Nanoscale coating manufacturing (NCM) process modeling is an important way to monitor and modulate coating quality. The multivariable prediction of coated film and the data augmentation of the NCM process are two common issues in smart factories. However, there has not been an artificial intelligence model to solve these two problems simultaneously. Focusing on the two problems, a novel auxiliary regression using a self-attention-augmented generative adversarial network (AR-SAGAN) is proposed in this paper. This model deals with the problem of NCM process modeling with three steps. First, the AR-SAGAN structure was established and composed of a generator, feature extractor, discriminator, and regressor. Second, the nanoscale coating quality was estimated by putting online control parameters into the feature extractor and regressor. Third, the control parameters in the recipes were generated using preset parameters and target quality. Finally, the proposed method was verified by the experiments of a solar cell antireflection coating dataset, the results of which showed that our method performs excellently for both multivariable quality prediction and data augmentation. The mean squared error of the predicted thickness was about 1.6~2.1 nm, which is lower than other traditional methods. Nanoscale coating technology is widely used in the advanced industrial manufacturing, such as solar cell antireflection films and new multifunctional materials for the automobile and aircraft industries . The proIn the literature, coating process modeling methods can be classified into statistical-model-based methods and artificial-intelligence-based methods ,4. Respo(1)The relations among different manufacturing steps are ignored when extracting features from the control recipes;(2)Data augmentation is an essential technique in DL-based process modeling in industrial manufacturing. Prior works have few studies about recipe augmentation, especially in NCM;(3)The multivariable quality prediction and data augmentation of NCM are rarely considered simultaneously, as these factors can increase the training cost.Generally, the defects in existing methods are summarized by following aspects:From a data-mapping perspective, NCM process modeling helps to establish the relationship between coating quality and corresponding recipes. Nevertheless, most research works have only studied modeling for coating quality prediction in which the input variables have been recipes, and the output variables have been coating quality factors. Modeling of coating recipe generation for desired quality or specific control conditions has been ignored. Theoretically, if recipe generation for particular quality factors is required, a model can be obtained by inverting the coating quality prediction model. In addition, the latent coupling information between the post-process recipes and the pre-process recipes is beneficial for the control of the multilayer coating process. Generative adversarial networks (GANs) provide the possibility of complete NCM processing modeling.Self-attention generative adversarial networks (SAGANs)  inspire The major novelties and contributions of this paper can be summarized in three aspects.(1)A data-driven NCM process model is proposed in an end-to-end way that can predict coating quality by learning features adaptively from complex industrial process data and can make data augmentation by generating recipes of coating processing.(2)The data augmentation of the multilayer coating processing is challenging work. The proposed model not only learns the connection information between the NCM output quality and the control parameters, but it also extracts latent knowledge between the former coating steps and the subsequent coating steps from history production data with the assistance of a self-attention technique.(3)The quality of the NCM output has multiple variables, which may include thickness, refractive index, or other reference values. In addition, there is a coupling relationship between these output values. The proposed framework can predict multivariable quality by sharing feature information of control parameters and regression weights.The rest of this paper is organized as follows. The preliminaries of NCM process modeling, as well as the self-attention mechanism and basic GAN, are described in In this section, background knowledge of NCM process modeling using ANNs, as well as self-attention mechanisms and generative adversarial networks, is demonstrated.ANNs have been proved for the application of coating process quality prediction, especially coating thickness estimation . The strA self-attention mechanism is used to connect and capture correlations among different vectors . They haD and a generator G, which are both fully connected. The generator can take noise data and create fake data. The discriminator can distinguish between the fake data and real data. An auxiliary classifier GAN (ACGAN) [The basic generative adversarial network (GAN) proposed by Goodfellow et al.  is compo (ACGAN)  adds an  (ACGAN) , which i(1)The generated data for target coating quality;(2)The discriminator to distinguish between real control parameters and generated parameters;(3)The regression for quality estimation using the input control parameters.Herein, NCM process modeling using GAN is responsible for satisfying three key points: Inspired by ACGAN, the aforementioned improved GAN was defined as AR-SAGAN (auxiliary regression using SAGAN).In order to model the NCM process and solve quality prediction and augmented recipe generation synchronously, an AR-SAGAN architecture was proposed. (1)Preprocessing. The collected data included control data and associated quality data. In addition to deposition time, the raw control data sampled from multiple sensors were continuous and fluctuated around the original control value. Thus, the median values in each coating step were extracted as the feature. After that, outlier elimination and normalization were carried out.(2)Model training. Our proposed AR-SAGAN was trained using an offline dataset. The AR-SAGAN was periodically trained and updated to adapt the real-time operating conditions.(3)Quality prediction. The online control parameters were collected, preprocessed, and then input to a regressor, which was trained using AR-SAGAN to predict quality.(4)Data augmentation. In this step, the online control parameters and the target quality data were preprocessed and input to a generator trained by AR-SAGAN to generate more control recipes.The specific AR-SAGAN model architecture is depicted in (1)The generator took random noise, desired quality data, and control parameters of the first (2)The feature extractor extracted latent information from the complete recipe. The control parameters were reshaped into the size To train the AR-SAGAN model, the losses were defined, including discriminator loss N data pairs, the mean absolute error (MAE) Due to multivariable outputs, the regressor loss was hybrid. For The Wasserstein-distance-based GAN (WGAN) is proven to be more suitable for stability training compared with using KL divergence and JS divergence . To ensuThe generator loss evaluated the generated fake data based on Wasserstein distance:Because the discriminator and regressor shared the weights and parameters of the feature extractor, there were three training conditions to update the feature extractor. Training condition 1 (TC1) was for training the feature extractor based on the discriminator loss and to then freeze the weights of the feature extractor to train the regressor. In the case of TC1, the learnable parameters were updated as follows:Algorithm 1: Training AR-SAGAN based on TC1.Input Initialize network parameters while not converged dofork steps doendend whileThe learning algorithm of the AR-SAGAN model based on TC1 is summarized in Algorithm 1.Training condition 2 (TC2) always updated the weights of the feature extractor based on the discriminator loss and regressor loss. In the case of TC2, the parameters were updated as follows:Algorithm 2: Training AR-SAGAN based on TC2.Input Initialize network parameters while not converged dofork steps doendend whileThe learning algorithm of the AR-SAGAN model based on TC2 is summarized in Algorithm 2.Training condition 3 (TC3) only trained the feature extractor using the regressor loss and froze the weights when training the discriminator. For the last case, the parameters were updated as follows:Algorithm 3: Training AR-SAGAN based on TC3.Input Initialize network parameters while not converged dofork steps doendend whileThe learning algorithm of the AR-SAGAN model based on TC3 is summarized in Algorithm 3.Plasma-enhanced chemical vapor deposition (PECVD) is a coating technique with the auxiliary of radio frequency that promotes the formation of a gaseous reaction ionization environment, boosting the deposition rate of the film . SiliconThe experimental data were sampled from a practical process consisting of 3 coating steps and 20 control parameters. The control parameters were sampled using multisensors, and the sampling frequency was 0.5 Hz. The average thickness (TN) and refractive index (RI) of the solar cells were measured using an ellipsometer after the coating process. The recorded ranges of TN and RI were 70~80 nm and 2.1~2.5, respectively. The control parameters included temperatures of different areas, cavity pressure, RF power, gas flow velocity, relative flow ratio among gases, and deposition time of each coating step. The variation trends of these control parameters are shown in The AR-SAGAN model was implemented, and the algorithms were compared under different training conditions. There were 500 training data and 183 test data. For the training data, the batch size for real data and fake data was 128. The first 2 coating steps were used as the input to output the 20 control parameters of the last coating step. The number of random noises was 1. An Adam learning optimizer was used. The mean absolute percentage error (MAPE) The regressor was always trained with the real data. However, the parameters of the feature extractor were influenced by the fake data in the cases of TC1 and TC2. The normalized outputs of regressor were inversely transformed into the original ranges, and the metrics were calculated. The loss weights of the thickness and refractive index were 1 and 2, respectively. The epoch number was 200. In addition to the MAPE, mean squared error (MSE) As shown in The compared regression results of AR-SAGAN and other methods are demonstrated in From the aspect of architecture, the AR-SAGAN model was mainly composed of ANN and a self-attention module. Compared with other GAN-based models, AR-SAGAN not only controlled the labels of generated data, but it also estimated the continuous regression values at the regressor. Moreover, AR-SAGAN studied temporal characteristics by learning the latent relationships between the preset characteristics and generating follow-up information. The regressor included multiple-output branches and estimated labels using regression. The sample amount of random noise and preset information that was taken to the generator resolved the mode collapse for the target labels. Overall, the AR-SAGAN overcome quality prediction and data augmentation issues better than other conventional methods and can be applied in practical engineering.To predict coating quality and augment recipe data for the NCM process in factories, this paper proposed a novel processing modeling method based on a self-attention mechanism and a GAN. First, the AR-SAGAN was proposed with data-driven auxiliary regression and self-attention-augmented adversarial generative structures. Furthermore, a case study on PECVD processing was provided to validate the effectiveness of the proposed AR-SAGAN. The results showed that AR-SAGAN effectively controlled the quality of the generated recipes by adjusting the preset control parameters. Especially when the feature extractor was trained with regressor loss using the real recipes and quality data, the AR-SAGAN had a better performance in data augmentation and quality prediction.Our future work will focus on two parts, given as follows: first, a solution for the regression for unbalanced distributed data by improving the proposed method; and second, an extension of AR-SAGAN application by combining multivariable process modeling with other areas.


Connectome maps region-to-region connectivities but does not inform which white matter pathways form the connections. Here we constructed a population-based tract-to-region connectome to fill this information gap. The constructed connectome quantifies the population probability of a white matter tract innervating a cortical region. The results show that ~85% of the tract-to-region connectome entries are consistent across individuals, whereas the remaining (~15%) have substantial individual differences requiring individualized mapping. Further hierarchical clustering on cortical regions revealed dorsal, ventral, and limbic networks based on the tract-to-region connective patterns. The clustering results on white matter bundles revealed the categorization of fiber bundle systems in the association pathways. This tract-to-region connectome provides insights into the connective topology between cortical regions and white matter bundles. The derived hierarchical relation further offers a categorization of gray and white matter structures. The brain connectome maps region-to-region connections but often ignores the role of the connecting pathways. Here, the authors mapped the tract-to-region relations to reveal the hierarchical relation of fiber bundles and dorsal, ventral, and limbic networks. Studies have used structural or functional connectivity to quantify the region-to-region connectivity as the connectome4 and delineate the network topology of the nervous system. The network topology revealed by the brain connectome further informed the functional implications of cortical regions and enabled graphical theoretical analysis5. However, the conventional region-to-region connectome is agnostic of the role played by white matter pathways and does not indicate which pathways form the cortical connections. Consequently, for many neuroscience studies investigating region-to-region connectivity, the white matter is still a black box with much unknown that needs further exploration.Mapping the human connectome is the key to understanding how brain structure gives rise to functions and how brain diseases cause dysfunctionsm brain regions and n white matter bundles, the tract-to-region connectome can be quantified by an m-by-n matrix, where each matrix entry records the corresponding population probability of a white matter pathway innervating a cortical region.Here we mapped the tract-to-region connectome to address this information gap. The connection probability between white matter pathways and cortical regions was evaluated on 1065 young adult subjects. For 11, most have used cortical parcellation to recognize tracts. These region-based methods could lead to circular analysis in the tract-to-region connectome. Therefore, this study used trajectory-based recognition12 and did not filter tractogram by brain regions. After trajectory-based recognition, connections substantially deviated from the expert-vetted tractography atlas were removed.Several technical advances were used to construct the tract-to-region connectome Fig. . The whi13, the Human Connectome Project’s multimodal parcellations (HCP-MMP)14, and a random parcellation, respectively. The tract-to-region information provided by this approach could complete the circuit diagram for many structure-function models and inform the likelihood of a white matter lesion causing a functional deficit in the dysconnectome studies. Further hierarchical clustering was applied to the tract-to-region connectome. The clustering results revealed the hierarchical relation of cortical regions and white matter pathways that informed their categorization.Four tract-to-region connectome matrices were quantified using the Brodmann parcellation, Kleist parcellation15 and existing tractography results17. The lateralization of left arcuate fasciculus (AF) can be readily observed by its substantially larger volume.We examined the tractography of 1065 subjects in the ICBM152 space. Figure 12. Figure 17.Figure The tract-to-region connectome based on Brodmann areas and Kleist parcellations are shown in Fig. 18 also showed a similar result  and Kleist parcellations  have population probabilities greater than 95% or smaller than 5%, meaning that these tract-to-region pairs are either connected or not connected in the majority of the study population. Around 15% of the matrix entries in Brodmann and Kleist parcellations show probabilities between 5 and 95% due to substantial individual variation. Interestingly, although HCP-MMP have more parcellation regions (180 regions) than Brodmann and Kleist parcellations (39 and 49 regions), it gives a remarkably similar figure. A total of 86.50% of its matrix entries (8096 out of 9360 entries) also have probability values greater than 95% or smaller than 5%. A random parcellation with 360 regions derived from Craddock’s random parcellations23 as well as premotor/motor regions19. The lateralization of AF to frontoparietal (yellow), angular (green), and superior temporal regions (red) can also be seen by comparing Fig. We further examined AF connections in the tract-to-region connectome using the Sankey flow diagrams shown in Fig. Figure Figure Here we quantify the tract-to-region connectome in the young adult population. The constructed matrices provide a resource for both neuroscience and clinical studies to evaluate the probability of a white matter tract connecting to a cortical region. Based on this tract-to-region connectome, we further applied hierarchical clustering between cortical regions and between white matter association pathways to understand their relations. The results in cortical regions revealed dorsal, ventral, and limbic networks, especially using more detailed parcellations such as HCP-MMP.27. The tract-to-region connectome matrices and all intermediate data, such as tractogram of each bundle, read-to-track subject data, and source code, are publicly available at https://brain.labsolver.org. The shared data could also construct the conventional region-to-region connectome for each white matter pathway, as illustrated in our previous connectome study28.The dorsal, ventral, and limbic networks can be applied to many existing functional models. The dorsal system includes most frontal lobe  and parietal lobe, whereas the ventral system includes the temporal lobe and occipital lobe. The dorsal and ventral subnetworks shared many similarities with the existing dual-stream models in the language and visual functions29. Existing studies have predominately focused on region-to-region connections and simplified the role of white matter bundles as “edges” in the network model. Consequently, the region-to-region connectome falls short of illustrating the association between cortical regions and white matter pathways. This limitation becomes obvious in lesion-symptom mapping studies of aphasia: damaging Broca’s area does not necessarily lead to Broca’s aphasia31, but lesions involving the anterior segment of the left AF are a strong symptom predictor32. Since cortical regions themselves may not be sufficient to explain functional deficits33, the role of white matter pathways should be considered in dysconnectome studies36. For these studies, the tract-to-region connectome could provide a population-based reference to understand the relation between cortical regions and white matter bundles.Neuroanatomical evidence has shown that brain regions in both human and non-human primates could be connected through more than one routeThe tract-to-region connectome can be utilized in various scenarios in which the white matter tracts are the targets of interest. For clinical cases involving a lesion in deep white matter structures, the population probability quantified by the tract-to-region connectome can provide the likelihood of an affected white matter pathway leading to functional deficits in a cortical region. Conversely, in fMRI, EEG, or SEEG studies identifying a cortical region of interest, the tract-to-region connectome can translate the findings to their corresponding white matter pathways based on population probabilities. Subsequently, the information can delineate the circuit mechanism behind a cognitive model or verify the structure-function hypotheses. Both of them may further help explore white matter targets for neurological modulations using deep brain stimulation, focused ultrasound ablation, or laser ablation.38, but clustering on the tract-to-region connectome concerns whether two cortical regions share similar white matter connections. As a result, the region-to-region connectome tends to group frontal and prefrontal regions due to their strong connections through short association pathways39. In comparison, the results from the tract-to-region connectome using three differential parcellations unanimously separated prefrontal and frontal regions due to their distinctly different connections to the limbic and dorsal networks. The prefrontal regions are closely connected with the limbic network through the cingulum, whereas frontal regions are closely connected with the dorsal network through SLF II and SLF III. The difference in clustering context will lead to entirely different results and application scenarios that answer different neuroscience questions.The tract-to-region and region-to-region connectome provide different perspectives on the organization of brain networks, as shown by their different clustering results. The clustering on the region-to-region connectome concerns whether two cortical regions are closely connected45, these clustering methods did not consider the connective pattern with the cortical regions. The clustering in this study showed that SLF II and SLF III are closely related to AF, whereas SLF I is closely related to the cingulum. These results may appear questionable and astonishing at first glance, but there are supporting references: Catani et al.20 showed SLF III as the anterior segment of the AF, which did not include SLF I. Wang et al.46 suggested that the SLF I could be viewed as part of the cingulum system. From the clinical perspective, especially in the surgical intervention of brain tumors, the neurosurgical consensus is that the eloquent area correlated with post-surgical functional deficits includes regions innervated by AF, SLF II, and SLF III49. These areas did not include SLF I because SLF I did not show significant language function50. Furthermore, SLF I was delineated by anterograde tract-tracer technique in rhesus macaques51, where detailed mapping was illustrated by Schmahmann and Pandya’s work52. In their work, among 15 cases enhancing the SLF I , 12 of them  also enhanced the cingulum bundle as labeled by the authors. In comparison, only two cases (cases 4 and 31) enhanced SLF II, and three  enhanced SLF III. This hinted at a closer relationship between the SLF I and cingulum than with the SLF II or SLF III. Nonetheless, it is noteworthy that the clustering in this study was based on the tract-to-region connectome entries, and by no means could this be used to confirm a new naming convention or provide a new neuroanatomical definition as each bundle has well-defined anatomical locations, as shown in Fig. We also derived the hierarchical relation between white matter bundles. While many studies have been conducted to cluster white matter tracts53. Moreover, for bundles mapped in this study, the tract-to-region relation was determined by a simple overlap in the binary mask. This setting was used to compensate for tractography’s “gyral bias” that failed to map connections at the “gyral bank.” However, there could be spurious connections because tractography could not confirm innervation. For example, the connection probabilities between IFOF and insula regions  were just due to IFOF passing by, and further histology validation is needed. On top of these limitations, the included tracts were also subject to errors such as trajectory deviation, premature termination, and incorrect routing, as discussed in a recent review54. Although multiple strategies have been leveraged to reduce false connections, we cannot rule out possible errors in the current form of the tract-to-region connectome.There are limitations to this study. The tract-to-region connectome did not include cerebellar, commissural, brainstem, or connections between subcortical structures. Excluding cerebellar and brainstem pathways are due to different slices coverage near the brainstem and insufficient spatial resolution to generate reliable fiber tracking results. The commissural pathways are excluded because of the limited ability of the fiber tracking methods to resolve crossing-kissing patterns when the corpus callosum crosses the hemispheres5 may not be readily applicable to the tract-to-region connectome because the tract-to-region concept is conceptually different from the conventional region-to-region one. While the region-to-region connectome implies an undirected graph, the tract-to-region matrix appears to be a subset of an undirected graph called a bipartite graph. The bipartite graph comprises two disjoint sets of nodes, one for tracts and one for regions. The nodes representing tracts could not be equally exchanged with nodes representing regions. Since most network measures view all nodes equally in the computation, applying these network analyses to the tract-to-region connectome could lead to questionable results. Further theoretical development is thus required to translate network measures to the tract-to-region connectome.Furthermore, the existing graph-theoretical analysis55 or end regions of tracts10 to recognize a tract. The tracts defined by cortical parcellation would show connections according to the supplied cortical parcellations, leading to circular results in the tract-to-region connectome. A solution is to use white matter trajectories to recognize tracts, but trajectories-based methods may not effectively utilize all existing atlases57. Most white matter atlases were voxel-based volumes that provided only masks of tract coverage and did not have trajectory coordinates needed by trajectory-based recognition. Few atlases provide trajectories coordinates for individual subjects, but a group average would be needed to minimize the individual differences. This averaging step is critical for classifiers that are sensitive to noisy data.This study mainly focuses on the concept of the tract-to-region connectome, and the variations due to different tracking recognition tools were not investigated. The tract-to-region relation could be derived using different tools or atlases, but additional customizations may be needed to address unique technical concerns when deriving the tract-to-region relation. Specifically, tract segmentation tools often used cortical parcellations58 or segmentation tools59. The differences due to tools were direct results of different input data: region-based recognitions used cortical parcellations, while trajectory-based recognition used the topology of white matter tracts. On the other hand, the differences in anatomical views were mainly due to discrepancies in the existing categorical systems and tract nomenclature60. Much of the recent disputes focus on detailed subcomponents and their categorical relations61. Resolving them would need new neuroanatomical evidence from tract-tracing or cadaver dissection studies. The population-based tractography and its corresponding tract-to-region connectome are thus subject to future revisions and updates to ensure their up-to-date accuracy. Despite those discrepancies, it is noteworthy that the anatomical locations of white matter pathways are well-defined, and this study did not invent new white matter structures. The pathways mapped in this study , which combined deterministic fiber tracking algorithm65, randomized parameter saturation12, topology-informed pruning66, and trajectory-based tract recognition12 (detailed in the next section) as an integrated interface. The default settings were used: the anisotropy threshold was uniformly and randomly selected from 0.5 to 0.7 Otsu threshold. The angular threshold was uniformly and randomly selected from 15 to 90 degrees. The step size was uniformly and randomly selected from 0.5 to 1.5 voxel spacing. The minimum length was 30 mm. The tracking was repeated until the ratio of streamlines to voxels reached 1.0.For each subject, 52 white matter bundles were mapped using the automated tractography pipeline in DSI Studio  was used in this study.The tract recognition used the nearest neighbor method to classify tracts. Since the nearest neighbor classifier is sensitive to noisy data and prone to overfitting, training data preparation was critical for best performance. Most population-based atlases have substantial individual variations and thus would require additional averaging to minimize individual differences. Therefore, in this study, the recognition used a population-averaged tractography atlas67 was computed between each subject and the atlas tract. The shortest distance then determined the label of subject tracts. Some tracts might substantially deviate from all atlas trajectories, and thus a maximum allowed Hausdorff distance (termed tolerance distance) of 16 was used to remove them. The minimum Hausdorff distance was increased to 18 and 20 mm if no bundle was found after topology-informed pruning66. In this study, 4 out of the 52 bundles did not reach a 100% yield rate for all 1065 subjects: left CBTs (983/1065), right CBTs (1054/1065), right AF (1046/1065), right occipital corticopontine tract (1064/1065). The missing of the corticobulbar and corticopontine tracts in some subjects could be due to the limitation of the fiber