Emulating Membrane Protein Environments─How Much Lipid Is Required for a Native Structure: Influenza S31N M2.

This report investigates the homotetrameric membrane protein structure of the S31N M2 protein from Influenza A virus in the presence of a high molar ratio of lipid. The structured regions of this protein include a single transmembrane helix and an amphipathic helix. Two structures of the S31N M2 conductance domain from Influenza A virus have been deposited in the Protein Data Bank (PDB). These structures present different symmetries about the channel main axis. We present new magic angle spinning and oriented sample solid-state NMR spectroscopic data for S31N M2 in liquid crystalline lipid bilayers using protein tetramer:lipid molar ratios ranging from 1:120 to 1:240. The data is consistent with an essentially 4-fold-symmetric structure very similar to the M2 WT structure that also has a single conformation for the four monomers, except at the His37 and Trp41 functional sites when characterized in samples with a high molar ratio of lipid. While detergent solubilization is well recognized today as a nonideal environment for small membrane proteins, here we discuss the influence of a high lipid to protein ratio for samples of the S31N M2 protein to stabilize an essentially 4-fold-symmetric conformation of the M2 membrane protein. While it is generally accepted that the chemical and physical properties of the native environment of membrane proteins needs to be reproduced judiciously to achieve the native protein structure, here we show that not only the character of the emulated membrane environment is important but also the abundance of the environment is important for achieving the native structure. This is a critical finding as a membrane protein spectroscopist's goal is always to generate a sample with the highest possible protein sensitivity while obtaining spectra of the native-like structure.

Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel.

Rimantadine hydrochloride (α-methyl-1-adamantane-methalamine hydrochloride) is a chiral compound which exerts antiviral activity against the influenza A virus by inhibiting proton conductance of the M2 ion channel. In complex with M2, rimantadine has always been characterized as a racemic mixture. Here, we report the novel enantioselective synthesis of deuterium-labeled (R)- and (S)-rimantadine and the characterization of their protein-ligand interactions using solid-state NMR. Isotropic chemical shift changes strongly support differential binding of the enantiomers to the proton channel. Position restrained simulations satisfying distance restraints from (13)C-(2)H rotational-echo double-resonance NMR show marked differences in the hydrogen-bonding pattern of the two enantiomers at the binding site. Together these results suggest a complex set of interactions between (R)-rimantadine and the M2 proton channel, leading to a higher stability for this enantiomer of the drug in the channel pore.

Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma.

Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA+CD39+ T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA+CD39+ T cells in non-responders and activated cytotoxic CLA+CD39+ T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.

The Scoliosis Research Society adult spinal deformity standard outcome set.

PURPOSE: Symptomatic adult spinal deformity (ASD) with an extremely variable presentation with pain, with and without neurogenic leg pain, and/or disturbed sagittal and coronal balance, causes a significant societal burden of disease. It is an important consequence of the aging adult population, generating a plethora of spine-related interventions with variable treatment efficacy and consistently high costs. Recent years have witnessed more than a threefold increase in the prevalence and treatment of ASD, and further increases over the coming decades are expected with the growing elderly population worldwide. The ability to monitor and assess clinical outcomes has not kept pace with these developments. This paper addresses the pressing need to provide a set of common outcome metrics for this growing group of patients with back pain and other disabilities due to an adult spinal deformity. METHODS: The standard outcome set was created by a panel with global representation, using a thorough modified Delphi procedure. The three-tiered outcome hierarchy (Porter) was used as a framework to capture full cycle of care. The standardized language of the International Classification of Functioning, Disability and Health (WHO-ICF) was used. RESULTS: Consensus was reached on a core set of 25 WHO-ICF outcome domains ('What to measure'); on the accompanying globally available clinician and patient reported measurement instruments and definitions ('How to measure'), and on the timing of the measurements ('When to measure'). The current work has brought to light domains not routinely reported in the spinal literature (such as pulmonary function, return to work, social participation), and domains for which no adequate instruments have yet been identified (such as how to clinically quantify in routine practice lumbar spinal stenosis, neurogenic claudication, radicular pain, and loss of lower extremity motor function). CONCLUSION: A standard outcome set was developed for patients undergoing treatment for adult spinal deformity using globally available outcome metrics. The current framework can be considered a reference for further work, and may provide a starting point for routine methodical and systematic monitoring of outcomes. Post-COVID e-health may accelerate the routine capture of these types of data.

