Estimating the prognostic value of cross-sectional network connectivity for treatment response in depression.

BACKGROUND: Tightly connected symptom networks have previously been linked to treatment resistance, but most findings come from small-sample studies comparing single responder v. non-responder networks. We aimed to estimate the association between baseline network connectivity and treatment response in a large sample and benchmark its prognostic value against baseline symptom severity and variance. METHODS: N = 40 518 patients receiving treatment for depression in routine care in England from 2015-2020 were analysed. Cross-sectional networks were constructed using the Patient Health Questionnaire-9 (PHQ-9) for responders and non-responders (N = 20 259 each). To conduct parametric tests investigating the contribution of PHQ-9 sum score mean and variance to connectivity differences, networks were constructed for 160 independent subsamples of responders and non-responders (80 each, n = 250 per sample). RESULTS: The baseline non-responder network was more connected than responders (3.15 v. 2.70, S = 0.44, p < 0.001), but effects were small, requiring n = 750 per group to have 85% power. Parametric analyses revealed baseline network connectivity, PHQ-9 sum score mean, and PHQ-9 sum score variance were correlated (r = 0.20-0.58, all p < 0.001). Both PHQ-9 sum score mean (ß = -1.79, s.e. = 0.07, p < 0.001), and PHQ-9 sum score variance (ß = -1.67, s.e. = 0.09, p < 0.001) had larger effect sizes for predicting response than connectivity (ß = -1.35, s.e. = 0.12, p < 0.001). The association between connectivity and response disappeared when PHQ-9 sum score variance was accounted for (ß = -0.28, s.e. = 0.19, p = 0.14). We replicated these results in patients completing longer treatment (8-12 weeks, N = 22 952) and using anxiety symptom networks (N = 70 620). CONCLUSIONS: The association between baseline network connectivity and treatment response may be largely due to differences in baseline score variance.

Are central eating disorder network symptoms sensitive to item selection and sample? Implications for conceptualization of eating disorder psychopathology from a network perspective.

Item selection is a critical decision in modeling psychological networks. The current preregistered two-study research used random selections of 1,000 symptom networks to examine which eating disorder (ED) and co-occurring symptoms are most central in longitudinal networks among individuals with EDs (N = 71, total observations = 6,060) and tested whether centrality changed based on which items were included in the network. Participants completed 2 weeks of ecological momentary assessment (five surveys/day). In Study 1, we obtained initial strength centrality values by estimating an a priori network using eight items with the highest means. We then estimated 1,000 networks and their centrality from a random selection of unique eight-item symptom combinations. We compared the strength centrality from the a priori network to the distribution of strength centrality estimates from the random-item networks. In Study 2, we repeated this procedure in an independent longitudinal dataset (N = 41, total observations = 4,575) to determine if our results generalized across samples. Shame, guilt, worry, and fear of losing control were consistently central across networks, regardless of items included in the network or sample. Results suggest that these symptoms may be important to the structure of ED psychopathology and have implications for how we understand the structure of ED psychopathology. Existing methods for item inclusion in psychological networks may distort the structure of ED symptom networks by either under- or overestimating strength centrality, or by omitting consistently central symptoms that are nontraditional ED symptoms. Future research should consider including these symptoms in models of ED psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Elevated emotion network connectivity is associated with fluctuations in depression.

Elevated emotion network connectivity is thought to leave people vulnerable to become and stay depressed. The mechanism through which this arises is however unclear. Here, we test the idea that the connectivity of emotion networks is associated with more extreme fluctuations in depression over time, rather than necessarily more severe depression. We gathered data from two independent samples of N = 155 paid students and N = 194 citizen scientists who rated their positive and negative emotions on a smartphone app twice a day and completed a weekly depression questionnaire for 8 wk. We constructed thousands of personalized emotion networks for each participant and tested whether connectivity was associated with severity of depression or its variance over 8 wk. Network connectivity was positively associated with baseline depression severity in citizen scientists, but not paid students. In contrast, 8-wk variance of depression was correlated with network connectivity in both samples. When controlling for depression variance, the association between connectivity and baseline depression severity in citizen scientists was no longer significant. We replicated these findings in an independent community sample (N = 519). We conclude that elevated network connectivity is associated with greater variability in depression symptoms. This variability only translates into increased severity in samples where depression is on average low and positively skewed, causing mean and variance to be more strongly correlated. These findings, although correlational, suggest that while emotional network connectivity could predispose individuals to severe depression, it could also be leveraged to bring about therapeutic improvements.

