A ring-like accretion structure in M87 connecting its black hole and jet.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.

Oxygen Evolution/Reduction Reaction Catalysts: From In Situ Monitoring and Reaction Mechanisms to Rational Design.

The oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) are core steps of various energy conversion and storage systems. However, their sluggish reaction kinetics, i.e., the demanding multielectron transfer processes, still render OER/ORR catalysts less efficient for practical applications. Moreover, the complexity of the catalyst-electrolyte interface makes a comprehensive understanding of the intrinsic OER/ORR mechanisms challenging. Fortunately, recent advances of in situ/operando characterization techniques have facilitated the kinetic monitoring of catalysts under reaction conditions. Here we provide selected highlights of recent in situ/operando mechanistic studies of OER/ORR catalysts with the main emphasis placed on heterogeneous systems (primarily discussing first-row transition metals which operate under basic conditions), followed by a brief outlook on molecular catalysts. Key sections in this review are focused on determination of the true active species, identification of the active sites, and monitoring of the reactive intermediates. For in-depth insights into the above factors, a short overview of the metrics for accurate characterizations of OER/ORR catalysts is provided. A combination of the obtained time-resolved reaction information and reliable activity data will then guide the rational design of new catalysts. Strategies such as optimizing the restructuring process as well as overcoming the adsorption-energy scaling relations will be discussed. Finally, pending current challenges and prospects toward the understanding and development of efficient heterogeneous catalysts and selected homogeneous catalysts are presented.

Ribosomal RNA 2'-O-methylations regulate translation by impacting ribosome dynamics.

SignificanceThe presence of RNA chemical modifications has long been known, but their precise molecular consequences remain unknown. 2'-O-methylation is an abundant modification that exists in RNA in all domains of life. Ribosomal RNA (rRNA) represents a functionally important RNA that is heavily modified by 2'-O-methylations. Although abundant at functionally important regions of the rRNA, the contribution of 2'-O-methylations to ribosome activities is unknown. By establishing a method to disturb rRNA 2'-O-methylation patterns, we show that rRNA 2'-O-methylations affect the function and fidelity of the ribosome and change the balance between different ribosome conformational states. Our work links 2'-O-methylation to ribosome dynamics and defines a set of critical rRNA 2'-O-methylations required for ribosome biogenesis and others that are dispensable.

Type 1 Diabetes in care homes: A practical guide on management.

The primary purpose of the original NAPCHD project was to develop a national Strategic Document of Diabetes Care for Care Homes which has now been completed and well received as a worthwhile, sustainable, and effective guidance for delivering quality diabetes care in the UK. A Working Group of NAPCHD was established to produce a Position Statement on type 1 diabetes in care homes since this area was recommended as a topic to further develop. There are currently limited data on the prevalence and clinical outcomes associated with type 1 diabetes in care homes and management policies have been non-existent in the UK. Communication among all key stakeholders involved in direct care of residents with type 1 diabetes is generally fragmented and lacks coordination. This is compounded by a slowly growing utilisation of diabetes technology and the absence of a standard/agreed community-based model of interdisciplinary collaboration. The Rationale and Objectives were defined prior to commencing the work and a work plan with individual tasks was initially set out. After multiple correspondences and Team calls over a period of 9 months, the Group successfully generated a first draft in October 2023. This draft was then finalised the following month and circulated among stakeholders for feedback. Nine chapters have been provided including minimum standards of diabetes care, insulin regimens, avoiding hospitalisation and discharge planning. A scheme for a community-based model of care for type 1 diabetes has been included. Eight key messages were developed. In addition, an Appendix has been created which includes key assessments such as nutritional assessment, detection of frailty, sick day rules and foot risk stratification (available online).

Exercise During Chemotherapy for Cancer: A Systematic Review.