tracking algorithm to capture substantial turning of the pathways. The right AF in some subjects was entirely labeled as SLF III due to no connection to the superior temporal lobe.For each subject, the tractography atlas was nonlinearly warped to subject space using the diffeomorphic mapping derived between the subject’s anisotropy image and the ICBM152-space anisotropy image. The Hausdorff distancehttps://github.com/frankyeh/DSI-Studio.The steps mentioned above, including subject-space fiber tracking, parameter saturation, randomized parameters, topology-informed pruning, anisotropy-based warping, Hausdorff distance computation, were integrated as the automated tractography function in DSI Studio. The source code is also available on GitHub repository at 68. The tractography result for each subject and each white matter tract are shared on http://brain.labsolver.org.The computation was conducted at the Pittsburgh Supercomputing Center provided through the Extreme Science and Engineering Discovery Environment (XSEDE) resourceThe white matter bundles of each subject were then exported to the ICBM152 2009 nonlinear space to facilitate integration across the entire subject group. As shown in Fig. 13. On the other hand, the ICBM152-space version of HCP-MMP was obtained from https://neurovault.org/collections/1549/  and further inspected for each cortical region to manually remove the cross-sulci leakage using DSI Studio. The revised version of the HCP-MMP was shared with the DSI Studio package and is publicly available at http://dsi-studio.labsolver.org. The random parcellation was derived from level 33 of Craddock’s fine-grained random parcellations18 by assigning the labels to a gray matter mask in the ICBM152 space using the shortest distance.We used the ICBM152-space version of newly reconstructed Brodmann and Kleist atlaseshttp://brain.labsolver.org.A binary tract-to-region connection matrix was obtained for each subject by calculating the intersection between the voxel-wise mapping of white matter bundles and cortical regions Fig. . The bin69 provided by the “linkage” function in MATLAB to avoid the high variability drawback of simple single linkage clustering. For each cortical parcellation , a dendrogram was generated to reveal the hierarchical relation of the cortical regions. The hierarchical clustering for white matter bundles was conducted using the column vector of the HCP-MMP connectome matrices (Fig. We used row vectors of the tract-to-region matrices as the feature vectors to derive the hierarchical relation between cortical regions Fig. . The simces Fig. . The cluFurther information on research design is available in the Supplementary InformationPeer Review FileReporting Summary


Of the 38 million people currently living with Human Immunodeficiency Virus type-1 (HIV-1), women, especially adolescents and young women, are disproportionally affected by the HIV-1 pandemic. Acquired immunodeficiency syndrome (AIDS) - related illnesses are the leading cause of death in women of reproductive age worldwide. Although combination antiretroviral therapy (cART) can suppress viral replication, cART is not curative due to the presence of a long-lived viral reservoir that persists despite treatment. Biological sex influences the characteristics of the viral reservoir as well as the immune responses to infection, factors that can have a significant impact on the design and quantification of HIV-1 curative interventions in which women are grossly underrepresented. This mini-review will provide an update on the current understanding of the impact of biological sex on the viral reservoir and will discuss the implications of these differences in the context of the development of potential HIV-1 curative strategies, with a focus on the shock and kill approach to an HIV-1 cure. This mini-review will also highlight the current gaps in the knowledge of sex-based differences in HIV-1 persistence and will speculate on approaches to address them to promote the development of more scalable, effective curative approaches for people living with HIV-1. More than half of the 38 million people worldwide living with Human Immunodeficiency Virus Type-1 (HIV-1) are women. Combination antiretroviral therapy (cART) to control HIV-1 is lifesaving, but not curative due to the establishment of a persistent, latent, viral reservoir that is not eliminated by cART. cART must therefore be taken lifelong and people living with HIV-1 (PLWH) are burdened with detrimental side effects, social stigma, costs and the possibility of developing drug resistance. Importantly, more than one in four PLWH are currently not on cART, rendering them vulnerable to acquired immunodeficiency syndrome (AIDS)-related complications that could otherwise be prevented by effective cART. Women, in particular, are disproportionally affected by HIV-1 with high burdens of comorbidities . DespiteBoth the biological attribute of sex and the socio-cultural factor of gender are critical variables to consider in biomedical research, and they have also been reported to influence HIV-1 transmission, pathogenesis and response to treatment . AltThe main obstacle to an HIV-1 cure is the establishment of a viral reservoir by HIV-1 upon infection that persists during cART. HIV-1 curative strategies are aimed at either eliminating or reducing the viral reservoir, or permanently silencing it, thereby abrogating the need for lifelong cART , 8. An on = 243, 28% women)    and (n =% women)  that aim% women) . In semi% women) . They ob% women) . Three l% women) –15. This% women)  were mea% women) .One longitudinal study also addressed sex-specific differences in reservoir dynamics during aging using more than 400 samples collected longitudinally from 90 donors (56% WLHIV) . They foIn a study by Scully et al. to assess sex-specific differences in the HIV-1 reservoir, no differences in cell-associated US-vRNA were observed between WLHIV and men. However, they reported that WLHIV have a six-fold lower expression of cell-associated MS-vRNA than men . This stn = 61, 36% women) could not find any differences in the frequency of cells harboring replication-competent virus as measured both by qVOA or by quantifying the intact HIV-1 DNA  measure the induction of replication-competent virus by measuring released viral proteins or vRNA in the produced virus. Using this technique, two groups describe conflicting reports on the effect of sex on the inducible viral reservoir , 14. In One of the most widely investigated strategies for an HIV-1 cure is known as the “Shock and Kill” approach which employs the use of latency-reversing agents (LRAs) to reactivate the viral reservoir followed by the use of pharmacological or immunomodulatory interventions to eliminate the reactivated infected cells . How sexPost-integration HIV-1 latency is controlled by multiple epigenetic mechanisms like nucleosome positioning, histone modifications, DNA methylations or silencing activities mediated by non-coding RNAs [reviewed in Verdikt et al. ]. Most lAlthough latency was earlier speculated to be due to an inhibition of transcription initiation, it has recently come to light that latency is also regulated at post-transcriptional levels like vRNA splicing , 33. Altin vivo than SAHA alone  by enhancing humoral or cell-mediated immune responses with broadly neutralizing antibodies, therapeutic vaccinations, engineered T-cells or other immunomodulatory agents to eliminate reactivating cells . Immune In the HIV-1 cure field, studies indicate that the complete elimination of the viral reservoir is unlikely to be achieved with the current approaches. Therefore, shock and kill can be used to reduce the size of the reservoir, not eliminate it, followed by approaches to enhance post-ART viral control, a strategy known collectively as “reduce and control” providing a functional cure for HIV-1 . Effectiin vitro efficacy of gene editing strategies have been reported, in vivo delivery of these therapies may be require a different approach in WLHIV because of the distinct pharmacokinetic profiles of women. Time to viral rebound followed by analytical treatment interruption is a common endpoint in HIV-1 cure trials, and since women are better at controlling viral replication, they may take longer to viral rebound  and from the Gilead Research Scholars award to SR.