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BACKGROUND Blunt traumatic abdominal wall hernias (TAWH) occur in approximately 15,000 patients per year. Limited data are available to guide the timing of surgical intervention or the feasibility of nonoperative management. METHODS A retrospective study of patients presenting with blunt TAWH from January 2012 through December 2018 was conducted. Patient demographic, surgical, and outcomes data were collected from 20 institutions through the Western Trauma Association Multicenter Trials Committee. RESULTS Two hundred and eighty-one patients with TAWH were identified. One hundred and seventy-six (62.6%) patients underwent operative hernia repair, and 105 (37.4%) patients underwent nonoperative management. Of those undergoing surgical intervention, 157 (89.3%) were repaired during the index hospitalization, and 19 (10.7%) underwent delayed repair. Bowel injury was identified in 95 (33.8%) patients with the majority occurring with rectus and flank hernias (82.1%) as compared with lumbar hernias (15.8%). Overall hernia recurrence rate was 12.0% (n = 21). Nonoperative patients had a higher Injury Severity Score (24.4 vs. 19.4, p = 0.010), head Abbreviated Injury Scale score (1.1 vs. 0.6, p = 0.006), and mortality rate (11.4% vs. 4.0%, p = 0.031). Patients who underwent late repair had lower rates of primary fascial repair (46.4% vs. 77.1%, p = 0.012) and higher rates of mesh use (78.9% vs. 32.5%, p < 0.001). Recurrence rate was not statistically different between the late and early repair groups (15.8% vs. 11.5%, p = 0.869). CONCLUSION This report is the largest series and first multicenter study to investigate TAWHs. Bowel injury was identified in over 30% of TAWH cases indicating a significant need for immediate laparotomy. In other cases, operative management may be deferred in specific patients with other life-threatening injuries, or in stable patients with concern for bowel injury. Hernia recurrence was not different between the late and early repair groups. LEVEL OF EVIDENCE Therapeutic/care management, Level IV.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of CJD and is believed to be caused by the misfolding and aggregation of endogenous prion protein. Several classification systems have been developed to correlate the molecular characteristics of these misfolded prions (PrPSc) to the heterogeneous clinical presentations of sCJD. A central component of these systems is glycotyping, which involves the interpretation of the results of western immunoblotting of the protease-resistant fragment of the misfolded prion protein (PrPres). The two main classification systems differ in their recognition of a unique banding pattern on electrophoretic gels correlating to a putative clinical subtype. The perpetuation of both classification systems within scientific literature is, in part, due to a paucity of high-level evidence that conclusively addresses the merit of recognising each unique banding pattern. Here, 110 post-mortem confirmed cases of sCJD collected at the Australian Creutzfeldt-Jakob Disease Registry (ANCJDR) between 1993 and 2018 were analysed and classified as per the London classification system. The data presented here demonstrated that sCJD cases with 'type 1' and 'type 2' PrPSc as defined by the London classification system differ in their disease duration. No other differences in clinical phenotype or biological characteristics were found to be statistically significant. These findings highlight the importance of sample size and replicability in analyses of this rare disease process. Recognising these glycotypes as phenotypically distinct may represent 'best practice' in the collection and processing of sCJD samples within international registries for research purposes.

Background The intrinsic muscles of the foot are key contributors to foot function and are important to evaluate in lower limb disorders. Magnetic resonance imaging (MRI), provides a non-invasive option to measure muscle morphology and composition, which are primary determinants of muscle function. Ultra-high-field (7-T) magnetic resonance imaging provides sufficient signal to evaluate the morphology of the intrinsic foot muscles, and, when combined with chemical-shift sequences, measures of muscle composition can be obtained. Here we aim to provide a proof-of-concept method for measuring intrinsic foot muscle morphology and composition with high-field MRI. Methods One healthy female (age 39 years, mass 65 kg, height 1.73 m) underwent MRI. A T1-weighted VIBE – radio-frequency spoiled 3D steady state GRE – sequence of the whole foot was acquired on a Siemens 7T MAGNETOM scanner, as well as a 3T MAGNETOM Prisma scanner for comparison. A high-resolution fat/water separation image was also acquired using a 3D 2-point DIXON sequence at 7T. Coronal plane images from 3T and 7T scanners were compared. Using 3D Slicer software, regions of interest were manually contoured for each muscle on 7T images. Muscle volumes and percentage of muscle fat infiltration were calculated (muscle fat infiltration % = Fat/(Fat + Water) x100) for each muscle. Results Compared to the 3T images, the 7T images provided superior resolution, particularly at the forefoot, to facilitate segmentation of individual muscles. Muscle volumes ranged from 1.5 cm3 and 19.8 cm3, and percentage muscle fat infiltration ranged from 9.2–15.0%. Conclusions This proof-of-concept study demonstrates a feasible method of quantifying muscle morphology and composition for individual intrinsic foot muscles using advanced high-field MRI techniques. This method can be used in future studies to better understand intrinsic foot muscle morphology and composition in healthy individuals, as well as those with lower disorders.

As global pig health diseases, porcine respiratory disease complex (PRDC) and porcine circovirus associated disease (PCVAD) generate substantial economic losses despite pigs been vaccinated against the primary causative virus, highlighting the importance of understanding virome interactions and specifically co-factor infections. Established primary endemic pathogens for PRDC include porcine circovirus 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSv) and swine influenza virus (SIV), and PCV2 aetiology in interaction with other co-infecting viruses can result in PCVAD. Porcine parvovirus (PPV) 1 is a well characterised virus with an available vaccine preventing reproductive failure in sows. However, whilst novel PPV 2 to 7 viruses have been identified since 2001, their viral pathogenic potential in clinical and subclinical disease remains to be determined. Therefore, this study has sought to develop a better understanding of their potential role as associated co-infections in PRDC and PCVAD by examining archival samples for the presence of PCV2 and the novel parvoviruses PPV2-4 from clinically diseased pigs across production age stages. Epidemiologically, the novel PPV2 was found to be the most prevalent within the fattener age group with PPV2-4 statistically associated with pig respiratory disease and enteric ulcers. Additionally, statistical modelling by latent class analysis (LCA) on veterinary pathology scored pigs found a clustering co-factor association between PPV2 and PCV2, suggesting the novel PPV may be involved in PRDC and PCVAD. Phylogenetic analysis of novel PPVs revealed the PPV2 capsid evolution to be diverged from the original strains with a low nucleotide homology of 88-96% between two distinct clades. These findings determine that novel PPV 2-4 viruses are statistically associated as co-infectors in a diseased pig population, and significantly detected PPV2 clustering co-infection frequency with PCV2 in PRDC and PCVAD diseased pigs through LCA analysis.

Leber hereditary optic neuropathy (LHON) is a neurodegenerative disorder characterised by bilateral, painless, subacute, central vision loss caused by pathogenic sequence variants in mitochondrial DNA (mtDNA). Over the course of 20 years, 734 people were systematically screened by our diagnostic laboratory for suspected LHON or for being at risk of LHON, with 98 found to harbour one of the three primary pathogenic mtDNA variants. Detection incidences were: 0.95% for NC_012920.1(MT-ND1):m.3460G>A; 9.4% for (MT-ND4):m.11778G>A; and 2.9% for (MT-ND6):m.14484T>C. The median age for symptomatic males was 27.3 years and for females 29.5 years, with a male to female ratio of 4.4:1 (62 males; 14 females). Most pathogenic variant carriers were propositi with the other individuals belonging to one of 14 pedigrees with noteworthy intra-family variability of clinical severity of the disease.

Background Patellofemoral pain (PFP) is a common cause of knee pain in adolescents, but there are limited evidence-based treatment options for this population. Foot orthoses can improve pain and function in adults with PFP, and may be effective for adolescents. The primary aim of this study is to determine the feasibility of conducting a full-scale randomised controlled trial (RCT) evaluating the effects of contoured foot orthoses on knee pain severity and patient-perceived global change, compared to flat shoe insoles, in adolescents with PFP. The secondary aim is to provide an estimate of treatment effects for foot orthoses, compared to flat insoles, in adolescents with PFP. Methods This randomised, controlled, participant- and assessor-blinded, feasibility trial has two parallel groups. Forty adolescents (aged 12–18 years) with clinical symptoms of PFP will be recruited from Queensland, Australia. Participants will be randomised to receive either prefabricated contoured foot orthoses or flat shoe insoles. Both interventions will be fit by a physiotherapist, and worn for 3 months. Feasibility will be evaluated through assessing willingness of volunteers to enrol, number of eligible participants, recruitment rate, adherence with the study protocol, adverse effects, success of blinding, and drop-out rate. Secondary outcomes will evaluate knee-related pain, symptoms, function, quality of life, global rating of change, patient acceptable symptom state, and use of co-interventions, at 6 weeks and 3 months. Primary outcomes will be reported descriptively, while estimates of standard deviation and between-group differences (with 95% confidence intervals) will be reported for secondary outcomes. Discussion Findings of this study will inform the feasibility of a full-scale RCT investigating the efficacy of contoured foot orthoses in adolescents with PFP. This full-scale study is necessary to improve the evidence base for management of adolescent PFP, and enhance outcomes for this population. Trial registration ACTRN12619000957190.

Purpose: Near work has been linked with myopia development; however, the underlying mechanism remains unclear. Small increases in axial length during accommodation have previously been reported in adults, and therefore, this study aimed to examine if accommodation-induced changes in ocular biometry also occur in school-aged children. Methods: A range of ocular biometric measurements were captured during brief accommodation tasks at four demands (0, 3, 6, and 9 D), in a group of 87 non-myopic, school-aged children using a Badal optometer mounted to a non-contact optical biometer (Zeiss IOLMaster 700, https://www.zeiss.com/meditec/int/product-portfolio/optical-biometers/iolmaster-700.html). Reliable biometry measurements and active accommodation were observed for 76 participants who were included in the analysis. The average central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (LT), anterior segment length (ASL), vitreous chamber depth (VCD), and axial length (AL) were determined for each accommodation demand. Raw measurements of AL and VCD were corrected to account for the effect of LT changes during accommodation. Results: On average, AL increased with increasing levels of accommodation (p = 0.005). The mean (SEM, standard error of the mean) AL increase from 0 D to the 3, 6, and 9 D demands was 4 (1), 8 (1), and 15 (2) µm, respectively. All other biometric parameters, except CCT, changed significantly during accommodation. LT and ASL increased, and ACD and VCD decreased significantly with increasing accommodation (all p ≤ 0.02). A longer baseline AL was associated with greater levels of accommodation-induced axial elongation at the 9 D demand (p Conclusions: AL increased significantly during accommodation in children, consistent with previous findings in adults up to a 6 D demand. AL continued to increase for higher levels of accommodation (9 D demand), which children may experience during near tasks. These findings provide further insights into potential mechanisms linking near work, axial elongation, and myopia development. However, no myopic children participated in this experiment; therefore, further research is required.

The human eye is capable of responding to the presence of blur by changing its axial length, so that the retina moves towards the defocused image plane. We measured how quickly the eye length changed in response to both myopic and hyperopic defocus and how quickly the eye length changed when the defocus was removed. Axial length was measured at baseline and every 10 minutes during 1 hour of exposure to monocular defocus (right eye) with the left eye optimally corrected for two defocus conditions (+3 D and −3 D) and a control condition. Recovery was measured for 20 minutes after blur removal. A rapid increase in axial length was observed after exposure (~2 minutes) to hyperopic defocus (+7 ± 5 μm, p

Background Foot orthoses are a recommended treatment for patellofemoral (PF) pain and a number of lower limb osteoarthritic (OA) conditions. However, their mechanism of effect is poorly understood. Research question To compare the immediate effects of foot orthoses and flat inserts on lower limb biomechanics, knee pain and confidence in individuals with PFOA. Methods Twenty-one participants (14 females; mean ± SD age 58 ± 8 years) with PFOA underwent three-dimensional motion analysis during level-walking, stair ascent, and stair descent under three footwear conditions: (i) their own shoes; (ii) prefabricated foot orthoses; and (iii) flat shoe inserts. Participants reported their average levels of knee pain and confidence after each task. Data were analysed with repeated-measures analysis of variance (ANOVA), effect sizes (partial eta squared), and Bonferroni post-hoc tests. Results During level-walking, there was a significant main effect of foot orthoses on peak ankle dorsiflexion angle (F2 = 0.773, p Significance Prefabricated foot orthoses altered sagittal plane biomechanics of the ankle during level-walking and stair descent in individuals with PFOA. Further research is required to determine whether these changes are clinically beneficial.

Background Patellofemoral pain (PFP) affects one-quarter of adolescents, yet there are few evidence-informed recommendations to treat PFP in this population. HAPPi Kneecaps! is a randomised, controlled, participant- and assessor-blind, parallel-group feasibility trial of shoe inserts for adolescents with PFP. The aim of this qualitative study was to explore adolescents’ perspectives of participating in HAPPi Kneecaps!. Methods All 36 adolescents with PFP from the HAPPi Kneecaps! study were invited to participate in semi-structured interviews. We used a descriptive qualitative methodology underpinned by a relativist framework to investigate adolescents’ perspectives on participating in the trial. Inductive thematic analysis was used to examine patterns regarding how each adolescent experienced the HAPPi Kneecaps! study within their social, cultural, and historical contexts. Results 14 out of 36 HAPPi Kneecaps! participants provided consent and participated in interviews (12 females; mean [SD] age 14.9 [2.4] years). Overall, most adolescents responded positively when discussing their experience, such as improvements in their knee pain and satisfaction with how the study was run. Major themes that were generated from the analysis and feedback were: (1) shoe inserts require little effort to use; (2) perceptions of the program were generally positive; (3) participation in the trial could be made easier; (4) warm weather matters; and (5) life happens. Conclusion Adolescents with PFP who participated in the HAPPi Kneecaps! study found that shoe inserts were easy to wear. Most adolescents experienced an improvement in their symptoms and enhanced participation in sport and exercise. Adolescents with PFP prefer an option for warmer climates (e.g. flip flops or sandals), access to online logbooks, and clinicians who are easily accessible. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000957190. Date registered: 8/07/2019.

Schistosomes cause morbidity and death throughout the developing world due to the massive numbers of eggs female worms deposit into the blood of their host. Studies dating back to the 1920s show that female schistosomes rely on constant physical contact with a male worm both to become and remain sexually mature; however, the molecular details governing this process remain elusive. Here, we uncover a nonribosomal peptide synthetase that is induced in male worms upon pairing with a female and find that it is essential for the ability of male worms to stimulate female development. We demonstrate that this enzyme generates β-alanyl-tryptamine that is released by paired male worms. Furthermore, synthetic β-alanyl-tryptamine can replace male worms to stimulate female sexual development and egg laying. These data reveal that peptide-based pheromone signaling controls female schistosome sexual maturation, suggesting avenues for therapeutic intervention and uncovering a role for nonribosomal peptides as metazoan signaling molecules.

Nutrients with the ability to modulate the immune system (immune-modulating nutrients, IMN) may help prevent the development and progression of atherosclerosis, the main disease process underlying peripheral artery disease (PAD). Currently, no screening tool exists to measure IMN intake, therefore, the aim of this project is to develop and validate a short food frequency questionnaire (FFQ) that measures dietary intake of 14 nutrients with proposed immune-modulating effects, identified by the literature (copper, iron and zinc, vitamins A, C, D and E, alpha linolenic acid, total long-chain omega-3 fatty acids, arginine, glutamic acid, isoleucine, leucine and valine) in patients with established PAD. A 21-item FFQ was developed to measure average daily intake of IMNs over the past 12 months. Participants (n = 106) were recruited from Flinders Medical Centre, where they completed the FFQ followed by the reference method, a diet history reflecting usual intake over the past week. The mean age of participants was 72 years, with 83% being male (n = 88). Bland–Altman analysis resulted in a statistically non-significant p-value (p-value &gt, 0.05) for 12 out of 14 nutrients, demonstrating good agreement between the two methods. Additionally, over 50% of nutrients had a sensitivity or specificity &gt, 70%. Consequently, the novel 21-item FFQ was determined to be a promising measure of dietary intake of 14 IMNs in patients with PAD when compared to the reference method of a diet history, and it is recommended that further investigations of the utility against biomarkers be explored in the future.

