Coronavirus disease 2019 (COVID-19) is the pandemic of major global concern that has been causing several tragic events ever since December 2019. Infection with COVID-19 varies from being asymptomatic or mild with general unwellness to severe with difficulty in breathing and even mortality. Recently, several reports signified the persistence of symptoms or the development of new ones for weeks or months after the virus has gone, the so-called “post-acute COVID-19 syndrome.” This article presents a 31-year-old female with post-acute COVID-19 syndrome showing parosmia, dysgeusia, and tongue feature changes as simultaneous newly developed manifestations after the viral clearance. Follow-up revealed complete remission of manifestations after one month. Post-acute COVID-19 syndrome can show oral manifestations. Despite the lack of evidence regarding the etiology, risk factors, and consequences of post-COVID-19 syndrome, it is important to monitor COVID-19 survivors to avoid complications during their recovery period. Coronaviridae family [Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped RNA virus and a member of the e family –5.Post-acute COVID-19 syndrome, also called “long COVID,” “COVID long haul syndrome,” and “post-COVID syndrome” (PCS), is known as the persistence of symptoms or the development of complications for more than three to four weeks after the onset of acute viral symptoms and where SARS-CoV-2 is not isolated , 7. FatiThe aim of this report is to contribute to the current literature by presenting a case of the newly described entity post-acute COVID-19 syndrome showing parosmia , dysgeusia, and greasy white coated tongue with prominent papillae as simultaneous newly developed manifestations for four weeks after polymerase chain reaction (PCR) negativity. To the best of our knowledge, this is the first case report to document tongue manifestations in PCS.A 31-year-old female patient presented to the oral medicine clinic complaining of dysgeusia; she lost the ability to distinguish food with the retention of sweet and salty sensations only. Moreover, she was concerned about an unpleasant greasy white tongue and a distorted sense of olfaction where everything smelled like chemicals (parosmia). The patient reported the onset of these symptoms two days earlier with significant worsening. The condition was persistent and affected her quality of life, the thing that made her seek professional assistance.Past medical history revealed that the patient is atopic; she reported occasional administration of antihistamines (loratadine 10 mg once daily) whenever hypersensitivity reactions are experienced. The patient was also suffering from episodes of irritable bowel syndrome for ten years. She is used to administering simethicone (125 mg 2-3 times daily) during exacerbations to relief bloating. Dental and family histories were negative.Fourteen days earlier, the patient was COVID-19 positive. She suffered from sore throat, persistent low-grade fever 38°C), nasal congestion and itching, conjunctivitis, nausea, abdominal pain, diarrhea, fatigue, and severe joint pain. Chest computed tomography and all the relevant laboratory investigations were normal. The patient was scheduled on a treatment protocol for COVID-19 in accordance to her current medical condition following the guidelines set by the Egyptian Ministry of Health and Population [°C, nasalExtraoral examination was normal. Intraoral examination revealed an unscrapable white coat over the dorsum of the tongue with prominent papillae. Bilateral indentation marks from reported continuous tongue sucking were also noted . Tongue Based on history and clinical examination, the patient was diagnosed with post-acute COVID-19 syndrome.The patient was reassured, and a comprehensive explanation about her condition was performed. She was instructed about the appropriate oral hygiene measures, and prophylactic medications were prescribed to prevent superimposed infections . Daily vitamin C (1000 mg) and zinc (50 mg) supplements were also prescribed to enhance recovery.Follow-up appointments were scheduled at short intervals (one to two visits per week throughout four weeks) to monitor manifestation improvement Figures . Phone cAfter one month of treatment , the tongue features were restored to normal, and the patient reported complete resolution of parosmia and dysgeusia. No adverse side effects were noted. A detailed documentation of the changes in all manifestations of PCS is shown as a timeline in Coronavirus disease 2019 outbreak has been gaining the world's attention to date. Several studies have discussed the nature and manifestations of COVID-19. However, scientists cannot predict its course and sequelae in patients during and after the viral infection [There is a growing body of evidence about the symptoms and risk factors of PCS. In the present case, the patient's sex and some of the clinical features at the viral stage as persistent fever and infection duration are coincident with the emerging literature. Mahmud et al.  in theirOlfactory dysfunction and dysgeusia have been notably discussed in the context of SARS-CoV-2 infection. The pathogenesis of anosmia (loss of smell sensation) in COVID-19 can be explained by several mechanisms like nasal airway obstruction, olfactory center and sensory neural damage, olfactory epithelium, and supporting cell dysfunction. On the other hand, it was found that salivary glands and the oral mucosa are vulnerable to being attacked by SARS-CoV-2 through angiotensin converting enzyme 2 receptors (ACE2) leading to dysgeusia. Other mechanisms for dysgeusia have been proposed as zinc deficiency, cranial nerve dysfunction, and others .In general, chemosensory dysfunction (olfactory and gustatory) was found to be linked to stress, anxiety, and depression. Depression was found to be associated with high levels of glucocorticoids and inflammatory cytokines which can result in compromised olfactory neural proliferation . MoreoveDifferent tongue coat changes were reported in COVID-19 patients. Pang et al.  found thTo date, the exact pathophysiology of PCS is not well established. Nonetheless, the implication of physiologic viral changes, host immune, and inflammatory response to the invading pathogen and critical illness have all been proposed as possible mechanisms of PCS . The preDue to the increasing sequelae of COVID-19 in the postviral stages on a multiorgan scale, studies highlighted the importance of monitoring COVID-19 patients for longer durations after the viral clearance. This would help understand more about this pandemic through rigorous investigation, management, and documentation of the newly evolving symptoms. The provided care should involve multidisciplinary cooperation in both inpatient and outpatient settings in accordance to the prevailing symptoms and their severity .One possible limitation of the present case is the lack of reagents and materials used for olfactory and taste function tests. Chemosensory function testing would have provided more details about the changes of parosmia and dysgeusia throughout the treatment and follow-up durations.Coronavirus disease 2019 is an infectious disease with heterogeneous literature and international health challenges. New symptoms can develop post-COVID-19 clearance. Parosmia, dysgeusia, and white tongue coating with greasiness can be symptoms of post-acute COVID-19 syndrome. Meticulous patient care through long-term follow-up is crucial to avoid complications during convalescence.


Background and purpose — We have previously shown that children with minimally displaced metaphyseal both-bone forearm fractures, who were treated with a below-elbow cast (BEC) instead of an above-elbow cast (AEC), experienced more comfort, less interference in daily activities, and similar functional outcomes at 7 months’ follow-up (FU). This study evaluates outcomes at 7 years’ follow-up.Patients and methods — A secondary analysis was performed of the 7 years’ follow-up data from our RCT. Primary outcome was loss of forearm rotation compared with the contralateral forearm. Secondary outcomes were patient-reported outcome measures (PROMs) consisting of the ABILHAND-kids and the DASH questionnaire, grip strength, radiological assessment, and cosmetic appearance.Results — The mean length of FU was 7.3 years (5.9–8.7). Of the initial 66 children who were included in the RCT, 51 children were evaluated at long-term FU. Loss of forearm rotation and secondary outcomes were similar in the 2 treatment groups.Interpretation — We suggest that children with minimally displaced metaphyseal both-bone forearm fractures should be treated with a below-elbow cast. Long-term follow-up of children with forearm fractures is scarce but essential, because the remodeling capacity by growth can behave as a friend or an enemy. Previous studies with short-term follow-up shown that metaphyseal both-bone fractures of the distal forearm could safely be treated with a below-elbow cast (BEC) : using the Dutch version of the DASH and ABILHAND-kids questionnaire, wrist and elbow range of motion, grip strength (using a JAMAR Dynamometer), VAS scores regarding cosmetic appearance (scars and angulation of the forearm), and radiological assessment of malunion  measured forearm rotation, flexion, and extension of wrist and elbow using visual estimation and a goniometer with increments of 2°. The follow-up was organized in the patient’s original hospital of inclusion. Both arms were examined to determine functional loss. Grip strength was measured using a Jamar dynamometer , conducting one measurement comparing both arms. Patients were asked to fill in 2 PROMs, the DASH and the ABILHAND-kids questionnaire, and a VAS for cosmetic appearance. Cosmetic appearance was assessed by the patient, or by the parents in children < 12 years, and by the investigator (LD).The radiological assessment consisted of a anteroposterior and lateral radiograph of the wrist. One of the authors (PE), measured the angulation of the radius and ulna  between the included patients versus those lost to follow-up. Long-term results of primary and secondary outcome measures of the 2 treatment groups (AEC vs. BEC) were compared. Differences were analyzed using 1-way ANOVA to correct for multiple comparisons. Results are presented as mean SD or 95% confidence interval (CI). To assess the inter-rater reproducibility of radiographic assessment 2 authors (PE and LD) measured angulations of the radius and ulna of 25 cases . Intra-class correlation coefficient was calculated. Statistical analyses were performed using IBM SPSS Statistics version 23.Ethics approval was obtained for this post-trial FU study from regional medical ethics committee (NL41839.098.12). The original RCT was registered in ClinicalTrials.gov NCT 00397995. The current author did not receive any funding. The author of the primary study received a grant from the Anna Foundation, the Netherlands. None of the authors declare any conflicts of interest.Between 2006 and 2010, 66 children were included in the RCT by Colaris et al.  and 51 oWe present the results of a multicenter randomized controlled study with 7-year follow-up, concerning children with a minimally displaced metaphyseal both-bone fracture of the distal forearm who had been treated with either AEC or BEC. Short-term follow-up of these patients at 7 months showed no statistically significant differences, except more cast comfort and less interference with daily activities in the group treated with BEC. The 7-year follow-up revealed similar outcome between the 2 groups concerning loss of forearm rotation, patient-reported outcome measures (PROMs): DASH and ABILHAND-kids questionnaire, grip strength (using a JAMAR dynamometer), VAS scores regarding cosmetic appearance (scars and angulation of the forearm), and radiological assessment of malunion.A meta-analysis by Hendrickx et al.  includedLiterature on long-term follow-up of nonoperative treatment of forearm fractures in children is scarce. A retrospective study of Zimmerman et al. (2004) included 220 children with 232 distal forearm fractures between 1980 and 1992. The mean age of included children was 9 years (1–16) and the mean time of follow-up 10 years (5–16). In 40 children both the radius and ulna were fractured. The purpose of this study was to investigate the frequency and extent of clinical and radiological late sequelae and identify predicting factors. The overall outcome was very good in 72%, and children < 10 years of age showed more favorable results, even with a malunion. Children > 10 years of age with an angulatory deformity > 20 degrees and/or more than 50% displacement at consolidation showed more pain and less function. Further factors having a negative influence on the outcome were repeated reduction and an additional fracture of the ulna.We would like to address the ongoing debate on how much fracture angulation can be accepted at what age. The highest remodeling capacity is expected in young children with fractures close to the most active distal growth plate, and angulation in the sagittal plane. However, the literature on acceptable angulation in pediatric forearm fractures is scarce. Ploegmakers and Verheyen  carried Our main limitation is the long-term follow-up percentage of only 77% of the primarily included children, but previous literature on acceptable loss to follow-up suggests that up to 40% loss to follow-up results in minimal attrition of the results (Kristman et al. Limitations of the original study still apply. The reduction criteria were adjusted to only 2 age groups without gender distinction, and the reduction criteria were used for both metaphyseal and diaphyseal forearm fractures. Therefore, the reduction criteria for metaphyseal fractures in the youngest children, especially boys, could probably have been too strict.At long-term follow-up we found similar loss of forearm rotation after treatment of minimally displaced metaphyseal both-bone fractures of the distal forearm in children treated with AEC or BEC. Furthermore patient-reported outcome measures and radiological assessment were similar. Based on short- and long-term results, we suggest that children with minimally displaced metaphyseal both-bone forearm fractures should be treated with a below-elbow cast.


Differential privacy (DP) enables the provision of information-theoretic privacy guarantees to patients and can be implemented in the setting of deep neural network training through the differentially private stochastic gradient descent (DP-SGD) algorithm. We here present deepee, a free-and-open-source framework for differentially private deep learning for use with the PyTorch deep learning framework. Our framework is based on parallelised execution of neural network operations to obtain and modify the per-sample gradients. The process is efficiently abstracted via a data structure maintaining shared memory references to neural network weights to maintain memory efficiency. We furthermore offer specialised data loading procedures and privacy budget accounting based on the Gaussian Differential Privacy framework, as well as automated modification of the user-supplied neural network architectures to ensure DP-conformity of its layers. We benchmark our framework’s computational performance against other open-source DP frameworks and evaluate its application on the paediatric pneumonia dataset, an image classification task and on the Medical Segmentation Decathlon Liver dataset in the task of medical image segmentation. We find that neural network training with rigorous privacy guarantees is possible while maintaining acceptable classification performance and excellent segmentation performance. Our framework compares favourably to related work with respect to memory consumption and computational performance. Our work presents an open-source software framework for differentially private deep learning, which we demonstrate in medical imaging analysis tasks. It serves to further the utilisation of privacy-enhancing techniques in medicine and beyond in order to assist researchers and practitioners in addressing the numerous outstanding challenges towards their widespread implementation.The successful training of deep learning models for diagnostic deployment in medical imaging applications requires large volumes of data. Such data cannot be procured without consideration for patient privacy, mandated both by legal regulations and ethical requirements of the medical profession.  Considering that state-of-the-art generic computer vision models are customarily trained on datasets such as ImageNet2 containing orders of magnitude more images, it becomes readily apparent that the access to more data will be strictly necessary for the development of the majority of deep learning applications in medical imaging to achieve the same success. Privacy-preserving machine learning is a nascent area of AI which proposes to bridge the gap between data utilisation and data protection through the application of privacy-enhancing techniques3. Among these, collaborative learning protocols such as federated learning have arguably witnessed the widest publicity4. They allow a confederation of clients to train ML models in a decentralised fashion and without sharing the raw data. However, a number of works suggest7 that on its own, federated learning is an insufficient measure of privacy preservation. In the setting of medical imaging, this can result in catastrophic privacy loss for affected patients. Prior work demonstrates that federated learning without additional privacy-enhancing techniques can be reverse-engineered to reconstruct high-fidelity images which encode diagnostic information about patients, such as the absence of a breast indicative of a prior history of breast cancer8. Moreover, three-dimensional medical imaging can be volumetrically rendered to reconstruct facial contours which enable patient re-identification9. Lastly, even when identifying attributes are not directly present in the image, the exploitation of side information by adversaries in the setting of linkage attacks, proven to represent a highly effective method for membership inference10, is also applicable to medical imaging databases given that large-scale public datasets of medical images are being assembled and—increasingly—publicly released. Thus, solutions based on information-theoretic privacy measures are required to provide comprehensive and quantifiable guarantees to the involved parties. Differential privacy (DP)11 has arisen as the gold standard in this regard. In brief, DP is the attribute of an algorithm to be approximately invariant to the inclusion or exclusion of individual patients, providing them with formal and quantifiable privacy guarantees. Although formally an information-theoretic privacy guarantee, in practice DP is typically achieved through computationally secure means, that is, an addition of carefully calibrated noise to the training process, making individual contributions indistinguishable from each other. In their seminal paper, Abadi et al.12 demonstrated the successful application of DP in the training of deep neural networks, termed differentially private stochastic gradient descent (DP-SGD). However, the authors of this and subsequent works noted that the utilisation of DP-SGD unavoidably negatively affects the utility of the resulting models, a well-known effect termed the privacy-utility trade-off13. Addressing this trade-off14 and ultimately enabling the widespread real-world utilisation of privacy-preserving ML in medical imaging and beyond requires the introduction of robust software tools, suitable for implementation within widely-used deep learning libraries and implementing current best practices.Artificial Intelligence (AI) is a heavily data-centric domain: the success of machine learning (ML) models depends on the quality and quantity of data that is available during training. This is especially problematic in applications such as medical image analysis, in which high quality data is sparse and data utilisation is restricted. Medical data is highly sensitive, and regulatory, ethical and moral requirements restrict its sharing. These restrictions, although crucial, hinder the development of algorithms that generalise well and therefore prevent widespread deployment. Recent workdeepee, a software framework for differentially private deep learning based on the PyTorch15 machine learning library. Our main contributions can be summarised as follows:We present a technical implementation of the DP-SGD algorithm based on parallelised execution, which makes our framework universally compatible with any neural network layer while enabling substantial performance improvements.Gaussian Differential Privacy (GDP) framework which offers a tight analysis of privacy consumed.We implement state-of-the-art tools for production-level DP-SGD application including cryptographically secure random noise generation, automatic architecture modifications and privacy budgeting based on the We benchmark our toolkit against comparable DP-SGD implementations and analyse the behaviour of DP-SGD in the setting of two medical imaging deep learning tasks: classification and semantic segmentationPyTorch deep learning framework and automatically enforces the relevant details to ensure the formal correctness of the DP-SGD algorithm application.Our framework is aimed at facilitating the application of DP-SGD to arbitrary data by non-experts. For this purpose, it exposes standardised application programming interfaces, is highly compatible with the The source code of our framework is documented in detail, fully tested and available publicly and freely under a permissive, open-source license to enable easy maintenance, rapid detection and correction of potential security vulnerabilities and to encourage open-source contributions.Two notable works have presented DP frameworks for the PyTorch machine learning library based on different technical implementations. The Opacus framework16 provides an implementation of the DP-SGD algorithm based on temporarily caching intermediate backpropagation results. This enables very high performance for specific deep neural network layer types. However, it does not ensure generic compatibility with any given neural network operation unless the procedure for obtaining said backpropagation results is explicitly defined on the user’s side. At the time of writing, the framework’s privacy analysis is still based on Rényi DP (RDP)17, whose guarantees are not as tight as Gaussian DP (GDP). The Pyvacy18 framework implements a generic version of DP-SGD based on serial execution. Despite its broad compatibility, this implementation is highly computationally inefficient, rendering it impractical for production-level use. The framework also lacks cryptographically secure random number generation and utility functions for automatic neural network architecture modification.We here present TensorFlow Privacy framework19 and previous work based on the JAX machine learning framework20 share some characteristics of our library, such as utilisation of the GDP accounting technique or parallelisation, but they are based around different base libraries and thus are not directly comparable to our work.The deepee implements the DP-SGD algorithm in a memory-efficient and parallelised manner by increasing the efficiency of the per-sample-gradient calculation step drastically compared to serial processing. This occurs by creating one zero-memory-cost reference to the network’s weights for each sample in the minibatch, then performing a simultaneous  forward and backward pass. This process introduces no additional assumptions about the network’s architecture and thus allows the application of the DP-SGD algorithm to any neural network architecture. This represents an improvement compared to prior work, which requires substantial user effort to manually specify the per-sample gradient calculations for unsupported layer types  or relies on performing forward and backward passes serially, thus magnifying time complexity. The framework furthermore is designed to guarantee the formal correctness of the DP-SGD procedure by e.g. removing Batch Normalisation layers from the architecture, employing cryptographically secure random noise and automatic privacy budgeting.We begin by providing a brief technical overview of our framework. Implementation details can be found in the “Opacus and Pyvacy frameworks.In the following, we demonstrate the utilisation of our framework in the settings of medical image classification and semantic segmentation. We present model performance in private and non-private settings to evaluate the expected privacy-utility trade-offs. Moreover, we compare our library’s computational performance with alternative implementations of the algorithm offered by the DeLong-test DeLong-test vs. the strict privacy setting DeLong-test vs. non-private training The classification model achieved a mean receiver-operator characteristic area-under-the-curve (ROC-AUC) of 0.848 (range 0.814 to 0.881) in the private setting and of 0.960 (range 0.946 to 0.971) in the non-private setting , and 0.950 , respectively. This segmentation performance of the privately trained model was attained at an entclass1pt{minimaOpacus and Pyvacy libraries in the classification and segmentation settings. We found our framework to offer significantly faster computational performance in the segmentation setting compared to Opacus  Diminished task-specific performance, e.g. in classification or segmentation tasks; (2) computational performance penalties through an increase in training time and memory consumption and (3) incompatibilities of the DP-SGD algorithm with the neural network architecture. Our work attempts to address all three of these points.28 utilises a different DP technique, whose utilisation results in a high privacy expenditure of over 120 under the study’s assumptions, compared to 0.12 in our work. No previous work—to our knowledge—reports 29.The use-cases chosen in our study, image classification and segmentation, represent two typical workflows in medical imaging analysis. Interestingly, we observed a marked performance decrease in the private classification task compared to non-private model training even under relaxed privacy guarantees. Semantic segmentation was possible under very strong privacy notions with unexpectedly strong performance. The only other work to report an 31 will increase the granularity of privacy tracking further, allowing for the preservation of even higher utility during algorithm training.Besides these factors, more refined techniques for privacy accounting are able to offer an improved analysis of the DP mechanism and thus allow higher utility. In the medical imaging domain, the combination of high utility and low privacy budget is particularly important. As datasets are complex, highly sensitive and typically small, each individual in the dataset experiences a relatively higher privacy loss. A tight privacy analysis allows training the models for a longer time before the privacy budget is exhausted, enabling higher task-specific performance and therefore, a better diagnostic prediction. Our work utilises Gaussian Differential Privacy, a recently introduced DP formulation which—through a tight characterisation of the sub-sampled Gaussian noise mechanism utilised in DP-SGD—improves the outlook on the spent privacy budget compared to previous frameworks. It is expected that further advances, such as individual privacy accountingPyTorch framework, which enables both fast performance and efficient memory utilisation. In addition, our technique-contrary to frameworks relying on the a priori specification of per-sample gradient calculations such as Opacus- is compatible by default with any neural network operation including (but not limited to) transformer architectures or transposed convolutions, as seen above. This disparity is discussed in20, a line of work complementary to ours, whose authors utilise just-in-time compilation and vectorised execution to increase DP-SGD performance, albeit within a different machine learning framework. We moreover see a target for future work focused around automatic differentiation with inbuilt support for obtaining and manipulating per-sample gradients. After all, the requirement to calculate per-sample gradients in current DP-SGD frameworks stems from the inherent design philosophy of reverse-mode automatic differentiation systems, which are focused on efficiently obtaining gradients for minibatches but not for individual samples. We moreover note that techniques concerned with approximate gradient calculations32 have some overlap with the objectives of DP-SGD, which inherently performs an “imprecise” gradient update step through noise addition, and could thus be utilised for increased performance, after considering their effect on privacy guarantees.Our main technical contribution is the introduction of a parallelised execution model for the DP-SGD algorithm within the 16, our work offers the capability to automatically modify the neural network architecture in case layers incompatible with DP-SGD are included. An example of this phenomenon in the current work is the deactivation of running statistics collection for Batch Normalisation layers. Moreover, our framework includes support for cryptographically secure random noise generation which is crucial to avoid vulnerabilities associated with default pseudo-random number generators33.Similar to previous work34 could yield improved privacy-utility trade-offs in the classification use-case compared to DP-SGD, however at the cost of not generalising well to other tasks such as segmentation28 and an additional assumption of a publicly available dataset that cannot be reliably expected in a sensitive setting, such as medical imaging.We consider some limitations of our work: Our framework’s focus is to provide a generic framework for DP-SGD and the examples presented represent a simplification of real-life use-cases intended to illustrate its utilisation in medical imaging. In the segmentation case-study in particular, we provide image-level privacy guarantees, whereas a real-life deployment would be adjusted to offer patient-level guarantees . Moreover, DP techniques purpose-designed for high performance in classification, such as PATEIn conclusion, our work aims to facilitate the utilisation of differentially private deep learning in everyday practice. It is well-suited to privacy-sensitive tasks such as medical imaging analysis. We publicly release our framework and experiments in the hope that it will stimulate future research and lead to the design of improved algorithms and training techniques to enable privacy-preserving machine learning with improved algorithm utility in medical imaging and beyond.per-sample gradient calculations, which are required in DP-SGD. (2) A data structure encapsulating the user-supplied model architecture, responsible for the main model training and evaluation loop. This wrapper internally maintains one copy of the user-supplied model per sample in the minibatch, performs a parallelised forward and backward pass over the minibatch and abstracts the gradient clipping and noise application of the DP-SGD procedure. (3) A privacy accounting mechanism for keeping track of the privacy spent at each training step and including a procedure to automatically interrupt the training if the privacy budget is exhausted. The system is supplemented by a cryptographically secure random number generator35 suitable for use on the graphics processing unit and capable of parallelising the random noise generation step of the DP-SGD algorithm.Our framework provides the following high-level user-facing components: (1) A collection of procedures to automatically modify the neural network architecture in case it contains layers which are incompatible for utilisation with DP-SGD. One example is the Batch Normalisation layer which maintains a (non-private) running average of statistics over more than one training example and is thus not compatible with the notion of 12. In brief, the algorithm consists of the following steps: Performing a forward pass on a minibatch of samplesper-sample gradients)Calculating the gradient of the loss with respect to each sample individually (clipping) the per-sample gradients to a predefined Normalising  of the above-mentioned procedure is the most time-consuming subroutine of the algorithm, as automatic differentiation systems are not designed with per-sample gradient computation in mind. To tackle this problem, our framework first creates a copy of the neural network for each sample in the minibatch and then performs step (1) of the algorithm above in parallel by dispatching one execution thread per minibatch sample. Thus, the backpropagation procedure yields per-sample gradients per definition (step (2) above). This approach has several benefits: It is computationally efficient as it is performed in parallel over the minibatch leveraging multi-threaded execution on e.g. the graphics processing unit (GPU). Moreover, memory only needs be allocated once for the neural network weights . Lastly, the process is entirely generic and can be used for any arbitrary neural network architecture without the requirement for user interaction. A similar technique to ours, albeit based on serial execution instead of a parallelised forward pass and only demonstrated for convolutional neural networks, is presented in36, reportedly going back to (unpublished) work by Goodfellow et al.We implement the DP-SGD algorithm as described in37. Originally, the task was formulated as three-class classification, however we merged the viral and bacterial pneumonia labels to obtain a binary classification task, in which the algorithm attempts to predict whether the radiograph shows signs of pneumonia or not. The dataset contains 1339 training images of healthy patients and 3824 images of patients that present evidence of pneumonia. The dataset is pre-split into a training (n = 5163) and a test set (n = 624). We further split the training set into 38 and set to 0.005 in both settings. Learning rate scheduling with halving of the learning rate on stagnation of the validation loss for two consecutive epochs was employed.We evaluated our framework on a classification task on chest radiographs from the Paediatric Pneumonia dataset originally described in39. We split the available data into a training set (n = 5184), a validation set (n = 640) and a held-out test set (n = 2560), mindful to enforce strict patient independence between the training/validation sets and the test set. The task was re-formulated as a binary segmentation task, in which the liver tissue pixels (including tumours) are labelled as 1 and the background as 0. For augmentation purposes, affine transformations  alongside random Gaussian noise were applied to the input images. Every occurence of an image from the same patient, regardless whether it was augmented or not, was counted against the total privacy expenditure. The model was trained for 20 epochs in the non-private setting. In the private setting, we limited the number of epochs to 5 in order to maintain a low privacy budget. Learning rates were determined using the same learning rate finding algorithm and set to 0.01, while utilising the Adam optimiser in both cases. Learning rate scheduling was performed in the same manner as for the classification task.For the semantic segmentation task, we used the Medical Segmentation Decathlon (MSD) Liver segmentation dataset40 architecture with Batch Normalisation. However, in order to satisfy the assumptions essential for DP training, the collection of running statistics of Batch Normalisation layers was disabled for both non-private and DP training. For the segmentation task, we use a modified U-Net architecture21 utilising VGG-11 with Batch Normalisation as a backbone41. Similarly to the classification task, the running statistics collection was disabled. The For the classification task, we utilised the same model architecture in the private and non-private setting, namely a VGG-11For the purposes of computational performance benchmarking we measured the time to train for 25 steps with a minibatch size of 32 on the tasks we presented above, i.e., binary classification on 224x224 sized images and the segmentation of 256x256 images. Each measurement was repeated five times.macOS 11.2.3 and GNU Linux on the 5.4.0-72 kernel . Peak memory consumption was measured using the Python programming language (CPython v. 3.8.8) standard library module resource.For memory utilisation benchmarking, a minibatch size of 32 images at a resolution of DeLong-test as described in42. Continuous variables were compared using the Student’s t-test. Bonferroni’s correction was used for three-way comparisons with the adjusted statistical significance threshold set to Areas under the ROC-curve were compared using the


SARS-CoV-2 binds to membrane-bound angiotensin-converting enzyme 2 (ACE2) which may result in downregulation of membrane-bound ACE2. ACE2 is a key regulator of the renin-angiotensin system (RAS) and is responsible for degrading angiotensin II and thereby counteracting its pro-inflammatory, pro-fibrotic effects mediated through the angiotensin II type 1 receptor (AT1R). As AT1R is directly blocked by angiotensin receptor blockers (ARBs), these agents may offer a safe, low-cost solution for reducing COVID-19 respiratory outcomes.CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial that examines whether ARBs reduce COVID-19 severity among high-risk patients. Recruiting in India and Australia, the trial will compare treatment with a maximum tolerated daily dose of an ARB to standard of care. Treatment allocation is blinded in India but open-label in Australia due to interruptions to placebo supply in the latter. The primary endpoint is a 7-point ordinal scale of clinical states, ranging from no limitation of activities (category 1) to death (category 7), assessed on day 14. Secondary outcomes include the 7-point scale assessed at day 28 and 28- and 90-day mortality. The design adapts the sample size based on accumulating data via frequent interim analyses and the use of predictive probability to determine whether the current sample size is sufficient or continuing accrual would be futile. The trial commenced recruitment on 18 August 2020.NCT04394117. Registered on 19 May 2020. Clinical Trial Registry of India: CTRI/2020/07/026831)ClinicalTrials.gov, The online version contains supplementary material available at 10.1186/s13063-021-05521-0. CLARITY will test the effectiveness of repurposing a widely available class of medications for the treatment of COVID-19.The risk of COVID-19 transmission is minimised by restricting trial-specific in-person encounters between participants and health care workers.The trial burden on sites is reduced by aligning trial processes with routine clinical care and targeting study data collection to measures of COVID-19-related effectiveness and selected safety endpoints.Adaptive Bayesian sample size re-estimation methodology are employed to protect the trial from an indeterminate result, an approach chosen because of the absence of information on potential effect size.The unavoidable use of open-label study medication in Australia is a limitation but is offset by the inclusion of a large number of sites in India (where placebo is available) and mitigated by the blinding of the central study team, including trial statisticians.2) [Coronavirus disease 2019 (COVID-19) is a recent and one of the deadliest examples of cross-species viral transmission affecting the human population. By the end of July 2021, COVID-19 has resulted in more than 190 million confirmed cases and 4.1 million confirmed deaths worldwide –7. Risk 2) , 12.Whilst there have been unprecedented advances in public health and clinical strategies, therapeutics and vaccine development for reducing the impact of COVID-19, outbreaks of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continue, with emerging variants adding to uncertainty on its curtailment –15. WideSARS-CoV-2 causes COVID-19 through binding to angiotensin-converting enzyme 2 (ACE2) , 17, a tARBs are a commonly prescribed, widely available and affordable class of medications that are used to treat a range of chronic conditions, including hypertension, heart failure, and chronic kidney disease . ObservaBy directly blocking the AT1R and reducing the tissue-damaging effects of angiotensin II, we hypothesise that ARBs will reduce the severity of COVID-19 respiratory clinical outcomes. The Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease (CLARITY) trial will test whether treatment with an ARB in addition to standard of care improves clinical outcomes in high-risk COVID-19 patients, compared to standard care alone using a pragmatic trial design.CLARITY is a pragmatic, adaptive, two-arm, multi-centre, comparative effectiveness phase III randomised controlled trial, conducted in India and Australia, designed to evaluate whether ARBs reduce the severity of COVID-19 among high-risk patients. The trial, designed in accordance with SPIRIT guidelines, will recruit patients with COVID-19 deemed to be at high risk of severe illness   < 30 mL/min/1.73mProspective patients are approached by the site’s principal investigator or study co-ordinator and provided with a written information sheet, physically or electronically, that remains with them for infection control reasons. Informed consent is obtained verbally either via audio-recording or with appropriate documentation by an independent, third-party witness.Randomisation takes place within 10 days of the confirmed SARS-CoV-2 diagnosis, using a central interactive web response system that contains a computer-generated randomisation schedule. Participants are randomly assigned in a 1:1 ratio to standard of care plus an ARB or standard of care with or without matched placebo , stratified by country. In Australia, further stratification is performed by baseline hospital admission status . Unless they withdraw their consent, participants who prematurely discontinue study treatment will continue to be followed according to intention-to-treat (ITT) principles.Participant recruitment is reviewed weekly by the research team. A close ongoing relationship has been maintained with all sites including regular meetings, newsletters, and phone calls. Challenges associated with recruitment are discussed and troubleshooted at each Executive Trial Steering Committee meeting held monthly.The intervention is a daily dose of an ARB for 28 days. The intention at the time of study design was for placebo control where possible, although open label was deemed an acceptable alternative and preferable to not conducting the study at all. In India, where placebo could be sourced, the study intervention is telmisartan, supplied as 40 mg tablets or matching placebo. In Australia, placebo was not available at the time of study commencement due to COVID-19-related interruptions to supply chains and the study was initiated open-label with an intention to pursue placebo procurement if it became available. Australian Principal Investigators were given information on the half-life, receptor binding affinities and pressor effect for common ARBs, and were permitted to select an ARB as per the hospital formulary (detailed in the study Guidance document).The central study team remain blinded to study allocation in both countries throughout the course of the trial. In India, both the participant and the treating site staff are also blinded to treatment allocation. A separate, unblinded statistician will conduct the pre-planned interim analyses required for reporting to the independent Data Safety Monitoring Board (DSMB).In both countries, treating practitioners are encouraged to commence treatment with a low to moderate starting dose (or placebo) and to increase if tolerated. Study sites are provided guidance on ARB prescribing, monitoring, and adjustment derived from national educational material in the public domain , 33. IndAdherence to ARB prescription and records on daily dosing will be verified using medical records by the study staff. Treating clinicians are encouraged to manage blood pressure according to their usual practices with the caveat that they avoid prescription of ARB and they prioritise cessation or down-titration of concomitant medications rather than study drug for the management of low blood pressure. Daily monitoring of blood pressure of all study participants is recommended. In Australia, community-based participants who are being managed virtually at the time of randomisation are provided an electronic blood pressure monitor and instructed on its use. Clinicians and patients are advised to avoid non-steroidal anti-inflammatory agents (NSAIDs) during the 28-day treatment period. Regular monitoring of serum potassium is recommended for inpatients, as would be consistent with routine clinical care for hospitalised patients.In the event that knowledge of the treatment will significantly influence a participant’s clinical management, emergency unblinding will be permitted via a 24-h emergency unblinding phone line staffed by an authorised representative. The decision to unblind ultimately rests with the Principal Investigator at the site or the treating/attending clinician.The primary outcome is a 7-point ordinal categorical scale of clinical outcomes, assessed on day 14 Table , modelleSecondary and exploratory outcomes are selected because they reflect the clinical severity of COVID-19 disease or are well-known adverse events related to ARBs. They include the 7-point ordinal scale assessed at day 28; 28- and 90-day all-cause mortality (binary outcome); any requirement for intensive care unit (ICU) admission between baseline and days 28 and 90 (binary outcomes); median length of ICU stay, in days, between baseline and day 90; any occurrence of respiratory failure  (binary outcome); occurrence of kidney failure  (binary outcome); median number of dialysis days between baseline and day 28; median length of hospital stay, in days, between baseline and days 28 and 90; median number of ventilator-free days between baseline and days 28; presence or absence of acute kidney injury (AKI); and presence or absence of hypotension requiring vasopressors.2) saturation/fraction of inspired (FiO2) at days 8 and 14.Exploratory outcomes include any occurrence of hyperkalaemia between baseline and day 28 (defined as any serum potassium result > 6.0 mmol/L) (binary outcome) and the proportional outcome of oxygen . Where appropriate, these data will be supplemented with information provided by the treating staff or participants themselves (e.g. information relating to medication adherence and blood pressure). The eCRFs are housed within a REDCap (Research Electronic Data Capture) database , 36, a sData that are essential for assessing the primary outcome and relevant secondary outcomes will be collected daily for the first 28 days. This includes information on blood pressure, dialysis requirement, any serum creatinine and serum potassium levels, medication adherence, and clinical health status on the 7-point ordinal scale. The timing of serum creatinine and serum potassium testing will be determined by treating staff and will be monitored by study staff. As above, safety monitoring practices that are inconsistent with standard guidance will be queried by the study team but will not constitute a protocol deviation. All other secondary and exploratory outcomes will be extracted from the patients’ medical records after days 28 and 90. In the event that a patient is discharged from hospital or stops receiving virtual care prior to day 14, follow-up of the primary outcome will be performed via telephone contact. Other secondary outcomes will be collected from patient’s medical records or via telephone contact after day 90. No biological specimens will be collected as part of the trial; however, the study consent includes an optional consent to retain, store, and use leftover blood samples obtained during routine clinical care for further research, for another, separate, ethically approved research project based at one Australian site . Adjudication of study endpoints will not be performed.In the absence of prior information on the potential effect size of ARBs on COVID-19 severity, the trial will follow adaptive sample size re-estimation principles. This approach protects the trial against an indeterminate result, whilst avoiding over-sampling. The study uses Bayesian methods to model the outcomes of interest at pre-planned interim analyses. All inferences will be based on the joint posterior distribution of the model parameters, and this distribution will be sampled using Markov chain Monte Carlo methods.The estimated treatment effect on the primary endpoint will be expressed as the common odds ratio, corresponding to the odds of a better outcome in the ARB versus the comparator arm on the 7-point ordinal scale at day 14 and its 95% credible interval. This will be modelled using a proportional odds logistic regression model , furtherThe primary analysis will be an ITT analysis, whereby comparisons will be made between all participants randomised to the treatment arms irrespective of whether they received or completed their course of allocated treatment.Secondary analyses will comprise assessment of the primary endpoint in patients who were randomised and treated as per the trial protocol (i.e. per-protocol population), as well as analyses of pre-specified secondary and exploratory outcomes, using statistical models that are appropriate for the specific outcome.Analyses of the primary endpoint will be Bayesian. Details of these approaches, and how missing data will be handled, are described in the statistical analysis plansPrior to the start of the trial, trial simulations were performed to evaluate the trial operating characteristics under a range of scenarios, data configurations, interim timings, and decision thresholds (1000 simulations for every scenario). A maximum sample size of 2200 was applied. The simulations showed that, across a variety of scenarios, the trial is expected to yield a power > 80% if the odds ratio for the intervention is ≥ 1.25, with the chance of declaring a false positive being < 0.08. Of note, the average sample size required to achieve this was considerably lower than the imposed maximum sample size of 2200. Further details of these simulations, the different scenarios considered, and their underlying assumptions will be provided in the statistical analysis plan prior to the first scheduled interim analysis.The first interim analysis will be conducted 14 days after the 700th participant has been enrolled. Thereafter, an interim analysis will be conducted approximately 14 days after every 300 additional participants have been enrolled (to ensure follow-up is reached for the last enrolled patient) until the trial stops or the maximum sample size of 2200 has been reached. All interim analyses will be based on the primary outcome. At each interim analysis, the predictive probability that the intervention is effective, or that the trial is futile, will be estimated and assessed against pre-defined decision thresholds  in order to maximise the generation of evidence. Sites are encouraged to coordinate recruitment approaches for trials involving participants with COVID-19.The CLARITY trial will be conducted in accordance with the principles of the Declaration of Helsinki, the National Ethical Guidelines for Biomedical and Health-Related Research Involving Human Participants in India and the National Statement on Ethical Conduct in Human Research in Australia. The study has received ethical approval from The George Institute for Global Health Ethics Committee in India (ref. no. 14/2020) and the Sydney Local Health District Ethics Review Committee  (Code: EC0113) in Australia (ref. no. X20-0118 & 2020/ETH00742). The trial design was informed by specific guidance including ethical principles relevant to the conduct of COVID-19 trials , 39. AnyA pre-formatted template has received pre-approval by the relevant Ethics committees to allow rapid dissemination of results to surviving participants at the conclusion of the trial  embedded within the National Health Service (NHS)  has meanThe pandemic setting has also inspired review by oversight bodies on the necessity and justification of common trial features –49. The Lastly, there has been the development of specific guidance on the ethical principles informing the design and conduct of COVID-19 research, such as requirements to consider the impact of COVID-19 research on participant safety, on potentially strained health systems and on the safety of research staff . These cDespite remarkable advances in the evidence-based treatment of COVID-19, it remains unclear whether treatment with ARBs—a readily available and low-cost class of medications—can reduce COVID-19 severity in patients who are otherwise not indicated. CLARITY is a pragmatic, multi-centre randomised controlled trial designed to assess the effectiveness of ARBs in reducing disease severity in COVID-19. As one of only two large-scale ARB trials currently recruiting in the Asia-Pacific region, CLARITY will make important contributions to the global evidence base for whether this class of medications are effective in the treatment of COVID-19. If found to be effective, the implementation of ARB treatment for COVID-19 into clinical practice is likely to be rapid.Additional file 1. CLARITY Trial Team.Additional file 2. CLARITY Participant Information and Informed Consent Document (in English).Additional file 3. CLARITY SPIRIT Fillable Checklist.Additional file 4. CLARITY Trial Results Template.Additional file 5. CLARITY WHO Trial Registration Data.


Foil or latex glove interpositions did not prevent screw stripping. Thus, in the current experimental study, T-handle screwdriver or hex key wrench usage decreased the incidence rate of screw stripping during removal compared to straight-handle screwdriver use.There have been several reports about the difficulties in removing 3.5-mm titanium locking screws from plates due to the stripping or rounding of the hexagonal screw socket. We investigated whether stripping the locking screw sockets can be prevented by using different screwdrivers or interposing materials into the socket during removal. We overtightened 120 3.5-mm titanium locking screws  equally into locking plates on sawbone tibia models, applying a uniform torque of 4.5 Nm, exceeding the recommended torque of 1.5 Nm. Twenty screws each were removed using a straight-handle 2.5-mm screwdriver, T-handle screwdriver, hex key wrench, and straight-handle screwdriver with a non-dominant hand. In addition, 20 screws were removed using foil from a suture packet inserted into the screw socket or using parts of a latex glove inserted into the screw socket. The incidence rates of screw stripping using the straight-handle screwdriver, T-handle screwdriver, hex key wrench, non-dominant hand, foil interposition, and latex glove interposition were 75%, 40%, 35%, 90%, 60%, and 70%, respectively. When a T-handle screwdriver or hex key wrench was used, the probability of screw stripping was 4.50 times (odds ratio = 4.50, 95% confidence interval = 1.17 to 17.37,  However, titanium is prone to cross-threading or cold welding under strong metal-to-metal contact9. There have been several reports about the difficulties in removing 3.5-mm titanium locking screws from the locking plates after healing of the fractured bone16. Removal is challenging when the hexagonal socket of the screw is stripped, rendering the drivers useless. Various techniques have been suggested to remove stripped locking screws18. However, once the screw is stripped, the surgery duration is prolonged, despite the broken screw or stripped screw removal techniques, which increases the possibility of complications such as more bleeding, infection, neurovascular injury, and even iatrogenic fractures11. Therefore, the prevention of screw stripping is essential.Locking plates can provide high fixation stability for reliable healing in various fractures. These plates are usually manufactured from titanium alloys with higher biocompatibility, higher fatigue strength, and lower risk of infection and are isoelastic with the bone compared to stainless steel19. Some authors suggest the insertion of aluminum foil or part of a sterile glove into the screw socket to increase the friction between the driver and the socket; nevertheless, these tips are anecdotal, and none have been proven effective22. Currently, star-shaped  sockets, which are less prone to stripping, are now widely used for locking screws23. However, conventional locking screws with hexagonal sockets, widely used in the past and still used, may require removal someday.Appropriate use of aiming sleeves and torque-limiting screwdrivers is important to prevent cross-threading or overtightening of the screws during insertion. However, there are few suggestions that can be followed during screw removal to prevent screw strippingWe performed an experimental study on sawbone tibia models to determine whether the incidence of stripping of the hexagonal socket of 3.5-mm titanium locking screws  can be minimized by using a T-handle driver with a relatively larger dimension of the driver tip or a hex key wrench. We also tested whether there was a difference in the incidence of screw stripping by using the dominant hand and the non-dominant hand. In addition, we tested whether the interposition of the aluminum foil or parts of the latex glove into the screw socket effectively reduces the incidence of screw stripping.We prepared 6 sawbone tibia models and 12 3.5-locking compression plates  with 10 holes each and 120 3.5-mm titanium locking screws (Depuy Synthes). Two plates were attached to each sawbone tibia model. To overtighten and jam the locking screws into the locking plates with the same amount of torque, a torque driver with the torque limit set at 4.5 Nm was used. A total of 120 screws were overtightened by applying a torque of 4.5 Nm, which exceeded the recommended torque of 1.5 Nm for the 3.5-mm locking screw insertion , a T-handle screwdriver , and a hex key wrench  were used to remove 20 screws each  and the use of different screwdrivers or the interposition of materials. A chi-square test was performed on the two-way contingency table with the row variable set as the use of different screwdrivers or the interposition of materials  and the column variable set as the binary outcomes (stripped and irremovable screws/removed screws). The use of straight-handle screwdrivers was used as the reference. We calculated the odds ratio and its 95% confidence interval (95% CI) on this two-way contingency table to measure the association between the use of different screwdrivers or interposition of materials and prevention of screw stripping. We used Fisher's exact test to analyze whether the non-dominant hand was associated with a high incidence of screw stripping. Statistical significance was set at p < 0.05. Statistical analysis was performed using SPSS version 22.0 .We performed a pilot study on 20 3.5-mm titanium locking screws jammed into the locking plate to determine the appropriate sample size for the study. As a result, 8 out of 10 (80%) and 3 out of 10 (30%) screws were stripped using the straight-handle driver and the T-handle screwdriver, respectively. Assuming 95% power and a 0.05 significance level, 20 samples in each group were calculated to detect a decrease in the incidence of screw stripping from 80% in the control group to 30% in the experimental groupThis study was approved by the IRB of Hallym University Kangnam Sacred Heart Hospital (IRB-2020-12-015). The study did not involve humans or animals.The results are presented in Table p = 0.03), and 5.57 times  when the T-handle screwdriver and the hex key wrench were used, respectively, compared to that using the straight-handle screwdriver  (Tables p = 0.002), and 16.71 times  when the dominant hand was used with the T-handle screwdriver and the hex key wrench, respectively, compared to that using the non-dominant hand with the straight-handle screwdriver  Tables ,3. The p25. However, there are reports of difficulties in removing 3.5-mm titanium locking screws due to stripping of hexagonal sockets16. This may be because titanium is more malleable than stainless steel, and the difference in the mechanical resistance between the stainless-steel screwdriver and the titanium screw may lead to stripping of the titanium screw. Titanium has a high degree of biocompatibility, which leads to increased osteointegration and thus a higher risk of screws becoming encased26. Furthermore, LCP is used for the minimally invasive plate osteosynthesis technique. Hence, when the locking screw hole of the plate is not well exposed, the locking screw may be inserted at the wrong angle and jam into the plate22. During screw removal, the screwdriver may sometimes engage with the screw at an incorrect angle, or the driver tip may not be fully engaged in the screw socket before the screwdriver is turned. The surgeon can feel the first slippage of the screwdriver inside the socket. A biomechanical study demonstrated up to a 50% decrease in the maximal torque values after a single event of screwdriver slippage13. Although the straight handle is easy to rotate when there is no considerable resistance, as in screw insertion, when a high torque for the counterclockwise rotation force is required to remove a jammed locking screw, the straight-handle screwdriver is relatively thin for a full grip compared to the T-handle. The axis of the straight-handle driver may not be in alignment with the axis of the screw when considerable wrist movement is required in addition to finger movement to rotate the screwdriver. This may cause the tip of the driver to deviate inside the screw socket  has been introduced as a new standard of AO plating osteosynthesis. It is widely used for various fractures, such as comminuted tibia fractures, or even in joint sparing salvage surgery after articular oncological resections13.However, for convenience during screw insertion, most manufacturers provide a straight-handle driver; moreover, the 2.5-mm straight-handle screwdriver (Depuy Synthes) is commonly provided by the scrub nurse to remove 3.5-mm titanium locking screws (Depuy Synthes). The diameter, length, and design of the 2.5-mm hexagonal driver tip can differ between the products by different manufacturers. Many manufacturers provide a screwdriver shaft that can be connected to the power tool for power insertion of the screws. This screwdriver shaft can be connected to the T-handle. We recommend that surgeons source the largest available 2.5-mm driver tip with sharp edges by testing the engagement of the driver tip in the screw socket, checking how firmly it can hold the screw, and reserving it for screw removal. In some situations, surgeons may have to change their position to use their dominant hand for screw removal. But some may prefer to use their non-dominant hand rather than change their position to use the dominant hand. Because one inadvertent missed turn of the screwdriver with the non-dominant hand can ream the socket, leading to screw stripping, we recommend that surgeons use their dominant hand for screw removal on all occasions17. Strong cortical bone ingrowth at the terminal flutes of the screw can cause screw stripping; however, this situation could not be simulated with sawbone models27. Second, the amount of torque that leads to screw stripping can be different in different cases. However, for the experimental study, we overtightened all locking screws by applying a 4.5-Nm torque. The results may be different, with different torques applied to overtighten the screw. Third, although the interposition of the foil or parts of the latex glove did not significantly decrease the incidence of screw stripping in the current study, it may potentially be effective with different torques applied on the screws. However, we believe that the interposition of the material can impede the engagement of the driver tip into the screw socket to its full depth, which can lead to a decrease in the contact area  to remove3.5-mm titanium locking screws (Depuy Synthes). There are several screw removal devices that are designed to remove stripped screwsThe use of a T-handle screwdriver reduced the incidence of screw stripping by 4.50 times compared to the use of a straight-handle screwdriver.The use of a hex key wrench decreased the incidence of screw stripping by 5.57 times compared to the use of a straight handle screwdriver;The interposition of foil or parts of the latex glove into the screw socket did not decrease the incidence of screw stripping.There have been several reports about the difficulties in removing 3.5-mm titanium locking screws from the locking plate due to the stripping of the hexagonal screw socket. However, there is a lack of research on methods to prevent screw stripping during screw removal. We hypothesized that screw stripping can be prevented by using different screwdrivers or interposing materials into the socket during removal. We performed an experimental study on swabone tibia models, and tested the incidence rate of screw stripping using a straight-handle screwdriver, T-handle screwdriver, hex key wrench, non-dominant hand, foil interposition, and latex glove interposition. In the current experimental study;A future study on the surface morphology of stripped screws using emission scanning electron microscopy may enable a more accurate analysis of the effects of different screwdrivers on screw stripping. Furthermore, clinical application results are required to confirm the above findings.


Carbon nanotubes (CNTs) and graphene nanoplatelets (GNPs) with exceptional mechanical, thermal, chemical, and electrical properties are enticing reinforcements for fabricating lightweight, high-strength, and wear-resistant metal matrix composites with superior mechanical and tribological performance. Nickel–carbon nanotube composite (Ni-CNT) and nickel–graphene nanoplatelet composite (Ni-GNP) were fabricated via mechanical milling followed by the spark plasma sintering (SPS) technique. The Ni-CNT/GNP composites with varying reinforcement concentrations  were ball milled for twelve hours to explore the effect of reinforcement concentration and its dispersion in the nickel microstructure. The effect of varying CNT/GNP concentration on the microhardness and the tribological behavior was investigated and compared with SPS processed monolithic nickel. Ball-on-disc tribological tests were performed to determine the effect of different structural morphologies of CNTs and GNPs on the wear performance and coefficient of friction of these composites. Experimental results indicate considerable grain refinement and improvement in the microhardness of these composites after the addition of CNTs/GNPs in the nickel matrix. In addition, the CNTs and GNPs were effective in forming a lubricant layer, enhancing the wear resistance and lowering the coefficient of friction during the sliding wear test, in contrast to the pure nickel counterpart. Pure nickel demonstrated the highest CoF of ~0.9, Ni-0.5CNT and Ni-0.5GNP exhibited a CoF of ~0.8, whereas the lowest CoF of ~0.2 was observed for Ni-2CNT and Ni-5GNP composites. It was also observed that the uncertainty of wear resistance and CoF in both the CNT/GNP-reinforced composites increased when loaded with higher reinforcement concentrations. The wear surface was analyzed using scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) analysis to elucidate the wear mechanism in these composites. Metal matrix composites (MMCs), consisting of a metal matrix reinforced with high-strength ceramic reinforcement, exhibit a very high strength to weight ratio and can be employed at elevated temperatures and severe working