Discovery of small molecule guanylyl cyclase A receptor positive allosteric modulators.

The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.

Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators.

NAD+ is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD+ have been linked to numerous diseases including metabolic disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD+ is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD+ salvage pathway. We previously showed that NAMPT activators increase NAD+ levels in vitro and in vivo. Herein we describe the optimization of our NAMPT activator prototype (SBI-0797812) leading to the identification of 1-(4-((4-chlorophenyl)sulfonyl)phenyl)-3-(oxazol-5-ylmethyl)urea (34) that showed far more potent NAMPT activation and improved oral bioavailability.

Discovery of small molecule antagonists of chemokine receptor CXCR6 that arrest tumor growth in SK-HEP-1 mouse xenografts as a model of hepatocellular carcinoma.

The chemokine system plays an important role in mediating a proinflammatory microenvironment for tumor growth in hepatocellular carcinoma (HCC). The CXCR6 receptor and its natural ligand CXCL16 are expressed at high levels in HCC cell lines and tumor tissues and receptor expression correlates with increased neutrophils in these tissues contributing to poor prognosis in patients. Availability of pharmacologcal tools targeting the CXCR6/CXCL16 axis are needed to elucidate the mechanism whereby neutrophils are affected in the tumor environment. We report the discovery of a series of small molecules with an exo-[3.3.1]azabicyclononane core. Our lead compound 81 is a potent (EC50 = 40 nM) and selective orally bioavailable small molecule antagonist of human CXCR6 receptor signaling that significantly decreases tumor growth in a 30-day mouse xenograft model of HCC.

An orally available, brain-penetrant CAMKK2 inhibitor reduces food intake in rodent model.

Hypothalamic CAMKK2 represents a potential mechanism for chemically affecting satiety and promoting weight loss in clinically obese patients. Single-digit nanomolar inhibitors of CAMKK2 were identified in three related ATP-competitive series. Limited optimization of kinase selectivity, solubility, and pharmacokinetic properties were undertaken on all three series, as SAR was often transferrable. Ultimately, a 2,4-diaryl 7-azaindole was optimized to afford a tool molecule that potently inhibits AMPK phosphorylation in a hypothalamus-derived cell line, is orally bioavailable, and crosses the blood-brain barrier. When dosed orally in rodents, compound 4 t limited ghrelin-induced food intake.

Intracranial Pressure Monitoring in Acute Liver Failure: Institutional Case Series.

Acute liver failure (ALF) has been associated with cerebral edema and elevated intracranial pressure (ICP), which may be managed utilizing an ICP monitor. The most feared complication of placement is catastrophic intracranial hemorrhage in the setting of severe coagulopathy. Previous studies reported hemorrhage rates between 3.8-22 % among various devices, with epidural catheters having lower hemorrhage rates and precision relative to subdural bolts and intraparenchymal catheters. We sought to identify institutional hemorrhagic rates of ICP monitoring in ALF and its associated factors in a modern series guided by protocol implantation. Patient records treated for ALF with ICP monitoring at Mayo Clinic in Rochester, MN from 1995 to 2014 were reviewed. Protocalized since 1995, epidural (EP) ICP monitors were first used followed by intraparenchymal (IP) for stage III-IV hepatic encephalopathy. The following variables and outcomes were collected: patient demographics, ICPs and treatment methods, laboratory data, imaging studies, number of days for ICP monitoring, radiographic and symptomatic hemorrhage rates, orthotopic liver transplantation rates, and death. A total of 20 ICP monitors were placed for ALF, 7 EP, and 13 IP. International normalized ratio (INR) at placement of an EP monitor was 2.4 (1.7-3.2) with maximum of 2.7 (2.0-3.6) over the following 2.3 (1-3) days. Mean EP ICP at placement was 36.3 (11-55) and maximum of 43.1 (20-70) mm Hg. INR at placement of an IP monitor was 1.3 (<0.8-3.0) with maximum value of 2.9 (1.6-5.4) over the following 4.2 (2-6) days. Mean IP ICP at placement was 9.9 (2-19) and maximum was 39.8 (11-100) mm Hg. There was one asymptomatic hemorrhage in the EP group (14.3 % hemorrhage rate) and two hemorrhages in the IP group (hemorrhage rate was 15.4 %), both of which were fatal. Overall mortality rate in the EP group was 71.4 % (5/7) with two patients receiving transplantation, and one death in the transplant group. Overall mortality in the IP group was 38.5 % (5/13) with nine liver transplantations; three of the transplanted patients died, including one of the fatal hemorrhages due to monitor placement. Intracranial hypertension is common in patients with ALF with severe hepatic encephalopathy. Monitored patients in both groups experienced elevations of ICP in the setting of intermittent coagulopathy. Severity of coagulopathy did not influence hemorrhage rate. Yet, hemorrhages related to IP monitoring can be catastrophic and may add to the overall mortality.

