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Study Design: Retrospective case series.Purpose: This study aimed to examine the efficacy of composite grip strength as a marker of surgical outcome in patients with moderate to severe degenerative cervical myelopathy.Overview of Literature: Degenerative cervical myelopathy causes loss of dexterity, muscle strength, and sensations in the hand. The impact of surgical management on improvement in composite grip strength has received scant attention.Methods: This retrospective study was performed on degenerative cervical myelopathy patients with a complete composite grip strength assessment between January 2013 to January 2019. The Biometrics E-link hand kit was used for the assessment. The following parameters were measured: maximum grip strength, sustained grip strength, three-jaw pinch, maximum key pinch, and sustained key pinch. The pre- and postoperative functional status was assessed using the Nurick grade and the modified Japanese Orthopaedic Association (mJOA) score.Results: A total of 40 patients were included in the study. The mean patient age was 51.9 years. The mean preoperative Nurick grade was 3.5 and the mJOA score was 10.9. The anterior approach was used in 25 patients, and the posterior approach was used in 15 patients. Four patients developed complications. Degenerative cervical myelopathy resulted in decreased handgrip and pinch strength as compared to normative Indian data. There was a significant improvement in the postoperative composite grip strength for all five parameters. There was no differential improvement between the anterior and posterior surgical groups. The improvement in the composite grip strength correlated with the improvement in functional scores.Conclusions: Composite grip strength analysis is an objective method for assessing the impact of degenerative cervical myelopathy on grip strength and monitoring the postoperative improvement. Decompressive surgery resulted in global improvement in all the parameters of composite grip strength.

Study Design: Prospective cohort study.Purpose: To evaluate the association between nutritional parameters related to postoperative surgical site infections and duration of hospital stay and intensive care unit (ICU) stay in patients undergoing major spine surgery.Overview of Literature: Malnutrition is highly prevalent in surgical patients. Malnourished patients are considered to be at higher risk for postoperative morbidity and mortality due to impaired wound healing, delayed inflammation, impaired fibroblast proliferation, and collagen synthesis. Decreased lymphocyte count also impairs the ability of the immune system to eradicate or prevent infection, which predisposes these patients to infections. However, this association between malnutrition and postoperative morbidity is not consistent across studies, thus necessitating further investigation.Methods: The values of serum albumin, prealbumin, total lymphocyte counts, and transferrin were documented preoperatively and postoperatively on day 5 for all patients undergoing major spine surgery (surgery involving instrumentation of at least three motion segments). In addition, patients’ surgical wound healing status, duration of hospital stay, and duration of ICU stay in the postoperative period were documented. Finally, the statistical correlation between the nutritional markers and these complications was determined.Results: Low postoperative prealbumin levels was significantly associated with increased complication rates. ICU stay demonstrated a statistically significant association with low postoperative albumin, prealbumin, and transferrin levels. Similarly, we observed that low postoperative albumin and prealbumin levels could significantly predict the need for prolonged hospital stay in patients undergoing major spine surgery.Conclusions: The magnitude of the decrease in nutritional status due to surgery with respect to albumin and prealbumin levels is a significant (p

Background Physicians treating COVID-19 patients increasingly believe that the hyperinflammatory acute stage of COVID-19 results in a cytokine storm. The circulating biomarkers seen across the spectrum of COVID-19 have not been characterized compared to healthy controls, but such analyses are likely to yield insights into the pursuit of interventions that adequately reduce the burden of these cytokine storms. Objective To identify and characterize the host inflammatory response to SARS-CoV-2 infection, we assessed levels of proteins related to immune responses and cardiovascular disease, in patients stratified as mild, moderate, and severe, versus matched healthy controls. Methods Blood samples from adult patients hospitalized with COVID-19 were analyzed using high-throughput and ultrasensitive proteomic platforms and compared with age- and sex-matched healthy controls to provide insights into differential regulation of 185 markers. Results Results indicate a dominant hyperinflammatory milieu in the circulation and vascular endothelial damage markers within COVID-19 patients, and strong biomarker association with patient response as measured by Ordinal scale. As patients progress, we observe statistically significant dysregulation of IFNγ, IL-1RA, IL-6, IL-10, IL-19, MCP-1, -2, -3, CXCL9, CXCL10, CXCL5, ENRAGE and PARP-1. Furthermore, in a limited series of patients who were sampled frequently confirming reliability and reproducibility of our assays, we demonstrate that intervention with baricitinib attenuates these circulating biomarkers associated with the cytokine storm. Conclusion These wide-ranging circulating biomarkers show an association with increased disease severity and may help stratify patients and selection of therapeutic options. They also provide insights into mechanisms of SARS-CoV-2 pathogenesis and the host response., Capsule Summary: This detailed analysis of plasma biomarkers in COVID-19 patients provides definitive understanding of the cytokine storm and changes in vascular endothelial markers that may inform us of the changes in the Ordinal scale for COVID-19.

Study Design: Retrospective case series.Purpose: This study aimed to analyze how the sagittal spinopelvic alignment is influenced by an attempted surgical reduction of the L5–S1 segment in patients with high-grade spondylolisthesis (HGS).Overview of Literature: Conventional treatment strategies stress the importance of achieving fusion across the lumbosacral junction in patients with HGS. The role of reduction in this subset of patients is controversial.Methods: This is a retrospective case series of 35 patients with Meyerding grades III, IV, or V spondylolisthesis who underwent surgical treatment in our institution. Before and after surgery, we took standing lateral radiographs from L1 vertebra to pelvis, including the femoral heads, and measured the slip grade, pelvic incidence, sacral slope, pelvic tilt, lumbosacral angle, and lumbar lordosis. Patients were subdivided into “balanced” and “unbalanced” pelvis groups. To determine the effect and correlation of reduction on these spinopelvic parameters, we statistically compared the pre- and postoperative measurements.Results: The average follow-up was 9 months (range, 3–169 months). Slip grade improved from an average 74.0%±13.2% to 30.0%±14.0% (p

Study Design: A biomechanical study.Purpose: To determine the actual load path and compare pullout strengths as a function of screw size used in revision surgeries using postmortem human subject specimens.Overview of Literature: Pedicle screw fixation has become the standard of care in the surgical management of spinal instability. However, pullout failures are widely observed in osteoporotic spines and treated by revision surgeries using a higher diameter screw, performing cement augmentation, or increasing the levels of fixation. While the peak forces to final pullout are reported, the actual load path to achieve the final force level is not available. Methods: Six osteoporotic lumbar spines (L2–L5) were instrumented with 5.5×40 mm polyaxial screws and loaded along the axis of the screw using a material testing machine according to American Society for Testing of Materials 543-07 test protocol. Tests were again conducted by replacing them with 6.5×40 mm (group A) or 7.5×40 mm (group B) screws. Force-displacement data were grouped and load paths (mean±1 standard deviation) were compared.Results: Pullout strength decreased by 36% when the size of the revision screw was increased by 1 mm, while it increased by 35% when the size of the revision screw was increased by 2 mm compared to the index screw value. While the morphologies of the load paths were similar in all cases, they differ between the two groups: the larger screw responded with generally elevated stiffer path than the smaller screw, suggesting that revision surgery using a larger screw has more purchase along the inserted body-pedicle axis.Conclusions: A larger screw enhances strength and increases biomechanical stability in revision surgeries, although the final surgical decision is made by the clinician, which includes the patient’s anatomy and associated characteristics.

