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Arylazopyrazoles represent a new family of molecular photoswitches characterized by a near-quantitative conversion between two states and long thermal half-lives of the metastable state. Here, we investigated the behavior of a model arylazopyrazole in the presence of a self-assembled cage based on Pd-imidazole coordination. Owing to its high water solubility, the cage can solubilize the E isomer of arylazopyrazole, which, by itself, is not soluble in water. NMR spectroscopy and X-ray crystallography have independently demonstrated that each cage can encapsulate two molecules of E -arylazopyrazole. UV-induced switching to the Z isomer was accompanied by the release of one of the two guests from the cage and the formation of a 1:1 cage/ Z -arylazopyrazole inclusion complex. DFT calculations suggest that this process involves a dramatic change in the conformation of the cage. Back-isomerization was induced with green light and resulted in the initial 1:2 cage/ E -arylazopyrazole complex. This back-isomerization reaction also proceeded in the dark, with a rate significantly higher than in the absence of the cage., (Copyright © 2019, Hanopolskyi et al.; licensee Beilstein-Institut.)

Introduction: Multimorbidity and polypharmacy are major risk factors for potentially inappropriate prescribing (eg, overprescribing and underprescribing), and systematic medication reviews are complex and time consuming. In this trial, the investigators aim to determine if a systematic software-based medication review improves medication appropriateness more than standard care in older, multimorbid patients with polypharmacy., Methods and Analysis: Optimising PharmacoTherapy In the multimorbid elderly in primary CAre is a cluster randomised controlled trial that will include outpatients from the Swiss primary care setting, aged ≥65 years with ≥three chronic medical conditions and concurrent use of ≥five chronic medications. Patients treated by the same general practitioner (GP) constitute a cluster, and clusters are randomised 1:1 to either a standard care sham intervention, in which the GP discusses with the patient if the medication list is complete, or a systematic medication review intervention based on the use of the 'Systematic Tool to Reduce Inappropriate Prescribing'-Assistant (STRIPA). STRIPA is a web-based clinical decision support system that helps customise medication reviews. It is based on the validated 'Screening Tool of Older Person's Prescriptions' (STOPP) and 'Screening Tool to Alert doctors to Right Treatment' (START) criteria to detect potentially inappropriate prescribing. The trial's follow-up period is 12 months. Outcomes will be assessed at baseline, 6 and 12 months. The primary endpoint is medication appropriateness, as measured jointly by the change in the Medication Appropriateness Index (MAI) and Assessment of Underutilisation (AOU). Secondary endpoints include the degree of polypharmacy, overprescribing and underprescribing, the number of falls and fractures, quality of life, the amount of formal and informal care received by patients, survival, patients' quality adjusted life years, patients' medical costs, cost-effectiveness of the intervention, percentage of recommendations accepted by GPs, percentage of recommendation rejected by GPs and patients' willingness to have medications deprescribed., Ethics and Dissemination: The ethics committee of the canton of Bern in Switzerland approved the trial protocol. The results of this trial will be published in a peer-reviewed journal., Main Funding: Swiss National Science Foundation, National Research Programme (NRP 74) 'Smarter Healthcare'., Trial Registration Numbers: Clinicaltrials.gov (NCT03724539), KOFAM (Swiss national portal) (SNCTP000003060), Universal Trial Number (U1111-1226-8013)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Multimorbidity and polypharmacy are important risk factors for drug-related hospital admissions (DRAs). DRAs are often linked to prescribing problems (overprescribing and underprescribing), as well as non-adherence with drug regimens for different reasons. In this trial, we aim to assess whether a structured medication review compared with standard care can reduce DRAs in multimorbid older patients with polypharmacy., Methods and Analysis: OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people is a European multicentre, cluster randomised, controlled trial. Hospitalised patients ≥70 years with ≥3 chronic medical conditions and concurrent use of ≥5 chronic medications are included in the four participating study centres of Bern (Switzerland), Utrecht (The Netherlands), Brussels (Belgium) and Cork (Ireland). Patients treated by the same prescribing physician constitute a cluster, and clusters are randomised 1:1 to either standard care or Systematic Tool to Reduce Inappropriate Prescribing (STRIP) intervention with the help of a clinical decision support system, the STRIP Assistant. STRIP is a structured method performing customised medication reviews, based on Screening Tool of Older People's Prescriptions/Screening  Tool to Alert to Right Treatment criteria to detect potentially inappropriate prescribing. The primary endpoint is any DRA where the main reason or a contributory reason for the patient's admission is caused by overtreatment or undertreatment, and/or inappropriate treatment. Secondary endpoints include number of any hospitalisations, all-cause mortality, number of falls, quality of life, degree of polypharmacy, activities of daily living, patient's drug compliance, the number of significant drug-drug interactions, drug overuse and underuse and potentially inappropriate medication., Ethics and Dissemination: The local Ethics Committees in Switzerland, Ireland, The Netherlands and Belgium approved this trial protocol. We will publish the results of this trial in a peer-reviewed journal., Main Funding: European Union's Horizon 2020 programme., Trial Registration Number: NCT02986425 , SNCTP000002183 , NTR6012, U1111-1181-9400., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses., Objective: To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism., Data Sources: PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018., Study Selection: Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers., Data Extraction and Synthesis: Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied., Main Outcomes and Measures: General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months., Results: Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high., Conclusions and Relevance: Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.

Context: Anemia and thyroid dysfunction often co-occur, and both increase with age. Human data on relationships between thyroid disease and anemia are scarce., Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia., Design: Individual participant data meta-analysis., Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n = 42,162)., Main Outcome Measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women)., Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants [overt hypothyroidism, pooled OR 1.84 (95% CI 1.35 to 2.50), subclinical hypothyroidism 1.21 (1.02 to 1.43), subclinical hyperthyroidism 1.27 (1.03 to 1.57), and overt hyperthyroidism 1.69 (1.00 to 2.87)]. Hemoglobin levels were lower in all groups compared with participants with euthyroidism. In the longitudinal analyses (n = 25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 (95% CI 0.86 to 2.20) for overt hypothyroidism, 1.18 (1.00 to 1.38) for subclinical hypothyroidism, 1.15 (0.94 to 1.42) for subclinical hyperthyroidism, and 1.47 (0.91 to 2.38) for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups., Conclusion: Higher odds of having anemia were observed in participants with both hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

