Publications by authors named "David A Spiegel"

116 Publications

Open Reduction and Suture Fixation of Acute Sternoclavicular Fracture-Dislocations in Children.

JBJS Essent Surg Tech 2020 Jul-Sep;10(3). Epub 2020 Sep 18.

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: Acute sternoclavicular fracture-dislocation is associated with high-energy trauma and is being increasingly recognized in children. These injuries are associated with compression of mediastinal structures and can be life-threatening. The management of acute sternoclavicular fracture-dislocation includes closed reduction or open surgical stabilization; however, limited success is reported with closed reduction. To our knowledge, there are no detailed descriptions of open reduction and suture fixation of acute sternoclavicular fracture-dislocation in children.

Description: Following diagnosis of acute sternoclavicular fracture-dislocation, the timing of surgical treatment is determined according to several patient and surgical factors. Among patients with hemodynamic instability, respiratory compromise, or evidence of asymmetric perfusion, surgical treatment is needed on an emergency basis. In the absence of these factors, surgical treatment can be performed on an urgent basis. It is important to communicate with vascular or thoracic surgeons prior to proceeding to the operating room because of the rare case in which advanced surgical access or vascular repair is required. In the operating room, general anesthesia and large-bore intravenous access are required. Patients are positioned supine on a radiolucent table, and a small bump is placed between the scapulae to elevate the medial aspect of the clavicle. The contralateral sternoclavicular joint and medial aspect of the clavicle should be prepared into the sterile field, as well as both sides of the groin in case vascular access is needed. A 6 to 8-cm incision is centered on the medial aspect of the clavicle, extending to the manubrium. Standard dissection to the clavicle is performed, and care is taken to maintain the integrity of the sternoclavicular ligament complex. Circumferential dissection of the medial clavicular metaphysis is usually required in order to mobilize the dislocated fragment. Reduction of the physeal fracture usually requires axial traction and extension of the ipsilateral shoulder with the aid of a reduction clamp on the medial clavicular metaphysis. In some cases, a Freer elevator can be placed between the metaphysis and epiphysis to shoehorn the clavicle from posterior to anterior. Once reduced, the fracture-dislocation is usually stable; however, the reduction is augmented with suture fixation. The sternoclavicular joint capsule should be repaired if disrupted, and the incision should be closed in layers. Postoperatively, the arm is placed in a sling, and range of motion is commenced at 4 weeks.

Alternatives: Alternative management of acute sternoclavicular fracture-dislocation includes closed reduction, plate fixation, and ligament reconstruction.

Rationale: In our experience, closed reduction is often unsuccessful, which is consistent with the experiences reported by other authors. In addition, suture fixation is sufficient and plate fixation is not required because this injury is relatively stable following reduction. Lastly, ligament reconstruction with use of autograft or allograft may be indicated but is more relevant in chronic cases with injury or attenuation of the sternoclavicular ligament complex. Open reduction allows for direct visualization of the fracture reduction, and suture fixation allows for increased stability without the need for hardware or secondary surgical procedures.

Expected Outcomes: We expect patients to achieve full range of motion and strength without any joint instability as reported by Waters et al..

Important Tips: There is an inherent risk of vascular injury with open reduction and suture fixation. This risk is mitigated with perioperative planning and consultation with vascular or thoracic surgeons. General surgeons should always be available when these procedures are performed in case of vascular issues or emergencies.It is sometimes difficult to reduce the dislocation, but additional maneuvers allow for controlled reduction of the displaced clavicle, such as using a Freer elevator and serrated clamp.Assessing fracture reduction can be difficult intraoperatively. Including the contralateral sternoclavicular joint in the sterile surgical field can be helpful in assessing fracture reduction and osseous contour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2106/JBJS.ST.19.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154393PMC
September 2020

Comment on a suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands.

J Biol Chem 2021 Jan-Jun;296:100331. Epub 2021 Mar 1.

Department of Chemistry, Yale University, New Haven, Connecticut, USA; Department of Pharmacology, Yale University, New Haven, Connecticut, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949160PMC
March 2021

Sirtuin 2 Regulates Protein LactoylLys Modifications.

Chembiochem 2021 Jun 9;22(12):2102-2106. Epub 2021 Apr 9.

Department of Pharmacology and Toxicology College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.

Post-translational modifications (PTMs) play roles in both physiological and pathophysiological processes through the regulation of enzyme structure and function. We recently identified a novel PTM, lactoylLys, derived through a nonenzymatic mechanism from the glycolytic by-product, lactoylglutathione. Under physiologic scenarios, glyoxalase 2 prevents the accumulation of lactoylglutathione and thus lactoylLys modifications. What dictates the site-specificity and abundance of lactoylLys PTMs, however, remains unknown. Here, we report sirtuin 2 as a lactoylLys eraser. Using chemical biology and CRISPR-Cas9, we show that SIRT2 controls the abundance of this PTM both globally and on chromatin. These results address a major gap in our understanding of how nonenzymatic PTMs are regulated and controlled.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.202000883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205944PMC
June 2021

Model studies of advanced glycation end product modification of heterograft biomaterials: The effects of in vitro glucose, glyoxal, and serum albumin on collagen structure and mechanical properties.

Acta Biomater 2021 03 11;123:275-285. Epub 2021 Jan 11.

