The CombE-IDMS Alternate Potency Method for H5N1 and H5N8 Cell-Based Vaccines.

Assaying the potency of inactivated viral influenza vaccines is performed using single radial immunodiffusion, which is the globally accepted release method for potency. Under conditions of a rapidly emerging pandemic, such as the 2009 H1N1 influenza pandemic, a recognized obstacle in the delivery of vaccines to the public is the time needed for the distribution of calibrated SRID reagents (antisera and antigen standards) to vaccine manufacturers. Previously, we first described a novel streamlined MS-based assay, CombE-IDMS, which does not rely on antisera/antibodies or reference antigens, as a potential rapidly deployable alternate potency method through a comparison with SRID on adjuvanted seasonal quadrivalent vaccine cell-based (aQIVc) materials. In this report, we further demonstrate that the CombE-IDMS method can also be applied to measure the potency of pre-pandemic H5N1 and H5N8 monovalent vaccine materials, each subtype both unadjuvanted and adjuvanted, through a forced degradation study. Overall, CombE-IDMS results align with those of the gold standard SRID method on both H5N1 and H5N8 materials under conditions of thermal, pH, oxidative and freeze/thaw stress, lending further evidence for the CombE-IDMS method's suitability as an alternate assay for potency of both seasonal and pandemic influenza vaccines.

The CombE-IDMS Assay as an Alternate Potency Method for Adjuvanted Quadrivalent Influenza Vaccines.

The potency of all currently licensed inactivated influenza viral vaccines is assayed by the single radial immunodiffusion (SRID) method. SRID relies upon antisera and reference antigen reagents which are produced, standardized, and distributed in the mass quantities needed for vaccine manufacturers only after a significant amount of time has elapsed from the seasonal strain recommendations issued by the WHO; this time delay is exacerbated under conditions of an emerging pandemic. Previously, the limited trypsin digestion isotope dilution mass spectrometry (LTD-IDMS) method, which does not require antisera or reference antigens, demonstrated comparable quantitation of immunologically active hemagglutinin, the primary viral antigen, to SRID in stressed vaccine materials. Here, we demonstrate a streamlined improvement to the LTD-IDMS method by eliminating the need for its precipitation and washing steps, saving time and labor in the sample preparation process while paving the way for plate-based high-throughput analysis. This is accomplished using dissimilar proteases in the pretreatment (a combination of chymotrypsin and elastase) and analytical (trypsin) digestion steps so that any pretreatment digests will not cause interference while monitoring analytical tryptic digests by IDMS. The combination of enzymes (CombE)-IDMS method is tested alongside LTD-IDMS and SRID for the first time on MF59 adjuvanted seasonal cell-based quadrivalent influenza vaccines (aQIVc) under stressed conditions of heating, oxidation, lowered and elevated pH, and freeze-thaw. Overall, a correlation in the degradation trend is observed between CombE-IDMS and SRID in the four strains of the quadrivalent formulation, highlighting the method's stability indicating capability as a rapid alternate potency assay in a highly complex formulation of aQIVc.

Ligand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice.

Phosphatidylcholine transfer protein (PC-TP; synonym StarD2) is a soluble lipid-binding protein that transports phosphatidylcholine (PC) between cellular membranes. To better understand the protective metabolic effects associated with hepatic PC-TP, we generated a hepatocyte-specific PC-TP knockdown (L-Pctp-/-) in male mice, which gains less weight and accumulates less liver fat compared to wild-type mice when challenged with a high-fat diet. Hepatic deletion of PC-TP also reduced adipose tissue mass and decreases levels of triglycerides and phospholipids in skeletal muscle, liver and plasma. Gene expression analysis suggest that the observed metabolic changes are related to transcriptional activity of peroxisome proliferative activating receptor (PPAR) family members. An in-cell protein complementation screen between lipid transfer proteins and PPARs uncovered a direct interaction between PC-TP and PPARδ that was not observed for other PPARs. We confirmed the PC-TP- PPARδ interaction in Huh7 hepatocytes, where it was found to repress PPARδ-mediated transactivation. Mutations of PC-TP residues implicated in PC binding and transfer reduce the PC-TP-PPARδ interaction and relieve PC-TP-mediated PPARδ repression. Reduction of exogenously supplied methionine and choline reduces the interaction while serum starvation enhances the interaction in cultured hepatocytes. Together our data points to a ligand sensitive PC-TP- PPARδ interaction that suppresses PPAR activity.

Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19.

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.

Suave-Kapandji Reconstruction After Excision of the Distal Ulna for Chondrosarcoma: A Case Report.

An active, 62-year-old man presented with a nondisplaced pathological fracture through a low-grade, central chondrosarcoma of the distal ulnar diaphysis after minor trauma. After obtaining diagnostic imaging, the patient was successfully treated with marginal en-bloc resection of the right distal ulnar diaphysis and wrist reconstruction via a Sauve-Kapandji arthroplasty. Suave-Kapandji arthroplasty is an alternative reconstruction to complete the excision of the distal ulna following resection of the distal ulnar diaphysis.

Evidence of a population of leaf-eared mice Phyllotis vaccarum above 6,000 m in the Andes and a survey of high-elevation mammals.

Biologists have long pondered the extreme limits of life on Earth, including the maximum elevation at which species can live and reproduce. Here we review evidence of a self-sustaining population of mice at an elevation that exceeds that of all previously reported for mammals. Five expeditions over 10 years to Volcán Llullaillaco on the Argentina/Chile border observed and collected mice at elevations ranging from 5,070 m at the mountain's base to the summit at 6,739 m (22,110 feet). Previously unreported evidence includes observations and photographs of live animals and mummified remains, environmental DNA, and a soil microbial community reflecting animal activity that are evaluated in combination with previously reported video recordings and capture of live mice. All of the evidence identifies the mouse as the leaf-eared mouse Phyllotis vaccarum, and it robustly places the population within a haplotype group containing individuals from the Chilean Atacama Desert and nearby regions of Argentina. A critical review of the literature affirms that this population is not only an elevational record for mammals but for all terrestrial vertebrates to date, and we further find that many extreme elevations previously reported for mammals are based on scant or dubious evidence.

Durante mucho tiempo los biólogos han reflexionado sobre los límites extremos de altura a la que las especies pueden vivir y reproducirse. Aquí presentamos nueva evidencia sobre la existencia de una población de ratones establecida a una elevación que supera todos los reports previos para mamíferos. Durante 10 años fueron realizadas 5 expediciones al Volcán Llullaillaco, ubicado en la frontera entre Argentina y Chile; observando y colectando ratones en elevaciones que van desde los 5,070 m hasta la cima de 6,739 m (22,110 feet). La nueva evidencia incluye fotografías de restos momificados, ADN ambiental y la actividad microbiana del suelo que confirman la presencia del animal, la cual fue analizada junto a videos reportados anteriormente y la captura de ejemplares vivos. Toda esta información indica que dicha población corresponde al ratón orejudo amarillento Phyllotis vaccarum y lo posicionan dentro de un grupo de haplotipos compuesto por individuos del Desierto de Atacama y regiones cercanas en Argentina. La revisión crítica de la literatura demostró que esta población no solo es un récord de elevación para los mamíferos, sino para todos los vertebrados terrestres; igualmente, que los reportes de elevaciones extremas reportados para mamíferos se derivan de evidencias escasas y dudosas.

The Accident Environment Resulting in Fragility Fractures: A 20-year National Epidemiologic Study.

INTRODUCTION: Fragility fractures are an enduring source of morbidity in the elderly with unfortunate frequency and rising costs. Although the predominant cause of fractures is generally understood to be falls, the exact stratification of the causes of fractures presenting to the emergency department has not yet been described in the literature. We sought out to stratify the primary products associated with fractures in the elderly, further describing the anatomic location of the fracture and setting of injury. METHODS: We queried the National Electronic Injury Surveillance System database for all fractures in patients older than 65 years from January 1, 2000, to December 31, 2019. We analyzed demographic data, patient disposition, anatomic fracture location, and injury setting for the top 20 causes of fractures. Trends, proportions and distributions were analyzed using descriptive statistics. RESULTS: A total of 901,418 visits to the Emergency Department were reviewed. Of these, 216,657 (24%) were found to have fractures. The top 20 causes for fractures accounted for a total of 173,557 (19%) fractures. The average age in our population was 80.1 years (SD 8.7). Women constituted most of the patients (127,753 [74%]). Flooring (58,347 [33.6%]) was the most common product associated with the cause of fractures, with stairs/steps (29,804 [17.2%]) and bed/bed frames (19,004 [10.9%]) being the second and third most common, respectively. Lower extremity fractures (97,195 [56%]) were more common than upper extremity fractures (63,899 [37%]). The lower trunk (pelvis, femoral neck, and lower spine) was the most common anatomic location of fractures reported (64,132 [37.0%]). Most fractures occurred either at home (113,158 [65.2%]) or at a public setting (31,162 [18.0%]). CONCLUSIONS: Most products associated with fractures among mature adults were related to flooring, stairs, or bedding. This study offers a detailed understanding on the common products associated with fractures in mature adults and aids in discussing preventive measures for lowering fracture risk with patients, communities, and healthcare systems.