Context: Subclinical hypothyroidism (SHypo) has been associated with atherosclerosis, but no conclusive clinical trials assessing the levothyroxine impact on carotid atherosclerosis exist., Objective: To assess the impact of treatment of SHypo with levothyroxine on carotid atherosclerosis., Design and Setting: Randomized, double-blind, placebo-controlled trial nested within the Thyroid Hormone Replacement for Subclinical Hypothyroidism trial., Participants: Participants aged ≥65 years with SHypo [thyroid-stimulating hormone (TSH), 4.60 to 19.99 mIU/L; free thyroxine level within reference range]., Intervention: Levothyroxine dose-titrated to achieve TSH normalization or placebo, including mock titrations., Main Outcome Measures: Carotid intima media thickness (CIMT), maximum plaque thickness measured with ultrasound., Results: One hundred eighty-five participants (mean age 74.1 years, 47% women, 96 randomized to levothyroxine) underwent carotid ultrasound. Overall mean TSH ± SD was 6.35 ± 1.95 mIU/L at baseline and decreased to 3.55 ± 2.14 mIU/L with levothyroxine compared with 5.29 ± 2.21 mIU/L with placebo (P < 0.001). After a median treatment of 18.4 months (interquartile range 12.2 to 30.0 months), mean CIMT was 0.85 ± 0.14 mm under levothyroxine and 0.82 ± 0.13 mm under placebo [between-group difference = 0.02 mm; 95% CI, -0.01 to 0.06; P = 0.30]. The proportion of carotid plaque was similar (n = 135; 70.8% under levothyroxine and 75.3% under placebo; P = 0.46). Maximum carotid plaque thickness was 2.38 ± 0.92 mm under levothyroxine and 2.37 ± 0.91 mm under placebo (between-group difference -0.03; 95% CI, -0.34 to 0.29; P = 0.86). There were no significant interactions between levothyroxine treatment and mean CIMT, according to sex, baseline TSH (categories 4.6 to 6.9, 7.0 to 9.9, and ≥10 mIU/L), or established cardiovascular disease (all P for interaction ≥ 0.14)., Conclusion: Normalization of TSH with levothyroxine was associated with no difference in CIMT and carotid atherosclerosis in older persons with SHypo.

The unique synthesis and reactivity of [( R PNP*)NiH] complexes ( 1a , b ), based on metal-ligand cooperation (MLC), are presented ( R PNP* = deprotonated PNP ligand, R = i Pr, t Bu). Unexpectedly, the dearomatized complexes 1a , b were obtained by reduction of the dicationic complexes [( R PNP)Ni(MeCN)](BF 4 ) 2 with sodium amalgam or by reaction of the free ligand with Ni 0 (COD) 2 . Complex 1b reacts with CO via MLC, to give a rare case of a distorted-octahedral PNP-based pincer complex, the Ni(0) complex 3b . Complexes 1a , b also react with CO 2 via MLC to form a rare example of η 1 binding of CO 2 to nickel, complexes 4a , b . An unusual CO 2 cleavage process by complex 4b , involving C-O and C-P cleavage and C-C bond formation, led to the Ni-CO complex 3b and to the new complex [(P i Pr 2 NC 2 O 2 )Ni(P(O) i Pr 2 )] ( 5b ). All complexes have been fully characterized by NMR and X-ray crystallography., Competing Interests: The authors declare no competing financial interest.

Both CO and N 2 O are important, environmentally harmful industrial gases. The reaction of CO and N 2 O to produce CO 2 and N 2 has stimulated much research interest aimed at degradation of these two gases in a single step. Herein, we report an efficient CO oxidation by N 2 O catalyzed by a (PNN)Ru-H pincer complex under mild conditions, even with no added base. The reaction is proposed to proceed through a sequence of O-atom transfer (OAT) from N 2 O to the Ru-H bond to form a Ru-OH intermediate, followed by intramolecular OH attack on an adjacent CO ligand, forming CO 2 and N 2 . Thus, the Ru-H bond of the catalyst plays a central role in facilitating the OAT from N 2 O to CO, providing an efficient and novel protocol for CO oxidation.

The first example of oxidative addition of a C-H bond to a square planar d8-Iridium complex, without any external additive, such as an acid, is described. Our mechanistic investigations show that metal-ligand cooperation through aromatization-dearomatization of the lutidine backbone is involved in this process, and that the actual C-H activation step occurs through an Ir(iii) intermediate.

Background: Even though the association between thyroid dysfunction and anemia is commonly described, it is not known whether it is clinically relevant. This study set out to quantify the association of thyroid dysfunction on hemoglobin (Hb) concentration and risk of anemia. A systematic review (MEDLINE and EMBASE, from inception until May 15, 2017) was conducted to interpret the findings in context., Methods: Participants from the EPIC-Norfolk cohort with available baseline thyrotropin (TSH), free thyroxine (fT4), and Hb were included. Euthyroidism was defined as TSH 0.45-4.49 mIU/L (reference category), hypothyroidism as TSH ≥4.50 mIU/L (subclinical [SHypo] with normal fT4 or overt [OHypo] with low fT4), and hyperthyroidism as TSH ≤0.44 mIU/L (subclinical [SHyper] with normal fT4 or overt [OHyper] with elevated fT4). Anemia was defined as Hb <12 g/dL in women and Hb <13 g/dL in men. In the cross-sectional analyses, multiple linear regression was used to compare Hb across TSH categories. In the prospective analysis, participants with OHypo/OHyper at baseline were excluded, as it was assumed that they were treated for overt thyroid disease. A covariance model was used to determine change in Hb concentration from baseline to last follow-up, and multivariable Cox regression was used to analyze anemia risk., Results: In the cross-sectional population (n = 12,337), the adjusted Hb was 0.22 g/dL lower [confidence interval (CI) 0.07-0.38] in OHypo compared to euthyroids, and 0.08 g/dL lower [CI -0.23 to 0.38] in OHyper. In the prospective analysis, 460/7031 participants developed anemia over a median follow-up of 4.7 years. The adjusted mean Hb change over time was -0.04 g/dL in SHypo [CI -0.14 to 0.06] and 0.05 g/dL in SHyper [CI -0.10 to 0.20]. The adjusted hazard ratio for anemia was 0.99 [CI 0.67-1.48] in SHypo, and 0.52 [CI 0.23-1.16] in SHyper. The systematic review returned no other prospective studies on this association, but cross-sectional and case-control studies showed comparable results., Conclusion: In this first prospective population-based cohort, subclinical thyroid dysfunction was not associated with a change in Hb concentration during follow-up and was not an independent risk factor for developing anemia; variations in Hb concentration in patients with overt thyroid dysfunction were not clinically relevant.

Objective: Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one-step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction., Design: Cross-sectional analysis of the population-based Busselton Health Study., Methods: We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta-coefficient based scoring method., Results: Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing., Conclusion: The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4.