Division of Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, United States. Electronic address:

Glutaraldehyde cross-linked heterograft tissues, bovine pericardium (BP) or porcine aortic valves, are the leaflet materials in bioprosthetic heart valves (BHV) used in cardiac surgery for heart valve disease. BHV fail due to structural valve degeneration (SVD), often with calcification. Advanced glycation end products (AGE) are post-translational, non-enzymatic reaction products from sugars reducing proteins. AGE are present in SVD-BHV clinical explants and are not detectable in un-implanted BHV. Prior studies modeled BP-AGE formation in vitro with glyoxal, a glucose breakdown product, and serum albumin. However, glucose is the most abundant AGE precursor. Thus, the present studies investigated the hypothesis that BHV susceptibility to glucose related AGE, together with serum proteins, results in deterioration of collagen structure and mechanical properties. In vitro experiments studied AGE formation in BP and porcine collagen sponges (CS) comparing C-glucose and C-glyoxal with and without bovine serum albumin (BSA). Glucose incorporation occurred at a significantly lower level than glyoxal (p<0.02). BSA co-incubations demonstrated reduced glyoxal and glucose uptake by both BP and CS. BSA incubation caused a significant increase in BP mass, enhanced by glyoxal co-incubation. Two-photon microscopy of BP showed BSA induced disruption of collagen structure that was more severe with glucose or glyoxal co-incubation. Uniaxial testing of CS demonstrated that glucose or glyoxal together with BSA compared to controls, caused accelerated deterioration of viscoelastic relaxation, and increased stiffness over a 28-day time course. In conclusion, glucose, glyoxal and BSA uniquely contribute to AGE-mediated disruption of heterograft collagen structure and deterioration of mechanical properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2020.12.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176536PMC
March 2021

Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue.

ACS Chem Biol 2020 10 7;15(10):2655-2661. Epub 2020 Oct 7.

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, United States.

Although there is ample evidence that the advanced glycation end-product (AGE) glucosepane contributes to age-related morbidities and diabetic complications, the impact of glucosepane modifications on proteins has not been extensively explored due to the lack of sufficient analytical tools. Here, we report the development of the first polyclonal anti-glucosepane antibodies using a synthetic immunogen that contains the core bicyclic ring structure of glucosepane. We investigate the recognition properties of these antibodies through ELISAs involving an array of synthetic AGE derivatives and determine them to be both high-affinity and selective in binding glucosepane. We then employ these antibodies to image glucosepane in aging mouse retinae via immunohistochemistry. Our studies demonstrate for the first time accumulation of glucosepane within the retinal pigment epithelium, Bruch's membrane, and choroid: all regions of the eye impacted by age-related macular degeneration. Co-localization studies further suggest that glucosepane colocalizes with lipofuscin, which has previously been associated with lysosomal dysfunction and has been implicated in the development of age-related macular degeneration, among other diseases. We believe that the anti-glucosepane antibodies described in this study will prove highly useful for examining the role of glycation in human health and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.0c00093DOI Listing
October 2020

Glycation and Serum Albumin Infiltration Contribute to the Structural Degeneration of Bioprosthetic Heart Valves.

JACC Basic Transl Sci 2020 Aug 5;5(8):755-766. Epub 2020 Aug 5.

Department of Surgery, Columbia University, New York, New York.

Valvular heart diseases are associated with significant cardiovascular morbidity and mortality, and often require surgical and/or percutaneous repair or replacement. Valve replacement is limited to mechanical and biological prostheses, the latter of which circumvent the need for lifelong anticoagulation but are subject to structural valve degeneration (SVD) and failure. Although calcification is heavily studied, noncalcific SVD, which represent roughly 30% of BHV failures, is relatively underinvestigated. This original work establishes 2 novel and interacting mechanisms-glycation and serum albumin incorporation-that occur in clinical valves and are sufficient to induce hallmarks of structural degeneration as well as functional deterioration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2020.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452200PMC
August 2020

The Frequency of Mediastinal Injury in Acute Posterior Sternoclavicular Dislocations: A Multicenter Study.

J Pediatr Orthop 2020 Nov/Dec;40(10):e927-e931

Department of Orthopaedic Surgery and Biomechanical Engineering, University of Tennessee-Campbell Clinic, Memphis, TN.

Background: Acute posterior sternoclavicular dislocations (APSCD) are rare injuries that historically have prompted concern for injury to the great vessels and other mediastinal structures from initial trauma or subsequent treatment, resulting in the recommendation that a thoracic or vascular surgeon be present or available during operative treatment. The objectives of the study were to characterize the demographic, clinical, and radiographic characteristics of a large series of APSCDs in skeletally immature patients and to describe the rate and nature of any vascular or mediastinal complications that occurred during treatment.

Methods: Following Institutional Review Board approval, records of consecutive patients under 25 years of age treated for APSCD were collected from each of 6 participating centers. Only acute injuries (sustained fewer than 10 days before presentation) were included. Patient demographics, injury mechanism, associated mediastinal injuries, and need for thoracic/vascular surgery were recorded. Mediastinal structures injured or compressed by mass effect were specifically characterized by review of preoperative computed tomography imaging.

Results: Review identified 125 patients with a mean age of 14.7 years; 88% were male. APSCD most commonly resulted from a sporting injury (74%) followed by falls from standing height (10%) and high-energy motor vehicle trauma (10%). The most common finding on cross-sectional imaging was compression without laceration of the ipsilateral brachiocephalic vein (50%). Eleven patients had successful closed reduction, and 114 (90%) had open reduction and internal fixation, with 25 failed or unstable closed reductions preceding open treatment. There were no vascular or mediastinal injuries during reduction or fixation that required intervention.

Conclusions: In this multicenter series of 125 APSCDs no injuries to the great vessels/mediastinal structures requiring intervention were identified. Although more than half of patients had evidence of extrinsic vascular compression at the time of injury, careful open reduction of acute injuries can be safely performed. Although vascular injuries following APSCD seem to be quite rare, vascular complications can be catastrophic. Treating providers should consider these data and their own institutional resources to maximize patient safety during the treatment of APSCD.

Level Of Evidence: Level III-therapeutic case control study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BPO.0000000000001649DOI Listing
February 2021

Fluorescent stem peptide mimics: In situ probes for peptidoglycan crosslinking.

Methods Enzymol 2020 8;638:57-67. Epub 2020 Apr 8.