Characterizing the Risk of Long-Term Opioid Utilization in Patients Undergoing Lumbar Spine Surgery.

STUDY DESIGN: Single-institution retrospective cohort study. OBJECTIVE: To determine whether prescribing practices at discharge are associated with opioid dependence (OD) in patients undergoing discectomy or laminectomy procedures for degenerative indications. SUMMARY OF BACKGROUND DATA: Long-term opioid use in spine surgery is associated with higher healthcare utilization and worse postoperative outcomes. The impact of prescribing practices at discharge within this surgical population is poorly understood. METHODS: A query of an administrative database was conducted to identify all patients undergoing discectomy or laminectomy procedures at our high-volume tertiary referral center between 2007 and 2016. For patients included in the analysis, opioid prescription data on admission and discharge were manually abstracted from the electronic health record, including opioid type, frequency, route, and dose, and then converted to daily morphine equivalent dose (MED) values. We defined OD as a consecutive narcotic prescription lasting for at least 90 days within the first 12 months after the index surgical procedure. RESULTS: Of the 819 total patients, 499 (60.9%) patients had an active opioid prescription before surgery. Postoperatively, 813 (99.3%) received at least one narcotic prescription within 30 days of index surgery, and 162 (19.8%) continued with sustained opioid use in the 12 months after surgery. In adjusted analysis, patients with OD had a higher incidence of preoperative depression (P = 0.012) and preoperative opioid use (P < 0.001), as well as a higher frequency of preoperative benzodiazepine prescriptions (P = 0.009), and discharge MED value exceeding 120 mg/day (P = 0.013). Postoperative OD was observed in 7.5% of previously opioid-naïve patients. CONCLUSION: This is the first study to test for an association between MED values prescribed at discharge and sustained opioid use after lumbar spine surgery. In addition to previously reported risk factors, discharge prescription dose exceeding 120 mg/day is independently associated with OD after spine surgery. LEVEL OF EVIDENCE: 3.

Implementation of an Opioid Reduction Protocol for Simple Outpatient Neurosurgical Procedures: A Single-Center Experience.

STUDY DESIGN: Quality improvement with before and after evaluation of the intervention. OBJECTIVE: To evaluate postoperative opioid utilization at a high-volume tertiary referral center following implementation of an opioid reduction protocol for simple outpatient neurosurgical procedures. SUMMARY OF BACKGROUND DATA: The opioid epidemic has been well-publicized both in the scientific and lay press over the last few years. As a response to this crisis many state-wide and national medical groups have sought to develop opioid prescribing guidelines for both acute and chronic pain states. Some guidelines have studied opioid prescribing in orthopedic procedures but have primarily limited their recommendations to simple outpatient orthopedic joint procedures. Although, it is not clear that these opioid prescribing reductions are directly translatable to neurosurgical procedures. METHODS: We implemented an opioid reduction protocol geared towards the postoperative management for simple outpatient neurosurgical procedures and measured the effect on number of pills and total morphine equivalent dose (MED) prescribed, postoperative readmissions, refill requests, and conversion to long-term opiate use. RESULTS: Our study population was 246 patients, with 109 patients in the pre-intervention (PRE) group and 137 patients in the post-intervention (POST) group. The vast majority of patients in both groups were discharged with an opioid prescription (93% PRE, 91% POST, P = 0.87). The POST group had significantly lower total discharge opioid medication quantity (52 tabs PRE, 27 tabs POST, P < 0.001), discharge day MED (51.3 PRE, 45.3 POST, P = 0.01), and total discharge MED (287 PRE, 149 POST, P < 0.001). CONCLUSION: A standardized discharge protocol for postoperative neurosurgery can lead to significant reductions in opioid discharge quantity without compromising patient safety or increasing the utilization of hospital resources through readmissions, refill requests, or clinic phone calls. This study provides an example of a feasible and effective discharge prescription regimen that may be generalizable to some of the most common outpatient neurosurgical procedures. LEVEL OF EVIDENCE: 3.

Is there bias in the treatment of degenerative spine disease? Analysis of anonymous voting via a multidisciplinary conference.

Many institutions have developed shared decision-making conferences as a mechanism for reducing treatment costs and improving patient outcomes. Little is known about the process of shared decision-making that takes place in these conferences, and there is the possibility of bias among surgeons and nonsurgeons for treatment within their respective specialties. This study was conducted to determine who is contributing to the decision-making process in a multidisciplinary spine conference and to what extent treatment biases exist among the surgical and nonsurgical members of this conference. Voting data were collected during weekly multidisciplinary spine conferences. Descriptive statistics were calculated on the cases presented and the number and type of physicians voting for each case. The likelihood of a particular vote in the surgeon and nonsurgeon cohorts was evaluated using relative risk calculation and multinomial logistic regression. A total of 262 consecutive cases were analyzed. No significant differences in treatment recommendation were observed between surgery and nonsurgical management (relative risk, 1.1; 95% CI, 0.97-1.25) when comparing votes from the surgeon and nonsurgeon cohorts. Multinomial logistic regression showed the odds of nonsurgeons recommending nonsurgical management over surgery was 20% greater than receiving that recommendation from their surgeon colleagues. Individual surgeon and nonsurgeon voters were evenly distributed above and below the mean for treatment recommendation. Individual and group biases exist among surgeons and nonsurgeons treating degenerative spine diseases. Multidisciplinary conferences may or may not level these biases, depending on how they are conducted.

Team Approach: Safety and Value in the Practice of Complex Adult Spinal Surgery.

Surgical management of complex adult spinal deformities is of high risk, with a substantial risk of operative mortality. Current evidence shows that potential risk and morbidity resulting from surgery for complex spinal deformity may be minimized through risk-factor optimization. The multidisciplinary team care model includes neurosurgeons, orthopaedic surgeons, physiatrists, anesthesiologists, hospitalists, psychologists, physical therapists, specialized physician assistants, and nurses. The multidisciplinary care model mimics previously described integrated care pathways designed to offer a structured means of providing a comprehensive preoperative medical evaluation and evidence-based multimodal perioperative care. The role of each team member is illustrated in the case of a 66-year-old male patient with previous incomplete spinal cord injury, now presenting with Charcot spinal arthropathy and progressive vertebral-body destruction resulting in lumbar kyphosis.

Postoperative Ileus: Old and New Observations on Prevention and Treatment in Adult Spinal Deformity Surgery.

BACKGROUND: The reported incidence of postoperative ileus (POI) after spine surgery depends on the surgical approach and definition used. It is therefore possible that the overall incidence is substantially higher than previously thought. POI has consequences for both the patient and hospital resources, and can significantly increase health care costs. METHODS: We retrospectively reviewed all patients aged 18 years or older who underwent elective complex spine surgery at our tertiary referral institution from 2011 through 2017. Preoperative comorbidities, operating time and approach, estimated blood loss, postoperative complications, and length of stay (LOS) were analyzed for patients meeting the inclusion criteria. RESULTS: Of 174 patients included in the study, 32 patients (18.4%) developed POI, leading to a significant increase in their median LOS (9 vs. 7 days; P = 0.020). Total estimated blood loss (1649.5 ± 1266.2 vs. 1124.6 ± 936.3 mL; P = 0.009) and total surgical time (501.6 ± 170.5 vs. 388.4 ± 159.8 minutes; P < 0.001) were significantly higher in the POI cohort. The use of nonselective µ-opioid receptor antagonists in 66% of patients with POI did not significantly impact the median LOS (9 vs. 8 days; P = 0.477) compared with patients with POI who did not receive this intervention. The incidence of postoperative adverse events other than ileus was similar between the 2 patient groups. CONCLUSIONS: Despite use of early interventions, the median LOS remains significantly longer in patients who develop POI after complex spine surgery. Knowledge of the associated predictive risk factors could potentially assist with the development of rigorous, evidence-based preventative strategies.