Summary Background Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov , NCT04421027 . Findings Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. Funding Eli Lilly and Company. Translations For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-β signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.

BackgroundThe efficacy and safety of baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC) in hospitalised adults with COVID-19 is unknown.MethodsIn this phase 3, global, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America (ClinicalTrials.govNCT04421027). Hospitalised adults with COVID-19 receiving SOC were randomly assigned (1:1) to once-daily baricitinib 4-mg or placebo for up to 14 days. SOC included systemic corticosteroids in 79·3% of participants (dexamethasone ∼90%). The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. All-cause mortality by days 28 and 60 were key secondary and exploratory endpoints, respectively. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.FindingsBetween June 11, 2020 and January 15, 2021, 1525 participants were randomly assigned to baricitinib 4-mg (n=764) or matched placebo (n=761). Overall, 27·8% of participants receiving baricitinib vs 30·5% receiving placebo progressed (primary endpoint, odds ratio 0·85, 95% CI 0·67-1·08; p=0·18). The 28-day all-cause mortality was 8·1% (n=62) for baricitinib and 13·1% (n=100) for placebo, corresponding to a 38·2% reduction in mortality (hazard ratio [HR] 0·57, 95% CI 0·41-0·78; nominal p=0·0018). The 60-day all-cause mortality was 10·3% (n=79) for baricitinib and 15·2% (n=116) for placebo (HR 0·62, 95% CI 0·47-0·83; p=0·0050). Frequency of serious adverse events (14·7% [n=110] vs 18·0% [n=135]), serious infections (8·5% [n=64] vs 9·8% [n=74]), and venous thromboembolic events (2·7% [n=20] vs 2·5% [n=19]) was similar between baricitinib and placebo, respectively.InterpretationWhile reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (including dexamethasone) significantly reduced mortality, with a similar safety profile to SOC, in hospitalised COVID-19 participants.FundingEli Lilly and Company.Research in contextEvidence before this studyWe searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib” and “JAK inhibitor” for articles in English published up to April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib, before undertaking this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and limited phase 3 randomised placebo-controlled studies had been completed. Limited phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir/ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential for targeting host proteins for its antiviral mechanism. Additionally, early case series evaluating the efficacy and safety of baricitinib in the hospitalised patient population supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While COV-BARRIER was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir was completed showing that baricitinib added to remdesivir improved time to recovery and other outcomes.Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC) and included antivirals, anticoagulants, and corticosteroids. After the earliest publication of the RECOVERY study in June 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as SOC. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit/risk of baricitinib when added to the most current SOC (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high flow oxygen, invasive mechanical ventilation, or death for baricitinib plus SOC (including dexamethasone) compared to placebo plus SOC did not reach statistical significance. However, in a pre-specified key secondary endpoint, treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared to placebo (HR 0·57, 95% CI 0·41-0·78; nominal p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained by day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.Implications of all the available evidenceIn this phase 3 trial, baricitinib given in addition to SOC (which predominantly included dexamethasone) did not reduce a composite endpoint of disease progression, but showed a strong effect on reducing mortality by 28 days, an effect which was maintained by 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.

STUDY DESIGN Retrospective case series. PURPOSE The aim of the study is to report the clinical characteristics, early diagnosis, management, and outcome of children with multidrug-resistant (MDR) tubercular spondylodiscitis and to assess the early detection of rifampicin resistance using the Xpert MTB/ RIF assay. OVERVIEW OF LITERATURE MDR tuberculosis is on the rise, especially in developing countries. The incidence rate of MDR has been reported as 8.9% in children. METHODS A retrospective study of children aged

Study design Retrospective case series. Purpose The aim of this study was to analyze functional and radiological outcomes in patients with culture-negative pyogenic vertebral osteomyelitis (PVO). Overview of literature There were only few literature available for these group of patients. Methods Patients with biopsy-positive but culture-negative PVO were included. We analyzed records for data on demography, comorbidities, coexisting infections, neurological status, prior antibiotic therapy, pre- and postoperative erythrocyte sedimentation rate, C-reactive protein levels, and Oswestry Disability Index, and Japanese Orthopedics Association scores. Results Sixty-one patients were included, of which data of 45 patients were available for follow-up. The patients were predominantly males (71%), with a mean age of 53.2 years. Seventy-seven percent patients had comorbidities. Echocardiography, blood culture, and urine culture were performed on 8%, 24%, and 18% of patients, respectively. Thirty-one percent patients had neurological deficits. Computed tomography-guided biopsy was performed on 67% patients. Fifty-two percent patients were treated surgically, and 48% were treated non-surgically. Nineteen percent patients were treated according to the results of cultures from other foci, and the rest were treated empirically. For the initial 2 weeks, all patients were treated with intravenous antibiotics empirically or based on culture from other foci. This treatment was followed by 10 weeks of oral cloxacillin/cephalexin for gram-positive organisms or ciprofloxacin for gram-negative organisms. The mean follow-up time was 18 months (range, 12-120 months). All patients had improvement in Japanese Orthopedics Association, Oswestry Disability Index, and Visual Analog Scale scores (p Conclusions Treatment with empirical antibiotics for 12 weeks with watchful clinical and radiological follow-up yields good resolution of the disease. Further multicenter clinical research needs to be performed for obtaining an algorithmic treatment plan for these patients.

The purpose of this study is to evaluate the role of spinal angiography and arterial embolization in avoiding spinal cord ischemia in patients undergoing CT-guided alcohol injection of aggressive vertebral hemangiomas. In this retrospective study, patients with vertebral hemangioma who underwent CT-guided direct alcohol injection between January 2007 and October 2018 were identified. Of 28 such patients, 26 had neurological deficits, and 2 had only back pain or radiculopathy. Direct alcohol injection without prior arterial embolization was done in 17 patients. Direct alcohol injection with prior arterial embolization was done in 11 patients. Clinical outcome was assessed immediately after the intervention and at follow-up. Three patients, who underwent alcohol injection without trans-arterial embolization, had worsening of neurological deficits in the post procedure period due to spinal cord ischemia. No complications related to spinal cord ischemia were noted in the embolization group. There was no significant difference in the outcomes between the two groups if the three patients with complications are excluded (p = 0.34). While CT-guided direct alcohol injection is effective in the management of symptomatic and aggressive vertebral hemangiomas, spinal angiography and trans-arterial embolization of the blood supply to the vertebral body hemangioma, prior to the direct transpedicular alcohol embolization of the lesion, improves the safety of the procedure.

Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI)‐algorithms, to be useful for COVID‐19 infection via a proposed anti‐cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID‐19 infection. We validated the AI‐predicted biochemical inhibitory effects of baricitinib on human numb‐associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID‐19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS‐CoV‐2 viral load, inflammatory markers, and IL‐6 levels. Collectively, these data support further evaluation of the anti‐cytokine and anti‐viral activity of baricitinib and supports its assessment in randomized trials in hospitalized COVID‐19 patients.

Estrogen and androgen deficiency have been associated with the incidence of osteoporosis in postmenopausal women and elderly men over the last many decades. Estrogen and androgen function through signaling pathways that originate from binding to their cognate nuclear receptors, which collectively impact sexual function, growth and development, and skeletal health. These effects range from gain-of-function paradigms involving their cognate ligands that target these nuclear hormone receptor-mediated signaling pathways to loss-of-function paradigms that involve menopause/aging or rare allelic variants that abrogate ligand or receptor function. This review summarizes our current knowledge of the gain-of-function and loss-of-function attributes of these two steroid hormones with specific emphasis on androgens and male skeletal health.

