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Objective Use of colour duplex ultrasound (CDUS) and computed tomography angiography (CTA) for infrarenal endovascular aortic aneurysm repair (EVAR) surveillance differs in internationally published guidelines. This study aimed firstly to compare CDUS detection of significant sac abnormalities with CTA. Secondly, a sensitivity analysis was conducted to compare financial estimates of the, predominantly CDUS based, local and Society of Vascular Surgery (SVS) protocols, the risk stratified European Society of Vascular Surgery (ESVS) protocol, and the CTA based National Institute of Health and Care Excellence (NICE) protocol. Methods Agreement between CDUS and CTA was assessed for detection of significant sac abnormalities. Surveillance protocols were extrapolated from published guidelines and applied to infrarenal EVAR patients active on local surveillance at a large, single centre. Surveillance intensity was dependent on presence of endoleak and subsequent risk of treatment failure in accordance with surveillance recommendations. Estimates for each surveillance protocol were inclusive of a range of published incidences of endoleak, contrast associated acute kidney injury (AKI), and excess hospital bed days, and estimated for a hypothetical five year surveillance period. Results The kappa coefficient between CDUS and CTA for detecting sac abnormalities was 0.68. Maximum five year surveillance cost estimates for the 289 active EVAR patients were £272 359 for SVS, £230 708 for ESVS, £643 802 for NICE, and £266 777 for local protocols, or £1 270, £1 076, £3 003, and £1 244 per patient. Differences in endoleak incidence accounted for a 1.1 to 1.4 fold increase in costs. AKI incidence accounted for a 3.3 to 6.2 fold increase in costs. Conclusion A combined CTA and CDUS EVAR surveillance protocol, with CTA reserved for early seal assessment and confirmatory purposes, provides an economical approach without compromising detection of sac abnormalities. AKI, as opposed to direct imaging costs, accounted for the largest differences in surveillance cost estimates.

Instability of the craniocervical junction in paediatric patients with skeletal dysplasia poses a unique set of challenges including anatomical abnormalities, poor bone quality, skeletal immaturity and associated general anaesthetic risks. Instrumented fixation provides optimal stabilisation and fusion rates. The small vertebrae make the placement of C2 pedicle screws technically demanding with low margins of error between the spinal canal and the vertebral artery. We describe a novel clinical strategy utilising 3D-printed spinal screw trajectory guides (3D-SSTG) for individually planned C2 pedicle and laminar screws. The technique is based on a pre-operative CT scan and does not require intraoperative CT imaging. This reduces the radiation burden to the patient and forgoes the associated time and cost. The time for model generation and sterilisation was

The aim of this study was to develop and validate a deep learning-based system to detect peripheral neuropathy (DN) from retinal colour images in people with diabetes. Retinal images from 1561 people with diabetes were used to predictDN diagnosed on vibration perception threshold. A total of 189 had diabetic retinopathy (DR), 276 had DN, and 43 had both DR and DN. 90% of the images were used for training and validation and 10% for testing. Deep neural networks, including Squeezenet, Inception, and Densenet were utilized, and the architectures were tested with and without pre-trained weights. Random transform of images was used during training. The algorithm was trained and tested using three sets of data: all retinal images, images without DR and images with DR. Area under the ROC curve (AUC) was used to evaluate performance. The AUC to predict DN on the whole cohort was 0.8013 (±0.0257) on the validation set and 0.7097 (±0.0031) on the test set. The AUC increased to 0.8673 (±0.0088) in the presence of DR. The retinal images can be used to identify individuals with DN and provides an opportunity to educate patients about their DN status when they attend DR screening.

Background: Increasing numbers of adolescents and young adults with cancer (AYACs) are surviving long term, highlighting the importance of effective oncofertility communication. We undertook this s...

