Johnson & Johnson (Sweden)

BACKGROUND: The efficacy of music for the treatment of pain has not been established. OBJECTIVES: To evaluate the effect of music on acute, chronic or cancer pain intensity, pain relief, and analgesic requirements. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, PsycINFO, LILACS and the references in retrieved manuscripts. There was no language restriction. SELECTION CRITERIA: We included randomized controlled trials that evaluated the effect of music on any type of pain in children or adults. We excluded trials that reported results of concurrent non-pharmacological therapies. DATA COLLECTION AND ANALYSIS: Data was extracted by two independent review authors. We calculated the mean difference in pain intensity levels, percentage of patients with at least 50% pain relief, and opioid requirements. We converted opioid consumption to morphine equivalents. To explore heterogeneity, studies that evaluated adults, children, acute, chronic, malignant, labor, procedural, or experimental pain were evaluated separately, as well as those studies in which patients chose the type of music. MAIN RESULTS: Fifty-one studies involving 1867 subjects exposed to music and 1796 controls met inclusion criteria. In the 31 studies evaluating mean pain intensity there was a considerable variation in the effect of music, indicating statistical heterogeneity ( I(2) = 85.3%). After grouping the studies according to the pain model, this heterogeneity remained, with the exception of the studies that evaluated acute postoperative pain. In this last group, patients exposed to music had pain intensity that was 0.5 units lower on a zero to ten scale than unexposed subjects (95% CI: -0.9 to -0.2). Studies that permitted patients to select the music did not reveal a benefit from music; the decline in pain intensity was 0.2 units, 95% CI (-0.7 to 0.2). Four studies reported the proportion of subjects with at least 50% pain relief; subjects exposed to music had a 70% higher likelihood of having pain relief than unexposed subjects (95% CI: 1.21 to 2.37). NNT = 5 (95% CI: 4 to 13). Three studies evaluated opioid requirements two hours after surgery: subjects exposed to music required 1.0 mg (18.4%) less morphine (95% CI: -2.0 to -0.2) than unexposed subjects. Five studies assessed requirements 24 hours after surgery: the music group required 5.7 mg (15.4%) less morphine than the unexposed group (95% CI: -8.8 to -2.6). Five studies evaluated requirements during painful procedures: the difference in requirements showed a trend towards favoring the music group (-0.7 mg, 95% CI: -1.8 to 0.4). AUTHORS' CONCLUSIONS: Listening to music reduces pain intensity levels and opioid requirements, but the magnitude of these benefits is small and, therefore, its clinical importance unclear.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuantum Chemical Studies of Intermediates and Reaction Pathways in Selected Enzymes and Catalytic Synthetic SystemsLouis Noodleman, Timothy Lovell, Wen-Ge Han, Jian Li, and Fahmi HimoView Author Information Department of Molecular Biology TPC-15, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, Johnson & Johnson Pharmaceutical Research and Development LLC, Welsh and McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477, and Theoretical Chemistry, Department of Biotechnology, Royal Institute of Technology, ALBANOVA, S-106 91 Stockholm, Sweden Cite this: Chem. Rev. 2004, 104, 2, 459–508Publication Date (Web):January 27, 2004Publication History Received11 August 2003Published online27 January 2004Published inissue 1 February 2004https://pubs.acs.org/doi/10.1021/cr020625ahttps://doi.org/10.1021/cr020625aresearch-articleACS PublicationsCopyright © 2004 American Chemical SocietyRequest reuse permissionsArticle Views2766Altmetric-Citations341LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Cluster chemistry,Ligands,Peptides and proteins,Reaction mechanisms,Redox reactions Get e-Alerts

BACKGROUND: TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS: In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. CONCLUSIONS: Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.