Study design A biomechanical study of pedicle-screw pullout strength. Purpose To develop a decision tree based on pullout strength for evaluating pedicle-screw instrumentation. Overview of literature Clinically, a surgeon's understanding of the holding power of a pedicle screw is based on perioperative intuition (which is like insertion torque) while inserting the screw. This is a subjective feeling that depends on the skill and experience of the surgeon. With the advent of robotic surgery, there is an urgent need for the creation of a patient-specific surgical planning system. A learning-based predictive model is needed to understand the sensitivity of pedicle-screw holding power to various factors. Methods Pullout studies were carried out on rigid polyurethane foam, representing extremely osteoporotic to normal bone for different insertion depths and angles of a pedicle screw. The results of these experimental studies were used to build a pullout-strength predictor and a decision tree using a machine-learning approach. Results Based on analysis of variance, it was found that all the factors under study had a significant effect (p l0.05) on the holding power of a pedicle screw. Of the various machine-learning techniques, the random forest regression model performed well in predicting the pullout strength and in creating a decision tree. Performance was evaluated, and a correlation coefficient of 0.99 was obtained between the observed and predicted values. The mean and standard deviation of the normalized predicted pullout strength for the confirmation experiment using the current model was 1.01±0.04. Conclusions The random forest regression model was used to build a pullout-strength predictor and decision tree. The model was able to predict the holding power of a pedicle screw for any combination of density, insertion depth, and insertion angle for the chosen range. The decision-tree model can be applied in patient-specific surgical planning and a decision-support system for spine-fusion surgery.

Study Design A biomechanical study. Purpose A new biomechanical model of the vertebra has been developed that accounts for the inhomogeneity of bone and the contribution of the pedicle toward the holding strength of a pedicle screw. Overview of Literature Pullout strength studies are typically carried out on rigid polyurethane foams that represent the homogeneous vertebral framework of the spine. However, the contribution of the pedicle region, which contributes to the inhomogeneity in this framework, has not been considered in previous investigations. Therefore, we propose a new biomechanical model that can account for the vertebral inhomogeneity, especially the contribution of the pedicles toward the pullout strength of the pedicle screw. Methods A bilayer foam model was developed by joining two foams representing the pedicle and the vertebra. The results of the pullout strength tests performed on the foam models were compared with those from the tests performed on the cadaver lumbar vertebra. Results Significant differences (p 0.05) in the pullout strength of pedicle screws between osteoporotic (0.85±0.08 kN) and extremely osteoporotic bone models (0.94±0.08 kN), but there was a significant difference (p 0.05) in pullout strength between cadaver and bilayer foam model in normal bones. Conclusions The new synthetic bone model that reflects the contribution of the pedicles to the pullout strength of the pedicle screws could provide a more efficacious means of testing pedicle-screw pullout strength. The bilayer model can match the pullout strength value of normal lumbar vertebra bone whereas the monolayer foam model was able to match that of the extremely osteoporotic lumbar vertebra.

We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate. When LY305 was tested in animal models of skeletal atrophy it restored the skeletal muscle mass through accelerated repair. In a bone fracture model, LY305 remained osteoprotective in the regenerating tissue and void of deleterious effects. Finally, in a small cohort of healthy volunteers, we assessed the safety and tolerability of LY305 when administered transdermally. LY305 showed a dose-dependent increase in serum exposure and was well tolerated with minimal adverse effects. Notably, there were no statistically significant changes to hematocrit or HDL after 4-week treatment period. Collectively, LY305 represents a first of its kind de novo development of a non-steroidal transdermal SARM with unique properties which could find clinical utility in hypogonadal men.

Summary There is substantial inter-individual variability in serum testosterone levels in hypogonadal men treated with testosterone gels. We aimed to elucidate participant-level factors that contribute to inter-individual variability in testosterone levels during testosterone therapy. An exploratory aim was to determine whether polymorphisms in genes encoding testosterone-metabolizing enzymes could explain the variation in on-treatment testosterone concentrations in men who were randomized to testosterone arm in TOM Trial. We used data from three randomized trials that used 1% transdermal testosterone gels and had testosterone levels measured 2–4 weeks after randomization for dose adjustment: Testosterone in Older Men with Mobility Limitation (TOM), Effects of Testosterone on Pain Perception (TAP), and Effects of Testosterone on Atherosclerosis Progression (TEAAM). Forty-seven percent, 38%, and 9% of participants in TAP, TEAAM, and TOM trials, respectively, failed to raise testosterone levels >400 ng/dL; 6, 8, and 30% of participants had on-treatment testosterone levels >1000 ng/dL. Even after dose adjustment, there was substantial variation in on-treatment levels at subsequent study visits. Baseline characteristics (age, height, weight, baseline testosterone, SHBG, hematocrit, and creatinine) accounted for only a small fraction of the variance (

This study aims to assess the accuracy of the Xpert MTB/RIF assay in the diagnosis of tubercular spondylodiscitis and to identify its role in detecting Rifampicin resistance in patients with infective spondylodiscitis. A retrospective study including 348 patients suspected to have infective spondylodiscitis was done. Tissue/pus samples obtained were sent for culture, histopathology and Xpert MTB/RIF assay. All patients who were confirmed to have tubercular spondylodiscitis and those patients who were suspected on clinico-radiological basis were also treated with anti-tuberculous chemotherapy for a period of 9 months. The efficacy of the Xpert MTB/RIF assay was assessed in terms of sensitivity and specificity when compared to culture, histopathology, and Composite reference standard (CRS). During this study period of 24 months, a total of 348 patients were treated for infective spondylodiscitis. 254 patients were treated for tuberculosis following a smear positivity, culture positivity, and histopathology report or empirically based on clinico-radiological findings. The sensitivity and specificity of the Xpert MTB/RIF assay when compared to culture were 88.4 and 63.7%, respectively. When compared to both culture and histopathology reports it was 80.9 and 80.6%. The sensitivity and specificity of the Xpert MTB/RIF assay when compared to composite reference standard were 71.2 and 100%, respectively. The sensitivity of the assay to detect Rifampicin resistance was 100%. The prevalence of Rifampicin resistance was 5.1%. This study recommends Xpert MTB/RIF assay for early detection of Mycobacterium tubercular spondylodiscitis and Rifampicin resistance.

Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomised clinical trial in patients with moderate-to-severe UC (NCT02589665). This abstract explores gene expression changes in colonic tissue from study patients and their association with clinical outcomes. Methods Patients were randomised 1:1:1:1 to receive intravenous placebo (PBO, N = 63), miri 50 mg (N = 63) or 200 mg (N = 62) with the possibility of exposure-based dose increases, or fixed miri 600 mg (N = 61) every 4 weeks for 12 weeks. Patient biopsies were collected at baseline (BL) and Week 12, and differential gene expression was measured using an Affymetrix HTA2.0 exon-format microarray workflow. Genes were represented by their largest groups of highly correlated exons. Weeks 0 and 12 data were compared in all treatment groups to produce differential expression values (DEVs). Mean fold changes in DEVs between PBO and each dose group were calculated in a mixed-effect model. A threshold of false discovery rate-adjusted p-value ≤ 0.05 was applied to the significance of the fold change values, and a filter of an absolute value for the fold changes of ≥0.5 log2 units was applied. Results The greatest improvement in clinical outcomes at Week 12 was observed in the 200 mg miri group1; likewise, the greatest PBO-adjusted change from BL in transcripts was observed in this group. Transcripts correlating with key UC disease activity indices at BL, including modified Mayo score (MMS), ulcerative colitis Endoscopic Index of Severity (UCEIS), Geboes score, and Robarts Histopathology Index (RHI), included MMP1, MMP3, S100A8, IL1B, and UGT2A3, with the highest correlations occurring with the histopathologic indices (Figure 1). Miri treatment modulated the expression of transcriptional modules predicted to be enriched in cell profiles identified as key drivers of UC2 (Table 1, columns 1–2) as well as genes determined to be associated with UC by genome-wide association studies (GWAS; Table 1, column 3). Moreover, miri treatment affected transcripts involved in resistance to anti-TNF treatments (Table 1, column 4). A number of the genes in these categories were among those most affected by miri treatment (Table 1, columns 5–6). Conclusion This is the first large-scale gene expression study of diseased tissue from UC patients treated with anti-IL23p19 therapy. It is the first study to show how anti-IL23p19 therapy modulates biological pathways involved in resistance to anti-TNFs. These results are consistent with the demonstrated efficacy of miri in patients in whom TNF antagonists have failed. References

Study Design Retrospective clinical analysis. Purpose To delineate the clinical presentation of melioidosis in the spine and to create awareness among healthcare professionals, particularly spine surgeons, regarding the diagnosis and treatment of melioidotic spondylitis. Overview of Literature Melioidosis is an emerging disease, particularly in developing countries, associated with a high mortality rate. Its causative pathogen, Burkholderia pseudomallei, has been labeled as a bio-terrorism agent. Methods We performed a retrospective analysis of patients who were culture positive for B. pseudomallei. Assessment of patients was performed using clinical, radiological, and blood parameters. Clinical measures included pain, neurological deficit, and return to work. Radiological measures included plain radiography of the spine and magnetic resonance imaging. Blood tests included erythrocyte sedimentation rate and C-reactive protein levels. Results Four patients having melioidosis with spondylitis were evaluated. All of them had diabetes mellitus; three had multiple abscesses which required incision and drainage. Their clinical spectrum was similar to that of tuberculous spondylitis; all had back pain and radiology revealed infective spondylodiscitis with prevertebral and paravertebral collections with psoas abscess. Three patients underwent ultrasound-guided drainage of the psoas abscess and one had aspiration of the subcutaneous abscess. Bacteriological cultures showed presence of B. pseudomallei, and histopathology showed non-caseating granulomatous inflammation. All patients were treated with intravenous Ceftazidime for 2 weeks, followed by oral bactrim double strength and Doxycycline for 20 weeks. All patients improved with treatment and were healed at follow up. Conclusions Melioidosis presents with a clinical spectrum similar to that of tuberculosis. A diagnosis of melioidotic spondylitis should be considered, particularly in patients with diabetes with neutrophilic leukocytosis and clinical-radiological features suggestive of infective spondylodiscitis. Bacteriological culture and histopathology helps in differentiating the two conditions. Health education for healthcare professionals is important for correctly diagnosing this disease.

Ovarian cancer and triple-negative breast cancer are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. Cancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic surface proteins called 'don't eat me' signals-including CD471, programmed cell death ligand 1 (PD-L1)2 and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M)3. Monoclonal antibodies that antagonize the interaction of 'don't eat me' signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers4,5. However, variability in the magnitude and durability of the response to these agents has suggested the presence of additional, as yet unknown 'don't eat me' signals. Here we show that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a promising target for cancer immunotherapy. We demonstrate a role for tumour-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10), which is expressed by tumour-associated macrophages. We find that many tumours overexpress CD24 and that tumour-associated macrophages express high levels of Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24-Siglec-10 interaction using monoclonal antibodies, robustly augment the phagocytosis of all CD24-expressing human tumours that we tested. Genetic ablation and therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumour growth in vivo and an increase in survival time. These data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy.

BackgroundBiomarkers that predict response to anabolic therapies could expedite the development of function-promoting anabolic drugs. This study aimed to identify serum biomarkers that are responsive to testosterone administration and associated with increases in fat-free mass (FFM).MethodsSerum samples were obtained from the 5α-Reductase Trial, a randomized trial that compared the effects of graded doses of testosterone enanthate for 20 weeks in healthy men randomized with placebo or dutasteride (dual SRD5A inhibitor). Testosterone’s effects on FFM or strength measures did not differ between placebo vs dutasteride groups. Accordingly, 54 subjects treated with testosterone plus placebo were included in the discovery cohort, and 48 subjects randomized to dutasteride were included in the validation cohort. A total of 1162 biomarkers were evaluated using prespecified criteria.ResultsIn the discovery cohort, testosterone administration increased propeptide of type III collagen (PRO-C3) and propeptide of type VI collagen (PRO-C6) levels in a dose- and concentration-dependent manner; increases in these biomarkers from baseline to week 12 were associated with changes in FFM from baseline to week 20 (PRO-C3: r2 = 0.437, P < 0.001; PRO-C6: r2 = 0.434, P < 0.001). Changes in PRO-C3 and PRO-C6 levels were significantly associated with changes in chest press strength (PRO-C3: r2 = 0.394, P < 0.001; PRO-C6: r2 = 0.530, P < 0.001). In the SOMAscan, changes in IGF binding protein-6 (IGFBP6) and glypican 3 (GPC3) were associated with changes in total and free testosterone levels and FFM. These findings were replicated in the Validation cohort.ConclusionPRO-C3, PRO-C6, IGFBP6, and GPC3 fulfilled the prespecified criteria for biomarkers of testosterone-induced muscle anabolism. Changes in these biomarkers were associated with changes in total and free testosterone concentrations and with testosterone-induced gains in FFM.

To provide an overview of the principles, safety and efficacy of adoptive cell therapy (ACT) in solid tumors particularly in gynecological cancers.Efforts to target solid tumors using tumor-infiltrating lymphocytes and genetically modified T cells have shown promising efficacy in some patients. Two food and drug administration approvals for the treatment of leukemia are the first gene therapies available for cancer treatment in the United States.Genetic engineering of antitumor immunity using T cells has the potential to target specific tumor-associated antigens and overcome obstacles to successful immunotherapy like immune-suppressive factors in the tumor microenvironment.

Purpose: The purpose of the study was to determine the rate and predictors of return to work (RTW) after surgery for cervical spondylotic myelopathy (CSM). Overview of Literature: RTW is arguably the most important outcome following spine surgery from a patient’s perspective. But, to the best of our knowledge, there have been no reports in the English literature describing RTW among patients undergoing surgery for moderate-to-severe CSM. Materials and Methods: We included adult patients with CSM with Nurick grade ≥ 3 who underwent surgery. They were divided into two groups: those who returned to work within 6 months (group 1) and those who did not (group 2) and their outcomes were analyzed. Results: A total of 34 patients were included in the study. Baseline characteristics were comparable between the groups. Only 18 (52.9%) patients returned to work by 6 months. The nature of work had a statistically significant association with RTW by 6 months (P = 0.005) with failure to RTW specifically seen in manual laborers. Age, body mass index, symptom duration, pre-operative absenteeism, smoking, diabetes mellitus, number of levels operated, surgical approach, and post-operative complications did not have significant association with RTW. Better functional outcomes were seen in patients who returned to work as calculated using Nurick grade (P = 0.000) and modified Japanese Orthopedic Association score (P = 0.001). All the patients who returned to work and 75% of the patients who did not RTW were satisfied with the outcome of surgery (P = 0.039). Conclusion: In spite of functional improvement, CSM was associated with poor RTW with manual laborers being the most vulnerable group. This study will help surgeons modulate patient expectations as well as provide a platform for counseling them.