Machine learning of language use on Twitter reveals weak and non-specific predictions.

Depressed individuals use language differently than healthy controls and it has been proposed that social media posts can be used to identify depression. Much of the evidence behind this claim relies on indirect measures of mental health and few studies have tested if these language features are specific to depression versus other aspects of mental health. We analysed the Tweets of 1006 participants who completed questionnaires assessing symptoms of depression and 8 other mental health conditions. Daily Tweets were subjected to textual analysis and the resulting linguistic features were used to train an Elastic Net model on depression severity, using nested cross-validation. We then tested performance in a held-out test set (30%), comparing predictions of depression versus 8 other aspects of mental health. The depression trained model had modest out-of-sample predictive performance, explaining 2.5% of variance in depression symptoms (R2 = 0.025, r = 0.16). The performance of this model was as-good or superior when used to identify other aspects of mental health: schizotypy, social anxiety, eating disorders, generalised anxiety, above chance for obsessive-compulsive disorder, apathy, but not significant for alcohol abuse or impulsivity. Machine learning analysis of social media data, when trained on well-validated clinical instruments, could not make meaningful individualised predictions regarding users' mental health. Furthermore, language use associated with depression was non-specific, having similar performance in predicting other mental health problems.

Using language in social media posts to study the network dynamics of depression longitudinally.

Network theory of mental illness posits that causal interactions between symptoms give rise to mental health disorders. Increasing evidence suggests that depression network connectivity may be a risk factor for transitioning and sustaining a depressive state. Here we analysed social media (Twitter) data from 946 participants who retrospectively self-reported the dates of any depressive episodes in the past 12 months and current depressive symptom severity. We construct personalised, within-subject, networks based on depression-related linguistic features. We show an association existed between current depression severity and 8 out of 9 text features examined. Individuals with greater depression severity had higher overall network connectivity between depression-relevant linguistic features than those with lesser severity. We observed within-subject changes in overall network connectivity associated with the dates of a self-reported depressive episode. The connectivity within personalized networks of depression-associated linguistic features may change dynamically with changes in current depression symptoms.

Cost-effectiveness of a community-based integrated care model compared with usual care for older adults with complex needs: a stepped-wedge cluster-randomised trial.

Objective: To assess the cost of implementation, delivery and cost-effectiveness (CE) of a flagship community-based integrated care model (OPEN ARCH) against the usual primary care. Design: A 9-month stepped-wedge cluster-randomised trial. Setting and participants: Community-dwelling older adults with chronic conditions and complex care needs were recruited from primary care (14 general practices) in Far North Queensland, Australia. Methods: Costs and outcomes were measured at 3-month windows from the healthcare system and patient's out-of-pocket perspectives for the analysis. Outcomes included functional status (Functional Independence Measure (FIM)) and health-related quality of life (EQ-5D-3L and AQoL-8D). Bayesian CE analysis with 10 000 Monte Carlo simulations was performed using the BCEA package in R (V.3.6.1). Results: The OPEN ARCH model of care had an average cost of $A1354 per participant. The average age of participants was 81, and 55% of the cohort were men. Within-trial multilevel regression models adjusted for time, general practitioner cluster and baseline confounders showed no significant differences in costs, resource use or effect measures regardless of the analytical perspective. Probabilistic sensitivity analysis with 10 000 simulations showed that OPEN ARCH could be recommended over usual care for improving functional independence at a willing to pay above $A600 (US$440) per improvement of one point on the FIM Scale and for avoiding or reducing inpatient stay for any willingness-to-pay threshold up to $A50 000 (US$36 500). Conclusions and implications: OPEN ARCH was associated with a favourable Bayesian CE profile in improving functional status and dependency levels, avoiding or reducing inpatient stay compared with usual primary care in the Australian context. Trial registration number: ACTRN12617000198325.

