Author Correction: Self-verifying variational quantum simulation of lattice models.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Self-verifying variational quantum simulation of lattice models.

Hybrid classical-quantum algorithms aim to variationally solve optimization problems using a feedback loop between a classical computer and a quantum co-processor, while benefiting from quantum resources. Here we present experiments that demonstrate self-verifying, hybrid, variational quantum simulation of lattice models in condensed matter and high-energy physics. In contrast to analogue quantum simulation, this approach forgoes the requirement of realizing the targeted Hamiltonian directly in the laboratory, thus enabling the study of a wide variety of previously intractable target models. We focus on the lattice Schwinger model, a gauge theory of one-dimensional quantum electrodynamics. Our quantum co-processor is a programmable, trapped-ion analogue quantum simulator with up to 20 qubits, capable of generating families of entangled trial states respecting the symmetries of the target Hamiltonian. We determine ground states, energy gaps and additionally, by measuring variances of the Schwinger Hamiltonian, we provide algorithmic errors for the energies, thus taking a step towards verifying quantum simulation.

Increased leaf area index and efficiency drive enhanced production under elevated atmospheric [CO2 ] in a pine-dominated stand showing no progressive nitrogen limitation.

Enhancement of net primary production (NPP) in forests as atmospheric [CO2 ] increases is likely limited by the availability of other growth resources. The Duke Free Air CO2 Enrichment (FACE) experiment was located on a moderate-fertility site in the southeastern US, in a loblolly pine (Pinus taeda L.) plantation with broadleaved species growing mostly in mid-canopy and understory. Duke FACE ran from 1994 to 2010 and combined elevated [CO2 ] (eCO2 ) with nitrogen (N) additions. We assessed the spatial and temporal variation of NPP response using a dataset that includes previously unpublished data from 6 years of the replicated CO2 × N experiment and extends to 2 years beyond the termination of enrichment. Averaged over time (1997-2010), NPP of pine and broadleaved species were 38% and 52% higher under eCO2 compared to ambient conditions. Furthermore, there was no evidence of a decline in enhancement over time in any plot regardless of its native site quality. The relation between spatial variation in the response and native site quality was suggested but inconclusive. Nitrogen amendments under eCO2 , in turn, resulted in an additional 11% increase in pine NPP. For pine, the eCO2 -induced increase in NPP was similar above- and belowground and was driven by both increased leaf area index (L) and production efficiency (PE = NPP/L). For broadleaved species, coarse-root biomass production was more than 200% higher under eCO2 and accounted for the entire production response, driven by increased PE. Notably, the fraction of annual NPP retained in total living biomass was higher under eCO2 , reflecting a slight shift in allocation fraction to woody mass and a lower mortality rate. Our findings also imply that tree growth may not have been only N-limited, but perhaps constrained by the availability of other nutrients. The observed sustained NPP enhancement, even without N-additions, demonstrates no progressive N limitation.

Natural and hybrid immunity after SARS-CoV-2 infection in children and adolescents.

PURPOSE: In contrast to adults, immune protection against SARS-CoV-2 in children and adolescents with natural or hybrid immunity is still poorly understood. The aim of this study was to analyze different immune compartments in different age groups and whether humoral immune reactions correlate with a cellular immune response. METHODS: 72 children and adolescents with a preceding SARS-CoV-2 infection were recruited. 37 were vaccinated with an RNA vaccine (BNT162b2). Humoral immunity was analyzed 3-26 months (median 10 months) after infection by measuring Spike protein (S), nucleocapsid (NCP), and neutralizing antibodies (nAB). Cellular immunity was analyzed using a SARS-CoV-2-specific interferon-γ release assay (IGRA). RESULTS: All children and adolescents had S antibodies; titers were higher in those with hybrid immunity (14,900 BAU/ml vs. 2118 BAU/ml). NCP antibodies were detectable in > 90%. Neutralizing antibodies (nAB) were more frequently detected (90%) with higher titers (1914 RLU) in adolescents with hybrid immunity than in children with natural immunity (62.5%, 476 RLU). Children with natural immunity were less likely to have reactive IGRAs (43.8%) than adolescents with hybrid immunity (85%). The amount of interferon-γ released by T cells was comparable in natural and hybrid immunity. CONCLUSION: Spike antibodies are the most reliable markers to monitor an immune reaction against SARS-CoV-2. High antibody titers of spike antibodies and nAB correlated with cellular immunity, a phenomenon found only in adolescents with hybrid immunity. Hybrid immunity is associated with markedly higher antibody titers and a higher probability of a cellular immune response than a natural immunity.

