prospective database. All patients fulfilled inclusion criteria (108) consisting of 1 year of having clinical follow-up, postoperative radiographs, and Foot & Ankle Outcome Scores (FAOS). The primary outcome evaluated was functional outcome as exhibited by the FAOS. The secondary outcomes included adequacy of reduction, loss of reduction, postoperative complications (wound complications, infection, pain-driven hardware removal), and range of motion., Results: Despite significantly higher rates of diabetes (P < .001) and peripheral vascular disease (P < .001), there were statistically significantly better FAOS outcomes in the symptoms subcategory among the geriatric population. There was no significant difference in the articular reduction, syndesmotic reduction, wound complications, postoperative infections, or range of motion between these groups., Conclusion: Geriatric patients exhibited equivalent complication rates, radiographic outcomes, and functional outcomes compared to nongeriatric patients in this series. Anatomic fixation and soft tissue management counter the inherent risks of operative intervention in geriatric populations that report higher rates of comorbidities. This study supports aggressive fracture- and ligament-specific operative intervention in geriatric patients presenting with unstable SER injuries.

The treatment of proximal humerus fractures continues to evolve. While the many of these injuries can be managed nonoperatively, a certain percentage require operative treatment. Open reduction internal fixation can offer excellent outcomes when performed in the appropriate patient and utilizing proper techniques. This article reviews the most up-to-date literature regarding all phases of proximal humerus fracture osteosynthesis, including diagnosis, imaging, anatomic considerations, surgical indications, fixation, and surgical outcomes.

Background: The subcutaneous location of the patella and the demand for early knee motion contribute to the difficulty in treating patients with patella fractures. The reported rates in the literature for hardware removal after patella open reduction and internal fixation range from 0% to 60%. The wide variability of these reports leaves the true frequency of re-operation and complications after patella open reduction and internal fixation in question. Furthermore, gaining a better understanding of the factors that contribute to re-operation and complications will help to generate hypotheses and research agendas to address these difficult problems., Methods: We performed a systematic review to identify publications in which adult patients with patella fractures were surgically treated with a minimum of 6-month follow-up. The surgical technique (tension band or other), infection rate, nonunion rate, and re-operation rate (including removal of hardware) were recorded. Meta-regression analysis was used to describe the potential contributory factors for re-operation, nonunion, and infection while controlling for age, gender, open fracture, surgical technique, and date of publication. Separate regression models were constructed for each outcome depending on the number of studies available for inclusion., Results: The frequency of re-operation was 33.6% in a meta-analysis of 24 studies (737 patella fractures). The frequency of infection was 3.2% in a meta-analysis of 18 studies (522 patella fractures). The frequency of nonunion was 1.3% in a meta-analysis of 15 studies (464 patella fractures). There were no significant predictors for re-operation, nonunion, or infection in any of the regression analyses., Conclusion: Although the frequencies of nonunion and infection are relatively low after surgical treatment of patella fractures, the modern rate of re-operation is substantial., Level of Evidence: Meta-analysis, level III+.

Graft-versus-host disease (GVHD) remains a cause of substantial morbidity for patients undergoing allogeneic hematopoietic cell transplantation (HCT). The present study was undertaken to investigate the effectiveness of RDP58, a peptide derived from the human leukocyte antigen class I heavy chain, in preventing GVHD in the established dog leukocyte antigen (DLA)-nonidentical canine model. Dogs underwent HCT from unrelated DLA-nonidentical donors after conditioning with 920 cGy total body irradiation. Engraftment and achievement of full donor chimerism was seen in five of six dogs, whereas one dog showed rejection and died of marrow aplasia. All five dogs with engraftment developed acute GVHD and were euthanized at an average of 20.6 days after HCT. Compared with historical controls, the Suse of RDP58 neither prevented acute GVHD nor significantly prolonged survival of DLA-nonidentical HCT recipients.