Impact of COPD and anemia on motor and cognitive performance in the general older population: results from the English longitudinal study of ageing.

BACKGROUND: Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on cognitive and motor performance in the general older population and assess potential interaction. METHODS: The English Longitudinal Study of Aging is a population-based cohort study including measurements of lung-function and HB levels together with cognitive and motor performance testing. Data were collected from 5709 participants including three measurement time over eight years. COPD was defined using lung-function-parameters and clinical symptoms. HB was assessed continuously and low HB was defined using clinical anemia cutoffs. Linear mixed-effects regression models were used to quantify the associations of COPD and HB with outcome measures, both individually and in combination. RESULTS: Participants with both low HB and COPD demonstrated worse motor performance compared to individuals with only one exposure, resulting in up to 1 s (95%CI, 0.04-1.8) longer time needed to complete the five times sit to stand task than what would be expected based on purely additive effects. Additionally in individuals with COPD, the time to complete the motor-performance task per unit decrease in continuous HB levels was longer than in participants without COPD after full adjustment for confounding (up to 1.38 s/unit HB level, 95% CI: 0.65-2.11). CONCLUSION: In persons with COPD low HB levels may contribute to low motor-performance in a supra additive fashion. Further studies should re-evaluate whether earlier treatment of lower HB in these individuals might be beneficial.

Result dissemination from clinical trials conducted at German university medical centers was delayed and incomplete.

OBJECTIVES: Timely and comprehensive reporting of clinical trial results builds the backbone of evidence-based medicine and responsible research. The proportion of timely disseminated trial results can inform alternative national and international benchmarking of university medical centers (UMCs). STUDY DESIGN AND SETTING: For all German UMCs, we tracked all registered trials completed between 2009 and 2013. The results and an interactive website benchmark German UMCs regarding their performance in result dissemination. RESULTS: We identified and tracked 2,132 clinical trials. For 1,509 trials, one of the German UMCs took the academic lead. Of these 1,509 "lead trials," 39% published their results (mostly via journal publications) in a timely manner (<24 months after completion). More than 6 years after study completion, 26% of all eligible lead trials still had not disseminated results. CONCLUSION: Despite substantial attention from many stakeholders to the topic, there is still a strong delay or even absence of result dissemination for many trials. German UMCs have several opportunities to improve this situation. Further research should evaluate whether and how a transparent benchmarking of UMC performance in result dissemination helps to increase value and reduce waste in medical research.

Missed injuries in combat casualties: Lessons from Iraq and Afghanistan.

INTRODUCTION: Once injured in the battlefield in Iraq and Afghanistan, U.S. and NATO troops receive medical treatment through tiered echelons of care with varying resources, from austere to state-of-the-art. Similar to civilian trauma systems, the aim is to provide rapid and safe patient movement toward definitive management. A consequence of the rapid transfer of patients is the possibility of missed or delayed diagnosis of injuries. With the new injury patterns seen during these conflicts, we aimed to identify and characterize which injuries are missed and what consequences do they have on our troops' road to recovery. PATIENTS AND METHODS: A retrospective review of a PI database (established 2007) for consecutively admitted combat casualties was performed between 2007-2013. Baseline patient characteristics, injury year, admitting service, injury type, and subsequent management decisions were categorized and analyzed. RESULTS: There were 301 missed injuries (MI) identified in 248 patients. The annual missed injury rate was 25 per 1000 admissions. Missed injuries were associated with a penetrating mechanism (82.7% vs 58.5%, p < 0.001), ICU admission (58.5% vs 27.4%, p < 0.001), higher ISS (median 14 vs 8, p < 0.001), and a longer length of stay (median 3 versus 2 days, p < 0.001). 194 (64.5%) missed injuries led to a change in management, with 68 (22.6%) requiring a surgical procedure. 1.3% of missed injuries were life threatening, 28.2% major and 65.4% minor. The most common injuries were distal extremity fractures (23.9%), followed by spine fractures (13.3%) and traumatic tympanic membrane rupture (12.6%), There were no deaths attributed to a missed injury. DISCUSSION: Missed injuries during combat operations occur on a low but consistent basis. Most injuries are orthopedic in nature and typically occur in critically ill patients admitted to the ICU. It is rare that a missed injury results in a life-threatening condition. CONCLUSION: As healthcare practitioners prepare for future deployments, this analysis may serve as a resource to focus on frequently missed injuries and possibly improve their detection.