Subclinical hypothyroidism, defined as an elevated level of thyrotropin hormone (TSH) and normal thyroxin, is more frequent in women and above 65 years old. This condition is associated with an increased cardiovascular risk, in particular with TSH > 10,0 mIU/L. Although overt hypothyroidism is rare (prevalence of 0,3 %), levothyroxine has become the most prescribed medication in the US, while its indications are still debated. The European-funded TRUST trial showed no improvement in Hypothyroid Symptoms and Tiredness scores among patients ≥ 65 years with subclinical hypothyroidism treated with levothyroxine, and no improvement in blood pressure, weight, muscle strength and cognition. The results of this study call for a revision of the current international recommendations on the treatment of subclinical hypothyroidism., Competing Interests: Les auteurs de cet article ont participé à des publications de la Thyroid Studies Collaboration (N.R. investigateur principal) et au déroulement de l’étude TRUST (tous les coauteurs ; N.R. investigateur principal pour la Suisse). Ces travaux de recherche ont été soutenus par des fonds de recherche de l’Union européenne (programme EU-FP7-HEALTH-2011, grant 278148), du Fonds national suisse (SNSF 320030‑150025, N.R.), de la Fondation Velux (Projet 974a) et de la Fondation suisse de cardiologie. Les autres projets de recherche des auteurs sont soutenus par le Fonds national suisse (T.H.C., C.B., M.R.B., N.R.), la Fondation Leenaards (G.P.S.) et la Société suisse d’endocrinologie et diabétologie (T.H.C., G.P.S.). Les auteurs n’ont pas de conflit d’intérêts potentiels à déclarer.

Background: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear., Objective: To investigate the association between subclinical thyroid dysfunction and bone loss., Methods: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946-2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45-4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50-19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach., Results: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = -0.18 (95% CI: -0.34, -0.02; I 2 = 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = -0.14 (95% CI: -0.38, 0.10; I 2 = 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: -0.30, 0.36; I 2 = 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = -0.59; [95% CI: -0.99, -0.19]) and total hip region (%ΔBMD = -0.46 [95% CI: -1.05, -0.13]). In contrast, SHypo was not associated with bone loss at any site., Conclusion: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk., (© 2017 The Association for the Publication of the Journal of Internal Medicine.)

Objective: Healthy subjects can learn to use cognitive-emotional strategies to suppress their spinal nociception, quantified by the nociceptive flexor reflex (RIII reflex), when given visual RIII feedback. This likely reflects learned activation of descending pain inhibition. Here, we investigated if training success persists 4 and 8 months after the end of RIII feedback training, and if transfer (RIII suppression without feedback) is possible., Methods: 18 and 8 subjects who had successfully completed feedback training were investigated 4 and 8 months later., Results: At 4 months, RIII suppression during feedback and transfer was similar to that achieved at the final RIII feedback training session (to 50 ± 22%, 53 ± 21% and 52 ± 21% of baseline, all differences n.s.). At 8 months, RIII suppression was somewhat (not significantly) smaller in the feedback run (to 64 ± 17%) compared to the final training session (56 ± 19%). Feedback and transfer runs were similar (to 64 ± 17% vs. 68 ± 24%, n.s.). Concomitant reductions in pain intensity ratings were stable at 4 and 8 months., Conclusions: RIII feedback training success was completely maintained after 4 months, and somewhat attenuated 8 months after training. Transfer was successful., Significance: These results are an important pre-requisite for application of RIII feedback training in the context of clinical pain., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF., Methods: We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF., Results: Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease., Conclusions: In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF., (© 2017 American Heart Association, Inc.)

Objective: Data on the association between subclinical thyroid dysfunction and dementia are limited and conflicting. We aimed to determine whether subclinical thyroid dysfunction was associated with dementia and cognitive decline., Design: Population-based prospective cohort study., Patients: Adults aged 70-79 years with measured thyroid function, but no dementia at baseline, and Modified Mini-Mental State (3MS) at baseline and follow-up., Measurements: Primary outcome was incident-adjudicated dementia, based on 3MS, hospital records and dementia drugs. Secondary outcome was change in 3MS. Models were adjusted for age, sex, race, education and baseline 3MS, and then further for cardiovascular risk factors., Results: Among 2558 adults, 85% were euthyroid (TSH 0.45-4.49mIU/L), 2% had subclinical hyperthyroidism with mildly decreased TSH (TSH 0.10-0.44 mIU/L), 1% subclinical hyperthyroidism with suppressed TSH (TSH < 0.10 mIU/L with normal free thyroxine [FT4]) and 12% subclinical hypothyroidism (TSH 4.50-19.99 mIU/L with normal FT4). Over 9 years, 22% developed dementia. Compared to euthyroidism, risk of dementia was higher in participants with subclinical hyperthyroidism with suppressed TSH (HR 2.38, 95% CI = 1.13;5.04), while we found no significant association in those with mildly decreased TSH (HR 0.79, 95% CI = 0.45;1.38) or with subclinical hypothyroidism (HR 0.91, 95% CI = 0.70;1.19). Participants with subclinical hyperthyroidism with suppressed TSH had a larger decline in 3MS (-3.89, 95% CI = -7.62; -0.15)., Conclusions: Among older adults, subclinical hyperthyroidism with a TSH < 0.10 mIU/L was associated with a higher risk of dementia and a larger cognitive decline, while subclinical hyperthyroidism with mildly decreased TSH or subclinical hypothyroidism were not., (© 2017 John Wiley & Sons Ltd.)

Images projected onto the retina of an animal eye are rarely still. Instead, they usually contain motion signals originating either from moving objects or from retinal slip caused by self-motion. Accordingly, motion signals tell the animal in which direction a predator, prey, or the animal itself is moving. At the neural level, visual motion detection has been proposed to extract directional information by a delay-and-compare mechanism, representing a classic example of neural computation. Neurons responding selectively to motion in one but not in the other direction have been identified in many systems, most prominently in the mammalian retina and the fly optic lobe. Technological advances have now allowed researchers to characterize these neurons' upstream circuits in exquisite detail. Focusing on these upstream circuits, we review and compare recent progress in understanding the mechanisms that generate direction selectivity in the early visual system of mammals and flies.

Background: The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition., Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points)., Results: The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest., Conclusions: Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

Due to its significant contribution to stratospheric ozone depletion and its potent greenhouse effect, nitrous oxide has stimulated much research interest regarding its reactivity modes and its transformations, which can lead to its abatement. We report the homogeneously catalyzed reaction of nitrous oxide (N 2 O) with H 2 . The reaction is catalyzed by a PNP pincer ruthenium complex, generating efficiently only dinitrogen and water, under mild conditions, thus providing a green, mild methodology for removal of nitrous oxide. The reaction proceeds through a sequence of dihydrogen activation, "O"-atom transfer, and dehydration, in which metal-ligand cooperation plays a central role. This approach was further developed to catalytic O-transfer from N 2 O to Si-H bonds.

