Optical signatures of the coupling between excitons and charge transfer states in linear molecular aggregates.

Charge Transfer (CT) has enjoyed continuous interest due to increasing experimental control over molecular structures, leading to applications in, for example, photovoltaics and hydrogen production. In this paper, we investigate the effect of CT states on the absorption spectrum of linear molecular aggregates using a scattering matrix technique that allows us to deal with arbitrarily large systems. The presented theory performs well for both strong and weak mixing of exciton and CT states, bridging the gap between previously employed methods, which are applicable in only one of these limits. In experimental spectra, the homogeneous linewidth is often too large to resolve all optically allowed transitions individually, resulting in a characteristic two-peak absorption spectrum in both the weak- and strong-coupling regime. Using the scattering matrix technique, we examine the contributions of free and bound states in detail. We conclude that the skewness of the high-frequency peak may be used as a new way to identify the exciton-CT-state coupling strength.

Probing size variations of molecular aggregates inside chlorosomes using single-object spectroscopy.

We theoretically investigate the possibility to use single-object spectroscopy to probe size variations of the bacteriochlorophyll aggregates inside chlorosomes. Chlorosomes are the light-harvesting organelles of green sulfur and non-sulfur bacteria. They are known to be the most efficient light-harvesting systems in nature. Key to this efficiency is the organization of bacteriochlorophyll molecules in large self-assembled aggregates that define the secondary structure inside the chlorosomes. Many studies have been reported to elucidate the morphology of these aggregates and the molecular packing inside them. It is widely believed that tubular aggregates play an important role. Because the size (radius and length) of these aggregates affects the optical and excitation energy transport properties, it is of interest to be able to probe these quantities inside chlorosomes. We show that a combination of single-chlorosome linear polarization resolved spectroscopy and single-chlorosome circular dichroism spectroscopy may be used to access the typical size of the tubular aggregates within a chlorosome and, thus, probe possible variations between individual chlorosomes that may result, for instance, from different stages in growth or different growth conditions.

Scaling relations of exciton diffusion in linear aggregates with static and dynamic disorder.

Exciton diffusion plays an important role in many opto-electronic processes and phenomena. Understanding the interplay of intermolecular coupling, static energetic disorder, and dephasing caused by environmental fluctuations (dynamic disorder) is crucial to optimize exciton diffusion under various physical conditions. We report on a systematic analysis of the exciton diffusion constant in linear aggregates using the Haken-Strobl-Reineker model to describe this interplay. We numerically investigate the static-disorder scaling of (i) the diffusion constant in the limit of small dephasing rate, (ii) the dephasing rate at which the diffusion is optimized, and (iii) the value of the diffusion constant at the optimal dephasing rate. Three scaling regimes are found, associated with, respectively, fully delocalized exciton states (finite-size effects), weakly localized states, and strongly localized states. The scaling powers agree well with analytically estimated ones. In particular, in the weakly localized regime, the numerical results corroborate the so-called quantum Goldilocks principle to find the optimal dephasing rate and maximum diffusion constant as a function of static disorder, while in the strong-localization regime, these quantities can be derived fully analytically.

Unraveling intra-aggregate structural disorder using single-molecule spectroscopy.

Structural disorder within self-assembled molecular aggregates may have strong effects on their optical functionality. Such disorder, however, is hard to explore using standard ensemble measurements. In this paper, we report on the characterization of intra-aggregate structural disorder through a linewidth analysis of fluorescence excitation experiments on individual zinc-chlorin (ZnChl) nanotubular molecular aggregates. Recent experiments suggest an anomaly in the linewidths of the two absorption bands that dominate the spectra: the higher-energy bands on average show a smaller linewidth than the lower-energy bands. This anomaly is explored in this paper by analyzing and modeling the correlation of the two linewidths for each aggregate. We exploit a Frenkel exciton model to show that the experimentally observed correlation of linewidths and other statistical properties of the single-aggregate spectra can be explained from small variations of the molecular orientations within individual aggregates.

Comparative Study of Real-Life Management Strategies in Gout: Data From Two Protocolized Gout Clinics.

OBJECTIVE: To compare outcomes of 2 gout clinics that implemented different treatment strategies. METHODS: Patients newly diagnosed with gout and a follow-up of 9-15 months were included. Co-primary outcomes were the proportion of patients reaching a serum uric acid (UA) ≤0.36 mmoles/liter and free of flares. Secondary outcomes were the proportion of patients requiring treatment intensification and experiencing adverse events. One clinic adopted a strict serum UA (≤0.30 mmoles/liter target) strategy, with early addition of a uricosuric to allopurinol, and the other clinic adopted a patient-centered (PC) strategy emphasizing a shared decision based on serum UA and patient satisfaction with gout control. Independent t-tests or chi-square tests were used to test differences in outcomes, and logistic regressions were used to adjust the effect of the treatment center on outcomes for confounders. RESULTS: In total, 126 and 86 patients had a follow-up mean ± SD of 11.3 ± 1.8 versus 11.1 ± 1.9 months. In the UA strategy, 105 of 126 patients (83%) compared to 63 of 86 (74%) in the PC strategy (P = 0.10) reached the threshold of ≤0.36 mmoles/liter; and 58 of 126 (46%) versus 31 of 86 (36%) were free of flares (P = 0.15). In the UA strategy, 76 of 126 patients (60%) were on allopurinol monotherapy compared to 63 of 86 (73%) in the PC strategy (P = 0.05), yet the number of adverse events was not different (n = 25 [20%] versus n = 20 [23%]; P = 0.55). Adjusting for confounders did not substantially change these associations. CONCLUSION: A strict UA strategy resulted in a nonsignificantly higher proportion of patients reaching a serum UA ≤0.36 mmoles/liter and being free of flares. This result was accomplished with significantly more therapy intensification. The small sample size plays a role in the significance of results.

Spectral and Structural Variations of Biomimetic Light-Harvesting Nanotubes.

Bioinspired, self-assembled nanotubes have been investigated by low-temperature, polarization-resolved single-tube spectroscopy. These assemblies are based on zinc chlorin monomers and are considered as model systems that resemble the secondary structural elements in the natural light-harvesting systems of green (non)sulfur bacteria. Compared to the natural systems, the spectral parameters extracted from the single-nanotube spectra feature distributions with significantly smaller widths, which is ascribed to a tremendous reduction of structural heterogeneity in the artificial systems. Employing quantum chemical molecular modeling the spectra of individual nanotubes can be explained consistently only for a molecular packing model that is fundamentally different from those considered so far for the natural systems. Subsequent theoretical simulations reveal that the remaining spectral variations between single nanotubes can be traced back to small variations of the mutual orientations of the monomer transition dipole moments that are far beyond the resolving power of high-resolution electron microscopy imaging techniques.

An Economic Evaluation of Stopping Versus Continuing Tumor Necrosis Factor Inhibitor Treatment in Rheumatoid Arthritis Patients With Disease Remission or Low Disease Activity: Results From a Pragmatic Open-Label Trial.

OBJECTIVE: To evaluate, from a societal perspective, the incremental cost-effectiveness of withdrawing tumor necrosis factor inhibitor (TNFi) treatment compared to continuation of these drugs within a 1-year, randomized trial among rheumatoid arthritis patients with longstanding, stable disease activity or remission. METHODS: Data were collected from a pragmatic, open-label trial. Cost-utility analysis was performed using the nonparametric bootstrapping method, and a cost-effectiveness acceptability curve was constructed using the net-monetary benefit framework, where a willingness-to-accept threshold (WTA) was defined as the minimal cost saved that a patient accepted for each quality-adjusted life year (QALY) lost. RESULTS: A total of 531 patients were randomized to the stop group and 286 patients to the continuation group. Withdrawal of TNFi treatment resulted in a >60% reduction of the total drug cost, but led to an increase of ∼30% in other health care expenditures. Compared to continuation, stopping TNFi resulted in a mean yearly cost saving of €7,133 (95% confidence interval [95% CI] €6,071, €8,234]) and was associated with a mean loss of QALYs of 0.02 (95% CI 0.002, 0.040). Mean saved cost per QALY lost and per extra flare incurred in the stop group compared to the continuation group was €368,269 (95% CI €155,132, €1,675,909) and €17,670 (95% CI €13,650, €22,721), respectively. At a WTA of €98,438 per QALY lost, the probability that stopping TNFi treatment is cost-effective was 100%. CONCLUSION: Although an official WTA is not defined, the mean saved cost of €368,269 per QALY lost seems acceptable in The Netherlands, given existing data on willingness to pay.

2016 updated EULAR evidence-based recommendations for the management of gout.

BACKGROUND: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. METHODS: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. RESULTS: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. CONCLUSIONS: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

Crystal identification of synovial fluid aspiration by polarized light microscopy. An online test suggesting that our traditional rheumatologic competence needs renewed attention and training.

Testing a reading exercise for identification of several typical crystal such as the negatively birefringent needle-shaped crystals that are under polarized light microscopy is the gold standard for diagnosing gout. The objective of this study was to assess current performance of crystal identification by professionals involved in examining synovial fluid in routine care. Rheumatologists, trainees, lab technicians, and other physicians with an interest in crystal arthritis completed an online test. The test consisted of 30 images: 8 monosodium urate (MSU) crystals, 5 calcium pyrophosphate (CPP), 4 cholesterol, 2 depot methylprednisolone, 2 calcium oxalate, 2 rice bodies, 1 hydroxyapatite, 1 liquid lipid, 1 fibrin, 1 Charcot-Leyden, and 5 different artifacts. Of the 22 non-MSU slides, a subset of 8 was pre-designated that were thought to be clinically important to be identified as non-MSU. The primary outcome was defined as the correct identification of all eight MSU slides plus the identification of all eight pre-defined non-MSU slides as non-MSU. The online test was completed by 110 participants. The primary outcome was achieved by 39%. Correct identification of all MSU images was achieved by 81%, correct identification of all 8 pre-defined non-MSU, CPP images, and all 22 non-MSU images as non-MSU by 68, 68, and 23%, respectively. MSU crystals were well identified, but incorrect identification of non-MSU crystals occurred frequently. This study suggests that there is room for improvement regarding crystal identification of particularly CPP and other non-MSU crystals even in this highly motivated group.

Functionally active NKG2A-expressing natural killer cells are elevated in rheumatoid arthritis patients compared to psoriatic arthritis patients and healthy donors.

OBJECTIVES: Natural killer cell receptors (NKR) have been implicated in rheumatoid (RA) and psoriatic arthritis (PsA) pathogenesis. To gain more insight into their role, we characterised NKR (co-)expression patterns on NK and T cells and NK cell function in RA and PsA. METHODS: The frequency of NK and T cells expressing killer like immunoglobulin (KIR) and NKG2 receptors and natural cytotoxicity receptors was assessed by 10-colour flow cytometry in peripheral blood of 23 RA, 12 PsA patients and 18 healthy donors (HD). NK cell cytotoxicity and IFN-gamma production was assessed in 8 RA patients and 8 HD. RESULTS: In RA but not PsA, the frequency of NK cells (median; range) expressing NKG2A (42%; 14-81%) was elevated compared to HD (23%; 9-58%). NKG2A⁺ NK cells predominantly lack KIR, but display normal cytotoxicity and IFN-γ production. In contrast, RA patients with normal NKG2A⁺ NK cell frequency have less functional NK cells compared to HD. T cells expressing Fc-gamma receptor CD16 were elevated in RA (median 0.75%) versus HD (0.3%). Furthermore, T cells expressing the KIRs CD158ah in both RA (0.7%) and PsA (0.3%), and CD158e1e2 in RA (1.5%) were elevated compared to HD (0.2% and 0.4%, respectively). In RA, CD4⁺ T cells expressing the KIRs CD158ah, CD158b1b2j and CD158e1e2 were low (<2%) but significantly elevated compared to HD. CONCLUSIONS: This study demonstrates the presence of an elevated, functionally active NKG2A⁺ KIR- NK cell population in RA. Together with an elevated frequency of NKR-expressing T cells, these changes may reflect differential pathogenetic involvement.

Atomistic modeling of two-dimensional electronic spectra and excited-state dynamics for a Light Harvesting 2 complex.

The Light Harvesting 2 (LH2) complex is a vital part of the photosystem of purple bacteria. It is responsible for the absorption of light and transport of the resulting excitations to the reaction center in a highly efficient manner. A general description of the chromophores and the interaction with their local environment is crucial to understand this highly efficient energy transport. Here we include this interaction in an atomistic way using mixed quantum-classical (molecular dynamics) simulations of spectra. In particular, we present the first atomistic simulation of nonlinear optical spectra for LH2 and use it to study the energy transport within the complex. We show that the frequency distributions of the pigments strongly depend on their positions with respect to the protein scaffold and dynamics of their local environment. Furthermore, we show that although the pigments are closely packed the transition frequencies of neighboring pigments are essentially uncorrelated. We present the simulated linear absorption spectra for the LH2 complex and provide a detailed explanation of the states responsible for the observed two-band structure. Finally, we discuss the energy transfer within the complex by analyzing population transfer calculations and 2D spectra for different waiting times. We conclude that the energy transfer from the B800 ring to the B850 ring is mediated by intermediate states that are delocalized over both rings, allowing for a stepwise downhill energy transport.

Disease recurrence in localized scleroderma: a retrospective analysis of 344 patients with paediatric- or adult-onset disease.

BACKGROUND: Localized scleroderma (LoS) is characterized by a phase of disease activity followed by remission. However, disease recurrences occur. Knowledge concerning these recurrences can help prompt treatment, thereby preventing disease damage. OBJECTIVES: To investigate the frequency and characteristics of disease recurrences in paediatric- and adult-onset LoS, and to identify patient variables that are associated with a higher risk of disease recurrence. METHODS: Retrospective chart reviews were performed of patients with LoS. Data concerning the frequency and characteristics of the disease recurrences were collected. A multivariate analysis was performed to identify patient variables that were associated with a higher risk of disease recurrence. RESULTS: In total, 344 patients were included in the analysis, of whom 119 (35%) had paediatric-onset LoS and 225 (65%) had adult-onset LoS. Disease recurrence was present in 27% (n = 32) of the paediatric-onset group and 17% (n = 39) of the adult-onset group (P = 0·037). Multivariate analysis identified a statistically significant association between disease recurrence and the linear LoS of the limbs subtype, independent of age at disease onset. CONCLUSIONS: Recurrences in LoS occurred in almost one-quarter of the patients and were most frequent in the linear LoS of the limbs subtype, independent of age at disease onset. These disease recurrences can occur even after many years of quiescent disease. Awareness of the high recurrence rates may help treating physicians to recognize reactivation of the disease, leading to a decreased delay in treatment reinitiation.

OH-stretching in synthetic hydrogen-bonded chains.

We study hydrogen bond dynamics in stereoselectively synthesized polyalcohols by combining linear and two-dimensional (2D) infrared spectroscopy experiments with simulations. We consider two variants of the polyalcohols: the all-syn and all-anti tetrol, which because of their different stereochemistry of the hydroxyl groups form a linear hydrogen-bonded chain that is stable for tens of picoseconds or a system where hydrogen bonds are formed and broken on a picosecond timescale, respectively. The differences in structure and hydrogen bond dynamics gives rise to significant differences in the linear spectra for the two compounds. Furthermore, we show that the stronger hydrogen bonding for the all-syn variant leads to faster fluctuations of the site frequencies than for the all-anti one, which is reflected in the higher degree of homogeneous broadening in the 2D spectra. Because of the different stereochemistry, the coupling in the all-syn molecule is stronger than for the all-anti one, which leads to a faster delocalization of a local excitation. This explains the previously observed pump-frequency independent vibrational lifetime for the all-syn variant, since the excitation loses the memory of the pump frequency before relaxation. For the all-anti form, the coupling is weak and the excitation remains in the initially excited state, maintaining the memory of the pump frequency.

Additive value for ultrasonographic signal in a screening algorithm for patients presenting with acute mono-/oligoarthritis in whom gout is suspected.

Crystal arthritides such as gout can be detected by ultrasonography (US). This study reveals the performance of joint US (double contour sign (DCS), tophus (T), hyperechoic spots cq. "snow storm" (SS)) for diagnosing gout and calcium pyrophosphate dihydrate crystal deposition disease (CPPD) in patients with acute mono- or oligoarthritis (MOA). The gold standard is the presence of monosodium urate (MSU)/CPPD crystals. Fifty-four Dutch patients had an acute MOA. US was performed on the following six joints maximum: the arthritic joint, the contra lateral side, metatarsophalangeal (MTP)-1, and knees bilaterally in case of arthritis in one of these joints. In case of wrist/PIP/MCP-arthritis, the knees and MTP-1 were scanned. These were examined for DCS, T, SS, and intercartilage rim (CPPD). Synovial fluid was aspirated from the affected joint for MSU proof. Twenty-six of the 54 (48 %) patients with MOA had MSU-proven gout. Sensitivity of DCS and any US abnormality (DCS, T, SS) was 77 and 96 %, respectively. The positive likelihood ratio (LR+) for DCS and any ultrasonographic abnormality (USabn) was 3.08 and 2.99, respectively, and the LR- was 0.31 and 0.06, respectively. In MSU-proven gout patients where the affected joint is not MTP-1, MTP-1 still showed USabn in 42 % of the patients. None of the CPPD patients had an intercartilage rim. In dedicated hands, ultrasonography deserves a place early in a screening algorithm of MOA patients, particularly if specificity is high enough to make punctures abundant or when microscopy is not available. In 86 % of the MSU-proven gout patients, the DCS is not present in another joint other than the affected or MTP-1 joint.

Calculating two-dimensional spectra with the mixed quantum-classical Ehrenfest method.

We present a mixed quantum-classical simulation approach to calculate two-dimensional spectra of coupled two-level electronic model systems. We include the change in potential energy of the classical system due to transitions in the quantum system using the Ehrenfest method. We study how this feedback of the quantum system on the classical system influences the shape of two-dimensional spectra. We show that the feedback leads to the expected Stokes shift of the energy levels in the quantum system. This subsequently leads to changes in the population transfer between quantum sites, which in turn influence the intensities of the peaks in two-dimensional spectra. The obtained spectra are compared with spectra calculated using the Hierarchical Equations of Motion method which is exact. While the spectra match perfectly for short waiting times, clear differences are found for longer waiting times. This is attributed to a violation of detailed balance between the quantum states in the Ehrenfest method. The energy of the total quantum-classical system however does obey a Boltzmann distribution, when coupled to a stochastic heat bath.

European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.

OBJECTIVES: To agree terminology and to develop recommendations for the diagnosis of calcium pyrophosphate deposition (CPPD). METHODS: The European League Against Rheumatism (EULAR) CPPD Task Force, comprising 15 experts from 10 countries, agreed the terms and recommendations for diagnosis of CPPD using a Delphi consensus approach. Evidence was systematically reviewed and presented in terms of sensitivity, specificity and positive likelihood ratio (LR) to support diagnosis; ORs were used for association. Strength of recommendation (SOR) was assessed by the EULAR visual analogue scale. RESULTS: It was agreed that 'CPPD' should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis. Chondrocalcinosis (CC) defines cartilage calcification, most commonly due to CPPD and detected by imaging or histological examination. A total of 11 key recommendations were generated on the topics of clinical features, synovial fluid (SF) examination, imaging, comorbidities and risk factors. Definitive diagnosis of CPPD relies on identification of SF CPP crystals. Rapid onset inflammatory symptoms and signs are suggestive but not definitive for acute CPP crystal arthritis. Radiographic CC is not highly sensitive or specific, whereas ultrasonography appears more useful (LR=24.2, 95% CI 3.51 to 168.01) for peripheral joints. Recognised risk factors for CPPD include ageing, OA and metabolic conditions such as primary hyperparathyroidism, haemochromatosis and hypomagnesaemia; familial forms are rare. SORs varied from 53 to 99 (maximum 100). CONCLUSION: New terms for CPPD were agreed and 11 key recommendations for diagnosis of CPPD were developed using research evidence and expert consensus.

EULAR recommendations for calcium pyrophosphate deposition. Part II: management.

OBJECTIVES: To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). METHODS: A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. RESULTS: Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5-1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low-dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. CONCLUSION: Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations.