Prostate cancer is the second most common male cancer worldwide showing the highest rates of incidence in Western Europe. Although the measurement of serum prostate-specific antigen levels is the current gold standard in PCa diagnosis, PSA-based screening is not considered a reliable diagnosis and prognosis tool due to its lower sensitivity and poor predictive score which lead to a 22%–43% overdiagnosis, unnecessary biopsies, and over-treatment. These major limitations along with the heterogeneous nature of the disease have made PCa a very unappreciative subject for diagnostics, resulting in poor patient management; thus, it urges to identify and validate new reliable PCa biomarkers that can provide accurate information in regard to disease diagnosis and prognosis. Researchers have explored the analysis of microRNAs (miRNAs), messenger RNAs (mRNAs), small proteins, genomic rearrangements, and gene expression in body fluids and non-solid tissues in search of lesser invasive yet efficient PCa biomarkers. Although the presence of miRNAs in body fluids like blood, urine, and saliva initially sparked great interest among the scientific community; their potential use as liquid biopsy biomarkers in PCa is still at a very nascent stage with respect to other well-established diagnostics and prognosis tools. Up to date, numerous studies have been conducted in search of PCa miRNA-based biomarkers in whole blood or blood serum; however, only a few studies have investigated their presence in urine samples of which less than two tens involve the detection of miRNAs in extracellular vesicles isolated from urine. In addition, there exists some discrepancy around the identification of miRNAs in PCa urine samples due to the diversity of the urine fractions that can be targeted for analysis such as urine circulating cells, cell-free fractions, and exosomes. In this review, we aim to discuss research output from the most recent studies involving the analysis of urinary EVs for the identification of miRNA-based PCa-specific biomarkers. Prostate cancer (PCa) is the most common type of male cancer and one of the leading causes of male cancer mortality worldwide . Advancevia solid biopsy upon palpation and detection of irregularities in the prostate nodules  and blood PSA levels followed by a solid biopsy to confirm and characterize the malignancy. DRE sensitivity and specificity are reported to be 80% and 48.6% respectively which makes it dependent on validation  nodules . Althoug nodules .In spite of the recent major developments in biochemical tests and imaging techniques, the primary biochemical tool for PCa diagnosis is serum PSA levels. PSA-based screening is a non-invasive and painless technique that has contributed to reducing the incidence of advanced disease and mortality improving overall PCa diagnosis and prognosis . HoweverPSA is a prostate-specific serine protease produced by the prostate epithelium whose function is to liquefy the seminal coagulum allowing sperm to swim freely . In normIn the last few years, biopsy-based approaches have been notably improved and highlighting guided biopsy techniques such as Transrectal ultrasound scan (TRUS)-guided biopsy, which have been developed with the goal of reducing procedural mistakes . DespiteThus, there is a clear need for identifying more accurate and reliable, and less invasive PCa biomarkers that overcome the limitations associated with PSA tests and guided biopsy techniques. Additionally, new biomarkers should ideally help improve treatment decision-making through more accurate detection of minimal residual disease and a more efficient clinical staging of the disease taking into account the complexity and heterogeneous nature of PCa at the different stages . Data so far suggest that novel biomarkers should not be considered as mutually exclusive parameters; instead, their effectiveness should be assessed in conjunction with the current approaches and decision-making algorithms .Over the last few decades, a new generation of PCa prognostics and diagnostics tests have emerged. Each test combines several parameters and biomarkers and provides a specific utility and timing of usage in line with the disease stages; for instance, PHI and 4K-score tests are used for diagnostics purposes , OncotypThe list of commercialized tests stated in Urine is considered a rich source of biomarkers for malignancies related to the urinary tract; since it contains cellular debris, proteins from glomerular filtration, and secretions of the urogenital tract, it can reflect a person’s real-time pathophysiology of a disease. For instance, expressed prostatic secretion (EPS) is a fluid released by the prostate to the urine through the urethra, following a digital rectal prostate massage ; it is rEVs are lipid-bound vesicles that originate from the