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Background: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings., Methods: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task)., Results: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula., Conclusions: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements., Trial Registration Number: NCT03679468., Competing Interests: Competing interests: MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche, and speaker honoraria from AstraZeneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva, she receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research and Fondazione Italiana Sclerosi Multipla, she is Associate Editor for Multiple Sclerosis and Related Disorders. PV received speaker honoraria from Biogen Idec. FR has nothing to disclose. NT has nothing to disclose. MPA received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Roche, Pharmaceutical Industries and Fondazione Italiana Sclerosi Multipla. GB has been awarded and receives research support from Roche, Fondazione Italiana Sclerosi Multipla, ARSEP, H2020 EU Call. VDB has nothing to disclose. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust, he is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK, he has been a local principal investigator for a trial in MS funded by the Canadian MS society, a local principal investigator for commercial trials funded by: Ionis, Novartis and Roche, and has taken part in advisory boards/consultancy for Azadyne, Biogen, Lucid, Janssen, Merck, NervGen, Novartis and Roche. NC is on an Advisory Board for Akili Interactive and is a member of the Editorial Boards of Multiple Sclerosis Journal and Frontiers in NeuroTrauma. GC is a member of Data and Safety Monitoring Boards for AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Mapi Pharmaceuticals LTD, Merck, Merck/Pfizer, Opko Biologics, OncoImmune, Neurim, Novartis, Ophazyme, Sanofi Aventis, Reata Pharmaceuticals, Teva pharmaceuticals, VielaBio Inc, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee), he is on Consulting or Advisory Boards for Biodelivery Sciences International, Biogen, Click Therapeutics, Genzyme, Genentech, GW Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Medday, Neurogenesis LTD, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, TG Therapeutics, he is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc, a private consulting company located in Birmingham AL. UD has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck-Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on scientific advisory boards of Biogen Idec and Genzyme. JD is an Associate Editor of the Archives of Physical Medicine and Rehabilitation, and Neuropsychology Review, received compensation for consulting services and/or speaking activities from Biogen Idec, Celgene, MedRhythms and Novartis, and receives research support from Biogen Idec, National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers and National Institutes of Health. RAF has received honoraria and served on advisory panels for Merck, TEVA, Novartis, Genzyme, GW pharma (Jazz pharmaceuticals), Allergan, Merz, Ipsen and Biogen, she is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. PF is editorial board member of NNR, MSJ and Frontiers in Rehabilitation Sciences (section ‘Strengthening Health Systems’), provides consultancy to NeuroCompass and was board of advisory board meetings for BIOGEN. JF has been awarded research grants from the NIHR, UK. MI is Co-Editor for Controversies for Multiple Sclerosis Journal, received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, and received research support from NIH, NMSS, the MS Society of Canada, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, H2020 EU Call. CM has nothing to disclose. RWM has nothing to disclose. AS receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense and is a member of editorial board for Neurology. BMS has nothing to disclose. AF is on Advisory Boards for Akili Interactive and Roche, and reports grants from the MS Society of Canada, book royalties from Johns Hopkins University Press, Cambridge University Press, Amadeus Press and Glitterati Editions, and speaker’s honoraria from Novartis, Biogen, Roche and Sanofi Genzyme. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology, received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda and TEVA, participation in Advisory Boards for Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda, scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme, he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Combining immunostimulatory chemotherapies with immunotherapy is an attractive strategy to enhance treatment responses in oesophagogastric junctional adenocarcinoma (OGJ). This study investigates the immunostimulatory properties of FLOT, CROSS and MAGIC chemotherapy regimens in the context of OGJ using in vitro and ex vivo models of the treatment-naïve and post-chemotherapy treated tumour microenvironment. FLOT and CROSS chemotherapy regimens increased surrogate markers of immunogenic cell death (HMGB1 and HLA-DR), whereas the MAGIC treatment regimen decreased HMGB1 and HLA-DR on OGJ cells (markedly for epirubicin). Tumour-infiltrating and circulating T cells had significantly lower CD27 expression and significantly higher CD69 expression post-FLOT and post-CROSS treatment. Similarly, the supernatant from FLOT- and CROSS-treated OGJ cell lines and from FLOT- and CROSS-treated OGJ biopsies cultured ex vivo also decreased CD27 and increased CD69 expression on T cells. Following 48 h treatment with post-FLOT and post-CROSS tumour conditioned media the frequency of CD69 + T cells in culture negatively correlated with the levels of soluble immunosuppressive pro-angiogenic factors in the conditioned media from ex vivo explants. Supernatant from FLOT- and CROSS-treated OGJ cell lines also increased the cytotoxic potential of healthy donor T cells ex vivo and enhanced OGJ patient-derived lymphocyte mediated-killing of OE33 cells ex vivo. Collectively, this data demonstrate that FLOT and CROSS chemotherapy regimens possess immunostimulatory properties, identifying these chemotherapy regimens as rational synergistic partners to test in combination with immunotherapy and determine if this combinatorial approach could boost anti-tumour immunity in OGJ patients and improve clinical outcomes., (© 2022. The Author(s).)

Competing Interests: Competing interests: None declared.

