Search

Chiral molecules, used in applications such as enantioselective photocatalysis 1 , circularly polarized light detection 2 and emission 3 and molecular switches 4,5 , exist in two geometrical configurations that are non-superimposable mirror images of each other. These so-called (R) and (S) enantiomers exhibit different physical and chemical properties when interacting with other chiral entities. Attosecond technology might enable influence over such interactions, given that it can probe and even direct electron motion within molecules on the intrinsic electronic timescale 6 and thereby control reactivity 7-9 . Electron currents in photoexcited chiral molecules have indeed been predicted to enable enantiosensitive molecular orientation 10 , but electron-driven chiral dynamics in neutral molecules have not yet been demonstrated owing to the lack of ultrashort, non-ionizing and perturbative light pulses. Here we use time-resolved photoelectron circular dichroism (TR-PECD) 11-15 with an unprecedented temporal resolution of 2.9 fs to map the coherent electronic motion initiated by ultraviolet (UV) excitation of neutral chiral molecules. We find that electronic beatings between Rydberg states lead to periodic modulations of the chiroptical response on the few-femtosecond timescale, showing a sign inversion in less than 10 fs. Calculations validate this and also confirm that the combination of the photoinduced chiral current with a circularly polarized probe pulse realizes an enantioselective filter of molecular orientations following photoionization. We anticipate that our approach will enable further investigations of ultrafast electron dynamics in chiral systems and reveal a route towards enantiosensitive charge-directed reactivity., (© 2024. The Author(s).)

Organophosphorus compounds (OPs), such as VX, pose a significant threat due to their neurotoxic and hazardous properties. Skin decontamination is essential to avoid irreversible effects. Fuller's earth (FE), a phyllosilicate conventionally employed in powder form, has demonstrated decontamination capacity against OPs. The aim of this study was to develop a formulation that forms a film on the skin, with a significant OP removal capacity (>95 %) coupled with sequestration capabilities, favorable drying time and mechanical properties to allow for easy application and removal, particularly in emergency context. Various formulations were prepared using different concentrations of polyvinyl alcohol (PVA), FE and surfactants. Their removal and sequestration capacity was tested using paraoxon-ethyl (POX), a chemical that simulates the behavior of VX. Formulations with removal capacity levels surpassing 95 % were mechanically characterized and cell viability assays were performed on Normal Human Dermal Fibroblast (NHDF). The four most promising formulations were used to assess decontamination efficacy on pig ear skin explants. These formulations showed decontamination levels ranging from 84.4 ± 4.7 % to 96.5 ± 1.3 %, which is equivalent to current decontamination methods. These results suggest that this technology could be a novel and effective tool for skin decontamination following exposure to OPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: This study aimed to determine the seroprevalence of immunoglobulin G antibodies targeting SARS-CoV-2 and other human coronaviruses after the first circulation of SARS-CoV-2 in New Caledonia, Pacific region., Methods: Blood samples were collected to detect the presence of SARS-CoV-2 immunoglobulin G antibodies. The sampling took place between July 2021 and July 2022 but was interrupted after the first circulation of SARS-CoV-2 (September 2021-March 2022) in New Caledonia. Data on ethnicity, age, gender, main residence, and anteriority of COVID-19 and vaccination were collected and analyzed., Results: A total of 747 participants, representative of New Caledonia's adult population, were included in the study. We found that 81% of the population had antibody responses to SARS-CoV-2 at the end of July 2022. The vaccination rate was 75%, whereas infections had affected 40% of the population. Individuals aged >45 years were significantly more vaccinated than those aged 18-44 years (80%, 95% confidence interval 74-84%). Oceanians were the most infected (50%, 95% confidence interval 42-57%)., Conclusion: In New Caledonia, we show a high immunity rate (81%) after the first waves of SARS-CoV-2 circulation and the vaccination campaign. The analyses showed spatial heterogeneities in the infection rate across the territory and revealed that Oceanians were the most infected. Our study also highlighted high exposure of New Caledonia's population to other human coronaviruses., Competing Interests: The authors have no competing interests to declare., (© 2024 The Author(s).)

Regenerative therapies show promise in reversing sight loss caused by degenerative eye diseases. Their precise subretinal delivery can be facilitated by robotic systems alongside with Intra-operative Optical Coherence Tomography (iOCT). However, iOCT's real-time retinal layer information is compromised by inferior image quality. To address this limitation, we introduce an unpaired video super-resolution methodology for iOCT quality enhancement. A recurrent network is proposed to leverage temporal information from iOCT sequences, and spatial information from pre-operatively acquired OCT images. Additionally, a patchwise contrastive loss enables unpaired super-resolution. Extensive quantitative analysis demonstrates that our approach outperforms existing state-of-the-art iOCT super-resolution models. Furthermore, ablation studies showcase the importance of temporal aggregation and contrastive loss in elevating iOCT quality. A qualitative study involving expert clinicians also confirms this improvement. The comprehensive evaluation demonstrates our method's potential to enhance the iOCT image quality, thereby facilitating successful guidance for regenerative therapies., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s).)

