Quantitative PCR (qPCR) assay for the specific detection of the Chinese mystery snail (Cipangopaludina chinensis) in the UK.

Cipangopaludina chinensis Gray 1833 is an East Asian freshwater snail and invasive species in many parts of the world (Global Invasive Species Database, 2022). Within the UK, it was first found at the Pevensey Levels, Sussex, and has since been reported at a second site at Southampton Common, Hampshire. Both sites are designated as Sites of Special Scientific Interest (SSSI) for their wildlife importance. Although the impacts of this species within the UK have not yet been investigated several exotic parasites of the snail have been reported and research suggests that its presence can negatively impact native snail species. This is especially important at the Pevensey Levels due to the presence of the rare freshwater mollusc Anisus vorticulus (Little Whirlpool Rams's-horn snail). Here, we have developed a qPCR-based eDNA assay for the detection of C. chinensis and compared water samples tested for eDNA with results from manual survey of the ditches at the Pevensey Levels. Our eDNA analysis exhibited an overall observed percentage agreement of 80% with a kappa coefficient of agreement between manual and eDNA surveys of 0.59 (95% CI 0.31 to 0.88). Some samples which were qPCR negative for C. chinensis were positive by manual survey, and vice versa revealing the potential for improved overall detection rates when using a combination of manual and eDNA methodologies. eDNA analysis can therefore augment manual survey techniques for C. chinensis as a relatively quick and inexpensive tool for collecting presence and distribution data that could be used to inform further manual surveys and control measures within the ditches.

Enhancing global and local decision making for chemical safety assessments through increasing the availability of data.

Toxicity safety assessments are a fundamental part of the lifecycle of products and aim to protect human health and the environment from harmful exposures to chemical substances. To make decisions regarding the suitability of testing strategies, the applicability of individual tests or concluding an assessment for an individual chemical requires data. This review outlines how different forms of data sharing, from enhancing publicly-available data to extracting knowledge from commercially-sensitive data, leads to increased quantity and quality of evidence being available for safety assessors to review. This can result in more confident decisions for different use cases in the context of chemical safety assessments. Although a number of challenges remain with progressing the evolution of toxicity safety assessments, data sharing should be considered as a key approach to accelerating the development and uptake of new best practices.

Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment

The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.

Automated vision screening of children using a mobile graphic device.

BACKGROUND/OBJECTIVE: Can measuring interocular brightness disparity, acuity, and colour vision classify children with amblyopia? SUBJECTS/METHODS: Two hundred eight subjects (3-14 years) were recruited for a prospective, observational protocol to measure interocular brightness disparity, uniocular acuities with and without a pinhole, and colour vision using an iPad. Subjects looked through polarizing filters and chose the brighter of two spaceships to measure interocular brightness disparity. The differential brightness of image pairs was varied through a staircase algorithm until equal brightness was perceived. Acuities and colour vision were tested with tumbling Es and AO-HRR colour plates, respectively. Unilateral amblyopia was later confirmed in two subjects. RESULTS: Binocular brightness balance on the iPad detected amblyopes with 100% sensitivity and specificity. Using 20/30 as cutoff for normal acuity, 1 of the amblyopes was detected, and non-amblyopes were excluded by visual acuity pinhole testing. The mean difference between iPad and E-Chart visual acuities with pinhole was 0.02 logMAR with limits of agreement from -0.08 to +0.11 logMAR. iPad and printed plates Colour vision testing produced identical results. Testing times were brief and exit pleasure responses were positive. Mean and range testing times for Brightness Sense, Colour vision, and Visual Acuity were 32.7 s (range = 12-63 s), 52.8 min (range = 17-95 s), and 88.75 s (range = 41-188 s), respectively. CONCLUSIONS: Interocular brightness disparity, acuity, and colour vision can be measured in children as young as 3 years old solely through playing a game on a mobile device. Interocular brightness disparity is a sensitive and specific method to detect unilateral amblyopia.

Pressures Exerted on the Hook of the Hamate in Collegiate Baseball Players: A Comparison of Grips, With Emphasis on Fracture Prevention.

BACKGROUND: Variations in batting technique may put baseball players at increased risk of hook of the hamate fractures. A better comprehension of the mechanism of such fractures is needed. PURPOSE/HYPOTHESIS: The purpose of the study was to compare 2 different grip types to quantify the pressures exerted on the hook of the hamate during batting. It was hypothesized that when compared with the conventional batting style, players holding the knob of the bat in the palm of the hand (termed the "palmar hamate grip") would have higher pressures exerted on the hook of the hamate. STUDY DESIGN: Controlled laboratory study. METHODS: Athletes were recruited for participation on a volunteer basis from the rosters of 2 National Collegiate Athletic Association Division I baseball teams and were divided into 2 groups based on their usual grip type. A force sensor system was applied to the nondominant hand of each participating player, with the central portion of the sensing mechanism placed on the batting glove directly over the hook of the hamate. All players used the same batting glove, which transmitted data from the sensor to a laptop computer. Measurements were collected on consecutive hits at a standardized distance using a ball machine at 70 mph. RESULTS: Nine collegiate baseball players underwent testing (5 players exclusively used the conventional grip, 3 players exclusively used the palmar hamate grip, and 1 player naturally alternated between the 2 grip types). The palmar hamate grip demonstrated a 366% increase in pressure exerted on the sensor overlying the hook of the hamate when compared with the conventional batting grip (536.42 kPa [95% confidence interval, 419.39-653.44 kPa] vs 115.84 kPa [95% confidence interval, 96.97-135.10 kPa]). The player who used both grips demonstrated significantly higher maximum pressure when using the palmar hamate versus conventional grip (482.90 vs 142.40 kPa; t = 6.95; P < .0001). CONCLUSION: Use of the palmar hamate grip may increase the risk of hook of the hamate fracture in National Collegiate Athletic Association Division I baseball players. CLINICAL RELEVANCE: Educating players on the risks associated with the palmar hamate grip may prevent injury and minimize time out of competition.

Beyond adverse outcome pathways: making toxicity predictions from event networks, SAR models, data and knowledge.

Adverse outcome pathways have shown themselves to be useful ways of understanding and expressing knowledge about sequences of events that lead to adverse outcomes (AOs) such as toxicity. In this paper we use the building blocks of adverse outcome pathways-namely key events (KEs) and key event relationships-to construct networks which can be used to make predictions of the likelihood of AOs. The networks of KEs are augmented by data from and knowledge about assays as well as by structure activity relationship predictions linking chemical classes to the observation of KEs. These inputs are combined within a reasoning framework to produce an information-rich display of the relevant knowledge and data and predictions of AOs both in the abstract case and for individual chemicals. Illustrative examples are given for skin sensitization, reprotoxicity and non-genotoxic carcinogenicity.

Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy.

OBJECTIVE: Evaluation of ophthalmologic safety with focus on retinal safety in patients with spinal muscular atrophy (SMA) treated with risdiplam (EVRYSDI®), a survival of motor neuron 2 splicing modifier associated with retinal toxicity in monkeys. Risdiplam was approved recently for the treatment of patients with SMA, aged ≥ 2 months in the United States, and is currently under Health Authority review in the EU. METHODS: Subjects included patients with SMA aged 2 months-60 years enrolled in the FIREFISH, SUNFISH, and JEWELFISH clinical trials for risdiplam. Ophthalmologic assessments, including functional assessments (age-appropriate visual acuity and visual field) and imaging (spectral domain optical coherence tomography [SD-OCT], fundus photography, and fundus autofluorescence [FAF]), were conducted at baseline and every 2-6 months depending on study and assessment. SD-OCT, FAF, fundus photography, and threshold perimetry were evaluated by an independent, masked reading center. Adverse events (AEs) were reported throughout the study. RESULTS: A total of 245 patients receiving risdiplam were assessed. Comprehensive, high-quality, ophthalmologic monitoring assessing retinal structure and visual function showed no retinal structural or functional changes. In the youngest patients, SD-OCT findings of normal retinal maturation were observed. AEs involving eye disorders were not suggestive of risdiplam-induced toxicity and resolved with ongoing treatment. INTERPRETATION: Extensive ophthalmologic monitoring conducted in studies in patients with SMA confirmed that risdiplam does not induce ophthalmologic toxicity in pediatric or adult patients with SMA at the therapeutic dose. These results suggest that safety ophthalmologic monitoring is not needed in patients receiving risdiplam, as also reflected in the United States Prescribing Information for risdiplam.

Suture Tape Augmentation for Scapholunate Ligament Repair: A Biomechanical Study.

PURPOSE: Scapholunate (SL) ligament tears in the acute setting can be treated by primary repair through various techniques. The purpose of this study was to compare repair of the SL ligament with suture anchors alone versus repair of the SL ligament augmented with suture tape. METHODS: Twelve fresh-frozen cadavers (6 matched pairs) underwent a dorsal approach to the wrist and the SL ligament was sharply dissected off of its scaphoid attachment. Six cadavers underwent direct repair of the SL ligament using 2 suture anchors. The other 6 underwent repair of the SL ligament, which was then augmented with suture tape. All specimens then underwent load to failure testing using tensile distraction forces applied by a universal testing system. Maximum load to failure and mode of failure were recorded. RESULTS: Maximum load to failure (135 N; SD, 44.94 N) for specimens that were repaired and augmented with the internal brace was higher than that for specimens in the repair-only group (68 N; SD, 14.69 N). CONCLUSIONS: Biomechanical testing demonstrated a higher maximum load to failure in SL ligament repairs augmented with suture tape compared with a repair-only technique in this cadaveric model. CLINICAL RELEVANCE: Acute SL ligament injuries may benefit from suture tape augmentation by increasing the stability of the primary repair. This may prove to be beneficial in higher-demand patients.

Failure of Goniosurgery for Glaucoma Associated With Sturge-Weber Syndrome.

PURPOSE: To report the surgical results of goniosurgery for children with glaucoma associated with Sturge-Weber syndrome. METHODS: Retrospective review of medical records of patients who had initial goniosurgery for glaucoma associated with Sturge-Weber syndrome. RESULTS: A total of 46 eyes of 42 patients who had glaucoma associated with Sturge-Weber syndrome and were treated with initial goniosurgery were identified to determine the efficacy of therapeutic goniotomy and trabeculotomy (goniosurgery). The average age at the time of goniosurgery was 1.5 years (range: 1 month to 23 years). Office intraocular pressure (IOP) measurements before goniosurgery were recorded in 76% of patients (32 of 42 patients) with an average measurement of 35 mm Hg (range: 25 to 50 mm Hg). The average interval to failure was 4 months (range: 1 to 48 months). Forty-six eyes underwent goniosurgery with a rate of failure of 98% (45 of 46 eyes) and a qualified success rate of 2% (1 of 46 eyes). Fifty-one goniotomy and 11 trabeculotomy procedures were performed. On gonioscopy, the filtration angles were all abnormal with variable width and visibility of the ciliary body band and less visible scleral spur. The trabecular meshwork was seen preoperatively in 100% of eyes (41 of 41 eyes) examined, all of which underwent goniosurgery. Five eyes underwent goniosurgery without documented gonioscopy. The ciliary body band was seen in 39% of eyes (16 of 41 eyes) and the scleral spur was visible in 10% of eyes (4 of 41 eyes). CONCLUSIONS: Goniosurgery is not an effective initial glaucoma surgery for glaucoma associated with Sturge-Weber syndrome. It can be used to temporize the IOP, but ultimately other forms of glaucoma surgery must be considered when indicated. [J Pediatr Ophthalmol Strabismus. 2020;57(6):384-387.].

The importance of expert review to clarify ambiguous situations for (Q)SAR predictions under ICH M7.

The use of in silico predictions for the assessment of bacterial mutagenicity under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 guideline is recommended when two complementary (quantitative) structure-activity relationship (Q)SAR models are used. Using two systems may increase the sensitivity and accuracy of predictions but also increases the need to review predictions, particularly in situations where results disagree. During the 4th ICH M7/QSAR Workshop held during the Joint Meeting of the 6th Asian Congress on Environmental Mutagens (ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society (JEMS) 2019, speakers demonstrated their approaches to expert review using 20 compounds provided ahead of the workshop that were expected to yield ambiguous (Q)SAR results. Dr. Chris Barber presented a selection of the reviews carried out using Derek Nexus and Sarah Nexus provided by Lhasa Limited. On review of these compounds, common situations were recognised and are discussed in this paper along with standardised arguments that may be used for such scenarios in future.

