Clinical Scores Predict Acute and Chronic Complications in Pediatric Osteomyelitis: An External Validation.

BACKGROUND: Pediatric acute hematogenous osteomyelitis (AHO) outcomes are highly dependent on the disease severity. Recently, the A-SCORE and C-SCORE, were proposed as predictors of an acute complicated course and chronic morbidity, respectively. The purpose of this study was to externally validate the A-SCORE and C-SCORE at a single institution. METHODS: This IRB-approved retrospective chart review included AHO patients admitted at a tertiary referral hospital between October 1, 2015 and December 31, 2019. The inclusion criteria were ages 0 to 18 and clinical response to treatment. The exclusion criteria were immunocompromised status or penetrating inoculation. RESULTS: The A-SCORE demonstrated an area under the receiver operator curve (ROC area) of >86% with regards to all acute complications. It also demonstrated sensitivities >85% and specificities >92% at the cut-off of 4 (Youden index) for all acute complications. The C-SCORE demonstrated an ROC area of 100% with regards to chronic osteomyelitis. It also demonstrated sensitivities >70% and specificities >93% for the chronic morbidity variables seen in our population at the cut-off of 3 (Youden index.). CONCLUSIONS: These novel composite clinical scores, in combination with clinical judgment, could help guide early care decisions. The A-SCORE and C-SCORE are useful risk stratification tools in the management of pediatric AHO and in predicting acute complicated courses or chronic sequelae of AHO, respectively. These scoring systems, if integrated into standardized pediatric AHO guidelines, can allow clinicians to stratify the AHO population and guide clinical decision making. LEVEL OF EVIDENCE: Level III (prognostic study, retrospective chart review).

Primary Bacterial Pyomyositis in Children: A Systematic Review.

BACKGROUND: Tropical pyomyositis has had a recent increase in the United States, Europe, and other nontropical areas. The purpose of this study was to provide an accurate description of the demographics, presenting features, sites of involvement, microbiology, imaging modalities, medical and surgical management, complications, and predictors of clinical course. METHODS: We searched PubMed, Cochrane, Web of Science Collection, Scopus, and Embase databases yielding 156 studies. Of these, 23 articles were selected for statistical analysis. RESULTS: The average age at presentation was 8.4±1.9 years with males more commonly affected. Fever, painful limp, and localized pain were the most common presenting symptoms. Pelvis, lower extremity, trunk and spine, in descending order, were the most commonly affected locations. Iliopsoas, obturator musculature, and gluteus musculature were the most commonly affected muscle groups. The mean time to diagnosis was 6.6±3.05 days. Staphylococcus aureus was the most common offending organism. The mean length of hospital stay was 12.0±4.6 days. Medical management alone was successful in 40% of cases (143/361) with an average duration of 9.5±4.0 and 22.7±7.2 days of intravenous and oral antibiotics, respectively. Surgical management consisted of open drainage in 91.3% (199/218) or percutaneous drainage in 8.7% (19/218) of cases. Painful limp, fever, and larger values of white cell count and erythrocyte sedimentation rate were associated with an increased need for surgery. Obturator and calf muscle involvement were strongly associated with multifocal involvement. There were 42 complications in 41 patients (11.3%). Methicillin-resistant S. aureus was associated with an increased risk of complications. The most common complications were osteomyelitis, septicemia, and septic arthritis. CONCLUSIONS: Primary pyomyositis should be considered in cases suggesting pediatric infection. Magnetic resonance imaging is the most commonly used imaging modality; however, ultrasound is useful given its accessibility and low cost. Medical management alone can be successful, but surgical treatment is often needed. The prognosis is favorable. Early diagnosis, appropriate medical management, and potential surgical drainage are required for effective treatment. LEVEL OF EVIDENCE: Level IV-systematic review.

Diversity and Inclusion in an Orthopaedic Surgical Society: A Longitudinal Study.