Objectives: Listeria monocytogenes is a food-borne pathogen that can cause meningitis. The listerial genotype ST6 has been linked to increasing rates of unfavourable outcome over time. We investigated listerial genetic variation and the relation with clinical outcome in meningitis., Methods: We sequenced 96 isolates from adults with listerial meningitis included in two prospective nationwide cohort studies by whole genome sequencing, and evaluated associations between bacterial genetic variation and clinical outcome. We validated these results by screening listerial genotypes of 445 cerebrospinal fluid and blood isolates from patients over a 30-year period from the Dutch national surveillance cohort., Results: We identified a bacteriophage, phiLMST6 co-occurring with a novel plasmid, pLMST6, in ST6 isolates to be associated with unfavourable outcome in patients (p 2.83e-05). The plasmid carries a benzalkonium chloride tolerance gene, emrC, conferring decreased susceptibility to disinfectants used in the food-processing industry. Isolates harbouring emrC were growth inhibited at higher levels of benzalkonium chloride (median 60 mg/L versus 15 mg/L; p <0.001), and had higher MICs for amoxicillin and gentamicin compared with isolates without emrC (both p <0.001). Transformation of pLMST6 into naive strains led to benzalkonium chloride tolerance and higher MICs for gentamicin., Conclusions: These results show that a novel plasmid, carrying the efflux transporter emrC, is associated with increased incidence of ST6 listerial meningitis in the Netherlands. Suggesting increased disease severity, our findings warrant consideration of disinfectants used in the food-processing industry that select for resistance mechanisms and may, inadvertently, lead to increased risk of poor disease outcome., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Forests are being clearcut over extensive areas of western North America, but plant community response to harvesting and slashburning under varying climatic conditions in central British Columbia, Canada is still largely unknown. Evaluation of resilience is hampered by the short history of logging, lack of long-term experiments and methodological limitations. To test the effect of clearcut logging, prescribed burning and reforestation on forest resilience, we recorded vascular plant cover repeatedly after treatment between 1981 and 2008 in 16 permanent research installations in three biogeoclimatic zones: Engelmann Spruce-Subalpine Fir, Interior Cedar-Hemlock and Sub-Boreal Spruce. We created a plant-trait dataset for the 181 recorded species to define plant functional types representing groups of plants that behave in similar ways and/or produce similar ecological outcomes. These plant functional types, along with taxonomic analysis of diagnostic and indicator species, were then used to evaluate plant community response to disturbance. Twenty years post-treatment, species diversity increased in all zones and plant abundance was greatest in the Interior Cedar-Hemlock. Cover of understory plant functional types associated with mature conifer forests increased in all zones, constituting a significant proportion (> 40%) of the vegetation community by year 20. Response patterns varied by zone and with time. Understory species diagnostic of mature forests were present in all zones by year 20, but we identified indicator species sensitive to slashburning or requiring more time for recovery, including white-flowered rhododendron (Rhododendron albiflorum) and devil's club (Oplopanax horridus). Overall, loss of compositional or functional diversity following harvest and site remediation was not detected, suggesting that montane and subalpine forests in British Columbia are resilient to this treatment. However, because these forests can be slow to recover from disturbance, the post-disturbance assessment window of this study may not have been long enough to detect diminishment of ecosystem resilience.

The use of carbon dioxide for synthetic applications presents a major goal in modern homogeneous catalysis. Rhodium-hydride PNP pincer complex 1 is shown to add CO2 in two disparate pathways: one is the expected insertion of CO2 into the metal-hydride bond, and the other leads to reductive cleavage of CO2, involving metal-ligand cooperation. The resultant rhodium-carbonyl complex was found to be photoactive, enabling the activation of benzene and formation of a new benzoyl complex. Organometallic intermediate species were observed and characterized by NMR spectroscopy and X-ray crystallography. Based on the series of individual transformations, a sequence for the photocarbonylation of benzene using CO2 as the feedstock was constructed and demonstrated for the production of benzaldehyde from benzene.

Accurate ground-based estimation of the carbon stored in terrestrial ecosystems is critical to quantifying the global carbon budget. Allometric models provide cost-effective methods for biomass prediction. But do such models vary with ecoregion or plant functional type? We compiled 15 054 measurements of individual tree or shrub biomass from across Australia to examine the generality of allometric models for above-ground biomass prediction. This provided a robust case study because Australia includes ecoregions ranging from arid shrublands to tropical rainforests, and has a rich history of biomass research, particularly in planted forests. Regardless of ecoregion, for five broad categories of plant functional type (shrubs; multistemmed trees; trees of the genus Eucalyptus and closely related genera; other trees of high wood density; and other trees of low wood density), relationships between biomass and stem diameter were generic. Simple power-law models explained 84-95% of the variation in biomass, with little improvement in model performance when other plant variables (height, bole wood density), or site characteristics (climate, age, management) were included. Predictions of stand-based biomass from allometric models of varying levels of generalization (species-specific, plant functional type) were validated using whole-plot harvest data from 17 contrasting stands (range: 9-356 Mg ha(-1) ). Losses in efficiency of prediction were <1% if generalized models were used in place of species-specific models. Furthermore, application of generalized multispecies models did not introduce significant bias in biomass prediction in 92% of the 53 species tested. Further, overall efficiency of stand-level biomass prediction was 99%, with a mean absolute prediction error of only 13%. Hence, for cost-effective prediction of biomass across a wide range of stands, we recommend use of generic allometric models based on plant functional types. Development of new species-specific models is only warranted when gains in accuracy of stand-based predictions are relatively high (e.g. high-value monocultures)., (© 2015 John Wiley & Sons Ltd.)

A unique mode of stoichiometric CO2 activation and reductive splitting based on metal-ligand-cooperation is described. The novel Ir hydride complexes [((t)Bu-PNP*)Ir(H)2] (2) ((t)Bu-PNP*, deprotonated (t)Bu-PNP ligand) and [((t)Bu-PNP)Ir(H)] (3) react with CO2 to give the dearomatized complex [((t)Bu-PNP*)Ir(CO)] (4) and water. Mechanistic studies have identified an adduct in which CO2 is bound to the ligand and metal, [((t)Bu-PNP-COO)Ir(H)2] (5), and a di-CO2 iridacycle [((t)Bu-PNP)Ir(H)(C2O4-κC,O)] (6). DFT calculations confirm the formation of 5 and 6 as reversibly formed side products, and suggest an η(1)-CO2 intermediate leading to the thermodynamic product 4. The calculations support a metal-ligand-cooperation pathway in which an internal deprotonation of the benzylic position by the η(1)-CO2 ligand leads to a carboxylate intermediate, which further reacts with the hydride ligand to give complex 4 and water.