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IntroductionThe Upper Extremity Functional Index (UEFI) is a region-specific questionnaire for patients with upper extremity disorders including patients with rotator cuff-related pain (RCRP). We aimed to translate and cross-culturally adapt the UEFI into Greek (UEFI-Gr) and evaluate its reliability and validity in a Greek-speaking population with RCRP.MethodsPublished guidelines for translation and cross-cultural adaptation of patient-rated outcome measures were followed. One hundred two patients were asked to complete the Greek versions of the UEFI; Disability of the Arm, Shoulder, and Hand (DASH) questionnaire; and RAND 36-Item Health Survey. Internal consistency, test-retest reliability, measurement error, content validity, concurrent validity, and ceiling and floor effects were evaluated.ResultsMinor linguistic discrepancies were identified and adopted in the Greek language. The UEFI-Gr presented high internal consistency , excellent test-retest reliability , and acceptable measurement error . No ceiling or floor effects were detected. Strong correlations were found with the Greek versions of the Disability of the Arm, Shoulder, and Hand questionnaire  and weak to moderate correlations with most subdomains of RAND 36-Item Health Survey .ConclusionsThe UEFI-Gr is a comprehensive, reliable, and valid self-reported instrument to evaluate symptoms in patients with RCRP. Further research on the responsiveness of the questionnaire is necessary. Shoulder pain is considered the third most common complaint of all musculoskeletal conditions with rotator cuff-related pain (RCRP) contributing to over 70% of these cases -3. SeverThe Upper Extremity Functional Index (UEFI) is a region-specific PROM proposed to capture the multiple dimensions of patients’ functional status in various musculoskeletal conditions of the upper limb . The UEFCross-cultural adaptation and validation of PROMs in different languages are essential for making comparisons among patient groups with the same condition and promoting international research in the same field of interest . The proBased on authors’ knowledge, a Greek version of the UEFI (UEFI-Gr) is not available yet. We hypothesized that a valid and reliable Greek version of the questionnaire will enable accurate monitoring of the efficacy of treatment procedures and facilitate clinical decision-making in patients with RCRP. The purpose of our study was to translate and cross-culturally adapt the English version of the UEFI into Greek and subsequently to examine its reliability and validity in patients with RCRP.Cross-cultural adaptationPrior to commencing the study, permission was obtained from the developer author (Prof. Paul W. Stratford). Translation and cross-cultural adaptation process followed a merged methodology of published guidelines -17.Two bilingual independent translators  who were blinded to the construct of the scale completed the forward translation of the UEFI into Greek. The two Greek translations were synthesized into one by a research committee . Discrepancies were resolved through a consensus process, and when a conceptual equivalence was achieved, a final translation was produced. Two bilingual native English speakers (a research assistant and a physiotherapist), who were blinded to the scale, completed independently the back translation. The two versions of the back translation were carefully reviewed through a consensus process by the research committee including the author of the original version as well. During this step, the research committee decided if semantic, idiomatic, experimental, and conceptual equivalence between the English and Greek versions of the UEFI was reached .To evaluate the comparability of language and similarity of interpretability of the pre-final version of the UEFI-Gr, we recruited seven bilingual physiotherapists who evaluated the pre-final version using a Likert scale  [To assess the content validity (relevance) of the questionnaire, five physiotherapy researchers with expertise in the current field were asked to judge each item using a four-point Likert scale  . Also, fPatientsWe recruited individuals with RCRP from various hospitals and outpatient rehabilitation practices in Greece between April and December 2022. Patients were assessed for eligibility by a physiotherapist with 18 years of experience in musculoskeletal conditions. Participants were males and females, older than 18 years old, and fluent in the Greek language. The exclusion criteria were as follows: not able to read Greek; age of less than 18 years old; suffering from neck, thoracic, or, other than the shoulder, upper extremity problems affecting their shoulder function; chronic inflammatory diseases such as rheumatoid arthritis; fracture; cancer; central nervous system disorders; and cognitive disability.ProceduresPrior to entering the study, all patients signed an informed consent form. At the initial visit, the participants’ demographic characteristics were recorded. The study was approved by the University of West Attica Ethics Committee (41370/18-04-2022).To assess convergent validity, participants were asked to complete the Greek versions of the UEFI; Disability of the Arm, Shoulder, and Hand (DASH) questionnaire; and RAND 36-Item Health Survey in a quiet place without any help. The DASH questionnaire has been previously used to validate the UEFI in different languages -14. It iTo assess the reliability of UEFI-Gr, participants were given a second copy of the questionnaire and were asked to fill and return it after 2-7 days. the data of the second UEFI-Gr was used only if the patients’ condition was considered unchanged in terms of symptoms and function from baseline.Statistical analysisBased on COSMIN recommendations, a minimum sample size of 100 participants was considered adequate for the purposes of the validation of the study ,21. For Five experts and 10 patients with RCRP were recruited to judge item-content relevance. We have used Aiken’s coefficient (V) to analyze each item’s content validity  .95=1.96×To assess internal consistency, we used Cronbach’s alpha with values of >0.70 considered of good internal consistency . To asseWe analyzed the content validity index (CVI) by calculating the items rated >3 divided by the number of experts. We assumed that item-CVI>0.83 and scale-CVI>0.80 correspond to acceptable values .Convergent validity was evaluated using Pearson’s correlation coefficient (r). The UEFI-Gr score (first administration) and the scores of the Greek versions of DASH questionnaire and RAND 36-Item Health Survey were used. Pearson’s correlation coefficient values of ≥0.60, between 0.40 and 0.59, and ≤0.39 were considered as strong, moderate, and weak correlation between the questionnaires, respectively . We hypoTime to complete the UEFI-Gr was also recorded. Further, floor and ceiling effects were estimated when more than 15% of all responders scored the minimum (0) or the maximum (80) possible score.Translation, cross-cultural adaptation, and item content validityThree linguistic discrepancies in items were identified and resolved by consensus during forward and backward translation Table . Five exParticipantsA total of 102 patients  with a mean age (±SD) of 48.7 (±16.1) years were included in the study. Table Reliability95 were 4.9 and 13.8 points , respectively.Two patients reported a substantial improvement between the first and second administration of the questionnaire and were excluded from the analysis. Seventy-three patients were finally included in the reliability analysis suggesting an excellent test-retest reliability  and a high internal consistency of the questionnaire   . Only the Turkish version presented a lower test-retest reliability , which can be partially attributed to the lower sample size (35 participants) used for the reliability analysis compared to the other studies  and similar to the original and other translated versions   confirming the strong association between the two PROMs. The correlations were found strong suggesting that the UEFI-Gr is a valid tool to assess shoulder function in patients with RCRP; however, they were not perfect and substantially differed between studies. A possible explanation is that both questionnaires as region-specific instruments include a wide range of functional impairments. Another reason may lie on the sample characteristics among the translated versions that consisted of patients with RCRP and various upper extremity musculoskeletal disorders or trauma -14. As w-0.95 conLimitations and future researchAlthough an optimal time period of 7-14 days is widely accepted for test-retest reliability in musculoskeletal research, we decided to use a short time interval (2-7 days) to ensure stability of the patients’ condition. However, the short time interval may have significantly increased the risk of recall bias in our study . Our stuThe Greek version of the UEFI presented a high internal consistency, excellent test-retest reliability, and strong negative correlation with a well-investigated and validated outcome measure such as the DASH questionnaire. Based on the present findings, the UEFI-Gr can be suggested as a standard outcome measure in Greek-speaking patients with RCRP. Further evaluation of the responsiveness of the PROM is essential.