Flight of an aeroplane with solid-state propulsion.

Since the first aeroplane flight more than 100 years ago, aeroplanes have been propelled using moving surfaces such as propellers and turbines. Most have been powered by fossil-fuel combustion. Electroaerodynamics, in which electrical forces accelerate ions in a fluid1,2, has been proposed as an alternative method of propelling aeroplanes-without moving parts, nearly silently and without combustion emissions3-6. However, no aeroplane with such a solid-state propulsion system has yet flown. Here we demonstrate that a solid-state propulsion system can sustain powered flight, by designing and flying an electroaerodynamically propelled heavier-than-air aeroplane. We flew a fixed-wing aeroplane with a five-metre wingspan ten times and showed that it achieved steady-level flight. All batteries and power systems, including a specifically developed ultralight high-voltage (40-kilovolt) power converter, were carried on-board. We show that conventionally accepted limitations in thrust-to-power ratio and thrust density4,6,7, which were previously thought to make electroaerodynamics unfeasible as a method of aeroplane propulsion, are surmountable. We provide a proof of concept for electroaerodynamic aeroplane propulsion, opening up possibilities for aircraft and aerodynamic devices that are quieter, mechanically simpler and do not emit combustion emissions.

Sexually Transmitted Infections: Compelling Case for an Improved Screening Strategy.

Sexually Transmitted Infections: Compelling Case for an Improved Screening Strategy Stephen Hull, MHS, Seán Kelley, MD, MSc, and Janice L. Clarke, RN, BBA Editorial: Sexually Transmitted Infections-A Fixable Problem: David B. Nash, MD, MBA S-3 Introduction S-3 Rising Prevalence of Sexually Transmitted Diseases (STIs) S-4 Current Screening Rates for Chlamydia and Gonorrhea S-4 The Human Toll and Economic Burden of STI-Related Illness S-5 Current Screening Guidelines for Chlamydia and Gonorrhea S-5 Factors Contributing to Inadequate Screening, Diagnosis, and Treatment for STIs S-6 Methods Used to Improve Screening Rates S-7 Benefits of Opt-Out Screening Strategies for STIs S-8 Cost-Effectiveness of Screening for STIs S-8 Discussion S-9 Conclusion S-10.

Sr(2+) induces unusually stable d(GGGTGGGTGGGTGGG) quadruplex dimers.

Guanine-rich sequences are able to form quadruplexes consisting of G-quartet structural units. Quadruplexes play an important role in the regulation of gene expression and have therapeutic and biotechnological potential. The HIV-1 integrase inhibitor, (GGGT)4 , and its variants demonstrate unusually high thermal stability. This property has been exploited in the use of quadruplex formation to drive various endergonic reactions of nucleic acids such as isothermal DNA amplification. Quadruplex stability is mainly determined by cations, which specifically bind into the inner core of the structure. In the present work, we report a systematic study of a variant of the HIV-1 integrase inhibitor, GGGTGGGTGGGTGGG (G3T), in the presence of alkali and alkaline-earth cations. We show that Sr(2+) -G3T is characterized by the highest thermal stability and that quadruplex formation requires only one Sr(2+) ion that binds with low micromolar affinity. These concentrations are sufficient to drive robust isothermal quadruplex priming DNA amplification reaction. The Sr(2+) -quadruplexes are also able to form unusually stable dimers through end-to-end stacking. The multimerization can be induced by a combination of quadruplex forming cations (i.e., K(+) or Sr(2+) ) and non-specific Mg(2+) .

Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study.

BACKGROUND: Dulanermin-a non-polyhistidine-tagged soluble recombinant human apoptosis ligand 2 (Apo2L) or tumour-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-has pro-apoptotic activity in a range of cancers and synergistic preclinical activity with rituximab against lymphoma in vivo. We aimed to assess the safety, pharmacokinetics, and efficacy of dulanermin and rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma. METHODS: We did an open-label phase 1b/2 randomised study. Four study centres in the USA enrolled patients into phase 1b, and 27 study centres in the USA, Italy, Australia, France, Czech Republic, New Zealand, and Poland enrolled patients into phase 2. In phase 1b, patients (age ≥18 years) with indolent B-cell non-Hodgkin lymphoma with stable disease or better lasting at least 6 months after the most recent rituximab-containing regimen were included. In phase 2, patients (age ≥18 years) with follicular lymphoma grades 1-3a were included. In phase 1b, patients received 4 mg/kg or 8 mg/kg intravenous dulanermin on days 1-5 of up to four 21-day cycles and intravenous rituximab 375 mg/m(2) weekly for up to eight doses. In phase 2, patients were randomly assigned (1:1:1) centrally by an interactive voice response system to dulanermin (8 mg/kg for a maximum of four 21-day cycles), rituximab (375 mg/m(2) weekly for up to eight doses), or both in combination, stratified by baseline follicular lymphoma International Prognostic Index (0-3 vs 4-5) and geographic site (USA vs non-USA). The primary endpoints of the phase 1b study were the safety, tolerability, and pharmacokinetics of dulanermin with rituximab. The primary endpoint of phase 2 was the proportion of patients who achieved an objective response. All patients who received any dose of study drug were included in safety analyses. Efficacy analyses were per protocol. Treatment was open label; all patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, NCT00400764. FINDINGS: Between June 6, 2006, and Feb 15, 2007, 12 patients were enrolled in phase 1b, and between April 4, 2007, and April 20, 2009, 60 patients were enrolled in phase 2, of whom 59 were included in safety analyses and 58 in efficacy analyses. No dose-limiting toxic effects were noted in phase 1b. The most common grade 1-2 adverse events in phase 1b were fatigue (nine; 75%), rash (five; 42%), and chills, decreased appetite, diarrhoea, and nausea (four each; 33%). 19 grade 3 or higher adverse effects were noted in five (42%) patients, with 14 occurring in one patient. After treatment with 8 mg/kg of dulanermin, in six patients the mean serum peak concentration was 80 µg/mL, dropping below the minimum detectable concentration (2 ng/mL) within 24 h after the dose. The mean steady state peak and trough concentrations of rituximab were 461 µg/mL (SD 97.5) and 303 µg/mL (92.8), respectively. In phase 2, eight (14%) of 59 patients experienced 12 grade 3 or higher adverse events. In phase 2, objective responses were noted in 14 of 22 (63.6%, 95% CI 41.8-81.3) patients treated with rituximab only, 16 of 25 (64.0%, 43.1-81.5) treated with dulanermin and rituximab, and one of 11 (9.1%, 0.5-39.0) treated with dulanermin only. The study was terminated early, on May 5, 2010, because of an absence of efficacy in the combination group. INTERPRETATION: The addition of dulanermin to rituximab in patients with indolent B-cell non-Hodgkin lymphoma was tolerable but did not lead to increased objective responses. This combination is not being developed further in non-Hodgkin lymphoma. FUNDING: Genentech and Amgen.

Effects of pore size, implantation time, and nano-surface properties on rat skin ingrowth into percutaneous porous titanium implants.

The main problem of percutaneous osseointegrated implants is poor skin-implant integration, which may cause infection. This study investigated the effects of pore size (Small, 40-100 µm and Large, 100-160 µm), nanotubular surface treatment (Nano), and duration of implantation (3 and 6 weeks) on skin ingrowth into porous titanium. Each implant type was percutaneously inserted in the back of 35 rats randomly assigned to seven groups. Implant extrusion rate was measured weekly and skin ingrowth into implants was determined histologically after harvesting implants. It was found that all three types of implants demonstrated skin tissue ingrowth of over 30% (at week 3) and 50% (at weeks 4-6) of total implant porous area under the skin; longer implantation resulted in greater skin ingrowth (p < 0.05). Only one case of infection was observed (infection rate 2.9%). Small and Nano groups showed the same implant extrusion rate which was lower than the Large group rate (0.06 ± 0.01 vs. 0.16 ± 0.02 cm/week; p < 0.05). Ingrowth area was comparable in the Small, Large, and Nano implants. However, qualitatively, the Nano implants showed greatest cellular inhabitation within first 3 weeks. We concluded that percutaneous porous titanium implants allow for skin integration with the potential for a safe seal.

Death receptor 5 agonistic antibody PRO95780: preclinical pharmacokinetics and concentration-effect relationship support clinical dose and regimen selection.

PURPOSE: PRO95780, a human monoclonal antibody (mAb) against death receptor 5 (DR5/TRAIL-R2/TNFRSF10B), was developed for the treatment for cancer. Our objective was to characterize pharmacokinetics (PK) in mice, rats, and cynomolgus monkeys and concentration-effect relationships of PRO95780 in xenograft mouse models of human cancers; this would guide the selection of dose and regimen for clinical trials. METHODS: The PK profiles were determined in mice, rats, and cynomolgus monkeys. Three xenograft models with a wide range of in vitro sensitivities to PRO95780 were selected for efficacy studies. Tumoristatic serum concentrations (TSCs) were determined using PK/pharmacodynamic (PD) modeling with tumor growth as a PD endpoint. A species-invariant time PK scaling method was employed to estimate disposition in humans using PK data in cynomolgus monkeys. Furthermore, the predicted human PK parameters were used to estimate dose and regimen to achieve TSC observed in mice at the steady-state trough concentrations (C trough ss) in the clinic. RESULTS: Linear PK was observed across species. A serum concentration of 22 µg/mL was identified to be the target TSC in mice. A dose of 10 mg/kg administered once every 2 weeks (Q2W) was predicted to achieve a TSC at C trough ss in 95 % of patients. CONCLUSIONS: PRO95780 has linear PK in mice, rats, and monkeys. Estimated TSCs varied among different xenograft models. A projected target dose in humans is achievable for Q2W administration within the dose range used for other commercial mAbs.

Reduced in vitro immune response on titania nanotube arrays compared to titanium surface.

Material surfaces that provide biomimetic cues, such as nanoscale architectures, have been shown to alter cell/biomaterial interactions. Recent studies have identified titania nanotube arrays as strong candidates for use in interfaces on implantable devices due to their ability to elicit improved cellular functionality. However, limited information exists regarding the immune response of nanotube arrays. Thus, in this study, we have investigated the short- and long-term immune cell reaction of titania nanotube arrays. Whole blood lysate (containing leukocytes, thrombocytes and trace amounts of erythrocytes), isolated from human blood, were cultured on titania nanotube arrays and biomedical grade titanium (as a control) for 2 hours and 2 and 7 days. In order to determine the in vitro immune response on titania nanotube arrays, immune cell functionality was evaluated by cellular viability, adhesion, proliferation, morphology, cytokine/chemokine expression, with and without lipopolysaccharide (LPS), and nitric oxide release. The results presented in this study indicate a decrease in short- and long-term monocyte, macrophage and neutrophil functionality on titania nanotube arrays as compared to the control substrate. This work shows a reduced stimulation of the immune response on titania nanotube arrays, identifying this specific nanoarchitecture as a potentially optimal interface for implantable biomedical devices.