conditions due to a synergetic combination of metallic properties, such as high toughness, strength, and ductility, as well as ceramic properties, such as high hardness, high tensile strength, and low coefficient of thermal expansion, with excellent resistance to wear and corrosion. This attractive set of properties with various reinforcing agents and processing routes makes MMCs a favorable material for various applications in the automotive and aerospace industries ,2,3. DepNickel exhibits numerous attractive properties, such as ductility, toughness, thermal and electrical conductivity, and exceptional resistance to oxidation, wear, and corrosion ,9. HowevIrrespective of the extraordinary strengthening potential and excellent tribological properties of CNTs/GNPS, the utilization of reinforcement to its full capacity is still a major bottleneck due to various difficulties. It is difficult to attain homogeneous dispersion of CNTs/GNPs within the metal matrix due to their agglomeration resulting from strong, cohesive van der Waals forces ,20,21. APreviously, several attempts were made to efficiently overcome the difficulties involved with the dispersion of CNTs/GNPs in the metal matrix alongside retaining the structural integrity of these carbon-based reinforcements ,26. The The self-lubricating nature of CNTs/GNPs is often utilized for tribological applications, where high wear resistance and a lower coefficient of friction are desired. These self-lubricating metal matrix composites are typically found in nanocomposite coatings or claddings or bulk metal matrix composite materials. However, these solid lubricant coatings have many limitations, such as poor adhesion, difficulty of replenishment, and relatively shorter life cycle compared to MMCs loaded with carbonaceous reinforcement . PreviouThe present research emphasizes the viability of processing carbon nanotube-reinforced nickel metal matrix composites (Ni-CNT) and graphene nanoplatelet-reinforced nickel matrix (Ni-GNP) composites using high-energy ball milling and the SPS technique to obtain a uniform dispersion of carbonaceous reinforcement in the nickel matrix and attain improvement in the tribological behavior. The microstructural characterization and wear testing of the as-processed composites was conducted to investigate the effect of concentration on the dispersion of these carbonaceous nanomaterials in the nickel matrix and the consequent effects on the tribological properties of the composites were investigated. The formation of a wear track due to friction and the wear mechanisms involved are also discussed.The elemental spherical nickel powder  was procured from Alfa Aesar , whereas the Ni-coated CNTs and raw GNPs were procured from Nanostructured & Amorphous Materials, Inc. . The schematics for the processing of Ni-CNT/GNP composites is shown in A similar processing technique was utilized for the fabrication of graphene nanoplatelet-reinforced nickel metal matrix composites with varying weight fractions  of the GNP reinforcement . In Ni-GNP composites, raw GNPs, unlike in Ni-CNT composites, where nickel-coated CNT reinforcement was utilized. −1 Raman active peak) before testing. Vickers microhardness was obtained using a Wilson VH1202 hardness tester by BUEHLER , with an accuracy of ±1.5%. The Vickers microhardness value of Ni-CNT and Ni-GNP composites was evaluated under a load of 0.5 N with a dwell of 10 s, as recommended by ASTM E384 standards [3N4 ball with a microhardness value of ~1620 HV. The test was carried at a constant sliding velocity of 50 mm/s with a track radius of 2 mm for 10,000 unidirectional revolutions. At least three wear tests were carried out to determine the coefficient of friction. The wear tracks were examined using the Energy dispersive spectroscopy (EDS) technique to observe the features of the wear tracks and elucidate the wear phenomena.The SPS-processed pure nickel and Ni-CNT and Ni-GNP composite samples were mounted using graphite-based conductive mounting powder  and polished using silicon carbide papers  with increasing grit sizes. The final metallographic finish was obtained via polishing with a 0.04 µm colloidal silica suspension on a microcloth for characterization. A scanning electron microscope (SEM)  was utilized to obtain micrographs and study the effects of CNT/GNP concentration on dispersion and the microstructure of the composites. The Horiba XploRA PLUS confocal Raman microscope  in combination with LabSpec 6 software  was employed to perform Raman spectroscopy characterization. The spectra were acquired with a laser excitation wavelength of 532 nm and a spatial resolution of 0.5 μm. The instrument was calibrated using a crystalline Si wafer . The D peak, which occurred due to the breathing modes of 2sp bonded carbon atoms, is associated with the defects induced in the structure, while the G peak corresponds to the C–C in-plane bond stretching of all the pairs of 2sp bonded carbon atoms in the rings and chains. The D′ peak is associated with the double resonance band induced due to disorders. These characteristic peaks are deemed as defect-dependent structural indicators and often depict changes in peak position and the intensity ratio depending upon the structural changes induced during processing [D/IG, slightly increases in all Ni-CNT composite samples, implying a slightly disordered form of carbon. However, the difference is very minimal in the Ni-5CNT composites, which is attributed to the higher concentration of carbonaceous reinforcement. These trends in the Raman spectra may indicate a minor structural disorder induced while processing these composites. They also reveal that as the CNT concentration in these composites is increased from 0.5 to 5 wt%, the structural disorder induced in the CNTs is reduced. This indicates that at higher CNT concentrations, the structural integrity of CNTs is relatively well preserved during ball milling followed by SPS processing.Raman spectroscopy analysis was performed to determine the structural changes/defects in the CNTs/GNPs that transpired during ball milling as well as those due to heat and pressure during SPS processing. The Raman spectra obtained for raw Ni-coated CNTs and raw GNPs, as well as the SPS-processed Ni-CNT and Ni-GNP composites with varying reinforcement content , are shown in mparison ,17,59,60ocessing ,62. CompD/IG) for these composites is that the intensity ratio is lower for Ni-0.5GNP composite, whereas the Ni-2GNP and Ni-5GNP composites exhibited relatively higher intensity ratios. This contradicts the observation made for CNT-reinforced composites, where a higher intensity ratio is observed for Ni-0.5CNT composite, implying a higher order of disorder in the CNT structure. In Ni-0.5GNP composite, the relatively lower intensity ratio could be associated with the phenomena linked to ID/IG exhibiting two distinct defect behaviors in graphene. In the low defect density regime, the ID/IG increases with increasing disorders up to the high defect density regime. After this stage, a transition in the pattern occurs, and the intensity ratio decreases due to the higher defect density, which essentially engenders a more elastic scattering of the spectra [ spectra . It can  spectra ,69.D/IG) is slightly increased compared with raw, pristine GNPs. This is mainly a disordered form of carbon on the surface of the GNPs due to impact forces during high-energy ball milling. However, no peak shift is observed in the spectra, which indicates that the structural integrity of GNPs in these composites is relatively well preserved after processing.Furthermore, the intensity of the D peak is directly proportionate to the defect level in the composite samples. The D band is usually weak in GNPs compared to carbon nanotubes ,71. As tVickers microhardness of SPS-processed pure nickel and Ni-CNT and Ni-GNP composites is listed in The plots representing the coefficient of friction (CoF) as a function of revolution for the SPS-processed pure nickel in contrast with Ni-CNT and Ni-GNP composites are shown in 3N4 counterface during sliding before interacting with lubricious GNPs. This resulted in significant plastic deformation during the initial cycles until a lubricant layer was formed by sheared GNPs, which reduced the plastic deformation and further stabilized the CoF during the rest of the test. Another possible reason could be surface irregularities, which increased the CoF until a lubricious layer was formed due to the presence of GNPs on the wear track. This phenomenon is usually witnessed in the case of monolithic metals or composites reinforced with a very minimal concentration of reinforcements [2O3 composites [In rcements ,80,81. Imposites . It was mposites ,84. Anotmposites ,86,87. H3N4 counterface. This is possibly due to the heat generated under the frictional force during sliding, which causes the thermal oxidation of the worn-out debris to form a transfer layer of SiO2 and possibly NiO2. However, the formation of NiO2 is considered beneficial in some cases, as it acts as a protective layer and reduces the wear rate [3N4 counterface, which reduces the oxidation and formation of SiO2 during interfacial sliding. From To further elucidate the wear mechanism and understand the tribological behavior involved, the SEM micrographs and corresponding elemental maps were obtained using the EDS technique. SEM micrographs, and elemental EDS map of the wear track, for pure nickel and Ni-CNT and Ni-GNP composites, are shown in ear rate ,88. FurtIn this research, nickel metal matrix composites reinforced with carbon nanotubes (CNTs) and graphene nanoplatelets (GNPs) were successfully fabricated via ball milling followed by the spark plasma sintering (SPS) technique. The variation in the reinforcement concentrations in these composites demonstrated disparity in the dispersion, microhardness, and tribological behavior of these composites. The results revealed that the increasing concentration of carbonaceous reinforcement in these composites resulted in a lowered coefficient of friction due to the formation of a lubricious carbon-rich tribolayer on the sliding interface. Ni-2CNT and Ni-5GNP composites exhibited the lowest CoF as compared with other CNT/GNP-reinforced counterparts with relatively lower reinforcement concentrations. The overall trend indicates that with an increasing concentration of reinforcement in these composites, the dispersion and grain refinement of the metal matrix are affected significantly, which resultantly affects the microhardness, wear resistance, and coefficient of friction of these composites. The present study emphasizes the potential of CNT/GNP reinforcement as a solid lubricant in nickel metal matrix composites for high-temperature surface engineering applications.


Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide. The preN-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine, via a flippase mechanism from the lumen to the cytoplasmic side of the disc membranes. This process removes retinoids from the photoreceptor discs and in so doing enables continuation of the visual cycle . T. TN-reti-retinal . Patientmuxistat . This deAbca4 KO model [The build-up of A2E and other bisretinoids can lead to activation of the complement system in RPE cells  and compKO model . ComplemKO model , and givKO model . These eKO model  and thertrans-retinol), which is a precursor to 11-cis-retinol. It is postulated that reducing levels of vitamin A could limit the production of all-trans-retinal/PE and subsequently A2E. Whilst supplements of standard vitamin A may be detrimental, as observed in the Abca4 KO model [Abca4 KO mice to prevent the disease phenotype [Abca4 KO mice [Abca4 KO model with no significant impact on ERG [A common target of the visual cycle is vitamin A , eicosapentaenoic acid (EPA) and alpha-linolenic acid (ALA) are omega-3 fatty acids. DHA is the major very-long-chain polyunsaturated fatty acid of the retina and is a particularly critical component of photoreceptor cells . DietaryGD3 mice  at 6–12 GD3 mice . The MADABCA4 mutations were randomly assigned to two groups and consumed either 20 mg oral saffron daily for 6 months followed by a switch to the placebo for 6 months (14 patients) or vice versa (17 patients). Macular cone-mediated responses were assessed with no significant findings achieved after 6 months [A final dietary supplementation used in clinical trials in attempt to counteract oxidative stress that can induce the accumulation of lipofuscin, is saffron (NCT01278277). A total of 31 patients with 6 months . HoweverMertk, a c-mer proto-oncogene kinase receptor specific to RPE cells [With atrophy of RPE and photoreceptor cells causing loss of visual acuity in patients in later stages of disease, the treatment options considered up to this point would only be beneficial for preventing further sight loss. In order to regain lost vision, transplantation of new cells would be required. Pre-clinical studies providing human embryonic stem cell (hESC)-derived RPE cells into the subretinal space of mice have provided encouraging proof-of-principle data. The hESC-RPE cells were transplanted into the Royal College of Surgeons rat model, which suffers vision deterioration over time due to a mutation in PE cells . Non-funPE cells . The hESPE cells . There hPE cells . Follow-A recent report presented data from 17 Stargardt disease patients that received autologous (patient-derived) bone-marrow-derived stem cells (BMSC) in both eyes (NCT01920867) . Whilst A key consideration with RPE transplantation for Stargardt disease is that it does not directly approach the cause of the disease, and therefore may not enable long-term effects. Providing RPE cells back into a retina that has lost these cells and the photoreceptor cells in the same area may not be the most therapeutic transplantation option given that in patients with Stargardt disease, the problem arises in the photoreceptor cells. Provision of new iPSC-derived RPE cells may only be a short-term solution, particularly as these cells will be prone to A2E and lipofuscin accumulation, as were the original RPE cells . The cliABCA4, ELOVL4 and PROM1 could be targeted with one or more of the currently described CRISPR-based approaches: genome editing, epigenetic repression, base editing or prime editing  creation that can be used for gene silencing . AlternaPROM1, although two other missense mutations have also been identified [PROM1 c.1117C > T site occurs within a good editing window for targeting by Cas9 proteins from Streptococcus pyogenes  in entified ,140. The (SpCas9 ), StaphyauriCas9 ) and a mH-SaCas9 ). This mH-SaCas9  and dualH-SaCas9 ,146,147 H-SaCas9 ; therefoABCA4 mutation, but as an autosomal recessive condition, the correction of one allele should be enough to provide a therapeutic benefit [ABCA4  enzymes fused with an RNA-targeting Cas protein such as Cas13 . Whilst ELOVL4 [Prime editing is a further CRISPR-based approach worth considering that targets DNA and consists of a Cas9 fused to an engineered reverse transcriptase . In combELOVL4 , it is aDespite the large cohort of Stargardt disease patients, in particular those with STGD1, development of an effective treatment has lagged behind other rarer recessive inherited diseases. As discussed in this review, researchers and clinicians have approached the problem from multiple directions with many therapeutic strategies showing promise. Indeed, some of the options that have shown pre-clinical success have yet to be applied in humans. For all the encouraging therapeutics tested in trials to date, it may be that the most effective treatment form is yet to come by way of CRISPR-based strategies. Regardless of the approach employed, it is clear that with the efforts made so far, there is hope an effective treatment for Stargardt disease will appear in the coming years.


IntroductionAdequate staffing in the intensive care units (ICUs) is the most important factor to provide optimal care and ensure favorable outcomes in critically ill patients. Recently, the need for ICU beds has reached unprecedented levels and the management and treatment of critically ill patients has been in focus. The aim of the study was to assess the targeted and actual nurse-to-patient (NPR) and physician-to-patient ratios (PPR) regarding patients with and without COVID-19.MethodsWe conducted a nationwide online survey assessing the standard of care in German ICUs treating patients with COVID-19. We asked questions regarding targeted PPR and NPR and their implementation in daily clinical practice to heads of German ICU departments.ResultsWe received 244 responses of which 171 were eligible for final analysis. Targeted median PPR ratio was 8 [interquartile range (IQR) = 4] and targeted NPR was 2 (IQR = 1). For COVID-19 patients, the median targeted PPR was 6 (IQR = 2) and the median targeted NPR was 2 (IQR = 0). Targeted PPRs were rarely met by 15.2% and never met by 3.5% of responding institutions. Targeted NPRs were rarely met in 32.2% and never in 5.3% of responding institutions.ConclusionIn contrast to PPR, targeted NPRs were largely unattainable in German ICUs. Our results raise concern in view of studies linking worse outcomes in critically ill patients to suboptimal NPRs. This warrants further health policy efforts regarding optimal staffing in the ICU. The intensive care treatment of critically ill patients places high demands on staffing. An adequate number of nurses and physicians per patient are substantial for individual outcome -4. MajorThe COVID-19 pandemic led to unprecedented adjustments in ICU organization and care processes. Bottlenecks in terms of availability of medical equipment were immanent and a serious problem in several countries, leading to severe strain. However, besides shortages in bed capacity or medical supplies, staff trained in the care of critically ill patients was the most limited resource.The key figures that best determine an association between available professionals and patients are the physician-to-patient (PPR) and nurse-to-patient ratios (NPR) .In the context of notorious staff shortage even before the SARS-CoV-2 pandemic, the problem was controversially discussed in daily politics. In Germany, this has been recently acknowledged by official authorities leading to a ministerial order  which has the intention to regulate a minimal standard of NPR on ICUs . AccordiThe current COVID-19 crisis highlights this familiar policy problem in a new, pandemic situation. Patients infected with SARS-CoV-2, like all infectious and isolated patients per se, require a much higher level of support than non-contagious patients, resulting in an unprecedented workload for medical personnel .Our aim was to answer two questions: first, the targeted PPR and NPR were queried by interviewing heads of ICU departments. The second question focused on the actual implementation of these self-proclaimed standards in daily practice during the COVID-19 pandemic.The survey was generated within a nationwide network established for clinical research in this on-going pandemic , funded by national authorities  . The intThe survey was created by using the SoSci survey online tool. Statistical analysis was performed using Microsoft Excel  and IBM SPSS version 27.0.0.0 . Python version 3.8.2  in a Jupyter notebook including the seaborn sublibrary was used for data visualization. We used the chi-square test to show differences between professional groups and calculated median and interquartile range (IQR) values. P-values less than .05 were considered significant.During the three-week processing period, we intended to contact 1340 ICUs from a register of the German Society of Intensive Care and Emergency Medicine (DIVI). Figure Four questions were asked to the heads of ICU departments or the physicians responsible for allocation of staff. The answers regarding staff-to-patient ratio in each institution are presented in Table The survey focused on target achievement by self-assessment of heads of ICUs. Table The purpose of this study was to identify self-pronounced staff-to-patient ratios by a structured, online-based approach followed by self-assessment of whether these ratios can be achieved.A targeted PPR of 1:8 for non-COVID-19 patients and 1:6 for COVID-19 patients and a minimum NPR of 1:2 regardless of COVID-19 was reported. While the majority of institutions are able to recruit physicians to achieve their targets, the bottleneck is the nursing staff. Our results underline an important issue in the German health care system. The expectation to the standard-of-care in terms of available ICU personnel is high. However, the reality shows that self-pronounced targets of the responsible ICU management are unachievable.Beyond all doubt an adequate staff-to-patient ratio is crucial in intensive care medicine , 7, 13. During the COVID-19 pandemic, with a significant percentage of critically ill patients requiring intensive care, a substantial increase in available ICU capacity without additional staffing can only be achieved by reducing the influx of non-COVID patients. However, because a large proportion of necessary ICU admission cannot be avoided without putting patients at risk, for example by reducing deferrable major surgical procedures , additioWhile most studies focused on NPR, data regarding ideal PPR is limited. For example, one study addressed the question of an ideal ratio of physician-to-ICU beds. The authors found that ICU length of stay is significantly prolonged if the ratio reaches 1:15 . AnotherAn important finding of our study is the identification of a discrepancy when comparing physicians and nurses. In summary, 37.5% of ICUs in our survey are "never" or "rarely" able to achieve the targeted NPR Table . This caAlthough our survey is not representative, which is clearly a limitation of this study, the response of 171 ICUs highlights a widely discussed problem in German public health. Furthermore, since 49% were larger hospitals with more than 600 beds, we cannot generalize our results but we are worried that the situation in smaller or non-responding hospitals might be even worse.Our survey suggests that the discrepancy between desired and actual staffing levels is significant, particularly among nurses. Because quality of care and complication rates are significantly correlated with NPR, it is reasonable to suspect that this shortage is leading to a reduction in quality. With more than one-third of reporting ICUs failing to achieve adequate nurse staffing during the COVID-19 pandemic, there is a risk that significant reductions in quality might have occurred. Our results warrant further health policy efforts regarding optimal staffing in the ICU.