Attempted characterisation of phenanthrene-4,5-quinone and electrochemical synthesis of violanthrone-16,17-quinone. How does the stability of bay quinones correlate with structural and electronic parameters?

In bay quinones, two carbonyl moieties are forced into close proximity by their spatial arrangement, resulting in an interesting axially chiral and nonplanar structure. Two representatives of this little-explored class of compounds were investigated experimentally in this work. Electrochemical oxidation of 4,5-dihydroxyphenanthrene failed to provide evidence for the reversible formation of phenanthrene-4,5-quinone. Even at temperatures as low as T = 229 K, cyclic voltammograms did not show any evidence for reversibility, indicating that phenanthrene-4,5-quinone likely is a reactive intermediate even at low temperatures. Electrochemical oxidation of the larger homologue 16,17-dihydroxyviolanthrone, on the other hand, was reversible, and the quinone could be characterised by spectroelectrochemical means. The results of quantum chemical calculations confirm the experimental findings and indicate that a bay dicarbonyl moiety, also found in a number of angucycline antibiotics, does not necessarily have to confer extreme reactivity. However, in a series of phenanthrene quinones with an equal number (zero) of Clar sextets and a varying number of bay carbonyl groups (zero to two), there was a clear correlation between the triplet energy, taken as a measure of biradical character, and the number of bay carbonyl moieties, with the lowest triplet energy predicted for phenanthrene-4,5-quinone (two bay carbonyl moieties)

Immune interaction between SARS-CoV-2 and Mycobacterium tuberculosis

SARS-CoV-2 and Mycobacterium tuberculosis (Mtb) are major infectious causes of death, with meta-analyses and population-based studies finding increased mortality in co-infected patients simultaneously diagnosed with COVID-19 and tuberculosis (TB). There is a need to understand the immune interaction between SARS-CoV-2 and Mtb which impacts poor outcomes for those co-infected. We performed a PubMed and preprint search using keywords [SARS-CoV-2] AND [tuberculosis] AND [Immune response], including publications after January 2020, excluding reviews or opinions. Abstracts were evaluated by authors for inclusion of data specifically investigating the innate and/or acquired immune responses to SARS-CoV-2 and Mtb in humans and animal models, immunopathological responses in co-infection and both trials and investigations of potential protection against SARS-CoV-2 by Bacille Calmette Guérin (BCG). Of the 248 articles identified, 39 were included. Incidence of co-infection is discussed, considering in areas with a high burden of TB, where reported co-infection is likely underestimated. We evaluated evidence of the clinical association between COVID-19 and TB, discuss differences and similarities in immune responses in humans and in murine studies, and the implications of co-infection. SARS-CoV-2 and Mtb have both been shown to modulate immune responses, particularly of monocytes, macrophages, neutrophils, and T cells. Co-infection may result in impaired immunity to SARS-CoV-2, with an exacerbated inflammatory response, while T cell responses to Mtb may be modulated by SARS-CoV-2. Furthermore, there has been no proven potential COVID-19 clinical benefit of BCG despite numerous large-scale clinical trials

A quinone-based cathode material for high-performance organic lithium and sodium batteries

With the increased application of batteries in powering electric vehicles as well as potential contributions to utility-scale storage, there remains a need to identify and develop efficient and sustainable active materials for use in lithium (Li)- and sodium (Na)-ion batteries. Organic cathode materials provide a desirable alternative to inorganic counterparts, which often come with harmful environmental impact and supply chain uncertainties. Organic materials afford a sustainable route to active electrodes that also enable fine-tuning of electrochemical potentials through structural design. Here, we report a bis-anthraquinone-functionalized s-indacene-1,3,5,7(2H,6H)-tetraone (BAQIT) synthesized using a facile and inexpensive route as a high-capacity cathode material for use in Li- and Na-ion batteries. BAQIT provides multiple binding sites for Li- and Na-ions, while maintaining low solubility in commercial organic electrolytes. Electrochemical Li-ion cells demonstrate excellent stability with discharge capacities above 190 mAh g–1 after 300 cycles at a 0.1C rate. The material also displayed excellent high-rate performance with a reversible capacity of 142 mAh g–1 achieved at a 10C rate. This material affords high power capabilities superior to current state-of-the-art organic cathode materials, with values reaching 5.09 kW kg–1. The Na-ion performance was also evaluated, exhibiting reversible capacities of 130 mAh g–1 after 90 cycles at a 0.1C rate. This work offers a structural design to encourage versatile, high-power, and long cycle-life electrochemical energy-storage materials

Lessons learnt from a discontinued randomised controlled trial:Adalimumab injection compared with placebo for patients receiving physiotherapy treatment for sciatica (Subcutaneous Injection of Adalimumab Trial compared with Control: SCIATiC)

Background Adalimumab, a biological treatment targeting tumour necrosis factor α, might be useful in sciatica. This paper describes the challenges faced when developing a new treatment pathway for a randomised controlled trial of adalimumab for people with sciatica, as well as the reasons why the trial discussed was stopped early. Methods A pragmatic, parallel group, randomised controlled trial with blinded (masked) participants, clinicians, outcome assessment and statistical analysis was conducted in six UK sites. Participants were identified and recruited from general practices, musculoskeletal services and outpatient physiotherapy clinics. They were adults with persistent symptoms of sciatica of 1 to 6 months’ duration with moderate to high level of disability. Eligibility was assessed by research physiotherapists according to clinical criteria, and participants were randomised to receive two doses of adalimumab (80 mg then 40 mg 2 weeks later) or saline placebo subcutaneous injections in the posterior lateral thigh. Both groups were referred for a course of physiotherapy. Outcomes were measured at baseline, 6-week, 6-month and 12-month follow-up. The main outcome measure was disability measured using the Oswestry Disability Index. The planned sample size was 332, with the first 50 in an internal pilot phase. Results The internal pilot phase was discontinued after 10 months from opening owing to low recruitment (two of the six sites active, eight participants recruited). There were several challenges: contractual delays; one site did not complete contract negotiations, and two sites signed contracts shortly before trial closure; site withdrawal owing to patient safety concerns; difficulties obtaining excess treatment costs; and in the two sites that did recruit, recruitment was slower than planned because of operational issues and low uptake by potential participants. Conclusions Improved patient care requires robust clinical research within contexts in which treatments can realistically be provided. Step changes in treatment, such as the introduction of biologic treatments for severe sciatica, raise complex issues that can delay trial initiation and retard recruitment. Additional preparatory work might be required before testing novel treatments. A randomised controlled trial of tumour necrosis factor-α blockade is still needed to determine its cost-effectiveness in severe sciatica

Periprosthetic Joint Infection After Total Knee Arthroplasty With or Without Antibiotic Bone Cement.

IMPORTANCE Despite increased use of antibiotic-loaded bone cement (ALBC) in joint arthroplasty over recent decades, current evidence for prophylactic use of ALBC to reduce risk of periprosthetic joint infection (PJI) is insufficient. OBJECTIVE To compare the rate of revision attributed to PJI following primary total knee arthroplasty (TKA) using ALBC vs plain bone cement. DESIGN, SETTING, AND PARTICIPANTS This international cohort study used data from 14 national or regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, New Zealand, Norway, Romania, Sweden, Switzerland, the Netherlands, the UK, and the US. The study included primary TKAs for osteoarthritis registered from January 1, 2010, to December 31, 2020, and followed-up until December 31, 2021. Data analysis was performed from April to September 2023. EXPOSURE Primary TKA with ALBC vs plain bone cement. MAIN OUTCOMES AND MEASURES The primary outcome was risk of 1-year revision for PJI. Using a distributed data network analysis method, data were harmonized, and a cumulative revision rate was calculated (1 - Kaplan-Meier), and Cox regression analyses were performed within the 10 registries using both cement types. A meta-analysis was then performed to combine all aggregated data and evaluate the risk of 1-year revision for PJI and all causes. RESULTS Among 2 168 924 TKAs included, 93% were performed with ALBC. Most TKAs were performed in female patients (59.5%) and patients aged 65 to 74 years (39.9%), fully cemented (92.2%), and in the 2015 to 2020 period (62.5%). All participating registries reported a cumulative 1-year revision rate for PJI of less than 1% following primary TKA with ALBC (range, 0.21%-0.80%) and with plain bone cement (range, 0.23%-0.70%). The meta-analyses based on adjusted Cox regression for 1 917 190 TKAs showed no statistically significant difference at 1 year in risk of revision for PJI (hazard rate ratio, 1.16; 95% CI, 0.89-1.52) or for all causes (hazard rate ratio, 1.12; 95% CI, 0.89-1.40) among TKAs performed with ALBC vs plain bone cement. CONCLUSIONS AND RELEVANCE In this study, the risk of revision for PJI was similar between ALBC and plain bone cement following primary TKA. Any additional costs of ALBC and its relative value in reducing revision risk should be considered in the context of the overall health care delivery system

The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania.

BACKGROUND AND PURPOSE Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). PATIENTS AND METHODS This observational study is based on 2,971,357 primary TKAs reported in 2010-2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. RESULTS ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). CONCLUSION The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year