Re-evaluating the Cu K pre-edge XAS transition in complexes with covalent metal–ligand interactions

Three [Me2NN]Cu(h2 -L2) complexes (Me2NN ¼ HC[C(Me)NAr]2; L2 ¼ PhNO (2), ArF 2N2 (3), PhCH]CH2 (4); Ar ¼ 2,6-Me2-C6H3; ArF ¼ 3,5-(CF3)2-C6H3) have been studied by Cu K-edge X-ray absorption spectroscopy, as well as single- and multi-reference computational methods (DFT, TD-DFT, CASSCF, MRCI, and OVB). The study was extended to a range of both known and theoretical compounds bearing 2p-element donors as a means of deriving a consistent view of how the pre-edge transition energy responds in systems with significant ground state covalency. The ground state electronic structures of many of the compounds under investigation were found to be strongly influenced by correlation effects, resulting in ground state descriptions with majority contributions from a configuration comprised of a Cu(II) metal center anti-ferromagentically coupled to radical anion O2, PhNO, and ArF 2N2 ligands. In contrast, the styrene complex 4, which displays a Cu K pre-edge transition despite its formal d10 electron configuration, exhibits what can best be described as a Cu(I):(styrene)0 ground state with strong pbackbonding. The Cu K pre-edge features for these complexes increase in energy from 1 to 4, a trend that was tracked to the percent Cu(II)-character in the ground state. The unexpected shift to higher preedge transition energies with decreasing charge on copper (QCu) contributed to an assignment of the pre-edge features for these species as arising from metal-to-ligand charge transfer instead of the traditional Cu1s / Cu3d designation

Lipedema: A Call to Action!

Lipedema is a chronic progressive disease characterized by abnormal fat distribution resulting in disproportionate, painful limbs. It almost exclusively affects women, leading to considerable disability, daily functioning impairment, and psychosocial distress. Literature shows both scarce and conflicting data regarding its prevalence. Lipedema has been considered a rare entity by several authors, though it may be a far more frequent condition than thought. Despite the clinical impact on women's health, lipedema is in fact mostly unknown, underdiagnosed, and too often misdiagnosed with other similarly presenting diseases. Polygenic susceptibility combined with hormonal, microvascular, and lymphatic disorders may be partly responsible for its development. Furthermore, consistent information on lipedema pathophysiology is still lacking, and an etiological treatment is not yet available. Weight loss measures exhibit minimal effect on the abnormal body fat distribution, resulting in eating disorders, increased obesity risk, depression, and other psychological complaints. Surgical techniques, such as liposuction and excisional lipectomy, represent therapeutic options in selected cases. This review aims to outline current evidence regarding lipedema epidemiology, pathophysiology, clinical presentation, differential diagnosis, and management. Increased awareness and a better understanding of its clinical presentation and pathophysiology are warranted to enable clinicians to diagnose and treat affected patients at an earlier stage

Randomized trial comparing proactive, high-dose versus reactive, low-dose intravenous iron supplementation in hemodialysis (PIVOTAL) : Study design and baseline data

Background: Intravenous (IV) iron supplementation is a standard maintenance treatment for hemodialysis (HD) patients, but the optimum dosing regimen is unknown. Methods: PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) is a multicenter, open-label, blinded endpoint, randomized controlled (PROBE) trial. Incident HD adults with a serum ferritin 700 μg/L and/or TSAT ≥40%) or a reactive, low-dose IV iron arm (iron sucrose administered if ferritin <200 μg/L or TSAT < 20%). We hypothesized that proactive, high-dose IV iron would be noninferior to reactive, low-dose IV iron for the primary outcome of first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure or death from any cause. If noninferiority is confirmed with a noninferiority limit of 1.25 for the hazard ratio of the proactive strategy relative to the reactive strategy, a test for superiority will be carried out. Secondary outcomes include infection-related endpoints, ESA dose requirements, and quality-of-life measures. As an event-driven trial, the study will continue until at least 631 primary outcome events have accrued, but the expected duration of follow-up is 2-4 years. Results: Of the 2,589 patients screened across 50 UK sites, 2,141 (83%) were randomized. At baseline, 65.3% were male, the median age was 65 years, and 79% were white. According to eligibility criteria, all patients were on ESA at screening. Prior stroke and MI were present in 8 and 9% of the cohort, respectively, and 44% of patients had diabetes at baseline. Baseline data for the randomized cohort were generally concordant with recent data from the UK Renal Registry. Conclusions: PIVOTAL will provide important information about the optimum dosing of IV iron in HD patients representative of usual clinical practice. Trial Registration: EudraCT number: 2013-002267-25.Peer reviewedFinal Published versio