Exercise prehabilitation may improve the tolerance and effectiveness of anticancer treatments such as chemotherapy. This systematic review assesses the impact of exercise on chemotherapy outcomes and identifies research priorities. Nineteen studies (1418 patients) were reviewed, including 11 randomised controlled trials and eight observational studies. Exercise led to improvements in body composition, fitness, strength and quality of life (QoL) across studies. Exercise can be safely and effectively delivered during chemotherapy. Limited standardisation and small sample sizes highlight the need for larger, better-designed studies to optimise this low-cost intervention.

Antiemetic medications for preventing chemotherapy-induced nausea and vomiting in children: a systematic review and Bayesian network meta-analysis.

PURPOSE: Children continue to experience chemotherapy-induced nausea and vomiting (CINV), despite effective antiemetic medications. Recommendations in clinical practice guidelines are underpinned by narrative syntheses and meta-analyses that compare only two treatments. This means not all antiemetics have been compared to one another, and estimates remain imprecise. We apply network meta-analysis (NMA) to overcome these limitations by comparing multiple treatments simultaneously. METHODS: A systematic review identified and critically appraised RCTs comparing antiemetics recommended and licensed for the prevention of CINV in children. Bayesian NMA compared and ranked antiemetic effectiveness for the outcomes complete (CR) and partial response (PR) in the acute, delayed, and overall phases, nausea, and decreased food intake. Antiemetics given with and without dexamethasone were compared in separate networks as their underlying populations differed. RESULTS: Sixteen RCTs (3115 patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC)) were included. When given with dexamethasone, NK1 antagonists with ondansetron ranked highest for CR and PR in the acute and overall phases, PR in the delayed phase, and decreased food intake. Post hoc analysis shows further a benefit of adding olanzapine to regimens of aprepitant and ondansetron. Ondansetron ranked lower than palonosetron, for CR in the delayed and overall phases, and ondansetron was less effective than palonosetron for nausea prevention. Rankings for other regimens, including those given without dexamethasone, were uncertain or inconsistent across outcomes. CONCLUSIONS: Our findings serve to support the current recommendations of olanzapine (when given with aprepitant and ondansetron) and NK1 antagonists' regimens receiving HEC, but note that evidence of a significant difference in relative benefit, between patients receiving MEC and HEC, does not yet exist. Recommendations for palonosetron as the preferred 5HT3 antagonists may be extended, particularly, to those who are at high risk of nausea.

Studies of mutations of assembly factor Hit1 in budding yeast suggest translation defects as the molecular basis for PEHO syndrome.

Regulation of protein synthesis is critical for control of gene expression in all cells. Ribosomes are ribonucleoprotein machines responsible for translating cellular proteins. Defects in ribosome production, function, or regulation are detrimental to the cell and cause human diseases, such as progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) syndrome. PEHO syndrome is a devastating neurodevelopmental disorder caused by mutations in the ZNHIT3 gene, which encodes an evolutionarily conserved nuclear protein. The precise mechanisms by which ZNHIT3 mutations lead to PEHO syndrome are currently unclear. Studies of the human zinc finger HIT-type containing protein 3 homolog in budding yeast (Hit1) revealed that this protein is critical for formation of small nucleolar ribonucleoprotein complexes that are required for rRNA processing and 2'-O-methylation. Here, we use budding yeast as a model system to reveal the basis for the molecular pathogenesis of PEHO syndrome. We show that missense mutations modeling those found in PEHO syndrome patients cause a decrease in steady-state Hit1 protein levels, a significant reduction of box C/D snoRNA levels, and subsequent defects in rRNA processing and altered cellular translation. Using RiboMethSeq analysis of rRNAs isolated from actively translating ribosomes, we reveal site-specific changes in the rRNA modification pattern of PEHO syndrome mutant yeast cells. Our data suggest that PEHO syndrome is a ribosomopathy and reveal potential new aspects of the molecular basis of this disease in translation dysregulation.

