The UK clinical eye research strategy: refreshing research priorities for clinical eye research in the UK.

OBJECTIVES: To validate and update the 2013 James Lind Alliance (JLA) Sight Loss and Vision Priority Setting Partnership (PSP)'s research priorities for Ophthalmology, as part of the UK Clinical Eye Research Strategy. METHODS: Twelve ophthalmology research themes were identified from the JLA report. They were allocated to five Clinical Study Groups of diverse stakeholders who reviewed the top 10 research priorities for each theme. Using an online survey (April 2021-February 2023), respondents were invited to complete one or more of nine subspecialty surveys. Respondents indicated which of the research questions they considered important and subsequently ranked them. RESULTS: In total, 2240 people responded to the survey (mean age, 59.3 years), from across the UK. 68.1% were female. 68.2% were patients, 22.3% healthcare professionals or vision researchers, 7.1% carers, and 2.1% were charity support workers. Highest ranked questions by subspecialty: Cataract (prevention), Cornea (improving microbial keratitis treatment), Optometric (impact of integration of ophthalmic primary and secondary care via community optometric care pathways), Refractive (factors influencing development and/or progression of refractive error), Childhood onset (improving early detection of visual disorders), Glaucoma (effective and improved treatments), Neuro-ophthalmology (improvements in prevention, diagnosis and treatment of neurodegeneration affecting vision), Retina (improving prevention, diagnosis and treatment of dry age-related macular degeneration), Uveitis (effective treatments for ocular and orbital inflammatory diseases). CONCLUSIONS: A decade after the initial PSP, the results refocus the most important research questions for each subspecialty, and prime targeted research proposals within Ophthalmology, a chronically underfunded specialty given the substantial burden of disability caused by eye disease.

Enhancing Ophthalmic Triage: identification of new clinical features to support healthcare professionals in triage.

OBJECTIVE: To investigate which features from a patient's history are either high or low risk that could support healthcare professionals in ophthalmic emergency triage. METHODS: Prospective, 12,584 visits from 11,733 adult patients attending an Accident and Emergency department at a single tertiary centre were analysed. Data were collected by ophthalmic nurses working in triage, using an online form from August 2021 to April 2022. Multivariate analysis (MVA) was conducted to identify which features from the patients' history would be associated with emergency care. RESULTS: This study found that 45.5% (5731 patient visits (PV)) required a same day eye emergency examination (SDEE), 11.3% (1416 PV) needed urgent care, and 43.2% (5437 PV) were appropriate for elective consultations with a GP or optometrist. The MVA top ten features that were statistically significant (p < 0.05) that would warrant SDEE with odds ratio (95% CI) were: bilateral eye injury 36.5 [15.6-85.5], unilateral eye injury 25.8 [20.9-31.7], vision loss 4.8 [2.9-7.8], post-operative ophthalmic ( < 4 weeks) 4.6 [3.8-5.7], contact lens wearer 3.9 [3.3-4.7], history of uveitis 3.9 [3.3-4.7], photophobia 2.9 [2.4-3.6], unilateral dark shadow/curtain in vision 2.4 [1.8-3.0], unilateral injected red eye 2.0 [1.8-2.2] and rapid change in visual acuity 1.8 [1.5-2.2]. CONCLUSION: This study characterises presenting features covering almost 100 ophthalmic acute presentations that are commonly seen in emergency and elective care. This information could supplement current red flag indicators and support healthcare professionals in ophthalmic triage. Further research is required to evaluate the cost effectivity and safety of our findings for triaging acute presentations.

Using genetics to investigate the association between lanosterol and cataract.

Background: Cataract is one of the most prevalent causes of blindness worldwide. Whilst surgery is the primary treatment for cataracts, it is not always an available option, particularly in developing countries. Non-surgical methods of treatment would increase treatment availability for more patients. Several studies have investigated how topical application of oxysterols, such as lanosterol, may break down aggregated proteins and restore lens transparency. However, the results are conflicting and inconclusive. Aim: In this study, we focus on combining genetic evidence for associations between lanosterol related genetic variation and cataract to explore whether lanosterol is a potentially suitable drug treatment option. Method: Using data from 45,449 available cataract cases from the UK Biobank, with participant ages ranging from 40-69, we conducted a genetic association study (GWAS) to assess the risk of cataract. Cataract cases were defined using diagnostic and operation codes. We focused on genetic variants in the lanosterol synthase gene region. We also compared our results with previously published genetic associations of phytosterol-to-lanosterol ratios. Finally, we performed a genetic risk score analysis to test the association between lanosterol within the cholesterol synthesis pathway and the risk of cataract. Results: No statistically significant single nucleotide polymorphisms (SNPs) associations with cataract were observed in the gene region of lanosterol synthase at a multiple testing adjusted significance threshold of p < 0.05/13. The comparison between cataract risk and genetic association of 8 phytosterol-to-lanosterol GWAS results also showed no evidence to support lanosterol's protective properties for cataract risk. No statistically significant association was found between the lanosterol within the cholesterol synthesis pathway genetic risk score and cataract outcomes (OR = 1.002 p = 0.568). Conclusion: There was no evidence observed for genetic associations between lanosterol and cataract risk. Our results do not support lanosterol's potential role in treating cataracts. Further research may be needed to address the effect of lanosterol on specific cataract subtypes.