This study aimed to examine the theoretical effects of replacing television (TV) viewing with different intensities of physical activity on COVID-19 mortality risk using isotemporal substitution models.The analytical sample was composed of 359,756 UK Biobank participants. TV viewing and physical activity were assessed by self-report. Logistic regressions adjusted for covariates were used to model the effects of substituting an hour a day of TV viewing with an hour of walking, moderate-intensity physical activity (MPA) or vigorous-intensity physical activity (VPA) on COVID-19 mortality risk.From 16 March 2020 to 12 November 2021, there were 879 COVID-19 deaths in the analytical sample. Substituting an hour a day of TV viewing with an hour of walking was associated with a 17% lower risk of COVID-19 mortality (odds ratio (OR)=0.83, 95% confidence interval (CI) 0.74–0.92). In sex-stratified analyses, the same substitution was associated with a lower risk in both men  and women . However, replacing an hour a day of TV viewing with an hour of MPA was only associated with a lower risk in women .Replacing TV viewing with walking was associated with a significant reduction in COVID-19 mortality risk. Public health authorities should consider promoting the replacement of TV viewing with walking as a protective strategy against COVID-19 mortality. Physical inactivity and a high television (TV) viewing time have been shown to be risk factors for severe disease and mortality from COVID-19 1. Whilst Isotemporal substitution models allow for the assessment of the theoretical effect on health outcomes of replacing one behaviour with another in an equal time-exchange manner . As highTherefore, using data provided by UK Biobank, isotemporal substitution models were used to explore the theoretical effect of replacing TV viewing with walking, moderate-intensity physical activity (MPA) and vigorous-intensity physical activity (VPA) on the risk of COVID-19 mortality.All data were provided by UK Biobank, a cohort of >500,000 individuals recruited from the general population, aged 37–73 years at the time of baseline assessment 2006–2010) [–2010 [6]2). A touchscreen questionnaire was completed by participants to determine ethnicity, tobacco smoking and alcohol intake frequency, and number of cancer and non-cancer illnesses. The Townsend Index was used as a proxy for material deprivation and was determined from each participant’s postcode at recruitment. The Townsend Index is an area-level deprivation metric calculated based on non-home ownership, non-car ownership, unemployment and overcrowding within any geographical area [Baseline age was calculated from date of birth, and NHS records were used to determine sex. Height and weight were used to calculate body mass index .Isotemporal substitution models were used to examine the effect of replacing an hour a day of TV viewing with an hour of walking, MPA or VPA on COVID-19 mortality risk. These models included walking time, MPA time, VPA time and the total time in all behaviours  . By remoSupplemental Table SI). A notable number of participants had missing data for either walking, MPA or VPA (23%). Participant demographics for those who did and did not die from COVID-19 are presented in the Supplemental Material .The final analytical sample was composed of 359,756 individuals after removing those who were lost to follow-up, those who died before 16 March 2020 and those with missing data. There were 879 COVID-19 deaths over the analytical period (16 March 2020 to 12 November 2021). Participant demographics for the full sample and stratified by sex are presented in the The isotemporal substitution models are shown in Supplemental Table SIII). However, replacing an hour a day of TV viewing with walking was still associated with a significantly lower risk of COVID-19 mortality when analysing the full sample.Including BMI into the regression models rendered several associations no longer significant  on COVID-19 mortality risk. Across the full sample and the sex-stratified analyses, substituting an hour a day of TV viewing with walking was associated with a lower risk of COVID-19 mortality. However, replacing an hour a day of TV viewing with MPA was only associated with a lower risk in women.When analysing the full sample, differential changes in COVID-19 mortality risk were found when replacing an hour a day of TV viewing with walking compared to MPA and VPA. The stronger associations observed for walking compared to MPA and VPA – which persisted even after adjustment for BMI in the sensitivity analysis – are interesting, given that some studies suggest that higher-intensity physical activity may confer greater health benefits ,17. HoweAlthough there were no statistically significant interaction effects for sex, replacing an hour a day of TV viewing with MPA was associated with a significantly lower risk of COVID-19 mortality in women but not in men. The potentially stronger protective association of physical activity in women observed herein is consistent with previous findings from Rowlands et al., who found stronger relationships for all of the analysed physical activity metrics in women compared to men in relation to risk of severe COVID-19 . Given tThe current study has several limitations. The analysed physical behaviours were measured by self-report, making them subject to recall and social desirability bias. The progression through walking to MPA to VPA reflects increases in activity intensity. However, the intensities within each activity domain are not necessarily homogenous. Indeed, research has shown that brisk walking may confer greater health benefits than slower walking ,21. FutuIn conclusion, the key finding of this short communication was that replacing TV viewing with walking was associated with a significant reduction in risk of COVID-19 mortality. Although future research investigating mechanisms is required to determine the biological plausibility of the present findings, the results are encouraging, especially considering that walking is a more convenient physical activity to partake in compared to MPA and VPA for most individuals. Based on the current results, public health authorities should consider promoting the replacement of TV viewing with walking as a protective strategy against COVID-19 mortality.Click here for additional data file.Supplemental material, sj-docx-1-sjp-10.1177_14034948231158441 for Effect of replacing television viewing with different intensities of physical activity on COVID-19 mortality risk: Short communication from UK Biobank by Malik Hamrouni and Nicolette Bishop in Scandinavian Journal of Public Health


The results of the RSMN assay were in 100% agreement with the in vivo micronucleus assay results. From this dataset, 18 materials were positive in an in vitro micronucleus assay but were negative in an in vivo micronucleus assay. All these 18 materials were also concluded to be negative in 3DRSMN assay, stressing the importance of the assay to help minimize misleading positive outcomes from the in vitro assay. Since the highest exposure for fragrances is through the dermal route, the RSMN assay fits the applicability domain for testing. Thus, RSMN assay is an important alternative to animal testing for characterization of the genotoxicity potential of fragrance materials.In order to evaluate the utility of the 3D reconstructed skin micronucleus assay (3DRSMN) to assess clastogenic/aneugenic potential of the fragrance chemicals, a set of 22 fragrance materials were evaluated in 3DRSMN assay. These materials evaluated were also evaluated in an  A folloMN assay  Fig. 4)in vitro eus test .in vitro mammalian cell micronucleus test. A follow-up 3D skin and in vivo study were evaluated to verify the in vitro results and their biological relevance. In a GLP-compliant RSMN assay, EpiDermTM tissues were treated with 2,2ʹ-(dithiodimethylene)difuran in DMSO for 48 and 72 hours, at concentrations up to 1.25 mg/ml. 2,2ʹ-(dithiodimethylene)difuran did not induce binucleated cells with micronuclei when tested up to cytotoxic levels, and therefore was concluded to be negative for the induction of micronuclei in the RSMN assay heptane (CAS # 31996-78-8) was also investigated. 1-ethyl-3-methoxytricycloheptane was administered in propylene glycol as a single dose of 3519 mg/kg body weight via intra gastric gavage to groups of male and female Hsd:ICR (CD-1) mice and euthanized at 24, 48, or 72 hours. 1-ethyl-3-methoxytricycloheptane did not induce a statistically significant increase in the incidence of micronucleated reticulocytes in the bone marrow and was concluded to be negative in the in vivo micronucleus test, and this result can be extended to isobornyl methyl ether octan-8-one-oxime may be due to the fact that oximes can form reactive sulfate conjugates that aminate DNA in the absence of appropriate metabolic transformation pathway. For example, 2-Butanone oxime (MEKO) can be directly conjugated with sulfate. Oxidation of MEKO to 2-nitrobutane has been demonstrated to occur in liver microsomal preparation [in vivo. In rats, hydrolysis of MEKO to 2-butanone is the major pathway of biotransformation and 2-butanone is further catabolized to CO2 [in vitro micronucleus assays were only seen in shorter treatment conditions both with and without metabolic activation treatment, but it was negative in the long-term (24-hour) treatment condition in the absence of metabolic activation. For thiol compounds, the metabolism pathway seems to follow this chronology: S-oxidation, S-methylation, and fission of the disulfide bond proceeding to oxidation at the SH group of the resulting hydrolyzed compounds [in vivo studies which also has these enzymes present at sufficient levels. Taken together, our results indicate that the RSMN study generates more biologically relevant outcomes to determine genotoxic potential of fragrance materials. As such, the RSMN assay is useful for following up positive results from the standard in vitro cytogenetic assays.These results support the conclusion that the RSMN assay is useful for follow-up testing of materials that are positive in standard overload , or may overload , whereas species . The misparation , but likd to CO2 . A finalompounds  . Negative results were obtained in the RSMN assay for all of these materials, and these results agree with the negative in vivo micronucleus result for methyl beta-phenylglycidate and the negative read-across in vivo micronucleus result for isobornyl methyl ether.The RSMN assay is also useful in cases where there is an equivocal or positive result that is considered non-biologically relevant in the traditional in vitro micronucleus assay in HBPL for isobornyl methyl ether. Isobornyl methyl ether induced a statistically significant increase in micronuclei in the S9-activated 4-hour exposure that was dose-dependent [P > .05). Overall, isobornyl methyl ether was concluded to be equivocal. By contrast, isobornyl methyl ether was clearly negative in the RSMN assay. It can be argued that conducting an RSMN assay earlier in this evaluation, instead of repeating the standard in vitro micronucleus assay, may have resulted in an expedited, definitive assessment of a lack of genotoxicity. In vivo, alicyclic ethers like isobornyl methyl ether are expected to undergo either ring hydroxylation or side-chain oxidation followed by conjugation with glucuronic acid and excretion in the urine [Use of the RSMN assay earlier in a test battery could avoid time consuming, costly repeat testing and additional analyses that occur for those materials that induce weak or questionable effects. This is illustrated by a detailed discussion of the results of the ependent . Micronuhe urine , 97, andet al. to directly conduct the 72-hour treatment exclusively [et al. which has discussed the advantages to doing a 72-hour dosing regimen [The current study design for the RSMN assay  involveslusively . Conside regimen .in vitro genotoxicity battery as it showed 100% concordance with in vivo outcomes. Importantly, since the primary route of exposure for fragrances is by the dermal route, the RSMN assay fits the applicability domain for testing fragrance materials.The RSMN assay is an important alternative to animal testing for characterization of the genotoxicity potential of fragrance materials. In the context of the results obtained here, the RSMN assay was a powerful tool to address potential misleading positive outcomes from the standard Conflict of interest statement: None declared.