Background: Bombay phenotype is rare and characterized by a lack of H antigen on the surface of red blood cells (RBCs) with naturally occurring anti-H antibodies. The presence of anti-H necessitates the exclusive use of Bombay phenotype RBCs for transfusion. We present a case of a pregnant woman with Bombay phenotype who required urgent cesarean section delivery due to high-risk placenta previa., Case Description: A 36-year-old G1P0 woman of Indian origin presented at 36 weeks and 4 days gestation for management of a high-risk pregnancy with complete placenta previa. Bombay phenotype was unexpectedly identified on routine testing. Given the rarity of the blood, advanced gestation, and risk of post-partum hemorrhage associated with complete placenta previa and spontaneous labor, prompt strategic planning commenced for a successful delivery. Two frozen allogeneic Bombay phenotype RBCs were available as part of a concise transfusion plan. Intraoperative cell salvage was successfully employed and allogeneic transfusion was not required., Conclusion: Management of patients with rare blood types can be extremely challenging and guidance for those presenting later in pregnancy is scarce. Our patient's gestational age precluded the use of well-known effective strategies, including hemoglobin optimization, autologous and directed donation, and procurement of large quantities of rare blood. Rather, our approach utilized multidisciplinary expertise and strategic planning to yield a successful outcome., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate the safety profile and the surgical outcomes in a large cohort of subjects undergoing early vitrectomy for unexplained fundus-obscuring vitreous haemorrhage (FOVH)., Methods: Retrospective, single-centre case series of 186 consecutive eyes presenting between January 2018 and February 2020. Primary outcomes included change in best-corrected visual acuity (BCVA), rate of intra-operative retinal tears or retinal detachment (RD), baseline proliferative vitreoretinopathy (PVR), association of demographics with clinical outcomes, and rate of significant adverse events characterised by reoperation., Results: Main final diagnosis was haemorrhagic posterior vitreous detachment (76%) and the overall risk of a retinal tear with or without RD found at the time of surgery was 69%. Vitrectomy was completed within 24 h in 94% of eyes. Rate of RD was 18%; all cases were macula-sparing with no PVR. Mean change in BCVA from baseline to final follow-up was -1.53 ± 0.69 LogMAR, p < 0.001. Time from presentation to surgery was significantly associated with final BCVA (p = 0.036, beta co-efficient 0.097). There was a significant association between presence of RD and age <60 y (OR 0.94, 95%CI [0.90-0.98], p = 0.003). 4.8% required repeated vitrectomy for post-operative RD (4), epiretinal membrane formation (3), removal of oil (1), and recurrent FOVH (1). None of these reoperations were induced by complications during the first surgery., Conclusion: There is a high rate of retinal breaks in cases with unexplained FOVH, and the risk of a concomitant RD is higher in younger subjects. Early vitrectomy within 24 h appears a safe first-line treatment and yields good clinical outcomes., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background/objectives: Pseudophakic macular oedema remains the most common sight-threatening complication following cataract surgery. This study aims to assess the effect of intraoperative subconjunctival steroids on the rate of pseudophakic cystoid macular oedema., Methods: A retrospective, observational database study of 20 066 consecutive phacoemulsification surgeries. The incidence of pseudophakic cystoid macular oedema was compared in eyes that did and did not receive intraoperative subconjunctival steroid injection during routine cataract surgery., Results: Intraoperative subconjunctival injection of dexamethasone or betamethasone sodium phosphate significantly reduced the odds of developing pseudophakic cystoid macular oedema across the cohort (odds ratio: 0.67; 95% confidence interval: 0.46-0.98, p = 0.039). The effect of subconjunctival steroids on pseudophakic macular oedema remained independently associated on multivariate logistic regression analysis (p = 0.028)., Conclusion: This study demonstrates that administration of intraoperative subconjunctival steroid injection is associated with a reduced incidence of pseudophakic cystoid macular oedema in routine, uncomplicated cataract surgery., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Introduction: The SARS-CoV-2 pandemic has had a great impact on the physical and psychological health of the population. The aim of this study was to evaluate child and adolescent mental health in a population cohort along the 2020-2021 school year., Methods: This was a prospective longitudinal study of a cohort of children from 5-14 years of age in Catalonia, Spain, performed from September 2020 to July 2021. The participants were randomly selected and accompanied by their primary care paediatrician. Evaluation of risk of psychopathology was performed using the Strengths and Difficulties Questionnaire (SDQ) carried out by one of the legal guardians of the child. We also collected sociodemographic and health variables of the participants and their nuclear family. Data were collected by an online survey through the RedCap platform at the beginning of the academic year and at the end of each trimester (4 cuts)., Results: At the beginning of the school year, 9.8% of the patients were probable cases of psychopathology compared to 6.2% at the end of the year. The perception of the level of preoccupation of the children for their health and that of their family was related to presenting psychopathology, especially at the beginning of the year, with the perception of a good family atmosphere being always related to lower risk. No variable related to COVID-19 was associated with an altered SDQ result., Conclusions: Along the 2020-2021 school year, the percentage of children with a probability of presenting psychopathology decreased from 9.8% to 6.2%., (Copyright © 2023 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Objectives: Delirium, an acute change in mental state, seen in hospitalized older adults is a growing public health concern with implications for both patients and caregivers; however, there is minimal research on educating caregivers about delirium. Utilizing family caregivers to assist with delirium management in acute care settings demonstrates improved health outcomes supporting the need for patient and family centered care. The primary aims of the study were to determine feasibility of implementing a delirium education video for caregivers of patients in an adult oncology intensive care unit and compare delirium knowledge to caregivers in a control group., Methods: A quasi-experimental design comprised of 31 family caregivers of adult patients in an oncology intensive care unit to determine feasibility of implementing a delirium education video., Results: The results demonstrate feasibility of implementing a caregiver education video in-person and virtually. While total delirium knowledge scores were not statistically significant, knowledge gained within the delirium presentation subgroup was significant ( p  = .05)., Conclusion: This study demonstrates feasibility of implementing a caregiver education video and findings support further research in this area., Innovation: Collaborating with caregivers to develop virtual video education for delirium allows for a versatile approach to connect with caregivers to support their caregiving role., Competing Interests: None., (© 2023 The Authors.)

Dynamic nuclear polarisation (DNP) can significantly enhance the sensitivity of solid-state nuclear magnetic resonance (SSNMR) experiments by transferring the electron spin polarisation of paramagnetic species to nuclei through microwave irradiation of the sample at cryogenic temperatures. Paramagnetic species required for DNP can be provided in the form of mesoporous silica materials containing nitroxide radicals either located on the porous surface or embedded in the pore walls. The present study focuses specifically on porous materials with wall-embedded radicals that were synthesised using conventional molecular imprinting protocols. More remarkably, by changing the molecular structure of the TEMPO precursor, the theoretical distance between the oxygen atoms in a pair of wall-embedded face-to-face TEMPO radicals was increased stepwise (0.7, 0.9, 1.1, 1.3 and 1.5 nm). The thermal activation of these five series of materials led to 37 TEMPO-functionalised silica materials with different radical concentrations. Their efficiency as DNP polarising agents was subsequently investigated at 9.4 T and ∼110 K under magic-angle spinning conditions (10 kHz) after impregnating them at room temperature with an aqueous solution of isotopically enriched proline. Our results show that the highest DNP efficiency was obtained for the silica materials that exhibited the shortest theoretical oxygen-oxygen distance between the TEMPO rings, suggesting that the design rules accepted for soluble DNP polarising agents may not be transposed to these materials with wall-embedded pairs of nitroxides.

We present a wearable device with III-V nanowires in a flexible polymer, which is used for active mechanical tuning of the second-harmonic generation intensity. An array of vertical GaAs nanowires was grown with metalorganic vapour-phase epitaxy, then embedded in polydimethylsiloxane and detached from the rigid substrate with mechanical peel off. Experimental results show a tunability of the second-harmonic generation intensity by a factor of two for 30% stretching which matches the simulations including the distribution of sizes. We studied the impact of different parameters on the band dispersion and tunability of the second-harmonic generation, such as the pitch, the length, and the diameter. We predict at least three orders of magnitude active mechanical tuning of the nonlinear signal intensity for nanowire arrays. The flexibility of the array together with the resonant wavelength engineering make such structures perspective platforms for future bendable or stretchable nanophotonic devices as light sources or sensors.

Purpose: Intra-retinal delivery of novel sight-restoring therapies will require the precision of robotic systems accompanied by excellent visualisation of retinal layers. Intra-operative Optical Coherence Tomography (iOCT) provides cross-sectional retinal images in real time but at the cost of image quality that is insufficient for intra-retinal therapy delivery.This paper proposes a super-resolution methodology that improves iOCT image quality leveraging spatiotemporal consistency of incoming iOCT video streams., Methods: To overcome the absence of ground truth high-resolution (HR) images, we first generate HR iOCT images by fusing spatially aligned iOCT video frames. Then, we automatically assess the quality of the HR images on key retinal layers using a deep semantic segmentation model. Finally, we use image-to-image translation models (Pix2Pix and CycleGAN) to enhance the quality of LR images via quality transfer from the estimated HR domain., Results: Our proposed methodology generates iOCT images of improved quality according to both full-reference and no-reference metrics. A qualitative study with expert clinicians also confirms the improvement in the delineation of pertinent layers and in the reduction of artefacts. Furthermore, our approach outperforms conventional denoising filters and the learning-based state-of-the-art., Conclusions: The results indicate that the learning-based methods using the estimated, through our pipeline, HR domain can be used to enhance the iOCT image quality. Therefore, the proposed method can computationally augment the capabilities of iOCT imaging helping this modality support the vitreoretinal surgical interventions of the future., (© 2022. The Author(s).)