A machine learning system to optimise triage in an adult ophthalmic emergency department: a model development and validation study.

Background: A substantial proportion of attendances to ophthalmic emergency departments are for non-urgent presentations. We developed and evaluated a machine learning system (DemDx Ophthalmology Triage System: DOTS) to optimise triage, with the aim of reducing inappropriate emergency attendances and streamlining case referral when necessary. Methods: DOTS was built using retrospective tabular data from 11,315 attendances between July 1st, 2021, to June 15th, 2022 at Moorfields Eye Hospital Emergency Department (MEH) in London, UK. Demographic and clinical features were used as inputs and a triage recommendation was given ("see immediately", "see within a week", or "see electively"). DOTS was validated temporally and compared with triage nurses' performance (1269 attendances at MEH) and validated externally (761 attendances at the Federal University of Minas Gerais - UFMG, Brazil). It was also tested for biases and robustness to variations in disease incidences. All attendances from patients aged at least 18 years with at least one confirmed diagnosis were included in the study. Findings: For identifying ophthalmic emergency attendances, on temporal validation, DOTS had a sensitivity of 94.5% [95% CI 92.3-96.1] and a specificity of 42.4% [38.8-46.1]. For comparison within the same dataset, triage nurses had a sensitivity of 96.4% [94.5-97.7] and a specificity of 25.1% [22.0-28.5]. On external validation at UFMG, DOTS had a sensitivity of 95.2% [92.5-97.0] and a specificity of 32.2% [27.4-37.0]. In simulated scenarios with varying disease incidences, the sensitivity was ≥92.2% and the specificity was ≥36.8%. No differences in sensitivity were found in subgroups of index of multiple deprivation, but the specificity was higher for Q2 when compared to Q4 (Q4 is less deprived than Q2). Interpretation: At MEH, DOTS had similar sensitivity to triage nurses in determining attendance priority; however, with a specificity of 17.3% higher, DOTS resulted in lower rates of patients triaged to be seen immediately at emergency. DOTS showed consistent performance in temporal and external validation, in social-demographic subgroups and was robust to varying relative disease incidences. Further trials are necessary to validate these findings. This system will be prospectively evaluated, considering human-computer interaction, in a clinical trial. Funding: The Artificial Intelligence in Health and Care Award (AI_AWARD01671) of the NHS AI Lab under National Institute for Health and Care Research (NIHR) and the Accelerated Access Collaborative (AAC).

Usability of an artificially intelligence-powered triage platform for adult ophthalmic emergencies: a mixed methods study.

There is growing demand for emergency-based eyecare services where the majority of those attending do not require urgent ophthalmic management. The Royal College of Ophthalmologists have recommended upskilling and supporting of allied health professionals to support eyecare delivery, where machine learning algorithms could help. A mixed methods study was conducted to evaluate the usability of an artificial intelligence (AI) powered online triage platform for ophthalmology. The interface, usability, safety and acceptability were investigated using a Think Aloud interview and usability questionnaires. Twenty participants who actively examine patients in ophthalmic triage within a tertiary eye centre or primary care setting completed the interview and questionnaires. 90% or more of participants found the platform easy to use, reflected their triage process and were able to interpret the triage outcome, 85% found it safe to use and 95% felt the processing time was fast. A quarter of clinicians reported that they have experienced some uncertainty when triaging in their career and were unsure of using AI, after this study 95% of clinicians were willing to use the platform in their clinical workflow. This study showed the platform interface was acceptable and usable for clinicians actively working in ophthalmic emergency triage.

Perspectives and experiences of the first geriatricians trained in Canada.