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak ® ) in multiple sclerosis (MS) patients., Methods: Litak ® was offered to MS-patients irrespective of disease course. Litak ® 10 mg was administered for 3-4 days during week 1. Based on lymphocyte count at week 4, patients received another 0-3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts., Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17-72) years and EDSS 0-8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n  = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n  = 13) had NEPAD. Of n  = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months., Conclusions: Litak ® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.A.P., S.D.T., Z.M., A.M., A.S., X.Z., O.Y., A.A., L.B., C.C., C.D., S.P., L.P.J., B.S. and S.W. have no conflicts of interest to declare. C.A.G. is a founder of NeuroCreare Ltd. J.M. has received honoraria and meeting support from Arvelle, Biogen, Novartis, Merck Serono, Roche and Sanofi Genzyme. C.B. has received travel costs and honoraria from Novartis, Genzyme, Teva and Biogen. K.C. has received honoraria and travel grants from Biogen, Sanofi-Genzyme and Roche. C.S.C. has received support for research, attendance of conferences, and consultancy from Biogen, GW Pharmaceuticals, Novartis, Teva, Merck, Morphosys, Roche, Sanofi Pasteur MSD and Sanofi Genzyme. R.A.F. has received honoraria and consultancy fees from Merck, TEVA, Novartis, Genzyme, GW Pharma, Allergan, Merz, Ipsen, and Biogen. R.A.F.’s current research activity is supported by the NIHR Biomedical Research Centre UCLH. L.F. has received consultancy fees from Biogen, Novartis, Roche and Genzyme. L.F. has received support for educational events from Biogen, Genzyme, Merck, Novartis, Teva, and the Neurology Academy. H.F. has received support from the Health Technology Assessment Programme (NIHR) and the UK MS Society. In the past 3 years, H.F. has been a local principal investigator for trials in MS funded by Novartis, Roche, and Biogen Idec and has taken part in advisory boards and consultancy for Biogen Idec, Merck, Novartis and Roche. B.G. has received personal compensation for consultancy from Merck, Roche, Biogen, Teva UK, and GW Pharma. B.G. has received unrestricted research grants from Biogen Idec, Merck, Bayer Healthcare, Teva UK, Novartis, and Genzyme. B.G. has received support for the attendance of clinical and research conferences from Biogen, Merck, Bayer Healthcare, Teva UK, Novartis, Genzyme, and CelGene. J.H. has received consultancy fees, meeting support, or grants to support clinical services or research from: Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, Celegene, Oxford pharmagenesis. Z.K. has received honoraria and travel costs from Roche, Biogen and Novartis. M.M. has received travel support and speaker honoraria from Biogen Idec, Genzyme, Merck-Sereno, Novartis, Roche and Teva and consultation for Celgene, Merck-Serono, Novartis and Roche. O.P. has received speaking fees and travel expenses from, and/or served on advisory boards for, Biogen, Bayer, Celegene, Janssen, Merck Novartis, Roche, Sanofi and Teva. A.S. has received honoraria, travel grants and been a member of advisory boards for Biogen, Novartis, Teva, Celgene, Sanofi, and Merck. E.S. has received consulting fees and/ or support to attend academic meetings from Merck. E.T. has received honorarium for consulting work from Novartis, Merck, Biogen, and Roche. E.T. has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche, Takeda, and Novartis. B.P.T. has received honoraria, travel grants, and been a member of advisory boards for Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Roche. M.M. has received honoraria and travel costs from Genzyme, AbbVie, Roche, and Novartis. S.G. has received honoraria from Biogen Idec, Sanofi Genzyme, Janssen Cilag, Merck, Neurodiem, Novartis, Roche, and Teva and grant support from ECTRIMS, Genzyme, Merck, National MS Society, Takeda, and UK MS Society. G.J. has received speaker honoraria from and is a member of advisory boards of AbbVie, Astellas, Celgene, and Novartis. G.G. has received honoraria and meeting support from AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex. He also serves as chief editor for Multiple Sclerosis and Related Disorders. D.B. has received compensation from InMuneBio, Lundbeck, Merck, Novartis, Rock, and Teva. K.S. has received research support from Biogen, Merck KGaA, and Novartis, speaking honoraria from, and/or served in an advisory role for, Amgen, Biogen, EMD Serono, Merck KGaA, Novartis, Roche, Sanofi-Genzyme, and Teva; and remuneration for teaching activities from AcadeMe, Medscape and the Neurology Academy., (© The Author(s), 2021.)

Competing Interests: Competing interests: None declared.

Background: Spasticity is a frequent and disabling symptom in people with Multiple Sclerosis (MS). Intrathecal baclofen (ITB) is an effective but infrequently used treatment in ambulant people., Objective: To evaluate the impact of ITB on ambulation in people with moderate to severe MS related spasticity., Methods: Data was collected prospectively regarding spasticity and ambulation at baseline, after ITB trial via lumbar puncture, 3 months and annually thereafter., Results: 30 subjects; Mean age 47.9 (26-64), 67% female, mean EDSS 6.5 [6.5-7.5]. Reduction in mean Ashworth score (pre 1.44: post 0.98, p<0.001) and Penn spasm score (pre 3: post 1; p<0.001) was shown. 20 people (67%) proceeded with implantation; lower limb MRC power was predictive of proceeding to pump (OR 2.98; 95% CI 1.01 - 8.7; p <0.05). In those proceeding to implantation there was no difference in 10mTW at 1 year (ANOVA (F(3,24) = 2.6, p=0.13). Currently, 15 (75%) remain ambulatory (mean 3.75 years, range 1-9). After implant, 17 (85%) discontinued all oral anti-spasticity treatments conferring other benefits., Conclusion: Ambulation in people with MS can be preserved for several years whilst effectively treating spasticity with ITB with careful patient selection; ITB should not be considered a last resort., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Coupled ferromagnetic and ferroelectric materials, known as multiferroics, are an important class of materials that allow magnetism to be manipulated through the application of electric fields. Bismuth ferrite, BiFeO3, is the most-studied intrinsic magnetoelectric multiferroic because it maintains both ferroelectric and magnetic ordering to well above room temperature. Here we report the use of epitaxy-free wet chemical methods to create strained nanoporous BiFeO3. We find that the strained material shows large changes in saturation magnetization on application of an electric field, changing from 0.04 to 0.84 μb per Fe. For comparison, non-porous films produced using analogous methods change from just 0.002 to 0.01 μb per Fe on application of the same electric field. The results indicate that nanoscale architecture can complement strain-layer epitaxy as a tool to strain engineer magnetoelectric materials.