Outcomes Surrounding Perioperative Transfusion Rates and Hemoglobin Nadir Values Following Complex Spine Surgery.

BACKGROUND: Optimal transfusion thresholds have been extensively studied for various surgical procedures; however, no transfusion threshold has been set for patients undergoing complex spine surgery. The aim of this study was to compare postoperative outcomes relative to perioperative hemoglobin (Hb) levels for patients undergoing complex spine surgery for adult spinal deformity and to evaluate impact of blood transfusion timing on clinical outcomes. METHODS: Retrospective chart review of patients with adult spinal deformity undergoing spine surgery lasting >6 hours or involving ≥6 levels of fusion was performed. Patients were divided into 2 cohorts based on whole hospitalization Hb nadir <9.0 g/dL versus ≥9.0 g/dL. RESULTS: Among 104 patients, 55 (52.9%) had Hb nadir <9.0 g/dL. Compared with the cohort with higher Hb nadir, patients with Hb nadir <9.0 g/dL were more likely to be female (84.5% vs. 65.3%, P = 0.016), present with lower preoperative Hb (12.6 [1.5] g/dL vs. 13.8 [1.2] g/dL, P < 0.001), experience greater change in Hb after surgery (4.4 [1.5] g/dL vs. 3.7 [1.5] g/dL, P = 0.030), receive a postoperative blood transfusion (69.1% vs. 44.9%, P = 0.013), and have a longer length of stay (9.1 [4.8] days vs. 6.2 [3.2] days, P < 0.001). CONCLUSIONS: In patients with adult spinal deformity undergoing complex spine surgery, earlier targeted blood transfusions during surgery, rather than in the postoperative period, may lead to improved postoperative outcomes.

Pre-operative smoking history increases risk of infection in deep brain stimulation surgery.

Although general risk of deep brain stimulation (DBS) therapy has been previously described, application of risk prediction at the individual patient level is still largely at the discretion of a treating physician or a multidisciplinary team. To explore associations between potentially modifiable patient characteristics and common adverse events following DBS surgery, we retrospectively reviewed consecutive adult patients who had undergone new DBS electrode placement surgeries at two high-volume tertiary referral centers between October 1997 and May 2018. Among 501 patients included in the analysis (mean age (SD), 64.6 (10.4) years), 165 (32.9%) were female, 67 (13.4%) had diabetes, 231 (46.1%) had hypertension, 25 (5.0%) were smokers, 27 (5.4%) developed an infection, 15 (3.0%) had intracranial or intraventricular hemorrhage, and 53 (10.6%) had an unplanned return to the operating room. Patients who developed a surgical site infection were more likely to report history of smoking before DBS surgery (16% vs 5%, p = 0.04). There was a trend for patients with hypertension to be at risk for intracranial hemorrhage (p = 0.11). In conclusion, this multicenter study demonstrated an association between preoperative smoking and increased risk of infection following new DBS implantation surgery. Counseling about this risk should be considered in preoperative evaluation of patients who are considering undergoing a DBS procedure.

The Role of Potentially Modifiable Factors in a Standard Work Protocol to Decrease Complications in Adult Spinal Deformity Surgery: A Systematic Review, Part 1.