Targeting GD2 after allogeneic SCT: effector cell composition defines the optimal use of ch14.18 and the bispecific antibody construct NG-CU (GD2-CD3).

We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT). Different antibody concentrations and effector-to-target ratios (E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1). Mean specific lysis of LS cells utilizing PBMCs from healthy donors and ch14.18 (1 µg/ml) was 40/66/75% after 12/24/48 h compared to 66/93/100% in the presence of NG-CU (100 ng/ml). NG-CU showed enhanced cytotoxicity compared to ch14.18, even at lower concentrations and E:T ratios, and completely eradicated LS cells after 72 h. To decipher the influence of effector cell subsets on lysis, different ratios of T and NK cells were tested. At a ratio of 1:1, ch14.18 was more effective than NG-CU. Using patient PBMCs taken at different time points posttransplant, significant lysis with both constructs was detectable depending on percentages and total numbers of T and NK cells; in the early posttransplant phase, NK cells were predominant and ch14.18 was superior, whereas later on, T cells represented the majority of immune cells and NG-CU was more effective. Our study highlights the importance of analyzing effector cell subsets in patients before initiating antibody-based therapy. Consequently, we propose an adjusted administration of both antibody constructs, considering the state of posttransplant immune recovery, to optimize anti-tumor activity.

[The challenges of managing thoracic pain in cystic fibrosis (CF)]. / Herausforderungen der Therapie thorakaler Schmerzen bei zystischer Fibrose (CF).

BACKGROUND: Cystic fibrosis (CF) is a rare genetic multisystemic disorder with progressive abdominal and pulmonary involvement. Pain is still an underestimated symptom in CF patients. METHODS: A comprehensive review of guidelines and scientific literature on the topic was performed and combined with findings from pain management in a young CF patient with progressive thoracic pain. RESULTS: German CF guidelines do not cover diagnosis and management of pain in these patients. Studies from Europe and the United States report interactions between intensity of pain and mortality in CF, but do not include data on the efficacy of pain management. These data and clinical observations of a CF patient with episodes of intense thoracic pain are used to illustrate the specific challenges in pain relief. CONCLUSION: Pain management in CF requires meticulous monitoring as well as an interdisciplinary approach and should be implemented in the German CF guidelines. The authors also want to suggest recommendations for the treatment of thoracic pain in CF. The range and severity of organ involvement complicates the use both of opioids and non-opioids. Especially opioid treatment carries the risk of hypoxia and opioid-induced constipation (OIC) and needs close medical supervision.

Quantitative sensory testing (QST). English version.

Quantitative sensory testing (QST) is a standardized and formalized clinical sensitivity test. Testing describes a subjective (psychophysical) method that entails a cooperation of the person to be examined. Within its framework, calibrated stimuli are applied to capture perception and pain thresholds, thus providing information on the presence of sensory plus or minus signs. The presented QST battery imitates natural thermal or mechanical stimuli. The aim is to acquire symptom patterns of sensory loss (for the functioning of the thick and thin nerve fibers) as well as a gain of function (hyperalgesia, allodynia, hyperpathia) with a simultaneous detection of cutaneous and deep tissue sensibility. Most of the tested QST parameters are normally distributed only after a logarithmic transformation (secondary normal distribution)-except the number of paradoxical heat sensations, of cold and heat pain thresholds, and vibration detection thresholds. A complete QST profile can be measured within 1 h. QST is suitable not only for clinical trials but also in practice as a diagnostic method to characterize the function of the somatosensory system-from the peripheral nerve fiber receptor to the projection pathways to the brain.

Distraction by a cognitive task has a higher impact on electrophysiological measures compared with conditioned pain modulation.