Cranioplasty in the deployed environment: experience for host-country nationals.

OBJECTIVE: Decompressive craniectomy (DC) is the definitive neurosurgical treatment for managing refractory malignant cerebral edema and intracranial hypertension due to combat-related severe traumatic brain injury (TBI). To date, the long-term outcomes and sequelae of this procedure on host-country national (HCN) populations during Operation Iraqi Freedom (Iraq, 2003-2011), Operation Enduring Freedom (Afghanistan, 2001-2014), and Operation Freedom's Sentinel (Afghanistan, 2015-2021) have not been described, specifically the process and results of delayed custom synthetic cranioplasty. The Joint Trauma System's Clinical Practice Guidelines (JTS-CPG) for severe head injury counsels surgeons to discard the cranial osseous explant when treating coalition service members. Ongoing political and healthcare system instabilities often preclude opportunities for delayed cranioplasty by host-country assets. Various surgical options (such as hinge craniectomy) are inadequate in the setting of complicated cranial comminution from blast or missile injuries, severe cerebral edema, grossly contaminated wounds, complex polytrauma, and tissue devitalization. Delayed cranioplasty with a custom synthetic implant is a viable but logistically challenging alternative. In this retrospective review, the authors present the first patient series describing delayed custom synthetic cranioplasty in an HCN population performed during active military conflict. METHODS: Patients were identified through the Joint Trauma System/Theater Medical Data Store, and subgroup analyses were performed to include mechanisms of injury, surgical complications, and clinical outcomes. RESULTS: Twenty-five patients underwent DC between 2012 and 2020 to treat penetrating, blast, and high-energy closed head injuries per JTS-CPG criteria. The average time from injury to surgery was 1.4 days, although 6 patients received delayed care (3-6 days) due to protracted evacuation from local hospitals. Delayed care correlated with an increased rate of intracranial abscess and empyema. The average time to cranioplasty was 134 days due to a lack of robust mechanisms for patient follow-up, tracking, and access to NATO hospitals. HCN patients who recovered from DC demonstrated overall benefit from custom synthetic cranioplasty, although formal statistical analysis was impeded by a lack of long-term follow-up. CONCLUSIONS: This review demonstrates that cranioplasty with a custom synthetic implant is a safe and feasible treatment for vulnerable HCN patients who survive their index DC surgery. This unique paradigm of care highlights the capabilities of deployed neurosurgical healthcare teams working in partnership with the prosthetics laboratory at Walter Reed National Military Medical Center.

Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor.

The recently discovered apelin/APJ system has emerged as a critical mediator of cardiovascular homeostasis and is associated with the pathogenesis of cardiovascular disease. A role for apelin/APJ in energy metabolism and gastrointestinal function has also recently emerged. We disclose the discovery and characterization of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221), a potent APJ functional antagonist in cell-based assays that is >37-fold selective over the closely related angiotensin II type 1 (AT1) receptor. ML221 was derived from an HTS of the ~330,600 compound MLSMR collection. This antagonist showed no significant binding activity against 29 other GPCRs, except to the κ-opioid and benzodiazepinone receptors (<50/<70%I at 10 µM). The synthetic methodology, development of structure-activity relationship (SAR), and initial in vitro pharmacologic characterization are also presented.

Kickstand Rod With Asymmetric Pedicle Subtraction Osteotomy for Treatment of Adult Kyphoscoliosis With Severe Coronal Imbalance.

BACKGROUND: The kickstand rod has been described for the treatment of severe coronal imbalance. We present a modified description that combines an asymmetric pedicle subtraction osteotomy (PSO) for correction of severe kyphoscoliosis. OBJECTIVE: To describe the use of a temporary kickstand rod. METHODS: Type 1 osteotomies were performed across the main and fractional curves. An asymmetric PSO was performed at the apex of the main curve, and a kickstand rod placed on the concavity anchored from the ilium to a temporary connector above the main curve. Distraction was applied across the kickstand rod because the PSO was closed on the convexity. A permanent rod was placed contralateral to the kickstand, followed by replacement of the kickstand with a permanent rod and bilateral accessory rods. RESULTS: A 66-year-old man presented with kyphoscoliosis causing severe coronal and sagittal imbalance. He underwent L4-S1 anterior lumbar interbody fusion followed by T4-pelvis instrumented fusion the following day. Type 1 osteotomies were performed from T6-T12 to L3-S1 and an asymmetric PSO at L2. A temporary kickstand rod was used to distract across the concavity because the PSO was closed on the convexity. The patient achieved excellent clinical and radiographical results. CONCLUSION: When used in conjunction with appropriate osteotomies, the kickstand rod can aid in correction of severe coronal imbalance. Use of a temporary kickstand rod is technically easier and allows for correction of the main and fractional curves when used with an asymmetric PSO.

Discovery of Anthranilic Acid Derivatives as Difluoromethylornithine Adjunct Agents That Inhibit Far Upstream Element Binding Protein 1 (FUBP1) Function.

Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9. FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1-FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.

Reduced proximal junctional failure with ligament augmentation in adult spinal deformity: a series of 242 cases with a minimum 1-year follow-up.

OBJECTIVE: Proximal junctional kyphosis (PJK) and proximal junctional failure (PJF) are well-recognized complications of long-segment spinal fusion. Previous studies have suggested that ligament augmentation can decrease rates of PJF by reducing junctional stress and strengthening upper instrumented vertebrae (UIVs) and adjacent segments. However, there is a paucity of long-term data on the efficacy of ligament augmentation in preventing PJF. In this study, the authors sought to determine the effect of ligament augmentation on rates of PJF in a cohort of adult spinal deformity patients with at least 1 year of follow-up. METHODS: They conducted a retrospective analysis of ligament augmentation in a consecutive series of surgical patients with adult spinal deformity. Data on patient demographics, surgical characteristics, and surgery for PJF were collected. The minimum follow-up was 12 months. Univariate and multivariate analyses were performed to identify factors associated with reoperation for PJF. RESULTS: The authors identified a total of 242 patients (166 women [68.6%]) with ligament augmentation whose mean age was 66 years. The mean number of fused levels was 10, with a UIV distribution as follows: 90 upper thoracic UIVs (37.2%) and 152 lower thoracic UIVs (62.8%). Compared to a historical cohort of 77 patients treated before implementation of ligament augmentation, reoperation for PJF was significantly lower with ligament augmentation (15.6% vs 3.3%, p < 0.001). In a multivariate model, only ligament augmentation (OR 0.184, 95% CI 0.071-0.478, p = 0.001) and number of fused levels (OR 0.762, 95% CI 0.620-0.937, p = 0.010) were associated with reductions in reoperation for PJF. CONCLUSIONS: Ligament augmentation was associated with significant reductions in the rate of reoperation for PJF at 12 months in a cohort of adult spinal deformity patients. The most dramatic reduction was seen among patients with lower thoracic UIV. These data suggest that in appropriately selected patients, ligament augmentation may be a valuable adjunct for PJF reduction; however, long-term follow-up is needed.

Outcomes in single-level posterior cervical spine surgeries performed in the sitting and prone positions.

OBJECTIVE: The sitting or semisitting position in neurosurgery allows for several technical advantages, including improved visualization of the surgical field. However, it has also been associated with an increased risk of venous air embolisms and positioning-related complications that limit its commonplace adoption. The authors report a large, single-center series of cervical spine procedures performed with patients in the sitting or prone position in order to assess the perceived risk of intraoperative and postoperative complications associated with the sitting position. METHODS: Noninstrumented, single-level posterior cervical spine procedures performed with patients in the sitting/semisitting or prone position from 2000 to 2016 at a single institution were reviewed. Institutional abstraction tools (DataMart and Chart Plus) were used to collect data from the medical records. The two positions were compared with regard to preoperative factors, intraoperative variables, and postoperative outcomes. Multivariable logistic regression models were fitted for 30-day readmission, 30-day return to the operating room, and complication rates. RESULTS: A total of 750 patients (sitting, n = 480; prone, n = 270) were analyzed. The median age was 53 years for those who underwent surgery in the prone position and 50 years for those who underwent surgery in the sitting position (IQRs 45-62 years and 43-60 years, respectively), and 35% of the patients were female. Sitting cases were associated with significantly longer anesthetic times (221 minutes [range 199-252 minutes] vs 205 minutes [range 179-254 minutes]) and operative times (126 minutes [range 101-163 minutes] vs 149 minutes [120-181 minutes]). Cardiorespiratory events in the postanesthesia care unit (PACU) were comparable between the two groups, with the exception of episodes of apnea (2.6% vs 0.6%, p = 0.041) and hypoventilation (4.4% vs 0.8%, p < 0.003), which were more frequent in the prone-position cohort. On multivariable analysis, the effect of the sitting versus the prone position was not significant for 30-day readmission (OR 0.77, 95% CI 0.34-1.71, p = 0.52) or reoperation (OR 0.71, 95% CI 0.31-1.60, p = 0.40). The sitting position was associated with lower odds of developing any complication (OR 0.31, 95% CI 0.16-0.62, p < 0.001). CONCLUSIONS: Based on the intraoperative and postoperative complications chosen in this study, the sitting position confers a similar safety profile to the prone position. This can be explained by a more anatomic positioning accounting for reduced temporary neurological deficits and reduced PACU-associated hypoventilation noted in this series. Nevertheless, the findings may also reflect institutional familiarity, experience, and mastery of this position type, and outcomes may not reflect practices in general.