STUDY DESIGN: Structured Literature Review. OBJECTIVES: We sought to evaluate the peer-reviewed literature for potentially modifiable patient and surgical factors that could be incorporated into a Standard Work protocol to decrease complications in adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: Lean Methodology uses Standard Work to improve efficiency and decrease waste and error. ASD is known to have a high surgical complication rate. Several patient and surgical potentially modifiable factors have been suggested to affect complications, including preoperative hemoglobin, bone density, body mass index (BMI), age-appropriate realignment, preoperative albumin/prealbumin, and smoking status. We sought to evaluate the literature for evidence supporting these factors to include in a Standard Work protocol to decrease complications. METHODS: Each of these six factors was developed into an appropriate clinical question that included the patient population, surgical intervention, a comparison group, and outcomes measure (PICO question). A comprehensive literature search was then performed. The authors reviewed abstracts and analyzed data from included studies. From 456 initial citations with abstract, 173 articles underwent full-text review. The best available evidence for clinical questions regarding the influence of these factors was provided by 93 included studies. RESULTS: We found fair evidence supporting a low preoperative hemoglobin level associated with increased transfusion rates and decreased BMD and increased BMI associated with increased complication rates. Fair evidence supported low albumin/prealbumin associated with increased complications. There was fair evidence associating smoking exposure to increased reoperations, but conflicting evidence associating it with increased complications. There was no evidence in the literature evaluating age-appropriate realignment and complications. CONCLUSION: Preoperative hemoglobin, bone density, body mass index, preoperative albumin/prealbumin, and smoking status all are potentially modifiable risk factors that are associated with increased complications in the adult spine surgery population. Developing a Standard Work Protocol for patient evaluation and optimization should include these factors. LEVEL OF EVIDENCE: Level II.

The Role of Potentially Modifiable Factors in a Standard Work Protocol to Decrease Complications in Adult Spinal Deformity Surgery: A Systematic Review, Part 2.

STUDY DESIGN: Structured literature review. OBJECTIVES: To review the current literature for potentially modifiable patient and surgical factors that could be incorporated into a Standard Work protocol to decrease complications in adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: Application of lean methodology to health care involves standardization of work flow. Successful implementation of LEAN management can lead to dramatic reduction in variability and waste. Frailty, hemoglobin A1c (HbA1c) concentration, vitamin D level, mental health status, intraoperative fluid management (IFM), and tranexamic acid (TXA) administration may be modified to reduce complications after ASD surgery. METHODS: Cochrane Central Register of Controlled Trials, MEDLINE/PubMed, Ovid, and Google Scholar databases were used to identify abstracts and citations for this review. Each topic was developed into an appropriate clinical question that included the patient population, surgical intervention, a comparison group, and outcomes measure (PICO question). From 373 initial citations with abstract, 134 articles underwent full-text review. The best available evidence for clinical questions regarding the influence of these factors was provided by 43 included studies. RESULTS: We found fair evidence supporting an association between preoperative mental health disorders, frailty, vitamin D deficiency, and higher HbA1c levels and increased complications. Conversely, we found good evidence supporting an association between the use of intraoperative TXA and an optimized intraoperative fluid management and decreased complications. CONCLUSION: Gaps in the existing literature limit our ability to evaluate if all of the patient and surgical factors selected for this review are associated with increased or decreased complications and reoperations in ASD surgery. However, for both intraoperative TXA usage and optimized intraoperative fluid management that were supported by good evidence, developing Standard Work Protocols may optimize care. LEVEL OF EVIDENCE: Level II.

Patient-Reported Outcome Measures: Utility for Predicting Spinal Surgery in an Integrated Spine Practice.