Many Canadian-trained geriatricians from the subspecialty's first decade of existence continue to practice today. The objective of this study was to examine the experiences and perspectives of the earliest cohort of geriatricians in Canada. Using qualitative description method, we conducted semi-structured interviews to explore participants' experiences in training and practice. We included geriatricians who trained in Canada between 1980-1989 and were in active clinical practice as of October 2021. Each transcript was coded independently by two investigators. Thematic analysis was used to develop key themes. Fourteen participants (43% female, mean years in practice 35.9) described their choice to enter geriatric medicine, their training process, the roles of a geriatrician, challenges facing the profession and advice for trainees. Two themes were developed from the data: (i) advocacy for the older adult and (ii) geriatrics as "the road less taken". Advocacy was described as the "core mission" of a geriatrician. Participants discussed the importance of advocacy in clinical practice, education, research and disseminating geriatric principles in the health system and society. "The road less taken" reflected the challenges participants faced during training, which led to relatively few geriatricians for the growing number of older adults in Canada. Despite these challenges, participants described rewarding careers and encouraged trainees to consider the profession.

Incidence of Microfolds Using a Standardized Three-Stage LASIK Flap Replacement Protocol.

PURPOSE: To describe a standardized three-stage flap replacement protocol and report the incidence of microfolds after femtosecond laser-assisted laser in situ keratomileusis (LASIK) surgery. METHODS: A retrospective analysis of 14,374 consecutive LASIK procedures with the VisuMax femtosecond laser (Carl Zeiss Meditec) by two surgeons was conducted. As per the standardized procedure, all eyes underwent the three-stage flap replacement protocol consisting of controlled standardized minimal irrigation and flap repositioning after ablation, followed by fluorescein-controlled slit-lamp adjustments and slit-lamp adjustments on day 1 (if required). Microfold incidence was recorded at all subsequent visits and recorded by independent observers classified using a standardized 6-point grading system including whether they were refractively or visually significant. RESULTS: Flap thickness used was 80 to 89 µm (7.2%), 90 to 99 µm (51.7%), 100 to 109 µm (17.8%), and 110 to 130 µm (23.2%). Slit-lamp adjustment at day 1 was performed in 956 eyes (6.77%), with the highest incidence in 80 to 89 µm flaps (27.6%). A flap slip occurred in 23 eyes (0.16%) and was managed at the slit lamp for 21 eyes and in the operating room for 2 eyes. At 3 months after surgery, trace microfolds were present in 158 eyes (1.10%), grade 1 in 26 eyes (0.184%), and grade 2 in 2 eyes (0.016%). Grade 1 microfold incidence per flap thickness group was 39.1% for 80 to 89 µm, 30.4% for 90 to 99 µm, 13% for 100 to 109 µm, and 17.4% for 110 to 130 µm. No eyes required a flap lift for microfolds in the operating room. Multivariate regression analysis found microfold incidence to be higher for thinner flaps, higher correction, and larger optical zone. CONCLUSIONS: The three-stage protocol for flap positioning and management resulted in a low incidence of clinically visible microfolds and no visually significant microfolds. Day 1 slit-lamp adjustment was required more frequently in ultra-thin 80 to 89 µm flaps. [J Refract Surg. 2023;39(6):388-396.].

Laser-assisted cataract surgery versus standard ultrasound phacoemulsification cataract surgery.