Atherosclerosis is a pro-oxidative and pro-inflammatory disease state, which is the underlying cause of most cardiovascular events, estimated to affect 5.2% of the Australian population. Diet, and specifically vitamin C, through its antioxidant properties can play a role in impeding the development and progression of atherosclerosis. This systematic review conducted comprehensive searches in Medline, Emcare, Scopus, PubMed, and Cochrane using key search terms for vitamin C, plasma vitamin C, supplementation, and cardiovascular disease (CVD). The results demonstrated that vitamin C supplementation resulted in a significant increase in vitamin C levels in populations with or without CVD, except for one study on the CVD population. It was also seen that the healthy population baseline and post-intervention vitamin C levels were high compared to the CVD population. However, further research is indicated for CVD population groups with varying baseline vitamin C levels, such as low baseline vitamin C, within a more representative elderly cohort in order to formulate and update vitamin C repletion guidelines.

Background Treatment of advanced epithelial ovarian cancer results in a relapse rate of 75%. Early markers of response would enable optimization of management and improved outcome in both primary and recurrent disease. Purpose To assess the apparent diffusion coefficient (ADC), derived from diffusion-weighted MRI, as an indicator of response, progression-free survival (PFS), and overall survival. Materials and Methods This prospective multicenter trial (from 2012-2016) recruited participants with stage III or IV ovarian, primary peritoneal, or fallopian tube cancer (newly diagnosed, cohort one; relapsed, cohort two) scheduled for platinum-based chemotherapy, with interval debulking surgery in cohort one. Cohort one underwent two baseline MRI examinations separated by 0-7 days to assess ADC repeatability; an additional MRI was performed after three treatment cycles. Cohort two underwent imaging at baseline and after one and three treatment cycles. ADC changes in responders and nonresponders were compared (Wilcoxon rank sum tests). PFS and overall survival were assessed by using a multivariable Cox model. Results A total of 125 participants (median age, 63.3 years [interquartile range, 57.0-70.7 years]; 125 women; cohort one, n = 47; cohort two, n = 78) were included. Baseline ADC (range, 77-258 × 10-5mm2s-1) was repeatable (upper and lower 95% limits of agreement of 12 × 10-5mm2s-1 [95% confidence interval {CI}: 6 × 10-5mm2s-1 to 18 × 10-5mm2s-1] and -15 × 10-5mm2s-1 [95% CI: -21 × 10-5mm2s-1 to -9 × 10-5mm2s-1]). ADC increased in 47% of cohort two after one treatment cycle, and in 58% and 53% of cohorts one and two, respectively, after three cycles. Percentage change from baseline differed between responders and nonresponders after three cycles (16.6% vs 3.9%; P = .02 [biochemical response definition]; 19.0% vs 6.2%; P = .04 [radiologic definition]). ADC increase after one cycle was associated with longer PFS in cohort two (adjusted hazard ratio, 0.86; 95% CI: 0.75, 0.98; P = .03). ADC change was not indicative of overall survival for either cohort. Conclusion After three cycles of platinum-based chemotherapy, apparent diffusion coefficient (ADC) changes are indicative of response. After one treatment cycle, increased ADC is indicative of improved progression-free survival in relapsed disease. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Purpose: To investigate the effect of uncorrected astigmatism on night driving performance on a closed-road circuit. Methods: Participants included 10 drivers (mean age 24.4 ± 7.0 years), with low to moderate bilateral astigmatism (0.75–1.50 DC), who were regular contact lens (CL) wearers. Vision and night driving performance were assessed in a cross-over design with a toric CL and a best-sphere spherical CL. Binocular visual function measures included photopic and mesopic visual acuity (VA), contrast sensitivity (CS), mesopic motion sensitivity and glare tests (Mesotest® II and Halometer). Night-time driving performance was assessed on a closed-road circuit, which included measures of sign recognition, hazard detection and avoidance, pedestrian recognition distances, lane keeping, speed and overall driving score. Results: Correction of astigmatism with toric CL significantly improved mesopic VA, photopic and mesopic CS, mesopic motion sensitivity, and reduced glare (p

Purpose: To describe a simple method to quantify scleral contact lens decentration using over-topography captured with a Placido ring videokeratoscope, and its repeatability. Methods: Scleral lens over-topography (E300 videokeratoscope, Medmont) was measured on 10 healthy participants following 15 min of lens settling (16.5 mm total diameter ICD miniscleral, Capricornia). Horizontal and vertical lens decentration was quantified from the translation of the front optic zone relative to the pupil centre derived from ellipses manually fitted to tangential power over-topography maps using both a standard and normalised dioptric scale. Intrasession (different maps captured within the same measurement session), intraobserver (identical maps analysed by the same observer), and intertechqniue (standard or normalised tangential power scales) repeatability were calculated. Results: The mean lens decentration was 0.62 ± 0.18 mm temporally and 0.91 ± 0.33 mm inferiorly. Lens decentration derived from tangential topography maps with a standard power scale were more repeatable (95% limits of agreement for intraobserver repeatability ± 0.07 mm and intrasession repeatability ± 0.15 mm) than measurements derived from normalised maps (95% limits of agreement for intraobserver repeatability ± 0.11 mm and intrasession repeatability ± 0.20 mm). Conclusions: Scleral lens decentration can be reliably quantified using tangential power maps with a standard (fixed) scale captured during over-topography without the need for customised instrumentation or image analysis software. This method has a range of potential applications in research and clinical practice.

This descriptive study sought to establish an oral health baseline of need for enrollees at a Program of All-Inclusive Care for the Elderly (PACE) and identify opportunities for nursing interventions. The Oral Health Assessment Tool (OHAT) was applied to a random sample of 120 enrollees, 64 of whom met inclusion criteria, agreed to participate to assess their oral health status, and were included in the analysis. The mean OHAT score was 4.4 (SD = 2.6; range 0–12). Higher scores indicate poorer oral health. The oral conditions found needing the most attention were gums, saliva, natural teeth, dentures, and oral cleanliness. Oral cleanliness scored the worst on the OHAT, highlighting opportunities for nursing interventions and the necessity for oral hygiene routines. This study also identifies the need for nurses to address enrollees’ oral health and relay information back to the PACE interdisciplinary team (IDT) to initiate referrals to the dentist as needed.

To investigate the effect of multiple lid eversions on lid wiper epitheliopathy (LWE), along with the effect of cumulative lid exposure time and the patterns of associated staining.The increase in area of lid wiper staining with lissamine green was compared by everting both the upper eyelids of each subject (i.e. contralateral design), with one eye being everted once for 45 s and the fellow eyelid everted three times, each time for 15 s. This pattern of contralateral eversion was repeated with a total of three eversions in one eye and nine eversions in the fellow eye, with each eye totalling 135 s cumulative exposure to eversion over about 9 min. The LWE area of staining was objectively quantified from slit lamp photography images captured at every lid eversion by 2 masked observers. Two-way repeated measures ANOVAs were used to determine the effect of number of lid eversions and cumulative exposure time on the amount of staining caused. Each image was also categorized into its primary LWE staining pattern, by a masked observer.The multiple eversions condition caused significantly greater LWE than the single eversion condition (p 0.001), while cumulative exposure time did not have a significant effect on LWE (p = 0.137). Classification of the primary staining patterns revealed that with more eyelid eversions there was a shift from mostly 'no staining' to minor patterns ('short horizontal bands' and 'vertical streaks') and then to more extensive patterns ('broad horizontal bands' and 'comb-shaped').The number of eyelid eversions is a confounding factor that should be controlled when investigating LWE, in particular when considering the link with dry eye or contact lens discomfort. However the cumulative exposure time did not appear to influence the LWE magnitude.