Case Description: A 7-year-old Golden Retriever was examined because of anorexia, lethargy, vomiting, and gradual weight loss., Clinical Findings: Splenomegaly, pancytopenia, high serum calcium concentration, and high alkaline phosphatase activity were detected. Magnetic resonance imaging revealed an enlarged mesenteric lymph node and increased signals from the bone marrow of the ilium and vertebral bodies. Histologic examination and immunophenotyping of biopsy specimens confirmed a stage V (b) T-cell malignant lymphoma., Treatment and Outcome: Clinical remission was attained by use of 2 chemotherapy cycles, followed by an allogeneic hematopoietic cell transplant performed at 18 weeks after diagnosis. A donor was identified by molecular dog leukocyte antigen typing methods. The patient was conditioned with 2 fractions of 4 Gy total body irradiation delivered 3 hours apart at 7 cGy/min, followed by an IV infusion of recombinant canine granulocyte colony-stimulating factor mobilized leukapheresis product and postgrafting immunosuppression with cyclosporine. Chimerism analyses revealed full donor engraftment that has been maintained for at least 58 weeks after transplant. Remission has been confirmed by normal results of serum thymidine kinase assays and the absence of peripheral blood clonal T-cell receptor gene rearrangements., Clinical Relevance: Systemic chemotherapy induces remissions; however, most dogs succumb to disease recurrence because of multidrug resistance. Outcome of allogeneic hematopoietic cell transplantation in dogs can be excellent because of improved donor-recipient selection by use of molecular dog leukocyte antigen typing, compared with early attempts, and better prevention of graft versus host disease, better supportive care, and substitution of peripheral blood mononuclear cells for bone marrow.

Sleep deprivation impairs hippocampal-dependent learning, which, in turn, is associated with increased survival of newborn cells in the hippocampus. We tested whether the deleterious effects of sleep restriction on hippocampus-dependent memory were associated with reduced cell survival in the hippocampus. We show that sleep restriction impaired hippocampus-dependent learning and abolished learning-induced neurogenesis. Animals were trained in a water maze on either a spatial learning (hippocampus-dependent) task or a nonspatial (hippocampus-independent) task for 4 days. Sleep-restricted animals were kept awake for one-half of their rest phase on each of the training days. Consistent with previous reports, animals trained on the hippocampus-dependent task expressed increased survival of newborn cells in comparison with animals trained on the hippocampus-independent task. This increase was abolished by sleep restriction that caused overall reduced cell survival in all animals. Sleep restriction also selectively impaired spatial learning while performance in the nonspatial task was, surprisingly, improved. Further analysis showed that in both training groups fully rested animals applied a spatial strategy irrespective of task requirements; this strategy interfered with performance in the nonspatial task. Conversely, in sleep-restricted animals, this preferred spatial strategy was eliminated, favoring the use of nonspatial information, and hence improving performance in the nonspatial task. These findings suggest that sleep loss altered behavioral strategies to those that do not depend on the hippocampus, concomitantly reversing the neurogenic effects of hippocampus-dependent learning.

Peripheral-blood mononuclear cells (PBMCs) mobilized with AMD3100, a CXCR4 antagonist, combined with granulocyte colony-stimulating factor (G-CSF) have reconstituted autologous hematopoiesis in cancer patients following myeloablative conditioning. The engraftment potential of PBMCs mobilized with AMD3100 alone, however, has remained unproven. We therefore studied AMD3100-mobilized PBMCs in a canine model. Four dogs received 920 cGy total body irradiation (TBI) before infusion of autologous AMD3100-mobilized PBMCs (median CD34 cell count, 3.9 x 10(6)/kg). Neutrophil (> 0.5 x 10(9)/L [500/microL]) and platelet (> 20 x 10(9)/L [> 20 000/microL]) recoveries occurred at medians of 9 (range, 7-10) days and 25 (range, 23-38) days, respectively, after TBI, and all dogs had normal marrow function at 1 year after transplantation. To evaluate the long-term engraftment potential of AMD3100-mobilized PBMCs, 5 dogs were given 920 cGy TBI followed by infusion of AMD3100-mobilized PBMCs (median CD34 cell dose, 4.7 x 10(6)/kg) from their dog leukocyte antigen (DLA)-identical littermates. Neutrophil and platelet recoveries occurred at medians of 8 (range, 8-10) days and 26 (range, 26-37) days, respectively, after TBI. With a median follow-up of 53 (range, 33-61) weeks, recipients' marrow function was normal, and blood-donor chimerism levels were 97% to 100%. In summary, both autologous and allogeneic AMD3100-mobilized PBMCs led to prompt and durable engraftment in dogs after 920 cGy TBI.