Yale University, Department of Chemistry, New Haven, CT, United States. Electronic address:

Understanding the mechanisms of bacterial cell wall synthesis is essential for microbiology and medicine alike. A key step in this process is peptidoglycan crosslinking, which confers mechanical strength to the cell wall and represents a target for numerous classes of antibiotics. However, the biology of crosslinking remains poorly understood due to a lack of tools for studying the reaction in vivo. Recently, we developed a class of synthetic probes called fluorescent stem peptide mimics (FSPMs) that meet this need, allowing quantification and localization of crosslinking activity in live bacteria. We have utilized FSPMs to describe novel aspects of peptidoglycan synthesis in the human pathogen, Staphylococcus aureus. To enable wider use of our methodology, we provide detailed protocols herein for the synthesis of FSPMs, labeling of live bacteria, and evaluation of crosslinking by flow cytometry and super-resolution microscopy. We believe that FSPMs, together with complementary biosynthetic probes and traditional bacteriologic methods, will help to advance our understanding of peptidoglycan biology and accelerate the search for new antibiotics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.mie.2020.02.016DOI Listing
June 2021

BMI change following spinal fusion for neuromuscular scoliosis surgery.

Spine Deform 2020 10 11;8(5):1081-1087. Epub 2020 May 11.

Shriners Hospital for Children, Philadelphia, PA, USA.

Study Design: Retrospective descriptive, multi-center study.

Objectives: We hypothesize that a post-operative weight gain will result in patients who are underweight prior to surgery. Cachexia and low body mass index is common among children with cerebral palsy (CP). Many interventions are undertaken to assist the child in nourishment and to obtain a more normal body mass. Additionally, scoliosis is common among children with CP. In our practice we have noted weight gain post operatively in severely underweight children after spinal fusion.

Methods: We underwent a retrospective review of a CP cohort from a multicenter prospective registry. Percentiles on the CP specific growth chart for which each child belonged were plotted based on the patients' age, weight, gender, GMFCS level, and tube feeding status. We then assessed percentile change in patients between pre-op visit, 1 year, 2 years and for those with available data, 5 years follow up visits. Patients with under two years of follow up, patients with GMFCS III and below, and patients without weight data were excluded.

Results: We identified a total of 211 potentially eligible patients from a multicenter prospective registry. 109 had complete 2 years data to analyze and 37 patients had full 5 years data to analyze. We found that patients under the 50th percentile pre-operatively increased their percentile on the CP growth chart for weight 12.1 percentiles (95% CI 6.7, 17.5 p value < 0.001) whereas patients that began at the 50th percentile or above on average lost 2.2 percentiles (95% CI -6.8, 2.3) though the change was not statistically significant (p value 0.330). These changes appeared stable at 5 years. Although regression analysis showed that Cobb correction and pelvic obliquity correction, and hyperlordosis were not independent predictors of the change, we noted that patients with residual curves after surgery of 40° or more experienced 13.3 percentile less weight gain than those with better corrections.

Conclusions: Patients with CP are at risk for cachexia, malnutrition, reflux and other GI disorders. Data presented here suggests that corrective spinal surgery may improve weight percentile in patients who start out at 50th percentile and lower. Patients with 40° or greater of residual scoliosis may benefit less from spinal fusion than those with a better correction.

Level Of Evidence: II; Prognostic retrospective cohort study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43390-020-00109-1DOI Listing
October 2020

Age-related changes in the physical properties, cross-linking, and glycation of collagen from mouse tail tendon.

J Biol Chem 2020 07 7;295(31):10562-10571. Epub 2020 May 7.

Babraham Institute, Cambridge, United Kingdom

Collagen is a structural protein whose internal cross-linking critically determines the properties and functions of connective tissue. Knowing how the cross-linking of collagen changes with age is key to understanding why the mechanical properties of tissues change over a lifetime. The current scientific consensus is that collagen cross-linking increases with age and that this increase leads to tendon stiffening. Here, we show that this view should be reconsidered. Using MS-based analyses, we demonstrated that during aging of healthy C57BL/6 mice, the overall levels of collagen cross-linking in tail tendon decreased with age. However, the levels of lysine glycation in collagen, which is not considered a cross-link, increased dramatically with age. We found that in 16-week-old diabetic db/db mice, glycation reaches levels similar to those observed in 98-week-old C57BL/6 mice, while the other cross-links typical of tendon collagen either decreased or remained the same as those observed in 20-week-old WT mice. These results, combined with findings from mechanical testing of tendons from these mice, indicate that overall collagen cross-linking in mouse tendon decreases with age. Our findings also reveal that lysine glycation appears to be an important factor that contributes to tendon stiffening with age and in diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.RA119.011031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397091PMC
July 2020

A low glycemic diet protects disease-prone Nrf2-deficient mice against age-related macular degeneration.

Free Radic Biol Med 2020 04 14;150:75-86. Epub 2020 Feb 14.

Laboratory for Nutrition and Vision Research, JM-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, 02111, USA; Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA, 02111, USA; Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, 02111, USA. Electronic address:

Age-related macular degeneration (AMD) is a major blinding disease, affecting over 14% of the elderly. Risk for AMD is related to age, diet, environment, and genetics. Dietary modulation of AMD risk is a promising treatment modality, but requires appropriate animal models to demonstrate advantages of diet. Mice lacking the antioxidant transcription factor Nrf2 (Nfe2l2) develop age-related retinopathy relevant to human AMD. Here we evaluated the effect of consuming high glycemic (HG) or low glycemic (LG) diets until 18-months of age on development of features relevant to AMD in Nrf2-null mice. Nrf2-null mice that consumed HG diets developed atrophic AMD, characterized by photoreceptor degeneration, retinal pigment epithelium (RPE) atrophy and pigmentary abnormalities, basal laminar deposits, and loss of the choriocapillaris. In contrast, Nrf2-null-mice that consumed LG diets did not develop retinal disease phenotypes. Consumption of HG diets was associated with accumulation of advanced glycation end-products in the RPE and systemically, whereas consumption of the LG diet was associated with increased levels of anti-glycative and anti-oxidative detoxification machinery. Together our data indicate that the Nrf2-null HG mouse is a good model for atrophic AMD studies and that the LG diet can activate protective pathways to prevent AMD, even in a genetically predisposed animal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747150PMC
April 2020

Synthetic Rhamnose Glycopolymer Cell-Surface Receptor for Endogenous Antibody Recruitment.