AIM For patients requiring haemodialysis, the risk of Staphylococcus aureus disease is higher in those colonized and persists while the person requires haemodialysis, necessitating frequent decolonization. However, the duration of successful decolonization is not known. This study aimed to determine the duration of efficacy of decolonization in intermittent and persistent S. aureus carriers requiring haemodialysis using two decolonization strategies. METHODS We screened 100 outpatients requiring haemodialysis for S. aureus carriage and then decolonized 14 intermittent carriers and 18 persistent carriers. Participants were invited to undertake two decolonization attempts, using systemic or topical antibiotics 12 weeks apart. Nasal swabs were taken weekly to determine the duration of successful decolonization. RESULTS Decolonization was successful in 24/32 (75%) participants and the median duration of decolonization was 35 days (95% confidence interval (CI) 11-59). The median duration of S. aureus decolonization was significantly shorter for persistent carriers (19 days, 95% CI 13-25 days) in comparison with intermittent carriers (70 days, 95% CI 61-79 days; P

To examine the regional changes in human choroidal thickness following short-term exposure to hemifield myopic defocus using optical coherence tomography (OCT).The central 26˚ visual field of the left eye of 25 healthy young adults (mean age 26 ± 5 years) was exposed to 60 min of clear vision (control session), +3 D full-field, +3 D superior retinal and +3 D inferior retinal myopic defocus, with the right eye occluded. Choroidal thickness across the central 5 mm (17°) macular region was examined before and after 60 min of defocus using a high-resolution, foveal centred vertical OCT line scan, with optical defocus simultaneously imposed using a Badal optometer and cold mirror system mounted on a Spectralis OCT device.Averaged across the central 5 mm macular area, choroidal thickness decreased by -4 ± 7 μm during the control session (p = 0.01), most likely due to the unique stimulus conditions of this study. The mean macular choroidal thickness increased during full-field (+2 ± 8 μm), inferior retinal (+3 ± 7 μm) and superior retinal myopic defocus (+5 ± 9 μm), representing a significant thickening of the choroid compared to the control session (all p 0.05). The defocus induced changes in macular choroidal thickness differed between the superior and inferior hemiretinal regions (FThese findings provide evidence supporting a local regional choroidal response to myopic defocus in the human eye, with hemifield myopic defocus leading to significant thickening of the choroid localised to the retinal region exposed to defocus. The novel finding of a localised response of the human choroid to hemifield myopic defocus, particularly in the superior hemiretina, may have important implications in optimising the optical design of myopia control interventions.

The distracting effects of mobile telephone use while driving are well known, however the effects of other sources of distraction, such as auditory navigation devices, are less well understood. Whether the effects of auditory distraction might interact with other sensory impairments, such as vision impairment, is of interest given that visual impairment is relatively common within the population, particularly as a result of uncorrected refractive error. In this experiment, 20 current drivers (mean age of 29.4 ± 3.2 years), binocularly viewed video recordings of traffic scenes presented as part of the Hazard Perception Test and responded to potential hazards within the traffic scenes. Half of the presented scenes included auditory navigation instructions as an auditory distractor. Additionally, some of the scenes were viewed through optical lenses to induce different levels of refractive blur (+0.50 DS, +1.00 DS and +2.00 DS). Hazard perception response times increased significantly (p

Introduction: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations. Methods: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients. Results: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52). Conclusions: The 2 patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve 59:357-362, 2019

To examine the magnitude and time course of central epithelial, stromal and total corneal thickness changes during sealed miniscleral contact lens wear and the influence of initial central corneal clearance upon these thickness changes.High-resolution OCT images were captured over an 8 h period of miniscleral contact lens wear (using a rotationally symmetric 16.5 mm diameter lens) in 15 young, healthy participants with normal corneae. Corneal thickness data were derived from OCT images using semi-automated image processing techniques over the central 4 mm.Changes in stromal and total corneal thickness followed a similar pattern throughout lens wear with oedema first detected 15 min after lens insertion (0.47 ± 0.09% increase in stromal and total corneal thickness, both p 0.01) which peaked after 90 min of lens wear (1.36 ± 0.24% increase in stromal and 1.18 ± 0.20% increase in total corneal thickness, both p0.01) and gradually decreased thereafter. Epithelial thickness increased slightly during the first 30 min of lens wear (0.56 ± 0.30% increase, p 0.05), then rapidly decreased reaching a minimum thickness 480 min after lens insertion (2.38 ± 0.70% decrease, p 0.05). The maximum total corneal oedema, maximum stromal oedema, and maximum epithelial thinning were not associated with the initial central corneal clearance or the extent of lens settling over the 8 h period (all p 0.05). Greater initial central corneal clearance resulted in less oxygen concentration reaching the cornea (∼2% less) based on previously published data, which manifested as ∼0.5% more central corneal oedema.Scleral lens induced corneal oedema is stromal in nature. On average, central stromal and total corneal thickness increased rapidly following lens insertion and peaked after 90 min, while central epithelial thickness gradually decreased throughout lens wear consistent with natural diurnal variation. A greater initial central corneal clearance resulted in reduced oxygen delivery to the cornea, which had minimal short-term impact upon healthy eyes, however, minimising central corneal clearance may be important in eyes with reduced endothelial cell function to minimise hypoxic stress.

Functional tests such as Motor Function Measure-32 (MFM-32), supine to stand, ascend/descend stairs permit the assessment of task-specific motor function in neuromuscular disease (NMD). The 6-min walk test (6MWT), though functional, is primarily used to assess endurance and disease progression in children with neuromuscular disorders. Barriers to 6MWT administration, in this population, can include reduced attention span due to age and inability to tolerate test length due to weakness. We propose task-specific functional deficits are related to endurance. Additionally, the 2-min walk test (2MWT) could effectively replace the 6MWT in this population. Seventy-seven participants, ages 5–18, with a variety of neuromuscular disorders performed the 6MWT, timed functional tests (TFT), and the MFM-32. Correlation and paired t-test analyses were used to compare the distance walked in the first 2 min (2MWD) to the distance walked in the entire 6 min (6MWD) and to the functional outcome measures above. The 2MWD strongly correlated with 6MWD and the other outcome measures. Paired t-test analysis also showed that the 2MWD did not differ from the distance walked in the last 2 min of the 6MWT. Although equivalence testing could not reject the claim that this difference exceeded the upper practical limit of 9.5 m, it only showed a modest overestimation of the 4-6MWD compared with the 2MWD. Together, our results support the ability of the 2MWD to predict the 6MWD, specifically in the pediatric neuromuscular disease population.

Background: The dialysis patient population in the United States continues to grow. Trends in rates of death and hospitalization among dialysis patients have important consequences for outpatient dialysis capacity and Medicare spending. Objectives: To estimate contemporary trends in rates of death and hospitalization among dialysis patients in the United States, overall and within subgroups. Methods: We used Medicare Limited Data Sets (100% sample) in 2014–2017 to estimate trends in rates of death and hospitalization among dialysis patients with Medicare Parts A and B enrollment. We used seasonal autoregressive integrated moving average models to identify secular trends in the incidence of outcomes. Results: There were 631,075 unique patients; 222,924 deaths; and 1,876,779 hospital admissions. Weekly risks of both death and hospitalization exhibited strong seasonality. However, overall weekly risks of death were 34.9, 35.4, 35.2, and 35.7 deaths per 10,000 patients in 2014–2017, respectively (p = 0.47, from a likelihood ratio test of secular trend). The overall weekly risk of hospitalization was 3.08, 3.05, 3.11, and 3.11% in 2014, 2015, 2016, and 2017, respectively (p = 0.30). There were significant secular trends in risk of death in subgroups defined by black race and residency in South Atlantic states (p < 0.05). There were also secular trends in risk of hospitalization in subgroups defined by age 20–44 years, concurrent enrollment in Medicaid, and residency in South Central states. Conclusion: For the first time since the beginning of this century, rates of both death and hospitalization among dialysis patients with Medicare fee-for-service coverage have stagnated. The reasons for this change are unknown and require detailed assessment. Persistent lack of change in clinical outcomes may alter the future expectations about dialysis patient population growth.