BACKGROUND: Diversity and inclusion are critical to providing the best possible health care. Previous studies have shown that diversity among physicians increases cultural competency, which in turn enhances the quality of care provided and increases minoritized patients' participation in decisions regarding their health care. However, physician diversity in both race and sex is lacking in orthopaedic surgery. This study seeks to determine the sex and racial diversity in the membership and leadership of the Pediatric Orthopaedic Society of North America (POSNA). METHODS: POSNA membership and leadership were reviewed for the years 2010, 2015, and 2020. This data was gathered from membership directories and committee reference books. All North American Active Members' race/ethnicity and sex were recorded for each year. The categories for race/ethnicity are Caucasian, East/South/Middle Eastern Asian American (Asian), Hispanic/Latin/South American (HLSA), and African American. RESULTS: From 2010 to 2020, Active Members of POSNA increased from 608 to 818, and the percentage of female (14.6% to 23.7%), Asian (7.4% to 11.2%), HLSA (2.5% to 2.9%), and African American membership (1.6% to 1.8%) increased. Male (85.4% to 76.3%) and Caucasian (88.5% to 84.0%) membership decreased. From 2010 to 2020, male leadership decreased on both the Board of Directors and Committee Chairs (89.5% to 81.8% and 86.4% to 64.7%, respectively), as did Caucasians (94.7% to 81.8% and 90.9% to 88.2%, respectively). The number of Asian members holding positions on both the Board of Directors and Committee Chairs increased (0% to 18.2% and 4.5% to 11.8%, respectively) as did the number of females (10.5% to 18.2% and 13.6% to 35.3%, respectively). HLSA and African American members were proportionally represented in leadership for the years 2010 and 2015. CONCLUSIONS: Membership in POSNA has increased between 2010 to 2020 for every diversity category examined and POSNA membership exhibits significantly more diversity than the orthopaedic specialty as a whole. Leadership as a whole is more diverse in 2020 than it was in 2010. LEVEL OF EVIDENCE: Level II-retrospective.

Cigarette smoke-induced autophagy impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis.

Cigarette-smoke (CS) exposure and aging are the leading causes of chronic obstructive pulmonary disease (COPD)-emphysema development, although the molecular mechanism that mediates disease pathogenesis remains poorly understood. Our objective was to investigate the impact of CS exposure and aging on autophagy and the pathophysiological changes associated with lung aging (senescence) and emphysema progression. Beas2b cells, C57BL/6 mice, and human (GOLD 0-IV) lung tissues were used to determine the central mechanism involved in CS/age-related COPD-emphysema pathogenesis. Beas2b cells and murine lungs exposed to cigarette smoke extract (CSE)/CS showed a significant ( P < 0.05) accumulation of poly-ubiquitinated proteins and impaired autophagy marker, p62, in aggresome bodies. Moreover, treatment with the autophagy-inducing antioxidant drug cysteamine significantly ( P < 0.001) decreased CSE/CS-induced aggresome bodies. We also found a significant ( P < 0.001) increase in levels of aggresome bodies in the lungs of smokers and COPD subjects in comparison to nonsmoker controls. Furthermore, the presence and levels of aggresome bodies statistically correlated with severity of emphysema and alveolar senescence. In addition to CS exposure, lungs from old mice also showed accumulation of aggresome bodies, suggesting this as a common mechanism to initiate cellular senescence and emphysema. Additionally, Beas2b cells and murine lungs exposed to CSE/CS showed cellular apoptosis and senescence, which were both controlled by cysteamine treatment. In parallel, we evaluated the impact of CS on pulmonary exacerbation, using mice exposed to CS and/or infected with Pseudomonas aeruginosa ( Pa), and confirmed cysteamine's potential as an autophagy-inducing antibacterial drug, based on its ability to control CS-induced pulmonary exacerbation ( Pa-bacterial counts) and resulting inflammation. CS induced autophagy impairment accelerates lung aging and COPD-emphysema exacerbations and pathogenesis.

Inhibition of histone-deacetylase activity rescues inflammatory cystic fibrosis lung disease by modulating innate and adaptive immune responses.

BACKGROUND: Chronic lung disease resulting from dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) and NFκB-mediated neutrophilic-inflammation forms the basis of CF-related mortality. Here we aimed to evaluate if HDAC inhibition controls Pseudomonas-aeruginosa-lipopolysaccharide (Pa-LPS) induced airway inflammation and CF-lung disease. METHODS: For in vitro experiments, HEK293-cells were transfected with IL-8 or NFκB-firefly luciferase, and SV40-renilla- luciferase reporter constructs or ΔF508-CFTR-pCEP, followed by treatment with suberoylanilide hydroxamic acid (SAHA), Trichostatin-A (TSA) and/or TNFα. For murine studies, Cftr +/+ or Cftr -/- mice (n = 3) were injected/instilled with Pa-LPS and/or treated with SAHA or vehicle control. The progression of lung disease was monitored by quantifying changes in inflammatory markers (NFκB), cytokines (IL-6/IL-10), neutrophil activity (MPO, myeloperoxidase and/or NIMP-R14) and T-reg numbers. RESULTS: SAHA treatment significantly (p < 0.05) suppresses TNFα-induced NFκB and IL-8 reporter activities in HEK293-cells. Moreover, SAHA, Tubacin (selective HDAC6-inhibitor) or HDAC6-shRNAs controls CSE-induced ER-stress activities (p < 0.05). In addition, SAHA restores trafficking of misfolded-ΔF508-CFTR, by inducing protein levels of both B and C forms of CFTR. Murine studies using Cftr +/+ or Cftr -/- mice verified that SAHA controls Pa-LPS induced IL-6 levels, and neutrophil (MPO levels and/or NIMP-R14), NFκB-(inflammation) and Nrf2 (oxidative-stress marker) activities, while promoting FoxP3+ T-reg activity. CONCLUSION: In summary, SAHA-mediated HDAC inhibition modulates innate and adaptive immune responses involved in pathogenesis and progression of inflammatory CF-lung disease.