Metal-organic frameworks (MOFs) can provide a matrix for the assembly of organic chromophores into well-defined geometries, allowing for tuning of the material properties and study of structure-property relationships. Here, we report on the effect of the coordinated metal ion on the luminescence properties of eight isostructural MOFs having the formula M(1)2M(2)L3(DMF)2 (M(1) = M(2) = Zn (1), Cd (2), Mn (3), Co (4); M(1) = Zn, M(2) = Cd (5), Mn (6), Co (7); M(1) = Co, M(2) = Mn (8); L = trans-4,4'-stilbene dicarboxylate), synthesized by reaction of the appropriate metal nitrate or mixtures of metal nitrates with LH2 in DMF. The crystal structures of 2, 3 and 5-8 were determined by X-ray diffraction to be composed of trinuclear metal clusters linked by stilbene dicarboxylate linkers in a paddlewheel geometry, extending to form a 2-D layered structure. In the mixed-metal cases, the larger metal ion was found to occupy the octahedral site in the cluster while the smaller ion occupies the tetrahedral positions, suggesting a selective, ligand-directed assembly process for the mixed-metal species. Variable temperature magnetic measurements for paramagnetic MOFs 3 and 6-8 were consistent with the site occupancies determined crystallographically, and indicated weak intra-cluster antiferromagnetic coupling for 3 and 8. Comparison between the crystal structures of 2, 3 and 5-8 and those reported for 1 and 4 in the literature reveal close resemblances between linker environments, with important intermolecular stilbene-stilbene geometries that are comparable in all cases. Interestingly, pale-colored 1-3 and 5-7 display very similar emission profiles upon excitation at λ(ex) = 350 nm, whereas dark-colored 4 and 8 do not exhibit detectable emission spectra. The bright, well-resolved luminescence of 1, 2 and 5 is ascribed to rigidification of the linker upon coordination to the d(10) metal ions, whereas the weaker emission observed for 3, 6 and 7 is presumably a result of quenching due to close proximity of the linker to one or more paramagnetic ions. Time-resolved measurements for 1, 2, 5 and 6 reveal biexponential emission decays, where the lifetime of the longer-lived state corresponds to observed variations in the nearest-neighbor cofacial stilbene-stilbene distances in their crystal structures. For 3, a monoexponential decay with shorter lifetime was determined, indicating significant paramagnetic quenching of its emissive state.

Biopharmaceuticals are drugs which are based on naturally occurring proteins (antibodies, receptors, cytokines, enzymes, toxins), nucleic acids (DNA, RNA) or attenuated microorganisms. Immunogenicity of these agents has been commonly described and refers to a specific antidrug antibody response. Such immunogenicity represents a major factor impairing the efficacy of biopharmaceuticals due to biopharmaceutical neutralization. Indeed, clinical experience has shown that induction of antidrug antibodies is associated with a loss of response to biopharmaceuticals and also with hypersensitivity reactions. The first disease-specific agent licensed to treat multiple sclerosis (MS) was interferon-β (IFNβ). In its various preparations, it remains the most commonly used first-line agent. The occurrence of antidrug antibodies has been extensively researched in MS, particularly in relation to IFNβ. However, much controversy remains regarding the significance of these antibodies and incorporation of testing into clinical practice. Between 2% and 45% of people treated with IFNβ will develop neutralizing antibodies, and this is dependent on the specific drug and dosing regimen. The aim of this review is to discuss the use of IFNβ in MS, the biological and clinical relevance of anti-IFNβ antibodies (binding and neutralizing antibodies), the incorporation of testing in clinical practice and ongoing research in the field.

We show the importance of sidewall chemistry for the graphoepitaxial alignment of PS-b-PDMS using prepatterns fabricated by electron beam lithography of hydrogen silsesquioxane (HSQ) and by deep ultraviolet (DUV) lithography on SiO(2) thin films. Density multiplication of polystyrene-block-polydimethylsiloxane (PS-b-PDMS) within both prepatterns was achieved by using a room temperature dynamic solvent annealing environment. Selective tuning of PS and PDMS wetting on the HSQ template sidewalls was also achieved through careful functionalization of the template and substrate surface using either brush or a self-assembled trimethylsilyl monolayer. PDMS selectively wets HSQ sidewalls treated with a brush layer of PDMS, whiereas PS is found to selectively wet HSQ sidewalls treated with hexamethyldisilazane (HMDS) to produce a trimethylsilyl-terminated surface. The etch resistance of the aligned polymer was also evaluated to understand the implications of using block copolymer patterns which have high etch resistance, self-forming (PDMS) wetting layers at both interfaces. The results outlined in this work may have direct applications in nanolithography for continued device scaling toward the end-of-roadmap era.

Extending the resolution and spatial proximity of lithographic patterning below critical dimensions of 20 nm remains a key challenge with very-large-scale integration, especially if the persistent scaling of silicon electronic devices is sustained. One approach, which relies upon the directed self-assembly of block copolymers by chemical-epitaxy, is capable of achieving high density 1 : 1 patterning with critical dimensions approaching 5 nm. Herein, we outline an integration-favourable strategy for fabricating high areal density arrays of aligned silicon nanowires by directed self-assembly of a PS-b-PMMA block copolymer nanopatterns with a L(0) (pitch) of 42 nm, on chemically pre-patterned surfaces. Parallel arrays (5 × 10(6) wires per cm) of uni-directional and isolated silicon nanowires on insulator substrates with critical dimension ranging from 15 to 19 nm were fabricated by using precision plasma etch processes; with each stage monitored by electron microscopy. This step-by-step approach provides detailed information on interfacial oxide formation at the device silicon layer, the polystyrene profile during plasma etching, final critical dimension uniformity and line edge roughness variation nanowire during processing. The resulting silicon-nanowire array devices exhibit Schottky-type behaviour and a clear field-effect. The measured values for resistivity and specific contact resistance were ((2.6 ± 1.2) × 10(5)Ωcm) and ((240 ± 80) Ωcm(2)) respectively. These values are typical for intrinsic (un-doped) silicon when contacted by high work function metal albeit counterintuitive as the resistivity of the starting wafer (∼10 Ωcm) is 4 orders of magnitude lower. In essence, the nanowires are so small and consist of so few atoms, that statistically, at the original doping level each nanowire contains less than a single dopant atom and consequently exhibits the electrical behaviour of the un-doped host material. Moreover this indicates that the processing successfully avoided unintentional doping. Therefore our approach permits tuning of the device steps to contact the nanowires functionality through careful selection of the initial bulk starting material and/or by means of post processing steps e.g. thermal annealing of metal contacts to produce high performance devices. We envision that such a controllable process, combined with the precision patterning of the aligned block copolymer nanopatterns, could prolong the scaling of nanoelectronics and potentially enable the fabrication of dense, parallel arrays of multi-gate field effect transistors.

All biotherapeutics have the potential to generate anti-drug antibodies (ADAs) in patients. The main factors leading to an immune response are thought to be product, treatment and patient related. In this review, reasons for the formation of ADAs, and particularly neutralizing antibodies (NAbs), are considered, with a focus on IFN-β as a well-studied example. The time course for the production of NAbs, the measurement of NAbs, the defining of IFN-β responders and non-responders, the implications for disease progression in patients, and future methods for avoiding the production of ADAs and of tolerizing patients are considered.

Background: Incorporation of routine clinical testing for neutralizing antibodies (NAbs) to interferon (IFN)-β has remained problematic. With increasing treatment choice for patients, routine NAb testing should be incorporated to aid therapeutic decisions., Objective: We sought to improve interpretation of NAb results by combining the luciferase NAb assay (luciferase gene expression assay under control of interferon-stimulated response element) and in-vivo biomarker (myxovirus A protein, MxA) induction in patients with MS., Methods: Blood samples (serum and PAXGene(®) for RNA) were obtained pre-injection and 12 hours post-injection of IFN-β from 144 subjects. Sera were tested for NAbs using the luciferase assay. MxA expression was quantified by real-time polymerase chain reaction (PCR)., Results: 26% of samples were NAb positive (titre > 20 NU). There was no difference in NAb titres in the pre- or post-dose sera (p = 0.643). MxA expression was inhibited in a dose-dependent fashion in NAb positive samples. Mean MxA level post-IFN-β: NAb negative 2330 (95% CI 1940-2719), NAb 20-99 NU 1533 (95% CI 741-2324), NAb 100-600 NU 832 (186-1478) and NAb > 600 NU 101 (95% CI 0-224). NAb titre and MxA level correlated strongly: MxA pre- (Spearman r = -0.72, p < 0.0001), MxA post- (Spearman r = -0.79, p < 0.0001) and MxA induction (Spearman r = -0.67, p = 0.0004)., Conclusion: A single, 12-hour post-injection sample should be used to test for NAbs using the luciferase assay and IFN-β bioactivity (MxA) in the clinical setting.

Functionalized trialkoxysilanes are widely used to modify the surface properties of materials and devices. It will be shown that the photoinitiated radical-based thiol-ene "click" reaction provides a simple and efficient route to diverse trialkoxysilanes. A total of 15 trialkoxysilanes were synthesized by reacting either alkenes with 3-mercaptopropyltrialkoxysilane or thiols with allyltrialkoxysilanes in the presence of a photoinitiator. The functionalized trialkoxysilanes were obtained in quantitative to near-quantitative yields with high purity. The photochemical reactions can be run neat in standard borosilicate glassware using a low power 15-W blacklight. A wide range of functional groups is tolerated in this approach, and even complex alkenes click with the silane precursors. To demonstrate that these silanes can be used as surface coating agents, several were reacted with iron oxide superparamagnetic nanoparticles and the loadings quantified. The photoinitiated thiol-ene reaction thus offers a facile and efficient method for preparing surface-active functional trialkoxysilanes.

Through a combination of nanoimprint lithography and block copolymer self-assembly, a highly regular dewetting process of a symmetric diblock copolymer occurs whereby the hierarchal formation of microdroplets and concentric nanorings emerges. The process is driven by the unique chemical properties and geometrical layout of the underlying patterned silsesquioxane micrometer-sized templates. Given the presence of nonpreferential substrate-polymer interactions, directed dewetting was utilized to produce uniform arrays of microsized droplets of microphase separated polystyrene-block-poly(methyl methylacrylate) (PS-b-PMMA), following thermal annealing at 180 °C. Microdroplets with diameters greater than 400 nm exhibited a hexagonal close-packed arrangement of nanodots on the surface with polydomain ordering. At the droplet periphery, the polydomain ordering was severely disrupted because of a higher in-plane radius of curvature. By reducing the droplet size, the in-plane radius of curvature of the microdroplet becomes significant and the PMMA cylinders adopt parallel structures in this confined geometry. Continuous scaling of the droplet results in the generation of isolated, freestanding, self-aligned, and self-supported oblique nanorings (long axis ∼250-350 nm), which form as interstitial droplets between the larger microdroplets. Optical and magnetic-based nanostructures may benefit from such hierarchal organization and self-supporting/aligned nanoring templates by combining more than one lithography technique with different resolution capabilities.

Ternary blends of cylinder-forming polystyrene-block-poly(methyl methacrylate) block copolymers and polystyrene and poly(methyl methacrylate) homopolymers were assembled in trench features of constant width. Increasing the fraction of homopolymer in the blend increased the spacing and size of block copolymer domains, which were oriented perpendicular to the substrate to form a hexagonal lattice within the trench. The number of rows of cylinders within the trench was controlled by the blend composition. Depending on the domain size and spacing, the hexagonal lattice was stretched or compressed perpendicular to the trench walls but not perturbed parallel to the walls, indicating a decoupling of the perturbation in the perpendicular and parallel directions. The row spacing was uniform across the trench as a function of position from the trench wall. The results are compared with an analytical model and with Monte Carlo simulations.

Interferon beta was the first specific disease-modifying therapy licensed for multiple sclerosis (MS) and in its many forms remains the most commonly prescribed agent worldwide. It, however, has a modest effect in reducing relapse rates, magnetic resonance imaging activity, and disability, and many patients are unable to tolerate it because of the associated side effects or mode of administration. With the licensing of glatiramer acetate, natalizumab and mitoxantrone as disease-modifying therapies for MS alternative options are available to people with MS. Many exciting new therapies are also in the pipeline, namely, the monoclonal antibodies alemtuzumab, rituximab, and daclizumab and the promising oral agents BG00012, cladribine, fingolimod, laquinimod, and teriflunomide. In this article we review the immunopathology of MS and the proposed mechanisms of action of currently available and anticipated treatments. We also review the efficacy of each drug, use of combination therapy strategies, and the potential role of the interferon beta preparations in the future.

Self-assembled nanoscale porous architectures, such as mesoporous silica (MPS) films, block copolymer films (BCP) and porous anodic aluminas (PAAs), are ideal hosts for templating one dimensional (1D) nano-entities for a wide range of electronic, photonic, magnetic and environmental applications. All three of these templates can provide scalable and tunable pore diameters below 20 nm [1-3]. Recently, research has progressed towards controlling the pore direction, orientation and long-range order of these nanostructures through so-called directed self-assembly (DSA). Significantly, the introduction of a wide range of top-down chemically and physically pre-patterning substrates has facilitated the DSA of nanostructures into functional device arrays. The following review begins with an overview of the fundamental aspects of self-assembly and ordering processes during the formation of PAAs, BCPs and MPS films. Special attention is given to the different ways of directing self-assembly, concentrating on properties such as uni-directional alignment, precision placement and registry of the self-assembled structures to hierarchal or top-down architectures. Finally, to distinguish this review from other articles we focus on research where nanostructures have been utilised in part to fabricate arrays of functioning devices below the sub 50 nm threshold, by subtractive transfer and additive methods. Where possible, we attempt to compare and contrast the different templating approaches and highlight the strengths and/or limitations that will be important for their potential integration into downstream processes., (Copyright 2010 Elsevier Inc. All rights reserved.)

Microphase separation of a polystyrene-block-polyisoprene-block-polystyrene triblock copolymer thin film under confined conditions (i.e., graphoepitaxy) results in ordered periodic arrays of polystyrene cylinders aligned parallel to the channel side-wall and base in a polyisoprene matrix. Polymer orientation and translational ordering with respect to the topographic substrate were elucidated by atomic force microscopy (AFM) while film thickness and polymer profile within the channel were monitored by cross-sectional transmission electron microscopy (TEM) as a function of time over a 6 h annealing period at 120 degrees C. Upon thermal annealing, the polymer film simultaneously undergoes three processes: microphase separation, evaporation of trapped solvent, and mass transport of polymer from the mesas into the channels. A significant volume of solvent is trapped within the polymer film upon spin coating arising from the increased polymer/substrate interfacial area due to the topographic pattern. Mass transport of polymer during this process results in nonuniform films, where subtle changes in the film thickness within the channel have profound effects on the microphase separation process. The initially disordered structure within the film underwent an orientation transition via an intermediate formation of perpendicular cylinders (nonequilibrium) to a parallel (equilibrium) orientation with respect to the channel base. Herein, we present a time-resolved study of the cylinder reorientation process detailing how changing film thickness during the annealing process dramatically affects both the local and lateral orientation of the observed structure. Finally, a brief mathematical model is provided to evaluate spin coating over a complex topography following a classical asymptotic approximation of the Navier-Stokes equations for the as-deposited films.

The thermodynamics of self-assembling systems are discussed in terms of the chemical interactions and the intermolecular forces between species. It is clear that there are both theoretical and practical limitations on the dimensions and the structural regularity of these systems. These considerations are made with reference to the microphase separation that occurs in block copolymer (BCP) systems. BCP systems self-assemble via a thermodynamic driven process where chemical dis-affinity between the blocks driving them part is balanced by a restorative force deriving from the chemical bond between the blocks. These systems are attracting much interest because of their possible role in nanoelectronic fabrication. This form of self-assembly can obtain highly regular nanopatterns in certain circumstances where the orientation and alignment of chemically distinct blocks can be guided through molecular interactions between the polymer and the surrounding interfaces. However, for this to be possible, great care must be taken to properly engineer the interactions between the surfaces and the polymer blocks. The optimum methods of structure directing are chemical pre-patterning (defining regions on the substrate of different chemistry) and graphoepitaxy (topographical alignment) but both centre on generating alignment through favourable chemical interactions. As in all self-assembling systems, the problems of defect formation must be considered and the origin of defects in these systems is explored. It is argued that in these nanostructures equilibrium defects are relatively few and largely originate from kinetic effects arising during film growth. Many defects also arise from the confinement of the systems when they are 'directed' by topography. The potential applications of these materials in electronics are discussed.