Children living near highways are exposed to higher concentrations of traffic-related carcinogenic pollutants. Several studies reported an increased risk of childhood cancer associated with traffic exposure, but the published evidence is inconclusive. We investigated whether cancer risk is associated with proximity of residence to highways in a nation-wide cohort study including all children aged <16 years from Swiss national censuses in 1990 and 2000. Cancer incidence was investigated in time to event analyses (1990-2008) using Cox proportional hazards models and incidence density analyses (1985-2008) using Poisson regression. Adjustments were made for socio-economic factors, ionising background radiation and electromagnetic fields. In time to event analysis based on 532 cases the adjusted hazard ratio for leukaemia comparing children living <100 m from a highway with unexposed children (≥500 m) was 1.43 (95 % CI 0.79, 2.61). Results were similar in incidence density analysis including 1367 leukaemia cases (incidence rate ratio (IRR) 1.57; 95 % CI 1.09, 2.25). Associations were similar for acute lymphoblastic leukaemia (IRR 1.64; 95 % CI 1.10, 2.43) and stronger for leukaemia in children aged <5 years (IRR 1.92; 95 % CI 1.22, 3.04). Little evidence of association was found for other tumours. Our study suggests that young children living close to highways are at increased risk of developing leukaemia.

We have recently shown that subjects can learn to use cognitive-emotional strategies to suppress their spinal nociceptive flexor reflex (RIII reflex) under visual RIII feedback and proposed that this reflects learned activation of descending pain inhibition. Here, we investigated whether learned RIII suppression also affects supraspinal nociception and whether previous relaxation training increases success. Subjects were trained over 3 sessions to reduce their RIII size by self-selected cognitive-emotional strategies. Two groups received true RIII feedback (with or without previous relaxation training) and a sham group received false feedback (15 subjects per group). RIII reflexes, late somatosensory evoked potentials (SEPs), and F-waves were recorded and pain intensity ratings collected. Both true feedback groups achieved significant (P < 0.01) but similar RIII suppression (to 79% ± 21% and 70% ± 17% of control). Somatosensory evoked potential amplitude (100-150 milliseconds after stimulation) was reduced in parallel with the RIII size (r = 0.57, P < 0.01). In the sham group, neither RIII size nor SEP amplitude was significantly reduced during feedback training. Pain intensity was significantly reduced in all 3 groups and also correlated with RIII reduction (r = 0.44, P < 0.01). F-wave parameters were not affected during RIII suppression. The present results show that learned RIII suppression also affects supraspinal nociception as quantified by SEPs, although effects on pain ratings were less clear. Lower motor neuron excitability as quantified by F-waves was not affected. Previous relaxation training did not significantly improve RIII feedback training success.

A unique mode of molecular oxygen activation, involving metal-ligand cooperation, is described. Ir pincer complexes [((t)BuPNP)Ir(R)] (R = C6H5 (1), CH2COCH3 (2)) react with O2 to form the dearomatized hydroxo complexes [((t)BuPNP*)Ir(R)(OH)] ((t)BuPNP* = deprotonated (t)BuPNP ligand), in a process which utilizes both O-atoms. Experimental evidence, including NMR, EPR, and mass analyses, indicates a binuclear mechanism involving an O-atom transfer by a peroxo intermediate.

Background: Descending pain modulatory systems control transmission of nociceptive information at the spinal level, and their activity can be modified by cognitive and emotional processes. Thus, it may be possible to learn using cognitive-emotional strategies to specifically target descending pathways in order to achieve pain reduction., Methods: The present study used visual feedback of the nociceptive flexor reflex (RIII reflex) to train healthy subjects over three sessions to reduce their spinal nociception (RIII reflex size) by self-selected cognitive-emotional strategies. The study included two feedback groups (fixed vs. random stimulation intervals) and a control group without feedback (15 subjects each)., Results: While all three groups successfully reduced their RIII reflexes (p < 0.01), reductions were larger in the feedback groups (p < 0.05). Success increased over training sessions in the feedback groups (p < 0.05). In the third session, RIII was reduced to 90 ± 15% of baseline in the control group, and to 72 ± 24 and 66 ± 22% in the feedback groups. Most subjects used mental imagery or relaxation to achieve RIII reduction. Pain reduction correlated with RIII reduction in the feedback groups, but was not significantly different between feedback and control groups., Conclusions: The present results suggest that healthy subjects are able to learn using cognitive and emotional strategies to reduce their spinal nociception under feedback of their RIII reflex size. However, future studies will have to include a sham feedback group to differentiate true learning effects from expectancy effects induced by the feedback procedure., (© 2014 European Pain Federation - EFIC®)

Rare cases of directly observed reductive elimination (RE) of methyl halides from Rh(III) complexes are described. Treatment of the coordinatively unsaturated complexes [((t)BuPNP)Rh(CH3)X][BF4] (1-3, X = I, Br, and Cl; (t)BuPNP = 2,6-bis-(di-tert-butylphosphinomethyl)pyridine) with coordinating and noncoordinating compounds results in the formation of the corresponding free methyl halides and Rh(I) complexes. The rate increase of CH3I and CH3Br RE in the presence of polar aprotic solvents argues in favor of an SN2 RE mechanism. However, the RE of CH3Cl is faster in polar protic solvents, which argues in favor of a concerted C-Cl RE. The RE of methyl halides from complexes 1-3 is induced by steric factors, as treatment of the less bulky complexes [((i)PrPNP)Rh(CH3)X][BF4] (19-21; X = I, Br, Cl, respectively) with coordinating compounds leads to the formation of the adducts complexes rather than RE of the methyl halides. The accumulated evidence suggests that the RE process is nonassociative.

Imines are selectively formed by coupling of nitriles and amines under mild hydrogen pressure. The reaction is catalyzed by a bipyridine-based PNN Ru(II) pincer complex and proceeds under mild, neutral conditions at 4 bar of H(2).

Tobacco smoking is a risk factor for atrial fibrillation (AF), but little is known about the impact of smoking in patients with AF. Of the 4060 patients with recurrent AF in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 496 (12%) reported having smoked during the past two years. Propensity scores for smoking were estimated for each of the 4060 patients using a multivariable logistic regression model and were used to assemble a matched cohort of 487 pairs of smokers and nonsmokers, who were balanced on 46 baseline characteristics. Cox and logistic regression models were used to estimate the associations of smoking with all-cause mortality and all-cause hospitalization, respectively, during over 5 years of follow-up. Matched participants had a mean age of 70 ± 9 years (± S.D.), 39% were women, and 11% were non-white. All-cause mortality occurred in 21% and 16% of matched smokers and nonsmokers, respectively (when smokers were compared with nonsmokers, hazard ratio=HR=1.35; 95% confidence interval=95%CI=1.01-1.81; p=0.046). Unadjusted, multivariable-adjusted and propensity-adjusted HR (95% CI) for all-cause mortality associated with smoking in the pre-match cohort were: 1.40 (1.13-1.72; p=0.002), 1.45 (1.16-1.81; p=0.001), and 1.39 (1.12-1.74; p=0.003), respectively. Smoking had no association with all-cause hospitalization (when smokers were compared with nonsmokers, odds ratio=OR=1.21; 95%CI=0.94-1.57, p=0.146). Among patients with AF, a recent history of smoking was associated with an increased risk of all-cause mortality, but had no association with all-cause hospitalization., (Published by Elsevier Ireland Ltd.)