Augmenting autophagy for prognosis based intervention of COPD-pathophysiology.

Chronic obstructive pulmonary disease (COPD) is foremost among the non-reversible fatal ailments where exposure to tobacco/biomass-smoke and aging are the major risk factors for the initiation and progression of the obstructive lung disease. The role of smoke-induced inflammatory-oxidative stress, apoptosis and cellular senescence in driving the alveolar damage that mediates the emphysema progression and severe lung function decline is apparent, although the central mechanism that regulates these processes was unknown. To fill in this gap in knowledge, the central role of proteostasis and autophagy in regulating chronic lung disease causing mechanisms has been recently described. Recent studies demonstrate that cigarette/nicotine exposure induces proteostasis/autophagy-impairment that leads to perinuclear accumulation of polyubiquitinated proteins as aggresome-bodies, indicative of emphysema severity. In support of this concept, autophagy inducing FDA-approved anti-oxidant drugs control tobacco-smoke induced inflammatory-oxidative stress, apoptosis, cellular senescence and COPD-emphysema progression in variety of preclinical models. Hence, we propose that precise and early detection of aggresome-pathology can allow the timely assessment of disease severity in COPD-emphysema subjects for prognosis-based intervention. While intervention with autophagy-inducing drugs is anticipated to reduce alveolar damage and lung function decline, resulting in a decrease in the current mortality rates in COPD-emphysema subjects.

Cigarette Smoke Exposure Inhibits Bacterial Killing via TFEB-Mediated Autophagy Impairment and Resulting Phagocytosis Defect.

INTRODUCTION: Cigarette smoke (CS) exposure is the leading risk factor for COPD-emphysema pathogenesis. A common characteristic of COPD is impaired phagocytosis that causes frequent exacerbations in patients leading to increased morbidity. However, the underlying mechanism is unclear. Hence, we investigated if CS exposure causes autophagy impairment as a mechanism for diminished bacterial clearance via phagocytosis by utilizing murine macrophages (RAW264.7 cells) and Pseudomonas aeruginosa (PA01-GFP) as an experimental model. METHODS: Briefly, RAW cells were treated with cigarette smoke extract (CSE), chloroquine (autophagy inhibitor), TFEB-shRNA, CFTR(inh)-172, and/or fisetin prior to bacterial infection for functional analysis. RESULTS: Bacterial clearance of PA01-GFP was significantly impaired while its survival was promoted by CSE (p < 0.01), autophagy inhibition (p < 0.05; p < 0.01), TFEB knockdown (p < 0.01; p < 0.001), and inhibition of CFTR function (p < 0.001; p < 0.01) in comparison to the control group(s) that was significantly recovered by autophagy-inducing antioxidant drug, fisetin, treatment (p < 0.05; p < 0.01; and p < 0.001). Moreover, investigations into other pharmacological properties of fisetin show that it has significant mucolytic and bactericidal activities (p < 0.01; p < 0.001), which warrants further investigation. CONCLUSIONS: Our data suggests that CS-mediated autophagy impairment as a critical mechanism involved in the resulting phagocytic defect, as well as the therapeutic potential of autophagy-inducing drugs in restoring is CS-impaired phagocytosis.

Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases.

The success of drug delivery to target airway cell(s) remains a significant challenge due to the limited ability of nanoparticle (NP) systems to circumvent protective airway-defense mechanisms. The size, density, surface and physical-chemical properties of nanoparticles are the key features that determine their ability to navigate across the airway-barrier. We evaluated here the efficacy of a PEGylated immuno-conjugated PLGA-nanoparticle (PINP) to overcome this challenge and selectively deliver drug to specific inflammatory cells (neutrophils). We first characterized the size, shape, surface-properties and neutrophil targeting using dynamic laser scattering, transmission electron microscopy and flow cytometry. Next, we assessed the efficacy of neutrophil-targeted PINPs in transporting through the airway followed by specific binding and release of drug to neutrophils. Finally, our results demonstrate the efficacy of PINP mediated non-steroidal anti-inflammatory drug-(ibuprofen) delivery to neutrophils in murine models of obstructive lung diseases, based on its ability to control neutrophilic-inflammation and resulting lung disease.