endosomal system or bud off from the plasma membrane and that contain miRNAs that are transported to target cells for intercellular communication. Prostate cell-derived EVs can be released into the urine through the urethra where they are detected by simple non-invasive techniques. EVs include exosomes (30–100 nm), prostasomes (50–500 nm), estosomes , oncosomes (50–500 nm) and microvesicles  . It has However, one of the main limitations of working with extracellular miRNAs is the restricted available published data on the optimal conditions for their isolation and analysis and even more limited in regard to prostate cell-derived extravesicular miRNAs.Thus, we aim here to review the PCa-specific studies involving the detection of urine-derived EVs-associated miRNAs in order to develop a reliable miRNA panel that can provide information about disease diagnosis, stage, and progression.Using the electronic database PubMed, we performed a review of studies published before July 2022 that involved the analysis of urine-derived EV-miRNAs in PCa diagnosis. Potentially relevant studies were identified using the PubMed string search and Boolean operators: (“urine”[Subheading] OR “urine”[Text Word] OR “urine”[MeSH Terms]) OR (“urinary tract”[MeSH Terms] OR “urinary tract”[Text Word]) AND (“microRNAs”[MeSH Terms] OR “microRNAs” [Text Word] OR “mirna”[Text Word]) AND (“prostatic neoplasms”[MeSH Terms] OR “prostate cancer”[Text Word]); AND (“exosome”[MeSH Terms] OR “microvesicles”[Text Word] OR “extracellular vesicles”[Text Word]).(1) Research articles that presented the diagnostic potential of urinary miRNAs in PCa ; studiesOnly the articles that fulfilled all the eligibility criteria, as below, were selected:We excluded non-English studies, studies using miRNAs from cell-free urine fractions, and studies dated before 2007.The following information was collected from the selected articles and tabulated in TargetScan and miRDB were used to extract the list of genes that are the most commonly reported as target genes for the particular miRNAs. Only the target genes with a score of >95 were taken into account. Using the term “Prostate cancer” in the gene-cards database, a different list of 12,400 genes related to prostate biology was retrieved. Items in both lists were then compared to find common elements, and the results were plotted in a Venn Diagram using Venny2.1 .Following the inclusion criteria, a total of 74 primary articles were found in Pubmed from which 38 were discarded as they were duplicated studies, methodology studies, or reviews. After applying the exclusion criteria, a final number of 18 worldwide studies were selected for this review , 3. SeveWe notice a considerable degree of inconsistency in the identified biomarkers if we solely concentrate on research that involves uEVs-related miRNAs. Interestingly, not only the differential expression patterns but also the differences in the miRNA distribution pattern, and the existence of miRNA isomeric forms have been crucial parameters for the identification of new PCa biomarkers. Outcomes of the studies that investigated miRNA levels in uEVs included but were not limited to, early diagnosis, differentiating BPH from cancer, predicting biochemical recurrence, and anti-miRNA-based treatment.The miRNAs that were assessed and identified as relevant biomarkers varied widely . Since mp < 0.05) was the lowest among the three. Another RNAseq study performed by p = 0.02) along with miR-375, and miR-204 as compared to healthy controlElevated expression of miR-21 has been reported in PCa tissue , plasma Many studies have proposed the establishment and analysis of batteries of miRNAs, instead of individual miRNA, in order to achieve higher sensitivity and specificity in the diagnosis and stratification of PCa patients . For insTo corroborate the association of miR-21-5p with PCa, in this review we have cross-checked the group of miR-21-5p target genes with the PCa-associated genes retrieved from GeneCards, resulting in a list of common genes shown in miR-141 is reported to affect angiogenesis, proliferation, and metastasis in colon cancer and nasopharyngeal carcinoma . AlthougWhen we cross-checked the miRNA-141-5p target genes with the PCa-specific genes, we observed that the top five common genes are mainly involved in cell survival which does not shed enough light on the role of this miRNA in PCa disease progression ; Table 4To summarize, the role of miR-41-5p as a PCa-specific biomarker remains questionable due to the low statistical significance of the results obtained in the referred studies; research involving larger case-control cohorts is required to obtain concluding results.There exist contradicting findings in regard to this miRNA. Published data shows increased miR-375 levels in the blood of PCa patients with metastatic