SARS-CoV-2 and other coronaviruses bind to phosphorylated glycans from the human lung.

SARS-CoV, MERS-CoV, and potentially SARS-CoV-2 emerged as novel human coronaviruses following cross-species transmission from animal hosts. Although the receptor binding characteristics of human coronaviruses are well documented, the role of carbohydrate binding in addition to recognition of proteinaceous receptors has not been fully explored. Using natural glycan microarray technology, we identified N-glycans in the human lung that are recognized by various human and animal coronaviruses. All viruses tested, including SARS-CoV-2, bound strongly to a range of phosphorylated, high mannose N-glycans and to a very specific set of sialylated structures. Examination of two linked strains, human CoV OC43 and bovine CoV Mebus, reveals shared binding to the sialic acid form Neu5Gc (not found in humans), supporting the evidence for cross-species transmission of the bovine strain. Our findings, revealing robust recognition of lung glycans, suggest that these receptors could play a role in the initial stages of coronavirus attachment and entry.

Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic Mice with Small Molecules Targeting MuRF1.

The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO (knockout) mice have elevated serum glucose, elevated triglycerides, and reduced glucose tolerance. In addition, MuRF2-KO mice have a reduced tolerance to a fat-rich diet. Western blot and enzymatic studies on MuRF1-KO skeletal muscle showed perturbed FoxO-Akt signaling, elevated Akt-Ser-473 activation, and downregulated oxidative mitochondrial metabolism, indicating potential mechanisms for MuRF1,2-dependent glucose and fat metabolism regulation. Consistent with this, the adenoviral re-expression of MuRF1 in KO mice normalized Akt-Ser-473, serum glucose, and triglycerides. Finally, we tested the MuRF1/2 inhibitors MyoMed-205 and MyoMed-946 in a mouse model for type 2 diabetes mellitus (T2DM). After 28 days of treatment, T2DM mice developed progressive muscle weakness detected by wire hang tests, but this was attenuated by the MyoMed-205 treatment. While MyoMed-205 and MyoMed-946 had no significant effects on serum glucose, they did normalize the lymphocyte-granulocyte counts in diabetic sera as indicators of the immune response. Thus, small molecules directed to MuRF1 may be useful in attenuating skeletal muscle strength loss in T2DM conditions.

Quantifying the relationship and contribution of mitochondrial respiration to systemic exercise limitation in heart failure.

AIMS: Heart failure with reduced ejection fraction (HFrEF) induces skeletal muscle mitochondrial abnormalities that contribute to exercise limitation; however, specific mitochondrial therapeutic targets remain poorly established. This study quantified the relationship and contribution of distinct mitochondrial respiratory states to prognostic whole-body measures of exercise limitation in HFrEF. METHODS AND RESULTS: Male patients with HFrEF (n = 22) were prospectively enrolled and underwent ramp-incremental cycle ergometry cardiopulmonary exercise testing to determine exercise variables including peak pulmonary oxygen uptake (V̇O2peak ), lactate threshold (V̇O2LT ), the ventilatory equivalent for carbon dioxide (V̇E /V̇CO2LT ), peak circulatory power (CircPpeak ), and peak oxygen pulse. Pectoralis major was biopsied for assessment of in situ mitochondrial respiration. All mitochondrial states including complexes I, II, and IV and electron transport system (ETS) capacity correlated with V̇O2peak (r = 0.40-0.64; P < 0.05), V̇O2LT (r = 0.52-0.72; P < 0.05), and CircPpeak (r = 0.42-0.60; P < 0.05). Multiple regression analysis revealed that combining age, haemoglobin, and left ventricular ejection fraction with ETS capacity could explain 52% of the variability in V̇O2peak and 80% of the variability in V̇O2LT , respectively, with ETS capacity (P = 0.04) and complex I (P = 0.01) the only significant contributors in the model. CONCLUSIONS: Mitochondrial respiratory states from skeletal muscle biopsies of patients with HFrEF were independently correlated to established non-invasive prognostic cycle ergometry cardiopulmonary exercise testing indices including V̇O2peak , V̇O2LT , and CircPpeak . When combined with baseline patient characteristics, over 50% of the variability in V̇O2peak could be explained by the mitochondrial ETS capacity. These data provide optimized mitochondrial targets that may attenuate exercise limitations in HFrEF.

Aerobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2α Modulation.

Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.

Skeletal muscle atrophy in heart failure with diabetes: from molecular mechanisms to clinical evidence.

Two highly prevalent and growing global diseases impacted by skeletal muscle atrophy are chronic heart failure (HF) and type 2 diabetes mellitus (DM). The presence of either condition increases the likelihood of developing the other, with recent studies revealing a large and relatively poorly characterized clinical population of patients with coexistent HF and DM (HFDM). HFDM results in worse symptoms and poorer clinical outcomes compared with DM or HF alone, and cardiovascular-focused disease-modifying agents have proven less effective in HFDM indicating a key role of the periphery. This review combines current clinical knowledge and basic biological mechanisms to address the critical emergence of skeletal muscle atrophy in patients with HFDM as a key driver of symptoms. We discuss how the degree of skeletal muscle wasting in patients with HFDM is likely underpinned by a variety of mechanisms that include mitochondrial dysfunction, insulin resistance, inflammation, and lipotoxicity. Given many atrophic triggers (e.g. ubiquitin proteasome/autophagy/calpain activity and supressed IGF1-Akt-mTORC1 signalling) are linked to increased production of reactive oxygen species, we speculate that a higher pro-oxidative state in HFDM could be a unifying mechanism that promotes accelerated fibre atrophy. Overall, our proposal is that patients with HFDM represent a unique clinical population, prompting a review of treatment strategies including further focus on elucidating potential mechanisms and therapeutic targets of muscle atrophy in these distinct patients.

Discovery of the world's highest-dwelling mammal.

Environmental limits of animal life are invariably revised when the animals themselves are investigated in their natural habitats. Here we report results of a scientific mountaineering expedition to survey the high-altitude rodent fauna of Volcán Llullaillaco in the Puna de Atacama of northern Chile, an effort motivated by video documentation of mice (genus Phyllotis) at a record altitude of 6,205 m. Among numerous trapping records at altitudes of >5,000 m, we captured a specimen of the yellow-rumped leaf-eared mouse (Phyllotis xanthopygus rupestris) on the very summit of Llullaillaco at 6,739 m. This summit specimen represents an altitudinal world record for mammals, far surpassing all specimen-based records from the Himalayas and other mountain ranges. This discovery suggests that we may have generally underestimated the altitudinal range limits and physiological tolerances of small mammals simply because the world's high summits remain relatively unexplored by biologists.

PPARGC1B Is Associated with Nontraumatic Osteonecrosis of the Femoral Head: A Genomewide Association Study on a Chart-Reviewed Cohort.