A recent study has found that spontaneous neural activity in the developing visual cortex has two distinct origins - local intracortical circuits and spontaneous activity in the retina., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Previous studies on childhood cancer and nuclear power plants (NPPs) produced conflicting results. We used a cohort approach to examine whether residence near NPPs was associated with leukaemia or any childhood cancer in Switzerland., Methods: We computed person-years at risk for children aged 0-15 years born in Switzerland from 1985 to 2009, based on the Swiss censuses 1990 and 2000 and identified cancer cases from the Swiss Childhood Cancer Registry. We geo-coded place of residence at birth and calculated incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing the risk of cancer in children born <5 km, 5-10 km and 10-15 km from the nearest NPP with children born >15 km away, using Poisson regression models., Results: We included 2925 children diagnosed with cancer during 21 117 524 person-years of follow-up; 953 (32.6%) had leukaemia. Eight and 12 children diagnosed with leukaemia at ages 0-4 and 0-15 years, and 18 and 31 children diagnosed with any cancer were born <5 km from a NPP. Compared with children born >15 km away, the IRRs (95% CI) for leukaemia in 0-4 and 0-15 year olds were 1.20 (0.60-2.41) and 1.05 (0.60-1.86), respectively. For any cancer, corresponding IRRs were 0.97 (0.61-1.54) and 0.89 (0.63-1.27). There was no evidence of a dose-response relationship with distance (P > 0.30). Results were similar for residence at diagnosis and at birth, and when adjusted for potential confounders. Results from sensitivity analyses were consistent with main results., Conclusions: This nationwide cohort study found little evidence of an association between residence near NPPs and the risk of leukaemia or any childhood cancer.

Background: To date, few risk factors for childhood acute lymphoblastic leukemia (ALL) have been confirmed and the scientific literature is full of controversial "evidence." We examined if family characteristics, particularly maternal and paternal age and number of older siblings, were risk factors for childhood acute lymphoblastic leukemia (ALL)., Methodology/principal Findings: In this population-based nationwide matched case-control study, patients 0-14 years of age with ALL diagnosed 1991-2006 and registered in the Swiss Childhood Cancer Registry were linked with their census records of 1990 and 2000. Eight controls per case were selected from the census. The association between family characteristics and ALL was analyzed by conditional logistic regressions. We found that increasing maternal age was associated with incidence of ALL in the offspring (OR per 5-year increase in maternal age 1.18, 95% CI 1.05-1.31; p = 0.004), remaining stable (trend OR 1.14, 95% CI 0.99-1.31; p = 0.060) after adjustment for other risk factors. The association with paternal age was weaker (OR per 5-year increase 1.14, 95% CI 1.01-1.28, p = 0.032) and disappeared after adjustments. Number of older siblings was not associated with risk of ALL in the overall group of children aged 0-14 years at diagnosis. However, we found a negative trend between number of older siblings and ALL diagnosed at age 0-4 years (OR per sibling 0.85, 95% CI 0.68-1.06; p = 0.141) and a positive trend for ALL diagnosed at age 5-9 (OR 1.34, 95% CI 1.05-1.72; p = 0.019), with some evidence for an effect modification (p-value for interaction  = 0.040)., Conclusions: As in other studies, increasing maternal, but not paternal age was associated with risk of ALL. We found only a weak association with the number of older siblings, suggesting a delay in disease manifestation rather than a decrease in incidence.

A series of cationic, neutral, and anionic Pd(II) and Pt(II) PNP (PNP = 2,6-bis-(di-tert-butylphosphinomethyl)pyridine) complexes were synthesized. The neutral, dearomatized complexes [(PNP*)MX] (PNP* = deprotonated PNP; M = Pd, Pt; X = Cl, Me) were prepared by deprotonation of the PNP methylene group of the corresponding cationic complexes [(PNP)MX][Cl] with 1 equiv of base (KN(SiMe(3))(2) or (t)BuOK), while the anionic complexes [(PNP**)MX](-)Y(+) (PNP** = double-deprotonated PNP; Y = Li, K) were prepared by deprotonation of the two methylene groups of the corresponding cationic complexes with either 2 equiv of KN(SiMe(3))(2) or an excess of MeLi. While the reaction of [(PNP)PtCl][Cl] with an excess of MeLi led only to the anionic complex without chloride substitution, reaction of [(PNP)PdCl][Cl] with an excess of MeLi led to the methylated anionic complex [(PNP**)PdMe](-)Li(+). NMR studies, X-ray structures, and density functional theory (DFT) calculations reveal that the neutral complexes have a "broken" aromatic system with alternating single and double bonds, and the deprotonated arm is bound to the ring by an exocyclic C=C double bond. The anionic complexes are best described as a pi system comprising the ring carbons conjugated with the exocyclic double bonds of the deprotonated "arms". The neutral complexes are reversibly protonated to their cationic analogues by water or methanol. The thermodynamic parameters DeltaH, DeltaS, and DeltaG for the reversible protonation of the neutral complexes by methanol were obtained.

Background: We investigated the effectiveness of long-term antibiotic treatment in patients with Crohn's disease., Methods: We performed a systematic review and meta-analysis of randomized clinical trials. Data sources were Medline (from 1966 through June 2009), EMBASE (from 1980 through June 2009), Cochrane Central Register of Controlled Trials (issue 3, 2009), and references from relevant publications. Trials that compared antibiotic therapy during at least 3 months with placebo were included. Outcomes were remission in patients with active disease and relapse in patients with inactive disease. Results from intention-to-treat analyses were combined in a random-effects meta-analysis, stratified by class of drug. Odds ratios (ORs) >1 indicate superiority of antibacterial treatment over placebo. Numbers needed to treat for 1 year to keep 1 additional patient in remission were calculated., Results: Sixteen trials that examined 13 treatment regimens in 865 patients were included in the meta-analysis. The median duration of treatment was 6 months (range, 3-24 months). Three trials of nitroimidazoles showed benefit, with a combined OR of 3.54 (95% confidence interval [CI], 1.94-6.47). Similarly, the combined OR from 4 trials of clofazimine was 2.86 (95% CI, 1.67-4.88). For patients with active disease, the number needed to treat was 3.4 (95% CI, 2.3-7.0) for nitroimidazoles and 4.2 (95% CI, 2.7-9.3) for clofazimine. The corresponding numbers needed to treat for inactive disease were 6.1 (95% CI, 5.0-9.7) and 6.9 (95% CI, 5.4-12.0). No benefit was evident for classic drugs against tuberculosis (3 trials; OR, 0.58; 95% CI, 0.29-1.18). Results for clarithromycin were heterogeneous (I(2)=77%; P=.005) and not combined in the meta-analysis., Conclusions: Long-term treatment with nitroimidazoles or clofazimine appears to be effective in patients with Crohn's disease.