Publicly available skin image datasets are increasingly used to develop machine learning algorithms for skin cancer diagnosis. However, the total number of datasets and their respective content is currently unclear. This systematic review aimed to identify and evaluate all publicly available skin image datasets used for skin cancer diagnosis by exploring their characteristics, data access requirements, and associated image metadata. A combined MEDLINE, Google, and Google Dataset search identified 21 open access datasets containing 106 950 skin lesion images, 17 open access atlases, eight regulated access datasets, and three regulated access atlases. Images and accompanying data from open access datasets were evaluated by two independent reviewers. Among the 14 datasets that reported country of origin, most (11 [79%]) originated from Europe, North America, and Oceania exclusively. Most datasets (19 [91%]) contained dermoscopic images or macroscopic photographs only. Clinical information was available regarding age for 81 662 images (76·4%), sex for 82 848 (77·5%), and body site for 79 561 (74·4%). Subject ethnicity data were available for 1415 images (1·3%), and Fitzpatrick skin type data for 2236 (2·1%). There was limited and variable reporting of characteristics and metadata among datasets, with substantial under-representation of darker skin types. This is the first systematic review to characterise publicly available skin image datasets, highlighting limited applicability to real-life clinical settings and restricted population representation, precluding generalisability. Quality standards for characteristics and metadata reporting for skin image datasets are needed.

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.

Introduction Despite the availability of Australian clinical practice guidelines, evidence suggests there are substantial variations in care within primary care settings. Use of web-based guidelines and tools has the potential to assist healthcare providers in meeting clinical guidelines, thereby reducing unwarranted variations in care. HealthPathways is a web-based clinical guide to assist primary care clinicians with assessment, management, and localised referral pathways for various health conditions. HealthPathways has been implemented in many areas across Australia to facilitate the achievement of better integration of care for patients. This study aimed to evaluate the effectiveness of HealthPathways in assisting GPs to provide appropriate care for five paediatric conditions. Theory/methods A quasi-experimental design was used to test the hypothesis that HealthPathways improves the quality of patient care. GPs documented their assessment of hypothetical patient scenarios with or without the use of HealthPathways. A marking rubric was used to assess adherence to clinical indicators, and percent agreement and inter-rater reliability tests were calculated. Clinical indicators were aligned to those from the CareTrack Kids project. Results Overall, 50 GPs and GP registrars participated in the study. Across all conditions, the proportion of indicators met were higher for those who used HealthPathways compared to those participants who didn’t use HealthPathways, but only one of these differences was statistically significant (GOR, p=0.03). On average, participants met only 57% of all clinical indicators used in the study. Discussion This study showed that participants who used HealthPathways scored higher than participants who did not, across all five conditions. However, these differences were generally not statistically significant, especially once demographic differences were accounted for. Nonetheless, statistical significance may not reflect clinical significance. For instance, adherence to an additional one or two clinical indicators may make an important clinical difference to the quality of treatment and care provided by a healthcare professional. Poor adherence to clinical indicators has been demonstrated in other similar studies in Australia and overseas, highlighting that these results are widespread and unlikely to be unique to western Sydney. Conclusions The study demonstrated that HealthPathways may have some impact on GPs’ ability to provide quality care, through better adherence to clinical guidelines. The results also suggest there may be a need for additional assistance for primary care practitioners to ensure their care meets clinical guidelines and results in positive outcomes for patients. Lessons learned Considerable time was allocated to clinical reviews of the patient scenarios, development of the rubric, and pilot testing the study procedure. This contributed substantially to the overall robustness and quality of the study protocol, allowing for replication in other regions, with very minimal changes required. Limitations The laboratory setting did not allow GPs to interact with a patient by asking follow-up questions, or to utilise visual, behavioural, and verbal cues in assessing the patient. The use of convenience sampling and the relatively small sample size limits the generalisability of the findings. Suggestions for future research Further research in other geographic regions would be beneficial to determine the impact of HealthPathways on a broader scale.

Preterm birth (PTB) is common and has negative impacts on infant health. While some maternal risk factors have been identified, including age under 20 or over 40, substance abuse, low BMI, and racism, less is known about the impact of environmental exposures like high heat. We combined 154,157 records of live births occurring in Minnesota between 2009 and 2015 with hourly weather records collected from the Minneapolis&ndash, St. Paul airport. We tested if maternal heat wave exposure (a seven-day period with a mean daily high temp of 37 &deg, C) immediately prior to birth leads to a higher risk of preterm birth. Additional covariates included maternal age, race/ethnicity, educational status, and residence in the seven-county Minneapolis&ndash, St. Paul metro area. Pregnant women exposed to a seven-day heat wave of 37 &deg, C or higher experienced a higher relative risk of PTB compared to women who did not experience a heat wave (1.14 risk ratio (RR), 1.0&ndash, 1.3 95% confidence interval (CI)). The result is robust to controls for a woman&rsquo, s age, race/ethnicity, educational attainment, place of residence, and year of the birth. Children born to Black women with college degrees who are exposed to heat waves experience a higher relative risk of PTB compared to White women with college degrees in a heat wave (2.97 RR, 1.5&ndash, 6.1 95% CI). Summer heat waves are associated with higher risk of PTB in late-term pregnancies in Minnesota.

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.

Dehydration can affect brain structure which has important implications for human health. In this study, we measured regional changes in brain structure following acute dehydration. Healthy volunteers received a structural MRI scan before and after an intensive 90‐min thermal‐exercise dehydration protocol. We used two techniques to determine changes in brain structure: a manual point counting technique using MEASURE, and a fully automated voxelwise analysis using SIENA. After the exercise regime, participants lost (2.2% ± 0.5%) of their body mass. Using SIENA, we detected expansion of the ventricular system with the largest change occurring in the left lateral ventricle (P = 0.001 corrected for multiple comparisons) but no change in total brain volume (P = 0.13). Using manual point counting, we could not detect any change in ventricular or brain volume, but there was a significant correlation between loss in body mass and third ventricular volume increase (r = 0.79, P = 0.03). These results show ventricular expansion occurs following acute dehydration, and suggest that automated longitudinal voxelwise analysis methods such as SIENA are more sensitive to regional changes in brain volume over time compared with a manual point counting technique. Hum Brain Mapp 2009. © 2007 Wiley‐Liss, Inc.

Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.

Background Determining the anatomic compartments that contribute to plasma HIV-1 is critical to understanding the sources of residual viremia during combination antiretroviral therapy (ART). We analyzed viral DNA and RNA populations in the plasma and tissues from macaques infected with SIV containing HIV-1 RT (RT-SHIV) to identify possible sources of persistent viremia and to investigate the effect of ART on viral replication in tissues. Tissues were collected at necropsy from four pigtailed macaques infected for 30 weeks with a diverse population of RT-SHIV. Two animals (6760 and 8232) were untreated and two animals (8030 and 8272) were treated with efavirenz, tenofovir, and emtricitabine for 20 weeks. Results A total of 1800 single-genome RT-SHIV pol and env DNA and RNA sequences were analyzed from the plasma, PBMCs, axillary and mesenteric lymph nodes, spleen, thymus, small intestine, bone marrow, lung, and brain. Analyses of intracellular DNA and RNA populations revealed that the majority of proviruses in tissues from untreated animal 8232 were not expressed, whereas a greater proportion of proviruses in tissues were expressed from 6760. Few intracellular RNA sequences were detected in treated animals and most contained inactivating mutations, such as frame shifts or large deletions. Phylogenetics showed that RT-SHIV DNA populations in tissues were not different from virus in contemporary plasma samples in the treated or untreated animals, demonstrating a lack of anatomic compartmentalization and suggesting that plasma viremia is derived from multiple tissue sources. No sequence divergence was detected in the plasma or between tissues in the treated animals after 20 weeks of ART indicating a lack of ongoing replication in tissues during treatment. Conclusions Virus populations in plasma and tissues did not differ significantly in either treated or untreated macaques, suggesting frequent exchange of virus or infected cells between tissues and plasma, consistent with non-compartmentalized and widely disseminated infection. There was no genetic evidence of ongoing replication in tissues during suppressive ART. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0212-2) contains supplementary material, which is available to authorized users.