Nonmyeloablative or reduced-intensity conditioning regimens have been used to condition elderly or ill patients with hematological malignancies for allogeneic hematopoietic cell transplantation (HCT). Initial mixed donor/host chimerism (i.e. the coexistence of hematopoietic cells of host and donor origin) has been observed in most patients after such transplants. Here, we describe both factors affecting engraftment kinetics in patients given a nonmyeloablative or a reduced-intensity conditioning, and associations between peripheral blood cell subset chimerism levels and HCT outcomes.

We investigated whether pretransplantation immunosuppression with canine-specific rabbit antithymocyte globulin (ATG), combined with a suboptimal dose of 1 Gy of total body irradiation (TBI), would permit engraftment of canine dog leukocyte antigen-identical marrow. Cumulative ATG doses of 2 to 5 mg/kg produced a T-cell depletion of 1 log in the peripheral blood and 50% in the lymph nodes. Serum levels of ATG peaked on days 4 to 6 after initiation of therapy and became undetectable by day 13 as a result of canine antibody responses to ATG. ATG prolonged allogeneic skin graft survival to 14 days (n = 5), compared with 8 days in control dogs (P = .0003). Five dogs were given marrow transplants after ATG (3.5-5 mg/kg) and 1 Gy of TBI. Posttransplantation immunosuppression consisted of mycophenolate mofetil and cyclosporine. All dogs showed initial engraftment, with maximum donor chimerism levels of 25%. However, only 1 dog achieved sustained engraftment, and 4 rejected their grafts. The duration of engraftment ranged from 8 to > or = 36 weeks (median, 11 weeks), and this is comparable to that in 6 historical controls not given ATG (range, 3-12 weeks; median, 10 weeks; P = .20). The total nucleated cell doses in the marrow grafts had the highest correlation coefficient with the duration of engraftment: 0.82 (P = .09). We concluded that administering ATG before an otherwise suboptimal conditioning dose of 1 Gy of TBI failed to secure uniform stable hematopoietic engraftment.

This report examines the impact of graft composition on outcomes in 130 patients with hematological malignancies given unrelated donor granulocyte-colony-stimulating-factor-mobilized peripheral blood mononuclear cells (G-PBMC) (n = 116) or marrow (n = 14) transplantation after nonmyeloablative conditioning with 90 mg/m(2) fludarabine and 2 Gy TBI. The median number of CD34(+) cells transplanted was 6.5 x 10(6)/kg. Higher numbers of grafted CD14(+) (P = 0.0008), CD3(+) (P = 0.0007), CD4(+) (P = 0.001), CD8(+) (P = 0.004), CD3(-)CD56(+) (P = 0.003), and CD34(+) (P = 0.0001) cells were associated with higher levels of day 28 donor T-cell chimerism. Higher numbers of CD14(+) (P = 0.01) and CD34(+) (P = 0.0003) cells were associated with rapid achievement of complete donor T-cell chimerism, while high numbers of CD8(+) (P = 0.005) and CD34(+) (P = 0.01) cells were associated with low probabilities of graft rejection. When analyses were restricted to G-PBMC recipients, higher numbers of grafted CD34(+) cells were associated with higher levels of day 28 donor T-cell chimerism (P = 0.01), rapid achievement of complete donor T-cell chimerism (P = 0.02), and a trend for lower risk for graft rejection (P = 0.14). There were no associations between any cell subsets and acute or chronic GVHD nor relapse/progression. These data suggest more rapid engraftment of donor T cells and reduced rejection rates could be achieved by increasing the doses of CD34(+) cells in unrelated grafts administered after nonmyeloablative conditioning.

We have studied the influence of cell subsets [CD34, CD3, CD4, CD8, CD14, CD20, natural killer (NK; CD3(-)/CD56(+)), NKT (CD3(+)/CD56(+)), DC1, and DC2 cells] of granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSC) on early T-cell chimaerism and later clinical outcomes in 125 patients with haematological malignancies who received human leucocyte antigen (HLA)-matched related grafts after non-myeloablative conditioning. Conditioning consisted of 2 Gy total body irradiation (TBI) alone (n = 28), or 2 Gy TBI preceded by either 90 mg/m(2) fludarabine (n = 62) or planned autologous haematopoietic cell transplantation (HCT) (n = 35). Post-transplant immunosuppression included mycophenolate mofetil and ciclosporin. Multivariate analysis showed that higher numbers of grafted NK cells predicted higher early T-cell chimaerism (P = 0.03), while higher numbers of B cells were associated with better clinical outcomes and a higher risk for chronic graft-versus-host disease (P = 0.05). Higher numbers of CD14(+) cells were associated with worse overall survival (P = 0.03), while higher numbers of CD34(+) cells showed better survival (P = 0.03). The addition of fludarabine or autologous HCT predicted higher early T-cell chimaerism (P = 0.001), while advanced donor age predicted lower chimaerism (P < or = 0.02). Patients with aggressive diseases were at higher risk for relapse/disease progression, and shorter progression-free and overall survival (P < 0.01). These results suggest that the dosing of certain cellular subsets of PBSC products can influence important outcomes post-HCT after non-myeloablative conditioning.