Allograft versus autograft in cervical and lumbar spinal fusions: an examination of operative time, length of stay, surgical site infection, and blood transfusions.

BACKGROUND: Autograft harvesting for spine arthrodesis has been associated with longer operative times and increased blood loss. Allograft compared to autograft in spinal fusions has not been studied in a multicenter cohort. METHODS: Patients enrolled in the ACS-NSQIP registry between 2012 and 2013 who underwent cervical or lumbar spinal fusion with either allograft or autograft through a separate incision were included for analysis. The primary outcomes of interest were operative time, length of stay, blood transfusion, and surgical site infection (SSI). RESULTS: A total of 6790 and 6718 patients received a cervical or lumbar spinal fusion, respectively. On unadjusted analysis in both cervical and lumbar cohorts, autograft was associated with increased rates of blood transfusion (cervical: 2.9% vs. 1.0%, P<0.001; and lumbar: 21.0% vs. 15.7%, P<0.001) and increased operative time (cervical: 167 vs. 128 minutes, P<0.001; and lumbar: 226 vs. 204 minutes, P<0.001) relative to allograft. On multivariable analysis in both the cervical and lumbar cohorts, autograft was associated with increased odds of blood transfusion (cervical: OR=2.3, 95% CI: 1.0-5.1; and lumbar: OR=1.3, 95% CI: 1.1-1.6) and longer operative times (cervical: 27.8 minutes, 95% CI: 20.7-35.0; and lumbar: 25.4 minutes, 95% CI: 17.7-33.1) relative to allograft. Autograft was not associated with either length of stay or SSI. CONCLUSIONS: In a multicenter cohort of patients undergoing cervical or lumbar spinal fusion, autograft was associated with increased rates of blood transfusion and increased operative time relative to allograft.

Paraneoplastic syndrome or metastatic sinonasal neuroendocrine carcinoma? Clinical conundrum.

We report a case of a middle-aged woman with a diffuse, nonenhancing, progressively atrophic T2-hyperintense lesion involving the left frontotemporal lobes and insula found to be synchronous high-grade sinonasal neuroendocrine carcinoma (SNEC) after initial endonasal resection. In 2014, a 47-year old woman underwent resection of a left-sided high-grade ethmoidal neuroendocrine carcinoma after presentation with weight gain and increased levels of serum and urine cortisol. Concurrent with the initial presentation, she was noted to have a nonenhancing, hyperintense signal change on T2-weighted images on the left frontotemporal lobes and insula thought to be paraneoplastic. Moreover, low titer antibodies to voltage-gated potassium channels were present, raising concern for limbic encephalitis. However, the patient was asymptomatic. A little more than a year after initial presentation, she noted excessive fatigue, daytime somnolence, and cognitive decline. Imaging revealed a gradually progressive, nonenhancing, T2-hyperintense signal abnormality with progressive atrophy in the left anteroinferior frontal lobe, anteromedial temporal lobe, insula bilateral cingulate gyri, and bilateral thalami. Given the progressive nature of the abnormality, stereotactic biopsy was performed, which confirmed the lesion to be metastatic, infiltrative SNEC. In summary, this is a rare case of a synchronous presentation of a high-grade SNEC with an unusual appearance that diffusely infiltrated the brain, likely directly involving the left olfactory nerve and spreading along olfactory projections. This case draws physicians' attention to the possibility that although paraneoplastic syndromes are most likely benign, dissemination of the primary cancer is a diagnostic possibility.

Skull base plasmacytoma: A unique case of POEMS syndrome with a plasmacytoma causing craniocervical instability.

INTRODUCTION: Plasmacytomas, considered to be the solitary counterparts of multiple myeloma, are neoplastic monoclonal plasma cell proliferations within soft tissue or bone. Plasmacytomas often present as a collection of findings known as POEMS-syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-Protein spike, and Skin changes). CASE DESCRIPTION: We present a report of a 47 yo male diagnosed with POEMS-syndrome secondary to a skull base plasmacytoma. The mass resulted in marked instability of the cranio-cervical junction due to bony erosion. Following an induction course of chemotherapy, he showed clinical improvement with a marked reduction in tumor size and underwent an autologous peripheral blood stem cell transplant for systemic treatment of his POEMS-syndrome. Following completion of systemic treatment, he then underwent a definitive occipital-cervical fusion without complications. His neurologic exam upon dismissal was stable with subjective improvement in left upper extremity strength. Postoperative radiographs confirmed spinal alignment and pathological examination of a small biopsy from C1 revealed benign fibrous tissue. CONCLUSION: To the best of our knowledge, this is the first report of a skull-base plasmacytoma associated with POEMS-syndrome, causing cranio-cervical instability. The approach of systemic therapy combined with temporary external fixation, followed by definitive occipital cervical fusion resulted in a good outcome for this patient.

Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization.

Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.

Osteosclerosis Secondary to Metastatic Oligodendroglioma.

This paper reviews a case of metastatic 1p/19q codeleted oligodendrioglioma causing diffuse osteosclerosis and pain. Primary central nervous system (CNS) tumors rarely metastasize outside the CNS, and metastatic oligodendroglioma is rarer still. The patient in this study had relief of pain after being treated with temozolomide. We discuss this rare presentation and potential treatment options, and review the literature in regards to metastatic oligodendrogliomas.

Chronic low-back pain in adult with diabetes: NHANES 2009-2010.

The aim of this study was to test the hypothesis that diabetes mellitus (DM) is associated with an increased prevalence of chronic low back pain (CLBP) in the general population. We analyzed data for 5106 adults (4591 without DM & 515 with diagnosed DM), who were part of the National Health and Nutrition Examination Survey (NHANES) from 2009 through 2010. Adults with DM were older (mean age 54.2years' vs. 42.1years), more likely to be obese (BMI>30, 69.5% vs. 33.3%), less educated (college or above 44.4% vs. 57.3%), had a lower annual income (<$20,000, 16.8% vs. 13.4%), were more likely to be a former smoker (31.5% vs. 20.9%), less physically active (43.5% vs. 59.4%). The prevalence of CLBP was 19.8% in adults with DM vs. 12.9% in adults without DM (age-adjusted OR 1.46; 95% CI, 1.00-1.94, P=.050). After the adjustments for CLBP's known risk factors, the association remained significant (OR 1.39; 95% CI, 1.02-1.92, P=.041). Adults with DM have a higher prevalence of CLBP. Further research is needed to examine the association and pathophysiology of DM and CLBP as well as the role of shared risk factors. SUMMARY: Adults with diabetes have higher prevalence of chronic low back pain (CLBP), and higher odds of CLBP after adjusting for LBP risk factors.

The effect of diabetes mellitus on 30-day outcomes following single-level open lumbar microdiscectomy: an aged-matched case-control study.

BACKGROUND: Diabetes mellitus (DM) is a known risk factor for post-surgical complications. However, few reports specifically study lumbar spine surgical outcomes in diabetics. The purpose of this study was to assess 30-day outcomes in patients with DM undergoing single-level open lumbar microdiscectomy (oLMD). METHODS: A retrospective case control study on patients with DM undergoing between 2001 and 2012. Patients who underwent a minimally invasive approach, repeat discectomy, or multilevel surgery were excluded. One hundred and twenty-six patients were age-matched with 126 non-diabetic controls. Outcomes assessed included length of stay (LOS), postoperative urinary retention (UR), total morbidity, infection, postoperative radiculitis, 30-day re-admissions and emergency department visits, and pain status at discharge and at 30 days. Categorical variables were evaluated with Pearson's χ2 tests. Student's t-tests were used to evaluate continuous variables. Univariate logistic regression was used to evaluate strength of association of DM with outcome variables. RESULTS: Mean LOS was significantly higher in diabetic patients (1.9 vs. 1.4 days, P<0.0001). DM was associated with increased morbidity (P=0.009, OR=3.3, CI: 1.3-9.5) and UR (P<0.0001, OR=8.2, CI: 3.4-24.8). No differences were found in 30-day readmission rates or emergency department visits, pain status at discharge and at 30 days, or postoperative radiculitis. CONCLUSIONS: Overall, short-term outcomes are worse in patients with DM. Following single-level oLMD, DM is associated with longer hospital stays, UR, and increased morbidity. These short term outcomes consequently lead to an overall increase in hospital costs.