disease . AdditioNGS of uEVs has revealed miR-10b-5p and other miRNAs such as let-7b-5p, miR-30a-5p, miR-10a-5p, and let-7a-5p, as the most abundant in urinary exosomes . Their pmiR-331-3p has been reported to affect long-term survival in hepatocellular cancer . It is ap = 0.025) (p = 0.002). The combination of miR331-3p and miR-106b in urine supernatant and microvesicles was also evaluated and could differentiate PCa from healthy and BPH cases with a 30% sensitivity (p = 0.036). This study concluded that a five-miRNA pairs panel could be used to develop an expression-based algorithm that allows us to classify PCa, BPH, and healthy with 100% specificity and 97.5% accuracy  . The samaccuracy .The presence of miR-19b in uEVs has been proposed as an auxiliary PCa differentiating criterion with a 100% specificity and a 93% sensitivity . High lemiR-204 is known to be an NF-kB pathway inhibitor and therefore hinders various tumor progression-related phenomena including metastasis . The relThe miRNA-30 (miR-30) family is a group of tumor suppressor miRNAs consisting of six mature miRNA molecules  . miR-30aFinally, there are other miRNAs that have been reported to show significantly low expression levels in PCa compared to a healthy population and these are miR-196a-5p, miR-34a-5p, miR-143-3p, miR-501-3p, and miR-92a-1-5p in uEVs . AccordiThe observations reported for the majority of the aforementioned uEV miRNAs show inconsistent or contradictory results despite the fact that few of them are common to the 18 studies included in this review: miR-21-5p, miR-375, miR-125, miR-19b, miR-191, miR-200, miR-30b, miR-574-3p . The oriNext, we will expand on these study limitations and potential cofounders that may be influencing the associations observed between the miRNAs and PCa diagnosis, prognosis, and stratification.We believe that the disparity in the results could be influenced by the variations in the selected control groups; whilst ten of the studies included in this review involved healthy donors as controls , three sStudies involving healthy subjects as control groups were subject to diversity of the population characteristics or previous history of infections which, together, may bias the miRNA-level differences between groups. With the exception of a few studies where controls were mentioned to be age-matched , most ofIn regard to the case group, all studies rightly disclosed detailed information on the patient population analyzed including PSA values, Gleason scores, and clinical presentation .The collection of urine samples for prostate-related analysis can take place before/pre-DRE or after/post-DRE. Prostate stimulation during a DRE generates the release of cells and vesicles to the urethra, thus urine collection post-DRE is advised for the identification of PCa biomarkers . Five puAnother limitation identified in this review is the variability in the criteria used for the initial selection of the miRNAs of study; only few studies employed initial microarrays  or deep In regard to the endogenous controls used in the miRNAs quantification, some studies utilized spike-in miRNA levels like cel-miR-39 , and othThe statistical approaches used in the analysis of the expression of uEV miRNAs evaluated by RT-qPCR also differed across studies. For instance, early studies in the field used the Mann–Whitney test and T-test  to deterWhile urine-derived EVs-associated miRNA biomarkers have shown promising results in the early detection and stratification of PCa, there is no current evidence for their application in the screening or diagnosis of the disease in clinical practice until their clinical significance is further validated. The field of liquid biopsies is expected to evolve in the next few years toward the standardization of the isolation and analysis methods; moreover, technological advances involving the development of more sensitive and specific uEV binding resins will also help mitigate the methodological limitations associated with urine EVs purification. miRNAs, single or in combination with other miRNAs or with other PCa diagnostic tools such as PSA and imaging techniques, are promising strategies yet to refine. On this note, future studies investigating the potential diagnostics value of uEV miRNAs should involve a minimum of a 1-year patient follow-up in order to be able to adequately assess the functionality of the reported biomarker. The approaches for miRNA screening and selection should be unbiased and broader, involving deep sequencing of urine miRNAs that provides a complete miRNA profile in liquid biopsy; as discussed in this review, only a few studies have been close to achieving these goals. The selection of only previously-described PCa miRNA markers for further analysis limits the results and does not open any option to the identification of