The resonance-enhanced multiphoton ionization of chiral molecules by elliptically polarized laser pulses produces photoelectron angular distributions that are forward/backward asymmetric with respect to the light propagation axis. We investigate this photoelectron elliptical dichroism in the (2 + 1)-photon ionization of fenchone molecules, using wavelength tunable femtosecond UV pulses. We show that the photoelectron elliptical asymmetry is extremely sensitive to the intermediate resonant states involved in the ionization process, and enables electronic couplings to be revealed that do not show up so clearly when using circularly polarized light.

Regenerative therapies have recently shown potential in restoring sight lost due to degenerative diseases. Their efficacy requires precise intra-retinal delivery, which can be achieved by robotic systems accompanied by high quality visualization of retinal layers. Intra-operative Optical Coherence Tomography (iOCT) captures cross-sectional retinal images in real-time but with image quality that is inadequate for intra-retinal therapy delivery. This paper proposes a two-stage super-resolution methodology that enhances the image quality of the low resolution (LR) iOCT images leveraging information from pre-operatively acquired high-resolution (HR) OCT (preOCT) images. First, we learn the degradation process from HR to LR domain through CycleGAN and use it to generate pseudo iOCT (LR) images from the HR preOCT ones. Then, we train a Pix2Pix model on the pairs of pseudo iOCT and preOCT to learn the super-resolution mapping. Quantitative analysis using both full-reference and no-reference image quality metrics demonstrates that our approach clearly outperforms the learning-based state-of-the art techniques with statistical significance. Achieving iOCT image quality comparable to pre-OCT quality can help this medical imaging modality be established in vitreoretinal surgery, without requiring expensive hardware-related system updates.

Background: The quality of an emergency department (ED) is highly dependent on its ability to supply efficient, as well as high-quality treatment for all patients. Key performance indicators are important when measuring the performance of an emergency department. This study aimed to perform an exploratory data analysis and to develop an admission prediction model based on a dataset that was constructed from key performance indicators selected by a panel of expert physicians, nurses and hospital administrators., Methods: A dataset of 172,695 records was retrospectively collected from an Emergency Department. The relationships within the dataset were analyzed and three machine learning algorithms were compared for an admission predictive model based on the initial patient information., Results: The dataset showed that mean length of stay was similar in the different weekdays, there was a positive linear relationship between the length of stay and patient age and the admission predictive model yielded an AUC of 0.79., Conclusions: The selected indicators can be used to study whether emergency department allocates its resources properly to cope with overcrowding and the predictive model may be employed by Hospital and ED administrates to fill information gaps and support decision making for the improvement of the key performance indicators., (Copyright © 2020. Published by Elsevier Ltd.)

Purpose: Stellate nonhereditary idiopathic foveomacular retinoschisis is a disorder characterized by splitting of the retina at the macula, without a known underlying mechanical or inherited cause. This study investigates demographic, anatomical, and functional characteristics of subjects with stellate nonhereditary idiopathic foveomacular retinoschisis, to explore potential underlying mechanisms., Methods: In this single-site, retrospective, and cross-sectional, observational study, data were collected from 28 eyes from 24 subjects with stellate nonhereditary idiopathic foveomacular retinoschisis. Descriptive statistics were reported, based on the observed anatomico-functional features., Results: The visual acuity remained stable (median 20/20) in all subjects over a median follow-up of 17 months. All cases demonstrated foveomacular retinoschisis within Henle's fiber layer, at the junction of the outer plexiform and outer nuclear layers. This schisis cavity extended beyond the limits of the macular OCT temporally in all eyes. In most affected eyes, there were documented features of peripheral retinoschisis and broad attachment of the posterior hyaloid at the macula. Functional testing in a cross-sectional subset demonstrated normal retinal sensitivity centrally but an absolute scotoma peripherally., Conclusion: Stellate nonhereditary idiopathic foveomacular retinoschisis seems to be associated with peripheral retinoschisis and anomalous or incomplete posterior hyaloid detachment. Despite chronic manifestation, this does not significantly affect central visual function but can manifest with profound loss of peripheral visual function., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Introduction: The aim of this project was to evaluate the psychopathological impact of home confinement and school closing between March and September 2020 on the mental health of Catalonian children., Methods: PEDSAME study: first cross-sectional section (beginning of the school year) and retrospective data (lockdown), carried out through the network of Primary Care pediatricians in the Catalan population between 5 and 14 years (included) from 09/14/2020 to 10/30/2020 in a random sample. Data were collected with an online survey through the RedCap platform at the beginning of the school year. The main variable was the result of the Strengths and Difficulties Questionnaire answered by parents to assess the risk of psychopathology, in addition to other related variable., Results: The results obtained at the beginning of the school year show that 9.8% of the patients were probable cases of psychopathology. The most affected group were those between 5 and 8 years. The perception of the children's level of concern for their health and that of their family was a risk factor for presenting psychopathology, while the good family environment was a protective factor. Emotional and behavioral symptoms, sleep disorders and problematic use of screens were detected more frequently during confinement than at the beginning of the school year., Conclusions: Confinement and the absence of schooling for 6 months had a negative impact on the mental health of the child-adolescent population who showed worse indicators than the previous year., (Copyright © 2021 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Color vision is considered a marker of cone function and its assessment in patients with retinal pathology is complementary to the assessments of spatial vision [best-corrected visual acuity (BCVA)] and contrast detection (perimetry). Rod-cone and chorioretinal dystrophies-such as choroideremia-typically cause alterations to color vision, making its assessment a potential outcome measure in clinical trials. However, clinical evaluation of color vision may be compromised by pathological changes to spatial vision and the visual field. The low vision Cambridge Color Test (lvCCT) was developed specifically to address these latter issues. We used the trivector version of the lvCCT to quantify color discrimination in a cohort of 53 patients with choroideremia. This test enables rapid and precise characterization of color discrimination along protan, deutan, and tritan axes more reliably than the historically preferred test for clinical trials, namely the Farnsworth Munsell 100 Hue test. The lvCCT demonstrates that color vision defects-particularly along the tritan axis-are seen early in choroideremia, and that this occurs independent of changes in visual acuity, pattern electroretinography and ellipsoid zone area on optical coherence tomography (OCT). We argue that the selective loss of tritan color discrimination can be explained by our current understanding of the machinery of color vision and the pathophysiology of choroideremia., Competing Interests: RM is a consultant in retinal gene therapy to Novartis, Gyroscope Therapeutics, and Biogen, but these companies had no input into the work presented. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jolly, Simunovic, Dubis, Josan, Robson, Bellini, Bloch, Georgiadis, da Cruz, Bridge and MacLaren.)

Objective: Antenatal anaemia is associated with increased peripartum transfusion requirement in South Africa. We studied whether HIV was associated with the response to treatment of iron-deficiency anaemia., Design: Prospective cohort study., Setting: Hospital-based antenatal anaemia clinic in South Africa., Sample: Equal-sized cohorts of pregnant women testing positive for HIV (HIV+) and testing negative for HIV (HIV-) with iron-deficiency anaemia., Methods: Haemoglobin trajectories of women with confirmed iron-deficiency anaemia (ferritin < 50 ng/ml) were estimated from the initiation of iron supplementation using mixed-effects modelling, adjusted for baseline HIV status, ferritin level, maternal and gestational ages and time-varying iron supplementation., Main Outcome Measures: Haemoglobin trajectories., Results: Of 469 women enrolled, 51% were HIV+, 90% of whom were on antiretroviral therapy (with a mean CD4+ lymphocyte count of 403 cells/mm 3 ). Anaemia diagnoses did not differ by HIV status. A total of 400 women with iron-deficiency anaemia were followed during treatment with oral or intravenous (6%) iron therapy. In multivariable analysis, haemoglobin recovery was 0.10 g/dl per week slower on average in women who were HIV+ versus women who were HIV- (P = 0.001), 0.01 g/dl per week slower in women with higher baseline ferritin (P < 0.001) and 0.06 g/dl per week faster in women who were compliant with oral iron therapy (P = 0.002)., Conclusions: Compared with women who were HIV-, women who were HIV+ with iron-deficiency anaemia had slower but successful haemoglobin recovery with iron therapy. Earlier effective management of iron deficiency could reduce the incidence of peripartum blood transfusion., Tweetable Abstract: Among pregnant women with iron-deficiency anaemia in South Africa, HIV slows haemoglobin recovery in response to oral iron therapy., (© 2021 John Wiley & Sons Ltd.)

Introduction: Juxtapapillary laser (JPL) photocoagulation in the region of the papillomacular bundle, temporal to the optic nerve, has become routine care in disorders such as optic disc pit maculopathy. Despite evidence demonstrating safe and effective use of this approach, there is still a lack of consensus in the literature, due to the perceived risk of loss of visual function. Instances of such misplaced caution could result in inadequate treatment protocols., Methods: An observational series of five cases of optic disc pit maculopathy, treated with dense temporal juxtapapillary endolaser, in a single tertiary ophthalmic hospital., Results: None of the reported cases of optic disc pit maculopathy treated with dense juxtapapillary laser demonstrated anatomical or perimetric findings consistent with nerve fiber layer damage in the region of the papillomacular bundle., Conclusions: This series demonstrates that dense laser photocoagulation, in the vicinity of the papillomacular bundle, does not cause structural damage to the nerve fiber layer or associated loss of visual function in optic disc pit maculopathy. Appropriate application of juxtapapillary laser is a safe and effective treatment for various macular pathologies.

In this work, the photoionization of chiral molecules by an elliptically polarized, high repetition rate, femtosecond laser is probed. The resulting 3D photoelectron angular distribution shows a strong forward-backward asymmetry, which is highly dependent not only on the molecular structure but also on the ellipticity of the laser pulse. By continuously varying the laser ellipticity, we can observe molecular and enantiomer changes in real time at a previously unseen speed and precision. The technique allows enantiomeric excess of a pure compound to be measured with a 5% precision within 3 s, and a 10-min acquisition yields a precision of 0.4%. The isomers camphor and fenchone can be easily distinguished, unlike with conventional mass spectrometry. Preliminary results for the pharmaceutically interesting ibuprofen are also given, showing the capability of photoionization as a means of distinguishing larger molecular systems., (© 2020 Wiley Periodicals LLC.)

Stargardt disease is a progressive retinal disorder caused by bi-allelic mutations in the ABCA4 gene that encodes the ATP-binding cassette, subfamily A, member 4 transporter protein. Over the past few years, we and others have identified several pathogenic variants that reside within the introns of ABCA4, including a recurrent variant in intron 36 (c.5196+1137G>A) of which the pathogenicity so far remained controversial. Detailed clinical characterization of this variant confirmed its pathogenic nature, and classified it as an allele of intermediate severity. Moreover, we discovered several additional ABCA4 variants clustering in intron 36. Several of these variants resulted in aberrant splicing of ABCA4, i.e., the inclusion of pseudoexons, while the splicing defects caused by the recurrent c.5196+1137G>A variant strongly increased upon differentiation of patient-derived induced pluripotent stem cells into retina-like cells. Finally, all splicing defects could be rescued by the administration of antisense oligonucleotides that were designed to specifically block the pseudoexon insertion, including rescue in 3D retinal organoids harboring the c.5196+1137G>A variant. Our data illustrate the importance of intronic variants in ABCA4 and expand the therapeutic possibilities for overcoming splicing defects in Stargardt disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

This article presents a medical robotic system for deep orbital interventions, with a focus on Optic Nerve Sheath Fenestration (ONSF). ONSF is a currently invasive ophthalmic surgical approach that can reduce potentially blinding elevated hydrostatic intracranial pressure on the optic disc via an incision on the optic nerve. The prototype is a multi-arm system capable of dexterous manipulation and visualization of the optic nerve area, allowing for a minimally invasive approach. Each arm is an independently controlled concentric tube robot collimated by a bespoke guide that is secured on the eye sclera via sutures. In this article, we consider the robot's end-effector design in order to reach/navigate the optic nerve according to the clinical requirements of ONSF. A prototype of the robot was engineered, and its ability to penetrate the optic nerve was analysed by conducting ex vivo experiments on porcine optic nerves and comparing their stiffness to human ones. The robot was successfully deployed in a custom-made realistic eye phantom. Our simulation studies and experimental results demonstrate that the robot can successfully navigate to the operation site and carry out the intervention.

Convalescent plasma is currently one of the leading treatments for COVID-19, but there is a paucity of data identifying therapeutic efficacy. A comprehensive analysis of the antibody responses in potential plasma donors and an understanding of the clinical and demographic factors that drive variant antibody responses is needed. Among 126 potential convalescent plasma donors, the humoral immune response was evaluated by a SARS-CoV-2 virus neutralization assay using Vero-E6-TMPRSS2 cells, commercial IgG and IgA ELISA to Spike (S) protein S1 domain (Euroimmun), IgA, IgG and IgM indirect ELISAs to the full-length S or S-receptor binding domain (S-RBD), and an IgG avidity assay. Multiple linear regression and predictive models were utilized to assess the correlations between antibody responses with demographic and clinical characteristics. IgG titers were greater than either IgM or IgA for S1, full length S, and S-RBD in the overall population. Of the 126 plasma samples, 101 (80%) had detectable neutralizing titers. Using neutralization titer as the reference, the sensitivity of the IgG ELISAs ranged between 95-98%, but specificity was only 20-32%. Male sex, older age, and hospitalization with COVID-19 were all consistently associated with increased antibody responses across the serological assays. Neutralizing antibody titers were reduced over time in contrast to overall antibody responses. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody levels.

Purpose: Sustained delivery of regenerative retinal therapies by robotic systems requires intra-operative tracking of the retinal fundus. We propose a supervised deep convolutional neural network to densely predict semantic segmentation and optical flow of the retina as mutually supportive tasks, implicitly inpainting retinal flow information missing due to occlusion by surgical tools., Methods: As manual annotation of optical flow is infeasible, we propose a flexible algorithm for generation of large synthetic training datasets on the basis of given intra-operative retinal images. We evaluate optical flow estimation by tracking a grid and sparsely annotated ground truth points on a benchmark of challenging real intra-operative clips obtained from an extensive internally acquired dataset encompassing representative vitreoretinal surgical cases., Results: The U-Net-based network trained on the synthetic dataset is shown to generalise well to the benchmark of real surgical videos. When used to track retinal points of interest, our flow estimation outperforms variational baseline methods on clips containing tool motions which occlude the points of interest, as is routinely observed in intra-operatively recorded surgery videos., Conclusions: The results indicate that complex synthetic training datasets can be used to specifically guide optical flow estimation. Our proposed algorithm therefore lays the foundation for a robust system which can assist with intra-operative tracking of moving surgical targets even when occluded.

This paper addresses retinal vessel segmentation on optical coherence tomography angiography (OCT-A) images of the human retina. Our approach is motivated by the need for high precision image-guided delivery of regenerative therapies in vitreo-retinal surgery. OCT-A visualizes macular vasculature, the main landmark of the surgically targeted area, at a level of detail and spatial extent unattainable by other imaging modalities. Thus, automatic extraction of detailed vessel maps can ultimately inform surgical planning. We address the task of delineation of the Superficial Vascular Plexus in 2D Maximum Intensity Projections (MIP) of OCT-A using convolutional neural networks that iteratively refine the quality of the produced vessel segmentations. We demonstrate that the proposed approach compares favourably to alternative network baselines and graph-based methodologies through extensive experimental analysis, using data collected from 50 subjects, including both individuals that underwent surgery for structural macular abnormalities and healthy subjects. Additionally, we demonstrate generalization to 3D segmentation and narrower field-of-view OCT-A. In the future, the extracted vessel maps will be leveraged for surgical planning and semi-automated intraoperative navigation in vitreo-retinal surgery., Competing Interests: The authors declare no conflicts of interest., (Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.)

A growing class of immunotherapeutics work by redirecting components of the immune system to recognize markers on the surface of cancer cells. However, such modalities will remain confined to a relatively small subgroup of patients because of the lack of universal targetable tumor biomarkers among all patients. Here, we designed a unique class of agents that exploit the inherent acidity of solid tumors to selectively graft cancer cells with immuno-engager epitopes. Our targeting approach is based on pHLIP, a unique peptide that selectively targets tumors in vivo by anchoring to cancer cell surfaces in a pH-dependent manner. We established that pHLIP-antigen conjugates trigger the recruitment of antibodies to the surface of cancer cells and induce cytotoxicity by peripheral blood mononuclear and engineered NK cells. These results indicate that these agents have the potential to be applicable to treating a wide range of solid tumors and to circumvent problems associated with narrow windows of selectivity.

Competing Interests: The following authors have no financial disclosures: EB, MM, GB and AS.

Background: The mechanisms underlying the finding of reduced child mortality in communities with biannual treatment with azithromycin remain unclear. We determined if there was a difference in morbidity in a cohort of children aged 1-36 months, residing in communities randomized to biannual treatment of preschool-aged children with azithromycin or placebo., Methods: Thirty villages in Kilosa, Tanzania, were randomly assigned to receive biannual treatment of all children aged 1-59 months with either azithromycin (20/mg/kg single dose) or placebo. Children who were aged 1-36 months and participated in the baseline survey were enrolled in this cohort study and followed prospectively for 2 years. Children were monitored every 6 months for signs and symptoms of diarrheal disease, acute respiratory illness, and anemia. Mixed-effects models that include age, time, treatment arm, and the interaction of treatment arm and time as independent predictors were used to evaluate differences between children by treatment assignment over time., Results: There was no difference in rates of diarrhea, fever, or anemia by treatment arm at baseline and at all phases of follow-up. The decline over time in reported cough was statistically significant in the children residing in the azithromycin communities, but not in the placebo communities. Once adjusting for clustering and age, the difference in decline between the 2 treatment arms was not significant (P = .09)., Conclusions: A beneficial effect of azithromycin treatment on morbidity outcomes was not evident at biannual surveys., Clinical Trials Registration: NCT02048007., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: The objective of this study was to report medium-term outcomes of a novel combination of phacoemulsification with transscleral cyclophotocoagulation (phaco-TCP) compared with combined phacoemulsification and endoscopic cyclophotocoagulation (phaco-ECP) in patients with uncontrolled or suboptimally controlled glaucoma and coexisting cataract., Materials and Methods: Retrospective case series of 80 consecutive patients with a minimum of 12 months of follow-up. In total, 46 eyes underwent phaco-ECP and 34 phaco-TCP. Success was defined as intraocular pressure (IOP) between 6 and 21 mm Hg with ≥20% reduction from preoperative IOP (with no increase in ocular hypotensive medications or further glaucoma surgery). Secondary outcomes were change in IOP, number of ocular hypotensive medications and safety., Results: The mean follow-up was 32.6 ±10.3 months. Preoperative clinical characteristics were similar in both groups. At latest follow-up, success rate was greater with phaco-TCP than phaco-ECP (67.6% and 47.8%, P=0.037). IOP was also significantly lower after phaco-TCP (14.88±5.57 mm Hg, from 22.62±6.52 mm Hg) than phaco-ECP (18.07±6.72 mm Hg, from 22.83±7.88, P=0.0273). Ocular hypotensive medications required reduced similarly after phaco-TCP (from 3.38±0.88 to 2.65±1.04 medications, P=0.0012) and phaco-ECP (from 3.07±0.929 to 2.63±1.42 medications, P=0.0108). There were no cases of hypotony or reduction in vision related to glaucoma with either surgical intervention and a similar proportion required further glaucoma surgery (phaco-ECP 15.2%, phako-TCP 5.9%, P=0.2884)., Conclusions: Phaco-TCP appears more successful in controlling IOP than phaco-ECP with similar safety. Further investigation is warranted of this newly proposed combination which may be particularly useful where access or experience with ECP or other minimally invasive glaucoma surgery is limited.

Receptor protein tyrosine phosphatases (RPTPs) play critical regulatory roles in mammalian signal transduction. However, the structural basis for the regulation of their catalytic activity is not fully understood, and RPTPs are generally not therapeutically targetable. This knowledge gap is partially due to the lack of known natural ligands or selective agonists of RPTPs. Contrary to what is known from structure-function studies of receptor tyrosine kinases (RTKs), RPTP activities have been reported to be suppressed by dimerization, which may prevent RPTPs from accessing their RTK substrates. We report here that homodimerization of protein tyrosine phosphatase receptor J (PTPRJ, also known as DEP-1) is regulated by specific transmembrane (TM) residues. We found that disrupting these interactions destabilizes homodimerization of full-length PTPRJ in cells, reduces the phosphorylation of the known PTPRJ substrate epidermal growth factor receptor (EGFR) and of other downstream signaling effectors, antagonizes EGFR-driven cell phenotypes, and promotes substrate access. We demonstrate these observations in human cancer cells using mutational studies and identified a peptide that binds to the PTPRJ TM domain and represents the first example of an allosteric agonist of RPTPs. The results of our study provide fundamental structural and functional insights into how PTPRJ activity is tuned by TM interactions in cells. Our findings also open up opportunities for developing peptide-based agents that could be used as tools to probe RPTPs' signaling mechanisms or to manage cancers driven by RTK signaling., (© 2019 Bloch et al.)

Objective: Achieving accurate prediction of sepsis detection moment based on bedside monitor data in the intensive care unit (ICU). A good clinical outcome is more probable when onset is suspected and treated on time, thus early insight of sepsis onset may save lives and reduce costs., Methodology: We present a novel approach for feature extraction, which focuses on the hypothesis that unstable patients are more prone to develop sepsis during ICU stay. These features are used in machine learning algorithms to provide a prediction of a patient's likelihood to develop sepsis during ICU stay, hours before it is diagnosed., Results: Five machine learning algorithms were implemented using R software packages. The algorithms were trained and tested with a set of 4 features which represent the variability in vital signs. These algorithms aimed to calculate a patient's probability to become septic within the next 4 hours, based on recordings from the last 8 hours. The best area under the curve (AUC) was achieved with Support Vector Machine (SVM) with radial basis function, which was 88.38%., Conclusions: The high level of predictive accuracy along with the simplicity and availability of input variables present great potential if applied in ICUs. Variability of a patient's vital signs proves to be a good indicator of one's chance to become septic during ICU stay., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Eli Bloch et al.)

Purpose: To investigate the natural history of optic disc pit maculopathy and explore the associations between demographic, anatomic, and functional characteristics., Design: Retrospective, comparative case series., Methods: This was a single-center medical record review of previously untreated optic disc pit maculopathy. Baseline data of visual function, demographics, and pit physiognomy were collected, and further subgroup analysis was undertaken on patients with long-term follow-up, according to whether they were monitored or received surgical intervention. LogMAR visual acuity was the primary outcome measure, and anatomic characteristics were reported where available., Results: Eighty-seven patients were identified with a new presentation of optic disc pit maculopathy. No demographic or pit features were correlated with vision at baseline. In 51 patients with available optical coherence tomography data, only the presence of subretinal fluid at baseline was associated with poorer visual acuity (P < .001). Fifty-two patients who were monitored without treatment had available long-term follow-up data. The mean change in visual acuity in this group was 0.01, with 77% maintaining visual acuity ≤0.30. Twenty-seven patients underwent surgery and showed significant postoperative improvement in vision (P < .001), with 59% achieving an acuity ≤0.30. Duration of postoperative follow-up was associated with better visual acuity (P = .007)., Conclusion: Many patients with optic disc pit maculopathy maintain good long-term visual acuity and may demonstrate resolution of subretinal fluid in the absence of surgical intervention. There may be evidence to support delaying surgical treatment until visual deterioration is observed because of the potential stability or spontaneous improvement of the condition, the high rate of reoperation, and the long-term positive outcomes of deferred intervention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The autoionization dynamics of the ( 2 P 1/2 )ns/d Rydberg states in krypton are investigated using spatially isolated wave-mixing signals generated with a short train of subfemtosecond extreme ultraviolet (XUV) pulses and noncollinear, few-cycle near infrared pulses. Despite ubiquitous quantum beat oscillations from XUV-induced coherences within the excited-state manifold, these wave-mixing spectra allow for the simultaneous evaluation of autoionization lifetimes from a series of Rydberg states above the first ionization potential. Experimentally measured lifetimes of 22 ± 8 fs, 33 ± 6 fs, and 49 ± 6 fs for the wave-mixing signals emitting from the ( 2 P 1/2 )6d/8s, ( 2 P 1/2 )7d/9s, and ( 2 P 1/2 )8d/10s resonances compare favorably with lifetimes for the ( 2 P 1/2 )6d, 7d, and 8d Rydberg states determined from spectral linewidths. Analysis of the quantum beats reveals that the enhancement of wave-mixing pathways that couple the ( 2 P 1/2 )nd states to themselves leads to individual reporter state-dependent decays in the wave-mixing signals. The results demonstrate the promise of wave-mixing spectroscopies with subfemtosecond XUV pulses to provide valuable insights into processes governed by electronic dynamics.

The development of new open shell systems is essential for advances in spin science. In this work, we report the synthesis and characterization of three nanostructured materials, namely SBA-15 silicas, periodic mesoporous organosilicas (PMOs) and lamellar polysilsesquioxanes, all functionalized with the same diazene-based phenoxyl radical precursor. The impact of the nature of the material, i.e. loading of radical precursor and structure, on half-lifetimes (t 1/2 ) and relaxation times of phenoxyl radicals was investigated. Although phenoxyl radicals are transient in solution, their t 1/2 range from hours to years at room temperature (RT) when they are embedded in nanostructured materials. The above mentioned functionalized materials were used to generate the corresponding phenoxyl radicals and their relaxation times were measured (〈T 1e 〉 and T m ) from 50 K to RT. The results were rationalized in terms of limited mobility of the radical as a result of supramolecular interactions and structure rigidity. All these data show that it is possible to design functionalized nanostructured material with radicals possessing specific electronic relaxation properties which can be of interest in fields like DNP, organic magnetism or spin qubit.

The generation of superoxide radical anion in biological systems is one of the major initiating events in the redox biology of NADPH oxidases and mitochondrial redox signalling. However, the pallette of chemical tools for superoxide detection is very limited, hampering progress in understanding the chemical biology of superoxide. Although EPR spin trapping is regarded as the most rigorous technique for superoxide detection, rapid reduction of the EPR-active superoxide spin adducts to EPR-silent hydroxylamines, or to hydroxyl radical adducts by bioreductants, significantly limits the applicability of this technique in biological systems. To overcome these limitations, in this work, we report the synthesis and characterization of a new mesoporous silica functionalized with a phosphorylated cyclic spin trap (DIPPMPO nitrone). The DIPPMPO-grafted silica is a versatile spin-trap agent enabling the identification of a wide range of carbon or oxygen-centered transient radicals in organic and in aqueous media. Moreover, superoxide was efficiently trapped under in vitro conditions in both cell-free and cellular systems. The generated superoxide adduct exhibited an exceptional half-life of 3.5 h and a resistance toward bioreductant agents such as glutathione for several hours.

Nonlinear spectroscopies are utilized extensively for selective measurements of chemical dynamics in the optical, infrared, and radio-frequency regimes. The development of these techniques for extreme ultraviolet (XUV) light sources facilitates measurements of electronic dynamics on attosecond timescales. Here, we elucidate the temporal dynamics of nonlinear signal generation by utilizing a transient grating scheme with a subfemtosecond XUV pulse train and two few-cycle near-infrared pulses in atomic helium. Simultaneous detection of multiple diffraction orders reveals delays of ≥1.5 fs in higher-order XUV signal generation, which are reproduced theoretically by solving the coupled Maxwell-Schrödinger equations and with a phase grating model. The delays result in measurable order-dependent differences in the energies of transient light induced states. As nonlinear methods are extended into the attosecond regime, the observed higher-order signal generation delays will significantly impact and aid temporal and spectral measurements of dynamic processes.

Purpose: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy., Experimental Design: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors. GZP PET imaging was performed to assess tumoral GZP uptake, and tumor volume changes were subsequently monitored to determine response. The average GZP PET uptake and response of each treatment group were correlated to evaluate the utility of GZP PET for comparing therapeutic efficacy., Results: In both tumor models, GZP PET imaging was highly accurate for predicting response, with 93% sensitivity and 94% negative predictive value. Mean tumoral GZP signal intensity of treatment groups linearly correlated with percent response across all therapies and schedules. Moreover, GZP PET correctly predicted that sequential dose scheduling of PD-1 and CTLA-4 targeted therapies demonstrates comparative efficacy to concurrent administration., Conclusions: Granzyme B quantification is a highly sensitive and specific early measure of therapeutic efficacy for checkpoint inhibitor regimens. This work provides evidence that GZP PET imaging may be useful for rapid assessment of therapeutic efficacy in the context of clinical trials for both novel drugs as well as dosing regimens., (©2018 American Association for Cancer Research.)

Retinal prosthesis systems have undergone significant advances in the past quarter century, resulting in the development of several different novel surgical and engineering approaches. Encouraging results have demonstrated partial visual restoration, with improvement in both coarse objective function and performance of everyday tasks. To date, four systems have received marketing approval for use in Europe or the United States, with numerous others undergoing preclinical and clinical evaluation, reflecting the established safety profile of these devices for chronic implantation. This progress represents the first notion that the field of visual restorative medicine could offer blind patients a hope of real and measurable benefit. However, there are numerous complex engineering and biophysical obstacles still to be overcome, to reconcile the gap that remains between artificial and natural vision. Current developments in the form of enhanced image processing algorithms and data transfer approaches, combined with emerging nanofabrication and conductive polymerization techniques, herald an exciting and innovative future for retinal prosthetics. This review provides an update of retinal prosthetic systems currently undergoing development and clinical trials while also addressing future challenges in the field, such as the assessment of functional outcomes in ultra-low vision and strategies for tackling existing hardware and software constraints., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Access to a safe, adequate blood supply has proven challenging in sub-Saharan Africa, where systemic deficiencies spanning policy, collections, testing, and posttransfusion surveillance have long been recognized. Progress in transfusion safety in the early 2000s was in large part due to intervention by the World Health Organization and other foreign governmental bodies, coupled with an influx of external funding., Study Design and Methods: A review of the literature was conducted to identify articles pertaining to blood safety in sub-Saharan Africa from January 2009 to March 2018. The search was directed toward addressing the major elements of the blood safety chain, in the countries comprising the World Health Organization African region. Of 1380 articles, 531 met inclusion criteria and 136 articles were reviewed., Results: External support has been associated with increased recruitment of voluntary donors and expanded testing for the major transfusion-transmitted infections (TTIs). However, the rates of TTIs among donors remain high. Regional education and training initiatives have been implemented, and a tiered accreditation process has been adopted. However, a general decline in funding for transfusion safety (2009 onwards) has strained the ability to maintain or improve transfusion-related services. Critical areas of need include data collection and dissemination, epidemiological surveillance for TTIs, donor recruitment, quality assurance and oversight (notably laboratory testing), and hemovigilance., Conclusion: Diminishing external support has been challenging for regional transfusion services. Critical areas of deficiency in regional blood transfusion safety remain. Nonetheless, substantive gains in education, training, and accreditation suggest durable gains in regional capacity., (© 2018 AABB.)

Nonlinear multidimensional spectroscopy is ubiquitous in the optical and radio frequency regions as a powerful tool to access structure and dynamics. The extension of this technique into the extreme ultraviolet (XUV) region with attosecond pulses holds promise for probing electronic dynamics and correlations with unprecedented time and spatial resolution. In this work, we use noncollinear four-wave mixing of a weak XUV attosecond pulse train (11-17 eV) and few-femtosecond NIR pulses (800 nm) to spectroscopically and dynamically probe the dipole-forbidden double-well potential of the a'' 1∑+g electronic state of nitrogen. The results demonstrate optical coupling of the inner and outer limits of the initial XUV-prepared vibrational wave packet in the valence character b' 1∑+u state to the inner and outer wells, respectively, of the a'' 1∑+g double well state by 800 nm light. Two four-wave mixing schemes with different pulse timing sequences and noncollinear beam geometries are used (one NIR pulse collinear and one NIR pulse noncollinear versus both NIR pulses noncollinear to the XUV beam) to measure the a'' dark state energetic structure and to control the dynamical preparation and motion of a dark state wave packet by selective population of either the inner Rydberg or outer valence-character potential well. Experimental measurements of the a'' 1∑+g outer well vibrational spacing and anharmonicity closely match the values theoretically predicted for this previously unobserved state.

The fast and accurate analysis of chiral chemical mixtures is crucial for many applications but remains challenging. Here we use elliptically-polarized femtosecond laser pulses at high repetition rates to photoionize chiral molecules. The 3D photoelectron angular distribution produced provides molecular fingerprints, showing a strong forward-backward asymmetry which depends sensitively on the molecular structure and degree of ellipticity. Continuously scanning the laser ellipticity and analyzing the evolution of the rich, multi-dimensional molecular signatures allows us to observe real-time changes in the chemical and chiral content present with unprecedented speed and accuracy. We measure the enantiomeric excess of a compound with an accuracy of 0.4% in 10 min acquisition time, and follow the evolution of a mixture with an accuracy of 5% with a temporal resolution of 3 s. This method is even able to distinguish isomers, which cannot be easily distinguished by mass-spectrometry.