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene on the X-chromosome that result in skeletal and cardiac muscle damage and premature death. Studies in mice, including the mdx mouse model of DMD, have demonstrated that circulating bone marrow-derived cells can participate in skeletal muscle regeneration, but the potential clinical utility of treating human DMD by allogeneic marrow transplantation from a healthy donor remains unknown. To assess whether allogeneic hematopoietic cell transplantation (HCT) provides clinically relevant levels of donor muscle cell contribution in dogs with canine X-linked muscular dystrophy (c-xmd), 7 xmd dogs were given hematopoietic cell (HC) transplants from nonaffected littermates. Compared with the pretransplantation baseline, the number of dystrophin-positive fibers and the amount of wild-type dystrophin RNA did not increase after HCT, with observation periods ranging from 28 to 417 days. Similar results were obtained when the recipient dogs were given granulocyte colony-stimulating factor (G-CSF) after their initial transplantation to mobilize the cells. Despite successful allogeneic HCT and a permissive environment for donor muscle engraftment, there was no detectable contribution of bone marrow-derived cells to either skeletal muscle or muscle precursor cells assayed by clonal analyses at a level of sensitivity that should detect as little as 0.1% donor contribution.

We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression.

Inducible costimulatory receptor (ICOS) is one recently identified member of the CD28 family of costimulatory molecules. Evidence suggests ICOS functions as a critical immune regulator and, to evaluate these effects, we employed the canine model system that has been used to develop strategies currently in clinical use for hematopoietic stem cell transplantation. To investigate the effects of blocking the ICOS pathway in the canine hematopoietic cell transplantation model, we tested existing murine and human reagents and cloned the full length of the open reading frame of canine ICOS cDNA to allow the development of reagents specific for the canine ICOS. Canine ICOS contains a major open reading frame of 624 nucleotides, encoding a protein of 208 amino acids, and localizes to chromosome 37. Canine ICOS shares 79% sequence identity with human ICOS, 70% with mouse, and 69% with rat. Canine ICOS expression is limited to stimulated PBMC., (Copyright 2004 Elsevier Inc.)

During the past 50 years, the role of allogeneic hematopoietic cell transplantation (HCT) has changed from a desperate therapeutic maneuver plagued by apparently insurmountable complications to a curative treatment modality for thousands of patients with hematologic diseases. Now, cure rates following human leukocyte antigen (HLA) allogeneic HCT with matched siblings exceed 85% for some otherwise lethal diseases, such as chronic myeloid leukemia, aplastic anemia, or thalassemia. In addition, the recent development of non-myeloablative conditioning and stem cell transplantation has opened the way to include elderly patients with a wide variety of hematologic malignancies. Further progress in adoptive transfer of T cell populations with relative tumor specificity would make the transplant procedure more effective and would extend the use of allogeneic HCT for treatment of non-hematopoietic malignancies.

