The impact of age and renal function on the pharmacokinetics and protein binding characteristics of fludarabine in paediatric and adult patients undergoing allogeneic haematopoietic stem cell transplantation conditioning.

AIM: To evaluate the population pharmacokinetics of unbound F-Ara-A (the circulating metabolite of fludarabine) in 211 patients (age range, 0.1-63.4 years) undergoing allogeneic haematopoietic stem cell transplantation conditioning. METHODS: Total (n = 2480) and unbound (n = 1403) F-Ara-A concentrations were measured in blood samples collected at timed intervals after fludarabine doses ranging from 10 to 50 mg/m2 and infused over 0.42-1.5 h. A three-compartment population pharmacokinetic model was developed based on unbound plasma concentrations and used to estimate F-Ara-A unbound pharmacokinetic parameters and fraction unbound (fu). A number of covariates, including glomerular filtration rate (GFR) and post-menstrual age (PMA), were evaluated for inclusion in the model. RESULTS: The base population mean estimates ± relative standard error (%RSE) for unbound clearance from the central compartment (CLu) and inter-compartmental clearances (Q2u, Q3u) were 3.42 ± 3%, 6.54 ± 24% and 1.47 ± 16% L/h/70 kg, respectively. The population mean estimates (%RSE) for the unbound volume of distribution into the central (V1u) and peripheral compartments (V2u, V3u) were 9.65 ± 8%, 8.17 ± 9% and 16.4 ± 10% L/70 kg, respectively, and that for fu was 0.877 ± 1%. Covariate model development involved differentiating F-Ara-A CLu into non-renal (1.81 ± 9% L/h/70 kg) and renal components (1.02 ± 9%*GFR L/h/70 kg). A sigmoidal maturation factor was applied to renal CLu, with population mean estimates for the Hill exponent and PMA at 50% mature of 2.97 ± 4% and 69.1 ± 8% weeks, respectively. CONCLUSION: Patient age and GFR are predictors of unbound F-Ara-A CLu. This has the potential to impact dose requirements. Dose individualisation by target concentration intervention will be facilitated by this model once it is externally validated.

Aripiprazole/Sertraline Combination: Clinical and Cost-Effectiveness in Comparison With Quetiapine for the Treatment of Bipolar Depression (ASCEnD Trial)-Protocol for a Nested Qualitative Study.

INTRODUCTION: Bipolar disorder is a recurrent mental health disorder with a prevalence rate of 1.4%. On average, there can be a delay of 9.5 years from the initial presentation of symptoms to a confirmed diagnosis. Individuals living with bipolar disorder have a reduced life expectancy. There is limited evidence regarding the effectiveness of antidepressants in treating bipolar disorder. The ASCEnD clinical trial will test the clinical and cost-effectiveness of the aripiprazole/sertraline combination in comparison with quetiapine for the treatment of bipolar depression (individuals who suffer from depressive episodes in bipolar disorder) and will include a nested qualitative study. METHODS: The qualitative study will use semi-structured interviews to explore pilot trial participants' and clinicians' perspectives on recruitment procedures, the acceptability of the intervention, the management of bipolar disorder and attitudes to medication combinations. CONCLUSION: Findings will inform recruitment strategies and optimise training for the participating sites in the ASCEnD full trial. They will also help to illuminate the lived experience of people with bipolar disorder and the clinicians who work with people with bipolar disorder. The discussion will explore perspectives on the delay in diagnosis, having a diagnosis, the impact of living with bipolar disorder and attitudes to treatment, including drug combinations. PATIENT OR PUBLIC CONTRIBUTION: A Lived Experience Advisory Panel (LEAP) has been convened with the support of the McPin Foundation, which will contribute to the ASCEnD trial and its nested qualitative study to provide input on the design and delivery of the trial and qualitative study, analysis of qualitative data and dissemination of findings.

Collaborative care approaches for people with severe mental illness.