Role of Cigarette Smoke-Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis.

Cigarette smoke (CS) exposure is known to induce proteostasis imbalance that can initiate accumulation of ubiquitinated proteins. Therefore, the primary goal of this study was to determine if first- and secondhand CS induces localization of ubiquitinated proteins in perinuclear spaces as aggresome bodies. Furthermore, we sought to determine the mechanism by which smoke-induced aggresome formation contributes to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Hence, Beas2b cells were treated with CS extract (CSE) for in vitro experimental analysis of CS-induced aggresome formation by immunoblotting, microscopy, and reporter assays, whereas chronic CS-exposed murine model and human COPD-emphysema lung tissues were used for validation. In preliminary analysis, we observed a significant (P < 0.01) increase in ubiquitinated protein aggregation in the insoluble protein fraction of CSE-treated Beas2b cells. We verified that CS-induced ubiquitin aggregrates are localized in the perinuclear spaces as aggresome bodies. These CS-induced aggresomes (P < 0.001) colocalize with autophagy protein microtubule-associated protein 1 light chain-3B(+) autophagy bodies, whereas U.S. Food and Drug Administration-approved autophagy-inducing drug (carbamazepine) significantly (P < 0.01) decreases their colocalization and expression, suggesting CS-impaired autophagy. Moreover, CSE treatment significantly increases valosin-containing protein-p62 protein-protein interaction (P < 0.0005) and p62 expression (aberrant autophagy marker; P < 0.0001), verifying CS-impaired autophagy as an aggresome formation mechanism. We also found that inhibiting protein synthesis by cycloheximide does not deplete CS-induced ubiquitinated protein aggregates, suggesting the role of CS-induced protein synthesis in aggresome formation. Next, we used an emphysema murine model to verify that chronic CS significantly (P < 0.0005) induces aggresome formation. Moreover, we observed that autophagy induction by carbamazepine inhibits CS-induced aggresome formation and alveolar space enlargement (P < 0.001), confirming involvement of aggresome bodies in COPD-emphysema pathogenesis. Finally, significantly higher p62 accumulation in smokers and severe COPD-emphysema lungs (Global Initiative for Chronic Obstructive Lung Disease Stage III/IV) as compared with normal nonsmokers (Global Initiative for Chronic Obstructive Lung Disease Stage 0) substantiates the pathogenic role of autophagy impairment in aggresome formation and COPD-emphysema progression. In conclusion, CS-induced aggresome formation is a novel mechanism involved in COPD-emphysema pathogenesis.

Lactosylceramide-accumulation in lipid-rafts mediate aberrant-autophagy, inflammation and apoptosis in cigarette smoke induced emphysema.

Ceramide-accumulation is known to be involved in the pathogenesis of chronic inflammatory lung diseases including cigarette smoke-induced emphysema (CS-emphysema) but the exact sphingolipid metabolite that initiates emphysema progression remains ambiguous. We evaluated here a novel role for the sphingolipid, lactosylceramide (LacCer), as a potential mechanism for pathogenesis of CS-emphysema. We assessed the expression of LacCer, and LacCer-dependent inflammatory, apoptosis and autophagy responses in lungs of mice exposed to CS, as well as peripheral lung tissues from COPD subjects followed by experimental analysis to verify the role of LacCer in CS-emphysema. We observed significantly elevated LacCer-accumulation in human COPD lungs with increasing severity of emphysema over non-emphysema controls. Moreover, increased expression of defective-autophagy marker, p62, in lung tissues of severe COPD subjects suggest that LacCer induced aberrant-autophagy may contribute to the pathogenesis of CS-emphysema. We verified that CS-extract treatment significantly induces LacCer-accumulation in both bronchial-epithelial cells (BEAS2B) and macrophages (Raw264.7) as a mechanism to initiate aberrant-autophagy (p62-accumulation) and apoptosis that was rescued by pharmacological inhibitor of LacCer-synthase. Further, we corroborated that CS exposure induces LacCer-accumulation in murine lungs that can be controlled by LacCer-synthase inhibitor. We propose LacCer-accumulation as a novel prognosticator of COPD-emphysema severity, and provide evidence on the therapeutic efficacy of LacCer-synthase inhibitor in CS induced COPD-emphysema.

Total Shoulder Arthroplasty Versus Reverse Shoulder Arthroplasty in Primary Glenohumeral Osteoarthritis With Intact Rotator Cuffs: A Meta-Analyses.