Venetoclax is a new type of BH3 mimetic compound that can target the binding site in the BCL-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptotic pathway. Venetoclax is especially used to treat haematological malignancies. However, with the recent expansion in the applications of venetoclax, some cases of venetoclax resistance have appeared, posing a major problem in clinical treatment. In this article, we explored several common mechanisms of venetoclax resistance. Increased expression of the antiapoptotic proteins MCL-1 and BCL-XL plays a key role in conferring cellular resistance to venetoclax. These proteins can bind to the released BIM in the context of venetoclax binding to BCL-2 and thus continue to inhibit mitochondrial apoptosis. Structural mutations in BCL-2 family proteins caused by genetic instability lead to decreased affinity for venetoclax and inhibit the intrinsic apoptosis pathway. Mutation or deletion of the BAX gene renders the BAX protein unable to anchor to the outer mitochondrial membrane to form pores. In addition to changes in BCL-2 family genes, mutations in other oncogenes can also confer resistance to apoptosis induced by venetoclax. TP53 mutations and the expansion of FLT3-ITD promote the expression of antiapoptotic proteins MCL-1 and BCL-XL through multiple signalling pathways, and interfere with venetoclax-mediated apoptosis processes depending on their affinity for BH3-only proteins. Finally, the level of mitochondrial oxidative phosphorylation in venetoclax-resistant leukaemia stem cells is highly abnormal. Not only the metabolic pathways but also the levels of important metabolic components are changed, and all of these alterations antagonize the venetoclax-mediated inhibition of energy metabolism and promote the survival and proliferation of leukaemia stem cells. In addition, venetoclax can change mitochondrial morphology independent of the BCL-2 protein family, leading to mitochondrial dysfunction. However, mitochondria resistant to venetoclax antagonize this effect, forming tighter mitochondrial cristae, which provide more energy for cell survival. The phenomenon of apoptosis resistance is an important indicator of the occurrence and development of haematological malignancies. Blocking apoptosis causes cancer cells to proliferate uncontrollably , 2. BCL-MCL-1 and BCL-XL are antiapoptotic proteins in the BCL-2 family that play an important role in the survival of cancer cells. They are overexpressed in AML, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) and other cancers , 14. TheThe antiapoptotic proteins MCL-1 and BCL-XL confer resistance to venetoclax, and their expression is regulated by related signalling pathways in the cell. The PI3K/AKT/mTOR signalling pathway is an important signalling pathway that regulates cell proliferation, apoptosis and autophagy , 36. AKTMutations in drug binding sites are a common mechanism by which tumour cells resist treatment. Many types of gene mutations have indeed been found in the laboratory and case studies of drug resistance to venetoclax; these mutations can inhibit apoptosis by reducing the affinity of the drug and its binding site or affecting the function of proapoptotic proteins . GeneticWith a mechanism similar to that of the BCL-2 Gly101Val mutation, the BCL-2 Phe104Ile mutation was found in a relapsed/refractory FL patient with decreased sensitivity to venetoclax. In this mutation, the phenylalanine at amino acid position 104 in the BCL-2 protein is replaced by isoleucine, which can decrease the affinity of venetoclax to BCL-2 to decrease approximately 40-fold . In addiThe BAX and BAK genes are the executive genes of the cellular mitochondrial apoptosis pathway. The BAX and BAK proteins encoded by these genes are indispensable for the formation of mitochondrial membrane pores during apoptosis. The function of any BH3 mimic compound requires its downstream effectors BAX and BAK , 44. TheTP53 is a highly conserved tumour suppressor gene located in the telomeric region of the short arm of chromosome 17. The encoded protein plays an important role in regulating apoptosis, ageing, DNA repair, autophagy and metabolism . In addiA study of the genome of CLL before treatment with venetoclax and after acquisition of venetoclax resistance revealed changes in cancer-related genes other than TP53, such as BRAF, CD274, NOTCH1, RB1, and SF3B1. In addition, mutations in BTG1 and homozygous deletions in CDKN2A/B were detected. These changes may be a major cause of resistance to venetoclax in CLL patients . In AML Amino acid metabolism plays an important role in a variety of malignant tumours—for example, leukaemia stem cells (LSCs) cannot upregulate glycolysis and their survival is thus dependent on mitochondrial amino acid metabolism –70. ThesThe imbalance between antiapoptotic proteins and proapoptotic proteins affects the survival of cells, and one of major mechanisms of resistance to venetoclax is the increase antiapoptotic proteins. We have mentioned that the combination of MCL-1 inhibitors, BCL-XL inhibitors and venetoclax is the most direct method to increase the sensitivity of cells to venetoclax. Based on this principle, BTK inhibitor (BTKi) is also a good choice , 92. It In addition to affecting the balance between antiapoptotic and proapoptotic proteins, some drugs improve prognosis in drug-resistant patients by altering the level of mitochondrial OXPHOS. Patients undergoing treatment with venetoclax + azacitidine showed not only restricted uptake of amino acid, but also disruption of the TCA cycle and inhibition of electron transport chain complex II. , 104 ThiWith the extensive application of venetoclax in haematological malignancies, cases of drug resistance to venetoclax have emerged in current clinical practice. The mechanisms of resistance to venetoclax include increased expression of other antiapoptotic proteins, genetic instability, and abnormal OXPHOS. The antiapoptotic proteins MCL-1 and BCL-XL, as regulatory factors, play a pivotal role in conferring resistance to venetoclax. Although venetoclax binds to BCL-2 and releases BIM, MCL-1 and BCL-XL can directly bind to BIM, which hinders its interaction with BAX/BAK and blocks apoptosis. Genetic instability is the most important reason for decreased sensitivity in patients treated with venetoclax, and mutation of BCL-2 has the most direct effect on this resistance. Although BCL-2 mutations are diverse, their effects are similar. They can reduce the affinity of the binding site for venetoclax and promote the tight binding of BCL-2 to regulatory proteins, making them unable to trigger the apoptotic response. Loss or mutation of the BAX gene also affects the venetoclax-mediated apoptosis process, especially mutations in the hydrophobic part of the C-terminal transmembrane domain, which directly prevents BAX from targeting the outer mitochondrial membrane to form pores. This effect ultimately leads to inhibition of the mitochondrial apoptotic pathway. In addition, mutations in other oncogenes play a regulatory role. In patients with MCL or AML, TP53 mutations induce cellular apoptosis in leukaemia by regulating the expression levels of BCL-2 family proteins through the MAPK signalling pathway. Moreover, in AML patients, reconstructed existing mutations, such as expansion of FLT3-ITD, promote the expression of the antiapoptotic protein MCL-1 and reduce the expression of proapoptotic proteins to interfere with intrinsic apoptosis pathways through the PI3K/AKT signalling pathway. Intrinsic apoptosis depends mainly on mitochondria (Fig.