Purpose We investigated the correlation between the number of examined lymph nodes (ELNs) and correct staging and long-term survival in non-small-cell lung cancer (NSCLC) by using large databases and determined the minimal threshold for the ELN count. Methods Data from a Chinese multi-institutional registry and the US SEER database on stage I to IIIA resected NSCLC (2001 to 2008) were analyzed for the relationship between the ELN count and stage migration and overall survival (OS) by using multivariable models. The series of the mean positive LNs, odds ratios (ORs), and hazard ratios (HRs) were fitted with a LOWESS smoother, and the structural break points were determined by Chow test. The selected cut point was validated with the SEER 2009 cohort. Results Although the distribution of ELN count differed between the Chinese registry (n = 5,706) and the SEER database (n = 38,806; median, 15 versus seven, respectively), both cohorts exhibited significantly proportional increases from N0 to N1 and N2 disease (SEER OR, 1.038; China OR, 1.012; both P < .001) and serial improvements in OS (N0 disease: SEER HR, 0.986; China HR, 0.981; both P < .001; N1 and N2 disease: SEER HR, 0.989; China HR, 0.984; both P < .001) as the ELN count increased after controlling for confounders. Cut point analysis showed a threshold ELN count of 16 in patients with declared node-negative disease, which were examined in the derivation cohorts (SEER 2001 to 2008 HR, 0.830; China HR, 0.738) and validated in the SEER 2009 cohort (HR, 0.837). Conclusion A greater number of ELNs is associated with more-accurate node staging and better long-term survival of resected NSCLC. We recommend 16 ELNs as the cut point for evaluating the quality of LN examination or prognostic stratification postoperatively for patients with declared node-negative disease.

BACKGROUND: Establishment of a consistent bedtime routine (the activities that occur right before lights out) is often recommended as part of healthy sleep habits. However, no studies have investigated the dose-dependent association of a bedtime routine with sleep outcomes, especially in young children for whom they are particularly recommended. Thus, the aim of this study was to examine the associations of a consistent bedtime routine with sleep outcomes in young children (ages 0 through 5 y) in a large global sample and assess whether there is a dose-dependent relationship between the frequency of a bedtime routine both concurrently and retrospectively with sleep outcomes. PARTICIPANTS: Mothers of 10,085 children (Australia-New Zealand, Canada, China, Hong Kong, India, Japan, Korea, Malaysia, Philippines, Singapore, Thailand, United Kingdom, United States) completed the Brief Infant/Child Sleep Questionnaire. RESULTS: A consistent bedtime routine was associated with better sleep outcomes, including earlier bedtimes, shorter sleep onset latency, reduced night wakings, and increased sleep duration. Decreased parent-perceived sleep problems and daytime behavior problems were also related to institution of a regular bedtime routine. Furthermore, there was a dose-dependent relationship, with better outcomes associated with increased "doses" of having a bedtime routine, both currently and retrospectively, and was found within both predominantly Asian and predominantly Caucasian cultural regions. CONCLUSIONS: These results indicate that having a regular nightly bedtime routine is associated with improved sleep in young children, and suggests that the more consistently a bedtime routine is instituted and the younger started the better.

AIMS: We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. METHODS AND RESULTS: ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. CONCLUSIONS: Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.

Short nucleic acid sequences specific to oncogene targets such as bcl-2, bcr-abl, and c-myc have been shown to exhibit specific anti-cancer activity in vitro through antigene or antisense activity. Efficient in vivo delivery of oligonucleotides remains a major limitation for the therapeutic application of these molecules. We report herein on the preparation of transferrin-modified nanoparticles containing DNAzymes (short catalytic single-stranded DNA molecules) for tumor targeting as well as their biodistribution using various methods of administration in the mouse. Linear, beta-cyclodextrin-based polymers are complexed with DNAyzme molecules to form sub-50 nm particles termed "polyplexes". The surface properties of the cyclodextrin-containing polyplexes are modified by exploiting the ability of the beta-cyclodextrin substructure and adamantane to form inclusion complexes. Accordingly, conjugates of adamantane with poly(ethylene glycol) (PEG) are prepared and combined with the polyplexes. The adamantane form inclusion complexes with the surface cyclodextrins of the polyplexes to provide a sterically stabilizing layer of PEG. The stabilized polyplexes are also modified with transferrin for increasing targeting to tumor cells expressing transferrin receptors. The preparation, characterization, and in vitro application of these nanoparticles are discussed. The transferrin-polyplexes containing fluorescently-labeled DNAzyme molecules are administered to tumor-bearing nude mice and their biodistribution and clearance kinetics are monitored using a fluorescence imaging system. Four methods of administration are studied: intraperitoneal bolus and infusion, intravenous bolus, and subcutaneous injection. DNAzymes packaged in polyplex formulations are concentrated and retained in tumor tissue and other organs, whereas unformulated DNAzyme is eliminated from the body within 24 hours post-injection. Intravenous and intraperitoneal bolus injections result in the highest fluorescent signal (DNAzyme) at the tumor site. Tumor cell uptake is observed with intravenous bolus injection only, and intracellular delivery requires transferrin targeting.

Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D.

OBJECTIVE: To evaluate the efficacy and safety of an extended-release (ER) formulation of paliperidone in patients with an acute episode of schizophrenia, in the dosage range of 3 to 15 mg daily. METHOD: A pooled analysis of 3 similarly designed 6-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled studies in 1326 patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score of 70-120) was performed. Patients were randomly assigned to receive 3, 6, 9, 12, or 15 mg daily of paliperidone ER or placebo. Efficacy and safety assessments were performed. The primary endpoint was change in PANSS total score from baseline to endpoint. RESULTS: PANSS total, PANSS subscale factor, and Personal and Social Performance scale scores significantly improved at endpoint for all doses of paliperidone ER relative to placebo (p <or= .001). A significantly greater proportion of paliperidone ER-treated patients at all doses achieved a clinical response compared with placebo (p <or= .001). Treatment-emergent adverse events (TEAEs) occurred in 66% to 77% of patients in the paliperidone ER groups and 66% of patients in the placebo group; serious TEAEs occurred in 6% of patients who received placebo and 5% to 6% of paliperidone ER-treated patients. Regardless of treatment group, median Simpson-Angus Rating Scale global, Abnormal Involuntary Movement Scale total, and Barnes Akathisia Rating Scale scores were 0 at both baseline and endpoint. There were no clinically relevant differences in measures of body weight gain, glucose handling, lipid metabolism, or proportion of patients with abnormal corrected QT intervals on electrocardiography and no important differences between the proportion of patients who received paliperidone ER or placebo who reported potentially glucose- or prolactin-related events. CONCLUSIONS: Paliperidone ER given once daily for 6 weeks appears to be a safe, well-tolerated, and effective treatment for patients with acute schizophrenia.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there are conflicting views on whether NSAIDs are associated with adverse renal effects. OBJECTIVES: The primary objective of this review was to determine the effects of NSAIDs on postoperative renal function in adults with normal preoperative renal function. SEARCH STRATEGY: Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Handsearching of conference abstracts published in major anaesthetic journals was also performed. (Search date: 7 February 2003) SELECTION CRITERIA: The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of postoperative pain, with relevant postoperative renal outcome measures, in adult surgical patients with normal renal function. DATA COLLECTION AND ANALYSIS: The data was extracted independently by two reviewers. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium, need for dialysis and need for diuretic or dopamine treatment for renal insufficiency. Weighted mean differences for continuous outcomes and relative risk for dichotomous outcomes were estimated. MAIN RESULTS: Nineteen trials ( n = 1204) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 ml/min (95%CI 5 to 28) and potassium output by 38 mmol/day (95%CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 umol/L, 95%CI -5 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenace and ketorolac (or indomethacin). No cases of postoperative renal failure requiring dialysis were described. The trials were homogeneous for the primary outcome. REVIEWERS' CONCLUSIONS: NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.

Hippocampal theta rhythm is thought to underlie learning and memory, and it is well established that "pacemaker" neurons in medial septum (MS) modulate theta activity. Recent studies in the rat demonstrated that brainstem-generated theta rhythm occurs through a multisynaptic pathway via the nucleus incertus (NI), which is the primary source of the neuropeptide relaxin-3 (RLN3). Therefore, this study examined the possible contribution of RLN3 to MS activity, and associated hippocampal theta activity and spatial memory. In anesthetized and conscious rats, we identified the ability of intraseptal RLN3 signaling to modulate neuronal activity in the MS and hippocampus and promote hippocampal theta rhythm. Behavioral studies in a spontaneous alternation task indicated that endogenous RLN3 signaling within MS promoted spatial memory and exploratory activity significantly increased c-Fos immunoreactivity in RLN3-producing NI neurons. Anatomical studies demonstrated axons/terminals from NI/RLN3 neurons make close contact with septal GABAergic (and cholinergic) neurons, including those that project to the hippocampus. In summary, RLN3 neurons of the NI can modulate spatial memory and underlying hippocampal theta activity through axonal projections to pacemaker neurons of the MS. NI/RLN3 neurons are highly responsive to stress and express corticotropin-releasing factor type-1 receptors, suggesting that the effects observed could be an important component of memory processing associated with stress responses.

