Synthesis, biological evaluation, theoretical calculations, QSAR and molecular docking studies of novel arylaminonaphthols as potent antioxidants and BChE inhibitors.

A completely green protocol was developed for the synthesis of a series of arylaminonaphthol derivatives in the presence of N-ethylethanolamine (NEEA) as a catalyst under ultrasonic irradiation and solventless conditions. The major assets of this methodology were the use of non-toxic organic medium, available catalyst, mild reaction condition, and good to excellent yield of desired products. All of the synthesized products were screened for their in vitro antioxidant activity using DPPH, ABTS, and Ferric-phenanthroline assays and it was found that most of them are potent antioxidant agents. Also, their butyrylcholinesterase inhibitory activity has been investigated in vitro. All tested compounds exhibited potential inhibitory activity toward BuChE when compared to standard reference drug galantamine, however, compounds 4r, 4u, 4 g and 4x gave higher butyrylcholinesterase inhibitory with IC50 values of 14.78 ± 0.65 µM, 16.18 ± 0.50 µM, 20.00 ± 0.50 µM, and 20.28 ± 0.08 µM respectively. On the other hand, we employed density functional theory (DFT), calculations to analyze molecular geometry and global reactivity descriptors, and MESP analysis to predict electrophilic and nucleophilic attacks. A quantitative structure-activity relationship (QSAR) investigation was conducted on the antioxidant and butyrylcholinesterase properties of 25 arylaminonaphthol derivatives, resulting in robust and satisfactory models. To evaluate their anti-Alzheimer's activity, compounds 4 g, 4q, 4r, 4u, and 4x underwent docking simulations at the active site of the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing why these compounds displayed superior activity, consistent with the biological findings.

Finite size effects on the metamagnetic phase transition in a thick B2 FeRh nanocluster film.

FeRh alloys in the CsCl-type (B2) chemically ordered phase present an antiferromagnetic to ferromagnetic order transition around 370 K observed in bulk and continuous films but absent in nanoclusters. In this study, we investigate the thermal magnetic behavior of a thick film composed of assembled FeRh nanoclusters preformed in the gas phase. This work reveals a broad and asymmetric metamagnetic transition with a consequent residual magnetization at low temperature. Due to the coexistence of different grain sizes in the sample, we confront the results with a description that involves two populations of B2-FeRh particles, and the existence of a discriminating size below which the magnetic order transition does not take place.

Glaucoma treatment and deprivation: time-series analysis of general practice prescribing in England.

BACKGROUND: Despite advances in glaucoma management, topical eyedrop treatment has been paramount, with prostaglandin analogues (PGAs) being first-line agents. While late presentation is linked with deprivation, there is no recent research examining associations between deprivation and prescribing within primary care. AIM: To explore PGA prescribing in general practice over a 6-year timeline, assessing for associations with deprivation. DESIGN & SETTING: Analysis of NHS Business Services Authority data for general practice prescribing in England from April 2016-March 2022. METHOD: Glaucoma treatments by GP prescriber were extracted, identifying ~9.11-9.58 million prescriptions/annum. Data were linked to indices of multiple deprivation (IMD) quintiles of GP practices. Crude rates per 1,000 population were calculated using population data from NHS Digital. Time-series analyses facilitated comparison in prescribing nationally and in deprived areas. Autoregressive Integrated Moving Average (ARIMA) modelling facilitated measurement of synchrony between time-series using cross correlation. RESULTS: PGAs and fixed combination eyedrops account for approximately two-thirds of glaucoma-related prescribing. Prescriptions per month increased slightly over a 6-year timeline, but rates per 1,000 of population reduced in 2020-21. PGA prescriptions dispensed in deprived areas is lower than all other quintiles. Cross-correlation analysis indicates a lag of ~12 months between average PGA prescribing nationally versus more deprived areas. CONCLUSION: The rate of PGA prescribing in primary care is substantially lower in deprived versus affluent areas, with delayed uptake of PGAs in more deprived areas of ~12 months. Further research is needed to explore reasons for this discrepancy, permitting strategies to be developed to reduce unwarranted variation.