BACKGROUND: Previous studies have demonstrated the influence of heritable factors on the development of nontraumatic osteonecrosis of the femoral head (ONFH). We hypothesized that genetic variation is associated with an increased risk of ONFH, and that variants could be identified by a genomewide association study (GWAS). METHODS: Using data collected from the MyCode Community Health Initiative, we identified 118 adult patients with radiographically confirmed nontraumatic ONFH. Study patients were statistically compared with a control population of 56,811 unrelated individuals without a diagnosis of ONFH. A case-control GWAS was performed to identify single nucleotide variants (SNVs) associated with ONFH. Sensitivity analyses were performed to evaluate the association of the top SNVs with (cortico)steroid-associated ONFH and ONFH with femoral head collapse. Gene-based analyses were performed to identify potential causal genes. RESULTS: Of the 118 patients, 114 (96.6%) had bilateral ONFH at a median of 5 years of follow-up; 90.7% had at least one 3-week steroid prescription compared with 68.3% in controls. A GWAS identified 4 SNVs reaching genomewide significance. rs116468452 near CACNA1E was significantly associated with ONFH (p = 3.26 × 10, odds ratio [OR] = 5.6, 95% confidence interval [CI] = 3.21 to 9.76). rs10953090 in SAMD9 was significantly associated with ONFH in the steroid-exposed subset (p = 2.96 × 10, OR = 2.57, 95% CI = 1.84 to 3.58). rs112467115 in PI4K1B showed enhanced association in the collapsed subset (p = 7.82 × 10, OR = 4.5, 95% CI = 2.60 to 7.79). Gene-based analyses identified PPARGC1B as the only gene significantly associated with ONFH after Bonferroni correction (p = 1 × 10), with the lead SNV being rs78814834 (OR = 2.86, 95% CI = 1.87 to 4.38). CONCLUSIONS: We identified 4 SNVs and 1 gene, PPARGC1B, associated with ONFH. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Preparative scale purification of natural glycans by closed-loop recycle HPLC.

While glycoscience has become well recognized as an indispensable area in biomedical research, studies on the function of individual glycans remains a great challenge due to the lack of tools and methods. One of the greatest impediments to progress in this area is the lack of biomedically relevant complex glycans in sufficient quantity and purity for structural and functional analysis. Despite recent advances in chemoenzymatic synthesis of complex glycans, generating significant amounts of pure glycans is limited to laboratories with specialized expertise. We have previously reported the oxidative release of natural glycans (ORNG) using household bleach, which provides large quantities of biologically relevant glycans that can be a source of glycans in quantities (>mg scale) suitable for functional studies. However, the preparative scale separation of complicated glycan mixtures has not been studied due largely to the fact that gram quantities of starting glycans have not been available until now. Here we report the adoption of closed-loop, recycle HPLC to resolve closely related glycan structures, including complex glycan isomers at preparative scale (10-100 mg).

Small-molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia.

BACKGROUND: Muscle ring finger 1 (MuRF1) is a muscle-specific ubiquitin E3 ligase activated during clinical conditions associated with skeletal muscle wasting. Yet, there remains a paucity of therapeutic interventions that directly inhibit MuRF1 function, particularly in vivo. The current study, therefore, developed a novel compound targeting the central coiled coil domain of MuRF1 to inhibit muscle wasting in cardiac cachexia. METHODS: We identified small molecules that interfere with the MuRF1-titin interaction from a 130 000 compound screen based on Alpha Technology. A subset of nine prioritized compounds were synthesized and administrated during conditions of muscle wasting, that is, to C2C12 muscle cells treated with dexamethasone and to mice treated with monocrotaline to induce cardiac cachexia. RESULTS: The nine selected compounds inhibited MuRF1-titin complexation with IC50 values <25 µM, of which three were found to also inhibit MuRF1 E3 ligase activity, with one further showing low toxicity on cultured myotubes. This last compound, EMBL chemical core ID#704946, also prevented atrophy in myotubes induced by dexamethasone and attenuated fibre atrophy and contractile dysfunction in mice during cardiac cachexia. Proteomic and western blot analyses showed that stress pathways were attenuated by ID#704946 treatment, including down-regulation of MuRF1 and normalization of proteins associated with apoptosis (BAX) and protein synthesis (elF2B-delta). Furthermore, actin ubiquitinylation and proteasome activity was attenuated. CONCLUSIONS: We identified a novel compound directed to MuRF1's central myofibrillar protein recognition domain. This compound attenuated in vivo muscle wasting and contractile dysfunction in cardiac cachexia by protecting de novo protein synthesis and by down-regulating apoptosis and ubiquitin-proteasome-dependent proteolysis.

Functional Gain and Pain Relief After Total Joint Replacement According to Obesity Status.