Degenerative spondylolisthesis is one of the commonest spinal pathologies encountered in the aging population. The clinical presentation of degenerative spondylolisthesis can be highly variable, and a large proportion of patients can be managed non-operatively. Operative treatment is reserved for patients with activity limiting disability. Decompression alone can be offered to patients with no radiological or clinical evidence of segmental instability. Fusion procedures have shown high rates of clinical success, although long-term effects such as adjacent segment degeneration have spurred the evolution of non-fusion technologies. These newer options have shown evidence of motion preservation, although long-term clinical benefits have yet to be confirmed.

STUDY DESIGN Biomechanical study. PURPOSE To determine the effect of density, insertion angle and reinsertion on pull-out strength of pedicle screw in single and two screw-rod configurations. OVERVIEW OF LITERATURE Pedicle screw pull-out studies have involved single screw construct, whereas two screws and rod constructs are always used in spine fusions. Extrapolation of results using the single screw construct may lead to using expensive implants or increasing the fusion levels specifically in osteoporotic bones. METHODS Single screw and two screw pull-out strength tests were carried out according to American Society for Testing and Materials F 543-07 on foam models to test the effect of density, insertion angle and reinsertion using poly axial pedicle screws. RESULTS Bone density was the most significant factor deciding the pull-out strength in both single and two screw constructs. The difference in pull-out strength between single screw and two screw configurations in extremely osteoporotic bone model (80 kg/m(3)) was 78%, whereas in the normal bone model it was 48%. Axial pull-out value was highest for the single screw configuration; in the two screw configuration the highest pull-out strength was at 10°-15°. There was an 18% reduction in pull-out strength due to reinsertion in single screw configuration. The reinsertion effect was insignificant in the two screw configuration. CONCLUSIONS A significant difference in response of various factors on holding power of pedicle screw between single and two-screw configurations is evident. The percentage increase in pull-out strength between single and two screw constructs is higher for osteoporotic bone when compared to normal bone. Reinsertion has no significant effect on pull-out strength in the two screw rod configuration.

// Steven Kregel 1 , James L. Chen 2 , Westin Tom 5 , Venkatesh Krishnan 5 , Jacob Kach 3 , Hannah Brechka 1 , Tim B. Fessenden 1 , Masis Isikbay 3, 5 , Gladell P. Paner 4 , Russell Z. Szmulewitz 3, * , Donald J. Vander Griend 1, 5, * 1 Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA 2 Department of Biomedical Informatics and Internal Medicine, The Ohio State University, Columbus, OH, USA 3 Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA 4 Department of Pathology, The University of Chicago, Chicago, IL, USA 5 Department of Surgery, Section of Urology, The University of Chicago, Chicago, IL, USA * These authors contributed equally to this work Correspondence to: Donald J. Vander Griend, email: prostate@uchicago.edu Keywords: androgen receptor, prostate cancer, castration-resistance, enzalutamide Received: October 06, 2015 Accepted: March 13, 2016 Published: March 29, 2016 ABSTRACT Enzalutamide (MDV3100) is a second generation Androgen Receptor (AR) antagonist with proven efficacy in the treatment of castration resistant prostate cancer (CRPC). The majority of treated patients, however, develop resistance and disease progression and there is a critical need to identify novel targetable pathways mediating resistance. The purpose of this study was to develop and extensively characterize a series of enzalutamide-resistant prostate cancer cell lines. Four genetically distinct AR-positive and AR-pathway dependent prostate cancer cell lines (CWR-R1, LAPC-4, LNCaP, VCaP) were made resistant to enzalutamide by long-term culture (> 6 months) in enzalutamide. Extensive characterization of these lines documented divergent in vitro growth characteristics and AR pathway modulation. Enzalutamide-resistant LNCaP and CWR-R1 cells, but not LAPC-4 and VCAP cells, demonstrated increased castration-resistant and metastatic growth in vivo . Global gene expression analyses between short-term enzalutamide treated vs. enzalutamide-resistant cells identified both AR pathway and non-AR pathway associated changes that were restored upon acquisition of enzalutamide resistance. Further analyses revealed very few common gene expression changes between the four resistant cell lines. Thus, while AR-mediated pathways contribute in part to enzalutamide resistance, an unbiased approach across several cell lines demonstrates a greater contribution toward resistance via pleiotropic, non-AR mediated mechanisms.

High grade serous ovarian cancer (HGSOC) is a leading cause of cancer related deaths among women. The primary cause of morbidity and mortality in HGSOC patients is metastasis to organs within the peritoneal cavity. Mesothelial cells line the surface of peritoneal organs and are a key stromal cell in HGSOC metastatic niche. However, the mechanisms by which mesothelial cells promote ovarian cancer peritoneal metastasis remain largely unknown. Here we demonstrate that tumor associated mesothelial cells promote tumor invasion by increasing collagen deposition and remodeling. Mechanistically, we demonstrate the tumor-mesothelial niche is hypoxic where both tumor cells and mesothelial cells express the hypoxia inducible factors HIF-1 and HIF-2 and their downstream target gene lysyl oxidase (LOX). LOX is an enzyme that crosslinks collagen fibrils to promote collagen remodeling. In tumor-mesothelial co-culture experiments, we demonstrate that hypoxia enhances extracellular fibrillar collagen deposition by mesothelial cells. Conditioned media from hypoxic tumor-mesothelial co-cultures promotes collagen remodeling and HGSOC tumor cell invasion. Genetic inactivation of either HIF-1 and HIF-2 or LOX reduces the hypoxic induction of collagen remodeling and tumor cell invasion. Importantly, pharmacologic inhibition of HIF-1 and HIF-2 with digoxin reduces the colonization of disseminated HGSOC cells to the omentum, the preferential migration site of peritoneal cancer metastasis. Moreover, pharmacologic inhibition of LOX with BAPN (beta-aminopropionitrile) is sufficient to inhibit metastatic tumor burden and collagen remodeling at metastatic sites in preclinical models of HGSOC metastasis. These data reveal a novel role for mesothelial cells in the production of type I collagen and collagen remodeling in the HGSOC metastatic microenvironment. Furthermore, these studies demonstrate a role for the HIF/LOX signaling axis in the HGSOC tumor-mesothelial niche that can be therapeutically targeted to inhibit collagen remodeling and ovarian cancer metastatic progression. Citation Format: Suchitra Natarajan, Katie Foreman, Michaela Soriano, Hussein Shehade, Daniel Fregoso, Joshua Eggold, Ninna S. Rosen, Sarah Heilshorn, Adam J. Krieg, Venkatesh Krishnan, Oliver Dorigo, Subarna Sinha, Katherine C. Fuh, Erinn B. Rankin. THE HYPOXIC TUMOR-MESOTHELIAL NICHE PROMOTES OVARIAN CANCER METASTASIS THROUGH COLLAGEN REMODELING [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-081.

Study design Retrospective study. Purpose To report the prevalence of patients with multidrug-resistant (MDR) tubercular spondylodiscitis and their outcomes. Additionally, to assess the role of Xpert MTB/RIF assay in early detection of MDR tuberculosis. Overview of literature MDR tuberculosis is increasing globally. The World Health Organization (WHO) has strongly recommended Xpert MTB/RIF assay for early detection of tuberculosis. Methods From 2006 to 2015, a retrospective study was conducted on patients treated for MDR tuberculosis of the spine. Only patients whose diagnosis was confirmed using either culture and/or the Xpert MTB/RIF assay were included. Diagnostic method, treatment regimen, time taken to initiate second-line antituberculosis treatment (ATT), drug-related complications, and cost of medications were analyzed. All patients with MDR were treated according to the WHO recommendations for 2 years. The outcome parameters analyzed included clinical, biochemical, and radiological criteria to assess healing status. Results From 2006 to 2015, a total of 730 patients were treated for tubercular spondylodiscitis. Of those, 36 had MDR tubercular spondylitis (prevalence, 4.9%), and three had extremely drug resistant tubercular spondylitis (prevalence, 0.4%). In this study, 30 patients, with a mean age of 29 years and a mean post-treatment follow-up of 24 months, were enrolled. The majority (77%) had secondary MDR, 17 (56%) underwent surgery, and 26 (87%) completed treatment for 2 years and were healed. Drug-related complications (33%) included ototoxicity, hypothyroidism, and hyperpigmentation of the skin. The average time taken for initiation of second line ATT for MDR patients with Xpert MTB/RIF assay as the diagnostic tool was 18 days, when compared to patients for whom the assay was not available which was 243 days. Conclusions The prevalence of MDR tubercular spondylodiscitis was 4.9%. In total, 87% of patients were healed with adequate treatment. The sensitivity and specificity of the Xpert MTB/RIF assay to detect MDR was 100% and 92.3%, respectively.

Background Erectile dysfunction (ED) is a major health issue in aged populations, and neurogenic ED is particularly difficult to treat. Novel therapeutic approaches are needed for treatment of neurogenic ED of peripheral origin. Objective To investigate the therapeutic effects of a neurotrophic tyrosine kinase receptor type 1 monoclonal antibody (TrkA-mAb) on erectile function and sexual behavior in a rat model of cavernous nerve injury (CNI). Design, setting, and participants In one experiment, 84 male rats were randomly assigned to seven groups. The groups underwent either CNI or sham surgery, subsequent injection into the major pelvic ganglion (IMPG) of phosphate-buffered saline (PBS), an immunoglobulin G (IgG) control, or TrkA-mAb, and then intracavernosal (IC) injection of either PBS or varying TrkA-mAb concentrations immediately after surgery and then 1 wk later. Erectile function was assessed and histologic/molecular analyses were performed at 6 wk after surgery. In a second experiment, 36 male rats were randomly divided into three groups. The groups underwent CNI or sham surgery and then IC injection of PBS, IgG, or TrkA-mAb immediately after surgery and for 5 wk thereafter. At 6 wk after surgery, the performance of the rats in sexual behavior tests was videotaped. Intervention CNI or sham surgery; IMPG of PBS, IgG, or TrkA-mAb; IC injection of PBS or TrkA-mAb. Outcome measurements and statistical analysis The intracavernous pressure response to cavernous nerve electrostimulation was measured and midpenile cross-sections were histologically examined. Western blotting (WB) of cavernous tissue protein was performed. Rats were assessed for chasing, mounting, intromission, and ejaculation behaviors during sexual behavior tests. The data were analyzed using one-way analysis of variance followed by the Tukey-Kramer t test. Results and limitations Recovery of erectile function of varying degrees was observed in the TrkA-mAb groups. TrkA-mAb treatment significantly suppressed tyrosine hydroxylase–positive nerve fibers in the corpus cavernosum and enhanced neuronal nitric oxide synthase–positive fibers in the dorsal nerve. The ratio of smooth muscle to collagen in the corpus cavernosum was significantly improved in TrkA-mAb treatment groups compared to PBS vehicle and IgG control groups. WB confirmed these biological changes. There was a nonsignificant increase in the average number of intromissions and ejaculations in the TrkA-mAb group. The study limitations include small sample size, variability in sexual behavior, lack of data on the neuromuscular mechanism involved, and lack of information of the role of neurotrophins or cytokines in regeneration. Conclusions TrkA-mAb successfully inhibits sympathetic nerve regeneration, leads to parasympathetic nerve regeneration, and has therapeutic effects on ED and sexual behavior disorder in a rat model of CNI. Patient summary This report provides strong evidence that a neurotrophic tyrosine kinase receptor type 1 monoclonal antibody (TrkA-mAb) inhibits sympathetic nerve regeneration, leads to parasympathetic nerve regeneration, and has therapeutic effects on erectile dysfunction and sexual behavior disorder in a rat model of cavernous nerve injury. The results raise the possibility that human patients with neurogenic erectile dysfunction may respond to TrkA-mAb in a manner that parallels the response seen in our rodent study.

Hemophilic pseudotumor involving the spine is extremely uncommon and presents a challenging problem. Preoperative planning, angiography, intra and perioperative monitoring with factor VIII cover and postoperative care for hemophilic pseudotumor is vital. Recognition of the artery of Adamkiewicz in the thoracolumbar junction helps to avoid intraoperative neurological injury. We report the case of a 26-year-old male patient with hemophilia A, who presented with a massive pseudotumor involving the first lumbar vertebra and the left iliopsoas. Preoperative angiography revealed the artery of Adamkiewicz arising from the left first lumbar segmental artery. Excision of pseudotumor was successfully carried out with additional spinal stabilization. At 2 years followup, there was no recurrence and the patient was well stabilized with a satisfactory functional status. Surgical excision gives satisfactory outcome in such cases.

// Justin M. Roberts 1 , Rebeca San Martin 1 , D. Badrajee Piyarathna 1, 2 , James G. MacKrell 3 , Guilherme V. Rocha 3 , Jeffery A. Dodge 3 , Cristian Coarfa 1, 2 , Venkatesh Krishnan 3 , David R. Rowley 1 and Nancy L. Weigel 1, 4 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA 2 Alkek Center for Molecular Discovery, Baylor College of Medicine, Houston, TX, USA 3 Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA 4 Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA Correspondence to: Nancy L. Weigel, email: nweigel@bcm.edu Keywords: vitamin D, prostate cancer, CYP24A1, TMPRSS2:ERG, VCaP Received: November 30, 2016 Accepted: May 04, 2017 Published: May 18, 2017 ABSTRACT Whether vitamin D is chemopreventive and/or has potential therapeutically in prostate cancer is unresolved. One confounding factor is that many prostate cancers express a TMPRSS2:ERG fusion gene whose expression is increased both by androgens and by vitamin D receptor (VDR) activation. Two challenges that limit VDR agonist use clinically are hypercalcemia and the cooperation of VDR with ERG to hyper-induce the 1α,25-dihydroxyvitamin D 3 metabolizing enzyme, CYP24A1, thus reducing VDR activity. Using the VCaP TMPRSS2:ERG positive cell line as a model, we found that a nonsecosteroidal CYP24A1 resistant VDR agonist, VDRM2, substantially reduces growth of xenograft tumors without inducing hypercalcemia. Utilizing next generation RNA sequencing, we found a very high overlap of 1,25D(OH) 2 D 3 and VDRM2 regulated genes and by drawing upon previously published datasets to create an ERG signature, we found activation of VDR does not induce ERG activity above the already high basal levels present in VCaP cells. Moreover, we found VDR activation opposes 8 of the 10 most significant ERG regulated Hallmark gene set collection pathways from Gene Set Enrichment Analysis (GSEA). Thus, a CYP24A1 resistant VDR agonist may be beneficial for treatment of TMPRSS2:ERG positive prostate cancer; one negative consequence of TMPRSS2:ERG expression is inactivation of VDR signaling.