Data mining disproportionality methods (PRR, ROR, EBGM, IC, etc.) are commonly used to identify drug safety signals in spontaneous report system (SRS) databases. Newer data sources such as longitudinal observational databases (LOD) provide time-stamped patient-level information and overcome some of the SRS limitations such as an absence of the denominator, total number of patients who consume a drug, and limited temporal information. Application of the disproportionality methods to LODs has not been widely explored. The scale of the LOD data provides an interesting computational challenge. Larger health claims databases contain information on more than 50 million patients and each patient has records for up to 10 years. In this article we systematically explore the application of commonly used disproportionality methods to simulated and real LOD data.

Thirteen patients with schizophrenia received injections of 25, 50, or 75 mg of long-acting risperidone every 2 wk. Brain D2 receptor occupancy was assessed with [11C]raclopride 2 wk after the last (fifth) injection (day 71) in seven subjects and 2 wk after the third injection (day 44) in one subject. Stable plasma concentrations were reached after the third injection and steady-state concentrations of the active moiety (risperidone + 9-hydroxyrisperidone) after the fourth injection. Steady-state plasma concentrations were maintained for 4-5 wk after the last injection and then declined rapidly. After injections of 25, 50 and 75 mg on day 44 or day 71, D2 receptor occupancy ranged from 25-48%, 59-83% and 62-72% respectively, while plasma active-moiety levels ranged from 4.4-8.8, 15.0-31.1 and 22.5-26.3 ng/ml respectively. The results indicate that brain D2 receptor occupancy at steady state after injections of long-acting risperidone was in the range found in patients effectively treated with 2-6 mg of oral risperidone.

BACKGROUND: Lidocaine administration produces pain due to its acidic pH. OBJECTIVES: The objective of this review was to determine if adjusting the pH of lidocaine had any effect on pain resulting from non-intravascular injections in adults and children. We tested the hypothesis that adjusting the pH of lidocaine solution to a level closer to the physiologic pH reduces this pain. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); ISI Web of Science (1999 to June 2010); and abstracts of the meetings of the American Society of Anesthesiologists (ASA). We checked the full articles of selected titles. We did not apply any language restrictions. SELECTION CRITERIA: We included double-blinded, randomized controlled trials that compared pH-adjusted lidocaine with unadjusted lidocaine. We evaluated pain at the injection site, satisfaction and adverse events. We excluded studies in healthy volunteers. DATA COLLECTION AND ANALYSIS: We separately analysed parallel-group and crossover trials; trials that evaluated lidocaine with or without epinephrine; and trials with pH-adjusted lidocaine solutions < 7.35 and ≥ 7.35. To explain heterogeneity, we separately analysed studies with a low and higher risk of bias due to the level of allocation concealment; studies that employed a low and a higher volume of injection; and studies that used lidocaine for different types of procedures. MAIN RESULTS: We included 23 studies of which 10 had a parallel design and 13 were crossover studies. Eight of the 23 studies had moderate to high risk of bias due to the level of allocation concealment.Pain associated with the infiltration of buffered lidocaine was less than the pain associated with infiltration of unbuffered lidocaine in both parallel and crossover trials. In the crossover studies, the difference was -1.98 units (95% confidence interval (CI) -2.62 to -1.34) and in the parallel-group studies it was -0.98 units (95% CI -1.49 to -0.47) on a 0 to 10 scale. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine. The risk of bias, volume of injection, and type of procedure failed to explain the heterogeneity of the results.Patients preferred buffered lidocaine (odds ratio 3.01, 95% CI 2.19 to 4.15). No adverse events or toxicity were reported. AUTHORS' CONCLUSIONS: Increasing the pH of lidocaine decreased pain on injection and augmented patient comfort and satisfaction.

