Applications of three-dimensional printing in ophthalmology

Three-dimensional (3D) printing is increasingly used to produce customised objects and is a promising alternative to traditional manufacturing methods in diverse fields, such as dentistry and orthopaedics. Already in use in other medical specialities, adoption in ophthalmology has been limited to date. This review aims to provide an overview of 3D printing technology with respect to current and potential applications in ophthalmic practice. Medline, Embase and internet search were performed with "3D printing", "ophthalmology", "dentistry", "orthopaedics" and their synonyms used as main search terms. In addition, search terms related to clinical applications such as "surgery" and "implant" were employed. 3D printing has multiple applications in ophthalmology, including in diagnosis, surgery, prosthetics, medications and medical education. Within the past decade, researchers have produced 3D printed models of objects such as implants, prostheses, anatomical models and surgical simulators. Further development is necessary to generate optimal biomaterials for various applications, and the quality and long-term performance of 3D models needs to be validated

A model of tuberculosis clustering in low incidence countries reveals more transmission in the United Kingdom than the Netherlands between 2010 and 2015

Tuberculosis (TB) remains a public health threat in low TB incidence countries, through a combination of reactivated disease and onward transmission. Using surveillance data from the United Kingdom (UK) and the Netherlands (NL), we demonstrate a simple and predictable relationship between the probability of observing a cluster and its size (the number of cases with a single genotype). We demonstrate that the full range of observed cluster sizes can be described using a modified branching process model with the individual reproduction number following a Poisson lognormal distribution. We estimate that, on average, between 2010 and 2015, a TB case generated 0.41 (95% CrI 0.30,0.60) secondary cases in the UK, and 0.24 (0.14,0.48) secondary cases in the NL. A majority of cases did not generate any secondary cases. Recent transmission accounted for 39% (26%,60%) of UK cases and 23%(13%,37%) of NL cases. We predict that reducing UK transmission rates to those observed in the NL would result in 538(266,818) fewer cases annually in the UK. In conclusion, while TB in low incidence countries is strongly associated with reactivated infections, we demonstrate that recent transmission remains sufficient to warrant policies aimed at limiting local TB spread

The reductive activation of CO2 across a Ti═Ti double bond: synthetic, structural, and mechanistic studies

[Image: see text] The reactivity of the bis(pentalene)dititanium double-sandwich compound Ti(2)Pn(†)(2) (1) (Pn(†) = 1,4-{Si(i)Pr(3)}(2)C(8)H(4)) with CO(2) is investigated in detail using spectroscopic, X-ray crystallographic, and computational studies. When the CO(2) reaction is performed at −78 °C, the 1:1 adduct 4 is formed, and low-temperature spectroscopic measurements are consistent with a CO(2) molecule bound symmetrically to the two Ti centers in a μ:η(2),η(2) binding mode, a structure also indicated by theory. Upon warming to room temperature the coordinated CO(2) is quantitatively reduced over a period of minutes to give the bis(oxo)-bridged dimer 2 and the dicarbonyl complex 3. In situ NMR studies indicated that this decomposition proceeds in a stepwise process via monooxo (5) and monocarbonyl (7) double-sandwich complexes, which have been independently synthesized and structurally characterized. 5 is thermally unstable with respect to a μ-O dimer in which the Ti–Ti bond has been cleaved and one pentalene ligand binds in an η(8) fashion to each of the formally Ti(III) centers. The molecular structure of 7 shows a “side-on” bound carbonyl ligand. Bonding of the double-sandwich species Ti(2)Pn(2) (Pn = C(8)H(6)) to other fragments has been investigated by density functional theory calculations and fragment analysis, providing insight into the CO(2) reaction pathway consistent with the experimentally observed intermediates. A key step in the proposed mechanism is disproportionation of a mono(oxo) di-Ti(III) species to yield di-Ti(II) and di-Ti(IV) products. 1 forms a structurally characterized, thermally stable CS(2) adduct 8 that shows symmetrical binding to the Ti(2) unit and supports the formulation of 4. The reaction of 1 with COS forms a thermally unstable complex 9 that undergoes scission to give mono(μ-S) mono(CO) species 10. Ph(3)PS is an effective sulfur transfer agent for 1, enabling the synthesis of mono(μ-S) complex 11 with a double-sandwich structure and bis(μ-S) dimer 12 in which the Ti–Ti bond has been cleaved

Diversity-Oriented Synthesis Yields a Novel Lead for the Treatment of Malaria

Here, we describe the discovery of a novel antimalarial agent using phenotypic screening of Plasmodium falciparum asexual blood-stage parasites. Screening a novel compound collection created using diversity-oriented synthesis (DOS) led to the initial hit. Structure–activity relationships guided the synthesis of compounds having improved potency and water solubility, yielding a subnanomolar inhibitor of parasite asexual blood-stage growth. Optimized compound 27 has an excellent off-target activity profile in erythrocyte lysis and HepG2 assays and is stable in human plasma. This compound is available via the molecular libraries probe production centers network (MLPCN) and is designated ML238.Chemistry and Chemical Biolog

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

Background & Aims We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10–9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10–6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10–6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Assessment of Brain Age in Posttraumatic Stress Disorder: Findings from the ENIGMA PTSD and Brain Age Working Groups

Background Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan

Species-specific responses of Late Quaternary megafauna to climate and humans

Despite decades of research, the roles of climate and humans in driving the dramatic extinctions of large-bodied mammals during the Late Quaternary remain contentious. We use ancient DNA, species distribution models and the human fossil record to elucidate how climate and humans shaped the demographic history of woolly rhinoceros, woolly mammoth, wild horse, reindeer, bison and musk ox. We show that climate has been a major driver of population change over the past 50,000 years. However, each species responds differently to the effects of climatic shifts, habitat redistribution and human encroachment. Although climate change alone can explain the extinction of some species, such as Eurasian musk ox and woolly rhinoceros, a combination of climatic and anthropogenic effects appears to be responsible for the extinction of others, including Eurasian steppe bison and wild horse. We find no genetic signature or any distinctive range dynamics distinguishing extinct from surviving species, underscoring the challenges associated with predicting future responses of extant mammals to climate and human-mediated habitat change.This paper is in the memory of our friend and colleague Dr. Andrei Sher, who was a major contributor of this study. Dr Sher died unexpectedly, but his major contributions to the field of Quaternary science will be remembered and appreciated for many years to come. We are grateful to Dr. Adrian Lister and Dr. Tony Stuart for guides and discussions. Thanks to Tina B. Brandt, Dr. Bryan Hockett and Alice Telka for laboratory help and samples and to L. Malik R. Thrane for his work on the megafauna locality database. Data taken from the Stage 3 project was partly funded by Grant #F/757/A from the Leverhulme Trust, together with a grant from the McDonald Grants and Awards Fund. We acknowledge the Danish National Research Foundation, the Lundbeck Foundation, the Danish Council for Independent Research and the US National Science Foundation for financial suppor