Severe hemolytic anemia in Basenji dogs secondary to pyruvate kinase deficiency can be corrected by allogeneic hematopoietic cell transplantation (HCT) from littermates with normal hematopoiesis after conventional myeloablative or nonmyeloablative conditioning regimens. If the levels of donor chimerism were low (<20%) after nonmyeloablative HCT, there was only partial correction of the hemolytic anemia. We next addressed whether allogeneic cell therapy after nonmyeloablative HCT would convert mixed to full hematopoietic chimerism, achieve sustained remission from hemolysis, and prevent progression of marrow fibrosis and liver cirrhosis. Three pyruvate kinase-deficient dogs were given HCT from their respective dog leukocyte antigen-identical littermates after nonmyeloablative conditioning with 200 cGy of total body irradiation. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. All 3 dogs engrafted and had mixed hematopoietic chimerism with donor levels ranging from 12% to 55% in bone marrow. In 2 of the 3 dogs, there were decreases in the levels of donor chimerism so that at 25 weeks after nonmyeloablative HCT, hemolysis recurred that was associated with increased reticulocyte counts. All 3 dogs then had 2 serial infusions of donor lymphocytes (DLI) from their respective donors at least 20 weeks apart to convert from mixed to full donor chimerism. Both dogs with recurrence of hemolytic anemia after nonmyeloablative HCT achieved higher levels of donor chimerism, with donor contributions ranging from 47% to 62% in the bone marrow and 50% to 69% and 16% to 25% in the granulocyte and mononuclear cell fractions of the peripheral blood, respectively, and with remission of the hemolytic anemia. One dog responded after the first DLI, and 5 weeks after the second DLI, the other dog converted to full donor chimerism. At last follow-up, all these dogs showed clinical improvement, as determined by increasing hematocrits and normal reticulocyte counts. Analysis of the marrow 3 years after HCT showed normal cellularity, a normal myeloid-erythroid ratio, and no or minimal marrow fibrosis. Liver biopsies demonstrated normal histologies with no or minimal fibrosis. We conclude that DLI after nonmyeloablative HCT can increase the levels of donor cells contributing to hematopoiesis in recipients, inducing remissions of the hemolytic process and preventing complications associated with iron overload.

Background: Acute graft-versus-host disease (GVHD) remains a significant impediment to successful hematopoietic stem-cell transplantation (HSCT). Here, we examined the effectiveness of 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720), an immunosuppressant that retraffics activated lymphocytes to secondary lymphoid organs, for the treatment of acute GVHD in an established dog leukocyte antigen-nonidentical unrelated canine HSCT model., Methods: Dogs were given HSCT after conditioning with 920 cGy total body irradiation. The dogs received methotrexate 0.4 mg/kg/day on days 1, 3, 6, and 11 and FTY720 (5 mg/kg/day orally) after developing GVHD., Results: Five of six dogs achieved engraftment, developed acute GVHD, and were treated with FTY720. FTY720 resulted in a profound decrease in lymphocytes and a temporary mitigation of clinical GVHD; however, GVHD recurred in all dogs. Four of five dogs were euthanized because of severe GVHD and the fifth because of severe inanition associated with moderate GVHD., Conclusions: Compared with controls, treatment of GVHD with FTY720 did not control this complication or significantly increase survival.

We studied the value of postgrafting immunosuppression with sirolimus (SRL) and cyclosporine (CSP) in enhancing engraftment of dog leukocyte antigen-identical littermate marrow after nonmyeloablative conditioning in a canine model. Dogs received either 2 Gy (n=7) or 1 Gy (n=5) total body irradiation (TBI), followed by postgrafting immunosuppression with SRL and CSP. In the first cohort, all 7 dogs showed rapid initial engraftment. One engrafted dog died on day 21 due to hemorrhagic pneumonitis. Durable engraftment was seen in 5 of 6 remaining dogs, with a median follow-up of >48 (range, >32 to >56) weeks. The sixth dog rejected the marrow graft (as assessed by variable number of tandem repeats) at 11 weeks; however, a subsequent skin graft from the same marrow donor did not undergo acute cellular rejection, suggesting donor-specific tolerance. In the second cohort, all 5 dogs rejected the marrow graft at a median of 9 weeks (range, 3-11 weeks). We conclude that SRL/CSP is as effective as a previously studied combination of mycophenolate mofetil and CSP at establishing durable marrow engraftment after sublethal conditioning.

Background: Graft-versus-host (GVH) reactions contribute to stable engraftment of allogeneic hematopoietic stem cell transplants. It was hypothesized that the in vivo expansion of recipient dendritic cells (DC) with the administration of ligand for Flt3 (FL) could promote allogeneic engraftment after reduced-intensity conditioning by enhancing the GVH effect., Methods: FL was first administered to three nonirradiated healthy dogs for 13 days at a dosage of 100 microg/kg/day. Next, nine dogs received 4.5 Gy total-body irradiation (TBI) and unmodified marrow grafts from dog leukocyte antigen (DLA)-identical littermates without posttransplant immunosuppression. FL was administered to the recipients at a dosage of 100 microg/kg/day from day -7 until day +5., Results: In normal dogs, FL produced significant increases in monocytes (CD14+) and neutrophils in the peripheral blood, a marked increase in CD1c+ cells with DC-type morphology in lymph nodes, and increased alloreactivity of third-party responders to peripheral blood mononuclear cells in mixed lymphocyte reactions (P<0.001). Sustained engraftment was observed in eight of nine (89%) FL-treated dogs compared with 14 of 37 (38%) controls (P=0.02, logistic regression). All engrafted FL-treated dogs became stable complete (n=2) or mixed (n=6) hematopoietic chimeras without significant graft-versus-host disease (GVHD). Recipient chimeric dogs (n=4) were tolerant to skin transplants from their marrow donors but rejected skin grafts from unrelated dogs within 7 to 9 days (median, 8 days)., Conclusions: In this study, the authors showed that FL administered to recipients promotes stable engraftment of allogeneic marrow from DLA-identical littermates after 4.5 Gy TBI without significant GVHD.