Biomacromolecules 2020 02 8;21(2):793-802. Epub 2020 Jan 8.

Department of Pharmaceutics , Ghent University , 9000 Ghent , Belgium.

Synthetic materials capable of engineering the immune system are of great relevance in the fight against cancer to replace or complement the current monoclonal antibody and cell therapy-based immunotherapeutics. Here, we report on antibody recruiting glycopolymers (ARGPs). ARGPs consist of polymeric copies of a rhamnose motif, which can bind endogenous antirhamnose antibodies present in human serum. As a proof-of-concept, we have designed ARGPs with a lipophilic end group that efficiently inserts into cell-surface membranes. We validate the specificity of rhamnose to attract antibodies from human serum to the target cell surface and demonstrate that ARGPs outperform an analogous small-molecule compound containing only one single rhamnose motif. The ARGP concept opens new avenues for the design of potent immunotherapeutics that mark target cells for destruction by the immune system through antibody-mediated effector functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biomac.9b01483DOI Listing
February 2020

Is Systemic Inflammatory Response Syndrome Relevant to Pulmonary Complications and Mortality in Multiply Injured Children?

J Pediatr Orthop 2020 Jan;40(1):1-7

The Children's Hospital of Philadelphia, Philadelphia, PA.

Background: Systemic inflammatory response syndrome (SIRS) is a well-recognized phenomenon in adult trauma populations. The "initial hit" of the traumatic event is often coupled with a systemic immune response characterized by changes in vital signs and laboratory indicators. A "second hit" from surgery during this time frame often results in acute lung injury, along with deterioration of the patient's clinical condition. We hypothesized that children and adolescents would experience SIRS physiology, but would not experience adult respiratory distress syndrome (ARDS) or "second hit" related death to the extent seen in the adult populations.

Methods: We queried the trauma database of our level 1 pediatric trauma center from January 2005 to December 2015 for patients with injury severity scores of >16. We used the electronic medical record to track SIRS criteria in patients days 1 to 4 posttrauma. Trends were examined in patients with an orthopaedic injury (OI) and with no orthopaedic injury. Patients were further subcategorized and analyzed by age group based on the convention for definition of pediatric SIRS. Patients in the orthopaedic cohort were further examined for pulmonary complications and death. Logistic regression was used to identify risk factors for SIRS physiology in the first 4 days of hospitalization.

Results: 81.4% (OI) and 69.1% no orthopaedic injury reached the threshold for SIRS within their first 4 days of hospitalization. Nine patients died in the hospital. Only 3 OI patients developed the criteria for ARDS, and only 3 patients with orthopaedic injuries died, 2 died within 24 hours of presentation and 1 within 48 hours, all had severe brain trauma. Increasing age groups showed increasing proportion of patients with SIRS. Increasing injury severity score and increasing age were independent predictors of SIRS during days 1 to 4.

Discussion: SIRS seems to be as common in children as the reported rates for adults, and the proportion of SIRS in children increases with increasing age and injury severity. The high mortality rate and rate of ARDS observed in adults was not observed in our cohort. The presence or absence of major orthopaedic injuries was not a significant predictor. The SIRS response in polytraumatized children is poorly understood. The clinical phenomenon of acute lung injury/ARDS is observed less often in children, but the exact mechanism by which this occurs is unknown.

Level Of Evidence: Level III-case control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BPO.0000000000001085DOI Listing
January 2020

Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes.

Cell Chem Biol 2020 02 22;27(2):206-213.e6. Epub 2019 Nov 22.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA. Electronic address:

Post-translational modifications (PTMs) regulate enzyme structure and function to expand the functional proteome. Many of these PTMs are derived from cellular metabolites and serve as feedback and feedforward mechanisms of regulation. We have identified a PTM that is derived from the glycolytic by-product, methylglyoxal. This reactive metabolite is rapidly conjugated to glutathione via glyoxalase 1, generating lactoylglutathione (LGSH). LGSH is hydrolyzed by glyoxalase 2 (GLO2), cycling glutathione and generating D-lactate. We have identified the non-enzymatic acyl transfer of the lactate moiety from LGSH to protein Lys residues, generating a "LactoylLys" modification on proteins. GLO2 knockout cells have elevated LGSH and a consequent marked increase in LactoylLys. Using an alkyne-tagged methylglyoxal analog, we show that these modifications are enriched on glycolytic enzymes and regulate glycolysis. Collectively, these data suggest a previously unexplored feedback mechanism that may serve to regulate glycolytic flux under hyperglycemic or Warburg-like conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chembiol.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395678PMC
February 2020

One-Step Synthesis of 2,5-Diaminoimidazoles and Total Synthesis of Methylglyoxal-Derived Imidazolium Crosslink (MODIC).

Angew Chem Int Ed Engl 2019 12 12;58(52):18913-18917. Epub 2019 Nov 12.

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.

Here we describe a general method for the synthesis of 2,5-diaminoimidazoles, which involves a thermal reaction between α-aminoketones and substituted guanylhydrazines without the need for additives. As one of the few known ways to access the 2,5-diaminoimidazole motif, our method greatly expands the number of reported diaminoimidazoles and further supports our previous observations that these compounds spontaneously adopt the non-aromatic 4(H) tautomer. The reaction works successfully on both cyclic and acyclic amino ketone starting materials, as well as a range of substituted guanylhydrazines. Following optimization, the method was applied to the efficient synthesis of the advanced glycation end product (AGE) methylglyoxal-derived imidazolium crosslink (MODIC). We expect that this method will enable rapid access to a variety of biologically important 2,5-diaminoimidazole-containing products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201911156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973230PMC
December 2019

The Clinical Utility of Flexion-extension Cervical Spine MRI in 22q11.2 Deletion Syndrome.