Multimodal intrathecal analgesia (MITA) with morphine for reducing postoperative opioid use and acute pain following hepato-pancreato-biliary surgery: A multicenter retrospective study.

INTRODUCTION: The optimal analgesic modality for patients undergoing hepato-pancreato-biliary (HPB) surgery remains unknown. The analgesic effects of a multimodal intrathecal analgesia (MITA) technique of intrathecal morphine (ITM) in combination with clonidine and bupivacaine compared to ITM alone have not been investigated in these patients. METHODS: We performed a multicenter retrospective study of patients undergoing complex HPB surgery who received ITM, bupivacaine, and clonidine (MITA group) or ITM-only (ITM group) as part of their perioperative analgesia strategy. The primary outcome was the unadjusted oral morphine equivalent daily dose (oMEDD) in milligrams on postoperative day 1. After adjusting for age, body mass index, hospital allocation, type of surgery, operation length, and intraoperative opioid use, postoperative oMEDD use was investigated using a bootstrapped quantile regression model. Other prespecified outcomes included postoperative pain scores, opioid-related adverse events, major complications, and length of hospital stay. RESULTS: In total, 118 patients received MITA and 155 patients received ITM-only. The median (IQR) cumulative oMEDD use on postoperative day 1 was 20.5 mg (8.6:31.0) in the MITA group and 52.1 mg (18.0:107.0) in the ITM group (P < 0.001). There was a variation in the magnitude of the difference in oMEDD use between the groups for different quartiles. For the MITA group, on postoperative day 1, patients in the 25th percentile required 14.0 mg less oMEDD (95% CI: -25.9 to -2.2; P = 0.025), patients in the 50th percentile required 27.8 mg less oMEDD (95% CI: -49.7 to -6.0; P = 0.005), and patients in the 75th percentile required 38.7 mg less oMEDD (95% CI: -72.2 to -5.1; P = 0.041) compared to patients in the same percentile of the ITM group. Patients in the MITA group had significantly lower pain scores in the postoperative recovery unit and on postoperative days 1 to 3. The incidence of postoperative respiratory depression was low (<1.5%) and similar between groups. Patients in the MITA group had a significantly higher incidence of postoperative hypotension requiring vasopressor support. However, no significant differences were observed in major postoperative complications, or the length of hospital stay. CONCLUSION: In patients undergoing complex HPB surgery, the use of MITA, consisting of ITM in combination with intrathecal clonidine and bupivacaine, was associated with reduced postoperative opioid use and resulted in superior postoperative analgesia without risk of respiratory depression when compared to patients who received ITM alone. A randomized prospective clinical trial investigating these two intrathecal analgesic techniques is justified.

ViscY nuclear magnetic resonance experiments for in situ chemical reaction monitoring under spin diffusion conditions.

Viscosity-enhanced spectroscopY (ViscY) offers a new way to analyze complex mixtures of time-varying composition. This communication reports the use of the viscous binary solvent DMSO-d6/water to induce NMR spin diffusion for in situ chemical reaction monitoring and real-time characterization of a 3-substituted 4-hydroxycoumarin derivative and its side-product.

Discovery of a new Bcl-2 inhibitor through synthesis, anticancer activity, docking and MD simulations.

A database of 300 compounds was virtually screened and docked against Bcl-2 protein; the stability of the best-formed complex was evaluated through Molecular dynamics, the top ten compounds with the best in-silico complexation affinities were synthesized, and their In-vitro cytotoxic activity was examined. Thiazolidinone (4e) and isoxazoline (4a-d) were evaluated in-silico. For further evaluation and examination, we designed and synthesized from naturally occurring (R)-carvone and characterized it via spectroscopic analysis, as well as tested for their anticancer activities towards human cancer cell lines such as HT-1080 (fibrosarcome cancer), MCF-7 and MDA-MB-231 (breast cancer) and A-549 (lung cancer) by using MTT method with Doxorubicin as standard drug. Among them, compound 4d showed the most promising anticancer activity against HT-1080, A-549, MCF-7, and MDA-MB-231 cell lines with IC50 values of 15.59 ± 3.21 µM; 18.32 ± 2.73 µM; 17.28 ± 0.33 µM and 19.27 ± 2.73 µM respectively.Communicated by Ramaswamy H. Sarma.

