A facile route to a novel aza-crown ether incorporating three thiophene moieties

The preparation of the first of a novel type of large thiophene-containing aza-crown ether is reported. The macrocycle is synthesised by linking a 3,4-dialkoxythiophene moiety with two 3-hydroxythiophene units and ring closure is effected by reaction with piperazine via the Mannich reaction

John N. Sherwood : studies of energetic materials

Studies on the physicomechanical properties of commonly used energetic materials (EMs) that were pursued by the group led by Professor John Sherwood are reviewed in this paper. The studies ranged from the growth of high quality single crystals and the characterization of their defect and dislocation structures, mechanical testing, through to the study of polymorphism of EM crystals and fundamental aspects of crystallization processes in general. The work performed led to the definition of good growth conditions for all the EMs studied and to the full characterization of the defect structure, slip systems, and hardness properties of cyclotrimethylene trinitramine (RDX) and pentaerythritol tetranitrate (PETN). Partial characterization of the defect structures and hardness properties of cyclotetramethylene tetranitramine (HMX) and 2,4,6-trinitrotoluene (TNT) was also achieved. Additionally, fundamental crystal growth and polymorph information were defined, allowing a deeper understanding of the crystallization and crystal structure of TNT. In addition to the general review, some thoughts were given as to possible future routes for further study that could suitably utilize the complementary nature of established and modern techniques

Actively forming Kuroko-type volcanic-hosted massive sulfide (VHMS) mineralization at Iheya North, Okinawa Trough, Japan

Modern seafloor hydrothermal systems provide important insights into the formation and discovery of ancient volcanic-hosted massive sulfide (VHMS) deposits. In 2010, Integrated Ocean Drilling Program (IODP) Expedition 331 drilled five sites in the Iheya North hydrothermal field in the middle Okinawa Trough back-arc basin, Japan. Hydrothermal alteration and sulfide mineralization is hosted in a geologically complex, mixed sequence of coarse pumiceous volcaniclastic and fine hemipelagic sediments, overlying a dacitic to rhyolitic volcanic substrate. At site C0016, located adjacent to the foot of the actively venting North Big Chimney massive sulfide mound, massive sphalerite-(pyrite-chalcopyrite ± galena)-rich sulfides were intersected (to 30.2% Zn, 12.3% Pb, 2.68% Cu, 33.1 ppm Ag and 0.07 ppm Au) that strongly resemble the black ore of the Miocene-age Kuroko deposits of Japan. Sulfide mineralization shows clear evidence of formation through a combination of surface detrital and subsurface chemical processes, with at least some sphalerite precipitating into void space in the rock. Volcanic rocks beneath massive sulfides exhibit quartz-muscovite/illite and quartz-Mg-chlorite alteration reminiscent of VHMS proximal footwall alteration associated with Kuroko-type deposits, characterized by increasing MgO, Fe/Zn and Cu/Zn with depth. Recovered felsic footwall rocks are of FII to FIII affinity with well-developed negative Eu anomalies, consistent with VHMS-hosting felsic rocks in Phanerozoic ensialic arc/back-arc settings worldwide. Site C0013, ∼100 m east of North Big Chimney, represents a likely location of recent high temperature discharge, preserved as surficial coarse-grained sulfidic sediments (43.2% Zn, 4.4% Pb, 5.4% Cu, 42 ppm Ag and 0.02 ppm Au) containing high concentrations of As, Cd, Mo, Sb, and W. Near surface hydrothermal alteration is dominated by kaolinite and muscovite with locally abundant native sulfur, indicative of acidic hydrothermal fluids. Alteration grades to Mg-chlorite dominated assemblages at depths of >5 mbsf (metres below sea floor). Late coarse-grained anhydrite veining overprints earlier alteration and is interpreted to have precipitated from down welling seawater as hydrothermal activity waned. At site C0014, ∼350 m farther east, hydrothermal assemblages are characterized by illite/montmorillonite, with Mg-chlorite present at depths below ∼30 mbsf. Recovered lithologies from distal, recharge site C0017 are unaltered, with low MgO, FeO and base metal concentrations. Mineralization and alteration assemblages are consistent with the Iheya North system representing a modern analogue for Kuroko-type VHMS mineralization. Fluid flow is focussed laterally along pumiceous volcaniclastic strata (compartmentalized between impermeable hemipelagic sediments), and vertically along faults. The abundance of Fe-poor sphalerite and Mg-rich chlorite (clinochlore/penninite) is consistent with the lower Fe budget, temperature and higher oxidation state of felsic volcanic-hosted hydrothermal systems worldwide compared to Mid Ocean Ridge black smoker systems

4-Oxocyclo­hexa­neacetic acid: catemeric hydrogen bonding and spontaneous resolution of a single conformational enanti­omer in an achiral ∊-keto acid

The asymmetric unit of the title compound, C8H12O3, consists of a single conformational enanti­omer, which aggregates in the catemeric acid-to-ketone hydrogen-bonding mode [O⋯O = 2.682 (4) Å and O—H⋯O = 172 (6)°]. Four hydrogen-bonding chains of translationally related mol­ecules pass through the cell orthogonal to the 43 screw axis along c, alternating in the 110 and the 10 direction, with alignment with respect to this axis of + + − −. Successive chains are rotated by 90° around the c axis. One C—H⋯O=C close contact, involving the carboxyl group, exists

A study of referral bias in NMOSD and MOGAD cohorts.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare disorders often seen in highly specialized services or tertiary centres. We aimed to assess if cohort characteristics depend on the origin of the referral catchment areas serviced by our centre (i.e. local, regional or national). METHODS: Retrospective cohort study using a national referral service database including local (Oxfordshire), regional (Oxfordshire and neighbouring counties), and national patients. We included patients with the diagnosis of NMOSD, seronegative NMOSD or MOGAD, followed at the Oxford Neuromyelitis Optica Service. RESULTS: We included 720 patients (331 with MOGAD, 333 with aquaporin-4 antibody (AQP4)-NMOSD, and 56 with seronegative NMOSD. The distribution of diagnoses was similar across referral cohorts. There were no significant differences in the proportion of pediatric onset patients, sex, or onset phenotype; more White AQP4-NMOSD patients were present in the local than in the national cohort (81 % vs 52 %). Despite no differences in follow-up time, more relapsing MOGAD disease was present in the national than in the local cohort (42.9 % vs. 24 %, p = 0.029). CONCLUSION: This is the first study assessing the impact of potential referral bias in cohorts of NMOSD or MOGAD. The racial difference in the AQP4-NMOSD cohorts likely reflects the variation in the population demographics rather than a referral bias. The over representation of relapsing MOGAD patients in the national cohort probably is a true referral bias and highlights the need to analyze incident cohorts when describing disease course and prognosis. It seems reasonable therefore to compare MOGAD and NMOSD patients seen withing specialised centres to general neurology services, provided both use similar antibody assays

Physical activity monitoring to assess disability progression in multiple sclerosis

Background: Clinical outcome measurement in multiple sclerosis (MS) usually requires a physical visit. Remote activity monitoring (RAM) using wearable technology provides a rational alternative, especially desirable when distance is involved or in a pandemic setting. Objective: To validate RAM in progressive MS using (1) traditional psychometric methods (2) brain atrophy. Methods: 56 people with progressive MS participated in a longitudinal study over 2.5 years. An arm-worn RAM device measured activity over six days, every six months, and incorporated triaxial accelerometry and transcutaneous physiological variable measurement. Five RAM variables were assessed: physical activity duration, step count, active energy expenditure, metabolic equivalents and a composite RAM score incorporating all four variables. Other assessments every six months included EDSS, MSFC, MSIS-29, Chalder Fatigue Scale and Beck’s Depression Inventory. Annualized brain atrophy was measured using SIENA. Results: RAM was tolerated well by people with MS; the device was worn 99.4% of the time. RAM had good convergent and divergent validity and was responsive, especially with respect to step count. Measurement of physical activity over one day was as responsive as six days. The composite RAM score positively correlated with brain volume loss. Conclusion: Remote activity monitoring is a valid and acceptable outcome measure in MS

FDG–PET. A possible prognostic factor in head and neck cancer

Previous studies have shown that high uptake of 18F-fluoro-2-deoxy-glucose in head and neck cancer, as determined by the standardized uptake value on positron emission tomography scan, was associated with poor survival. The aim of this study was to confirm the association and to establish whether a high standardized uptake value had prognostic significance. Seventy-three consecutive patients with newly diagnosed squamous cell carcinoma of the head and neck underwent a positron emission tomography study before treatment. Age, gender, performance status tumour grade, stage, maximal tumour diameter and standardized uptake value were analyzed for their possible association with survival. The median standardized uptake value for all primary tumours was 7.16 (90% range 2.30 to 18.60). In univariate survival analysis the cumulative survival was decreased as the stage, tumour diameter and standardized uptake value increased. An standardized uptake value of 10 was taken as a cut-off for high and low uptake tumours. When these two groups were compared, an standardized uptake value >10 predicted for significantly worse outcome (P=0.003). Multivariate analysis demonstrated that an standardized uptake value >10 provided prognostic information independent of the tumour stage and diameter (P=0.002). We conclude that high FDG uptake (standardized uptake value>10) on positron emission tomography is an important marker for poor outcome in primary squamous cell carcinoma of the head and neck. Standardized uptake value may be useful in distinguishing those tumours with a more aggressive biological nature and hence identifying patients that require intensive treatment protocols including hyperfractionated radiotherapy and/or chemotherapy

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. // METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. // RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). // CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. // CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883

Real-world clinical experience with Idebenone in the treatment of Leber hereditary optic neuropathy

Background: Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. Methods: Open-label, multicenter, retrospective, noncontrolled analysis of long-term visual acuity and safety in 111 LHON patients treated with idebenone (900 mg/day) in an expanded access program. Eligible patients had a confirmed mitochondrial DNA mutation and had experienced the onset of symptoms (most recent eye) within 1 year before enrollment. Data on visual acuity and adverse events were collected as per normal clinical practice. Efficacy was assessed as the proportion of patients with either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS) of visual acuity. In the case of CRR, time to and magnitude of recovery over the course of time were also assessed. Results: At time of analysis, 87 patients had provided longitudinal efficacy data. Average treatment duration was 25.6 months. CRR was observed in 46.0% of patients. Analysis of treatment effect by duration showed that the proportion of patients with recovery and the magnitude of recovery increased with treatment duration. Average gain in best-corrected visual acuity for responders was 0.72 logarithm of the minimal angle of resolution (logMAR), equivalent to more than 7 lines on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Furthermore, 50% of patients who had a visual acuity below 1.0 logMAR in at least one eye at initiation of treatment successfully maintained their vision below this threshold by last observation. Idebenone was well tolerated, with most adverse events classified as minor. Conclusions: These data demonstrate the benefit of idebenone treatment in recovering lost vision and maintaining good residual vision in a real-world setting. Together, these findings indicate that idebenone treatment should be initiated early and be maintained more than 24 months to maximize efficacy. Safety results were consistent with the known safety profile of idebenone

Incidence and Risk Factors for Retinal Detachment and Retinal Tear after Cataract Surgery: IRIS® Registry (Intelligent Research in Sight) Analysis

Objective To report the incidence of and evaluate demographic, ocular comorbidities, and intraoperative factors for rhegmatogenous retinal detachment (RRD) and retinal tear (RT) after cataract surgery in the American Academy of Ophthalmology IRIS® Registry (Intelligent Research in Sight). Design Retrospective cohort study. Participants Patients aged ≥ 40 years who underwent cataract surgery between 2014 and 2017. Methods Multivariable logistic regression was used to evaluate demographic, comorbidity, and intraoperative factors associated with RRD and RT after cataract surgery. Main Outcome Measures Incidence and risk factors for RRD or RT within 1 year of cataract surgery. Results Of the 3 177 195 eyes of 1 983 712 patients included, 6690 (0.21%) developed RRD and 5489 (0.17%) developed RT without RRD within 1 year after cataract surgery. Multivariable logistic regression odds ratios (ORs) showed increased risk of RRD and RT, respectively, among men (OR 3.15; 95% confidence interval [CI], 2.99–3.32; P \u3c 0.001 and 1.79; 95% CI, 1.70–1.89; P \u3c 0.001), and younger ages compared with patients aged \u3e 70, peaking at age 40 to 50 for RRD (8.61; 95% CI, 7.74–9.58; P \u3c 0.001) and age 50 to 60 for RT (2.74; 95% CI, 2.52–2.98; P \u3c 0.001). Increased odds of RRD were observed for procedure eyes with lattice degeneration (LD) (10.53; 95% CI, 9.82–11.28; P \u3c 0.001), hypermature cataract (1.61; 95% CI, 1.06–2.45; P = 0.03), complex cataract surgery (1.52; 95% CI, 1.4–1.66; P \u3c 0.001), posterior vitreous detachment (PVD) (1.24; 95% CI, 1.15–1.34; P \u3c 0.001), and high myopia (1.2; 95% CI, 1.14–1.27; P \u3c 0.001). Lattice degeneration conferred the highest odds of RT (43.86; 95% CI, 41.39–46.49; P \u3c 0.001). Conclusion In the IRIS Registry, RRD occurs in approximately 1 in 500 cataract surgeries in patients aged \u3e 40 years within 1 year of surgery. The presence of LD conferred the highest odds for RRD and RT after surgery. Additional risk factors for RRD included male gender, younger age, hypermature cataract, PVD, and high myopia. These data may be useful during the informed consent process for cataract surgery and help identify patients at a higher risk of retinal complications. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article