BACKGROUND: Cataract is the leading cause of blindness in the world and, as such, cataract surgery is one of the most commonly performed operations globally. Surgical techniques have changed dramatically over the past half century with associated improvements in outcomes and safety. Femtosecond lasers can be used to perform the key steps in cataract surgery, such as corneal incisions, lens capsulotomy and fragmentation. The potential advantage of femtosecond laser-assisted cataract surgery (FLACS) is greater precision and reproducibility of these steps compared to manual techniques. The disadvantages are the costs associated with FLACS technology. OBJECTIVES: To compare the effectiveness and safety of FLACS with standard ultrasound phacoemulsification cataract surgery (PCS) by gathering evidence from randomised controlled trials (RCTs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov; the WHO ICTRP and the US Food and Drug Administration (FDA) website. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 May 2022. SELECTION CRITERIA: We included RCTs where FLACS was compared to PCS. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the search results, assessed risk of bias and extracted data using the standard methodological procedures expected by Cochrane. The primary outcome for this review was intraoperative complications in the operated eye, namely anterior capsule, and posterior capsule tears. The secondary outcomes included corrected distance visual acuity (CDVA), quality of vision (as measured by any validated patient-reported outcome measure (PROM)), postoperative cystoid macular oedema complications, endothelial cell loss and cost-effectiveness. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 42 RCTs conducted in Europe, North America, South America and Asia, which enrolled a total of 7298 eyes of 5831 adult participants. Overall, the studies were at unclear or high risk of bias. In 16 studies the authors reported financial links with the manufacturer of the laser platform evaluated in their studies. Thirteen of the studies were within-person (paired-eye) studies with one eye allocated to one procedure and the other eye allocated to the other procedure. These studies were reported ignoring the paired nature of the data. There was low-certainty evidence of little or no difference in the odds of developing anterior capsular tears when comparing FLACS and PCS (Peto odds ratio (OR) 0.83, 95% confidence interval (CI) 0.40 to 1.72; 5835 eyes, 27 studies) There was one fewer anterior capsule tear per 1000 operations in the FLACS group compared with the PCS group (95% CI 4 fewer to 3 more).  There was low-certainty evidence of lower odds of developing posterior capsular tears with FLACS compared to PCS (Peto OR 0.50, 95% CI 0.25 to 1.00; 5767 eyes, 26 studies). There were four fewer posterior capsule tears per 1000 operations in the FLACS group compared with the PCS group (95% CI 6 fewer to same).  There was moderate-certainty evidence of a very small advantage for the FLACS arm with regard to CDVA at six months or more follow-up, (mean difference (MD) -0.01 logMAR, 95% CI -0.02 to 0.00; 1323 eyes, 7 studies). This difference is equivalent to 1 logMAR letter between groups and is not thought to be clinically important. From the three studies (1205 participants) reporting a variety of PROMs (Cat-PROMS, EQ-5D, EQ-SD-3L, Catquest9-SF and patient survey) up to three months following surgery, there was moderate-certainty evidence of little or no difference in the various parameters between the two treatment arms. There was low-certainty evidence of little or no difference in the odds of developing cystoid macular oedema when comparing FLACS and PCS (Peto OR 0.84, 95% CI 0.56 to 1.28; 4441 eyes, 18 studies). There were three fewer cystoid macular oedema cases per 1000 operations in the FLACS group compared with the PCS group (95% CI 10 fewer to 6 more).  In one study the incremental cost-effectiveness ratio (ICER) (cost difference divided by quality-adjusted life year (QALY) difference) was GBP £167,620 when comparing FLACS to PCS. In another study, the ICER was EUR €10,703 saved per additional patient who had treatment success with PCS compared to FLACS. Duration ranged from three minutes in favour of FLACS to eight minutes in favour of PCS (I2 = 100%, 11 studies) (low-certainty evidence).  There was low-certainty evidence of little or no important difference in endothelial cell loss when comparing FLACS with PCS (MD 12 cells per mm2 in favour of FLACS, 95% CI -40 to 64; 1512 eyes, 10 studies).  AUTHORS' CONCLUSIONS: This review of 42 studies provides evidence that there is probably little or no difference between FLACS and PCS in terms of intraoperative and postoperative complications, postoperative visual acuity and quality of life. Evidence from two studies suggests that FLACS may be the less cost-effective option. Many of the included studies only investigated very specific outcome measures such as effective phacoemulsification time, endothelial cell count change or aqueous flare, rather than those directly related to patient outcomes. Standardised reporting of complications and visual and refractive outcomes for cataract surgery would facilitate future synthesis, and guidance on this has been recently published.