Full-endoscopic versus micro-endoscopic and open discectomy: A systematic review and meta-analysis of outcomes and complications.

OBJECTIVES: The purpose of this study was to systematically compare the effectiveness and safety of full-endoscopic discectomy (FED) and micro-endoscopic discectomy (MED) with open discectomy (OD) for the treatment of symptomatic lumbar disc herniation. METHODS: Electronic searches were performed using six databases from their inception to February 2016, identifying all relevant randomized controlled trials and comparative observational studies comparing either FED or MED with OD. Data were extracted and analyzed according to predefined clinical endpoints. RESULTS: Twenty three studies were selected for analysis, including 421 FED, 6914 MED, and 21,152 OD cases. No significant difference was found between FED and OD in regards to postoperative visual analog scale (VAS) leg pain scores (WMD 0.03, P=0.93). Similar results were obtained for MED vs OD (WMD 0.09, P=0.18). In terms of postoperative Oswestry disability index (ODI), both FED and MED were similar to OD (WMD -2.60, P=0.32 and WMD -1.00, P=0.21, respectively). FED had a significantly shorter operative duration compared to OD (54.6 vs 102.6min, P=0.0001). MED alone and endoscopic approaches overall (including MED and FED) demonstrated significantly lower estimated blood loss (44.3 vs 194.4mL, P=0.03 and 38.2 vs 203.5mL, respectively, both p<0.05). FED alone demonstrated a trend towards lower estimated blood loss in comparison to OD (3.3 vs 244.9mL, P=0.07). No difference was found in overall complications, recurrence or reoperation rates, dural tears, root injury, wound infections, and spondylodiscitis between FED vs OD, or MED vs OD. CONCLUSIONS: Based on this meta-analysis, FED and MED appear to be safe and efficacious alternatives to traditional approaches, but these results require further investigation and validation by prospective randomized studies.

Quantitative analysis of the effect of institutional case volume on complications after surgical clipping of unruptured aneurysms.

OBJECTIVE The mechanism by which greater institutional case volume translates into improved outcomes after surgical clipping of unruptured intracranial aneurysms (UIAs) is not well established. The authors thus aimed to assess the effect of case volume on the rate of various types of complications after clipping of UIAs. METHODS Using information on the outcomes of inpatient admissions for surgical clipping of UIAs collected within a national database, the relationship of institutional case volume to the incidence of different types of complications after clipping was investigated. Complications were subdivided into different categories, which included all complications, ischemic stroke, intracerebral hemorrhage, medical complications, infectious complications, complications related to anesthesia, and wound complications. The relationship of case volume to different types of complications was assessed using linear regression analysis. The relationships between case volume and overall complication and stroke rates were fit with both linear and quadratic equations. The numerical cutoff for institutional case volume above and below which the authors found the greatest differences in mean overall complication and stroke rate was determined using classification and regression tree (CART) analysis. RESULTS Between October 2012 and September 2015, 125 health care institutions reported patient outcomes from a total of 6040 cases of clipping of UIAs. On linear regression analysis, increasing case volume was negatively correlated to both overall complications (r2 = 0.046, p = 0.0234) and stroke (r2 = 0.029, p = 0.0557) rate, although the relationship of case volume to the complication (r2 = 0.092) and stroke (r2 = 0.067) rate was better fit with a quadratic equation. On CART analysis, the cutoff for the case number that yielded the greatest difference in overall complications and stroke rate between higher- or lower-volume centers was 6 cases/year and 3 cases/year, respectively. CONCLUSIONS Although the authors confirm that increasing case volume is associated with reduced complications after clipping of UIAs, their results suggest that the relationship between case volume and complications is not necessarily linear. Moreover, these results indicate that the effect of case volume on outcome is most evident between very-low-volume centers relative to centers with a medium-to-high volume.