HIV-integrase aptamer folds into a parallel quadruplex: a thermodynamic study.

Short guanine-rich sequences have a tendency to form quadruplexes that are stabilized by G-quartets with specific cation coordination. Quadruplexes are part of telomeres at the ends of chromosomes and play an important role in the regulation of gene expression. In addition, there is a strong interest in the therapeutic and biotechnological potential of quadruplex oligonucleotides. The HIV-integrase aptamer, d(GGGT)(4), demonstrated unusually favorable van't Hoff thermodynamics, and based on NMR studies the aptamer was proposed to fold into an antiparallel structure. Here we probed an apparent discrepancy between the NMR structure and the quadruplex topology suggested by circular dichroism (CD). Systematic thermodynamic analyses of d(GGGT)(4) and variants containing sequence modifications or missing specific nucleotides are consistent with a parallel quadruplex fold. CD studies carried out over a wide concentration range did not support a possible structural transition upon increasing strand concentration. Taken together, both optical and thermodynamic studies performed here strongly support a parallel fold for the d(GGGT)(4) aptamer.

Preclinical pharmacokinetics, pharmacodynamics, and activity of a humanized anti-CD40 antibody (SGN-40) in rodents and non-human primates.

1. Cell-surface expression of CD40 in B-cell malignancies and multiple solid tumors has raised interest in its potential use as a target for antibody-based cancer therapy. SGN-40, a humanized monoclonal anti-CD40 antibody, mediates antibody-dependent cytotoxicity and inhibits B-cell tumor growth in vitro, properties of interest for the treatment of cancers, and is currently in Phase I clinical trials for B-cell malignancies. In this study, we determined in vivo activity and pharmacokinetics properties of SGN-40. 2. Effect of SGN-40 in xenograft model of CD40-expressing B-cell lymphoma in severe-combined immune deficiency mice and its in vivo pharmacokinetics properties in normal mice, rats and cynomolgus monkeys were studied. 3. Treatment with SGN-40 significantly increased the survival of mice xenografted with human B-cell lymphoma cell line. SGN-40 exhibited nearly 100% bioavailability in mice and it cleared faster when given at a low dose. In monkeys, clearance of SGN-40 was also much faster at low dose, suggesting nonlinear pharmacokinetics in these species. In rats, however, SGN-40 clearance at all tested doses was similar, suggesting that pharmacokinetics were linear in this dose range in rats. Administration of SGN-40 to monkeys also produced marked, dose-dependent, and persistent depletion of peripheral CD20(+) B lymphocytes. 4. Data presented in this report suggest that SGN-40 is active in in vivo, and based upon interspecies scaling, SGN-40 clearance in humans is predicted to be similar to observed SGN-40 clearance in monkeys. These data suggest that SGN-40 has appropriate pharmacokinetic properties that support its clinical use.

Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma.

The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmaco-kinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eightythree patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%-71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.

A biomechanical study on flexible intramedullary nails used to treat pediatric femoral fractures.

Flexible intramedullary nails have been indicated to treat femoral fractures in pediatric patients. The purpose of this study was to examine the stability of simulated transverse fractures after retrograde intramedullary flexible nail fixation. Various nail diameter combinations were tested using composite femurs in bending, torsion, and a combined axial/bending test where a vertical compressive force was applied to the femoral head. The cross-sectional percent area fill of the nails within the femurs was also determined. In 4 point bending, the greatest repair stiffness was 12% of the intact stiffness. In torsion, the greatest stiffness was 1% of the intact stiffness for either internal or external rotation. The greatest repair stiffness was 80% of the intact stiffness for a compressive load applied to the femoral head. Nail combinations with single nail diameters greater than 40% of the mid-shaft canal width, as measured from an AP radiograph, prevented the fracture from being reduced and left a posterior gap. Flexible intramedullary nails may be of value in the treatment of pediatric femoral fractures, but care must be taken to insert nails that are correctly sized for the canal and to protect the healing fracture from high torsional and bending loads.