J Pediatr Orthop 2019 Oct;39(9):e674-e679

The Children's Hospital of Philadelphia, Philadelphia, PA.

Background: Our goal is to correlate the findings on flexion and extension radiographs with dynamic magnetic resonance imaging (MRI), and the clinical history, in a nonrandomly selected cohort of patients with 22q11.2 deletion syndrome (22q).

Methods: All patients with the 22q who had a dynamic MRI from January 2004 to March 2015 were included. We analyzed multiple radiographic measurements on both the dynamic plain films and the MRIs, and correlated these findings with a review of each patient's medical record.

Results: Multiple congenital anomalies were identified as noted in previous studies, and 61% of the patients had a failure of fusion of the anterior (n=2, 9%), posterior (n=2, 9%), or anterior and posterior arches (n=10, 43%). Quantitative measurements were impossible to report with certainty because of the upper cervical anomalies, and no cases of instability were identified using a qualitative assessment. We identified spinal cord encroachment (30%) and impingement (18%); however, none of the patients had any signal change in their spinal cord. None of these findings could be definitively correlated with any clinical symptoms. A single patient was diagnosed with a Chiari I malformation, while another had cerebellar ectopia.

Conclusions: Although the upper cervical anomalies are extremely common in 22q, we did not identify cases of instability on dynamic plain radiographs and MRI. Although our findings do not support routine screening with flexion and extension MRI, this study may be required in patients with neurological symptoms and/or findings or abnormalities on dynamic plain radiographs.

Level Of Evidence: Level III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BPO.0000000000000994DOI Listing
October 2019

Biocatalytic Reversal of Advanced Glycation End Product Modification.

Chembiochem 2019 09 9;20(18):2402-2410. Epub 2019 Aug 9.

Department of Chemistry, Yale University, 225 Prospect Street, New Haven, CT, 06511, USA.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules that emerge from the condensation of sugars and proteins through the Maillard reaction. Despite a significant number of studies showing strong associations between AGEs and the pathologies of aging-related illnesses, it has been a challenge to establish AGEs as causal agents primarily due to the lack of tools in reversing AGE modifications at the molecular level. Herein, we show that MnmC, an enzyme involved in a bacterial tRNA-modification pathway, is capable of reversing the AGEs carboxyethyl-lysine (CEL) and carboxymethyl-lysine (CML) back to their native lysine structure. Combining structural homology analysis, site-directed mutagenesis, and protein domain dissection studies, we generated a variant of MnmC with improved catalytic properties against CEL in its free amino acid form. We show that this enzyme variant is also active on a CEL-modified peptidomimetic and an AGE-containing peptide that has been established as an authentic ligand of the receptor for AGEs (RAGE). Our data demonstrate that MnmC variants are promising lead catalysts toward the development of AGE-reversal tools and a better understanding of AGE biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.201900158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768434PMC
September 2019

Predicting Periarticular Infection in Children With Septic Arthritis of the Hip: Regionally Derived Criteria May Not Apply to All Populations.

J Pediatr Orthop 2019 May/Jun;39(5):268-274

The Children's Hospital of Philadelphia, Philadelphia, PA.

Background: The management of septic arthritis of the hip in children can be complicated by the presence of additional coexisting periarticular infections (PAIs). Criteria predicting the presence of PAI have recently been proposed by Rosenfeld and colleagues with the goal of using magnetic resonance imaging (MRI) efficiently in the workup of septic arthritis. The purpose of this study was to determine the applicability of recently published predictive criteria for PAI (developed in the Southwestern United States using a variety of joints) to septic arthritis of the hip treated at a large Northeastern tertiary care center.

Methods: We studied patients treated for septic arthritis of the hip with irrigation and debridement in a large Northeastern tertiary care center over a 10-year period. Laboratory and clinical variables related to presentation, treatment, and outcome were collected. Subjects with and without a perioperative MRI were compared with published criteria by Rosenfeld and colleagues.

Results: Fifty-one subjects (53 hips) were identified with a mean age of 7.0 years (range, 1.2 to 19.3 y) and mean follow-up was 16 months (range, 2 to 85 mo). MRIs were obtained in 20 subjects (43%). Coexisting osteomyelitis was revealed in 7/20 of these studies (35% of MRIs); 4 of which showed coexisting intramuscular abscesses. Within our MRI cohort, the Rosenfeld criteria were found to have a sensitivity of 86%, a specificity of 54%, and a false-positive rate of 50% for the hip (compared with originally reported sensitivity of 90%, specificity of 67%, and false-positive rate of 33%). Overall, advanced imaging changed management in 5/51 patients (9%) by influencing the need for further treatment, whereas the remainder underwent isolated treatment of the septic hip joint with no adverse outcomes. One patient in the MRI cohort (without PAI) developed osteonecrosis of the femoral head.

Conclusions: We found lower sensitivity and specificity and higher false-positive rates for the Rosenfeld criteria in the hip for our geographically distinct population. Using the Rosenfeld criteria, MRIs would have been ordered unnecessarily in half of our series. Because of potential differences in regional microbiology and anatomic-specific factors, general predictive criteria for coexisting PAI based a single geographic region may be less generalizable to cases of hip sepsis in other geographic areas such as the Northeastern United States.

Level Of Evidence: Level 4-retrospective cohort study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/BPO.0000000000000934DOI Listing
June 2019

An Estimation of the Burden of Sports Injuries among African Adolescents.

J Epidemiol Glob Health 2018 12;8(3-4):171-175

Department of Surgery, Columbia University College of Physicians and Surgeons, 177 Fort Washington Ave., New York, NY 10032, USA.