Background: The calcaneal displacement osteotomy is frequently used by foot and ankle surgeons to correct hindfoot angular deformity. Headed compression screws are often used for this purpose, but a common complication is postoperative plantar heel pain from prominent hardware. We evaluated hardware removal rates after calcaneal displacement osteotomies and analyzed technical factors including screw size, position, and angle. We hypothesized that larger screws placed more plantarly would have been removed more frequently. We also believed that although 2 smaller screws cost more initially, when removal rates and cost are accounted for, savings would be demonstrated with this technique. Methods: We retrospectively collected data on type of fixation, cost of fixation, and frequency of removal. After exclusions we had 30 patients in our screw removal cohort and 119 in our screws retained cohort. A basic cost analysis and statistical analysis was performed. Results: The small screw group had a hardware removal rate of 9% (4/43) compared to 25% (26/104) of the larger screw group ( P = .032). While the cost of 2 smaller screws is more than that of 1 larger screw, when the cost of removal and the rates of doing so are considered, the smaller screws resulted in substantial cost savings. Conclusion: Technical considerations for the medial displacement calcaneal osteotomy, including the use of multiple smaller screws, provided for a lower rate of hardware removal and likely decreased long-term costs. Level of Evidence: Level III, comparative series.

Despite continuous improvement of immunosuppression, small bowel transplantation (SBT) is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need to uncover novel insights that will lead to strategies to achieve better control of ACR. We hypothesized that particular miRNAs provide critical regulation of the intragraft immune response. The aim of our study was to identify miRNAs involved in intestinal ACR. We examined 26 small intestinal mucosal biopsies (AR/NR group; 15/11) obtained from recipients after SBT or multivisceral transplantation. We investigated the expression of 384 mature human miRNAs and 280 mRNAs associated with immune, inflammation and apoptosis processes. We identified differentially expressed 28 miRNAs and 58 mRNAs that characterized intestinal ACR. We found a strong positive correlation between the intragraft expression levels of three miRNAs (miR-142-3p, miR-886-3p and miR-132) and 17 mRNAs including CTLA4 and GZMB. We visualized these miRNAs within cells expressing CD3 and CD14 proteins in explanted intestinal allografts with severe ACR. Our data suggested that miRNAs have a critical role in the activation of infiltrating cells during intestinal ACR. These differences in miRNA expression patterns can be used to identify novel biomarkers and therapeutic targets for immunosuppressive agents.

A standardized grading scheme for the assessment of acute cellular rejection (ACR) in small-intestine transplantation was proposed in 2003 at the Eighth International Small Intestinal Transplantation Symposium. We have implemented the current grading scheme for ACR in small-bowel transplantation since October 2003. The pathologic diagnoses of those small-intestine biopsy samples, including ACR grade and other supplementary findings were evaluated. A total of 3484 small intestine biopsy samples from 155 patients were available for evaluation in this study. Frequency of grades 0, indeterminate, 1, 2, and 3 acute cellular rejection was 33.9%, 49.1%, 12.6%, 3.7%, and 0.8%, respectively. Duration of ACR episode strongly correlated with grade of ACR episode (P < .001). Other supplementary findings included acute vascular rejection component, 2.2%; increase in lymphoplasmacytic infiltrate in lamina propria, 15.7%; mucosal fibrosis, 0.4%; and regenerative changes, 0.3%. Our data substantiate that this grading system is reliable and useful for clinical decision making in bowel transplantation. We suggest that an assessment and quantification of supplementary findings be considered a component of the International Pathology Grading Scheme.

Mycophenolate mofetil (MMF) has become an important and commonly used drug for maintenance immunosuppression therapy in recipients of all types of organ transplants. The drug is an antimetabolite that blocks the de novo pathway of purine synthesis. Although it selectively inhibits B- and T-lymphocyte proliferation, enterocytes are partially susceptible to MMF. One of the main limitations of this drug is gastrointestinal toxicity, with diarrhea the most frequently reported adverse effect. Most studies of MMF-associated gastrointestinal toxicity have been performed in patients with solid-organ transplants, although no data on changes related to MMF toxicity in bowel allografts have been published in the English literature. We evaluated mucosal intestinal biopsy tissue from patients with multivisceral transplants receiving MMF therapy. Our objective was to find morphologic changes that might be attributed to MMF toxicity, as well as changes that could differentiate MMF toxicity from acute rejection. Examination of the surface epithelium, lamina propria, and crypts in this small group of patients showed no specific changes that could be associated with MMF toxicity. Changes such as graft-vs-host disease or inflammatory bowel disease described in previous studies of solid-organ transplantation were not observed. Larger studies and the use of special stains and new markers might be necessary to characterize possible patterns of MMF toxicity and their differences from acute rejection.