ANTECEDENTES: La catarata es la principal causa de ceguera en el mundo y, como tal, la cirugía de cataratas es una de las operaciones más realizadas en todo el mundo. Las técnicas quirúrgicas han cambiado radicalmente en el último medio siglo, con las consiguientes mejoras en los desenlaces y la seguridad. Los láseres de femtosegundo se pueden utilizar para realizar los pasos clave de la cirugía de cataratas, como las incisiones corneales, la capsulotomía y la fragmentación del cristalino. La ventaja potencial de la cirugía de cataratas asistida por láser de femtosegundo (FLACS por sus siglas en inglés) es la mayor precisión y reproducibilidad de estos pasos en comparación con las técnicas manuales. Las desventajas son los costes asociados con la tecnología FLACS. OBJETIVOS: Comparar la eficacia y la seguridad de la FLACS con la cirugía de cataratas estándar por facoemulsificación (PCS) con ultrasonido mediante la recopilación de evidencia de ensayos controlados aleatorizados (ECA). MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials [CENTRAL]; que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]; 2022, número 5); en Ovid MEDLINE; Ovid Embase; LILACS; el registro ISRCTN; ClinicalTrials.gov; la ICTRP de la OMS y el sitio web de la Food and Drug Administration (FDA) de los EE. UU. No se aplicaron restricciones de fecha ni de idioma en las búsquedas electrónicas de ensayos. La última búsqueda en las bases de datos electrónicas se realizó el 10 de mayo de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron los ECA en los que la FLACS se comparó con la PCS. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Tres autores de la revisión examinaron de forma independiente los resultados de la búsqueda, evaluaron el riesgo de sesgo y extrajeron los datos mediante los procedimientos metodológicos estándar previstos por Cochrane. El desenlace principal de esta revisión fueron las complicaciones intraoperatorias en el ojo operado, concretamente, desgarros de la cápsula anterior y posterior. Los desenlaces secundarios incluyeron la agudeza visual corregida a distancia (AVCD), la calidad de la visión (medida por cualquier medida de desenlace notificada por el paciente [PROM] validada), las complicaciones posoperatorias del edema macular cistoide, la pérdida de células endoteliales y la coste­efectividad. La certeza de la evidencia se evaluó mediante el método GRADE. RESULTADOS PRINCIPALES: Se incluyeron 42 ECA realizados en Europa, Norteamérica, Sudamérica y Asia, que reclutaron un total de 7298 ojos de 5831 participantes adultos. En general, los estudios tuvieron riesgo de sesgo incierto o alto. En 16 estudios, los autores informaron vínculos financieros con el fabricante de la plataforma láser evaluada en sus estudios. Trece de los estudios fueron estudios intrapersonales (ojo pareado) con un ojo asignado a un procedimiento y el otro ojo asignado al otro procedimiento. El informe de estos estudios no consideró la naturaleza pareada de los datos. Hubo evidencia de certeza baja de poca o ninguna diferencia en las probabilidades de desarrollar desgarros de la cápsula anterior al comparar FLACS y PCS (odds ratio [OR] de Peto 0,83; intervalo de confianza [IC] del 95%: 0,40 a 1,72; 5835 ojos, 27 estudios). Hubo un desgarro de la cápsula anterior menos por cada 1000 cirugías en el grupo de FLACS en comparación con el grupo de PCS (IC del 95%: 4 menos a 3 más).  Hubo evidencia de certeza baja de menores probabilidades de desarrollar desgarros de la cápsula posterior con FLACS en comparación con PCS (OR de Peto 0,50; IC del 95%: 0,25 a 1,00; 5767 ojos, 26 estudios). Hubo cuatro desgarros de la cápsula posterior menos por cada 1000 cirugías en el grupo de FLACS en comparación con el grupo de PCS (IC del 95%: 6 menos a igual).  Hubo evidencia de certeza moderada de una ventaja muy pequeña en el grupo de FLACS con respecto a la AVCD a los seis meses o más de seguimiento, (diferencia de medias [DM] ­0,01 logMAR; IC del 95%: ­0,02 a 0,00; 1323 ojos, siete estudios). Esta diferencia equivale a 1 letra logMAR entre los grupos y no se considera clínicamente importante. De los tres estudios (1205 participantes) que informaron sobre una variedad de PROM (Cat­PROMS, EQ­5D, EQ­SD­3L, Catquest9­SF y encuesta de pacientes) hasta tres meses después de la cirugía, hubo evidencia de certeza moderada de poca o ninguna diferencia en los diversos parámetros entre los dos grupos de tratamiento. Hubo evidencia de certeza baja de poca o ninguna diferencia en las probabilidades de desarrollar edema macular cistoide al comparar FLACS y PCS (OR de Peto 0,84; IC del 95%: 0,56 a 1,28; 4441 ojos, 18 estudios). Hubo tres casos menos de edema macular cistoide por cada 1000 cirugías en el grupo de FLACS en comparación con el grupo de PCS (IC del 95%: 10 menos a 6 más).  En un estudio, el cociente coste­efectividad incremental (ICER) (diferencia de coste dividida por la diferencia de años de vida ajustados por la calidad [AVAC]) fue de 167 620 GBP al comparar FLACS con SCP. En otro estudio, el ICER fue de 10 703 euros ahorrados por paciente adicional que tuvo un tratamiento exitoso con PCS en comparación con FLACS. La duración varió entre tres minutos a favor de FLACS y ocho minutos a favor de PCS (I 2 = 100%, 11 estudios) (evidencia de certeza baja).  Hubo evidencia de certeza baja de poca o ninguna diferencia importante en la pérdida de células endoteliales al comparar la FLACS con la PCS (DM 12 células por mm 2 a favor de la FLACS; IC del 95%: ­40 a 64; 1512 ojos, 10 estudios).  CONCLUSIONES DE LOS AUTORES: Esta revisión de 42 estudios aporta evidencia de que probablemente haya poca o ninguna diferencia entre la FLACS y la PCS en cuanto a las complicaciones intraoperatorias y posoperatorias, la agudeza visual posoperatoria y la calidad de vida. La evidencia de dos estudios indica que la FLACS podría ser la opción menos coste­efectiva. Muchos de los estudios incluidos solo investigaron medidas de desenlace muy específicas, como el tiempo efectivo de facoemulsificación, el cambio en el recuento de células endoteliales o el brote acuoso, en lugar de las directamente relacionadas con los desenlaces de los pacientes. La notificación estandarizada de las complicaciones y los desenlaces visuales y refractarios de la cirugía de cataratas facilitaría la síntesis futura, y recientemente se han publicado guías al respecto.