Hybrids of thiazolidinone with 1,2,3-triazole derivatives: design, synthesis, biological evaluation, in silico studies, molecular docking, molecular dynamics simulations, and ADMET profiling.

A new series of thiazolidinone linked 1,2,3-triazole hybrids 5a-h was designed and synthesized using the copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC) between thiazolidinone linked alkyne and aromatic azides. The structures of the newly synthesized compounds were established by NMR (1H and 13C) and HRMS. The targeted thiazolidinone-1,2,3-triazole hybrids were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliun bromide (MTT). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC50 values between 10.26 ± 0.71 and 53.93 ± 1.20 µM. The compound 5a exhibited higher activity with an IC50 value of 10.26 ± 0.71 µM, compared to 5d with an IC50 value of 11.56 ± 1.98 µM for the HT-1080 and MCF-7 cancer cells line, respectively. Moreover, Annexin-V apoptosis was assessed by flow cytometry for hybrid compounds 5a and 5d against HT-1080 and MCF-7 competitor cell lines, as they increase the level of active caspase 3/7. The experimental results were further confirmed by docking studies followed by molecular dynamic simulations. Both the potent derivatives i.e. 5a and 5d have comparable docking scores and MD simulations results showed that the docked complex of 5a is somewhat more stable than 5d primarily for protein p53. The ADMET profile of both derivatives established their safety zone and drug-like potential.Communicated by Ramaswamy H. Sarma.

Premaxillary Setback With Posterior Vomerine Ostectomy and Complete Bilateral Cleft Lip Repair: Report of a Case With Challenging Anatomy.

Congenital clefts of the lip and/or palate are among the most common craniofacial malformations. Patients with bilateral cleft of the lip often present with projected premaxilla. Premaxillary setback with a vomerine ostectomy posterior to the vomero-premaxillary suture, bilateral cleft lip repair, bilateral gingivoperiosteoplasties, and primary cleft lip rhinoplasty are achieved in a single-stage surgery that provides a valuable alternative to patients, especially in the outreach settings. In this article, we present a case report of a patient born with a bilateral cleft of the lip and a protruded premaxilla. He had collapsed secondary palatine shelves requiring intraoperative manual expansion to ensure access to the vomer bone.

Diffusion-weighted MRI to determine response and long-term clinical outcomes in muscle-invasive bladder cancer following neoadjuvant chemotherapy.

Objective: This study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis. Methods: Patients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19-0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08-0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05-0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07-0.47; p=0.0004). Conclusions: Quantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making. Advances in knowledge: We successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes.

Encapsulation of Vitamin C by Glycerol-Derived Dendrimers, Their Interaction with Biomimetic Models of Stratum corneum and Their Cytotoxicity.

Vitamin C is one of the most sensitive cosmetic active ingredients. To avoid its degradation, its encapsulation into biobased carriers such as dendrimers is one alternative of interest. In this work, we wanted to evaluate the potential of two biobased glycerodendrimer families (GlyceroDendrimers-Poly(AmidoAmine) (GD-PAMAMs) or GlyceroDendrimers-Poly(Propylene Imine) (GD-PPIs)) as a vitamin C carrier for topical application. The higher encapsulation capacity of GD-PAMAM-3 compared to commercial PAMAM-3 and different GD-PPIs, and its absence of cytotoxicity towards dermal cells, make it a good candidate. Investigation of its mechanism of action was done by using two kinds of biomimetic models of stratum corneum (SC), lipid monolayers and liposomes. GD-PAMAM-3 and VitC@GD-PAMAM-3 (GD-PAMAM-3 with encapsulated vitamin C) can both interact with the lipid representatives of the SC lipid matrix, whichever pH is considered. However, only pH 5.0 is suggested to be favorable to release vitamin C into the SC matrix. Their binding to SC-biomimetic liposomes revealed only a slight effect on membrane permeability in accordance with the absence of cytotoxicity but an increase in membrane rigidity, suggesting a reinforcement of the SC barrier property. Globally, our results suggest that the dendrimer GD-PAMAM-3 could be an efficient carrier for cosmetic applications.