The extent to which sports injuries contribute to the burden of injury among adolescents in low- and middle-income countries (LMICs) is unknown. The goal of this study was to estimate the incidence of sports injuries among adolescents in Africa. Data from the World Health Organization Global School-Based Student Health surveys were used to estimate the annual number of African adolescents sustaining sports injuries. Gender-stratified injury rates were calculated and applied to every African country's adolescent population to estimate country-specific and continent-wide injury totals. A total of 21,858 males and 24,691 females from 14 countries were included in the analysis. Country-specific annual sports injury rates ranged from 13.5% to 38.1% in males and 5.2% to 20.2% in females. Weighted average sports injury rates for males and females were 23.7% (95% CI 23.1%-24.2%) and 12.5% (95% CI 12.1%-12.9%), respectively. When these rates were extrapolated to the adolescent populations of the African continent, an estimated 15,477,798 (95% CI 15,085,955-15,804,333) males and 7,943,625 (95% CI 7,689,429-8,197,821) females sustained sports injuries. Our findings suggest that over 23 million African adolescents sustained sports injuries annually. Further work will help to more precisely define the burden of sports injuries in LMICs and the role that surgery can play in mitigating this burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2991/j.jegh.2017.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377560PMC
December 2018

Erratum to: Socioeconomic Status Influences Functional Severity of Untreated Cerebral Palsy in Nepal: A Prospective Analysis and Systematic Review.

Clin Orthop Relat Res 2019 01;477(1):262-263

D. G. LeBrun, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA B. Banskota, A. K. Banskota, T. Rajbhandari, Department of Orthopaedic Surgery, Hospital and Rehabilitation Centre for Disabled Children, Banepa, Nepal K. D. Baldwin, D. A. Spiegel, Department of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CORR.0000000000000553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345295PMC
January 2019

Outcomes of the Ponseti Method for Untreated Clubfeet in Nepalese Patients Seen Between the Ages of One and Five Years and Followed for at Least 10 Years.

J Bone Joint Surg Am 2018 Dec;100(23):2004-2014

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Background: To our knowledge, there are no reports of the Ponseti method initiated after walking age and with >10 years of follow-up. Our goal was to report the clinical findings and patient-reported outcomes for children with a previously untreated idiopathic clubfoot who were seen when they were between 1 and 5 years old, were treated with the Ponseti method, and had a minimum follow-up of 10 years.

Methods: A retrospective review of medical records was supplemented by a follow-up evaluation of physical findings (alignment and range of motion) and patient-reported outcomes using the Oxford Ankle Foot Questionnaire for Children (OxAFQ-C). The initial treatment was graded as successful if a plantigrade foot was achieved without the need for an extensive soft-tissue release and/or osseous procedure.

Results: We located 145 (91%) of 159 patients (220 clubfeet). The average age at treatment was 3 years (range, 1 to 5 years), and the average duration of follow-up was 11 years (range, 10 to 12 years). The initial scores according to the systems of Pirani et al. and Diméglio et al. averaged 5 and 17, respectively, and an average of 8 casts were required. Surgical treatment, most commonly a percutaneous Achilles tendon release (197 feet; 90%), was required in 96% of the feet. A plantigrade foot was achieved in 95% of the feet. Complete relapse was rare (3%), although residual deformities were common. Patient-reported outcomes were favorable.

Conclusions: A plantigrade foot was achieved in 95% of the feet initially and was maintained in most of the patients, although residual deformities were common. Patient-reported outcomes were satisfactory, and longer-term follow-up with age-appropriate outcome measures will be required to evaluate function in adulthood.

Level Of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2106/JBJS.18.00445DOI Listing
December 2018

Approaching Unusual Pediatric Distal Humerus Fracture Patterns.

J Am Acad Orthop Surg 2019 May;27(9):301-311

From the Department of Pediatric Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA.

Pediatric distal humerus fractures are common, and numerous variations can occur depending on patient's age, position of the extremity at the time of injury, and energy of impact. Classic injury patterns include the flexion/extension supracondylar humerus, medial epicondyle, lateral condyle, and the transphyseal distal humerus. We describe our treatment philosophy for pediatric elbow fractures and how these principles were applied to some unusual fractures that presented to our institution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5435/JAAOS-D-17-00326DOI Listing
May 2019

Intra-operative computed tomography guided navigation for pediatric pelvic instrumentation: A technique guide.

World J Orthop 2018 Oct 18;9(10):185-189. Epub 2018 Oct 18.

Department of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.

Pelvic instrumentation for neuromuscular scoliosis has been part of neuromuscular scoliosis surgery since the era of the Luque Galveston construct. Unit Rod (Medtronic Sofamor-Danek, Nashville, TN) instrumentation brought with it the concept of cantilever correction by placing the implants in the pelvis and then gradually bringing the rod to the spine by sequentially tightening the sublaminar wires, with the goal of creating a level pelvis over a straight spine. More recently surgeons have utilized pedicle screw constructs in which the corrective strategies have varied. Challenges with pelvic fixation using iliac screws linked to the spinal rod have led to the development of the S2-alar-iliac technique (S2AI) in which the spinal rod connects to the pelvic screw. The screw is placed in the S2 ala, crosses the sacro-iliac joint and into the ilium through a large column of supra-acetabular bone. This column is the same area used for anterior inferior iliac spine external fixation frames used in trauma surgery. S2AI screw placement can be technically difficult and can require experienced radiology technologists to provide the appropriate views. Additionally, although the technique was originally described being placed freehand technique with intra-operative flouroscopy, the freehand technique suffers from the anatomic anomalies present in the pelvis in neuromuscular scoliosis. As such, we prefer to place them using intra-operative navigation for all pediatric spinal deformity cases. Below in detail we report our intra-operative technique and an illustrative case example.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5312/wjo.v9.i10.185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198293PMC
October 2018

Socioeconomic Status Influences Functional Severity of Untreated Cerebral Palsy in Nepal: A Prospective Analysis and Systematic Review.