Transforming Parkinson's Care in Africa (TraPCAf): protocol for a multimethodology National Institute for Health and Care Research Global Health Research Group project.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder and, according to the Global Burden of Disease estimates in 2015, was the fastest growing neurological disorder globally with respect to associated prevalence, disability, and deaths. Information regarding the awareness, diagnosis, phenotypic characteristics, epidemiology, prevalence, risk factors, treatment, economic impact and lived experiences of people with PD from the African perspective is relatively sparse in contrast to the developed world, and much remains to be learned from, and about, the continent. METHODS: Transforming Parkinson's Care in Africa (TraPCAf) is a multi-faceted, mixed-methods, multi-national research grant. The study design includes multiple sub-studies, combining observational (qualitative and quantitative) approaches for the epidemiological, clinical, risk factor and lived experience components, as appropriate, and interventional methods (clinical trial component). The aim of TraPCAf is to describe and gain a better understanding of the current situation of PD in Africa. The countries included in this National Institute for Health and Care Research (NIHR) Global Health Research Group (Egypt, Ethiopia, Ghana, Kenya, Nigeria, South Africa and Tanzania) represent diverse African geographies and genetic profiles, with differing resources, healthcare systems, health and social protection schemes, and policies. The research team is composed of experts in the field with vast experience in PD, jointly led by a UK-based and Africa-based investigator. DISCUSSION: Despite the increasing prevalence of PD globally, robust data on the disease from Africa are lacking. Existing data point towards the poor awareness of PD and other neurological disorders on the continent and subsequent challenges with stigma, and limited access to affordable services and medication. This multi-site study will be the first of its kind in Africa. The data collected across the proposed sub-studies will provide novel and conclusive insights into the situation of PD. The selected country sites will allow for useful comparisons and make results relevant to other low- and middle-income countries. This grant is timely, as global recognition of PD and the public health challenge it poses builds. The work will contribute to broader initiatives, including the World Health Organization's Intersectoral global action plan on epilepsy and other neurological disorders. TRIAL REGISTRATION: https://doi.org/10.1186/ISRCTN77014546 .

Clinical outcomes following surgical management of insertional Achilles tendinopathy using a double-row suture bridge technique with mean two-year follow-up.

BACKGROUND: The clinical outcomes following surgical management of insertional Achilles tendinopathy (IAT) vary depending on the surgical technique used to reattach the Achilles tendon following debridement. The aim of this study was to investigate the clinical outcomes of patients with IAT who underwent surgical management with a double-row suture bridge technique used to reattach the Achilles tendon. METHODS: A retrospective review of consecutive patients diagnosed with IAT, who underwent surgical management utilising a double-row suture bridge technique (Arthex Speedbridge), and a minimum of 3-month follow-up were included. The primary outcome was the Manchester-Oxford Foot Questionnaire (MOXFQ) Index score which is a patient reported outcome measure (PROM). Secondary outcomes included EuroQol EQ-5D-5L health-related quality of life PROM and complication rates. RESULTS: Between July 2013 and June 2020, 50 consecutive patients (23 male; 27 female) were included. The mean age (± standard deviation) was 52.3 ± 11.3 (range 29.0-84.3). Pre- and post-operative PROM data were available for all cases. The mean follow-up was 2.4 ± 1.9 years. The MOXFQ Index score improved from 48.5 to 12.4 (p < 0.01), EQ-5D-5L improved from 2.7 ± 0.46 to 1.2 ± 0.37 (p < 0.01), and EQ-VAS improved from 48.0 ± 18.4 to 84.1 ± 12.6 (p < 0.01). Four patients had complications which were of minimal clinical relevance and caused no deviation from routine recovery. There were no cases of tendon rupture. CONCLUSION: This study has demonstrated that surgical management of IAT is safe and effective with clinical improvement in both clinical and general health-related quality of life outcome PROMs. LEVEL OF EVIDENCE: IV.

Health-related quality of life in patients with Achilles tendinopathy: Comparison to the general population of the United Kingdom.

BACKGROUND: There is little evidence available regarding the impact of Achilles Tendinopathy (AT) on health-related quality of life (HRQOL). The primary aim of this study was to quantify the clinical and health-related quality-of-life patient-reported outcome measures for a population presenting with either mid-substance or insertional Achilles tendinopathy. METHODS: A prospective comparative observational study of consecutive patients with AT presenting for extracorporeal shockwave therapy (ESWT) at a large teaching hospital. The primary outcome was assessment of a validated health-related quality of life PROMs (Euroqol EQ-5D-5L) and comparison to 2 general UK population datasets. The secondary outcomes were Visual Analogue Pain Scale (VAS-Pain) and two validated foot-specific patient reported outcome measures (Foot Function Index (FFI) and Victorian Institute of Sports Assessment-Achilles (VISA-A)). RESULTS: Between March 2014 and June 2021, 320 consecutive patients (125 male; 195 female) were diagnosed with AT and referred for a first course of ESWT. EQ-5D-5L PROMs were prospectively collected for 303 of these patients (94.7%). The mean age (± standard deviation(SD)) was 52.1 ± 11.4 years. The mean EQ-5D-5L Index score (mean±SD) for the AT cohort was 0.783 ± 0.131. Patients less than 55 years with AT had a statistically significantly worse quality of life compared with members of the same age group in the general population. The mean VAS-Pain, FFI, VISA-A clinical outcome scores were 6.0 ± 2.3, 49.5 ± 21.2 and 34.1 ± 14.4 respectively. There was a statistically significant moderate correlation between HRQOL and clinical PROMs (VAS-Pain and FFI vs EQ-5D) however there was no correlation with age. CONCLUSION: This study demonstrates that patients under the age of 55 with AT have a significantly reduced quality of life compared with the general population. LEVEL OF EVIDENCE: III.

Indomethacin markedly blunts cerebral perfusion and reactivity, with little cognitive consequence in healthy young and older adults.

KEY POINTS: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. In the present study, we used a placebo-controlled, single-blinded, randomized cross-over design to test the hypothesis that acutely-reduced CBF (using a pharmacological aid; indomethacin) would impair cognition in young and older healthy adults. At baseline, older adults had lower cognitive performance and CBF, but similar cerebrovascular reactivity to CO2 and dynamic cerebral autoregulation compared to young adults. In both young and older adults, cognitive performance on a mental switching task was slightly (7%) reduced after indomethacin, but not significantly associated with reductions in CBF (∼31%). These results indicate that cognitive performance is broadly resilient against a ∼31% reduction in CBF per se in healthy young and older adults. ABSTRACT: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. Using a placebo-controlled, single-blinded, randomized cross-over design, we tested the hypothesis that acutely-reduced CBF (using indomethacin [1.2 mg kg-1 oral dose]) would impair cognition in young (n = 13; 25 ± 4 years) and older (n = 12; 58 ± 6 years) healthy adults. CBF and cerebrovascular control were measured using middle cerebral artery blood velocity (MCAvmean ) and its reactivity to hypercapnia (CVRHYPER ) and hypocapnia (CVRHYPO ), respectively. Cognitive function was assessed using a computerized battery including response time tasks. Baseline comparisons revealed that older adults had 14% lower MCAvmean and 15% lower cognitive performance (all P ≤ 0.048), but not lower CVRHYPER/HYPO (P ≥ 0.26). Linear and rank-based mixed models revealed that indomethacin decreased MCAvmean by 31% (95% confidence interval = -35 to -26), CVRHYPER by 68% [interquartile range (IQR) = -94 to -44] and CVRHYPO by 50% (IQR = -83 to -33) (treatment-effect; all P < 0.01), regardless of age. Baseline CVRHYPER/HYPO values were strongly associated with their indomethacin-induced reductions (r = 0.70 to 0.89, P < 0.01). Mental switching performance was impaired 7% (IQR = 0-19) after indomethacin (P = 0.04), but not significantly associated with reductions in MCAvmean (Young: rho = -0.31, P = 0.30; Older: rho = 0.06, P = 0.86). In conclusion, indomethacin reduced MCAvmean and impaired cognition slightly; however, no clear association was evident in younger or older adults. Older adults had poorer cognition and lower MCAvmean , but similar CVRHYPER/HYPO .

NO Coupling by Nonclassical Dinuclear Dinitrosyliron Complexes to Form N2O Dictated by Hemilability.

Selective coupling of NO by a nonclassical dinuclear dinitrosyliron complex (D-DNIC) to form N2O is reported. The coupling is facilitated by the pyridinediimine (PDI) ligand scaffold, which enables the necessary denticity changes to produce mixed-valent, electron-deficient tethered DNICs. One-electron oxidation of the [{Fe(NO)2}]210/10 complex Fe2(PyrrPDI)(NO)4 (4) results in NO coupling to form N2O via the mixed-valent {[Fe(NO)2]2}9/10 species, which possesses an electron-deficient four-coordinate {Fe(NO)2}10 site, crucial in N-N bond formation. The hemilability of the PDI scaffold dictates the selectivity in N-N bond formation because stabilization of the five-coordinate {Fe(NO)2}9 site in the mixed-valent [{Fe(NO)2}]29/10 species, [Fe2(Pyr2PDI)(NO)4][PF6] (6), does not result in an electron-deficient, four-coordinate {Fe(NO)2}10 site, and hence no N-N coupling is observed.

Acceptability of childhood screening: a systematic narrative review.

OBJECTIVES: A systematic narrative literature review was undertaken to assess the acceptability of childhood screening interventions to identify factors to consider when planning or modifying childhood screening programs to maximize participation and uptake. STUDY DESIGN: This is a systematic narrative literature review. METHODS: Electronic databases were searched (MEDLINE, EMBASE, PsycINFO via Ovid, CINAHL, and Cochrane Library) to identify primary research studies that assessed screening acceptability. Studies were categorized using an existing theoretical framework of acceptability consisting of seven constructs: affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness, and self-efficacy. A protocol was developed and registered with PROSPERO (registration no. CRD42018099763) RESULTS: The search identified 4529 studies, and 46 studies met the inclusion criteria. Most studies involved neonatal screening. Programs identified included newborn blood spot screening (n = 22), neonatal hearing screening (n = 13), Duchenne muscular dystrophy screening (n = 4), cystic fibrosis screening (n = 3), screening for congenital heart defects (n = 2), and others (n = 2). Most studies assessed more than one construct of acceptability. The most common constructs identified were affective attitude (how a parent feels about the program) and intervention coherence (parental understanding of the program, and/or the potential consequences of a confirmed diagnosis). CONCLUSIONS: The main acceptability component identified related to parental knowledge and understanding of the screening process, the testing procedure(s), and consent. The emotional impact of childhood screening mostly explored maternal anxiety. Further studies are needed to examine the acceptability of childhood screening across the wider family unit. When planning new (or refining existing) childhood screening programs, it is important to assess acceptability before implementation. This should include assessment of important issues such as information needs, timing of information, and when and where the screening should occur.

Preformulation characterization and identification of excipients for nevirapine loaded niosomes.

Nevirapine (NVP) is used for the management of HIV/AIDS but must be dosed frequently, exhibits unpredictable bioavailability and a side effect profile that includes hepato- and dermo-toxicity. Niosomes are a colloidal drug delivery system that may be used to overcome the low bioavailability, side effect profile and frequent dosing needed when using conventional drug delivery systems. The compatibility of NVP with sorbitan esters, polysorbate, cholesterol and dihexadecyl phosphate (DCP) was investigated using Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), Fourier Transform Infra-red Spectroscopy (FTIR) and X-ray Powder Diffraction (XRPD). Screening studies were undertaken to identify potential excipients that would produce niosomes with target critical quality attributes (CQA) viz, a particle size (PS) < 1000 nm, a polydispersity index (PDI) < 0.500 and an entrapment efficiency >90%. The results revealed that sorbitan esters in combination with cholesterol and 5 µmol DCP produced niosomes with the best CQA and Zeta potential (ZP) < -30 mV which suggests good stability of the niosomes on storage. Sorbitan esters produced the smallest niosomes of < 400 nm diameter with a PDI < 0.400 and an entrapment efficiency > 78% without cholesterol. The addition of cholesterol and DCP was essential to form niosomes with target CQA.

Machine learning to predict early recurrence after oesophageal cancer surgery.

BACKGROUND: Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20-30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. METHODS: Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. RESULTS: A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal-external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). CONCLUSION: The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.

ANTECEDENTES: la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20-30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático. MÉTODOS: Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo. RESULTADOS: En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna-externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%). CONCLUSIÓN: El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.

Preformulation studies of efavirenz with lipid excipients using thermal and spectroscopic techniques.

Investigation and identification of potential lipids for the manufacture of efavirenz loaded solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) was undertaken. Polymorphic modification and characteristics of the lipids with the best solubilising potential for efavirenz was explored using Fourier Transform Infrared Spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC) and Wide-angle X-ray Scattering (WAXS). Lipid screening revealed that EFV is highly soluble in solid and liquid lipids, with glyceryl monostearate (GM) and Transcutol® HP (THP) exhibiting the best solubilising potential for EFV. GM exists in a stable ß-polymorphic modification prior to exposure to heat, but exists in an α-polymorphic modification following exposure to heat. However, it was established that the addition of THP to GM revealed the co-existence of the α- and ß'-polymorphic modifications of the lipid. EFV (60% w/w) exists in a crystalline state in a 70:30 mixture of GM and THP. Investigation of binary mixtures of EFV/GM and GM/THP, in addition to eutectic mixtures of EFV, GM and THP using FT-IR, DSC and WAXS revealed no potential interactions between EFV and the lipids selected for the production of the nanocarriers.

ASD restricted and repetitive behaviors associated at 17q21.33: genes prioritized by expression in fetal brains.

Autism spectrum disorder (ASD) is a behaviorally defined condition that manifests in infancy or early childhood as deficits in communication skills and social interactions. Often, restricted and repetitive behaviors (RRBs) accompany this disorder. ASD is polygenic and genetically complex, so we hypothesized that focusing analyses on intermediate core component phenotypes, such as RRBs, can reduce genetic heterogeneity and improve statistical power. Applying this approach, we mined Caucasian genome-wide association studies (GWAS) data from two of the largest ASD family cohorts, the Autism Genetics Resource Exchange and Autism Genome Project (AGP). Of the 12 RRBs measured by the Autism Diagnostic Interview-Revised, seven were found to be significantly familial and substantially variable, and hence, were tested for genome-wide association in 3104 ASD-affected children from 2045 families. Using a stringent significance threshold (P<7.1 × 10-9), GWAS in the AGP revealed an association between 'the degree of the repetitive use of objects or interest in parts of objects' and rs2898883 (P<6.8 × 10-9), which resides within the sixth intron of PHB. To identify the candidate target genes of the associated single-nucleotide polymorphisms at that locus, we applied chromosome conformation studies in developing human brains and implicated three additional genes: SLC35B1, CALCOCO2 and DLX3. Gene expression, brain imaging and fetal brain expression quantitative trait locus studies prioritize SLC35B1 and PHB. These analyses indicate that GWAS of single heritable features of genetically complex disorders followed by chromosome conformation studies in relevant tissues can be successful in revealing novel risk genes for single core features of ASD.

A comparison of short-term outcomes between laparoscopic and open emergent repair of perforated peptic ulcers.