Novel isoxazoline-linked 1,3,4-thiadiazole hybrids as anticancer agents: Design, synthesis, biological evaluation, molecular docking, and molecular dynamics simulation.

In the current study, natural (R)-carvone was utilized as a starting material for the efficient synthesis of two series of isoxazoline derivatives bearing the 1,3,4-thiadiazole moiety. The new compounds were obtained in good yields and were characterized by 1 H and 13 C NMR and HRMS analysis. The newly synthesized monoterpenic isoxazoline 1,3,4-thiadiazole and their thiosemicarbazone intermediate derivatives were evaluated for their anticancer activity in four cancer cell lines (HT-1080, A-549, MCF-7, and MDA-MB-231). Most of the synthesized compounds exhibited moderate to high anticancer effects. Compound 13c showed the highest anticancer activity with IC50 values ranging from 19.33 ± 1.81 to 34.81 ± 3.03 µM. Further investigation revealed that compounds 12e and 13c could inhibit the cell growth of HT-1080 and MCF-7 cells by inducing apoptosis through caspase-3/7 activation. The apoptotic effect was accompanied by an S phase and G2/M cell cycle arrest for 13c and 12e, respectively. Compounds 12e and 13c were assessed in silico using molecular docking and molecular dynamics. We found that compound 13c is moderately active against the caspase-3 protein, which triggers apoptosis via intrinsic and extrinsic routes, making compound 13c a promising candidate to activate the proapoptotic protein (caspase-3).

Design, synthesis, evaluation of new 3-acetylisoxazolines and their hybrid analogous as anticancer agents: In vitro and in silico analysis.

3-Acetylisoxazolines were synthesized by the reaction of natural (R)-limonene and (R)-carvone with acetone in the presence of iron (III) nitrate. The reaction showed to be highly peri- and regioselective. Next, using a 1,3-dipolar cycloaddition reaction, the mono-3-acylisoxazolines derived from these monoterpenes were evaluated for their reactivity with nitrilimines. Only the enone of carvone-isoxazoline was regioselectively reactive, providing a new fused isoxazoline-carvone-pyrazolines. The structure of all the newly synthesized mono-cycloadducts (3 & 5) and bis-cycloadducts (4 & 7a-c) were fully identified based on their HRMS and NMR spectral data. They have also been screened for their cytotoxic activity against four human cancer cell lines: fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast (MCF-7 and MDA-MB-231) cell lines. The obtained results showed that compound 4 was a potent cytotoxic agent against all selected cells. The possible mechanism of apoptosis induction by compound 4 was investigated using Annexin-V binding assay, caspase-3/7 activity and analysis cell cycle progression. The compound 4 induced the early apoptosis of both MCF-7 and MDA-MB-231 through caspase-3/7 activation, and the compound 4 have elicited S and G2/M phase arrest in MCF-7and MDA-MB-231 cancer cells, respectively. For further target investigations, a molecular docking study was employed and it showed that compound 4 has an inhibitory activity against Pim-1 protein kinase. Molecular dynamics study showed that compound 4/Pim-1 complex was stable during the simulation run at different time intervals. In-Silico ADMET predicted that compound 4 has good pharmacokinetic properties with high estimated oral bioavailability.

Dysfunctional Bronchial Cilia Are a Feature of Chronic Obstructive Pulmonary Disease (COPD).