The influence of irrigant activation, concentration and contact time on sodium hypochlorite penetration into root dentine: an ex vivo experiment

Aim To establish if irrigant activation techniques, namely manual‐dynamic‐activation (MDA), passive‐ultrasonic‐irrigation (PUI) and sonic‐irrigation (SI), improve the tubular penetration of sodium hypochlorite (NaOCl) into root dentine when compared with conventional‐needle‐irrigation (CNI). Secondly, investigate if increasing NaOCl concentration and/or contact‐time improves the performance of these techniques. Methodology A total of 83 extracted human maxillary permanent canines were decoronated to 15 mm and root canals prepared to a size 40,.10 taper. Root dentine was stained with crystal violet for 72 h and embedded in silicone. Eighty specimens were randomly distributed into 16 groups (n = 5) according to the irrigant activation technique, NaOCl concentration (2%; 5.25%) and irrigant contact‐time (10 min; 20 min). All activation techniques were used for 60 s in the last minute of irrigation. Additionally, 3 teeth were not exposed to NaOCl to confirm adequate dentine staining had occurred (i.e. negative control). All specimens were subsequently dissected, observed under a light microscope and NaOCl penetration depth (µm) determined by measuring the average width of bleached dentine using ImageJ software. Statistical comparisons were made with paired and unpaired t‐tests, ANOVAs followed by post‐hoc Tukey and Dunnett’s tests, and a general linear model (α < 0.05). Results Overall, NaOCl penetration ranged from 38.8 µm – 411.0 µm with MDA, PUI and SI consistently resulting in significantly greater tubular infiltration than CNI (P < 0.05). The deepest measurements in the coronal, middle and apical segments were all recorded in the MDA; 5.25%; 20 min group and the least in the CNI; 2%; 10 min group. Increasing either irrigant concentration or contact‐time resulted in significantly greater NaOCl penetration depths for all techniques and segments of the canal (P < 0.05). However, when irrigant concentration and contact‐time were increased together, a significant interaction effect between these two independent variables was observed on overall NaOCl penetration (P < 0.05). Conclusions Agitating irrigants with MDA, PUI or SI, as well as using greater irrigant concentrations or contact‐times, potentiated NaOCl penetration into root dentine. However, longer durations of NaOCl exposure at lower concentrations resulted in similar depths of tubular penetration as those achieved at higher concentrations

Association of anaemia in primary care patients with chronic kidney disease: cross sectional study of quality improvement in chronic kidney disease (QICKD) trial data.

BACKGROUND: Anaemia is a known risk factor for cardiovascular disease and treating anaemia in chronic kidney disease (CKD) may improve outcomes. However, little is known about the scope to improve primary care management of anaemia in CKD. METHODS: An observational study (N = 1,099,292) with a nationally representative sample using anonymised routine primary care data from 127 Quality Improvement in CKD trial practices (ISRCTN5631023731). We explored variables associated with anaemia in CKD: eGFR, haemoglobin (Hb), mean corpuscular volume (MCV), iron status, cardiovascular comorbidities, and use of therapy which associated with gastrointestinal bleeding, oral iron and deprivation score. We developed a linear regression model to identify variables amenable to improved primary care management. RESULTS: The prevalence of Stage 3-5 CKD was 6.76%. Hb was lower in CKD (13.2 g/dl) than without (13.7 g/dl). 22.2% of people with CKD had World Health Organization defined anaemia; 8.6% had Hb ≤ 11 g/dl; 3% Hb ≤ 10 g/dl; and 1% Hb ≤ 9 g/dl. Normocytic anaemia was present in 80.5% with Hb ≤ 11; 72.7% with Hb ≤ 10 g/dl; and 67.6% with Hb ≤ 9 g/dl; microcytic anaemia in 13.4% with Hb ≤ 11 g/dl; 20.8% with Hb ≤ 10 g/dl; and 24.9% where Hb ≤ 9 g/dl. 82.7% of people with microcytic and 58.8% with normocytic anaemia (Hb ≤ 11 g/dl) had a low ferritin (<100 ug/mL). Hypertension (67.2% vs. 54%) and diabetes (30.7% vs. 15.4%) were more prevalent in CKD and anaemia; 61% had been prescribed aspirin; 73% non-steroidal anti-inflammatory drugs (NSAIDs); 14.1% warfarin 12.4% clopidogrel; and 53.1% aspirin and NSAID. 56.3% of people with CKD and anaemia had been prescribed oral iron. The main limitations of the study are that routine data are inevitably incomplete and definitions of anaemia have not been standardised. CONCLUSIONS: Medication review is needed in people with CKD and anaemia prior to considering erythropoietin or parenteral iron. Iron stores may be depleted in over >60% of people with normocytic anaemia. Prescribing oral iron has not corrected anaemia

Variation between centres in access to renal transplantation in UK: longitudinal cohort study

Objective To assess whether equity exists in access to renal transplantation in the UK after adjustment for case mix in incident patients with end stage renal disease

Sudden Unexpected Death in Epilepsy: A PersonaliZed Prediction Tool

OBJECTIVE: To develop and validate a tool for individualised prediction of Sudden Unexpected Death in Epilepsy (SUDEP) risk, we re-analysed data from one cohort and three case-control studies undertaken 1980-2005. METHODS: We entered 1273 epilepsy cases (287 SUDEP, 986 controls) and 22 clinical predictor variables into a Bayesian logistic regression model. RESULTS: Cross-validated individualized model predictions were superior to baseline models developed from only average population risk or from generalised tonic-clonic seizure frequency (pairwise difference in leave-one-subject-out expected log posterior density = 35.9, SEM +/-12.5, and 22.9, SEM +/-11.0 respectively). The mean cross-validated (95% Credibility Interval) Area Under the Receiver Operating Curve was 0.71 (0.68 to 0.74) for our model versus 0.38 (0.33 to 0.42) and 0.63 (0.59 to 0.67) for the baseline average and generalised tonic-clonic seizure frequency models respectively. Model performance was weaker when applied to non-represented populations. Prognostic factors included generalized tonic-clonic and focal-onset seizure frequency, alcohol excess, younger age of epilepsy onset and family history of epilepsy. Anti-seizure medication adherence was associated with lower risk. CONCLUSIONS: Even when generalised to unseen data, model predictions are more accurate than population-based estimates of SUDEP. Our tool can enable risk-based stratification for biomarker discovery and interventional trials. With further validation in unrepresented populations it may be suitable for routine individualized clinical decision-making. Clinicians should consider assessment of multiple risk factors, and not only focus on the frequency of convulsions

Teratogenic risk and contraceptive counselling in psychiatric practice: analysis of anticonvulsant therapy

&lt;p&gt;Background: Anticonvulsants have been used to manage psychiatric conditions for over 50 years. It is recognised that some, particularly valproate, carbamazepine and lamotrigine, are human teratogens, while others including topiramate require further investigation. We aimed to appraise the documentation of this risk by psychiatrists and review discussion around contraceptive issues.&lt;/p&gt; &lt;p&gt;Methods: A retrospective review of prescribing patterns of four anticonvulsants (valproate, carbamazepine, lamotrigine and topiramate) in women of child bearing age was undertaken. Documented evidence of discussion surrounding teratogenicity and contraceptive issues was sought.&lt;/p&gt; &lt;p&gt;Results: Valproate was most commonly prescribed (n=67). Evidence of teratogenic risk counselling at medication initiation was sub-optimal – 40% of individuals prescribed carbamazepine and 22% of valproate. Documentation surrounding contraceptive issues was also low- 17% of individuals prescribed carbamazepine and 13% of valproate.&lt;/p&gt; &lt;p&gt;Conclusion: We found both low rates of teratogenic risk counselling and low rates of contraception advice in our cohort. Given the high rates of unplanned pregnancies combined with the relatively high risk of major congenital malformations, it is essential that a detailed appraisal of the risks and benefits associated with anticonvulsant medication occurs and is documented within patients’ psychiatric notes.&lt;/p&gt