Traditional practice favors total shoulder arthroplasty (TSA) for the treatment of primary glenohumeral osteoarthritis (PGHO) with an intact rotator cuff; however, the indications for reverse shoulder arthroplasty (RSA) have expanded to include PGHO. The purpose of this systematic review is to compare the mean differences in the range of motion and patient-reported outcomes between the TSA and RSA with an intact rotator cuff and to analyze the subgroup of the Walch type B2 glenoid. This IRB-exempt, PROSPERO-registered systematic review strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines. A literature search of five databases revealed 493 articles, of which 10 were included for quantitative synthesis. Level III evidence studies with the diagnosis of PGHO and ≥2 years of follow-up were included. Studies without preoperative and postoperative data were excluded. The Newcastle-Ottawa scale was used to evaluate the methodologic quality of the included studies. Preoperative and postoperative range of motion and patient-reported outcomes were collected. The random-effects model was employed, and p < 0.05 was considered statistically significant. There were a total of 544 and 329 studies in the TSA group and RSA group, respectively. The mean age in the TSA group and RSA groups were 65.36 ± 7.06 and 73.12 ± 2.40, respectively (p = 0.008). The percentages of males in the TSA and RSA groups were 73.2% and 51.1%, respectively (p = 0.02). The mean differences in forward elevation, external rotation in adduction, internal rotation scale, visual analog scale (VAS), American Shoulder and Elbow Surgeons (ASES) score, and Single Assessment Numeric Evaluation (SANE) scores were improved for both groups with no significant differences between the two. There were 9.6 times the revisions in the TSA group (8.8% vs. 0.91%; p = 0.014) and 1.5 times the complications in the TSA group (3.68% vs. 2.4%; p = 0.0096). Two hundred and forty-two glenoids were identified as Walch type B2 (126 in the TSA group and 116 in the RSA group). The mean ages in the B2 subgroup were 68.20 ± 3.25 and 73.03 ± 1.49 for the TSA and RSA, respectively (p = 0.25). The percentages of males in the B2 subgroup were 74.6% and 46.5% for the TSA and RSA groups, respectively (p = 0.0003). The ASES, SANE, forward elevation, and external rotation in the adduction results were descriptively summarized for this subgroup, with average mean differences of 49.0 and 51.2, 45.7 and 66.1, 77.6° and 58.6°, and 38.6° and 34.1° for the TSA and RSA groups, respectively. In the setting of primary glenohumeral osteoarthritis with an intact rotator cuff, the RSA has a similar range of motion and clinical outcomes but lower complication and revision rates as compared to the TSA. This may hold true in the setting of the B2 glenoid, although a high-powered study on this subgroup is required. Anatomic shoulder arthroplasty maintains an important role in select patients. Further studies are required to better elucidate the role of glenoid bone loss and posterior humeral head subluxation with regard to implant choice.

Hamstring Tendon Autograft Is Associated With Increased Knee Valgus Moment After Anterior Cruciate Ligament Reconstruction: A Biomechanical Analysis.

BACKGROUND: There is limited evidence related to the effects of autograft type on functional performance after anterior cruciate ligament reconstruction (ACLR). PURPOSE/HYPOTHESIS: This study aimed to compare biomechanical outcomes during a drop vertical jump (DVJ) between patients with a hamstring tendon (HT) autograft, quadriceps tendon (QT) autograft with bone block, QT autograft without bone block, and bone-patellar tendon-bone autograft at 6 months postoperatively in an adolescent population. The authors' hypothesized there would be differences in DVJ biomechanics between athletes depending on the type of autograft used. STUDY DESIGN: Controlled laboratory study. METHODS: Patients aged 8 to 18 years who underwent primary ACLR were included for analysis. Kinematic and kinetic data collected during a DVJ using a 3-dimensional computerized marker system were assessed at 6 months after ACLR and compared with the uninjured contralateral limb. RESULTS: A total of 155 participants were included. There were no significant differences in terms of age, sex, or affected leg (P≥ .1973) between groups. The HT group was significantly associated with a larger knee valgus moment at initial contact compared with the QT group (28 × 10-2 vs -35 × 10-2 N·m/kg, respectively; P = .0254) and a significantly larger maximum hip adduction moment compared with the QT with bone block group (30 × 10-2 vs -4 × 10-2 N·m/kg, respectively; P = .0426). Both the QT with bone block (-12 × 10-2 vs -3 × 10-2 N·m/kg, respectively; P = .0265) and QT (-13 × 10-2 vs -3 × 10-2 N·m/kg, respectively; P = .0459) groups demonstrated significantly decreased mean knee extension moments compared with the HT group. CONCLUSION: The findings of this study suggest that utilizing an HT autograft resulted in a significantly increased knee valgus moment at initial contact compared with a QT autograft without bone block at 6 months after ACLR in adolescent patients performing a DVJ. A QT autograft was found to be associated with significantly decreased extensor mechanism function compared with an HT autograft. CLINICAL RELEVANCE: This study adds unique kinematic and kinetic information regarding various ACLR autograft options and highlights the biomechanical deficits that should be taken into consideration in rehabilitation.

Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia.

Multiple sodium and chloride channels on the apical surface of nasal epithelial cells contribute to periciliary fluid homeostasis, a function that is disrupted in patients with cystic fibrosis (CF). Among these channels is the chloride channel CLCN2, which has been studied as a potential alternative chloride efflux pathway in the absence of CFTR. The object of the present study was to use the nasal potential difference test (NPD) to quantify CLCN2 function in an epithelial-directed TetOn CLCN2 transgenic mouse model (TGN-K18rtTA-hCLCN2) by using the putative CLCN2 pharmacological agonist lubiprostone and peptide inhibitor GaTx2. Lubiprostone significantly increased chloride transport in the CLCN2-overexpressing mice following activation of the transgene by doxycycline. This response to lubiprostone was significantly inhibited by GaTx2 after CLCN2 activation in TGN-CLCN2 mice. Cftr(-/-) and Clc2(-/-) mice showed hyperpolarization indicative of chloride efflux in response to lubiprostone, which was fully inhibited by GaTx2 and CFTR inhibitor 172 + GlyH-101, respectively. Our study reveals lubiprostone as a pharmacological activator of both CFTR and CLCN2. Overexpression and activation of CLCN2 leads to improved mouse NPD readings, suggesting it is available as an alternative pathway for epithelial chloride secretion in murine airways. The utilization of CLCN2 as an alternative chloride efflux channel could provide clinical benefit to patients with CF, especially if the pharmacological activator is administered as an aerosol.

Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema.

Ceramide accumulation mediates the pathogenesis of chronic obstructive lung diseases. Although an association between lack of cystic fibrosis transmembrane conductance regulator (CFTR) and ceramide accumulation has been described, it is unclear how membrane-CFTR may modulate ceramide signaling in lung injury and emphysema. Cftr(+/+) and Cftr(-/-) mice and cells were used to evaluate the CFTR-dependent ceramide signaling in lung injury. Lung tissue from control and chronic obstructive pulmonary disease patients was used to verify the role of CFTR-dependent ceramide signaling in pathogenesis of chronic emphysema. Our data reveal that CFTR expression inversely correlates with severity of emphysema and ceramide accumulation in chronic obstructive pulmonary disease subjects compared with control subjects. We found that chemical inhibition of de novo ceramide synthesis controls Pseudomonas aeruginosa-LPS-induced lung injury in Cftr(+/+) mice, whereas its efficacy was significantly lower in Cftr(-/-) mice, indicating that membrane-CFTR is required for controlling lipid-raft ceramide levels. Inhibition of membrane-ceramide release showed enhanced protective effect in controlling P. aeruginosa-LPS-induced lung injury in Cftr(-/-) mice compared with that in Cftr(+/+) mice, confirming our observation that CFTR regulates lipid-raft ceramide levels and signaling. Our results indicate that inhibition of de novo ceramide synthesis may be effective in disease states with low CFTR expression like emphysema and chronic lung injury but not in complete absence of lipid-raft CFTR as in ΔF508-cystic fibrosis. In contrast, inhibiting membrane-ceramide release has the potential of a more effective drug candidate for ΔF508-cystic fibrosis but may not be effectual in treating lung injury and emphysema. Our data demonstrate the critical role of membrane-localized CFTR in regulating ceramide accumulation and inflammatory signaling in lung injury and emphysema.

An Analysis of Global Orthopedic Organizations Through the Lens of the Four Pillars of Global Surgery.

Introduction The mortality of orthopedic trauma is very high, however, a large proportion is considered preventable. Global orthopedics was historically centered around the direct delivery of nonsurgical and surgical medical care. There has been an evolution towards increased sustainability. Purpose The purpose of this paper is to evaluate the accomplishment of the four pillars of global surgery by five commonly referenced orthopedic global surgery organizations. Methods This institutional review board (IRB)-exempt cross-sectional data studied Global Orthopedic Alliance, Operation Rainbow, the Institute for Global Orthopaedics and Traumatology (IGOT), One World Surgery (OWS), and the Canadian Orthopedic Association for Global Surgery (COAGS) through the lens of the four pillars of global surgery: knowledge exchange, advocacy, research initiative, surgical education. The knowledge exchange pillar was examined through the three most popular online knowledge exchange platforms in orthopedics. The advocacy pillar was examined through each organization's individually created website. The research initiative was examined through a comprehensive literature search. The surgical education pillar was examined through resident-level educational resources. The data was summarized descriptively. Results A total of four organizations demonstrated activity within the pillar of knowledge exchange. A total of three organizations demonstrated activity with the pillar of advocacy. A total of three groups demonstrated activity within the pillar of the research initiative. A total of two groups had activity within the pillar of surgical education. Conclusions The landscape regarding global orthopedic surgery programs has evolved greatly to encompass the four pillars of global surgery. Within the past 10 years, there has been increased emphasis on the knowledge exchange and research initiative pillars. Surgical education remains the pillar with the least emphasis. As global orthopedic surgery programs continue to evolve, increasing emphasis should be placed on all four of these pillars to increase sustainability.