BACKGROUND: Conditioned pain modulation (CPM) evaluates the effect of a painful conditioning stimulus (CS) on a painful test stimulus (TS). Using painful cutaneous electrical stimulation (PCES) as TS and painful cold water as CS, the pain relief was paralleled by a decrease in evoked potentials (PCES-EPs). We now aimed to compare the effect of CPM with cognitive distraction on PCES-induced pain and PCES-EP amplitudes. METHODS: PCES was performed using surface electrodes inducing a painful sensation of 60 (NRS 0-100) on one hand. In a crossover design healthy subjects (included: n = 38, analyzed: n = 23) immersed the contralateral hand into 10 °C cold water (CS) for CPM evaluation and performed the 1-back task for cognitive distraction. Before and during the CS and 1-back task, respectively, subjects rated the pain intensity of PCES and simultaneously cortical evoked potentials were recorded. RESULTS: Both CPM and cognitive distraction significantly reduced PCES-EP amplitudes (CPM: 27.6 ± 12.0 µV to 20.2 ± 9.5 µV, cognitive distraction: 30.3 ± 14.2 µV to 13.6 ± 5.2 µV, p < 0.001) and PCES-induced pain (on a 0-100 numerical rating scale: CPM: 58 ± 4 to 41.1 ± 12.3, cognitive distraction: 58.3 ± 4.4 to 38.0 ± 13.0, p < 0.001), though the changes in pain intensity and PCES-amplitude did not correlate. The changes of the PCES-EP amplitudes during cognitive distraction were more pronounced than during CPM (p = 0.001). CONCLUSIONS: CPM and cognitive distraction reduced the PCES-induced pain to a similar extent. The more pronounced decrease of PCES-EP amplitudes after distraction by a cognitive task implies that both conditions might not represent the general pain modulatory capacity of individuals, but may underlie different neuronal mechanisms with the final common pathway of perceived pain reduction.

[Changes in age distribution and frequency of comorbidities in patients in the occupational insurance association treatment process]. / Veränderung der Altersstruktur und Häufigkeit von Komorbiditäten bei Patienten im bg-lichen Heilverfahren.

BACKGROUND: Due to the demographic development the proportion of older patients has increased. These show at least a higher rate of comorbidities, which affects the length of inpatient hospital stay. Until now no uniform recording exists for such comorbidities within the occupational insurance association system even if the clinical relevance is beyond dispute. Adaptations within the system with increased interdisciplinary treatment are necessary. OBJECTIVE: The aim of this study was to analyze changes in the age distribution and the frequency of comorbidities in patients in the occupational insurance association system. METHODS: The study was a retrospective analysis of age distribution and comorbidities of all operatively treated occupational insurance association patients in 2005 (n = 631), 2010 (n = 1180) and 2015/2016 (n = 2315). A comparison of the age groups ≤29 years, 30-49 years, 50-65 years and ≥66 years was performed. RESULTS: The proportion of patients aged 50-65 years showed a significant increase: 2005 (26.5%), 2010 (30.5%) and 2015/2016 (37.3%) (p < 0.001) and an increased proportion of patients with at least 1 comorbidity: 2005 (38.7%), 2010 (52.5%) and 2015/2016 (52.9%) (p = 0.01). This was statistically significant (p < 0.001, p = 0.005) within the age group 30-49 years (2005: 31.1%, 2015/2016: 49.0%) and the age group 50-65 years (2005: 55.7%, 2015/2016: 67.1%). Significant changes were found for arterial hypertension, morbid obesity, thyroid and respiratory diseases. In addition, there was an increase in multimorbid patients. DISCUSSION: A changing age distribution with a tendency to an increased number of older patients and an increased frequency of comorbidities could be determined. In the present documentation system of the occupational insurance association treatment procedure these comorbidities are insufficiently recorded and considered, even though their clinical relevance is indisputable. Adaptations with respect to intensified interdisciplinary cooperation are necessary.

Metabotypes with elevated protein and lipid catabolism and inflammation precede clinical mastitis in prepartal transition dairy cows.