Effectiveness of combination endoscopic therapy for colonic anastomotic leaks.

BACKGROUND: Colonic anastomotic leaks are associated with significant morbidity and mortality. Whereas small case series suggest that fully covered self-expandable metal stents (FCSEMS) are effective, no larger studies have examined the impact of combination endoscopic therapy on colonic anastomotic leaks. METHODS: Our retrospective cohort study reviewed 51 patients undergoing endoscopic therapy for colonic anastomotic leaks between 2011 and 2018. Patients receiving combination therapy involving FCSEMS plus local closure (n = 24) were compared with patients receiving FCSEMS alone (n = 18) or endoscopic suturing alone (n = 9). The primary outcomes were technical and clinical success (resolution of leak, removal of percutaneous drains, avoidance of surgical reoperation, and reversal of temporary diversion). RESULTS: Clinical success was achieved in 55 % of patients. Clinical success was achieved in 18/24 patients (75 %) with combination therapy compared with 6/18 patients receiving FCSEMS alone (33 %, adjusted risk ratio [RR] 2.16, 95 % confidence interval [CI] 1.10 - 4.24; P = 0.02) and 4 /9 patients undergoing endoscopic suturing alone (44 %, RR 1.91, 95 %CI 0.84 - 4.31; P = 0.10). Stent migration occurred in 40 % of patients. CONCLUSIONS: This large series demonstrates that combination therapy was associated with a higher rate of clinical success, and future prospective studies are warranted.

Biomechanical Analysis of Ligatures and Technique for Managing Drainage Tubes in Pediatric Glaucoma.

PURPOSE: Absorbable ligatures are often used with glaucoma drainage tubes to avoid early postoperative hypotony. We sought to measure the force required to ligate a drainage tube, and develop a modified technique to promote earlier release in pediatric patients, where plate encapsulation occurs more quickly than adults. METHODS: A precision digital force gauge was used to measure the tensile strength of several common ophthalmic sutures, and the necessary tensile force required to achieve tube ligation. A novel technique for tube ligation was devised to allow sutures as small as 10-0 to be effectively used. RESULTS: The mean tensile strengths of unknotted sutures varied from 55.50±8.50 g for 10-0 vicryl to 477±69 g for 6-0 chromic gut. The mean tensile force required to ligate a Baerveldt or Ahmed tube was 35.9±0.9 g. However, 9-0 or 10-0 vicryl could not be reliably used for ligation, because of breakage, unless a modified technique was used, wherein the tube was first stretched to reduce its thickness and diameter. DISCUSSION: Frictional forces inherent to knot tying make it unfeasible to reliably use 9-0 or 10-0 vicryl to ligate a drainage tube, despite the unknotted threads possessing apparently sufficient tensile strength. Our modified ligation technique overcomes this issue, allowing a wider range of suture choices, and the potential for achieving more rapid release in pediatric cases.

Descemetorhexis Without Endothelial Keratoplasty Versus DMEK for Treatment of Fuchs Endothelial Corneal Dystrophy.

PURPOSE: To compare the visual outcomes and associated morbidity of patients with Fuchs endothelial corneal dystrophy who were treated with either Descemet membrane endothelial keratoplasty (DMEK) or descemetorhexis without endothelial keratoplasty (DWEK). METHODS: This is a retrospective comparative cohort study of 27 eyes with mild to moderate Fuchs dystrophy (with corneal guttae/edema limited to the central cornea with relatively clear periphery) that were treated at the University of Pittsburgh Medical Center from 2015 to 2017 with either DMEK (n = 15) or DWEK (n = 12). Descemetorhexis was performed by removing the central 4 mm of diseased Descemet membrane at the end of phacoemulsification for cataract surgery. Visual acuity was measured using the Snellen chart and then converted to logMAR for analysis. RESULTS: Average postoperative pinhole visual acuity was 20/25 - 1 (logMAR 0.16 ± 0.09) for DMEK eyes and 20/30 + 1 (logMAR 0.13 ± 0.10) for DWEK eyes (P = 0.44). The average time to 20/40 vision for DMEK was 2.2 ± 2.8 weeks compared with 7.1 ± 2.7 weeks for DWEK (P < 0.01). In our DMEK group, 8 (53%) patients had adverse events, including increased intraocular pressure (n = 7), anterior chamber inflammation (n = 1), and graft nonadherence (n = 1), with 1 patient requiring anterior chamber paracentesis (6.7%) and 1 patient (6.7%) requiring a rebubbling procedure. Our DWEK group had no adverse events (P < 0.01). CONCLUSIONS: DWEK effectively treats select patients with mild to moderate Fuchs dystrophy with equivalent visual outcomes compared with the current standard of care, DMEK. Although the recovery time may be longer, DWEK patients had reduced adverse events and need for additional procedures and did not require long-term immunosuppression or donor corneal tissue.