Over the last 50 years, entrepreneurship as a scientific field has grown significantly – from a small emerging venture in the 1970s to a global industry today with thousands of people around the world who consider themselves entrepreneurship scholars. In this fast growing field there is always a risk that our history will get lost, with consequences in terms of lack of knowledge accumulation and understanding of the concepts and theories that we use in our research. Research on entrepreneurship has a long history. In this review I will focus on the modern history of entrepreneurship research by describing and synthesizing the evolution of entrepreneurship as a scholarly field after the Second World War. The social and intellectual evolution of the field can be divided into five periods: the forerunners in mainstream disciplines, the formation of the field, the growth of entrepreneurship research, the golden era, and finally, the establishment of a scholarly field in its own right. Thus, to a large extent the evolution of entrepreneurship as a scientific field follows the path of Hambrick and Chen’s model (2008) from marginalization of the topic in the Post Second World War period to differentiation, mobilization, academic legitimacy, and conversion of the field in the 2010s.

Safety related drug failures continue to be a challenge for pharmaceutical companies despite the numerous complex and lengthy in vitro assays and in vivo studies that make up the typical safety screening funnel. A lack of complete translation of animal data to humans can explain some of those shortcomings. Differences in sensitivity and drug disposition between animals and humans may also play a role. Many gaps exist for potential target tissues of drugs that cannot be adequately modeled in vitro. Microphysiological systems (MPS) may help to better model these target tissues and provide an opportunity to better assess some aspects of human safety prior to clinical studies. There is hope that these systems can supplement current preclinical drug safety and disposition evaluations, filling gaps and enhancing our ability to predict and understand human relevant toxicities. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) MPS Affiliate is a group of pharmaceutical industry scientists who seek to expedite appropriate characterization and incorporation of MPS to potentially improve drug safety assessment and provide safer and more effective medicines to patients. In keeping with this mission, the IQ MPS Affiliate scientists have prepared a series of organotypic manuscripts for several key drug safety and disposition target tissues (lung, liver, kidney, skin, gastrointestinal, cardiovascular, and blood brain barrier/central nervous system). The goal of these manuscripts is to provide key information related to likely initial contexts of use (CoU) and key characterization data needed for incorporation of MPS in pharmaceutical safety screening including a list of characteristic functions, cell types, toxicities, and test agents (representing major mechanisms of toxicity) that can be used by MPS developers. Additional manuscripts focusing on testing biologically based therapeutics and ADME considerations have been prepared as part of this effort. These manuscripts focus on general needs for assessing biologics and ADME endpoints and include similar information to the tissue specific manuscripts where appropriate. The current manuscript is an introduction to several general concepts related to pharmaceutical industry needs with regard to MPS application and other MPS concepts that apply across the organ specific manuscripts.

BACKGROUND: Scoliosis surgery is often associated with substantial blood loss and potential detrimental effects in children. Antifibrinolytic agents are often used to reduce perioperative blood loss. Clinical trials have evaluated their effect in children undergoing surgical correction of scoliosis but no systematic review has been published. We performed a systematic review on the efficacy and safety of antifibrinolytic drugs in children undergoing scoliosis surgery. OBJECTIVES: To assess the efficacy and safety of aprotinin, tranexamic acid and aminocaproic acid in reducing blood loss and transfusion requirements in children undergoing scoliosis surgery. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2007, Issue 3), OVID MEDLINE (1950 to September 3rd 2007), LILACS (1992 to June 20th 2007) and EMBASE (1980 to July 23rd 2007). We also searched conference proceedings from 2003 to 2007 and the clinicaltrials.gov registry. No language restriction was applied. SELECTION CRITERIA: We included blinded or unblinded randomized controlled trials that evaluated the effect of antifibrinolytics on perioperative blood loss in children that were 18 years of age or younger and undergoing scoliosis surgery. DATA COLLECTION AND ANALYSIS: Two authors independently performed the data extraction. Primary outcomes were mortality and number of patients transfused. Secondary outcomes were number of patients transfused with allogeneic blood, amount of total blood transfused, total blood loss and adverse events. To assess heterogeneity we used the I(2) test and for the quantitative analysis we used a fixed-effect model. MAIN RESULTS: Six studies fulfilled the inclusion criteria. The total number of participants was 254, of whom 127 were allocated to placebo and 127 to antifibrinolytic drugs. Aprotinin, tranexamic acid and aminocaproic acid were evaluated in two studies each. All studies had placebo as the control group intervention. There were no deaths or any serious adverse events in any study, in either the active or the control group. The risk of being transfused was similar in patients receiving antifibrinolytic drugs or placebo. Antifibrinolytics drugs decreased the amount of blood transfused by 327 ml (95% CI -469.04 to -185.78) and the amount of blood loss by 427 ml (95% CI -602.51 to -250.56). There was no indication of publication bias, however, we cannot rule it out due to the small number of studies included. AUTHORS' CONCLUSIONS: The effect of antifibrinolytic drugs on mortality could not be assessed. Antifibrinolytic drugs reduced blood loss and the amount of blood transfused in children undergoing scoliosis surgery; however, their effect on the number of children requiring blood transfusion remains unclear. Aprotinin, tranexamic acid and aminocaproic acid seem to be similarly effective.