Rapid and sensitive detection of miRNA via light scatter-aided emulsion-based isothermal amplification using a custom low-cost device.

MicroRNAs are likely to be a next-generation clinical biomarker for many diseases. While gold-standard technologies, e.g., reverse transcription-quantitative polymerase chain reaction (RT-qPCR), exist for microRNA detection, there is a need for rapid and low-cost testing. Here, an emulsion loop-mediated isothermal amplification (eLAMP) assay was developed for miRNA that compartmentalizes a LAMP reaction and shortens the time-to-detection. The miRNA was a primer to facilitate the overall amplification rate of template DNA. Light scatter intensity decreased when the emulsion droplet got smaller during the ongoing amplification, which was utilized to moitor the amplification non-invasively. A custom low-cost device was designed and fabricated using a computer cooling fan, a Peltier heater, an LED, a photoresistor, and a temperature controller. It allowed more stable vortexing and accurate light scatter detection. Three miRNAs, miR-21, miR-16, and miR-192, were successfully detected using the custom device. Specifically, new template and primer sequences were developed for miR-16 and miR-192. Zeta potential measurements and microscopic observations confirmed emulsion size reduction and amplicon adsorption. The detection limit was 0.01 fM, corresponding to 2.4 copies per reaction, and the detection could be made in 5 min. Since the assays were rapid and both template and miRNA + template could eventually be amplified, we introduced the success rate (compared to the 95% confidence interval of the template result) as a new measure, which worked well with lower concentrations and inefficient amplifications. This assay brings us one step closer to allowing circulating miRNA biomarker detection to become commonplace in the clinical world.

Attitudes Towards Treatment as Prevention Among PrEP-Experienced Gay and Bisexual Men in Australia.

The introduction of HIV pre-exposure prophylaxis (PrEP) has the potential to impact the attitudes gay and bisexual men (GBM) who consequently choose to take PrEP have towards treatment as prevention (TasP), and the extent to which they are willing to have condomless anal intercourse (CLAI) with an HIV-positive sexual partner who has an undetectable viral load (UVL). Using a cross-sectional sample from an observational cohort study conducted from August 2018 to March 2020, we examined the extent to which PrEP-experienced GBM are willing to have CLAI with a partner who has a UVL. Simple and multiple logistic regression models were used to identify associated variables. Of the 1386 participants included in the analyses, 79.0% believed in the effectiveness of TasP, and 55.3% were willing to have CLAI with a partner who has a UVL. Wiling participants were less worried about getting HIV when taking PrEP and more likely to believe in TasP. Further research is needed to better understand the gap between belief in TasP and willingness to have CLAI with a partner who has a UVL among PrEP-experienced GBM.

Small molecule inhibitors of 15-PGDH exploit a physiologic induced-fit closing system.

15-prostaglandin dehydrogenase (15-PGDH) is a negative regulator of tissue stem cells that acts via enzymatic activity of oxidizing and degrading PGE2, and related eicosanoids, that support stem cells during tissue repair. Indeed, inhibiting 15-PGDH markedly accelerates tissue repair in multiple organs. Here we have used cryo-electron microscopy to solve the solution structure of native 15-PGDH and of 15-PGDH individually complexed with two distinct chemical inhibitors. These structures identify key 15-PGDH residues that mediate binding to both classes of inhibitors. Moreover, we identify a dynamic 15-PGDH lid domain that closes around the inhibitors, and that is likely fundamental to the physiologic 15-PGDH enzymatic mechanism. We furthermore identify two key residues, F185 and Y217, that act as hinges to regulate lid closing, and which both inhibitors exploit to capture the lid in the closed conformation, thus explaining their sub-nanomolar binding affinities. These findings provide the basis for further development of 15-PGDH targeted drugs as therapeutics for regenerative medicine.

Immediate sequential bilateral cataract surgery: patient perceptions and preferences.