BACKGROUND: We compared 30-day outcomes in patients undergoing emergent open and laparoscopic repair of perforated peptic ulcers in a large multicenter cohort. METHODS: Prospectively obtained data in the American College of Surgeons National Surgical Quality Improvement Program public use files from 2010 to 2016 were reviewed. Perioperative risks and outcomes were compared in unmatched and propensity-matched groups using parametric/non-parametric statistical tests as appropriate. RESULTS: A total of 4210 procedures were identified 345 (8.2%) laparoscopic and 3865 (91.8%) open. Laparoscopic repairs increased from 4.5% of 2010 cases to 11.4% of 2016 cases (p < .001). Open repair patients had more acute presentation including higher rates of ASA class, hypoalbuminemia, preoperative septic shock, dyspnea, and mechanical ventilation (all p < .01). Laparoscopic operations were longer than open procedures (p < .001). Mortality (8.5 vs. 3.5%), median length of stay (7 vs. 5 days), transfusion rates (13.7 vs. 7.0%), renal failure (3.7 vs. 1.2%), and respiratory failure (15.5 vs. 5.2%) were all worse in the unmatched open group (all p < .01). Propensity matching resulted in 342 laparoscopic and 626 open cases of similar ulcer type, demographics, ASA class, preoperative SIRS/sepsis, hypoalbuminemia, and wound class. Mortality was similar between matched groups (5.0 vs. 3.5%, p = .331). Median length of stay was longer in the open group (6 vs. 5 days, p < .001), which also had higher rates of prolonged ventilation/reintubation (9.6 vs. 5.3%, p = .019) and abdominal wall wound occurrences (6.2 vs. 2.3%, p = .042). Return to the operating room and 30-day readmissions did not differ between the matched groups. CONCLUSIONS: Emergent laparoscopic repair of perforated peptic ulcer is increasingly being performed, is safe relative to open repair (in patients without preoperative septic shock), and confers a modest benefit in terms of length of stay, respiratory, and abdominal wall wound complications.

Development, manufacture and characterization of niosomes for the delivery for nevirapine.

Nevirapine (NVP), used for the treatment of HIV/AIDS, exhibits unpredictable oral bioavailability, has a poor side effect profile and requires frequent dosing. Niosomes are novel drug delivery systems that have the potential to overcome these challenges. A thin layer hydration approach was used to produce niosomes and optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) establish and identify parameters that may affect the manufacture of niosomes. The impact of cholesterol and surfactant content, hydration time and temperature on manufacture was investigated. Critical quality attributes (CQA) in respect of particle size (PS), entrapment efficiency (EE), polydispersity index (PDI) and the amount of NVP released at 48 hours was also assessed. The optimised niosome composition was identified and manufactured and the CQA characterised prior to placing the batch on stability for 12 weeks at 4±2 °C and 22±2 °C. The PS, PDI, EE and % NVP released at 48 h was 523.36±23.16 nm, 0.386±0.054, 96.8 % and 25.3 % for niosomes manufactured with Span® 20. Similarly, the parameters were 502.87±21.77 nm and 0.394±0.027, 98.0 % and 25.0 % for mean PS, PDI, EE and %NVP released at 48 h for Span® 80 niosomes. All characterisation was undertaken on the day of manufacture. In conclusion, a simple, cheap, rapid and precise method of manufacture of NVP niosomes was developed, validated and optimised using DoE and RSM and the product exhibited the target CQA.

Design, evaluation and optimization of taste masked clarithromycin powder.

Clarithromycin (CLA) is an extremely bitter macrolide antibiotic used to treat paediatric and adult infections. The bitter taste affects patient adherence and may compromise therapy. This research developed a taste masked CLA resinate using Indion® 234, a weak acidic cation exchange resin. The factors affecting formation of the CLA-resin complex were assessed. Design of experiments was used to optimize response while evaluating input variables such as temperature, CLA-resin ratio,stirring time and pH. CLA loading efficiency was determined spectrophotometrically and CLA release using USP Apparatus II. Differential Scanning Calorimetry (DSC), Scanning Electron Microscop (SEM), Fourier Transform Infrared (FT-IR) Spectroscopy and X-ray Diffraction (XRD) were used to confirm complex formation. A spectrophotometric method was used to assess taste evaluation. The optimum CLA-resin ratio, temperature, and stirring time were 1:4, 80 °C, 3 hours, respectively, at pH 8. Characterization techniques revealed that CLA was crystalline and the complex amorphous in nature. FT-IR spectra of resinate revealed the absence of resonance due to the tertiary amine functional group that is responsible for the bitter taste of CLA. CLA was stable in simulated salivary fluid and was released within 3 hours in gastric fluid. All CLAresin batches revealed complete taste masking. Taste analysis highlighted the improvement of taste masking properties of the resinate as the CLA to resin ratio, increased.