Extension injuries of the cervical spine can result in a wide spectrum of clinical presentations. The very young as well as the elderly population may be uniquely predisposed to this group of injuries. Radiographic signs are often subtle, and therefore, a high index of suspicion followed by careful clinical examination and appropriate radiological evaluation are mandatory to minimize the danger of missing the diagnosis. Accurately identifying specific radiological injury patterns can ensure that appropriate treatment measures are promptly instituted, thereby potentially promoting the chances of recovery.

Sclerostin antibodies increase bone mass by stimulating bone formation. However, human and animal studies show that bone formation increases transiently and returns to pre-treatment level despite ongoing antibody treatment. To understand its mechanism of action, we studied the time course of bone formation, correlating the rate and extent of accrual of bone mass and strength after sclerostin antibody treatment. Ovariectomized (OVX) rats were treated with a sclerostin-antibody (Scle-ab) at 20mg/kg sc once weekly and sacrificed at baseline and 2, 3, 4, 6, and 8weeks post-treatment. In Scle-ab treated rats, serum PINP and OCN rapidly increased at week 1, peaked around week 3, and returned to OVX control levels by week 6. Transcript analyses from the distal femur revealed an early increase in bone formation followed by a sustained decrease in bone resorption genes. Lumbar vertebral (LV) osteoblast surface increased 88% by week 2, and bone formation rate (BFR/BS) increased 138% by week 4. Both parameters were below OVX control by week 8. Bone formation was primarily a result of modeling based formation. Endocortical and periosteal BFR/BS peaked around week 4 at 313% and 585% of OVX control, respectively. BFR/BS then declined but remained higher than OVX control on both surfaces through week 8. Histomorphometric analyses showed LV-BV/TV did not further increase after week 4, while BMD continued to increase at LV, mid femur (MF), and femoral neck (FN) through week 8. Biomechanical tests showed a similar improvement in bone strength through 8weeks in MF and FN, but bone strength plateaued between weeks 6 and 8 for LV. Our data suggest that bone formation with Scle-ab treatment is rapid and modeling formation dominated in OVX rats. Although transient, the bone formation response persists longer in cortical than trabecular bone.

Pedicle screw instrumentation is widely used in the treatment of spinal disorders and deformities. Currently, the surgeon decides the holding power of instrumentation based on the perioperative feeling which is subjective in nature. The objective of the paper is to develop a surrogate model which will predict the pullout strength of pedicle screw based on density, insertion angle, insertion depth and reinsertion.A Taguchi's orthogonal array was used to design an experiment to find the factors effecting pullout strength of pedicle screw. The pullout studies were carried using polyaxial pedicle screw on rigid polyurethane foam block according to American society for testing of materials (ASTM F543). Analysis of variance (ANOVA) and Tukey's honestly significant difference multiple comparison tests were done to find factor effect. Based on the experimental results, surrogate models based on Krigging, polynomial response surface and radial basis function were developed for predicting the pullout strength for different combination of factors. An ensemble of these surrogates based on weighted average surrogate model was also evaluated for prediction.Density, insertion depth, insertion angle and reinsertion have a significant effect (p 0.05) on pullout strength of pedicle screw. Weighted average surrogate performed the best in predicting the pull out strength amongst the surrogate models considered in this study and acted as insurance against bad prediction.A predictive model for pullout strength of pedicle screw was developed using experimental values and surrogate models. This can be used in pre-surgical planning and decision support system for spine surgeon.

The serotonergic neurons of the dorsal raphe (DR) nucleus in the CNS are involved in fear, anxiety and depression. Depression and anxiety occur quite frequently in postmenopausal women, but estrogen replacement to correct these CNS disorders is at present not favored because estrogen carries with it an increased risk for breast cancer. Serotonin synthesis, release and reuptake in the DR are targets of pharmaceuticals in the treatment of depression. In the present study we have examined by immunohistochemistry, the expression of two nuclear receptors, that is, the estrogen receptors ERα and ERβ. We found that ERβ but not ERα is strongly expressed in the DR and there is no sex difference and no change with ageing in the number of tryptophan hydroxylase (TPH)-positive neurons in the DR of wild-type (WT) mice. However, in ovariectomized (OVX) WT and in ERβ(-/-) mice, there was a marked reduction in the number of TPH-positive normal-looking neurons and a marked increase in TPH-positive spindle-shaped cells. These neuronal changes were prevented in mice 1-3 weeks (but not 10 weeks) after OVX by the selective ERβ agonist, LY3201, given as continuous release pellets for 3 days. The ERβ agonist had no effects on glucose homeostasis. Thus, the onset of action of the ERβ agonist is rapid but there is a limited window in time after estrogen loss when the drug is useful. We conclude that, rather than estradiol, ERβ agonists could be useful pharmaceuticals in maintaining functional DR neurons to treat postmenopausal depression.

Background: Incidental durotomy is among the most common complications of spine surgery with reported incidence ranging from 1.7% to 16%. Various management options including primary repair, fascial or fat graft, epidural blood patch, fibrin glue sealant, etc., have been proposed. The purpose of this study is to evaluate the incidence of incidental durotomy and the efficacy of different management options during a five year period at a tertiary care center.Methods: All patients who underwent various surgical procedures in thoracic and lumbar spine from January 2006 - December 2010 in our centre were retrospectively reviewed. Data on demographics, primary diagnosis, associated co morbidities, details of surgical procedure, training level of the operating surgeon, details of the incidental durotomy, the treatment, complications and the postoperative stay were recorded.Results: Of 2270 patients, 1401 patients were included in the study. The incidence of incidental durotomy was 3.49% (49 patients). We found a very high incidence of 33.33% incidental durotomies among patients who underwent revision procedures as compared to 3.23% for patients who underwent primary surgeries. 5.10% of incidental durotomies were caused by fellows under training, 4.27% by junior consultants and 2.92% by senior consultants. Of 49 durotomies, complication were 5 cases of intracranial hypotension, 5 postoperative neurological deficits, 2 deep wound infection, 2 pseudomeningocele and 1 meningitis.Conclusions: The risk of incidental durotomy in thoracolumbar surgeries is high in revision surgeries and when performed by fellows in training. Intraoperative identification and primary repair with suturing or sealant reduces postoperative complications.

Hematogenous septic arthritis of the lumbar facet is a well-recognized although rare1-5 primary infectious entity of the spine. Traditionally, the most commonly implicated organism has been Staphylococcus aureus1,2,6 . Although there have been reports of methicillin-resistant Staphylococcus aureus (MRSA) spondylodiscitis7, methicillin-resistant Staphylococcus aureus as a cause of hematogenous facet joint septic arthritis has not been described, to our knowledge. We report our experience with the treatment of two cases of facet joint septic arthritis due to methicillin-resistant Staphylococcus aureus . The patients were informed that data concerning these cases would be submitted for publication, and they consented. Case 1. A fifty-three-year-old man presented with an eighteen-day history of severe back pain radiating to the left lower limb. He was unable to walk because of the intensity of pain. He had retention of urine, for which he required catheterization. Apart from being a chronic smoker, he had no medical comorbidities. Clinical examination revealed severe tenderness over the left side of the lower back. Neurological examination of the left lower extremity revealed grade-2 (of 5) strength of the extensor hallucis longus and tibialis anterior muscles. Lower extremity sensation and deep tendon reflexes were normal. Rectal examination revealed a lax anal sphincter and an absent bulbocavernosus reflex. Hematological examination showed an erythrocyte sedimentation rate of 77 mm/hr (normal, 6 to 12 mm/hr), a total white blood-cell count of 17.4 × 109/L (normal, 4.3 to 10.8 × 109/L), and a C-reactive protein level of 60 mg/L (normal