While much has been written on how the HIV response laid the groundwork for the COVID-19 response, this analysis examined structural innovations used to respond to COVID-19 and assessed their potential utility for the future of the HIV response.Our analysis indicates certain COVID-19-related innovations are clearly relevant and have potential value for the HIV response moving forward.Public–private partnerships that catalysed the unprecedented, rapid development of COVID-19 vaccines and the numerous innovations in the design and conduct of clinical trials that made them more efficient and reduced burdens on trial participants have important lessons for the HIV response.Experience with COVID-19 diagnostics underscores the need to bring underused HIV point-of-care diagnostic technologies to scale and increase access to HIV viral load monitoring.COVID-19 also highlighted the importance of enhancing the timeliness and strategic use of data for HIV-related decision-making and programmatic adaptations.Other COVID-19-related innovations, such as the Access to COVID-19 Tools Accelerator and COVID-19 Vaccines Global Access initiative, are less immediately applicable to HIV, in part due to the success of the HIV response in developing analogous mechanisms.The failure of any manufacturer of a COVID-19 vaccine to use the voluntary licensing mechanism of the Medicines Patent Pool has slowed vaccination uptake and provides an important lesson for what the HIV response ought not to do for future HIV prevention, treatment and cure breakthroughs.The global community’s failure to ensure equitable access to COVID-19 vaccines and treatments highlights the enduring importance of principles of global solidarity and shared responsibility in addressing global health challenges.Substantial evidence indicates HIV investments have yielded important benefits for the world’s response to COVID-19.6While these synergies underscore the value of investments in the HIV response, it is also clear that the HIV response requires new energy and commitment. In 2021, 1.5 million people were newly infected with HIV, with the global pace of decline in new infections in 2021, the smallest in 5 years.7Given the urgency of rejuvenating the response to HIV, we sought to assess whether structural innovations used to respond to COVID-19 might hold promise for accelerating progress towards ending AIDS. We undertook an extensive review of the peer-reviewed and grey literature on COVID-19-related innovations and drew from our respective professional backgrounds in the HIV field to identify approaches that might be applicable to the HIV response moving forward. Our literature review was complemented by interviews with key informants who had experience working within or liaising with the mechanisms established to respond to COVID-19.In response to the COVID-19 pandemic, diverse stakeholders adopted new ways of doing business, in some cases by rapidly implementing innovations that had long been proposed but seldom brought to scale. Several of these innovations have clear relevance to HIV .Before COVID-19, the fastest time from the laboratory to introduction of a new vaccine was 4 years.9 10While a number of factors contributed to the unprecedented speed of COVID-19 vaccine development, extraordinary investments by governments in both ‘push’ and ‘pull’ mechanisms to drive innovation played an important role. Push mechanisms involve direct investments in applied research and development, while pull mechanisms  aim to minimise delays associated with perceived financial risks to the vaccine maker. Advance market commitments, for example, worked to accelerate the roll out of pneumococcal vaccines,12Through a combination of push and pull mechanisms, public investments were pivotal in the development and roll out of COVID-19 vaccines.While the public–private partnership model of Operation Warp Speed and other similar push–pull initiatives is unlikely to have immediate application in the HIV field, as no HIV vaccine appropriate for broad scale-up is currently on the horizon, they offer important models for the future. There is considerable excitement in the HIV vaccine field over potential applications of the mRNA technologies that have proven transformative in the case of COVID-19 vaccination.COVID-19 demonstrated that clinical trials of novel vaccines and therapeutics can be conducted much faster than in the past. According to a comprehensive analysis, operational efficiencies in COVID-19 vaccine trials shaved off at least 70% of the time that would have been required to yield trial results had pre-COVID-19 research approaches been followed.9Some of the innovations that helped expedite evaluation of COVID-19 vaccines and therapeutics—such as combining trial phases I, II and III or running them in parallel—are so costly that they may not be feasible in the case of an HIV vaccine, treatment or curative regimen unless and until early clinical trial data strongly suggest that one or more candidates are likely to be highly effective and feasible for rapid roll out. However, other efficiency-promoting innovations used during COVID-19 appear more clearly applicable to HIV-related research. These include contracting efficiencies, decentralised trial structure, digital patient support, real-time data processing, comprehensive organisational alignment of the research team and changes in behavioural and business norms, including new approaches to multistakeholder partnerships.The decades-long evolution in HIV testing continues, with an early focus on facility-based antibody testing giving way to a proliferating array of rapid point-of-care and home testing platforms.The WHO has endorsed HIV self-testing24COVID-19 also led to a substantial increase in PCR capabilities in low-income and middle-income countries. PCR tests remain either laboratory based or as point-of-care technologies, but are critical for monitoring HIV viral load. Historically, many countries have lacked access to PCR technology, but this has changed dramatically as a result of COVID-19. Furthermore, home-based viral load testing is an urgently needed technology, specifically for monitoring of HIV cure interventions. The explosion of innovations in COVID-19 diagnostics may well precipitate the development of home-based viral load monitoring for HIV.Leveraging lessons learnt from COVID-19, the HIV response now needs to invest in strategic actions to scale up these diagnostic innovations, which to date have achieved insufficient coverage. While the number of self-tests distributed is rising, self-testers represent only a small fraction of people who would benefit from HIV testing services.COVID-19 transformed the use of health data for impact. User-friendly dashboards, updated daily, have enabled rapid public health interventions,32The HIV response has generated a host of innovative approaches to the collection and strategic use of data.35Integrated, real-time data systems could enable more sophisticated, high-impact data collection and analysis for the HIV response. For example, integrated data systems could theoretically track pre-exposure prophylaxis (PrEP) efficacy in real-time by linking data on PrEP utilisation with reported cases of new HIV diagnosis. Although real-time molecular epidemiology has the potential to speed the identification and response to HIV transmission clusters and outbreaks,30Other COVID-19-related innovations are less immediately applicable to HIV, but still offer important lessons that the HIV response should heed .The Access to COVID-19 Tools (ACT) Accelerator has brought together governments, global health initiatives , civil society and the private sector for planning, problem-solving, innovation, advocacy and resource mobilisation around four pillars of COVID-19-related work—diagnostics, treatments, vaccines and health systems strengthening.The most prominent component of the ACT Accelerator, the COVID-19 Vaccines Global Access (COVAX) initiative, is also unlikely to serve as a meaningful model for eventual roll out of future HIV prevention, treatment and cure breakthroughs, if only because COVAX fell badly short of its goals.The ability of COVAX and the broader ACT Accelerator to drive rapid, effective action suffered as a result of the global community’s failure to mobilise the resources needed to ensure a globally equitable response to COVID-19.The COVID-19 response has struggled to enable and fully leverage pharmaceutical manufacturing capacity in all regions. Although these struggles can be traced to several factors, one important one is the refusal of the manufacturers of COVID-19 vaccines to use the access-promoting voluntary licensing scheme of the Medicines Patent Pool (MPP). As of July 2022, no COVID-19 vaccine was covered by a voluntary license. In June 2022, the World Trade Organization approved a temporary waiver of intellectual property protections for COVID-19 vaccines, but the deal was reached long after the point when the manufacture of vaccines in low-income and middle-income countries could have made a marked difference in vaccination uptake.To facilitate technology transfer for the manufacture of COVID-19 vaccines in low-income and middle-income countries, WHO, MPP and ACT Accelerator established the mRNA vaccine technology transfer hub.42Social protection systems aim to help poor and vulnerable people withstand crises, through such means as job programmes, cash transfers, food assistance and investments in training and education.Several innovations catalysed by COVID-19 warrant focused attention as innovations to be applied or adapted for the HIV response. These include the combination of push and pull mechanisms to accelerate product development, innovative trial designs coupled with expedited regulatory review, rapid dissemination of and enhanced access to breaking biomedical information, diagnostic innovations, enhanced use of real-time data and the energetic and innovative engagement of non-health sectors in the pandemic response. Other COVID-19-related innovations appear less clearly applicable to the HIV response moving forward, although their experiences offer useful lessons for the HIV response. Among these experiences are difficulties in mobilising sufficient resources, engaging the global South and civil society and overcoming barriers posed by intellectual property rules.The COVID-19 and HIV responses share a critical characteristic. While both pandemics galvanised global action and achieved important gains, the response to each has been undermined by inadequate attention to persistent inequalities and disparities, including many that stem from the unbalanced distribution of wealth embedded in the international economic order. A shared lesson from pandemic responses over the past half-century is that sustainable success demands attention to equity in access and outcomes in every aspect of the response.