BACKGROUND: The National Institute on Aging and Alzheimer’s Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer’s disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer’s disease. OBJECTIVES: To stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)). DESIGN: Individuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A-T-(N)-; A+T-(N)-; A+T+(N)-; A+T-(N)+; A+T+(N)+; A-T+(N)-; A-T-(N)+; A-T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers. SETTING: Two study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study. PARTICIPANTS: One-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays. INTERVENTION (if any): Not applicable. MEASUREMENTS: Three CSF biomarkers, namely amyloid β1-42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test – Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores. RESULTS: Thirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework’s definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures. CONCLUSIONS: Increasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials.

Context.—The number of neonates with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is increasing, and in a few there are reports of intrauterine infection.Objective.—To characterize the placental pathology findings in a preselected cohort of neonates infected by transplacental transmission arising from maternal infection with SARS-CoV-2, and to identify pathology risk factors for placental and fetal infection.Design.—Case-based retrospective analysis by a multinational group of 19 perinatal specialists of the placental pathology findings from 2 cohorts of infants delivered to mothers testing positive for SARS-CoV-2: live-born neonates infected via transplacental transmission who tested positive for SARS-CoV-2 after delivery and had SARS-CoV-2 identified in cells of the placental fetal compartment by molecular pathology, and stillborn infants with syncytiotrophoblast positive for SARS-CoV-2.Results.—In placentas from all 6 live-born neonates acquiring SARS-CoV-2 via transplacental transmission, the syncytiotrophoblast was positive for coronavirus using immunohistochemistry, RNA in situ hybridization, or both. All 6 placentas had chronic histiocytic intervillositis and necrosis of the syncytiotrophoblast. The 5 stillborn/terminated infants had placental pathology findings that were similar, including SARS-CoV-2 infection of the syncytiotrophoblast, chronic histiocytic intervillositis, and syncytiotrophoblast necrosis.Conclusions.—Chronic histiocytic intervillositis together with syncytiotrophoblast necrosis accompanies SARS-CoV-2 infection of syncytiotrophoblast in live-born and stillborn infants. The coexistence of these 2 findings in all placentas from live-born infants acquiring their infection prior to delivery indicates that they constitute a pathology risk factor for transplacental fetal infection. Potential mechanisms of infection of the placenta and fetus with SARS-CoV-2, and potential future studies, are discussed.

Importance Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist. Objective To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections. Design, Setting, and Participants This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers. Interventions A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder. Main Outcomes and Measures The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence. Results The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, –3.4%; 95% CI, –6.9% to 0.1%;P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, –3.7%; 95% CI, –6.7% to –0.8%;P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, –1.6% to 2.1%;P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections. Conclusions and Relevance Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin. Trial Registration ClinicalTrials.gov Identifier:NCT02227446

Potent antithrombotic agents are routinely prescribed after percutaneous coronary intervention (PCI) to reduce ischemic complications. However, in patients who are at an increased bleeding risk, this may pose significant risks. We sought to evaluate the association between a history of gastrointestinal bleeding (GIB) and outcomes after PCI. We linked clinical registry data from PCIs performed at 48 Michigan hospitals between 1/2013 and 3/2018 to Medicare claims. We used 1:5 propensity score matching to adjust for patient characteristics. In-hospital outcomes included bleeding, transfusion, stroke or death. Post-discharge outcomes included 90-day all-cause readmission and long-term mortality. Of 30,206 patients, 1.1% had a history of GIB. Patients with a history of GIB were more likely to be older, female, and have more cardiovascular comorbidities. After matching, those with a history of GIB (n = 312) had increased post-procedural transfusions (15.7% vs 8.4%; p0.001), bleeding (11.9% vs 5.2%; p0.001), and major bleeding (2.8% vs 0.6%; p = 0.004). Ninety-day readmission rates were similar among those with and without a history of GIB (34.3% vs 31.3%; p = 0.318). There was no significant difference in post-discharge survival (1 year: 78% vs 80%; p = 0.217; 5 years: 54% vs 51%; p = 0.189). In conclusion, after adjusting for baseline characteristics, patients with a history of GIB had increased risk of post-PCI in-hospital bleeding complications. However, a history of GIB was not significantly associated with 90-day readmission or long-term survival.

The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities., Most CAR designs lack control and computation features, limiting the sophistication of the engineered immune response. Here the authors leverage a split CAR design for engineering coordinated immune responses.

Key Points Question In a large county health care system with access to inpatient and outpatient testing, is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection associated with pregnancy outcomes, maternal illness severity, placental pathology, and neonatal infections? Findings In this cohort study of 252 SARS-CoV-2–positive and 3122 negative pregnant women tested in outpatient and inpatient settings at a large county medical center, adverse pregnancy outcomes were similar, and neonatal infection occurred in 3% of infants, predominantly among infants born to asymptomatic or mildly symptomatic women. Placental abnormalities were not associated with disease severity, and the rate of hospitalization was similar to rates among nonpregnant women. Meaning These findings suggest that SARS-CoV-2 infection in pregnancy is not associated with adverse pregnancy outcomes., This cohort study evaluates the adverse outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among pregnant women and describes clinical management, disease progression, hospital admission, placental abnormalities, and neonatal outcomes., Importance Published data suggest that there are increased hospitalizations, placental abnormalities, and rare neonatal transmission among pregnant women with coronavirus disease 2019 (COVID-19). Objectives To evaluate adverse outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy and to describe clinical management, disease progression, hospital admission, placental abnormalities, and neonatal outcomes. Design, Setting, and Participants This observational cohort study of maternal and neonatal outcomes among delivered women with and without SARS-CoV-2 during pregnancy was conducted from March 18 through August 22, 2020, at Parkland Health and Hospital System (Dallas, Texas), a high-volume prenatal clinic system and public maternity hospital with widespread access to SARS-CoV-2 testing in outpatient, emergency department, and inpatient settings. Women were included if they were tested for SARS-CoV-2 during pregnancy and delivered. For placental analysis, the pathologist was blinded to illness severity. Exposures SARS-CoV-2 infection during pregnancy. Main Outcomes and Measures The primary outcome was a composite of preterm birth, preeclampsia with severe features, or cesarean delivery for abnormal fetal heart rate among women delivered after 20 weeks of gestation. Maternal illness severity, neonatal infection, and placental abnormalities were described. Results From March 18 through August 22, 2020, 3374 pregnant women (mean [SD] age, 27.6 [6] years) tested for SARS-CoV-2 were delivered, including 252 who tested positive for SARS-CoV-2 and 3122 who tested negative. The cohort included 2520 Hispanic (75%), 619 Black (18%), and 125 White (4%) women. There were no differences in age, parity, body mass index, or diabetes among women with or without SARS-CoV-2. SARS-CoV-2 positivity was more common among Hispanic women (230 [91%] positive vs 2290 [73%] negative; difference, 17.9%; 95% CI, 12.3%-23.5%; P

Same-day discharge (SDD) surgery in total hip arthroplasty (THA) has been shown to have similar outcomes to non-SDD THA in select patient populations. Hip resurfacing arthroplasty (HRA) is an alternative to THA for young, active patients, making them ideal candidates for SDD. This study compared the safety and efficacy of non-SDD HRA and SDD HRA for specific postoperative outcomes. An electronic data warehouse query was performed for procedures labeled “hip resurfacing.” Data collected included demographics, surgical factors, and quality metrics. Statistical analyses were evaluated using a graphing and statistics software program. Categorical variables were analyzed with chi-square tests and continuous variables with Student's t tests, with P P P =.01). Rates of infection, periprosthetic fractures, emergency department visits, and hospital readmissions were equivalent ( P =.99). Same-day discharge HRA is a safe and effective procedure with similar outcomes to non-SDD HRA regarding infections, fractures, emergency department visits, and readmissions. The major benefit of SDD is a shorter hospital stay that may lead to decreased cost while preserving and enhancing quality of care and patient satisfaction. [ Orthopedics . 2020;43(6):e595–e600.]

ObjectiveDetermine the relation of symptomatic and structural features of patellofemoral osteoarthritis (PFOA) to psychological characteristics and measures of pain sensitization, in older adults with or at risk of knee osteoarthritis (OA).MethodsThis study included 1112 participants from the Multicenter Osteoarthritis Study (713 females, mean age 66.8 ± SD 7.6 yrs, body mass index 29.5 ± 4.8 kg/m2). Participants were grouped based on the presence of PFOA symptoms (anterior knee pain and pain on stairs) and magnetic resonance imaging (MRI) PFOA (full-thickness cartilage lesion with bone marrow lesion): (1) patellofemoral (PF) symptoms with MRI PFOA; (2) PF symptoms without MRI PFOA; (3) MRI PFOA without PF symptoms; and (4) no PF symptoms or MRI PFOA (no PFOA). Relation of PFOA classification to depressive symptoms, catastrophizing, temporal summation (TS) and pressure pain thresholds (PPT) was evaluated using logistic (categorical variables) and linear regression (continuous variables).ResultsCompared with no PFOA, those with PF symptoms with or without MRI PFOA had significantly greater odds of depressive symptoms, catastrophizing, and patellar TS (OR range 1.5–2.01), and those with PF symptoms without MRI PFOA had significantly greater odds of wrist TS (OR 1.66). Males with PF symptoms without MRI PFOA had significantly lower pressure PPT at the patella compared with no PFOA and those with MRI PFOA only (no symptoms). There were no significant differences at the wrist for males, or the patella or wrist for females.ConclusionPersons with PFOA symptoms, regardless of MRI PFOA status, are more likely to demonstrate depressive symptoms, catastrophizing, and TS. Males with PFOA symptoms without MRI PFOA demonstrate local hyperalgesia.

Schistosome biology illuminated Schistosomiasis is caused by a parasitic flatworm about which little is known. Therefore, options to combat human disease caused by schistosome infection are limited. To aid in our quest to develop treatments, two studies undertook molecular investigations of the parasite Schistosoma mansoni . By generating a single-cell atlas, Wendt et al. identified the developmental trajectory of the flatworm, including the blood-feeding gut required for its survival in the host. From these data, they found a gene required for gut development that, when knocked out through RNA interference, confers reduced pathology in infected mice. Wang et al. performed a large-scale RNA interference survey of S. mansoni and identified an essential pair of protein kinases that can be targeted by approved pharmacological intervention (see the Perspective by Anderson and Duraisingh). These molecular investigations add to our understanding of the schistosome parasite and provide biological information that may help to combat this neglected tropical disease. Science , this issue p. 1644 , p. 1649 ; see also p. 1562

Background Foot and ankle characteristics are associated with patellofemoral pain (PFP) and may also relate to patellofemoral osteoarthritis (PFOA). A greater understanding of these characteristics and PFOA, could help to identify effective targeted treatments. Objectives To determine whether foot and ankle characteristics are associated with knee symptoms and function in individuals with PFOA. Methods For this cross-sectional study we measured weightbearing ankle dorsiflexion range of motion, foot posture (via the Foot Posture Index [FPI]), and midfoot mobility (via the Foot Measurement Platform), and obtained patient-reported outcomes for knee symptoms and function (100 mm visual analogue scales, Anterior Knee Pain Scale [AKPS], Knee injury and Osteoarthritis Outcome Score, repeated single step-ups and double-leg sit-to-stand to knee pain onset). Pearson’s r with significance set at p Results 188 participants (126 [67%] women, mean [SD] age of 59.9 [7.1] years, BMI 29.3 [5.6] kg/m2) with symptomatic PFOA were included in this study. Lower weightbearing ankle dorsiflexion range of motion had a small significant association with higher average knee pain (partial r = − 0.272, p p = 0.028), and lower scores on the AKPS (indicative of greater disability; partial r = 0.151, p = 0.042). Higher FPI scores (indicating a more pronated foot posture) and greater midfoot mobility (foot mobility magnitude) were significantly associated with fewer repeated single step-ups (partial r = − 0.181, p = 0.023 and partial r = − 0.197, p = 0.009, respectively) and double-leg sit-to-stands (partial r = − 0.202, p = 0.022 and partial r = − 0.169, p = 0.045, respectively) to knee pain onset, although the magnitude of these relationships was small. The amount of variance in knee pain and disability explained by the foot and ankle characteristics was small (R2-squared 2 to 8%). Conclusions Lower weightbearing ankle dorsiflexion range of motion, a more pronated foot posture, and greater midfoot mobility demonstrated small associations with worse knee pain and greater disability in individuals with PFOA. Given the small magnitude of these relationships, it is unlikely that interventions aimed solely at addressing foot and ankle mobility will have substantial effects on knee symptoms and function in this population. Trial registration The RCT was prospectively registered on 15 March 2017 with the Australia and New Zealand Clinical Trials Registry (ANZCTRN12617000385347).

There is debate concerning corneal oxygenation during scleral lens wear due to the potential additive hypoxic effect of a lens plus a fluid reservoir. This study investigated the agreement between theoretical models and empirical measurements of scleral lens-induced corneal edema with respect to central fluid reservoir thickness.The purpose of this study was to examine the effect of altering the fluid reservoir thickness on central corneal edema during short-term open-eye scleral lens wear and to compare these empirical measurements with predictive theoretical models.Ten participants (age, 30 ± 4 years) with normal corneas wore highly oxygen-permeable scleral lenses (141 Dk ×10 cm O2 (cm)/[(s) (cm) (mmHg)]) on separate days with either a low (mean, 144; 95% confidence interval [CI], 127 to 160 μm), medium (mean, 487; 95% CI, 443 to 532 μm), or high (mean, 726; 95% CI, 687 to 766 μm) initial fluid reservoir thickness. Epithelial, stromal, and total corneal edema were measured using high-resolution optical coherence tomography after 90 minutes of wear, before lens removal. Data were calculated or extracted from published theoretical models of scleral lens-induced corneal edema for comparison.Scleral lens-induced central corneal edema was stromal in nature and increased with increasing fluid reservoir thickness; mean total corneal edema was 0.69% (95% CI, 0.34 to 1.04%), 1.81% (95% CI, 1.22 to 2.40%), and 2.11% (95% CI, 1.58 to 2.65%) for the low, medium, and high thickness groups, respectively. No significant difference in corneal edema was observed between the medium and high fluid reservoir thickness groups (P = .37). "Resistance in series" oxygen modeling overestimated the corneal edema observed for fluid reservoir thickness values greater than 400 μm.Scleral lens-induced central corneal edema increases with increasing reservoir thickness, but plateaus at a thickness of around 600 μm, in agreement with recent theoretical modeling that incorporates factors related to corneal metabolism.

IntroductionRelieving gastrointestinal (GI) symptoms was identified as a ‘top ten’ priority by our James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF). We conducted an online survey to find out more about the effect of GI symptoms in CF.MethodsWe co-produced an online survey distributed to the CF community via web-based platforms. The survey consisted of open and closed questions designed to help us learn more about the effects of GI symptoms for people with CF (pwCF). We analysed the data using descriptive statistics and thematic analysis. We promoted the survey via social media and web-based platforms which allowed respondents from any country to take part. Our participants came from the CF community, including: adults and children with CF, parents and close family of pwCF and healthcare professionals (HCPs) working with pwCF.ResultsThere were 276 respondents: 90 (33%) pwCF, 79 (29%) family, 107 (39%) HCPs. The most commonly reported symptoms by lay respondents were stomach cramps/pain, bloating and a ‘combination of symptoms’. The top three symptoms that HCPs said were reported to them were reduced appetite, bloating and constipation. Almost all (94% (85/90)) HCPs thought medications helped to relieve GI symptoms but only 58% (82/141) of lay respondents agreed.ConclusionsOur survey has shown that GI symptoms among our participants are prevalent and intrude on daily lives of pwCF. There is a need for well-designed clinical studies to provide better evidence for management of GI symptoms and complications.

A term infant with prenatally noted ambiguous genitalia and nonpalpable gonads presented with life-threatening hyponatremia, hypertension, acidosis, and anuric renal failure requiring peritoneal dialysis at age 3 months.Sequencing confirmed 46, XY Denys-Drash syndrome (DDS) due to heterozygous Wilms tumor-1 exon 8 mutation encoding p.His445Arg. Renal US identified bilateral multifocal renal masses at age 8 months. Bilateral retroperitoneal nephrectomies found bilateral nephroblastomatosis without Wilms' tumor avoiding chemotherapy, followed by bilateral laparoscopic orchiopexies. We suggest monthly screening of 46, XY DSD cases for DDS by evaluating for proteinuria and electrolyte disarray starting at diagnosis of DSD to prevent acute life-threatening renal failure presentation.

Purpose To examine the choroidal thickness (ChT) response to short-term with-the-rule (WTR) and against-the-rule (ATR) simple myopic astigmatic defocus, with the response to spherical myopic defocus and clear vision used as control conditions. Methods The left eye of 18 healthy adults aged 28 ± 6 years was exposed to clear vision, +3 D spherical myopic defocus, +3 D × 180 WTR, or +3 D × 90 ATR astigmatic defocus for 60 minutes, over four randomly ordered visits, while their right eye was optimally corrected. The macular ChT was measured with optical coherence tomography along the vertical and horizontal meridians before and after 20, 40, and 60 minutes of defocus. Results After 60 minutes of defocus, ChT increased by +8 ± 5 µm (P < 0.001) with spherical myopic defocus, but varied with simple myopic astigmatic defocus, depending on the axis of astigmatism (P < 0.001), increasing by +5 ± 6 µm (P = 0.037) with WTR and decreasing by -4 ± 5 µm (P = 0.011) with ATR astigmatic defocus. These changes were similar across the vertical and horizontal meridians (P = 0.22). The ChT changes were greater than the change during the clear vision control condition (-1 ± 4 µm) for WTR (+5 ± 5 µm, P = 0.002) but not ATR (-4 ± 6 µm, P = 0.09) astigmatic defocus. Conclusions These results provide insights into the human ChT response to short-term astigmatic defocus and highlight a potential difference in the myopiagenic signal associated with the orientation of astigmatic blur.

Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2019. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2019, 513 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as ‘incomplete’; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as ‘definite’ and seven as ‘probable’ prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified. Keywords: Creutzfeldt-Jakob disease, prion disease, transmissible spongiform encephalopathy, disease surveillance

This case series examines the clinical conditions associated with splenic infarction of adult patients between 2010 and 2015 from computed tomographic imaging scans.

BACKGROUND The United States is currently experiencing the largest hepatitis A virus (HAV) outbreak since the introduction of a vaccine in 1996. More than 31,000 cases have been reported since 2016. Although HAV had largely been considered a foodborne pathogen in recent years, this outbreak has been spread primarily through person-to-person transmission in urban settings and has been associated with homelessness and substance use. Michigan was one of the first states to report an outbreak, with 910 reported cases between August 2016 and December 2018. METHODS We analyzed surveillance and vaccination data from Michigan using a disease transmission model to investigate how vaccine timing and coverage influenced the spatiotemporal patterns of the outbreak, distinguishing between Southeast Michigan, where the outbreak began, and the rest of the state. RESULTS We estimated that vaccination had little impact in Southeast Michigan (3% cases averted [95% confidence interval (CI) = 1%, 8%]) but had a substantial impact in the rest of the state, preventing a larger outbreak (91% cases averted [95% CI = 85%, 97%]) lasting several more years. CONCLUSIONS Our results emphasize the value of targeting populations where local transmission is not yet sustained rather than populations where transmission is already waning. Simulation modeling can aid in proactive rather than reactive decision-making and may help direct the response to outbreaks emerging in other states. See video abstract: http://links.lww.com/EDE/B704.

Background Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2–4 months, and conducted a pilot longitudinal study over 10–20 months. Results CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2–4 months in N = 29 participants and over 10–20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma. Conclusions CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, “secondary prevention” based on prodromal pathology may prove challenging; instead, “primary prevention” trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.

BACKGROUND: Sitting-related pain is a common feature of patellofemoral pain (PFP). However, little is known regarding features associated with sitting-related PFP. The aim of this study was to determine whether sitting-related PFP is associated with patellofemoral alignment, morphology and structural magnetic resonance imaging (MRI) features of the patellofemoral joint (cartilage lesions, bone marrow lesions, fat pad synovitis).METHODS: 133 individuals with PFP were included from two unique but similar cohorts. Participants were classified into one of three groups based on their response to item 8 of the Anterior Knee Pain Scale: (i) problems with sitting; (ii) sitting pain after exercise; and (iii) no difficulty with sitting. All participants underwent 3T Magnetic Resonance Imaging (MRI) to enable: (i) scoring of structural features of the patellofemoral joint with MRI Osteoarthritis Knee Score (MOAKS); and (ii) patellofemoral alignment and morphology measurements using standardised methods. The association of sitting pain to bony alignment, morphology and MOAKS features were evaluated using multinomial logistic regression (adjusted for age, sex, BMI; reference group = no difficulty with sitting).RESULTS: 82 (61.7%) participants reported problems with sitting, and 24 (18%) participants reported sitting pain after exercise. There were no significant associations between the presence of sitting pain and any morphology, alignment or structural characteristics.CONCLUSIONS: Findings indicate that PFP related to sitting is not associated with patellofemoral alignment, morphology, or structural MRI features of the patellofemoral joint. Further research to determine mechanisms of sitting-related PFP, and inform targeted treatments, are required.

Background Plantar heel pain (PHP) is present in a wide range of individuals and creates significant burden to quality of life and participation in physical activity. The high recurrence rates and persistence of PHP suggests current management options may not address all potentially modifiable factors associated with the condition. Reports of intrinsic foot muscle (IFM) atrophy in individuals with PHP, together with biomechanical evidence of their important contribution to optimal foot function, suggests that an intervention focused on IFM training may be beneficial in managing PHP. We will test the feasibility of a prospective, assessor-blinded, parallel-group, randomised clinical trial that compares foot exercise plus education to brief advice in individuals with PHP. Methods Twenty participants with PHP will be randomly allocated to one of two groups for a 12-week intervention period: (i) foot exercise plus education, or (ii) brief advice. The foot exercise plus education group will attend eight sessions with a physiotherapist and receive detailed education on self-management strategies as well as a progressive exercise program for the IFMs. The brief advice group will attend one session with a physiotherapist and receive brief information about self-management strategies and reassurance. Outcome measures will be obtained at baseline and the primary end-point of 12 weeks. Primary outcomes will be the feasibility of conducting a full-scale randomised clinical trial (RCT), and the credibility and acceptability of the foot exercise plus education intervention. Secondary outcomes will explore treatment effects, which will consist of pain, physical function, physical activity level, pain self-efficacy, perceived treatment effect, magnetic resonance and ultrasound image measurement of IFM morphology, ultrasound imaging measurement of plantar fascia thickness, IFM motor performance, foot posture, foot mobility, ankle dorsiflexion range of motion, toe flexor and plantar flexor strength/endurance. Discussion To reduce the burden of PHP on individuals and society, there is a need to establish effective treatments that are feasible and accepted by patients and health professionals. This trial will be the first to evaluate the feasibility of conducting a full-scale RCT, as well as the credibility, acceptability, and treatment effects, of education and foot exercise for PHP. The findings of this study will inform the development of a full-scale RCT. Trial registration The trial protocol was prospectively registered with the Australia and New Zealand Clinical Trial Registry (ACTRN12619000987167) on 11th July 2019.