Primary Fibular Osteomyelitis in Children: A Systematic Review.

Osteomyelitis of the fibula is rare and is especially rare in children. The published literature is limited to case series and is thus lacking a comprehensive description of the disease. The purpose of this systematic review is to provide the first comprehensive summary of the demographics, presenting symptoms, laboratory values, microbiology, and treatment results of osteomyelitis of the fibula in children based on the existing literature. This institutional review board (IRB)-exempt systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines. Three search engines were used for a total of 239 studies. Twenty-six studies were screened by full text. Twelve articles underwent a quantitative analysis. Due to limited data and heterogenous reporting, the data were summarized descriptively. The methodologic quality of the studies was evaluated based on the Newcastle-Ottawa scale. The average age was 7.71±3.49 years, and males comprised 57% of the 21 cases. The most common presenting symptoms were fever (86%), antalgic gait (57%), and localized tenderness (81%). The most common site of involvement was the distal third of the fibula (90%). The average C-reactive protein (CRP) was 90.1±38.3 mg/L, and the average erythrocyte sedimentation rate (ESR) was 58.8±21.2 mm/hour. Staphylococcus aureus was the most cultured pathogen reported in 10/21 cases (48%). Open surgery was performed in 17/21 cases (81%), and there were no reported complications. Fever, antalgic gait, and localized tenderness should raise the index of suspicion. Prompt laboratory and radiographic evaluations can help reduce delays in diagnosis and improve outcomes. Blood and tissue cultures are currently performed in about half of the cases. Improvement in our microbiologic diagnosis has the potential to improve antibiotic selection. Local methicillin-resistant Staphylococcus aureus (MRSA) prevalence must be taken into consideration when starting empiric antibiotic treatment. Surgical treatment is often required with a low complication rate. The clinical and laboratory parameters identified in this study have the potential for integration into a composite clinical score.

Radiofrequency in arthroscopic shoulder surgery: a systematic review.

BACKGROUND: Radiofrequency has seen an increase in use in orthopedics including cartilage lesion debridement in the hip and knee as well as many applications in arthroscopic shoulder surgery. The purpose of this systematic review is to evaluate the safety and usage of radiofrequency in the shoulder. METHODS: This systematic review was registered with PROSPERO (international registry) and followed the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guidelines. Embase and PubMed were searched using: "shoulder," "rotator cuff," "biceps," "acromion" AND "monopolar," "bipolar," "ablation," "coblation," and "radiofrequency ablation." The title and abstract review were performed independently. Any discrepancies were addressed through open discussion. RESULTS: A total of 63 studies were included. Radiofrequency is currently utilized in impingement syndrome, fracture fixation, instability, nerve injury, adhesive capsulitis, postoperative stiffness, and rotator cuff disease. Adverse events, namely superficial burns, are limited to case reports and case series, with higher-level evidence demonstrating safe use when used below the temperature threshold. Bipolar radiofrequency may decrease operative time and decrease the cost per case. CONCLUSIONS: Shoulder radiofrequency has a wide scope of application in various shoulder pathologies. Shoulder radiofrequency is safe; however, requires practitioners to be cognizant of the potential for thermal burn injuries. Bipolar radiofrequency may represent a more efficacious and economic treatment modality. Safety precautions have been executed by institutions to cut down patient complications from shoulder radiofrequency. Future research is required to determine what measures can be taken to further minimize the risk of thermal burns.

Medial-Sided Ligamentous Injuries of the Athlete's Knee: Evaluation and Management.

The superficial medial collateral ligament (sMCL) is the most commonly injured ligamentous structure in the knee. The other medial knee stabilizers include the deep medial collateral ligament, the posterior oblique ligament, and the medial meniscus. Medial collateral ligament injuries frequently occur in young athletes. As a result of the good healing capacity of the sMCL, the majority of acute medial-sided knee injuries can be treated nonoperatively with good outcomes. However, missed concomitant injuries can lead to residual laxity and instability of the knee when treated conservatively. When surgical management is warranted, numerous techniques exist, including repair, augmentation, and reconstruction. Recent anatomic and biomechanical studies defining the attachment sites and functional roles of the individual medial knee structures have led to advancements in diagnosis, treatment, and rehabilitation. These studies have allowed for the development of an anatomic reconstruction technique that restores the native stability and load-sharing relationships among the medial knee structures. The purpose of this narrative review is to summarize the recent updates in the anatomy, biomechanics, evaluation, and treatment of ligamentous injuries on the medial side of the athlete's knee.

Prenatal radiographic evaluation of congenital transverse limb deficiencies: A scoping review.

BACKGROUND: Congenital transverse deficiencies are horizontal deficiencies of the long bones that occur with a reported incidence as high 0.38%. They can occur alone or represent a manifestation of a various clinical syndromes. Diagnosis has traditionally comprised of conventional radiography and prenatal imaging studies. There has been much advancement regarding prenatal imaging modalities to allow for early diagnosis and appropriate treatment. AIM: To summarize the current state of knowledge on congenital transverse limb deficiencies and to provide an update regarding the radiographic evaluation of congenital transverse limb deficiencies. METHODS: This IRB-exempt scoping review followed the PRISMA-ScR checklist for scoping reviews strictly. Five search engines were searched for a total of 265 publications. Four authors reviewed these during the screening process. Of these, 51 studies were included in our article. Prenatal magnetic resonance imaging (MRI), 3D Ultrasound, and multidetector Computed tomography (CT) exist are emerging modalities that have the potential to improve diagnosis. RESULTS: Use of the appropriate classification system, three-dimensional ultrasonography with a maximum intensity projection, and appropriate use of prenatal MRI and prenatal CT can improve diagnosis and inter-provider communication. CONCLUSION: Further scholarly efforts are required to develop improve standardized guidelines regarding the pre-natal radiographic evaluation of congenital limb deficiencies.

Biomechanical Comparison of Adjustable-Loop Femoral Cortical Suspension Devices for Soft Tissue ACL Reconstruction.

Background: Several new adjustable-loop devices (ALDs) for anterior cruciate ligament reconstruction (ACLR) have not been tested in vitro. Purpose: To compare the biomechanical performances of 5 ALDs under a high cyclic load and forces representative of the return-to-play conditions seen in the recovering athlete. Study Design: Controlled laboratory study. Methods: A total of 10 devices for each of 5 chosen ALDs (UltraButton [Smith & Nephew], RigidLoop [DePuy Mitek], ProCinch [Stryker], TightRope [Arthrex], and ToggleLoc [Biomet]) were tested in a device-only model. The devices were secured to a servohydraulic test machine and preconditioned from 10 to 75 N at a rate of 0.5 Hz for 20 cycles. They were then subjected to high cyclic forces (100-500 N for 4000 cycles) and subsequently pulled to failure at 50 mm/min. The preconditioning displacement, permanent deformation, cumulative peak displacement, stiffness coefficient, and load to failure data were collected. Results: The UltraButton displayed the greatest preconditioning displacement (0.22 ± 0.20 mm), followed by the RigidLoop (0.11 ± 0.03 mm), ProCinch (0.07 ± 0.04 mm), TightRope (0.07 ± 0.02 mm), and ToggleLoc (0.02 ± 0.03 mm). The TightRope displayed the greatest permanent deformation (3.19 ± 1.03 mm) followed by the UltraButton (2.14 ± 0.92 mm), ToggleLoc (2.02 ± 1.09 mm), RigidLoop (1.67 ± 0.1 mm), and ProCinch (1.38 ± 0.18 mm). The TightRope displayed the greatest cumulative peak displacement (3.69 ± 1.03 mm) followed by the UltraButton (2.46 ± 0.92 mm), ToggleLoc (2.37 ± 1.08 mm), RigidLoop (2.01 ± 0.1 mm), and ProCinch (1.75 ± 0.19 mm). The UltraButton displayed the largest stiffness coefficient (1347.22 ± 136.33 N/mm) followed by the RigidLoop (1325.4 ± 116.37 N/mm), ToggleLoc (1216.62 ± 131.32 N/mm), ProCinch (1155.56 ± 88.04), and TightRope (848.48 ± 31.94). The ToggleLoc displayed the largest load to failure (1874.42 ± 101.08 N) followed by the RigidLoop (1614.12 ± 129.11 N), UltraButton (1391.69 ± 142.04 N), ProCinch (1384.85 ± 58.62 N), and TightRope (991.8 ± 51.1 N.). Conclusion: The 5 ALDs exhibited different biomechanical properties. None of them had peak cumulative displacements for which the confidence interval lay above 3 mm, thus no single device was determined to have a higher rate of clinical failure compared with the others. Clinical Relevance: ALD choice may affect biomechanics after ACLR.