BACKGROUND: Recent national data suggests that less than 0.5% of NHS cataract patients undergo immediate sequential bilateral cataract surgery (ISBCS). Since ISBCS improves service efficiency, increasing its practice may help tackle the ever-growing burden of cataract in the UK, and reduce the COVID-19 cataract backlog. Surgeon attitudes are known to be a significant barrier to increasing the practice of ISBCS. However, little is known about patient perceptions of ISBCS. METHODS: Patients at cataract clinics across three NHS hospital sites were recruited to complete an investigator-led structured questionnaire. Open-ended and closed-ended questions were used to assess awareness of ISBCS, willingness to undergo ISBCS and attitudes towards ISBCS. RESULTS: Questionnaires were completed by 183 patients. Mean participant age was 70.5 (9.9) years and 58% were female. Forty-three percent were aware of ISBCS, chiefly via clinic staff. Just over a third would choose ISBCS if given the choice, and participants that perceived they were recommended ISBCS were more likely to opt for it. The most common motivator and barrier to uptake of ISBCS was convenience and the perceived risk of complications in both eyes respectively. Concerns related to the recovery period were common, including misunderstandings, such as the need to wear eye patches that obscure both eyes. CONCLUSIONS: Our study indicates that significantly more NHS patients would be willing to undergo ISBCS if given the choice. The reluctance of surgeons to recommend ISBCS and patient misunderstandings regarding the recovery period may be limiting its uptake.

Royal College of Ophthalmologists' National Ophthalmology Database study of cataract surgery: report 8, cohort analysis of the relationship between intraoperative complications of cataract surgery and axial length.

OBJECTIVES: To describe the relationships between axial length and intraoperative complications in patients undergoing cataract surgery. DESIGN: Cohort analysis of the Royal College of Ophthalmologists' National Ophthalmology Database (RCOphth NOD). SETTING: 110 National Health Service Trusts in England, Health Boards in Wales, Independent Sector Treatment Centres and Guernsey. PARTICIPANTS: 820 354 patients, aged 18 years or older, undergoing cataract surgery. Eligible operations were those from centres with at least 50 operations with a recorded axial length measurement and age at surgery between 1 April 2010 and 31 August 2019. INTERVENTIONS: Phacoemulsification where the primary intention was cataract surgery alone. OUTCOME MEASURES: Posterior capsule rupture (PCR) and other recorded intraoperative complications. RESULTS: 1 211 520 eligible operations were performed by 3210 surgeons. The baseline axial length was <21 mm (short eyes) for 17 170 (1.4%) eyes, 21-28 mm (medium eyes) for 1 182 513 (97.6%) eyes and >28 mm (long eyes) for 11 837 (1.0%) eyes. The median age at surgery was younger for patients with long eyes than those with short or medium eyes. The rate of any intraoperative complication was higher for short eyes than medium or long with complication rates of 4.5%, 2.9% and 3.3%, respectively (p<0.001). PCR occurred in 1.40% surgeries overall, and in 1.53%, 1.40% and 1.61% of short, medium and long eyes, respectively (p=0.043, not significant at the 1% level). CONCLUSIONS: Overall PCR rates for cataract surgery in RCOphth NOD contributing centres are lower than previously reported and there is little change in PCR rates by axial length. Short eyes were more likely to have an intraoperative complication than medium or long eyes.

Structure of the Anthrax Protective Antigen D425A Dominant Negative Mutant Reveals a Stalled Intermediate State of Pore Maturation.

The tripartite protein complex produced by anthrax bacteria (Bacillus anthracis) is a member of the AB family of ß-barrel pore-forming toxins. The protective antigen (PA) component forms an oligomeric prepore that assembles on the host cell surface and serves as a scaffold for binding of lethal and edema factors. Following endocytosis, the acidic environment of the late endosome triggers a pH-induced conformational rearrangement to promote maturation of the PA prepore to a functional, membrane spanning pore that facilitates delivery of lethal and edema factors to the cytosol of the infected host. Here, we show that the dominant-negative D425A mutant of PA stalls anthrax pore maturation in an intermediate state at acidic pH. Our 2.7 Å cryo-EM structure of the intermediate state reveals structural rearrangements that involve constriction of the oligomeric pore combined with an intramolecular dissociation of the pore-forming module. In addition to defining the early stages of anthrax pore maturation, the structure identifies asymmetric conformational changes in the oligomeric pore that are influenced by the precise configuration of adjacent protomers.

Machine learning classification of bacterial species using mix-and-match reagents on paper microfluidic chips and smartphone-based capillary flow analysis.

Traditionally, specific bioreceptors such as antibodies have rapidly identified bacterial species in environmental water samples. However, this method has the disadvantages of requiring an additional process to conjugate or immobilize bioreceptors on the assay platform, which becomes unstable at room temperature. Here, we demonstrate a novel mix-and-match method to identify bacteria species by loading the bacterial samples with simple bacteria interacting components (not bioreceptors), such as lipopolysaccharides, peptidoglycan, and bovine serum albumin, and carboxylated particles, all separately on multiple channels. Neither covalent conjugation nor surface immobilization was necessary. Interactions between bacteria and the above bacteria interacting components resulted in varied surface tension and viscosity, leading to various flow velocities of capillary action through the paper fibers. The smartphone camera and a custom Python code recorded multiple channel flow velocity, each loaded with different bacteria interacting components. A multi-dimensional data set was obtained for a given bacterial species and concentration and used as a machine learning training model. A support vector machine was applied to classify the six bacterial species: Escherichia coli, Salmonella Typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecium, and Bacillus subtilis. Under optimized conditions, the training model predicts the bacterial species with an accuracy of > 85% of the six bacteria species.

Evaluating an innovative integrated training for child and youth services: Lessons learned.

This article highlights one child and youth services agency's journey to develop and pilot a system for tracking training effectiveness for staff. Given the importance of intentional and strong staff training to the success of an agency, the purpose of this study was to report training outcomes across four-time intervals (i.e., immediately after training considered here as baseline, 6 months, 12 months, and 18 months) using a tracking system based on best practices in staff development. Results indicated that the tracking system allowed this agency to measure and describe post-training outcomes for staff across the four-time intervals. It can be inferred that such training positively influenced youth outcomes. Specifically, the training and follow-up expanded staff's ability to effectively internalize concepts and be more intentional with their time for the benefit of youth care.

Natural killer cell detection, quantification, and subpopulation identification on paper microfluidic cell chromatography using smartphone-based machine learning classification.

Natural killer (NK) cells are immune cells that defend against viral infections and cancer and are used in cancer immunotherapies. Subpopulations of NK cells include CD56dim and CD56bright which either produce cytokines or cytotoxically kill cells directly. The absolute number and proportion of these cells in peripheral blood are tied to proper immune function. Current methods of cytokine detection and proportion of NK cell subpopulations require fluorescent dyes and highly specialized equipment, e.g., flow cytometry, thus rapid cell quantification and subpopulation analysis are needed in the clinical setting. Here, a smartphone-based device and a two-component paper microfluidic chip were used towards identifying NK cell subpopulation and inflammatory markers. One unit measured flow velocity via smartphone-captured video, determining cytokine (IL-2) and total NK cell concentrations in undiluted buffy coat blood samples. The other, single flow lane unit performs spatial separation of CD56dim and CD56bright and cells over its length using differential binding of anti-CD56 nanoparticles. A smartphone microscope combined with cloud-based machine learning predictive modeling (utilizing a random forest classification algorithm) analyzed both flow data and NK cell subpopulation differentiation. Limits of detection for cytokine and cell concentrations were 98 IU/mL and 68 cells/mL, respectively, and cell subpopulation analysis showed 89% accuracy.

Effect of surgical abstinence on the risk for posterior capsule rupture during cataract surgery.

PURPOSE: To evaluate the impact of surgery restrictions on cataract surgery performance. SETTING: Moorfields Eye Hospital, NHS Foundation Trust, London, United Kingdom. DESIGN: Retrospective, observational cross-sectional study. METHODS: A single-center, retrospective review of all patients who underwent phacoemulsification surgery at Moorfields Eye Hospital between September 2019 and January 2021 was conducted. The main outcome measure was posterior capsule rupture (PCR) rate before and after COVID-19-imposed restrictions to elective cataract surgery. RESULTS: A total of 15 688 surgeries were performed by 256 different surgeons in the study period. In the prerestriction period (September 2019 to March 2020), the PCR rate was 0.99%, whereas in the 19-week postrestriction period, the PCR rate spiked to 1.62% (odds ratio 1.65; P = .001; CI 1.24 to 2.20; relative risk: 1.64). CONCLUSIONS: The COVID-19 pandemic provided a unique opportunity to assess a large group of surgeons' performances after prolonged surgical abstinence. A 19-week restriction period in surgical activity showed an increased incidence of PCR complications. This is relevant because it can concern any surgeon on the extended time off from work such as sick, sabbatical, research, and parental leave. Supporting strategies should be implemented by associated regulators to minimize this negative impact.