Ten patients who use the Ineraid cochlear implant were tested on a consonant identification task. The stimuli were 16 consonants in the "aCa" environment. The patients who scored greater than 60 percent correct were found to have high feature information scores for amplitude envelope features and for features requiring the detection of high-frequency energy. The patients who scored less than 60 percent correct exhibited lower scores for all features of the signal. The difference in performance between the two groups of patients may be due, at least in part, to differences in the detection or resolution of high-frequency components in the speech signal.

Pitch scaling was assessed for 10 normal-hearing listeners and 8 patients who use the Ineraid multichannel cochlear implant. For two patients who were excellent users of the prosthesis, pitch increased over a wide range of frequencies (100 Hz to 2333-3000 Hz). For three patients who were above average users of the prosthesis, pitch increased with frequency over a smaller range (100 Hz to 1200-2300 Hz). For three patients who demonstrated poor word recognition ability, pitch increased with frequency over a very small range (100 Hz to 600-1000 Hz). These results suggest that differences in speech understanding among patients who use the Ineraid may be accounted for, in part, by the range of pitch available through the implant.

The intelligibility of a 16-item consonant set was assessed for 10 patients who use the Symbion four-channel cochlear implant. The patients were selected on the basis of "good" speech recognition scores. For each patient, consonant intelligibility was assessed when his/her processor was configured to pass from one to four channels of information. The results suggest, most generally, that two channels, one low frequency and one high frequency, provide most of the information about consonant identity.

In this report we describe the vowel identification ability of eight patients who scored above 70% correct on a test of spondee word identification. The stimuli were 12 synthetic vowels in "bVt" format. The vowels differed in the frequency of F1, F2, and F3. The mean identification accuracy was 60% correct. Front vowels and dipthongs, (3), and (u) were relatively well identified. The vowels in "but," "bought," and "bout," which were characterized by high F1s and low F2s were not well identified. The results are consistent with a model of recognition in which F1 is specified, with relatively good accuracy, by a rate code and in which extreme values of F2 are specified by a rate/place code.

We describe the word recognition ability of 50 patients who use the multichannel cochlear implant manufactured by Symbion, Inc. The median scores for open set tests involving auditory stimulation alone were: 14% correct (range 0 to 60) for monosyllabic words, 44% correct (range 0 to 100) for spondees, and 45% correct (range 0 to 100) for words in the Everyday CID Sentences. In the visual stimulation condition of the Everyday CID Sentences, the median score was 64% correct (range 0 to 100). In the visual plus auditory stimulation condition, the median score was 99% correct (range 46 to 100). These results demonstrate that relatively good speech understanding can be achieved using a cochlear implant which employs only a few channels of stimulation and which simultaneously activates monopolar electrodes.

The phonetic identification ability of an individual (SS) who exhibits the best, or equal to the best, speech understanding of patients using the Symbion four‐channel cochlear implant is described. It has been found that SS: (1) can use aspects of signal duration to form categories that are isomorphic with the phonetic categories established by listeners with normal auditory function; (2) can combine temporal and spectral cues in a normal fashion to form categories; (3) can use aspects of fricative noises to form categories that correspond to normal phonetic categories; (4) uses information from both F1 and higher formants in vowel identification; and (5) appears to identify stop consonant place of articulation on the basis of information provided by the center frequency of the burst and by the abruptness of frequency change following signal onset. SS has difficulty identifying stop consonants from the information provided by formant transitions and cannot differentially identify signals that have identical F1’s and relatively low‐frequency F2’s. SS’s performance suggests that simple speech processing strategies (filtering of the signal into four bands) and monopolar electrode design are viable options in the design of cochlear prostheses.