Donor cytotoxic T lymphocytes (CTL) specific for minor histocompatibility antigens (mHA) mediate the graft-versus-host effect whereas host mHA-specific CTL mediate graft rejection in the setting of major histocompatibility complex identical allogeneic hematopoietic stem cell transplantation. Development of a large animal model from which mHA-specific CTL can be isolated would accelerate translation in clinical studies to improve control of the graft-versus-host effect as well as prevention of graft rejection in sensitized hosts. The aims of the current study were to isolate mHA-specific CTL from dog leukocyte antigen-identical littermate nonsensitized recipients before transplantation, from stable mixed hematopoietic chimeras, and from dogs sensitized to mHA after graft rejection. Donor dendritic cells (DCs) were cultured from bone marrow-derived CD34(+) cells and were used to stimulate recipient T lymphocytes on days 1, 10, and 20 of CTL culture. We reliably generated and expanded mHA-specific CTL ex vivo from sensitized dogs that were given a donor-specific blood transfusion to boost immune recall after graft rejection after a nonmyeloablative transplantation. The mHA-specific cytotoxicity measured by (51)Cr release assay was enriched from less than 5% in the starting population of sensitized peripheral blood mononuclear cells to a median of 63% after 4 weeks in CTL culture. The expanded mHA-specific CTLs were not tissue-specific: hematopoietic cells, fibroblast, and stromal cell lines were lysed in an mHA-specific manner. Allogeneic DCs, but not peripheral blood mononuclear cells, were necessary for stimulating ex vivo expansion of mHA-specific CTL. We were unable to generate mHA-specific CTL from nonsensitized dogs before transplantation, from previously sensitized dogs but without recent recall immunization, or from stable mixed hematopoietic chimeras. We conclude that after recent in vivo sensitization, large-scale ex vivo expansion of mHA-specific CTL was feasible using allogeneic DCs., (Copyright 2003 American Society for Blood and Marrow Transplantation)

Background: Stable mixed-donor-host-hematopoietic chimerism can serve as a platform for adoptive immunotherapy. Infusions of donor lymphocytes (DLI) sensitized against hematopoietic cells converted mixed hematopoietic into full-donor chimerism in dog-leukocyte antigen (DLA)-identical littermates. Whether sensitization against tissue of solid organs leads to organ-specific immunity that can be transferred by DLI was unknown and was investigated in these experiments using the kidney as target., Methods: DLA-identical recipients with established stable mixed-donor-host-hematopoietic chimerism were used. In five pairs, hematopoietic stem-cell transplant (HSCT) donors were sensitized by kidney transplantation from the respective chimeras. In a second group, five HSCT donors received vaccinations that were generated from kidney cells of the respective mixed chimeras. Twenty-eight days after sensitization, DLI were administered to the mixed-hematopoietic chimeras., Results: All HSCT donors rejected their kidney grafts from their mixed-chimeric recipients within 22 to 45 days. DLI caused no sustained graft-versus-kidney effects in the mixed-chimeric recipients. However, DLI donors sensitized by kidney transplantation converted 4 of 5 mixed chimeras into virtually complete (>95%) donor-type chimeras, compared with 1 of 5 mixed chimeras given DLI by vaccination from sensitized donors., Conclusion: Although DLA-identical kidney grafts from mixed-hematopoietic chimeras were readily rejected by their HSCT donors, subsequent transfusions of sensitized-donor lymphocytes into mixed chimeras converted mixed to all-donor chimerism but failed to induce graft-versus-kidney effects. Vaccination strategies in lieu of kidney grafts failed to convert mixed chimerism.