Recent clinical data on selective estrogen receptor modulators (SERMs) have provided the basis for reassessment of the SERM concept. The molecular basis of SERM activity involves binding of the ligand SERM to the estrogen receptor (ER), causing conformational changes which facilitate interactions with coactivator or corepressor proteins, and subsequently initiate or suppress transcription of target genes. SERM activity is intrinsic to each ER ligand, which accomplishes its unique profile by specific interactions in the target cell, leading to tissue selective actions. We discuss the estrogenic and anti-estrogenic effects of early SERMs, such as clomiphene citrate, used for treatment of ovulation induction, and the triphenylethylene, tamoxifen, which has ER antagonist activity in the breast, and is used for prevention and treatment of ER-positive breast cancer. Since the development of tamoxifen, other triphenylethylene SERMs have been studied for breast cancer prevention, including droloxifene, idoxifene, toremifene, and ospemifene. Other SERMs have entered clinical development more recently, including benzothiophenes (raloxifene and arzoxifene), benzopyrans (ormeloxifene, levormeloxifene, and EM-800), lasofoxifene, pipendoxifene, bazedoxifene, HMR-3339, and fulvestrant, an anti-estrogen which is approved for breast cancer treatment. SERMs have effects on tissues containing ER, such as the breast, bone, uterine and genitourinary tissues, and brain, and on markers of cardiovascular risk. Current evidence indicates that each SERM has a unique array of clinical activities. Differences in the patterns of action of SERMs suggest that each clinical end point must be evaluated individually, and conclusions about any particular SERM can only be established through appropriate clinical trials. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to summarize the complex function and interactions of selective estrogen receptor modulators (SERMs); recall their suppression or initiation of target genes leading them to their actions; and explain their important roles in breast cancer treatment and possible side effects on bone, the genitourinary system, and on markers of cardiovascular risk.

A highly error resilient mode of the newly standardized 3GPP EVS speech codec is described. Compared to the AMR-WB codec and other conversational codecs, the EVS channel aware mode offers significantly improved error resilience in voice communication over packet-switched networks such as Voice-over-IP (VoIP) and Voice-over-LTE (VoLTE). The error resilience is achieved using a form of in-band forward error correction. Source-controlled coding techniques are used to identify candidate speech frames for bitrate reduction, leaving spare bits for transmission of partial copies of prior frames such that a constant bit rate is maintained. The self-contained partial copies are used to improve the error robustness in case the original primary frame is lost or discarded due to late arrival. Subjective evaluation results from ITU-T P.800 Mean Opinion Score (MOS) tests are provided, showing improved quality under channel impairments as well as negligible impact to clean channel performance.

We present a new hardware adaptive filter architecture for very high throughput LMS adaptive filters using distributed arithmetic (DA). DA uses bit-serial operations and look-up tables (LUTs) to implement high throughput filters that use only about one cycle per bit of resolution regardless of filter length. However, building adaptive DA filters requires recalculating the LUTs for each adaptation which can negate any performance advantages of DA filtering. By using an auxiliary LUT with special addressing, the efficiency and throughput of DA adaptive filters can be of the same order as fixed DA filters. In this paper, we discuss a new hardware adaptive filter structure for very high throughput LMS adaptive filters. We describe the development of DA adaptive filters and show that practical implementations of DA adaptive filters have very high throughput relative to multiply and accumulate architectures. We also show that DA adaptive filters have a potential area and power consumption advantage over digital signal processing microprocessor architectures.

Recently, novel vector quantization techniques in multiple nonorthogonal domains for both waveform and model-based signal characterization that give an improved qualitative and quantitative signal coding performance as compared to vector quantization in single domain have been reported. In these techniques, vectors are formed either directly from the signal waveform or from the model parameters extracted from the signal. Then, the vectors are represented in multiple nonorthogonal domains. The encoder chooses the domain that best represents the vector according to a predetermined criterion. An iterative codebook enhancement algorithm, applicable to both waveform and model-based vector quantization in nonorthogonal domains is developed and presented in this paper. In this algorithm, each set of codebooks in a given domain is retrained by the vectors that were best represented by that particular set of codebooks in the most recent iteration. The algorithm is applied successfully and extensive simulation results yield considerable performance enhancement of the vector quantization in nonorthogonal domains, for a given bit rate. Sample results are provided which demonstrate the improved performance.

Linear prediction (LP) is a powerful technique for efficient source-system model based representation of signals, such as speech, and video, with useful applications including compression, and recognition. This has been found to be particularly true when vector quantization is used to code the linear predictor coefficients. Recently, signal processing in multiple nonorthogonal domains has been reported that further enhances the efficiency of signal representation. In this contribution, a novel LP model based coding technique is presented where the advantages of multiple nonorthogonal domain representations of the LP coefficients and the prediction residuals are exploited in conjunction with vector quantization to yield considerable LP coding enhancement. The proposed signal coding technique is applied to one of the most commonly used signals, namely, speech. The resulting performance improvement is clearly demonstrated in terms of reconstruction quality for the same bit rate compared to the existing single domain vector quantization techniques.

The convergence of Web technology, wireless networks, and portable client devices provides new design opportunities for computer/communications systems. In the HP Labs' Cooltown project we have been exploring these opportunities through an infrastructure to support Web presence for people, places and things. We put Web servers into things like printers and put information into Web servers about things like artwork; we group physically related things into places embodied in Web servers. Using URLs for addressing, physical URL beaconing and sensing of URLs for discovery, and localized Web servers for directories, we can create a location-aware but ubiquitous system to support nomadic users. On top of this infrastructure we can leverage Internet connectivity to support communications services. Web presence bridges the World Wide Web and the physical world we inhabit, providing a model for supporting nomadic users without a central control point.

This chapter presents an overview of recent developments in conversational speech coding technologies, important new algorithmic advances, and recent standardization activities in ITU-T, 3GPP, 3GPP2, MPEG and IETF that offer a significantly improved user experience during voice calls on existing and future communication systems. User experience is determined by speech quality, hence network operators are very concerned about quality of speech coders. Operators are also concerned about capacity, hence coding efficiency is another important measure. Advanced speech coding technologies provide the capability to both improve coding efficiency and user experience. One option to improve quality is to extend the audio bandwidth from traditional narrowband to wideband (16 kHz sampling) and super-wideband (32 kHz sampling). Another method is in increasing the robustness of the coder against transmission errors. Error concealment algorithms are used which substitute the missing parts of the audio signal as far as possible. In packet-switched applications (VoIP systems), special mechanisms are included in jitter buffer management (JBM) algorithms to maximize sound quality. It is of high importance to ensure standardization and deployment of speech coders that meet quality expectations. As an example of this, we refer to the Enhanced Voice Services (EVS) project in 3GPP that is developing the next generation speech coder in 3GPP. The basic motivation for 3GPP to start the EVS project was to extend the path of codec evolution by providing super-wideband experience at around 13 kb/s and better quality for music and mixed content in conversational applications. Optimized behavior in VoIP applications is achieved through the introduction of high error robustness, jitter buffer management, inclusion of source-controlled variable bit rate operation, support of various audio bandwidths, and stereo.