BACKGROUND: Obesity has been associated with lower function and more pain before and after total hip or knee replacement (THR or TKR). We examined the changes between preoperative and postoperative function and pain in a large representative U.S. cohort to determine if there was a relationship to obesity status. METHODS: Preoperative and 6-month postoperative data on function (Short Form-36 Physical Component Summary [PCS] score), joint pain (Hip disability and Osteoarthritis Outcome Score and Knee injury and Osteoarthritis Outcome Score), and body mass index (BMI) were collected from a national sample of 2,040 patients who had undergone THR and 2,964 who had undergone TKR from May 2011 to March 2013. Preoperative and postoperative function and pain were evaluated according to BMI status, defined as under or of normal weight, overweight, obese, severely obese, or morbidly obese. RESULTS: Patients undergoing THR were an average of 65 years of age; 59% were women, 94% were white, and 14% were severely or morbidly obese. A greater obesity level was associated with a lower (worse) PCS score at baseline and 6 months postoperatively. Severely and morbidly obese patients had less postoperative functional gain than the other BMI groups. A greater obesity level was associated with more pain at baseline but greater postoperative pain relief, so the average postoperative pain scores did not differ significantly according to BMI status. Patients undergoing TKR had an average age of 69 years; 61% were women, 93% were white, and 25% were severely or morbidly obese. A greater obesity level was associated with a lower PCS score at baseline and 6 months. The postoperative gain in PCS score did not differ by BMI level. A greater obesity level was associated with worse pain at baseline but greater pain relief at 6 months, so the average pain scores at 6 month were similar across the BMI levels. CONCLUSIONS: Six months after total joint replacement (TJR), severely or morbidly obese patients reported excellent pain relief and substantial functional gain that was similar to the findings in other patients. While obesity is associated with a greater risk of early complications, obesity in itself should not be a deterrent to undergoing TJR to relieve symptoms. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Pediatric all-terrain vehicle (ATV) injuries: An epidemic of cost and grief.

OBJECTIVE: Evaluate cost of care of all-terrain vehicle (ATV) related injuries sustained by riders 16 years and younger in Pennsylvania. METHODS: Population-based retrospective cohort design reviewing costs of care of 78 patients (≤16 years), admitted (01/01/2007-12/31/2009) to our institution for injuries sustained during an ATV accident. RESULTS: Cost of care varied from $322 to $310,435. Mean and median costs for all patients were $25,760 and $8,066, respectively. Average costs increased with increasing age. Patients wearing helmets or driving the ATV had lower mean costs, but these trends were not statistically significant. Crashes with stationary objects not involving rollover or ejection had significantly lower mean costs than other crash types (p = 0.01). Patients involved in rollover accidents were significantly more likely to require an overnight hospital stay (OR = 3.45, p = 0.02). Patients wearing helmets were marginally less likely to require an overnight admission (OR = 0.34, p = 0.07). CONCLUSION: ATV crashes involving unhelmeted riders and rollover accidents result in significant medical costs. Interventions to increase helmet use and measures to improve stability are likely to reduce these costs and shorten hospital stays. LEVEL OF EVIDENCE: Level IV, Economic study.

Preoperative Use of Clopidogrel Does Not Affect Outcomes for Femoral Neck Fractures Treated With Hemiarthroplasty.

BACKGROUND: The antiplatelet effect of clopidogrel on blood loss and perioperative complications after surgical intervention remains ambiguous. The purpose of this study was to determine if patients on clopidogrel before hemiarthroplasty for femoral neck fracture are predisposed to greater surgical bleeding and perioperative complications compared with those not taking clopidogrel before surgery. METHODS: We conducted a review of our electronic medical record from 2006-2013 and identified 602 patients who underwent 623 hemiarthroplasty procedures for displaced femoral neck fracture, of which 54 cases (9%) were taking clopidogrel before hospital admission. Patient demographics and comorbidities, operative and surgical variables, and perioperative complications at 90 days were compared between the clopidogrel and nonclopidogrel user groups. RESULTS: The 2 groups of patients had similar baseline characteristics, but patients taking clopidogrel preoperatively were sicker with higher American Society of Anesthesiologists scores (P = .049) and age-adjusted Charlson index (P = .001). They also had a greater incidence of cerebrovascular disease (P = .01), chronic obstructive pulmonary disease (P = .03), diabetes (0.03), and malignancy (P < .001). There was no significant difference between the 2 patient groups with respect to 90-day postoperative medical readmissions (P = .85), surgical readmissions (P = .26), infection (P = .99), and mortality (P = .89). CONCLUSION: Patients taking clopidogrel who present with a displaced femoral neck fracture can safely undergo a hemiarthroplasty while actively on clopidogrel without an increase in medical or surgical complications and mortality. We do not recommend delaying surgical intervention until the antiplatelet effects of clopidogrel subside.