Clinical mastitis (CM), the most prevalent and costly disease in dairy cows, is diagnosed most commonly shortly after calving. Current indicators do not satisfactorily predict CM. This study aimed to develop a robust and comprehensive mass spectrometry-based metabolomic and lipidomic workflow using untargeted ultra-performance liquid chromatography high-resolution mass spectrometry for predictive biomarker detection. Using a nested case-control design, we measured weekly during the prepartal transition period differences in serum metabolites, lipids, inflammation markers, and minerals between clinically healthy Holstein dairy cows diagnosed with mastitis postcalving (CMP; n = 8; CM diagnosis d 1 = 3 cows, d 2 = 2 cows, d 4 = 1 cow; d 25 = 1 cow, and d 43 = 1 cow that had subclinical mastitis since d 3) or not (control; n = 9). The largest fold differences between CMP and control cows during the prepartal transition period were observed for 3'-sialyllactose in serum. Seven metabolites (N-methylethanolamine phosphate, choline, phosphorylcholine, free carnitine, trimethyl lysine, tyrosine, and proline) and 3 metabolite groups (carnitines, AA metabolites, and water-soluble phospholipid metabolites) could correctly classify cows for their future CM status at both 21 and 14 d before calving. Biochemical analysis using lipid and metabolite-specific commercial diagnostic kits supported our mass spectrometry-based omics results and additionally showed elevated inflammatory markers (serum amyloid A and visfatin) in CMP cows. In conclusion, metabolic phenotypes (i.e., metabotype) with elevated protein and lipid metabolism and inflammation may precede CM in prepartal transition dairy cows. The discovered serum metabolites and lipids may assist in predictive diagnostics, prevention strategies, and early treatment intervention against CM, and thereby improve cow health and welfare.

[Unsuccessful pain treatment over 6 years of a thoracic radiculopathy caused by an unrecognized Tarlov cyst]. / 6 Jahre erfolglose Schmerztherapie bei thorakaler Radikulopathie durch eine unerkannte Tarlov-Zyste.

This article presents a case of unsuccessful pharmaceutical and invasive pain treatment for 6 years without any adequate diagnostics in a female suffering from unilateral thoracic radiculopathy (Th8, right) leading to severe disability and unemployment. The origin was an undetected Tarlov cyst. After resection of the cyst the pain and other complaints disappeared (follow up: 8 months) without need for further pain medication. This case underlines the necessity of adequate diagnostics ahead of long-term pain treatment. Thoracic Tarlov cysts are very uncommon but should be included in the differential diagnosis because curative treatment may be possible.

Direct Observation of Dynamical Quantum Phase Transitions in an Interacting Many-Body System.

The theory of phase transitions represents a central concept for the characterization of equilibrium matter. In this work we study experimentally an extension of this theory to the nonequilibrium dynamical regime termed dynamical quantum phase transitions (DQPTs). We investigate and measure DQPTs in a string of ions simulating interacting transverse-field Ising models. During the nonequilibrium dynamics induced by a quantum quench we show for strings of up to 10 ions the direct detection of DQPTs by revealing nonanalytic behavior in time. Moreover, we provide a link between DQPTs and the dynamics of other quantities such as the magnetization, and we establish a connection between DQPTs and entanglement production.

New Insight into the Chemical Nature of the Plasmonic Nanostructures Synthesized by the Reduction of Au(III) with Sulfide Species.

We have studied the products of the controversial synthesis of HAuCl4 with Na2S, which include gold nanostructures (Au NSs) that absorb in the near-infrared (NIR) region and are highly promising for photothermal therapies and other nanomedical applications. From high-resolution transmission electron microscopy, X-ray absorption spectroscopy, and small-angle X-ray scattering, we have found that only metallic Au NSs are formed as a result of this synthesis, with no detectable amount of gold sulfide or other oxidized gold species that could account for the NIR absorption. Different sulfur species are adsorbed on the Au NSs, mainly sulfides (monomeric sulfur) and polysulfides, similar to what is found on the planar gold surfaces, therefore precluding the idea that thiosulfate or other oxidized species are the actual reducing agents for Au(III) ions. The presence of strongly adsorbed S species, which are difficult to remove from the gold surface, is of great importance for their applications as regards toxicity and use of postfunctionalization strategies to anchor biomolecules and/or to increase circulation time after administration.