Impaired mucociliary clearance may increase COPD exacerbation risk. We aimed to compare bronchial ciliary function and epithelial ultrastructure of COPD patients to healthy controls and explore its relationship to exacerbator phenotypes (frequent [FE] and infrequent [IFE] exacerbator). In this cross-sectional study, 16 COPD patients and 12 controls underwent bronchial brushings. Ciliary beat frequency (CBF) and dyskinesia index (DI; % of dyskinetic cilia) were assessed using digital high-speed video microscopy, and epithelial ultrastructure using transmission electron microscopy (TEM). Bronchial epithelium in COPD showed lower CBF and higher DI, compared to controls (median [IQR] CBF: 6.8 (6.1-7.2) Hz vs 8.5 (7.7-8.9) Hz, p<0.001 and DI: 73.8 (60.7-89.8) % vs 14.5 (11.2-16.9) %, p<0.001, respectively). This was true for FE and IFE phenotypes of COPD, which were similar in terms of bronchial CBF or DI. Subgroup analyses demonstrated lower CBF and higher DI in FE and IFE COPD phenotypes compared to controls, irrespective of smoking status. TEM showed more loss of cilia, extrusion of cells, cytoplasmic blebs and dead cells in COPD patients versus controls. Profound dysfunction of bronchial cilia is a feature of COPD irrespective of exacerbation phenotype and smoking status, which is likely to contribute to poor mucus clearance in COPD.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1963695 .

Implant brand portfolios, the potential for camouflage of data, and the role of the Orthopaedic Data Evaluation Panel in total knee arthroplasty.

AIMS: Knee arthroplasty surgery is a highly effective treatment for arthritis and disorders of the knee. There are a wide variety of implant brands and types of knee arthroplasty available to surgeons. As a result of a number of highly publicized failures, arthroplasty surgery is highly regulated in the UK and many other countries through national registries, introduced to monitor implant performance, surgeons, and hospitals. With time, the options available within many brand portfolios have grown, with alternative tibial or femoral components, tibial insert materials, or shapes and patella resurfacings. In this study we have investigated the effect of the expansion of implant brand portfolios and where there may be a lack of transparency around a brand name. We also aimed to establish the potential numbers of compatible implant construct combinations. METHODS: Hypothetical implant brand portfolios were proposed, and the number of compatible implant construct combinations was calculated. RESULTS: A simple knee portfolio with cemented cruciate-retaining (CR) and posterior-stabilized (PS) components, with and without a patella, has four combinations. If there are two options available for each component, the numbers double for each option, resulting in 32 combinations. The effect of adding a third option multiplies the number by 1.3. Introducing compatible uncemented options, with the effect of hybrids, multiplies the number by 4. An implant portfolio with two femoral components (both in CR and PS), with two insert options and a patella, all in cemented and uncemented versions leads to 192 possible compatible implant construct combinations. There are implant brands available to surgeons with many more than two options. CONCLUSION: This study demonstrates that the addition of multiple variants within a knee brand portfolio leads to a large number (many hundreds) of compatible implant construct combinations. Revision rates of implant combinations are not currently reviewed at this level of granularity, leading to the risk of camouflage of true outcomes. Cite this article: Bone Joint J 2021;103-B(10):1555-1560.

Thiazolidinone-linked1,2,3-triazoles with monoterpenic skeleton as new potential anticancer agents: Design, synthesis and molecular docking studies.

A novel series of 1,2,3-triazole-thiazolidinone-carvone hybrid compounds has been designed and synthesized using the copper-catalyzed Huisgen azide-alkyne 1,3-dipolar cycloaddition (CuAAC) process based on (R)-Carvone-O-propargylated 5-hydroxybenzylidene-thiazolidin-4-one derivative as starting material. All compounds were characterized and identified based on their NMR and HRMS spectroscopic data. HMBC correlations confirm that under the CuAAC reaction conditions, only the 1,4-disubstituted triazole regioisomers were formed. The targeted 1,2,3-triazole-thiazolidinone-carvone hybrids and their precursors were evaluated for their cytotoxic activity against four human cancer cell lines, including fibrosarcoma (HT-1080), lung carcinoma (A-549), and breast carcinoma (MCF-7 and MDA-MB-231). The obtained data showed that most of these compounds have moderate anti-proliferative activity with IC50 values between 15.04 ± 0.71 and 42.22 ± 1.20 µM. The mechanism of action of the most active compounds 14e and 14f suggested that they induce apoptosis through caspase-3/7 activation, and the compound 14e elicited S-phase arrest, while compound 14f evoked G2/M phase blockade. The molecular docking confirmed that compounds 14e and 14f were nicely bonded with caspace-3 leading up to stable protein-ligand complexes.

Anaesthesia techniques and advanced monitoring in CANVAS patients - Implications for postoperative morbidity and patient recovery: A case report.

INTRODUCTION: Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a rare multisystem neurodegenerative disorder. We describe our perioperative evaluation and care of a patient with CANVAS undergoing a pancreaticoduodenectomy for an ampullary adenocarcinoma, with a focus on perioperative risk stratification and optimisation, intraoperative advanced haemodynamic monitoring and the postoperative care. CASE PRESENTATION: A 69-year-old female with CANVAS presented with asymptomatic obstructive jaundice, icterus and abdominal pain. She had limited mobility and deconditioning due to severe generalised neuropathy. Computed tomography confirmed a resectable periampullary tumour. Her Duke Activity Status Index was 8.25 points and Edmonton Frailty Scale score was 11, confirming moderate frailty. However, the Charlson Comorbidity Index was five, indicative of a 21% estimated 10-year survival. Further risk stratification including respiratory function testing, echocardiography and cardiopulmonary exercise testing was conducted. The patient proceeded with surgery after multidisciplinary discussions with her treating medical teams. DISCUSSION: CANVAS is a rare and challenging condition requiring careful perioperative planning and management. There is no effective treatment for CANVAS. The management approach focuses on mitigating symptoms and improving quality of life. Given that no specific guidelines for managing these patients in the perioperative period have been provided, this report highlights several critical medical issues and implications that should be considered for the successful management of these patients. We demonstrate the role of specific anaesthesia techniques and advanced haemodynamic monitoring in both preventing postoperative morbidity and optimising patient recovery. CONCLUSION: CANVAS is a rare and challenging condition in anaesthesia requiring careful perioperative planning and management.

Emerging Role for Linear and Circular Spermine Oxidase RNAs in Skeletal Muscle Physiopathology.

Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. Spermine oxidase (SMOX), a polyamine catabolic enzyme plays a critical role in muscle differentiation and the existence of a circRNA arising from SMOX gene has been recently identified. In this study, we evaluated the expression profile of circular and linear SMOX in both C2C12 differentiation and dexamethasone-induced myotubes atrophy. To validate our findings in vivo their expression levels were also tested in two murine models of amyotrophic lateral sclerosis: SOD1G93A and hFUS+/+, characterized by progressive muscle atrophy. During C2C12 differentiation, linear and circular SMOX show the same trend of expression. Interestingly, in atrophy circSMOX levels significantly increased compared to the physiological state, in both in vitro and in vivo models. Our study demonstrates that SMOX represents a new player in muscle physiopathology and provides a scientific basis for further investigation on circSMOX RNA as a possible new therapeutic target for the treatment of muscle atrophy.

Hydrocephalus and diffuse choroid plexus hyperplasia in primary ciliary dyskinesia-related MCIDAS mutation.

OBJECTIVE: To report a neuroradiologic phenotype associated with reduced generation of multiple motile cilia (RGMC) and mutations in the multicilin gene. We hypothesize that the observed phenotype may reflect the emerging role that ependymal cilia play in regulating CSF production. METHOD: Clinical and radiologic records were retrospectively reviewed for 7 consecutive patients diagnosed by the Leicester UK national primary ciliary dyskinesia (PCD) diagnostic laboratory. RESULTS: On MRI scanning, all patients demonstrated hydrocephalus, choroid plexus hyperplasia (CPH), and arachnoid cysts. No patient had any sign of neurologic deficit. All patients had significant lung disease. CONCLUSIONS: We conclude that there is a high incidence of hydrocephalus, arachnoid cysts, and CPH in MCIDAS-associated RGMC. In all cases, the observed hydrocephalus seems arrested in childhood without progression or adverse neurologic sequelae. Our new observation of CPH, which is associated with CSF overproduction, is the first macroscopic evidence that ependymal cilia may be involved in the regulation of CSF production and flow. We suggest that brain imaging should be performed in all cases of RGMC and that a diagnosis of PCD or RGMC be strongly considered in patients with unexplained hydrocephalus and a lifelong "wet"-sounding cough.

Clinical features and management of children with primary ciliary dyskinesia in England.

OBJECTIVE: In England, the National Health Service commissioned a National Management Service for children with primary ciliary dyskinesia (PCD). The aims of this study were to describe the health of children seen in this Service and compare lung function to children with cystic fibrosis (CF). DESIGN: Multi-centre service evaluation of the English National Management PCD Service. SETTING: Four nationally commissioned PCD centres in England. PATIENTS: 333 children with PCD reviewed in the Service in 2015; lung function data were also compared with 2970 children with CF. RESULTS: Median age at diagnosis for PCD was 2.6 years, significantly lower in children with situs inversus (1.0 vs 6.0 years, p<0.001). Compared with national data from the CF Registry, mean (SD) %predicted forced expiratory volume in one second (FEV1) was 76.8% in PCD (n=240) and 85.0% in CF, and FEV1 was lower in children with PCD up to the age of 15 years. Approximately half of children had some hearing impairment, with 26% requiring hearing aids. Children with a lower body mass index (BMI) had lower FEV1 (p<0.001). One-third of children had positive respiratory cultures at review, 54% of these grew Haemophilus influenzae. CONCLUSIONS: We provide evidence that children with PCD in England have worse lung function than those with CF. Nutritional status should be considered in PCD management, as those with a lower BMI have significantly lower FEV1. Hearing impairment is common but seems to improve with age. Well-designed and powered randomised controlled trials on management of PCD are needed to inform best clinical practice.

Assessing the risk of early unplanned rehospitalisation in preterm babies: EPIPAGE 2 study.

BACKGROUND: Gaining a better understanding of the probability, timing and prediction of rehospitalisation amongst preterm babies could help improve outcomes. There is limited research addressing these topics amongst extremely and very preterm babies. In this context, unplanned rehospitalisations constitute an important, potentially modifiable adverse event. We aimed to establish the probability, time-distribution and predictability of unplanned rehospitalisation within 30 days of discharge in a population of French preterm babies. METHODS: This study used data from EPIPAGE 2, a population-based prospective study of French preterm babies. Only those babies discharged home alive and whose parents responded to the one-year survey were eligible for inclusion in our study. For Kaplan-Meier analysis, the outcome was unplanned rehospitalisation censored at 30 days. For predictive modelling, the outcome was binary, recording unplanned rehospitalisation within 30 days of discharge. Predictors included routine clinical variables selected based on expert opinion. RESULTS: Of 3841 eligible babies, 350 (9.1, 95% CI 8.2-10.1) experienced an unplanned rehospitalisation within 30 days. The probability of rehospitalisation progressed at a consistent rate over the 30 days. There were significant differences in rehospitalisation probability by gestational age. The cross-validated performance of a ten predictor model demonstrated low discrimination and calibration. The area under the receiver operating characteristic curve was 0.62 (95% CI 0.59-0.65). CONCLUSIONS: Unplanned rehospitalisation within 30 days of discharge was infrequent and the probability of rehospitalisation progressed at a consistent rate. Lower gestational age increased the probability of rehospitalisation. Predictive models comprised of clinically important variables had limited predictive ability.