Background and purpose Recent scientific reports and epidemiological studies have engendered mounting concerns regarding the potential human-to-human transmissibility of non-prion neurodegenerative and related diseases. This study investigated whether recipients of cadaveric pituitary hormone treatments are at increased risk of death from non-prion neurodegenerative and related diseases. Methods A retrospective national cohort study based on death certificates of recipients of the cadaveric pituitary hormone treatments (n = 184) as part of the Australian Human Pituitary Hormone Program (AHPHP; n = 2940) 1967–1985. Standardised mortality ratios (SMR) from non-prion neurodegenerative and other diseases were estimated based on the Australian population. Results Allowing for potential diagnostic mis-attributions, there was no significant increase in the SMR from non-prion central nervous system (CNS) neurodegenerative disease, especially dementia and/or Alzheimer’s disease (0.47; [95% CI: 0.19, 1.12] P = 0.081). The SMR for intra-cerebral haemorrhage, potentially related to cerebral amyloid angiopathy (CAA), was increased (2.77; [95% CI: 1.12–5.75] P = 0.009), although accommodation of possible mis-diagnosis through conflation of this category with other stroke causes of death emphasising likely intra-cranial haemorrhage showed no persisting significant increase in mortality in cadaveric pituitary hormone recipients, including all deaths recorded as due to intra-cranial haemorrhage (1.72; [95% CI: 0.80, 3.26] P = 0.123). Conclusion In the setting of recent evidence strongly supporting the likelihood of brain-to-brain horizontal transmission and subsequent propagation and deposition of abnormally folded proteins associated with non-prion neurodegenerative and related disorders, this study offers further tentative support for deaths directly stemming from transmission of non-prion disease related to cadaveric pituitary hormone treatment. Acknowledging the limitations of the present study, however, ongoing detailed assessments of this potential risk are necessary.

Early detection of Primary Immunodeficiencies Disorders (PIDDs) is of paramount importance for effective treatment and disease management. Many PIDDs would be strong candidates for newborn screening (NBS) if robust screening methods could identify patients from dried blood spots (DBS) during the neonatal period. As majority of congenital PIDDs result in the reduction or absence of specific proteins, direct quantification of these target proteins represents an attractive potential screening tool. Unfortunately, detection is often limited by the extremely low protein concentrations in blood cells and limited blood volume present in DBS. We have recently developed a robust novel method for quantification of low abundance proteins in DBS for PIDDs using peptide immunoaffinity enrichment coupled to selected reaction monitoring (immuno-SRM). Here, we further generated a multiplexed Immuno-SRM panel for simultaneous screening of eight signature peptides representing five PIDD-specific and two cell-type specific proteins from DBS. In samples from 28 PIDD patients including two carriers, representing X-Linked Agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), X-Linked Chronic Granulomatous Disease (XL-CGD), DOCK8 Deficiency and ADA deficiency, peptides representing each disease are significantly reduced relative to normal controls and patient identification had excellent agreement with clinical and molecular diagnosis. Also included in the multiplex panel are cell specific markers for platelets (CD42) and Natural Killer Cells (CD56). In patients with WAS, CD42 levels were found to be significantly reduced consistent with characteristic thrombocytopenia. A patient with WAS analyzed before and after bone marrow transplant showed normalized WAS protein and platelet CD42 after treatment highlighting the ability of immuno-SRM to monitor the effects of PIDD treatment. The assay was readily reproduced in two separate laboratories with similar analytical performance and complete agreement in patient diagnosis demonstrating the effective standardized methods. A high-throughput Immuno-SRM method screens PIDD-specific peptides in a 2.5-min runtime meeting high volume NBS workflow requirements was also demonstrated in this report. This high-throughput method returned identical results to the standard Immuno-SRM PIDD panel. Immuno-SRM peptide analysis represents a robust potential clinical diagnostic for identifying and studying PIDD patients from easily collected and shipped DBS and supports a significant potential for early PIDD diagnosis through newborn screening.

Purpose: The sclera plays an important role in the biomechanical stability of the eye. We aimed to examine if changes in the shape of the anterior sclera occur in response to accommodation and convergence. Methods: Thirty-six healthy young adult participants aged between 18 and 30 years including 18 myopes (–0.5 to –4.0 D) and 18 emmetropes (+0.5 to –0.25 D) were recruited. Eye surface profilometry was used to evaluate the anterior eye surface shape before and during visual tasks involving accommodation (5.0 D demand), simulated convergence (9° demand) and their combination. The changes in the sagittal height and axial radius of curvature of the nasal (n = 25) and temporal (n = 31) corneal periphery and anterior sclera were analysed in those participants with complete and reliable data on these sides. Results: Significant changes were confined to the nasal anterior scleral surface. A significant forward movement of the surface accompanied accommodation (mean change: 5 ± 2 µm), convergence (19 ± 6 µm), and their combination (16 ± 6 µm). There was flattening with convergence (0.092 ± 0.044 mm) and with the combination of accommodation and convergence (0.201 ± 0.071 mm). The changes in response to accommodation and convergence increased peripherally. Changes were not significantly different between low to moderate myopes and emmetropes. Conclusions: Accommodation and simulated convergence affect the nasal anterior scleral shape, with the greatest changes associated with convergence and being most evident in the more peripheral nasal scleral regions.

Background β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer’s disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology. Methods Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1–42) (Aβ42), Aβ (1–40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging. Results Ratios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic—area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement ~ 90%), compared with individual biomarkers. Conclusion Strong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.

Introduction Definitive clinical studies to determine the optimal dialysate lactate concentration to prescribe during frequent hemodialysis when using the NxStage System One dialysis delivery system at low dialysate flow rates have not been reported. Methods We used clinical data from patients who transferred from in-center thrice-weekly hemodialysis (ICHD) to daily home hemodialysis using the NxStage System One and the H+ mobilization model to calculate acid generation rates in patient sub-groups during the FREEDOM study. Assuming those acid generation rates were representative, we then predicted using the H+ mobilization model the effect of using dialysate lactate concentrations of 40 and 45 mEq/L on predialysis serum total carbon dioxide (tCO2 ) concentrations in patients who transfer from ICHD to short and nocturnal frequent hemodialysis prescriptions used in current clinical practice; the prescriptions evaluated varied by treatment frequency, dialysate volume per treatment, and treatment times. Findings With frequencies of four to six treatments per week and treatment times of 170 to 210 minutes per treatment, the effect of dialysate lactate concentration was primarily dependent on weekly dialysate volume. For weekly dialysate volumes of 150 to 160 L per week, use of dialysate lactate concentrations of 45 mEq/L, but not 40 mEq/L, resulted in an increase of predialysis serum tCO2 concentration. When longer treatment times typical of nocturnal frequent hemodialysis were evaluated, model predictions showed that the use of dialysate lactate concentration of 45 mEq/L may not be appropriate for many patients because of excessive increases in predialysis serum tCO2 concentration. Reducing dialysate volume from 60 to 30 L may limit the increase in predialysis serum tCO2 concentration when patients transfer from ICHD to nocturnal frequent hemodialysis. Discussion Predictions from the H+ mobilization model show that dialysate lactate concentration and weekly dialysate volume are the primary prescription parameters for optimizing predialysis serum tCO2 concentration during short and nocturnal frequent hemodialysis.