Tremendous efforts are currently dedicated to the development of novel therapies targeting the androgen receptor (AR), the major driver of prostate cancer disease and its progression to castration resistance. The ability to noninvasively interrogate AR expression over time in murine models of prostate cancer would permit longitudinal preclinical analysis of novel compounds that could not otherwise be accomplished ex vivo. Although PET imaging with 16β- 18 F-fluoro-5α-dihydrotestosterone ( 18 F-FDHT) has successfully quantified AR levels clinically, no rodent model of 18 F-FDHT imaging has been reported so far. One difference between humans and rodents is the absence in the latter of the sex hormone-binding globulin (SHBG), a glycoprotein that binds to testosterone in the bloodstream, Here, we explore the role of SHBG in developing a working model of rodent AR imaging. Methods: Three human prostate cancer cell lines and xenografts (LNCaP, 22Rv1, and PC3) were used to examine the uptake of free 18 F-FDHT and SHBG-bound 18 F-FDHT. Both ligands were examined for stability and competitive binding to AR over time in vitro before in vivo studies. PET/CT imaging was used to dynamically measure the uptake of both tracers over 4 h, whereas specificity was determined by competitive binding with the AR antagonist enzalutamide. Results: AR levels correlated with the uptake of both 18 F-FDHT and SHBG- 18 F-FDHT in prostate cancer cell lines. Interestingly, whereas both free and SHBG-bound 18 F-FDHT had a similar cellular accumulation at 1 and 2.5 h, SHBG- 18 F-FDHT accumulated at significantly higher levels after 4 h-evidence that receptor-mediated uptake of SHBG accounted for later time-point differences. This observation was also seen in 22Rv1 tumor-bearing mice, in which SHBG- 18 F-FDHT exhibited a significantly increased uptake (average tumor-to-background ratio [TBR], 1.62 ± 0.62) in comparison to unbound 18 F-FDHT (TBR, 0.81 ± 0.08) at 4 h. Furthermore, the specificity of the SHBG- 18 F-FDHT accumulation at 4 h was demonstrated by a reduced tumor uptake after AR blockade with enzalutamide (TBR, 1.07 ± 0.13). Conclusion: Prebinding of 18 F-FDHT to SHBG allows accurate and quantitative PET imaging of AR levels in murine models of prostate cancer. This procedure may permit the use of PET imaging to study the longitudinal effects of AR-targeting therapies, accelerating novel-drug development., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Overexpression and deregulation of the epidermal growth factor receptor (EGFR) are implicated in multiple human cancers and therefore are a focus for the development of therapeutics. Current strategies aimed at inhibiting EGFR activity include monoclonal antibodies and tyrosine kinase inhibitors. However, activating mutations severely limit the efficacy of these therapeutics. There is thus a growing need for novel methods to inhibit EGFR. One promising approach involves blocking the association of the cytoplasmic juxtamembrane (JM) domain of EGFR, which has been shown to be essential for receptor dimerization and kinase function. Here, we aim to improve the selectivity and efficacy of an EGFR JM peptide mimic by utilizing the pH(low) insertion peptide (pHLIP), a unique molecule that can selectively target cancer cells solely based on their extracellular acidity. This delivery strategy potentially allows for more selective targeting to tumors than current methods and for anchoring the peptide mimic to the cytoplasmic leaflet of the plasma membrane, increasing its local concentration and thus efficacy. We show that the conjugated construct is capable of inhibiting EGFR phosphorylation and downstream signaling and of inducing concentration- and pH-dependent toxicity in cervical cancer cells. We envision that this approach could be expanded to the modulation of other single-span membrane receptors whose activity is mediated by JM domains.

Background and Objectives: Babesia spp. are tick-borne, intraerythrocytic protozoan parasites, several of which are transfusion-transmissible. Transfusion-transmitted babesiosis poses serious risk to a diverse patient population, including neonates, patients aged >50 years, the asplenic and the immunocompromised that are over-represented among transfusion recipients. Despite reports of B. microti and B. venatorum in People's Republic of China (PRC), no surveillance of blood donors for Babesia has previously been undertaken. We sought to determine the rates of B. microti seroreactivity in a sample of blood donors in the PRC., Materials and Methods: A pilot serosurvey was conducted of community blood donors (n = 1000) who donated July-August 2016 at Mudanjiang Blood Center (Heilongjiang Province) using indirect fluorescent antibody testing for antibodies against B. microti. The slides were prepared using B. microti-infected hamster blood. Samples that were initially positive to a titre of 64 were subjected to repeat IFA testing. Final seroreactivity was based on repeat reactivity to ≥64., Results: A total of 1000 individual donor samples were evaluated, comprising 888 whole blood and 112 platelet donations. Thirteen of 1000 (1·3%) donors were seroreactive for B. microti [8 (0·8%) and five (0·05%) at titres of 64 and 128, respectively]., Conclusion: Our preliminary findings support the need for expanded Babesia surveillance in Chinese blood donors, replete with molecular evaluation, to evaluate the risk to the blood supply., (© 2018 International Society of Blood Transfusion.)

Purpose: To examine the efficacy and safety of combined phacoemulsification and endoscopic cyclophotocoagulation (phaco-ECP) compared to phacoemulsification alone in patients with primary open-angle glaucoma (POAG)., Methods: We performed a retrospective notes review of 99 consecutive clinical records of patients with POAG from 2 London eye departments. A total of 69 patients who underwent phaco-ECP and 30 sex- and age-matched control patients who underwent cataract surgery alone were included. Data on intraocular pressure (IOP), visual acuity (VA), number of ocular hypotensive medications, and postoperative complications were collected over 12 months. The primary outcome measure was defined as an IOP within normal limits (<21 mm Hg) and at least a 20% reduction in IOP from baseline., Results: Mean IOP was significantly decreased in both groups after 1 year (p<0.001 from baseline). The success rate was significantly higher in the phaco-ECP group (69.6%) than in the phaco group (40%) after 1 year (p = 0.004). Reduction in mean IOP and number of medications was also greater in the phaco-ECP group after 1 year (IOP reduction: 4.5 ± 5.13 mm Hg vs 1.83 ± 3.61 mm Hg; p = 0.007; number of medications reduction: 0.73 ± 0.71 vs 0.23 ± 0.56; p = 0.001). Both groups achieved a similar improvement in VA. There was a higher incidence of minor and self-limiting complications in the phaco-ECP group (p<0.047)., Conclusions: Phaco-ECP resulted in a greater reduction in IOP and number of medications than phacoemulsification alone in POAG.

Purpose: Pigmentary maculopathy can occur in the context of various inherited and acquired diseases. Anterior segment dysgenesis arises due to developmental anomalies and may be associated with systemic disease, as in Rieger syndrome., Case Report: A 49-year-old woman presented with longstanding reduction in vision, evidence of anterior segment dysgenesis, and multiple discrete pigmented lesions throughout the macula bilaterally. Electroretinographic findings were consistent with severe macular dysfunction. Gene array analysis did not reveal any chromosomal imbalances or other specific abnormalities., Conclusions: This is a unique case of bilateral pigmentary maculopathy and anterior segment dysgenesis, with clinical findings that are not characteristic of previously reported disease.

Transfusion-transmitted infection risk remains an enduring challenge to blood safety in Africa. A high background incidence and prevalence of the major transfusion-transmitted infections (TTIs), dependence on high-risk donors to meet demand, suboptimal testing and quality assurance collectively contribute to the increased risk. With few exceptions, donor testing is confined to serological evaluation of human immunodeficiency virus (HIV), hepatitis B and C (HBV and HCV) and syphilis. Barriers to implementation of broader molecular methods include cost, limited infrastructure and lack of technical expertise. Pathogen reduction (PR), a term used to describe a variety of methods (e.g. solvent detergent treatment or photochemical activation) that may be applied to blood following collection, offers the means to diminish the infectious potential of multiple pathogens simultaneously. This is effective against different classes of pathogen, including the major TTIs where laboratory screening is already implemented (e.g. HIV, HBV and HCV) as well pathogens that are widely endemic yet remain unaddressed (e.g. malaria, bacterial contamination). We sought to review the available and emerging PR techniques and their potential application to resource-constrained parts of Africa, focusing on the advantages and disadvantages of such technologies. PR has been slow to be adopted even in high-income countries, primarily given the high costs of use. Logistical considerations, particularly in low-resourced parts of Africa, also raise concerns about practicality. Nonetheless, PR offers a rational, innovative strategy to contend with TTIs; technologies in development may well present a viable complement or even alternative to targeted screening in the future., (© 2017 International Society of Blood Transfusion.)

Plasmablastic lymphoma is an unusual and aggressive form of diffuse large B-cell lymphoma, which arises more commonly within the oronasal mucosa. It should be considered as a differential diagnosis for rapidly growing periorbital lesions, particularly in the context of HIV positivity.