BACKGROUND: For the majority of patients, spinal surgery is an elective treatment. The decision as to whether and when to pursue surgery is complicated and influenced by myriad factors, including pain intensity and duration, impact on functional activities, referring physician recommendation, and surgeon preference. By understanding the factors that lead a patient to choose surgery, we may better understand the decision-making process, improve outcomes, and provide more effective care. OBJECTIVE: To investigate the relationship between patient-reported outcome measures (PROMs) at initial physiatry clinic consultation and subsequent decision to pursue surgical treatment. We hypothesized that measures of function, pain, and mental health might identify which patients eventually elect to pursue surgical management. DESIGN: Retrospective chart review study. SETTING: Physiatry spine clinic in a tertiary hospital. PATIENTS: A total of 395 consecutive patients meeting our inclusion criteria were assessed for the presence of chronic pain, self-perceived disability, history of prior spinal surgery, and provision of chronic opioid therapy at the time of their initial visit to the integrated spine clinic. METHODS: Retrospective chart review of all patients presenting to our spine clinic between August 1, 2014, and July 31, 2015, was performed. At the initial spine clinic consultation, patients were asked to complete the General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-8 (PHQ-8), Oswestry Disability Index (ODI), and Patient-Reported Outcomes Measurement Information System (PROMIS) 10-item short-form questionnaire. The primary outcome was surgical intervention within 18 months from their first visit to the integrated spine clinic. We surveyed all patient records until February 2017 for CPT codes associated with spinal surgery, excluding from analysis those patients who were lost to follow-up within 1 year of the index visit. Analysis focused on the risk of spinal surgery, with data points treated as both continuous and categorical variables. We used logistic regression models to determine whether PROMs, either alone or in combination, predicted later decision to pursue surgical intervention. MAIN OUTCOME MEASUREMENTS: Decision to pursue spinal surgery. RESULTS: The baseline PROM scores spanning functional, mental health, and pain domains were collected for 94% of the patients presenting to our spine program during the interval of this study. In total, 146 patients were excluded because of missing patient-reported outcome data or less than 1 year of follow-up, leaving 395 patients for analysis. Of these, 40.3% were male with a median age of 58 years, 4.6% presented with a history of prior spinal surgery, and 3.8% were being treated with chronic opioids at their initial consultation. Male gender (P = .01) and older age (P = .05) were associated with subsequent surgery, but no relationship was observed between measured patient-reported outcomes and decision to undergo spinal surgery within 18 months of the index visit. CONCLUSIONS: Contrary to our hypothesis, this analysis demonstrates that the PROMs evaluated in this study, alone are insufficient to identify patients who may elect to pursue spinal surgery. Male gender and increasing age correlate with decision for later spinal surgery. LEVEL OF EVIDENCE: II.

Effect of Tranexamic Acid on Blood Loss, D-Dimer, and Fibrinogen Kinetics in Adult Spinal Deformity Surgery.

BACKGROUND: Antifibrinolytics such as tranexamic acid reduce operative blood loss and blood product transfusion requirements in patients undergoing surgical correction of scoliosis. The factors involved in the unrelenting coagulopathy seen in scoliosis surgery are not well understood. One potential contributor is activation of the fibrinolytic system during a surgical procedure, likely related to clot dissolution and consumption of fibrinogen. The addition of tranexamic acid during a surgical procedure may mitigate the coagulopathy by impeding the derangement in D-dimer and fibrinogen kinetics. METHODS: We retrospectively studied consecutive patients who had undergone surgical correction of adult spinal deformity between January 2010 and July 2016 at our institution. Intraoperative hemostatic data, surgical time, estimated blood loss, and transfusion records were analyzed for patients before and after the addition of tranexamic acid to our protocol. Each patient who received tranexamic acid and met inclusion criteria was cohort-matched with a patient who underwent a surgical procedure without tranexamic acid administration. RESULTS: There were 17 patients in the tranexamic acid cohort, with a mean age of 60.7 years, and 17 patients in the control cohort, with a mean age of 60.9 years. Estimated blood loss (932 ± 539 mL compared with 1,800 ± 1,029 mL; p = 0.005) and packed red blood-cell transfusions (1.5 ± 1.6 units compared with 4.0 ± 2.1 units; p = 0.001) were significantly lower in the tranexamic acid cohort. In all single-stage surgical procedures that met inclusion criteria, the rise of D-dimer was attenuated from 8.3 ± 5.0 µg/mL in the control cohort to 3.3 ± 3.2 µg/mL for the tranexamic acid cohort (p < 0.001). The consumption of fibrinogen was 98.4 ± 42.6 mg/dL in the control cohort but was reduced in the tranexamic acid cohort to 60.6 ± 35.1 mg/dL (p = 0.004). CONCLUSIONS: In patients undergoing spinal surgery, intravenous administration of tranexamic acid is effective at reducing intraoperative blood loss. Monitoring of D-dimer and fibrinogen during spinal surgery suggests that tranexamic acid impedes the fibrinolytic pathway by decreasing consumption of fibrinogen and clot dissolution as evidenced by the reduced formation of D-dimer. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Multidisciplinary Evaluation Leads to the Decreased Utilization of Lumbar Spine Fusion: An Observational Cohort Pilot Study.

STUDY DESIGN: Observational cohort pilot study. OBJECTIVE: To determine the impact of a multidisciplinary conference on treatment decisions for lumbar degenerative spine disease. SUMMARY OF BACKGROUND DATA: Multidisciplinary decision making improves outcomes in many disciplines. The lack of integrated systems for comprehensive care for spinal disorders has contributed to the inappropriate overutilization of spine surgery in the United States. METHODS: We implemented a multidisciplinary conference involving physiatrists, anesthesiologists, pain specialists, neurosurgeons, orthopaedic spine surgeons, physical therapists, and nursing staff. Over 10 months, we presented patients being considered for spinal fusion or who had a complex history of prior spinal surgery. We compared the decision to proceed with surgery and the proposed surgical approach proposed by outside surgeons with the consensus of our multidisciplinary conference. We also assessed comprehensive demographics and comorbidities for the patients and examined outcomes for surgical patients. RESULTS: A total of 137 consecutive patients were reviewed at our multidisciplinary conference during the 10-month period. Of these, 100 patients had been recommended for lumbar spine fusion by an outside surgeon. Consensus opinion of the multidisciplinary conference advocated for nonoperative management in 58 patients (58%) who had been previously recommended for spinal fusion at another institution (χ  = 26.6; P < 0.01). Furthermore, the surgical treatment plan was revised as a product of the conference in 28% (16 patients) of the patients who ultimately underwent surgery (χ  = 43.6; P < 0.01). We had zero 30-day complications in surgical patients. CONCLUSION: Isolated surgical decision making may result in suboptimal treatment recommendations. Multidisciplinary conferences can reduce the utilization of lumbar spinal fusion, possibly resulting in more appropriate use of surgical interventions with better candidate selection while providing patients with more diverse nonoperative treatment options. Although long-term patient outcomes remain to be determined, such multidisciplinary care will likely be essential to improving the quality and value of spine care. LEVEL OF EVIDENCE: 3.

Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A.

A series of 2-adamantanamines with alkyl adducts of various lengths were examined for efficacy against strains of influenza A including those having an S31N mutation in M2 proton channel that confer resistance to amantadine and rimantadine. The addition of as little as one CH2 group to the methyl adduct of the amantadine/rimantadine analogue, 2-methyl-2-aminoadamantane, led to activity in vitro against two M2 S31N viruses A/Calif/07/2009 (H1N1) and A/PR/8/34 (H1N1) but not to a third A/WS/33 (H1N1). Solid state NMR of the transmembrane domain (TMD) with a site mutation corresponding to S31N shows evidence of drug binding. But electrophysiology using the full length S31N M2 protein in HEK cells showed no blockade. A wild type strain, A/Hong Kong/1/68 (H3N2) developed resistance to representative drugs within one passage with mutations in M2 TMD, but A/Calif/07/2009 S31N was slow (>8 passages) to develop resistance in vitro, and the resistant virus had no mutations in M2 TMD. The results indicate that 2-alkyl-2-aminoadamantane derivatives with sufficient adducts can persistently block p2009 influenza A in vitro through an alternative mechanism. The observations of an HA1 mutation, N160D, near the sialic acid binding site in both 6-resistant A/Calif/07/2009(H1N1) and the broadly resistant A/WS/33(H1N1) and of an HA1 mutation, I325S, in the 6-resistant virus at a cell-culture stable site suggest that the drugs tested here may block infection by direct binding near these critical sites for virus entry to the host cell.