[Botulinum toxin A injections in neuropathic pain : A post-hoc subgroup analysis of patients with peripheral nerve injury]. / Botulinumtoxin-A-Injektionen bei neuropathischem Schmerz : Eine Post-hoc-Subgruppenanalyse bei Patienten mit peripherer Nervenverletzung.

The randomized controlled trial (RCT) presented in this article showed significant relief in neuropathic pain following subcutaneous injections of botulinum toxin A over 24 weeks compared to placebo. This result was confirmed in a novel post-hoc analysis of the subgroup of 46 patients with peripheral nerve injury. Relevant adverse effects did not occur during the RCT.

[EMDR as a psychotherapeutic approach in the treatment of chronic pain : Is Eye Movement Desensitization and Reprocessing an effective therapy for patients with chronic pain who do not suffer from posttraumatic stress disorder?] / EMDR als psychotherapeutischer Ansatz in der Schmerztherapie : Ist "eye movement desensitization and reprocessing" eine wirksame Therapie bei Patienten mit chronischen Schmerzen ohne posttraumatische Belastungsstörung?

The efficacy of Eye Movement Desensitization and Reprocessing (EMDR) has been demonstrated for posttraumatic stress disorder. Despite promising research, it is still not clear if EMDR is a similarly effective treatment for chronic pain. Controlled trials are lacking and whether specific mechanisms underlie the effects remains unknown. The treatment of chronic pain aims at a reduction of subjective pain sensations. To achieve this goal without the usage of pain medications, i. e. through psychotherapy, is desirable for many reasons (e. g. reduction of treatment costs and side effects). Whether or not EMDR is an effective intervention for all chronic pain patients (or just a specific subgroup) constitutes an important question for psychological pain research.

[Deaths from propofol abuse : Survey of institutes of forensic medicine in Germany, Austria and Switzerland]. / Todesfälle durch Propofolmissbrauch : Befragung in rechtsmedizinischen Instituten in Deutschland, Österreich und der Schweiz.

Previous references suggesting a high mortality of propofol addiction in medical personnel were mostly based on surveys of the heads of medical departments or case reports; therefore, a questionnaire was sent to 48 forensic medicine departments in Germany, Austria and Switzerland concerning the number of autopsies carried out between 2002-2112 on medical personnel with the suspicion of abuse of propofol or other analgesics. The response rate was 67%. In 16 out of the 32 responding departments 39 deaths (27 males) were observed with previous connections to anesthesiology, intensive care or emergency departments of which 22 were physicians, 13 nurses, 2 other personnel and 2 were unknown. Propofol was the major cause of death in 33 cases (85%), in 8 cases including 7 with propofol, an unintentional accident was recorded and 29 were determined to be suicide. In 14 cases chronic abuse was denied but actually excluded by toxicological analysis in only 2 cases. In 11 cases involving suicide the question of abuse was not investigated. This survey confirmed previous data about the central role of propofol for the fatal outcome of addiction and suicide of anesthetists and other medical personnel. A dual prevention strategy with low-threshold offers for persons at risk and strategies for early detection is urgently needed including a stricter control of dispensing, improvement in forensic medical documentation and the use of toxicological investigations in every case of suspected abuse.

[Role of anesthesiology in pain medicine and palliative care treatment in German hospitals : Survey of department heads of anesthesiology on treatment structures]. / Rolle der Anästhesiologie in der schmerzmedizinischen und palliativmedizinischen Versorgung in deutschen Krankenhäusern : Befragung von Chefärzten der Anästhesiologie zu Versorgungsstrukturen.

BACKGROUND: The aim of this analysis was to describe the role of anesthesiology departments in pain medicine and palliative care services in German hospitals. METHOD: In the year 2012, all heads of departments of anesthesiology registered with the German Society of Anesthesiology and Intensive Care Medicine were surveyed about structures of pain medicine and palliative care services in their hospitals using a standardized postal questionnaire. RESULTS: Out of 408 returned questionnaires (response rate 47%) 403 could be evaluated. Of the hospitals 58% had a designated pain medicine service, in 36 (9%) of the hospitals this was organized as an independent department and in 195 (57%) as part of another department, mostly the department of anesthesiology. The "pain clinic" as an outpatient service was the most common form of structure for pain medicine services (41%). Inpatient pain medicine units were available in 77 (19%) of the hospitals and a partial inpatient unit in the form of a day hospital in 26 (7%) of the hospitals. For the care of inpatients from other departments, there was an intrahospital pain consultation service in 166 of the hospitals, which was the only structure for pain medicine in 32 of the 231 hospitals that reported having a designated pain medicine service. In 160 pain medicine services anesthesiologists were the only medical practitioners and in a further 18 both anesthesiologists and other specialists were available (orthopedist/orthopedic surgeons n = 6, internal medicine n = 4, psychiatrist n = 2, general practitioner = 1 and neurologist n = 1). Only two hospitals had no anesthesiologist in the pain medicine team and for the remaining 51 hospitals no information was provided. In 189 of the 231 hospitals with pain medicine services, there was at least 1 physician with special qualifications in pain management. In 97 (44%) of the hospitals psychologists were part of the team with 53 having at least 1 psychologist with a special qualification in chronic pain management. Of the hospitals, 16% had a specialized department for palliative care, in 32% a specialized palliative care service was part of another department, which was the department of anesthesiology in 30%. Of the hospitals 56% had a palliative care consultation service, 41% had a specialized inpatient palliative care unit, 6% an outpatient clinic, 4% a day hospital and in 16% a specialized outpatient palliative care (SOPC) serving the community was incorporated. Inpatient consultation services and the SOPC were more common when the department of anesthesiology was involved in the palliative care services. CONCLUSION: In German hospitals, the departments of anesthesiology make a significant contribution to the provision of both pain medicine and palliative care services. Nevertheless, the respective structures of care are often incomplete or even lacking. There were shortcomings in terms of organization and qualification of the team in pain medicine services (e.g. no doctor with special qualifications in pain management or no psychologist). Palliative care services are more often organized as independent departments than as pain medicine services. Engagement of the anesthesiology department in palliative care is linked to a broader scope of the services provided, which might reflect the capacity of many anesthesiologists to work in an interdisciplinary manner and across interfaces.

HESI/FDA workshop on immunomodulators and cancer risk assessment: Building blocks for a weight-of-evidence approach.

Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed.

[Survey of pain after ambulatory surgery: An internet-based instrument]. / Erhebung von Schmerzen nach ambulanten Operationen : Ein internetbasiertes Instrument.

BACKGROUND AND AIM: Pain after surgery continues to be undermanaged. Studies and initiatives aiming to improve the management of postoperative pain are growing; however, most studies focus on inpatients and pain on the first day after surgery. The management of postoperative pain after ambulatory surgery and for several days thereafter is not yet a major focus. One reason is the low return rate of the questionnaires in the ambulatory sector. This article reports the development and feasibility of a web-based electronic data collection system to examine pain and pain-related outcome on predefined postoperative days after ambulatory surgery. MATERIAL AND METHODS: In this prospective pilot study 127 patients scheduled for ambulatory surgery were asked to participate in a survey to evaluate aspects related to pain after ambulatory surgery. The data survey was divided in (1) a preoperative, intraoperative and postoperative part and (2) a postoperative internet-based electronic questionnaire which was sent via e-mail link to the patient on days 1, 3 and 7 after surgery. A software was developed using a PHP-based platform to send e-mails and retrieve the data after web-based entries via a local browser. Feasibility, internet-based hitches and compliance were assessed by an additional telephone call after day 7. RESULTS: A total of 100 patients (50 female) between 18 and 71 years (mean 39.1 ± 12.7 years) were included in the pilot study. Return rates of the electronic questionnaires were 86% (days 3 and 7) and 91% (day 1 after surgery). All 3 electronic questionnaires were answered by 82% of patients. Aspects influencing the return rate of questionnaires were work status but not age, gender, education level and preoperative pain. Telephone interviews were performed with 81 patients and revealed high operability of the internet-based survey without any major problems. CONCLUSION: The user-friendly feasibility and operability of this internet-based electronic data survey system explain the high compliance and return rate of electronic questionnaires by patients at home after ambulatory surgery. This survey tool therefore provides unique opportunities to evaluate and improve postoperative pain management after ambulatory surgery.

Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification.

OBJECTIVE/METHOD: Aggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA). RESULTS: Structural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover. CONCLUSION: This data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic.