Purinyl N-directed aroylation of 6-arylpurine ribo- and 2'-deoxyribonucleosides, and mechanistic insights.

The purinyl ring contains four embedded nitrogen atoms of varying basicities. Selective utilization of these ring nitrogen atoms can lead to relatively facile remote functionalization, yielding modified purinyl motifs that are otherwise not easily obtained. Herein, we report previously undescribed N-directed aroylation of 6-arylpurine ribo and the more labile 2'-deoxyribonucleosides. Kinetic isotope analysis as well as reaction with a well-defined dimeric, palladated 9-benzyl 6-arylpurine provided evidence for N-directed cyclometallation as a key step, with a plausible rate-limiting C-H bond cleavage. Radical inhibition experiments indicate the likely intermediacy of aroyl radicals. The chemistry surmounts difficulties often posed in the functionalization of polynitrogenated and polyoxygenated nucleosidic structures that possess complex reactivities and a labile glycosidic bond that is more sensitive in the 2'-deoxy substrates.

Post-craniotomy leptomeningeal cyst: a new presentation of an old problem.

Leptomeningeal cyst (LMC) is a known complication of pediatric head injury but has not been described following a craniotomy other than for craniosynostosis. We present the case of a 20-month-old boy who underwent craniotomy for a traumatic epidural hematoma. There was an inadvertent tear of the dura which was repaired with a pericranial patch and dural sealant. The patient presented with a progressive surgical site swelling 5 months post-surgery and a CT scan revealed an LMC with elevation of the bone flap. He underwent re-exploration with watertight repair of the dural defect and rigid fixation of the bone flap. This iatrogenic LMC provides an opportunity to compare and confirm the pathogenesis vis a vis the more common spontaneous post-traumatic LMC. Our report highlights the importance of proper dural closure and bone fixation after craniotomy in children whose skulls are still growing.

Tension Subdural Hygroma Following Resection of Posterior Fossa Tumour in a Child: A new clinico-radio-pathological entity.

Persistent hydrocephalus is common in children after resection of posterior fossa tumours. However, occurrence of subdural hygroma is very rare. We report the case of a 14-month-old child who presented at a paediatric neurology clinic in Muscat, Oman in 2021 who developed a tense subdural hygroma with stable hydrocephalus, in the early postoperative period, following posterior fossa tumour resection. We describe the distinctive clinical, radiological and pathological features associated with the development of a tense subdural hygroma. We also discuss the management by cerebrospinal fluid diversion, which includes either a ventriculoperitoneal or subduroperitoneal shunt. This unique condition is distinguished from external hydrocephalus by features that are critical to the management strategy.

Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics.

BACKGROUND: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s). This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design. METHODS: We outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit. RESULTS: Pre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level. CONCLUSIONS: Multi-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Interaction of obesity and proteins associated with the NLRP3 inflammasome following mild traumatic brain injury.

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been associated with worse outcomes from severe traumatic brain injury (TBI). The NLRP3 inflammasome is also strongly associated with other pro-inflammatory conditions, such as obesity. Little is known about the potential effect of mild TBI (mTBI) on the NLRP3 inflammasome and the extent to which modifying factors, such as obesity, may augment the inflammatory response to mTBI. The purpose of this study was to evaluate the association of NLRP3 inflammasome proteins with obese body mass index (BMI ≥ 30) within 24 h of mTBI after presenting to a level 1 trauma center emergency department. This is a secondary analysis of prospectively enrolled patients with mTBI who presented to the emergency department of one U.S. Level 1 trauma center from 2013 to 2018 (n = 243). A series of regression models were built to evaluate the association of NLRP3 proteins obtained from blood plasma within 24 h of injury and BMI as well as the potential interaction effect of higher BMI with NLRP3 proteins (n = 243). A logistic regression model revealed a significant association between IL-18 (p < 0.001) in mTBI patients with obese BMI compared to mTBI patients with non-obese BMI (< 30). Moderation analyses revealed statistically significant interaction effects between apoptotic speck-like protein (ASC), caspase-1, IL-18, IL-1ß and obese BMI which worsened symptom burden, quality of life, and physical function at 2 weeks and 6 months post-injury. Higher acute concentrations of IL-1ß in the overall cohort predicted higher symptoms at 6-months and worse physical function at 2-weeks and 6-months. Higher acute concentrations of IL-18 in the overall cohort predicted worse physical function at 6-months. In this single center mTBI cohort, obese BMI interacted with higher acute concentrations of NLRP3 inflammasome proteins and worsened short- and long-term clinical outcomes.

Unraveling the Luminescence Quenching Mechanism in Strong and Weak Quantum-Confined CsPbBr3 Triggered by Triarylamine-Based Hole Transport Layers.

Luminescence quenching by hole transport layers (HTLs) is one of the major issues in developing efficient perovskite light-emitting diodes (PeLEDs), which is particularly prominent in blue-emitting devices. While a variety of material systems have been used as interfacial layers, the origin of such quenching and the type of interactions between perovskites and HTLs are still ambiguous. Here, we present a systematic investigation of the luminescence quenching of CsPbBr3 by a commonly employed hole transport polymer, poly[(9,9-dioctylfluorenyl-2,7diyl)-co-(4,4'-(N-(4-sec-butylphenyl) diphenylamine)] (TFB), in LEDs. Strong and weak quantum-confined CsPbBr3 (nanoplatelets (NPLs)/nanocrystals (NCs)) are rationally selected to study the quenching mechanism by considering the differences in their morphology, energy level alignments, and quantum confinement. The steady-state and time-resolved Stern-Volmer plots unravel the dominance of dynamic and static quenching at lower and higher concentrations of TFB, respectively, with a maximum quenching efficiency of 98%. The quenching rate in NCs is faster than that in NPLs owing to their longer PL lifetimes and weak quantum confinement. The ultrafast transient absorption results support these dynamics and rule out the involvement of Forster or Dexter energy transfer. Finally, the 1D 1H and 2D nuclear overhauser effect spectroscopy nuclear magnetic resonance (NOESY NMR) study confirms the exchange of native ligands at the NCs surface with TFB, leading to dark CsPbBr3-TFB ensemble formation accountable for luminescence quenching. This highlights the critical role of the triarylamine functional group on TFB (also the backbone of many HTLs) in the quenching process. These results shed light on the underlying reasons for the luminescence quenching in PeLEDs and will help to rationally choose the interfacial layers for developing efficient LEDs.

To assess the analgesic efficacy of adjuvant magnesium sulfate added with ropivacaine over ropivacaine alone as a continuous infiltration in total abdominal hysterectomy wound: A randomized controlled trial.

Background and Aims: Magnesium sulfate (MgSO4) has been demonstrated to have analgesic property in various clinical settings. This study explores if addition of MgSO4 to ropivacaine increases its analgesic efficacy when infiltrated continuously in the postsurgical wound following total abdominal hysterectomy. Material and Methods: This randomized controlled trial was conducted at a tertiary care referral hospital in New Delhi, India. Fifty-two patients were randomized into two groups to receive the intervention of which 48 were able to complete the study. The first group (n = 26) received 0.25% ropivacaine infiltration and the second group (n = 26) received 0.25% ropivacaine with 5% MgSO4 at the incision site for 48 h postoperatively. Primary objective was to compare the total postoperative opioid (morphine) consumption by the study participants in both the groups and the secondary objectives were pain scores at rest and at movement, patient satisfaction score, and wound quality of life on the 7th postoperative day among the two groups. Results: Both the groups were comparable in their demographic characteristics. The median morphine consumed at 48 h postoperatively was 16.5 [0-77] mg in the ropivacaine group and 13[1-45] mg in the ropivacaine with MgSO4 group and the difference was statistically insignificant (P = 0.788). There was no statistical difference between the groups with respect to the pain scores, patient satisfaction, or wound quality of life at 7 days. Conclusion: The addition of MgSO4 to ropivacaine does not confer any additional postoperative analgesic benefits over ropivacaine alone in continuous wound infiltration following total abdominal hysterectomy.

Determinants, profile and outcomes of hepatitis A virus-associated severe acute liver injury in adults.

BACKGROUND AND OBJECTIVES: Hepatitis A virus (HAV)-related hepatitis is witnessing an epidemiological transition with increasing trends in adults. While uncomplicated hepatitis remains common, evidence suggests it to be a growing cause for acute liver failure (ALF). In between the two extremes exists severe acute liver injury (s-ALI) which has a propensity to transition to ALF. We aimed at describing the clinical profile of patients with HAV-related s-ALI and identifying potential predictors of progression to ALF. METHODS: This was a single-center retrospective analysis of adult patients admitted with HAV-related s-ALI between April 2022 and December 2023. Demographic and laboratory parameters were compared between patients with only s-ALI and those with ALF. Predictors of progression from s-ALI to ALF were identified using logistic regression. RESULTS: Forty-three patients satisfied criteria of s-ALI, of which 33 (76.7%) had only s-ALI, while 10 (23.3%) had ALF. Patients with s-ALI had lesser leukocytosis (6.3 ± 3 vs. 13.2 ± 4.8), less incidence of acute kidney injury (9.1% vs. 40%) and lower model for end-stage liver disease (MELD) (20 [18-24.5] vs. 31.5 [26-42]), arterial lactate (2.1 [1.3-3.1] vs. 6.3 [5.2-8.0]), arterial ammonia (94 [72-118] vs. 299 [188-573]), procalcitonin (0.5 [0.28-1.25] vs. 3.2 [1.2-6.1]) and ferritin (482 [213-1633] vs. 5186 [1341-11,053]) compared to HAV-ALF (p < 0.05 for all). Three patients (9.09%) with s-ALI progressed to ALF of whom one (3%) died. Baseline ammonia levels (unadjusted odds ratio [OR] 1.03 [1.01-1.06]) and leukocyte count (OR 1.00 [1.00-1.01]) tended to be associated with ALF progression, although none was significant after multi-variable adjustment. Ammonia levels had an area under receiver operating curve of 0.816 (0.64-0.93) (p = 0.009) (cut-off of 144 µmol/L). Additional comorbidities did not impact overall outcomes. CONCLUSION: HAV presents as s-ALI in young adults, with almost one in 10 progressing to ALF. Baseline ammonia may be an important predictor of progression even in s-ALI, but mandates larger well-designed studies.

Particle Dynamics in a Diblock-Copolymer-Based Dodecagonal Quasicrystal and Its Periodic Approximant by X-Ray Photon Correlation Spectroscopy.

Temperature-dependent x-ray photon correlation spectroscopy (XPCS) measurements are reported for a binary diblock-copolymer blend that self-assembles into an aperiodic dodecagonal quasicrystal and a periodic Frank-Kasper σ phase approximant. The measured structural relaxation times are Bragg scattering wavevector independent and are 5 times faster in the dodecagonal quasicrystal than the σ phase, with minimal temperature dependence. The underlying dynamical relaxations are ascribed to differences in particle motion at the grain boundaries within each of these tetrahedrally close-packed assemblies. These results identify unprecedented particle dynamics measurements of tetrahedrally coordinated micellar block polymers, thus expanding the application of XPCS to ordered soft materials.

The 3,4-methylenedioxymethamphetamine enhances early visual processing for salient socio-emotional stimuli.

The 3,4-methylenedioxymethamphetamine (MDMA) has long been used non-medically, and it is currently under investigation for its potential therapeutic benefits. Both uses may be related to its ability to enhance empathy, sociability, emotional processing and its anxiolytic effects. However, the neural mechanisms underlying these effects, and their specificity to MDMA compared to other stimulants, are not yet fully understood. Here, using electroencephalography (EEG), we investigated the effects of MDMA and a prototypic stimulant, methamphetamine (MA), on early visual processing of socio-emotional stimuli in an oddball emotional faces paradigm. Specifically, we examined whether MDMA or MA enhance the processing of facial expressions, compared to placebo, during the early stages of visual perception. MDMA enhanced an event-related component that is sensitive to detecting faces (N170), specifically for happy and angry expressions compared to neutral faces. MA did not affect this measure, and neither drug altered other components of the response to emotional faces. These findings provide novel insights into the neural mechanisms underlying the effects of MDMA on socio-emotional processing and may have implications for the therapeutic use of MDMA in the treatment of social anxiety and other psychiatric disorders.

GPCR-IPL score: multilevel featurization of GPCR-ligand interaction patterns and prediction of ligand functions from selectivity to biased activation.

G-protein-coupled receptors (GPCRs) mediate diverse cell signaling cascades after recognizing extracellular ligands. Despite the successful history of known GPCR drugs, a lack of mechanistic insight into GPCR challenges both the deorphanization of some GPCRs and optimization of the structure-activity relationship of their ligands. Notably, replacing a small substituent on a GPCR ligand can significantly alter extracellular GPCR-ligand interaction patterns and motion of transmembrane helices in turn to occur post-binding events of the ligand. In this study, we designed 3D multilevel features to describe the extracellular interaction patterns. Subsequently, these 3D features were utilized to predict the post-binding events that result from conformational dynamics from the extracellular to intracellular areas. To understand the adaptability of GPCR ligands, we collected the conformational information of flexible residues during binding and performed molecular featurization on a broad range of GPCR-ligand complexes. As a result, we developed GPCR-ligand interaction patterns, binding pockets, and ligand features as score (GPCR-IPL score) for predicting the functional selectivity of GPCR ligands (agonism versus antagonism), using the multilevel features of (1) zoomed-out 'residue level' (for flexible transmembrane helices of GPCRs), (2) zoomed-in 'pocket level' (for sophisticated mode of action) and (3) 'atom level' (for the conformational adaptability of GPCR ligands). GPCR-IPL score demonstrated reliable performance, achieving area under the receiver operating characteristic of 0.938 and area under the precision-recall curve of 0.907 (available in gpcr-ipl-score.onrender.com). Furthermore, we used the molecular features to predict the biased activation of downstream signaling (Gi/o, Gq/11, Gs and ß-arrestin) as well as the functional selectivity. The resulting models are interpreted and applied to out-of-set validation with three scenarios including the identification of a new MRGPRX antagonist.

Diagnosis of abdominal tuberculosis: Detection of mycobacterial CFP-10 and HspX proteins by gold nanoparticle-PCR amplified immunoassay.

Attempts were made to improve the efficacy of PCR amplified immunoassay (I-PCR) for diagnosing abdominal TB cases by utilizing the gold nanoparticle (AuNP)-based I-PCR, where AuNPs were functionalized with detection antibodies/oligonucleotides that exhibited 84.3% sensitivity and 95.1% specificity. This assay would improve the ongoing algorithms used in abdominal TB diagnosis.