Background: Graft right ventricular (RV) function is compromised directly posttransplant, especially in heart transplantation (HTx) recipients with pretransplant pulmonary hypertension (PH). Graft RV size and systolic function, and the effect of the recipient's pulmonary haemodynamics on the graft extracellular matrix are not well characterised in the patients long-term after HTx., Aim: Comparison of RV size and systolic function in HTx recipients' long-term posttransplant stratified by the presence of pretransplant PH., Methods: HTx survivors >or=2 years posttransplant were divided into group I without pretransplant PH (pulmonary vascular resistance, PVR <2.5 Wood units, n=37) and group II with PH (PVR >or=2.5 Wood units, n=16). RV size and systolic function were measured using cardiac magnetic resonance imaging (CMR). The collagen content was assessed in septal endomyocardial biopsies obtained at HTx and at study inclusion., Results: Mean posttransplant follow-up was 5.2+/-2.9 years (group I) and 4.9+/-2.2 years (group II) (p=0.70). PVR was 1.5+/-0.6 vs 4.1+/-1.7 Wood units pretransplant (p<0.001), and 1.2+/-0.5 vs 1.3+/-0.5 Wood units at study inclusion (p=0.43). Allograft RV size and systolic function were similar in both groups (p always >or=0.07). Collagen content at transplantation and at follow-up were not different (p always >or=0.60)., Conclusion: Posttransplant normalisation of pretransplant PH is associated with normal graft RV function long-term after HTx., (Copyright 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Exercise capacity after heart transplantation (HTx) remains limited despite normal left ventricular systolic function of the allograft. Various clinical and haemodynamic parameters are predictive of exercise capacity following HTx. However, the predictive significance of chronotropic competence has not been demonstrated unequivocally despite its immediate relevance for cardiac output., Aims: This study assesses the predictive value of various clinical and haemodynamic parameters for exercise capacity in HTx recipients with complete chronotropic competence evolving within the first 6 postoperative months., Methods: 51 patients were enrolled in this exercise study. Patients were included when at least >6 months after HTx and without negative chronotropic medication or factors limiting exercise capacity such as significant transplant vasculopathy or allograft rejection. Clinical parameters were obtained by chart review, haemodynamic parameters from current cardiac catheterisation, and exercise capacity was assessed by treadmill stress testing. A stepwise multiple regression model analysed the proportion of the variance explained by the predictive parameters., Results: The mean age of these 51 HTx recipients was 55.4 +/- 13.2 yrs on inclusion, 42 pts were male and the mean time interval after cardiac transplantation was 5.1 +/- 2.8 yrs. Five independent predictors explained 47.5% of the variance observed for peak exercise capacity (adjusted R2 = 0.475). In detail, heart rate response explained 31.6%, male gender 5.2%, age 4.1%, pulmonary vascular resistance 3.7%, and body-mass index 2.9%., Conclusion: Heart rate response is one of the most important predictors of exercise capacity in HTx recipients with complete chronotropic competence and without relevant transplant vasculopathy or acute allograft rejection.

Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Lipopolysaccharide (LPS), a major component of the Gram-negative bacterial outer membrane, is sensed by mammalian cells through Toll-like receptor 4 (TLR4), resulting in activation of proinflammatory cytokine pathways. TLR4 recognizes the lipid A moiety of the LPS molecule, and the chemical composition of the lipid A determines how well it is recognized by TLR4. N. meningitidis has been reported to produce lipid A with six acyl chains, the optimal number for TLR4 recognition. Indeed, meningococcal sepsis is generally seen as the prototypical endotoxin-mediated disease. In the present study, we screened meningococcal disease isolates from 464 patients for their ability to induce cytokine production in vitro. We found that around 9% of them were dramatically less potent than wild-type strains. Analysis of the lipid A of several of the low-activity strains by mass spectrometry revealed they were penta-acylated, suggesting a mutation in the lpxL1 or lpxL2 genes required for addition of secondary acyl chains. Sequencing of these genes showed that all the low activity strains had mutations that inactivated the lpxL1 gene. In order to see whether lpxL1 mutants might give a different clinical picture, we investigated the clinical correlate of these mutations in a prospective nationwide observational cohort study of adults with meningococcal meningitis. Patients infected with an lpxL1 mutant presented significantly less frequently with rash and had higher thrombocyte counts, consistent with reduced cytokine induction and less activation of tissue-factor mediated coagulopathy. In conclusion, here we report for the first time that a surprisingly large fraction of meningococcal clinical isolates have LPS with underacylated lipid A due to mutations in the lpxL1 gene. The resulting low-activity LPS may have an important role in virulence by aiding the bacteria to evade the innate immune system. Our results provide the first example of a specific mutation in N. meningitidis that can be correlated with the clinical course of meningococcal disease.

The RhIII complex [(PNP)Rh(CN)(CH3)][I] 5, obtained by oxidative addition of methyl iodide to [(PNP)Rh(CN)] 2, reacts selectively in two pathways: In aprotic solvents C-I reductive elimination of methyl iodide followed by its electrophilic attack on the cyano ligand takes place, giving the methyl isonitrile RhI complex [(PNP)Rh(CNCH3)][I] 3, while in protic solvents C-C reductive elimination of acetonitrile takes place forming an iodo RhI complex [(PNP)RhI] 9. Reaction of 2 with ethyl iodide in aprotic solvents gave the corresponding isonitrile complex, while in protic solvents no reactivity was observed. The selectivity of this reaction is likely due to a hydrogen bond between the cyano ligand and the protic solvent, as observed by X-ray diffraction, which retards electrophilic attack on this ligand.

The two-partner secretion (TPS) pathway is widespread among gram-negative bacteria and facilitates the secretion of very large and often virulence-related proteins. TPS systems consist of a secreted TpsA protein and a TpsB protein involved in TpsA transport across the outer membrane. Sequenced Neisseria meningitidis genomes contain up to five TpsA- and two TpsB-encoding genes. Here, we investigated the distribution of TPS-related open reading frames in a collection of disease isolates. Three distinct TPS systems were identified among meningococci. System 1 was ubiquitous, while systems 2 and 3 were significantly more prevalent among isolates of hyperinvasive clonal complexes than among isolates of poorly invasive clonal complexes. In laboratory cultures, systems 1 and 2 were expressed. However, several sera from patients recovering from disseminated meningococcal disease recognized the TpsAs of systems 2 and 3, indicating the expression of these systems during infection. Furthermore, we showed that the major secreted TpsAs of systems 1 and 2 depend on their cognate TpsBs for transport across the outer membrane and that the system 1 TpsAs undergo processing. Together, our data indicate that TPS systems may contribute to the virulence of N. meningitidis.

Dual-energy X-ray absorptiometry (DXA) method is the main device for diagnosing osteoporosis; this method, however, involves the use of expensive equipment. Ultrasound method, being portable, noninvasive, and cost-effective, seems to be an appropriate screening device to identify subjects at risk of osteoporosis. Two hundred and twenty-four postmenopausal women (mean age: 57.9+/-6.2yr) were recruited at 2 Menopause Centers. All subjects were assessed by phalangeal Quantitative Ultrasound (QUS) and by DXA at femur and rachis. Applying the first-level screening strategy, the following risk factors were considered: (1) Amplitude Dependent Speed-of-Sound T-score<-1.8 standard deviation (SD) or Ultrasound Bone Profile Index T-score<-1.8SD; (2) body mass index (BMI)<20kg/m(2). BMI identified 25 subjects (11%) of the total population as at risk, the QUS parameters 100 subjects (45%), and the combination of the 2 showed 118 subjects (53%). The percentage of osteoporotics identified by BMI was 17%, by QUS 78%, and by the combination of the two 90%. The sensitivity of this algorithm was 90%; 53% of the subjects would undergo a further densitometric evaluation, the remaining 47% were correctly identified as not at risk. The diagnostic work up proposed appears effective to be indicated for extensive clinical employment, thanks also to its simplicity.

The Rh(II) mononuclear complexes [(PNPtBu)RhCl][BF4] (2), [(PNPtBu)Rh(OC(O)CF3)][OC(O)CF3] (4), and [(PNPtBu)Rh(acetone)][BF4]2 (6) were synthesized by oxidation of the corresponding Rh(I) analogs with silver salts. On the other hand, treatment of (PNPtBu)RhCl with AgOC(O)CF3 led only to chloride abstraction, with no oxidation. 2 and 6 were characterized by X-ray diffraction, EPR, cyclic voltammetry, and dipole moment measurements. 2 and 6 react with NO gas to give the diamagnetic complexes [(PNPtBu)Rh(NO)Cl][BF4] (7) and [(PNPtBu)Rh(NO)(acetone)][BF4]2 (8) respectively. 6 is reduced to Rh(I) in the presence of phosphines, CO, or isonitriles to give the Rh(I) complexes [(PNPtBu)Rh(PR3)][BF4] (11, 12) (R = Et, Ph), [(PNPtBu)Rh(CO)][BF4] (13) and [(PNPtBu)Rh(L)][BF4] (15, 16) (L = tert-butyl isonitrile or 2,6-dimethylphenyl isonitrile), respectively. On the other hand, 2 disproportionates to Rh(I) and Rh(III) complexes in the presence of acetonitrile, isonitriles, or CO. 2 is also reduced by triethylphosphine and water to Rh(I) complexes [(PNPtBu)RhCl] (1) and [(PNPtBu)Rh(PEt3)][BF4] (11). When triphenylphosphine and water are used, the reduced Rh(I) complex reacts with a proton, which is formed in the redox reaction, to give a Rh(III) complex with a coordinated BF4, [(PNPtBu)Rh(Cl)(H)(BF4)] (9).

This systematic review assesses the evidence for an association between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohn's disease. We analysed 28 case-control studies comparing MAP in patients with Crohn's disease with individuals free of inflammatory bowel disease (IBD) or patients with ulcerative colitis. Compared with individuals free of IBD, the pooled odds ratio (OR) from studies using PCR in tissue samples was 7.01 (95% CI 3.95-12.4) and was 1.72 (1.02-2.90) in studies using ELISA in serum. ORs were similar for comparisons with ulcerative colitis patients (PCR, 4.13 [1.57-10.9]; ELISA, 1.88 [1.26-2.81]). The association of MAP with Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined.

The reaction of the cationic (PNP)Ir(I)(cyclooctene) complex (1) (PNP = 2,6-bis-(di-tert-butylphosphinomethyl)pyridine) with 2-butanone or 3-pentanone results in the selective, quantitative activation of a beta C-H bond, yielding O,C-chelated complexes. Calculations show that the selectivity is both kinetically (because of steric reasons in the rate determingin step (RDS)) and thermodynamically controlled, the latter as a result of carbonyl oxygen coordination in the product. The RDS is formation of the eta2-C,H intermediates from the complexed ketone intermediates. Water has a strong influence on the regioselectivity, and in its presence, reaction of 1 with 2-butanone gives also the alpha terminal C-H activation product. Computational studies suggest that water can stabilize the terminal alpha C-H activation product by hydrogen bonding, forming a six-membered ring with the ketone, as experimentally observed in the X-ray structure of the acetonyl hydride aqua complex.

Previous studies demonstrated that impaired left ventricular (LV) relaxation in cardiac allografts limits exercise tolerance post-transplant despite preserved systolic ejection fraction (EF). This study tested in human cardiac allografts whether the isovolumic relaxation time (IVRT), which provides the basis for most of diastolic LV filling, relates with gene expression of regulatory proteins of calcium homeostasis or cardiac matrix proteins. Gene expression was studied in 31 heart transplant recipients (25 male, 6 female) 13-83 months post-transplant with LVEF >50%, LV end-diastolic pressure <20 mmHg, normal LV mass index and without allograft rejection or significant cardiac pathology. IVRT related with the other diastolic parameters e-wave velocity (r = -0.46; p = 0.01), e/a-wave ratio (r = -0.5; p < 0.01) but not with heart frequency (r = -0.16; p = 0.4). No relation of IVRT was observed for immunosuppression, mean rejection grade or other medication. IVRT was not related with gene expression of desmin, collagen I, phospholamban, the Na+-Ca2+ exchanger, the ryanodine receptor or interstitial fibrosis but correlated inversely with SERCA2a (r = -0.48; p = 0.02). Prolonged IVRT is associated with decreased SERCA2a expression in cardiac allografts without significant other pathology. Similar observations in non-transplanted patients with diastolic failure suggest that decreased SERCA2a expression is an important common pathomechanism.

Background: Large incisional hernias are mainly repaired today by tension free implantations of prosthetic meshes using various placement methods. The advantages of the intraperitoneal open technique (IPOM) using a polypropylene mesh that is coated with ePTFE on the side facing the intestine, are described., Methods and Results: 62 patients underwent an incisional hernia operation with the intraperitoneal positioning of a prosthetic mesh. The follow-up examinations after a range of 16.1 months showed a hernial recurrence rate of 6.4 %. A part of the resulting mesh infections (11.2 %) healed without surgical removal of the mesh. Clinical complications due to adhesion formation were not observed., Conclusion: The tissue sparing intraabdominal positioning technique simplifies the necessary overlap using healthy tissue as a prerequisite for a sufficient hernia repair exploiting the intraabdominal pressure.