Viral Genomic DNA Packaging Machinery.

Tailed double-stranded DNA bacteriophage employs a protein terminase motor to package their genome into a preformed protein shell-a system shared with eukaryotic dsDNA viruses such as herpesviruses. DNA packaging motor proteins represent excellent targets for antiviral therapy, with Letermovir, which binds Cytomegalovirus terminase, already licensed as an effective prophylaxis. In the realm of bacterial viruses, these DNA packaging motors comprise three protein constituents: the portal protein, small terminase and large terminase. The portal protein guards the passage of DNA into the preformed protein shell and acts as a protein interaction hub throughout viral assembly. Small terminase recognises the viral DNA and recruits large terminase, which in turn pumps DNA in an ATP-dependent manner. Large terminase also cleaves DNA at the termination of packaging. Multiple high-resolution structures of each component have been resolved for different phages, but it is only more recently that the field has moved towards cryo-EM reconstructions of protein complexes. In conjunction with highly informative single-particle studies of packaging kinetics, these structures have begun to inspire models for the packaging process and its place among other DNA machines.

Biochemical and structural basis of sialic acid utilization by gut microbes.

The human gastrointestinal (GI) tract harbors diverse microbial communities collectively known as the gut microbiota that exert a profound impact on human health and disease. The repartition and availability of sialic acid derivatives in the gut have a significant impact on the modulation of gut microbes and host susceptibility to infection and inflammation. Although N-acetylneuraminic acid (Neu5Ac) is the main form of sialic acids in humans, the sialic acid family regroups more than 50 structurally and chemically distinct modified derivatives. In the GI tract, sialic acids are found in the terminal location of mucin glycan chains constituting the mucus layer and also come from human milk oligosaccharides in the infant gut or from meat-based foods in adults. The repartition of sialic acid in the GI tract influences the gut microbiota composition and pathogen colonization. In this review, we provide an update on the mechanisms underpinning sialic acid utilization by gut microbes, focusing on sialidases, transporters, and metabolic enzymes.

The human gut symbiont Ruminococcus gnavus shows specificity to blood group A antigen during mucin glycan foraging: Implication for niche colonisation in the gastrointestinal tract.

The human gut symbiont Ruminococcus gnavus displays strain-specific repertoires of glycoside hydrolases (GHs) contributing to its spatial location in the gut. Sequence similarity network analysis identified strain-specific differences in blood-group endo-ß-1,4-galactosidase belonging to the GH98 family. We determined the substrate and linkage specificities of GH98 from R. gnavus ATCC 29149, RgGH98, against a range of defined oligosaccharides and glycoconjugates including mucin. We showed by HPAEC-PAD and LC-FD-MS/MS that RgGH98 is specific for blood group A tetrasaccharide type II (BgA II). Isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR confirmed RgGH98 affinity for blood group A over blood group B and H antigens. The molecular basis of RgGH98 strict specificity was further investigated using a combination of glycan microarrays, site-directed mutagenesis, and X-ray crystallography. The crystal structures of RgGH98 in complex with BgA trisaccharide (BgAtri) and of RgGH98 E411A with BgA II revealed a dedicated hydrogen network of residues, which were shown by site-directed mutagenesis to be critical to the recognition of the BgA epitope. We demonstrated experimentally that RgGH98 is part of an operon of 10 genes that is overexpresssed in vitro when R. gnavus ATCC 29149 is grown on mucin as sole carbon source as shown by RNAseq analysis and RT-qPCR confirmed RgGH98 expression on BgA II growth. Using MALDI-ToF MS, we showed that RgGH98 releases BgAtri from mucin and that pretreatment of mucin with RgGH98 confered R. gnavus E1 the ability to grow, by enabling the E1 strain to metabolise BgAtri and access the underlying mucin glycan chain. These data further support that the GH repertoire of R. gnavus strains enable them to colonise different nutritional niches in the human gut and has potential applications in diagnostic and therapeutics against infection.

AI-Driven Discovery of SARS-CoV-2 Main Protease Fragment-like Inhibitors with Antiviral Activity In Vitro.

SARS-CoV-2 is the causative agent of COVID-19 and is responsible for the current global pandemic. The viral genome contains 5 major open reading frames of which the largest ORF1ab codes for two polyproteins, pp1ab and pp1a, which are subsequently cleaved into 16 nonstructural proteins (nsp) by two viral cysteine proteases encoded within the polyproteins. The main protease (Mpro, nsp5) cleaves the majority of the nsp's, making it essential for viral replication and has been successfully targeted for the development of antivirals. The first oral Mpro inhibitor, nirmatrelvir, was approved for treatment of COVID-19 in late December 2021 in combination with ritonavir as Paxlovid. Increasing the arsenal of antivirals and development of protease inhibitors and other antivirals with a varied mode of action remains a priority to reduce the likelihood for resistance emerging. Here, we report results from an artificial intelligence-driven approach followed by in vitro validation, allowing the identification of five fragment-like Mpro inhibitors with IC50 values ranging from 1.5 to 241 µM. The three most potent molecules (compounds 818, 737, and 183) were tested against SARS-CoV-2 by in vitro replication in Vero E6 and Calu-3 cells. Compound 818 was active in both cell models with an EC50 value comparable to its measured IC50 value. On the other hand, compounds 737 and 183 were only active in Calu-3, a preclinical model of respiratory cells, showing selective indexes twice as high as those for compound 818. We also show that our in silico methodology was successful in identifying both reversible and covalent inhibitors. For instance, compound 818 is a reversible chloromethylamide analogue of 8-methyl-γ-carboline, while compound 737 is an N-pyridyl-isatin that covalently inhibits Mpro. Given the small molecular weights of these fragments, their high binding efficiency in vitro and efficacy in blocking viral replication, these compounds represent good starting points for the development of potent lead molecules targeting the Mpro of SARS-CoV-2.

Morphogenesis of Liquid Indium Microdroplets on Solid Molybdenum Surfaces during Solidification at Normal Pressure and under Vacuum Conditions.

Electrical and optical applications based on micro- and nanoparticles have specific demands on their interfacial properties. These properties are strongly related to atmospheric conditions to which the particles were exposed during their formation. In this study, metallic In microparticles are synthesized by solidification of In droplets on an amorphous Mo substrate at normal pressure and under vacuum conditions. The influence of ambient pressure on the interface and surface shape is investigated. While solidification at atmospheric pressure leads to collapsed particles with undisturbed contact to the substrate, low pressures result in smooth spherical particles but with cavities inside. Numerical simulations with COMSOL Multiphysics reveal different temperature profiles and heat flux in particles during solidification for both cases. This indicates different starting conditions of the solidification, which leads to the described phenomenon eventually. The investigation of the varying process conditions on the particle shape in combination with the calculated and measured temperature curves over time gives valuable insights into new approaches to synthesize micro- and nanoparticles with defined interfacial properties. Both ambient pressure and cooling rate provide well-controllable and reliable parameters for the realization of different interfacial shapes.

Bayesian-Inference-Driven Model Parametrization and Model Selection for 2CLJQ Fluid Models.

A high level of physical detail in a molecular model improves its ability to perform high accuracy simulations but can also significantly affect its complexity and computational cost. In some situations, it is worthwhile to add complexity to a model to capture properties of interest; in others, additional complexity is unnecessary and can make simulations computationally infeasible. In this work, we demonstrate the use of Bayesian inference for molecular model selection, using Monte Carlo sampling techniques accelerated with surrogate modeling to evaluate the Bayes factor evidence for different levels of complexity in the two-centered Lennard-Jones + quadrupole (2CLJQ) fluid model. Examining three nested levels of model complexity, we demonstrate that the use of variable quadrupole and bond length parameters in this model framework is justified only for some chemistries. Through this process, we also get detailed information about the distributions and correlation of parameter values, enabling improved parametrization and parameter analysis. We also show how the choice of parameter priors, which encode previous model knowledge, can have substantial effects on the selection of models, penalizing careless introduction of additional complexity. We detail the computational techniques used in this analysis, providing a roadmap for future applications of molecular model selection via Bayesian inference and surrogate modeling.

Changes in Emergency Department Visits, Diagnostic Groups, and 28-Day Mortality Associated With the COVID-19 Pandemic: A Territory-Wide, Retrospective, Cohort Study.

STUDY OBJECTIVE: We aimed to evaluate and characterize the scale and relationships of emergency department (ED) visits and excess mortality associated with the early phase of the COVID-19 pandemic in the territory of Hong Kong. METHODS: We conducted a territory-wide, retrospective cohort study to compare ED visits and the related impact of the COVID-19 pandemic on mortality. All ED visits at 18 public acute hospitals in Hong Kong between January 1 and August 31 of 2019 (n=1,426,259) and 2020 (n=1,035,562) were included. The primary outcome was all-cause mortality in the 28 days following an ED visit. The secondary outcomes were weekly number of ED visits and diagnosis-specific mortality. RESULTS: ED visits decreased by 27.4%, from 1,426,259 in 2019 to 1,035,562 in 2020. Overall period mortality increased from 28,686 (2.0%) in 2019 to 29,737 (2.9%) in 2020. The adjusted odds ratio for 28-day, all-cause mortality in the pandemic period of 2020 relative to 2019 was 1.26 (95% confidence interval 1.24 to 1.28). Both sexes, age more than 45 years, all triage categories, all social classes, all ED visit periods, epilepsy (odds ratio 1.58, 95% confidence interval 1.20 to 2.07), lower respiratory tract infection, and airway disease had higher adjusted ORs for all-cause mortality. CONCLUSION: A significant reduction in ED visits in the first 8 months of the COVID-19 pandemic was associated with an increase in deaths certified in the ED. The government must make provisions to encourage patients with alarming symptoms, mental health conditions, and comorbidities to seek timely emergency care, regardless of the pandemic.

Fucosidases from the human gut symbiont Ruminococcus gnavus.

The availability and repartition of fucosylated glycans within the gastrointestinal tract contributes to the adaptation of gut bacteria species to ecological niches. To access this source of nutrients, gut bacteria encode α-L-fucosidases (fucosidases) which catalyze the hydrolysis of terminal α-L-fucosidic linkages. We determined the substrate and linkage specificities of fucosidases from the human gut symbiont Ruminococcus gnavus. Sequence similarity network identified strain-specific fucosidases in R. gnavus ATCC 29149 and E1 strains that were further validated enzymatically against a range of defined oligosaccharides and glycoconjugates. Using a combination of glycan microarrays, mass spectrometry, isothermal titration calorimetry, crystallographic and saturation transfer difference NMR approaches, we identified a fucosidase with the capacity to recognize sialic acid-terminated fucosylated glycans (sialyl Lewis X/A epitopes) and hydrolyze α1-3/4 fucosyl linkages in these substrates without the need to remove sialic acid. Molecular dynamics simulation and docking showed that 3'-Sialyl Lewis X (sLeX) could be accommodated within the binding site of the enzyme. This specificity may contribute to the adaptation of R. gnavus strains to the infant and adult gut and has potential applications in diagnostic glycomic assays for diabetes and certain cancers.

Can we learn from hidden mistakes? Self-fulfilling prophecy and responsible neuroprognostic innovation.

A self-fulfilling prophecy (SFP) in neuroprognostication occurs when a patient in coma is predicted to have a poor outcome, and life-sustaining treatment is withdrawn on the basis of that prediction, thus directly bringing about a poor outcome (viz. death) for that patient. In contrast to the predominant emphasis in the bioethics literature, we look beyond the moral issues raised by the possibility that an erroneous prediction might lead to the death of a patient who otherwise would have lived. Instead, we focus on the problematic epistemic consequences of neuroprognostic SFPs in settings where research and practice intersect. When this sort of SFP occurs, the problem is that physicians and researchers are never in a position to notice whether their original prognosis was correct or incorrect, since the patient dies anyway. Thus, SFPs keep us from discerning false positives from true positives, inhibiting proper assessment of novel prognostic tests. This epistemic problem of SFPs thus impedes learning, but ethical obligations of patient care make it difficult to avoid SFPs. We then show how the impediment to catching false positive indicators of poor outcome distorts research on novel techniques for neuroprognostication, allowing biases to persist in prognostic tests. We finally highlight a particular risk that a precautionary bias towards early withdrawal of life-sustaining treatment may be amplified. We conclude with guidelines about how researchers can mitigate the epistemic problems of SFPs, to achieve more responsible innovation of neuroprognostication for patients in coma.

Internal neurolysis: 'nerve combing' for trigeminal neuralgia without neurovascular conflict - early UK outcomes.

INTRODUCTION: Internal neurolysis (INL) is a surgical procedure where trigeminal nerve fibres are separated between the pons and porus trigeminus to relieve trigeminal neuralgia (TN). We report pain and functional outcomes to evaluate its safety and efficacy. MATERIALS AND METHODS: Prospective cohort of all patients undergoing retrosigmoid craniotomy and INL between 2015 and 2017 at University Hospital Southampton. Patients with type I (6) or type II (2) refractory TN and no clear neurovascular conflict were offered INL as an alternative to partial sensory rhizotomy. Barrow Pain Intensity Scale (BNI) and Brief Pain Inventory Facial scores (BPI-Facial) were assessed. Minimum follow-up was 2 years'. RESULTS: Eight patients (7F:1M) underwent INL. Two had MS. Pre-operatively, all had severe pain (BNI grade V) and the median BPI-Facial score was 115 (range 79-123).. There were no unexpected complications. On last follow-up, six (75%) had no pain (BNI grade I), while two (25%) had recurred (at 5 and 27 months). Median BPI-Facial score for all patients on the last follow-up was 20 (range 18-91) reflecting dramatically improved quality of life and activities. CONCLUSIONS: INL is a potentially safe and effective treatment for refractory TN. Long-term efficacy is unknown, but early results are promising.

A comparison of different methods and materials for establishing maximal intercuspal position: A clinical study.

STATEMENT OF PROBLEM: Which method or material used to record the intercuspal position yields the best accuracy of location of the maxillary and mandibular casts is unclear. PURPOSE: The purpose of this clinical study was to determine the most reliable method of recording a patient's maximal intercuspal position by comparing 2 common methods with 2 popular registration materials. MATERIAL AND METHODS: Complete-arch impressions were made of both jaws with a polyvinyl siloxane impression material in a metal stock tray followed by 4 interocclusal registrations for each of the 17 participants. Two registration techniques were used. More than 1 record was obtained in the first technique, as the participant had to close through a wax sheet or a polyvinyl siloxane material. In the second technique, a polyvinyl siloxane material was injected from the buccal aspect between occluded tooth surfaces. Casts were made from Type 4 stone and vertical measurements of the casts were carried out by using digital vernier calipers, accurate to 100 µm. Hand articulation of the casts was used as the control. Consistency of measurement was assessed by the intraclass correlation coefficient, and comparisons were made by using repeated-measures regression analysis. RESULTS: Statistical analysis showed significant discrepancies when the participant closed through both wax and polyvinyl siloxane material (P<.001). No statistically significant differences to the control group were present when polyvinyl siloxane was injected laterally after closure. CONCLUSIONS: Hand articulation was the most accurate method of reproducing the maximal intercuspal position in a completely dentate individual with horizontal and vertical occlusal stability and was therefore considered the control. Recording the position after the participant had closed by using a polyvinyl siloxane material was the most accurate.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Investigation of Masked N-Acyl-N-isocyanates: Support for Oxadiazolones as Blocked N-Isocyanate Precursors.

In contrast to carbon-substituted isocyanates that are common building blocks, N-substituted isocyanates remain underdeveloped and reports on their N-acyl derivatives (i. e. amido-isocyanates) are exceedingly rare. Herein, amido-isocyanates were investigated in the context of syntheses of aza-tripeptide and hydantoins subunits starting from simple bench-stable precursors. A key finding is that the amido-isocyanate formed in situ cyclized to yield an oxadiazolone, and that under suitable reaction conditions this heterocycle is a traceless blocked (masked) N-isocyanate. Using organic bases as catalysts and upon heating, oxadiazolone formation is observed, and various nucleophiles to provide the desired aza-dipeptides or hydantoins in moderate to high yields. Further support for an amido-isocyanate intermediate was obtained using carboxylic acids as nucleophiles, affording N-acylhydrazide products.

Thiol adsorption on metal oxide nanoparticles.

The adsorption of 2-naphthalenethiol (2-NPT) and methanethiol (MT) on 13 different metal oxide nanoparticles, of approximately 30 nm average primary particle size, has been investigated. In the case of 2-NPT, which is fluorescent, a screening method to assess adsorption was developed that consists of mixing the nanoparticles with a dilute ethanolic solution of 2-NPT and performing several cycles of centrifuging and rinsing with ethanol. Fluorescence measurements on the re-dispersed particle suspensions were then used to diagnose whether or not adsorption had occurred. Complementary experiments were performed by mounting powder samples of each of the metal oxide nanoparticles onto sample stubs and performing X-ray photoelectron spectroscopy (XPS) before and after in situ dosing with MT. In both cases, adsorption was observed only on ZnO, TiO2, and In2O3. Adsorption did not occur on Al2O3, CeO2, Fe2O3, Gd2O3, Ho2O3, NiO, SiOx, WO3, Y2O3, and ZrO2. Density functional theory (DFT) calculations were performed using small metal oxide clusters, assuming that dissociative adsorption occurs by replacement of a hydroxyl group attached to a metal site and the formation of water. The theoretical and experimental results generally agree, suggesting that this is indeed the adsorption mechanism for most of the nanoparticles. The agreement also suggests that the size and geometry of the nanoclusters play a minor role and that the relative strengths of the metal-sulfur and metal-hydroxyl bonds dictate thiol adsorption. This work has important implications related to the functionalization of metal oxide nanoparticles and surfaces.

Extremely metal-poor stars from the cosmic dawn in the bulge of the Milky Way.

The first stars are predicted to have formed within 200 million years after the Big Bang, initiating the cosmic dawn. A true first star has not yet been discovered, although stars with tiny amounts of elements heavier than helium ('metals') have been found in the outer regions ('halo') of the Milky Way. The first stars and their immediate successors should, however, preferentially be found today in the central regions ('bulges') of galaxies, because they formed in the largest over-densities that grew gravitationally with time. The Milky Way bulge underwent a rapid chemical enrichment during the first 1-2 billion years, leading to a dearth of early, metal-poor stars. Here we report observations of extremely metal-poor stars in the Milky Way bulge, including one star with an iron abundance about 10,000 times lower than the solar value without noticeable carbon enhancement. We confirm that most of the metal-poor bulge stars are on tight orbits around the Galactic Centre, rather than being halo stars passing through the bulge, as expected for stars formed at redshifts greater than 15. Their chemical compositions are in general similar to typical halo stars of the same metallicity although intriguing differences exist, including lower abundances of carbon.

Ruptured intra-cranial arachnoid cysts: a case series from a single UK institution.

INTRODUCTION: Intracranial arachnoid cysts are a common incidental finding; however presentation with cyst rupture is a recognised complication. Patients are advised to avoid contact sports to reduce the risk of cyst rupture but the risk of rupture is not currently known. The aim of this study is to describe a single institution's experience of managing ruptured intra-cranial arachnoid cysts. METHOD: A retrospective case note review of all patients admitted to a single institution with a ruptured intra-cranial arachnoid cyst between 2005 and 2016 (inclusive). Medical records were reviewed for demographics, history of trauma, surgical treatment and radiological evidence of cyst rupture. RESULTS: Fourteen patients were identified for inclusion with an average age of 23.4 years (range 7-57) and 10 (71%) were male. Nine patients (64%) had a documented history of head trauma. Eleven patients (78.6%) required neurosurgical intervention which included hygroma/haematoma evacuation only (n = 5), haematoma evacuation with cyst fenestration (n = 4) and cyst fenestration/shunting only (n = 2). Twelve patients (85%) experienced full recovery and the remaining two had persisting headaches or neurological symptoms. DISCUSSION: Cyst rupture remains an uncommon cause for presentation with arachnoid cysts. However the majority are associated with head trauma and thus current advice to avoid contact sports seems justified.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta-analysis.

BACKGROUND: The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development. OBJECTIVES: To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis. METHODS: We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency. RESULTS: We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution. CONCLUSIONS: Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.

Prenatal diagnosis of arachnoid cysts: a case series and systematic review.

INTRODUCTION: Primary cysts are believed to arise from the splitting of the arachnoid membrane during prenatal development and can be diagnosed in utero. Prenatal diagnosis is uncommon; therefore, the evidence base for counselling expectant mothers is limited. The purpose of this article is to present a case series and review the current literature on prenatally diagnosed arachnoid cysts. METHOD: A keyword search of hospital electronic records was performed for all patients with a prenatally diagnosed arachnoid cyst at a tertiary neurosurgical centre. Case notes were reviewed for all patients diagnosed between 2005 and 2017. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to structure a systematic review of all English language articles published up to May 2018. RESULTS: A total of eight eligible patients were identified from our own records and 123 from the literature. Sixty-eight per cent of patients had a normal outcome. Sixty-three per cent of patients underwent surgical intervention which was not associated with abnormal outcome. The diagnosis of syndromic/genetic diagnosis (p < 0.001) and the presence of other intra-cranial anatomical abnormalities (p = 0.05) were significant predictors of abnormal outcome. CONCLUSION: The pathogenesis and prognosis of a prenatal arachnoid cyst diagnosis remain unclear. These results suggest favourable outcomes from simple cysts without associated abnormalities and expectant mothers should be counselled accordingly. A wider prospective review is required to better established evidence-based practice.