Herein we report on the alignment of mesoporous silica, a potential host for sub-10 nm nanostructures, by controlling its deposition within patterned substrates. In-depth characterization of the correlation lengths (length of a linear porous channel), defects of the porous network (delamination), and how the silica mesopores register to the micrometer-sized substrate pattern was achieved by means of novel focused ion beam (FIB) sectioning and in situ SEM imaging, which to our knowledge has not previously been reported for such a system. Our findings establish that, under confinement, directed deposition of the sol within channeled substrates, where the cross-sectional aspect ratio of the channels approaches unity, induces alignment of the mesopores along the length of the channels. The pore correlation length was found to extend beyond the micrometer scale, with high pore uniformity from channel to channel observed with infrequent delamination defects. Such information on pore correlation lengths and defect densities is critical for subsequent nanowire growth within the mesoporous channels, contact layout (electrode deposition etc.), and possible device architectures.

Interferon Beta is well established as a first line agent to treat relapsing remitting Multiple Sclerosis. It frequently induces the formation of neutralising anti-Interferon Beta Antibodies (Nabs) which may abrogate the clinical efficacy of the drug. Numerous studies have shown a loss of bioactivity of the drug in the presence of Nabs. The focus has shifted to reliable quantification of Nabs and their appropriate incorporation into clinical practice. Here we review the development and persistence of Nabs, the effect on Interferon beta bioactivity, clinical and para-clinical autocome measures in trials, Nab assays and discuss management strategies to optimise the use of Interferon beta in relapsing remitting MS.

The extended Jones formulation is used to investigate propagation at nonnormal incidence through two- and three-layer systems of birefringent material in which the optic axes of the individual layers are in the plane of the layers. Such systems are equivalent to two optical elements in series-an equivalent retardation plate and a polarization rotator. Analytical solutions are obtained for the equivalent retardation and rotation. The major finding is that, in general, there are two nonnormal incidence directions for which the retardation vanishes; therefore these two directions are optic axes of the composite system. These simple layered systems therefore behave in a manner similar to biaxial crystals. Moreover, the results illustrate the fact that even if the optic axes of individual layers in composite systems are in the plane of the layers, the optic axes of the system are, in general, out of this plane.

Purpose: Techniques employing polarized light propagation and scattering are useful in examining the cornea's lamellar structure. Recent advances in theoretical methods have significantly increased the ability to relate features of lamellar arrangements to measurements of transmitted polarized light. The chick cornea, because of its hypothesized structure of a gradual helical rotation of lamellar pairs, presents an interesting model for further development of this methodology., Methods: Small-angle light scattering (SALS) and polarized transmission measurements were made on 7-week-old chick corneas under conditions that closely approximate the physiological state. Birefringence properties were determined from the transmission measurements and compared to the results of model calculations of polarized light propagating through lamellae organized according to the hypothesized structure for chick cornea., Results: The I+ small-angle light scattering pattern had 4 cloverleaf lobes aligned with the crossed polarizer and analyzer axes. The lobes disappeared when the transcorneal pressure was increased from zero to 18 mmHg. Retardation measured at 18 mmHg was very small (approximately 0.01 microm)., Conclusion: The disappearance of the I+ small-angle light scattering pattern when IOP is increased suggests that the lamellae undulate in their relaxed state and the undulations straighten when IOP is increased. Measured birefringence properties are consistent with the hypothesized lamellar structure.

The propagation of polarized light through the cornea is affected by the orientations of the corneal lamellae and by the refractive imbalance between the collagen fibrils and the ground substance. Thus, well-designed measurements and analyses of polarized light propagation through the cornea can be used to obtain information regarding the cornea's lamellar and fibrillar structures. This paper shows that, for the rabbit, measured values of the optical parameters strongly suggest that the distribution of lamellae orientations is not random, but has one (or two) preferred orientation directions. Also, there is considerable evidence that collagen is intrinsically anisotropic. The Weiner formula gives the effective birefringence of an assembly of parallel isotropic fibrils and its generalization to the case of anisotropic fibrils is presented. Finally, calculations based on preferred orientation models having lamellae composed of anisotropic fibrils show that comparison with experimental values can yield structural information.

In this paper polarized light transmission measurements are made under conditions that closely approximate the physiological state in order to probe lamellar structure in the central cornea of New Zealand white rabbits. The results are interpreted with the aid of a newly developed theory (published elsewhere) in which the cornea is modeled as stacked birefringent layers corresponding to the lamellae. The theory enables predictions of the statistical properties of lamellar ordering based on characteristics of the transmission of polarized light. The experimental results are consistent with a structure in which a number of lamellae have a fixed azimuthal orientation (i.e. about an axis normal to the corneal surface), whereas the remainder are essentially randomly oriented. Comparisons with the theoretical predictions are consistent with a model in which the preferred direction in the apical region of the cornea does not vary significantly among rabbits; and the preferred lamellar orientation direction determined for the population measured here is very close to that suggested in previous experiments on a smaller number of rabbits. Mapping experiments using a new goniometric holder showed that the preferential order at the apical region is closely preserved throughout the central approximately 4 mm diameter optical zone in individual corneas.

In Saccharomyces cerevisiae, at least 12 genes are important for cells to propagate in medium containing elevated concentrations of copper salts (J. Welch, S. Fogel, C. Buchman, and M. Karin, EMBO J. 8:255-260, 1989). Complementation studies were carried out on a copper-sensitive mutation (cup14) from this group. A new yeast gene, designated SLF1, was identified as a multicopy suppressor of the cup14 mutation. Slf1 is important for the physiological process of copper sulfide (CuS) mineralization on the surface of cells cultured in medium containing copper salts. CuS mineralization causes the cells to turn brown. Disruption of SLF1, which is located close to the telomere region of chromosome IV, leads to limited copper sensitivity, and the resulting cells lack the normal brownish coloration when grown in CuSO4-containing medium. Overproduction of Slf1 in wild-type cells confers superresistance to CuSO4 and enhances the coloration of cells cultured in the presence of CuSO4. Upon addition of KCN to Cu-grown cells, the brownish coloration was bleached instantly, and copper ions were solubilized. These data are consistent with Slf1-dependent accumulation of CuS complexes on the cell surface. Disruption of SFL1 also results in loss of the ability of yeast cells to deplete Cu but not Cd ions from the growth medium, whereas overexpression enhances Ca depletion ability and the resulting deposition of CuS particles. It is proposed that Slfl participates in a copper homeostasis pathway, distinct from the Cup1 detoxification system, that leads to sulfide generation and CuS biomineralization on the cell surface. This process may coordinate with the Cup1 pathway at different copper concentrations to prevent copper-induced toxicity.

The suggestion that the central cornea can be modeled as a uniaxial birefringent material with its optic axis normal to the surface is explicitly tested by numerical calculations. A theoretical framework is presented to model the corneal stroma as a series of stacked, uniaxial birefringent layers (lamellae). Calculations are then made of the transmission of normally incident, linearly polarized light through model systems having various azimuthal orientations of the layers, motivated by the suggestion of an overall "random" organization of the stromal lamellae. It is concluded that the uniaxial description, and the assumptions upon which that description is based, do not hold for the cornea. In particular, the calculations are in agreement with recent experiments in which one always observes a non-zero cross-polarized transmission (hence birefringence) at normal incidence.

The N-terminal metal-binding domains of the copper-activated yeast transcription factors, ACE1 and AMT1, bind to specific DNA sequences in a Cu-dependent fashion. Recombinant AMT1 and ACE1 metal-binding domains are isolated as Cu4Zn1-protein complexes. Site-directed mutagenesis of AMT1 was used in this study to map the ligands of the Cu(I) and Zn(II) ions. The results are consistent with the N-terminal halves of AMT1 and ACE1 consisting of two independent submodules, one binding a single Zn(II) ion and the second binding the tetracopper cluster. The basis of this conclusion is, first, that mutations of two cysteinyl codons and a histidyl codon in the first 42 residues of AMT1 do not alter DNA binding. In contrast, serine substitutions at four cysteine positions at codons 43, 61, 90, and 98 abolish DNA binding. We demonstrated previously that population of the Zn(II) site in AMT1 does not alter the ability of the protein to bind DNA but bound Cu(I) ions are essential for DNA binding [Thorvaldsen, J. L., et al. (1994) Biochemistry 33, 9566-9577]. Second, mutations in the N-terminal 42 residue segment reduce the Zn(II) content of purified mutant AMT1 molecules. Third, a synthetic peptide consisting of the N-terminal 42 residues in AMT1 forms a stable Zn(II) complex and substitution with Co(II) reveals an electronic spectrum identical to that of the Co-substituted intact Cu4AMT1 protein. 113Cd(II) NMR studies reveal that the divalent metal site consists of ligands provided by three cysteinyl thiolates and a single histydyl imidazole. The sequence homology between AMT1, ACE1, and MAC1 in the N-terminal 42 residues suggests that ACE1 and MAC1 will, likewise, contain N-terminal Zn modules. A 42-residue ACE1 synthetic peptide gives identical metal binding properties to the corresponding AMT1 synthetic peptide. Thus, AMT1 and likely ACE1 consist of two contiguous modules, residues 1-42 forming an independent Zn(II) module and residues 43-110 enfolding a tetracopper cluster.

A model of the cornea's lamellar structure is proposed that is capable of explaining experimental results obtained for the transmission of normal-incidence polarized light through rabbit and bovine cornea. The model consists of a large number of planar lamellae, each approximated as a uniaxial birefringent layer, stacked one upon another with various angular orientations. Polarized light transmission through the composite system is modeled theoretically by use of the Jones matrix formalism. The light transmission is calculated numerically for a large number of model lamellae arrangements, each generated from a statistical description, and histograms are constructed of various properties of the light transmission, including the minimum and maximum cross-polarized output intensities. It is demonstrated that various structural and optical parameters of the lamellae arrangements of actual corneas may be estimated by comparison of the calculations with detailed experimental data. Certain characteristics of the histograms are identified that permit a clear distinction between random and partially ordered systems. Comparisons with previously published experimental data provide strong evidence that the lamellae orientations are not entirely random, but rather a significant fraction are oriented in a fixed, preferred direction.

Purpose: The authors sought to discover whether there are differences in the degree of spatial order in the fibrillar ultrastructure between anterior and posterior stroma., Methods: Human corneas were obtained from eye bank eyes. Although they had been classified as normal, some swelling remained after 3 hours of deturgescence. Freshly excised, unswollen rabbit corneas also were used. Image analysis methods were applied to transmission electron micrographs of the anterior, middle, and posterior stroma of these corneas to determine the positions and radii of fibrils, the fraction of total area occupied by fibrils, and the fibril number density. Results were used to calculate the interference factor that appears in the direct summation of the fields for light scattering theory and to estimate the total scattering cross-section per fibril. The interference factor is a measure of the spatial order in the positions and sizes of the fibrils., Results: Electron micrographs showed anterior-posterior variations in size and number density of fibrils. The interference factor at wavelengths of visible light was lower in posterior stroma than in anterior stroma for humans and rabbits. In some instances in humans, the anterior interference factor was characteristic of mildly swollen cornea. When averaged for the electron micrographs analyzed, the anterior stroma was predicted to scatter approximately twice as much light per unit depth as the posterior stroma in humans (at any given wavelength) and approximately three times as much in rabbits., Conclusions: Calculations of the interference factor showed that there were differences in the anterior-posterior spatial ordering of fibrils. In human corneas, the differences could have been caused by intrinsic in vivo differences between anterior and posterior stroma; however, possible anterior-posterior variations in swelling between the two regions in vitro also could have affected the results.

The determination of average net pulsatile ocular blood flow form measurements of the intraocular pressure (IOP) pulse is based upon 1) an accurate measurement of IOP and its time variation; 2) a knowledge of the relation between the volume of the living eye and its IOP; 3) a physical model for the flow of blood through the eye: and 4) a concept of steady venous outflow from the eye. Each of these premises needs to be examined. The present analysis assesses the validity of the pneumatic tonometer for measuring the pressure in a flowing column of gas that is directed toward a thin membrane that is in contact with the surface of the cornea. The pressure of this stream of gas exerts a force against the cornea that depresses the corneal surface against the opposing force of the IOP. The balance of these forces and the resultant effect on the tonometer pressure sensor is described by the theories of elasticity, thermodynamics and fluid mechanics. In this treatment, differential equations are solved for the elastic deflections of the cornea subject to the opposing intraocular and tonometer pressures. This permits the pressure in the chamber of the pneumatic tonometer to be related through first principles to the IOP. The response of the tonometer pressure sensor to a range of IOPs (5-60 mmHg) is obtained, as well as the dynamical response of the tonometer to IOP oscillations. The conclusion is that the pneumatic tonometer provides a high fidelity, noninvasive measure of the IOP and its time variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Theoretical light scattering calculations, when applied to models based on structures seen in electron micrographs of corneal stroma, require knowledge of the constituent fibril positions and radii. Obtaining this information manually is a difficult and time-consuming task. In order to facilitate this problem, we present a simple and flexible computer algorithm that allows the process to be automated using a Macintosh computer. The accuracy of the results is checked by comparing light scattering calculations using fibril positions and radii found manually with those found by the computer. The results show that the computer algorithm is a viable and accurate means of obtaining the needed data.

Systematic studies have been undertaken to compare the effects of cell lysis and chromatography conditions on the observed distribution of Cu amongst Cu-binding proteins in cultured cells. The variables included rate of centrifugation, presence or absence of non-ionic detergent, and presence or absence of dithiothreitol. The application of an improved FPLC gel filtration system has permitted us to examine the effects of the addition of exogenous metallothionein (MT) to cell extracts. When the cell extract contains low levels of endogenous MT, the addition of MT in the presence of dithiothreitol causes a shift of copper to the MT peak. High levels of MT can therefore remove copper from other Cu-binding ligands during cell homogenization, hence producing artifactual Cu distribution results. The use of an anaerobic buffer system has greatly reduced the observed level of Cu exchange, and has allowed comparison of Cu distribution in normal cells and cells from patients with Menkes' disease.

We have determined exposure conditions for minimal damage to the corneal epithelium in rabbit using a continuous wave Tm: YAG laser operating in the TEM00 mode at incident powers between 80 and 450 mW. The 1/e beam diameter was 0.94 mm and exposure durations for threshold damage ranged from 4.3 to 0.08 sec. Calculated temperature increases on the beam axis 10 microns beneath the surface at the measured thresholds were essentially constant and averaged 44 degrees C. This is basically the same temperature increase found for threshold CO2 laser damage and suggests that the critical temperature damage model, which correlates CO2 laser damage, can predict damage thresholds for mid-infrared laser radiation. We also showed that reliable thresholds can be determined in freshly enucleated eyes, thus opening up the possibility of using available laser sources in laboratories not equipped and approved for animal experiments to determine damage thresholds.

A Schwinger-type variational principle is presented for the scattered field in the case of scalar wave scattering with an arbitrary field incident on an object of arbitrary shape with homogeneous Dirichlet boundary conditions. The result is variationally invariant at field points ranging from the surface of the scatterer to the farfield and is an important extension of the usual Schwinger variational principle for the scattering amplitude, which is a farfield quantity. Also, a generic procedure, physically motivated by the general principles of boundary conditions and shadowing, is presented for constructing simple trial functions to approximate the fields. The variational principle and the trial function design are tested for the special case of a spherical scatterer and accurate answers are found over the entire frequency range.

Corneal injury thresholds are determined for conditions not previously explored for CO2 laser radiation, including multiple-pulse exposures and a systematic investigation of the effect of beam diameter on single-pulse damage thresholds. Multiple-pulse exposures from pulse trains up to 999 pulses, having pulse repetition frequencies between 1 and 100 Hz and individual pulse durations between 10(-3) and 0.5 s, were explored. Damage thresholds are discussed in terms of an approximate critical temperature model, the damage integral model and other empirical correlations. Single-pulse exposures are accurately correlated by an empirical critical temperature model in which the critical temperatures have a weak dependence on exposure duration. However, certain aspects of the single-pulse damage data led us to propose a new thermal damage model that incorporates an endothermic phase transition as the damage mechanism. This physical model accurately correlates single-pulse damage for exposures between 10(-3) and approximately 10 s.