Cardiac Arrest and Death Attributable to the "Diving Response" Triggered During Incision and Debridement of an Abscess of the Forehead.

The authors discuss about a patient who, while undergoing a routine procedure to drain a subcutaneous abscess within his forehead, suffered cardiac arrest that we conclude was caused by an activation of the diving response. This reflex affects homeostatic function which alters respiration and preferentially distributes oxygen stores to the heart and brain. Under some conditions, however, this reflex can also trigger cardiovascular collapse and death. The diving reflex is can begin with triggering receptors that are sensitive to cold water, submersion, or pressure within the nasal cavity and other areas supplied by the trigeminal nerve. Studies have shown that this afferent response primarily involves branches of the infraorbital nerve and the anterior ethmoidal nerve. However, other more superior nerves such as those exclusive to the forehead region may also be involved. This study demonstrates for the first time the risks and dangers involved in surgical procedures or manipulation of the trigeminal innervated areas of the human face and in particular the forehead.

Characterisation of novel biomass degradation enzymes from the genome of Cellulomonas fimi.

Recent analyses of genome sequences belonging to cellulolytic bacteria have revealed many genes potentially coding for cellulosic biomass degradation enzymes. Annotation of these genes however, is based on few biochemically characterised examples. Here we present a simple strategy based on BioBricks for the rapid screening of candidate genes expressed in Escherichia coli. As proof of principle we identified over 70 putative biomass degrading genes from bacterium Cellulomonas fimi, expressing a subset of these in BioBrick format. Six novel genes showed activity in E. coli. Four interesting enzymes were characterised further. α-l-arabinofuranosidase AfsB, ß-xylosidases BxyF and BxyH and multi-functional ß-cellobiosidase/xylosidase XynF were partially purified to determine their optimum pH, temperature and kinetic parameters. One of these enzymes, BxyH, was unexpectedly found to be highly active at strong alkaline pH and at temperatures as high as 100 °C. This report demonstrates a simple method of quickly screening and characterising putative genes as BioBricks.

Paroxysmal eye-head movements in Glut1 deficiency syndrome.

OBJECTIVE: To describe a characteristic paroxysmal eye-head movement disorder that occurs in infants with Glut1 deficiency syndrome (Glut1 DS). METHODS: We retrospectively reviewed the medical charts of 101 patients with Glut1 DS to obtain clinical data about episodic abnormal eye movements and analyzed video recordings of 18 eye movement episodes from 10 patients. RESULTS: A documented history of paroxysmal abnormal eye movements was found in 32/101 patients (32%), and a detailed description was available in 18 patients, presented here. Episodes started before age 6 months in 15/18 patients (83%), and preceded the onset of seizures in 10/16 patients (63%) who experienced both types of episodes. Eye movement episodes resolved, with or without treatment, by 6 years of age in 7/8 patients with documented long-term course. Episodes were brief (usually <5 minutes). Video analysis revealed that the eye movements were rapid, multidirectional, and often accompanied by a head movement in the same direction. Eye movements were separated by clear intervals of fixation, usually ranging from 200 to 800 ms. The movements were consistent with eye-head gaze saccades. These movements can be distinguished from opsoclonus by the presence of a clear intermovement fixation interval and the association of a same-direction head movement. CONCLUSIONS: Paroxysmal eye-head movements, for which we suggest the term aberrant gaze saccades, are an early symptom of Glut1 DS in infancy. Recognition of the episodes will facilitate prompt diagnosis of this treatable neurodevelopmental disorder.