Importance: Early-onset depression has been linked to poor health outcomes. However, it is unclear the extent to which this disorder is associated with specific diseases and premature death and whether these associations remain after controlling for psychiatric comorbidity. Objective: To quantify the association of youth depression with subsequent diagnoses of numerous somatic diseases and mortality. Design, Setting, and Participants: A population-based cohort study was conducted using Swedish national registers containing data on all individuals born in Sweden between 1982 and 1996. A total of 1 487 964 participants were followed up from age 5 years through 2013 if no censoring occurred. Data analysis was performed from January 15, 2019, to August 10, 2020. Exposures: Youth depression was defined as having received at least 1 diagnosis of depression from inpatient or outpatient care between ages 5 and 19 years. Main Outcomes and Measures: This study examined 69 somatic conditions diagnosed after youth depression, as well as all-cause and cause-specific mortalities. Overall and sex-specific hazard ratios (HRs), together with 95% CIs, were estimated using Cox proportional hazards regression with attained age as underlying timescale and time-varying exposure, and adjusted for birth year and sex. All analyses were repeated controlling for psychiatric comorbidities. Absolute risk differences were calculated using standardization with Cox proportional hazards regression. Results: Of 1 487 964 individuals included in the analysis, 51.2% were male. A total of 37 185 patients (2.5%; 67.4% female) had an inpatient or outpatient contact for depression between ages 5 and 19 years (mean [SD] age at first recorded diagnosis of depression, 16.7 [2.1] years for males and 16.7 [1.8] years for females). Age at the end of follow-up ranged between 17 and 31 years. Individuals with youth depression had higher relative risks for 66 of the 69 somatic diagnoses. Strong associations were observed for certain injuries, especially self-harm in females (HR, 14.4; 95% CI, 13.8-15.1), sleep disorders (HR, 8.1; 95% CI, 7.6-8.7), viral hepatitis (HR, 6.1; 95% CI, 5.4-6.8), all-cause mortality (HR, 5.9; 95% CI, 5.3-6.6), and cause-specific mortalities, especially death by intentional self-harm (HR, 14.6; 95% CI, 12.6-16.9). Most associations were attenuated but persisted after adjusting for psychiatric comorbidity. The absolute risk difference of a specific disease within 12 years from the first diagnosis of depression during youth ranged from -0.2% (95% CI, -1.0% to 0.6%) for arthropathies among males to 23.9% (95% CI, 22.7%-25.0%) for the broader category of injuries among females. Conclusions and Relevance: In this Swedish population cohort study, patients with depression diagnosed during their youth appeared to have increased risks for many somatic diseases as well as for mortality, even after controlling for other psychiatric disorders. These findings suggest that several medical conditions should be considered when investigating youth depression.

Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis ( ClinicalTrials.gov Identifier: NCT02243787).

The aim of this study was to assess the relationship between young children's sleep and maternal sleep from both a developmental and a cross-cultural perspective. Mothers of 10,085 young children completed the Brief Infant/Child Sleep Questionnaire and the Pittsburgh Sleep Quality Index. Overall, there were significant relationships between maternal and child sleep for bedtime, waketime, number of night wakings, and total nighttime sleep time across ages and cultures, although these relationships were stronger with younger children than preschool-aged children. Mothers report that their child's sleep pattern significantly impacts their sleep and daytime function, and they do not feel confident in managing their child's sleep pattern. Thus, interventions to improve children's sleep and develop good sleep habits, especially in early childhood, are likely to improve the quality of life of the whole family.