Clin Orthop Relat Res 2019 01;477(1):10-21

D. G. LeBrun, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA B. Banskota, A. K. Banskota, T. Rajbhandari, Department of Orthopaedic Surgery, Hospital and Rehabilitation Centre for Disabled Children, Banepa, Nepal K. D. Baldwin, D. A. Spiegel, Department of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Cerebral palsy (CP) comprises a heterogeneous group of disorders whose clinical manifestations and epidemiologic characteristics vary across socioeconomic and geographic contexts. The functional severity of untreated CP in low-income countries has been insufficiently studied; a better understanding of how these children present for care in resource-constrained environments is important because it will better characterize the natural history of CP, guide clinical decision-making, and aid in the prognostication of children with untreated CP.

Questions/purposes: The purposes of this study were (1) to determine the etiologies, motor subtypes, topographic distributions, and functional classifications of a large cohort of Nepali children with untreated CP presenting to a large pediatric rehabilitation center in Nepal; and (2) to compare the Gross Motor Function Classification System (GMFCS), the Manual Ability Classification System (MACS), and the Communication Function Classification System (CFCS) scores of a subset of patients with spastic CP in the Nepali cohort with control subjects from high-income countries.

Methods: A cross-sectional study was conducted at the Hospital and Rehabilitation Centre for Disabled Children in Nepal. Two hundred six consecutive Nepali children (76 girls; median age 4.0 years [interquartile range {IQR}, 2.5-9.0 years]) were evaluated to determine the demographic, clinical, and functional characteristics of a cohort of Nepali children with untreated CP. A systematic review of the Medline and Cochrane databases was then performed to obtain reference classification scores from high-income countries. Cross-sectional, noninterventional studies reporting at least one functional classification system with a sample size of at least 50 participants were included. Only studies of patients with spastic CP were included to allow for compatible comparisons with a subset of our study sample with spastic CP. A random-effects analysis was used to pool functional scores from participants in the included studies. Among the 206 children in our sample, 102 had spastic CP (35 girls; median age 5.5 years [IQR, 3.5-9.0 years]). Functional scores from these children were compared with pooled scores obtained from the systematic review by assessing the proportions of children in each sample with GMFCS, MACS, and CFCS score categories of I or II versus III to V.

Results: Children with spastic hemiplegia from high-income countries were more likely to have a GMFCS score of I or II (96% [95% confidence interval {CI}, 92%-99%] versus 78% [95% CI, 62%-89%]) and a MACS score of I or II (83% [95% CI, 77%-88%] versus 50% [95% CI, 32%-68%]) relative to those from Nepal, but they were less likely to have a CFCS score of I or II (67% [95% CI, 51%-80%] versus 97% [95% CI, 87%-99%]). No differences were seen in children with spastic diplegia or quadriplegia.

Conclusions: Children in Nepal with hemiplegic CP display less difficulty in communicating and social engagement (CFCS) despite more-severe upper- and lower-extremity impairments in gross motor function (GMFCS) and manual ability (MACS) than do children with hemiplegic CP from high-income countries. Targeted interventions, including perhaps simple orthopaedic interventions to treat soft-tissue contractures, may therefore provide more-substantial improvements in function and quality of life to Nepali children than could be achieved for the same deployment of resources in more-affluent settings.

Level Of Evidence: Level II, prognostic study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CORR.0000000000000476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345316PMC
January 2019

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks.

Proc Natl Acad Sci U S A 2018 09 27;115(37):9228-9233. Epub 2018 Aug 27.

A.B. Hancock Memorial Laboratory for Cancer Research, Vanderbilt University, Nashville, TN 37232;

Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code. Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation. Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO). Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation. These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding. In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications. Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1. Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO. Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1802901115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140490PMC
September 2018

Factors that Predict Overall Health and Quality of Life in Non-Ambulatory Individuals with Cerebral Palsy.

Iowa Orthop J 2018 ;38:147-152

Background: It is unknown what role specific tasks associated with personal care, positioning, communication and social interaction, and comfort and emotions play in predicting the overall health and quality of life of individuals with non-ambulatory cerebral palsy (CP). In this study, we prospectively evaluated which of these factors were significant predictors of overall health and quality of life.

Methods: Parents and guardians of non-ambulatory children, adolescents and young adults with CP were prospectively recruited from the Cerebral Palsy Clinic of a large pediatric academic hospital. Caregivers completed the CP Child Questionnaire®. Univariate analyses were used to identify relationships between overall health, overall quality of life (QOL), and responses in the following categories: personal care and activities of daily living, positioning and transfer mobility, comfort and emotions, and communication and social interaction. Significant predictors of overall health and QOL were then determined via logistic regression.

Results: 64 patients ages 0-20 years and Gross Motor Function Classification System levels IV and V were included in our study (mean age 9.16 ±4.96 years). Overall QOL (OR 194.2, 95% CI, 9.5-3964.9) and comfort while sitting (OR 15.9, 95% CI, 1.2-205.3) were significant predictors of overall health. Feelings of unhappiness or sadness (OR 59.9, 95% CI, 1.6-2209.8), difficulty understanding the parent or guardian (OR 29.8, 95% CI, 1.6-543.7), and not attending school (OR 57.2, 95% CI, 2.6-1274.4) were significant predictors of lower overall quality of life.

Conclusions: Overall QOL appears to predict overall health. Factors associated with comfort and emotions and communication and social interaction appear to predict overall QOL to a greater extent than personal care and transfer mobility.Level of Evidence: Prognostic II.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047378PMC
December 2018

Releasing the tether: Weight normalization following corrective spinal fusion in cerebral palsy.

J Orthop Surg (Hong Kong) 2018 May-Aug;26(2):2309499018782556

1 Division of Orthopaedics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Feeding difficulties are common among patients with cerebral palsy (CP) and neuromuscular (NM) scoliosis. We theorize that posterior spinal fusion (PSF) reduces intra-abdominal pressure, resulting in improved feeding and subsequent weight gain. We hypothesized that, among nonambulatory patients with CP and NM scoliosis, we would observe significant gain in weight following PSF.

Methods: Fifty subjects with nonambulatory CP who underwent PSF for NM scoliosis were included. Age and weight were recorded for the preoperative year; on the day of surgery; and at 6-month, 1-year, and 2-year follow-up. Weights were converted to weight percentiles using CP-specific growth charts. The weight percentile distributions were compared between time points using descriptive statistics as well as regression analysis.

Results: The average change in weight from the day of surgery to 2-year follow-up was +3.4 percentiles. Patients who started out under the 50th percentile gained an average of 17.3 percentiles in the first year after PSF ( p = 0.009). Regression analysis showed that patients with baseline weight <50th percentile tended to gain in weight percentile over the first postoperative year ( β = 1.990, p = 0.001). No trend was present among this group prior to surgery ( p = 0.692) or during the second postoperative year ( p = 0.945). No trends were noted prior to or after surgery for patients with baseline weights ≥50th percentile. No significant association was observed between curve severity (measured by preoperative Cobb angle) and weight change.

Conclusions: This series is the first to document significant weight gain after PSF for NM scoliosis, supporting the theory that spinal correction improves digestive function.

Level Of Evidence: Prognostic level II.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2309499018782556DOI Listing
September 2019

Access to Orthopaedic Surgical Care in Northern Tanzania: A Modelling Study.

World J Surg 2018 10;42(10):3081-3088

Department of Orthopaedic Surgery, Pennsylvania Hospital, University of Pennsylvania, 800 Spruce Street, 8th Floor Preston Building, Philadelphia, PA, 19107, USA.

Background: The global burden of musculoskeletal disease and resulting disability is enormous and is expected to increase over the next few decades. In the world's poorest regions, the paucity of information defining and quantifying the current state of access to orthopaedic surgical care is a major problem in developing effective solutions. This study estimates the number of individuals in Northern Tanzania without adequate access to orthopaedic surgical services.

Methods: A chance tree was created to model the probability of access to orthopaedic surgical services in the Northern Tanzanian regions of Arusha, Kilimanjaro, Tanga, Singida, and Manyara, with respect to four dimensions: timeliness, surgical capacity, safety, and affordability. Timeliness was estimated by the proportion of people living within a 4-h driving distance from a hospital with an orthopaedic surgeon, capacity by comparing number of surgeries performed to the number of surgeries indicated, safety by applying WHO Emergency and Essential Surgical Care infrastructure and equipment checklists, and affordability by approximating the proportion of the population protected from catastrophic out-of-pocket healthcare expenditure. We accounted for uncertainty in our model with one-way and probabilistic sensitivity analyses. Data sources included the Tanzanian National Bureau of Statistics and Ministry of Finance, World Bank, World Health Organization, New Zealand Ministry of Health, Google Corporation, NASA population estimator, and 2015 hospital records from Kilimanjaro Christian Medical Center, Machame Hospital, Nkoroanga Hospital, Mt. Meru Hospital, and Arusha Lutheran Medical Center.

Results: Under the most conservative assumptions, more than 90% of the Northern Tanzanian population does not have access to orthopaedic surgical services.

Conclusion: There is a near absence of access to orthopaedic surgical care in Northern Tanzania. These findings utilize more precise country and region-specific data and are consistent with prior published global trends regarding surgical access in Sub-Saharan Africa. As the global health community must develop innovative solutions to address the rising burden of musculoskeletal disease and support the advancement of universal health coverage, increasing access to orthopaedic surgical services will play a central role in improving health care in the world's developing regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-018-4630-xDOI Listing
October 2018

Total Synthesis of (±)-Phomoidride D.

Angew Chem Int Ed Engl 2018 02 17;57(7):1991-1994. Epub 2018 Jan 17.

Department of Chemistry and Biochemistry, Baylor University, One Bear Place 97348, Waco, TX, 76798, USA.

Described herein is a synthetic strategy for the total synthesis of (±)-phomoidride D. This highly efficient and stereoselective approach provides rapid assembly of the carbocyclic core by way of a tandem phenolic oxidation/intramolecular Diels-Alder cycloaddition. A subsequent SmI -mediated cyclization cascade delivers an isotwistane intermediate poised for a Wharton fragmentation that unveils the requisite bicyclo[4.3.1]decene skeleton and sets the stage for synthesis completion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201712369DOI Listing
February 2018

Predictors of healthcare seeking delays among children with chronic musculoskeletal disorders in Nepal.

J Epidemiol Glob Health 2017 12 12;7(4):299-304. Epub 2017 Oct 12.

Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Orthopaedics, Hospital and Rehabilitation Centre for Disabled Children, Banepa, Nepal. Electronic address:

Background: Healthcare seeking behaviors among children with musculoskeletal disorders are poorly understood. We sought to analyze healthcare seeking delays among children with chronic musculoskeletal conditions in Nepal and identify predictors of clinically significant delays.

Methods: A cross-sectional study was conducted at a large pediatric musculoskeletal rehabilitation center in Nepal. Baseline sociodemographic data and healthcare seeking behaviors were assessed via interviews with 75 randomly selected caregivers. Delays of at least 3 months between disease recognition and presentation to a health worker were considered clinically significant. Predictors of significant delay were assessed via multivariable logistic regression.

Results: Clubfoot was the most common condition seen in the study sample (N = 33; 37%). Mean and median presentation delays were 33 months and 14 months, respectively. Sixty-seven percent of children were delayed at least 3 months and 40% were delayed at least 2 years. Caregiver occupation in agriculture or unskilled labor was associated with an increased risk of delayed presentation (adjusted OR = 4.05; 95% CI: 1.36-12.09).

Conclusions: Children with chronic musculoskeletal disorders in Nepal face significant delays in accessing healthcare. This poses a major clinical problem as the delayed diagnosis and treatment of childhood musculoskeletal disorders can complicate management options and decrease long-term quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jegh.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384576PMC
December 2017