BACKGROUND: Collaborative care for severe mental illness (SMI) is a community-based intervention that promotes interdisciplinary working across primary and secondary care. Collaborative care interventions aim to improve the physical and/or mental health care of individuals with SMI. This is an update of a 2013 Cochrane review, based on new searches of the literature, which includes an additional seven studies. OBJECTIVES: To assess the effectiveness of collaborative care approaches in comparison with standard care (or other non-collaborative care interventions) for people with diagnoses of SMI who are living in the community. SEARCH METHODS: We searched the Cochrane Schizophrenia Study-Based Register of Trials (10 February 2021). We searched the Cochrane Common Mental Disorders (CCMD) controlled trials register (all available years to 6 June 2016). Subsequent searches on Ovid MEDLINE, Embase and PsycINFO together with the Cochrane Central Register of Controlled Trials (with an overlap) were run on 17 December 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) where interventions described as 'collaborative care' were compared with 'standard care' for adults (18+ years) living in the community with a diagnosis of SMI. SMI was defined as schizophrenia, other types of schizophrenia-like psychosis or bipolar affective disorder. The primary outcomes of interest were: quality of life, mental state and psychiatric admissions at 12 months follow-up. DATA COLLECTION AND ANALYSIS: Pairs of authors independently extracted data. We assessed the quality and certainty of the evidence using RoB 2 (for the primary outcomes) and GRADE. We compared treatment effects between collaborative care and standard care. We divided outcomes into short-term (up to six months), medium-term (seven to 12 months) and long-term (over 12 months). For dichotomous data we calculated the risk ratio (RR) and for continuous data we calculated the standardised mean difference (SMD), with 95% confidence intervals (CIs). We used random-effects meta-analyses due to substantial levels of heterogeneity across trials. We created a summary of findings table using GRADEpro. MAIN RESULTS: Eight RCTs (1165 participants) are included in this review. Two met the criteria for type A collaborative care (intervention comprised of the four core components). The remaining six met the criteria for type B (described as collaborative care by the trialists, but not comprised of the four core components). The composition and purpose of the interventions varied across studies. For most outcomes there was low- or very low-certainty evidence. We found three studies that assessed the quality of life of participants at 12 months. Quality of life was measured using the SF-12 and the WHOQOL-BREF and the mean endpoint mental health component scores were reported at 12 months. Very low-certainty evidence did not show a difference in quality of life (mental health domain) between collaborative care and standard care in the medium term (at 12 months) (SMD 0.03, 95% CI -0.26 to 0.32; 3 RCTs, 227 participants). Very low-certainty evidence did not show a difference in quality of life (physical health domain) between collaborative care and standard care in the medium term (at 12 months) (SMD 0.08, 95% CI -0.18 to 0.33; 3 RCTs, 237 participants). Furthermore, in the medium term (at 12 months) low-certainty evidence did not show a difference between collaborative care and standard care in mental state (binary) (RR 0.99, 95% CI 0.77 to 1.28; 1 RCT, 253 participants) or in the risk of being admitted to a psychiatric hospital at 12 months (RR 5.15, 95% CI 0.67 to 39.57; 1 RCT, 253 participants). One study indicated an improvement in disability (proxy for social functioning) at 12 months in the collaborative care arm compared to usual care (RR 1.38, 95% CI 0.97 to 1.95; 1 RCT, 253 participants); we deemed this low-certainty evidence. Personal recovery and satisfaction/experience of care outcomes were not reported in any of the included studies. The data from one study indicated that the collaborative care treatment was more expensive than standard care (mean difference (MD) international dollars (Int$) 493.00, 95% CI 345.41 to 640.59) in the short term. Another study found the collaborative care intervention to be slightly less expensive at three years. AUTHORS' CONCLUSIONS: This review does not provide evidence to indicate that collaborative care is more effective than standard care in the medium term (at 12 months) in relation to our primary outcomes (quality of life, mental state and psychiatric admissions). The evidence would be improved by better reporting, higher-quality RCTs and the assessment of underlying mechanisms of collaborative care. We advise caution in utilising the information in this review to assess the effectiveness of collaborative care.

Do high-protein diets have the potential to reduce gut barrier function in a sex-dependent manner?

PURPOSE: Impaired gut barrier function is associated with systemic inflammation and many chronic diseases. Undigested dietary proteins are fermented in the colon by the gut microbiota which produces nitrogenous metabolites shown to reduce barrier function in vitro. With growing evidence of sex-based differences in gut microbiotas, we determined whether there were sex by dietary protein interactions which could differentially impact barrier function via microbiota modification. METHODS: Fermentation systems were inoculated with faeces from healthy males (n = 5) and females (n = 5) and supplemented with 0.9 g of non-hydrolysed proteins sourced from whey, fish, milk, soya, egg, pea, or mycoprotein. Microbial populations were quantified using fluorescence in situ hybridisation with flow cytometry. Metabolite concentrations were analysed using gas chromatography, solid phase microextraction coupled with gas chromatography-mass spectrometry and ELISA. RESULTS: Increased protein availability resulted in increased proteolytic Bacteroides spp (p < 0.01) and Clostridium coccoides (p < 0.01), along with increased phenol (p < 0.01), p-cresol (p < 0.01), indole (p = 0.018) and ammonia (p < 0.01), varying by protein type. Counts of Clostridium cluster IX (p = 0.03) and concentration of p-cresol (p = 0.025) increased in males, while females produced more ammonia (p = 0.02), irrespective of protein type. Further, we observed significant sex-protein interactions affecting bacterial populations and metabolites (p < 0.005). CONCLUSIONS: Our findings suggest that protein fermentation by the gut microbiota in vitro is influenced by both protein source and the donor's sex. Should these results be confirmed through human studies, they could have major implications for developing dietary recommendations tailored by sex to prevent chronic illnesses.

4f/5d Hybridization Induced Single-Electron Delocalization in an Azide-Bridged Dicerium Complex.

Dilanthanide complexes with one-electron delocalization are important targets for understanding the specific 4f/5d-bonding feature in lanthanide chemistry. Here, we report an isolable azide-bridged dicerium complex 3 [{(TrapenTMS)Ce}2(µ-N3)]• [Trapen = tris (2-aminobenzyl)amine; TMS = SiMe3], which is synthesized by the reaction of tripodal ligand-supported (TrapenTMS)CeIVCl complex 2 with NaN3. The structure and bonding nature of 3 are fully characterized by X-ray crystal diffraction analysis, electron paramagnetic resonance (EPR), magnetic measurement, cyclic voltammetry, X-ray absorption spectroscopy, and quantum-theoretical studies. Complex 3 presents a trans-bent central Ce-N3-Ce unit with a single electron of two mixed-valent Ce atoms. The unique low-temperature (2 K) anisotropic EPR signals [g = 1.135, 2.003, and 3.034] of 3 indicate that its spin density is distributed on the central Ce-N3-Ce unit with marked electron delocalization. Quantum chemical analyses show strong 4f/5d orbital mixing in the singly occupied molecular orbital of 3, which allows for the unpaired electron to extend throughout the cerium-azide-cerium unit via a multicentered one-electron (Ce-N3-Ce) interaction. This work extends the family of mixed-valent dilanthanide complexes and provides a paradigm for understanding the bonding motif of ligand-bridged dilanthanide complexes.

Ultrasound Incorporation in Gross Anatomy Labs in a Master of Medical Sciences Program: A Mixed-Methods Analysis of Student Performance and Perception.

OBJECTIVES: Teaching ultrasound imaging is on the rise in undergraduate medical anatomy education. However, there is little research exploring the use of ultrasound in preparatory graduate programs. The purpose of this study is to identify the effects of ultrasound imaging inclusion in a graduate gross anatomy course. METHODS: Master of Medical Sciences students were enrolled in a prosection-based anatomy course that included pinned cadaver stations and an ultrasound station. Using ultrasound, teaching assistants imaged volunteers demonstrating anatomical structures students previously learned at cadaver stations. Students answered one ultrasound image question on each practical exam and were asked to participate in a pre- and post-course survey. Student practical and lecture exam scores and final course grades from the 2022 cohort were compared to a historical control cohort from 2021 via statistical analysis, including a survey administered to the 2022 cohort. RESULTS: Two hundred students from the 2021 cohort and 164 students from the 2022 cohort participated in this study. Students in the 2022 cohort had significantly higher scores in 1 of the 5 practical exams (P < .05, d = .289), and 2 of the 5 written exams (P < .05, d = .207), (P < .05, d = .311). Survey data revealed increased (P < .05, d = 1.203) learning outcome achievement from pre-survey to post-survey in the intervention cohort. Students who correctly answered the ultrasound question performed significantly better on practical's 3 (P < .05) and 4 (P < .05) than those who missed the ultrasound question. CONCLUSIONS: These findings suggest that ultrasound imaging in a cadaver lab is beneficial to graduate students' learning and understanding of gross anatomy.

Prevalence and odds of anxiety and depression in cutaneous malignant melanoma: a proportional meta-analysis and regression.

BACKGROUND: The psychological burden of cutaneous malignant melanoma (CM) is all-encompassing, affecting treatment adherence, recurrence and mortality. However, the prevalence and risk factors of anxiety and depression in CM remain unclear. OBJECTIVES: To establish a benchmark pooled prevalence of anxiety and depression in CM, to provide magnitudes of association for clinical, therapeutic and demographic correlates, and to elucidate temporal trends in anxiety and depression from the time of diagnosis. METHODS: This review followed the MOOSE guidelines. MEDLINE, Embase, PsychINFO, Web of Science and the Cochrane Library were queried from database inception to 24 August 2023. Study selection, data extraction and quality assessment were performed by two independent authors, utilizing both the Joanna Briggs Institute (JBI) and National Institutes of Health risk-of-bias tools for the latter. The GRADE approach was used to rate the certainty of evidence. Prevalence rates, 95% confidence intervals (CIs) and prediction intervals (PIs) were derived using a random-effects model and estimating between- and within-study variance. RESULTS: Nine longitudinal and 29 cross-sectional studies were included (7995 patients). Based on the JBI and NIH tools, respectively, quality assessment found 20 and 17 to be at low risk of bias, 12 and 15 to be at moderate risk and 6 and 5 to be at high risk of bias. The prevalence of anxiety [30.6% (95% CI 24.6-37.0; PI 18-47%)] and depression [18.4% (95% CI 13.4-23.9; PI 10-33%)] peaked during treatment, declining to pretreatment levels after 1 year [anxiety: 48% vs. 20% (P = 0.005); depression: 28% vs. 13% (P = 0.03)]. Female sex [odds ratio (OR) 1.8, 95% CI 1.4-2.3; P < 0.001], age < 60 years (OR 1.5, 95% CI 1.2-2.0; P = 0.002) and low educational level (OR 1.5, 95% CI 1.2-2.0; P < 0.001) were likely to result in a large increase in the odds of anxiety. Depression was 12.3% higher in those with stage IV vs. those with stage I CM (P = 0.05). Relative to immune checkpoint inhibition, the rates of depression were 22% (P = 0.002) and 34% (P < 0.001) higher among patients with advanced-stage CM receiving interferon-α and chemotherapy, respectively. A significant reduction in self-reported depression scores was demonstrated over time (P = 0.003). CONCLUSIONS: Notably, anxiety and depression in CM affect women, those younger than 60 years of age and the less educated, with up to 80% higher odds of anxiety in these groups. Anxiety and depression surge during chemotherapy and interferon treatment, especially in advanced CM. Our findings facilitate risk stratification and underscore the need for multidisciplinary vigilance.

Melanoma is a serious type of skin cancer that is becoming more prevalent, particularly in people with lighter skin. The UK-based ReconRegen research group conducted a study to understand the psychological impact of melanoma on people, focusing on anxiety and depression. To do this, a systematic review approach was used to analyse data from existing studies and gather a comprehensive perspective. The study discovered that 30% of people with melanoma are affected by anxiety and 18% by depression, significantly higher than the general population. Key risk factors for anxiety included being female, being younger than 60 years of age and having lower educational attainment. Women are 1.8 times more likely to experience anxiety than men, those under 60 years of age are 1.5 times more likely to experience it and individuals with lower educational levels are also 1.5 times more likely to experience anxiety. Findings showed that anxiety and depression levels peaked during treatment phases, especially in people undergoing chemotherapy and immunotherapy. This highlights the need for targeted mental health support during these treatment periods. The findings advocate for mental health considerations in melanoma care, suggesting regular mental health assessments, particularly for high-risk groups and during intense treatment phases. Highlighting the importance of a holistic treatment approach, the study suggests that future research should include long-term studies to understand the chronic impacts of anxiety and depression. Improved clarity and detail in research reporting are essential for developing effective mental health support for people with melanoma, enhancing overall patient care by addressing both physical and emotional health needs.

Service implications of the revised 2022 National Institute for Health and Care Excellence (NICE) follow-up guidelines for stage IA-IIC melanoma.

BACKGROUND: The 2022 National Institute for Health and Care Excellence melanoma guideline update made significant changes to follow-up. The aim of this study was to assess the impact these changes will have on a national melanoma cohort over a 5-year follow-up interval. METHODS: Anonymized, individual-level, population-scale, linkable primary and secondary care National Health Service data for an 18-year interval (2000-2018) in Wales, UK were analysed. These data were used to predict the number of patients over a 10-year interval (2020-2030) that would be diagnosed with melanoma. Follow-up schedules for the 2015 and 2022 National Institute for Health and Care Excellence melanoma guidelines were then used to calculate the number of clinician-led appointments, the number of radiological investigations, and the total healthcare cost between 2025 and 2030, corresponding to a 5-year patient follow-up interval, for those with stage IA-IIC melanoma. RESULTS: Between 2025 and 2030 it is predicted that implementation of the 2022 guidelines would lead to 21 122 (range 19 194-23 083) fewer clinician-led appointments for patients with stage IA-IIC melanoma. However, there would be a significant increase in the number of radiological investigations (7812; range 7444-8189). These changes would lead to a €2.74 million (€1.87 million-€3.61 million) reduction in the total cost of follow-up over the interval 2025-2030. CONCLUSION: Melanoma follow-up guideline changes will result in a substantial reduction in the number of clinical follow-up appointments, but a significant additional burden to radiological services. The overall cost of follow-up at a national level will be reduced.

Pathogenesis and management of immune dysfunction secondary to B cell haematological malignancies.

Malignancies of the B-lymphocyte lineage are among the most diagnosed haematological malignancies in clinical practice. In our community, multiple myeloma (MM) and its precursor condition monoclonal gammopathy of undetermined significance are the commonest, accounting for ~12% of diagnoses, followed by chronic lymphocytic leukaemia (CLL) and its precursor condition monoclonal B lymphocytosis, ~9%. Along with diffuse large B cell lymphoma, follicular lymphoma and marginal zone lymphoma, these conditions comprise around a third of all haematological malignancies diagnosed. Infection remains an important cause of mortality and morbidity in the management of patients with these conditions. This is in part treatment-related but also reflective of disease-related immune dysfunction. Infectious complications account for up to 50% of early mortality in patients with myeloma and up to 50% of all mortality in patients with CLL. A variety of strategies are available to decrease the morbidity and mortality of infectious complications; however, practices vary between countries and often between treating physicians. Treatment options have evolved significantly over the last decade, with the introduction of monoclonal antibodies, small molecule inhibitors, second- and third-generation immunomodulatory agents and CAR-T cell therapy. Much of the data that inform clinical practice in infection management predates current therapeutic approaches. This is in part because of the rapid development of new therapies but also reflective of the long natural history of many of these diseases and the need for prolonged periods of observation. In this article, we review the aspects of disease and treatment that contribute to immune dysfunction in MM, CLL and B-cell non-Hodgkin lymphoma and review the current strategies used to manage immune dysfunction and infection.

The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

Organolanthanide Complexes Containing Ln-CH3 σ-bonds: Unexpectedly Similar Hydrolysis Rates for Trivalent and Tetravalent Organocerium.

We report the gas-phase preparation, isolation, and reactivity of a series of organolanthanides featuring the Ln-CH3 bond. The complexes are formed by decarboxylating anionic lanthanide acetates to form trivalent [LnIII(CH3)(CH3CO2)3]- (Ln = La, Ce, Pr, Nd, Sm, Tb, Tm, Yb, Lu), divalent [EuII(CH3)(CH3CO2)2]-, and the first examples of tetravalent organocerium complexes featuring CeIV-Calkyl σ-bonds: [CeIV(O)(CH3)(CH3CO2)2]- and [CeIV(O)(CH3)(NO3)2]-. Attempts to isolate PrIV-CH3 and TbIV-CH3 were unsuccessful; however, fragmentation patterns reveal that the oxidation of LnIII to a LnIV-oxo-acetate complex is more favorable for Ln = Pr than for Ln = Tb. The rate of Ln-CH3 hydrolysis is a measure of bond stability, and it decreases from LaIII-CH3 to LuIII-CH3, with increasing steric crowding for smaller Ln stabilizing the harder Ln-CH3 bond against hydrolysis. [EuII(CH3)(CH3CO2)2]- engages in a much faster hydrolysis versus LnIII-CH3. The surprising observation of similar hydrolysis rates for CeIV-CH3 and CeIII-CH3 is discussed with respect to sterics, the oxo ligand, and bond covalency in σ-bonded organolanthanides.

The association of anxiety disorders and depression with facial scarring: population-based, data linkage, matched cohort analysis of 358 158 patients.

BACKGROUND: Estimates suggest that 1 in 100 people in the UK live with facial scarring. Despite this incidence, psychological support is limited. AIMS: The aim of this study was to strengthen the case for improving such support by determining the incidence and risk factors for anxiety and depression disorders in patients with facial scarring. METHOD: A matched cohort study was performed. Patients were identified via secondary care data sources, using clinical codes for conditions resulting in facial scarring. A diagnosis of anxiety or depression was determined by linkage with the patient's primary care general practice data. Incidence was calculated per 1000 person-years at risk (PYAR). Logistic regression was used to determine risk factors. RESULTS: Between 2009 and 2018, 179 079 patients met the study criteria and were identified as having a facial scar, and matched to 179 079 controls. The incidence of anxiety in the facial scarring group was 10.05 per 1000 PYAR compared with 7.48 per 1000 PYAR for controls. The incidence of depression in the facial scarring group was 16.28 per 1000 PYAR compared with 9.56 per 1000 PYAR for controls. Age at the time of scarring, previous history of anxiety or depression, female gender, socioeconomic status and classification of scarring increased the risk of both anxiety disorders and depression. CONCLUSIONS: There is a high burden of anxiety disorders and depression in this patient group. Risk of these mental health disorders is very much determined by factors apparent at the time of injury, supporting the need for psychological support.

The cation-leaky hereditary stomatocytosis syndromes: A tale of six proteins.

This review concerns a series of dominantly inherited haemolytic anaemias in which the membrane of the erythrocyte 'leaks' the univalent cations, compromising the osmotic stability of the cell. The majority of the conditions are explained by mutations in one of six genes, coding for multispanning membrane proteins of different structure and function. These are: RhAG, coding for an ammonium carrier; SLC4A1, coding for the band 3 anion exchanger; PIEZO1, coding for a mechanosensitive cation channel; GLUT1, coding for a glucose transporter; KCNN4, coding for an internal-calcium-activated potassium channel; and ABCB6, coding for a porphyrin transporter. This review describes the five clinical syndromes associated with genetic defects in these genes and their variable genotype/phenotype relationships.

Males with sickle cell disease have higher risks of cerebrovascular disease, increased inflammation, and a reduced response to hydroxyurea.

Biological sex is important. Male sex is associated with worse outcomes in most measures, including cerebrovascular disease, hospital admissions, and blood transfusions, but not survival. Females also appear to have a better response to hydroxyurea therapy, reduced markers of inflammation, and better liver function.

Unusual Actinyl Complexes with a Redox-Active N,S-Donor Ligand.

Understanding the fundamental chemistry of soft N,S-donor ligands with actinides across the series is critical for separation science toward sustainable nuclear energy. This task is particularly challenging when the ligands are redox active. We herein report a series of actinyl complexes with a N,S-donor redox-active ligand that stabilizes different oxidation states across the actinide series. These complexes are isolated and characterized in the gas phase, along with high-level electronic structure studies. The redox-active N,S-donor ligand in the products, C5H4NS, acts as a monoanion in [UVIO2(C5H4NS-)]+ but as a neutral radical with unpaired electrons localized on the sulfur atom in [NpVO2(C5H4NS•)]+ and [PuVO2(C5H4NS•)]+, resulting in different oxidation states for uranium and transuranic elements. This is rationalized by considering the relative energy levels of actinyl(VI) 5f orbitals and S 3p lone pair orbitals of the C5H4NS- ligand and the cooperativity between An-N and An-S bonds that provides additional stability for the transuranic elements.

Tetravalent Uranium and Thorium Complexes: Elucidating Disparate Reactivities of AnIVCl2 (An = U, Th) Supported by a Pyridine-Decorated Dianionic Ligand.

Although synthesis, reactivity, and bonding of U(IV) and Th(IV) complexes have been extensively studied, direct comparison of fully analogous compounds is rare. Herein, we report corresponding complexes 1-U and 1-Th, in which U(IV) and Th(IV) are supported by the tetradentate pyridine-decorated dianionic ligand N2NN' (1,1,1-trimethyl-N-(2-(((pyridin-2-ylmethyl)(2-((trimethylsilyl)amino)benzyl)amino)methyl)phenyl)silanamine). Although 1-U and 1-Th are structurally very similar, they display disparate reactivities with TMS3SiK (tris(trimethylsilyl)silylpotassium). The reaction of (N2NN')UCl2 (1-U) and 1 equiv of TMS3SiK in THF unexpectedly formed [Cl(N2NN')U]2O (2-U) featuring an unusual bent U-O-U moiety. In contrast, a salt elimination reaction between (N2NN')ThCl2 (1-Th) and 1 equiv of TMS3SiK led to thorium complex 2-Th, in which the pyridyl group has undergone a 1,4-addition nucleophilic attack. Complex 2-Th serves as a synthon for preparing dimetallic bis-azide complex 3-Th by reaction with NaN3. The complexes were characterized by X-ray crystal diffraction, solution NMR, FT-IR, and elemental analysis. Computations of the formation mechanism of 2-U from 1-U suggest reduced U(III) as a key intermediate for promoting the cleavage of the C-O bonds of THF. The inaccessible nature of Th(III) as an intermediate oxidation state explains the very different reactivity of 1-Th versus 1-U. Given that reactants 1-U and 1-Th and products 2-U and 2-Th all comprise tetravalent actinides, this is an unusual case of very disparate reactivity despite no net change in the oxidation state. Complexes 2-U and 3-Th provide a basis for the synthesis of other dinuclear actinide complexes with novel reactivity and properties.

The psychosocial impact of microtia and ear reconstruction: A national data-linkage study.

Introduction: Children with visible facial differences are believed to be at increased risk of negative psychosocial behaviours which may manifest as affective disorders. The aim of this study was to determine whether a diagnosis of microtia, and the associated surgical intervention, is associated with psychosocial implications including impaired educational attainment and a diagnosis of an affective disorder. Methods: A retrospective case-control study was conducted using data linkage to identify patients in Wales with a diagnosis of microtia. Matched controls were sought on the basis of age, gender and socioeconomic deprivation status to yield a total sample size of 709. incidence was calculated using annual and geographic birth rates. Surgical operation codes were used to classify patients into those that had no surgery, autologous reconstruction or prosthetic reconstruction. Educational attainment at 11 years of age, plus a diagnosis of depression or anxiety were used as markers of adverse psychosocial outcomes and the relative risk was attained using logistic regression analyses. Results: There were no significant associations between a diagnosis of microtia and an increased risk of adverse educational attainment or a risk of an affective disorder diagnosis. Male gender and higher deprivation scores were significantly associated with poorer educational attainment, irrespective of a diagnosis of microtia. Surgical intervention of any nature was also not associated with any increased risk of adverse educational or psychosocial outcomes in microtia patients. Discussion: Microtia patients in Wales do not appear to be at greater risk of developing affective disorders or impaired academic performance as a result of their diagnosis or associated surgical intervention. Whilst reassuring, the need for appropriate support mechanisms to maintain positive psychosocial wellbeing and academic achievement in this patient cohort is reinforced.

A critical role for altered red cell cation permeability in pathogenesis of sickle cell disease and other haemolytic anaemias.

The aetiology of sickle cell disease is well known, but pathogenesis is complicated and details remain uncertain. A thorough understanding may suggest novel ways for designing more effective therapies. One area of importance, covered here in Nader et al., is the altered cation permeability of sickle cells and how the co-ordinated operation of a number of membrane transport proteins contributes to disease progression, all driven by the initial event of HbS polymerisation. There are echoes here of the cation leaks of hereditary stomatocytosis. Nader et al. propose a central role for PIEZO1, a novel mechanosensitive channel found in red cells, which may be aberrantly activated in sickle cells following HbS polymerisation and which may have potential as a novel target for future chemotherapies. Commentary on: Nader et al. Piezo1 activation augments sickling propensity and the adhesive properties of sickle red blood cells in a calcium-dependent manner. Br J Haematol 2023;202:657-668.