new biomarkers; this is substantially relevance given that this is a relatively new field lacking further information and knowledge on the biological mechanisms of miRNA. In addition, to avoid measurement bias, all the studies should consider stringent quality checks during sample processing and miRNA measurements such as staged non-human spiked in miRNA and the inclusion of biological and experimental replicates. They should also take into account potential confounders including patients’ risk factors and medications. This review has also detected a lack of consensus in the scientific community in regard to the urine sampling timing, pre- or post-DRE, and the sample volume. Another important point needing improvement in order to ensure data reproducibility is the use of both a discovery and a validation cohort; this approach will help in identifying significantly dysregulated microRNAs in a discovery cohort followed by validation of these findings in an independent larger validation cohort.This review did not apply any quality assessment tool like QUADAS for diagnostic accuracy studies, as it was not feasible due to the heterogeneity of the data. For this review, we only selected papers that have been published in the English language.Taken together, the results of the studies covered in this review suggest that the application of uEVs miRNAs in PCa prognostics, diagnostic, and stratification could be effective in combination with traditional tools such as PSA and imaging. There are several limiting factors in the studies published so far involving uEV miRNAs and PCa in regard to the analysis of small case-control populations, the inconsistencies in sample collection times and processing, the limited patient follow-up over time, and the criteria used for miRNA selection.In this review, we have considered studies on uEV miRNAs that differentiated the control population from BPH subjects and compared them with PCa patients. Based on the collected information, we propose here a panel of eight miRNAs, including miR-21-5p, miR-375, miR-125, miR-19b, miR-191, miR-200, miR-30b, and miR-574-3p, to further investigate and apply in PCa diagnosis, prognosis and stratification.In the near future, the application of standardized protocols along with the development of multicentre studies involving large cohorts of patients and controls will allow us to define and validate the role of the uEV miRNAs as PCa biomarkers that can be applied in clinical practice.


Current global pain-induced disability  was identified as a risk factor for an increased intake of PO pain medication. The degree of reduction in social support and in social networks were independent predictors of an increased intake of PO analgesics in a univariate logistic regression analysis, but lost significance when adjusted for additional possible influencing factors. (4) Conclusions: In this population, an increased intake of OTC analgesics was related to a higher educational level and having a depressive disorder, while a higher pain-induced disability was an independent risk factor for an increased intake of PO analgesics. Pandemic-specific factors did not significantly and independently influence an increased intake of analgesics in women with endometriosis during the first wave of the COVID-19 pandemic in Germany. Healthcare providers should be aware of the possible factors related to increased analgesic use in women with endometriosis in order to identify persons at risk for the misuse of pain medication and to prevent potential adverse effects.(1) Background: Endometriosis is a frequent chronic pain condition in women of fertile age. Pain management with analgesics is frequently used by women with endometriosis. During the COVID-19 pandemic, access to health services was temporarily restricted in various countries for persons without serious conditions, resulting in increased physical and mental health issues. The present study was conducted in order to assess the risk factors predicting increased analgesic intake by women with endometriosis during the COVID-19 pandemic. (2) Methods: The increased intake of over-the-counter (OTC) and prescription-only (PO) analgesics was assessed with an anonymous online questionnaire, along with demographic, pandemic-specific, disease-specific, and mental health characteristics. Anxiety and depression were assessed with the Generalized Anxiety Disorder Scale (GAD-2) and the Patient Health Questionnaire for Depression (PHQ-2), respectively. Pain-induced disability was assessed with the pain-induced disability index (PDI). (3) Results: A high educational level (OR 2.719; 95% CI 1.137–6.501;  Endometriosis is a common medical condition caused by the presence of endometrial-like tissue outside the uterine cavity, affecting up to 10–15% of women of fertile age ,3. The mChronic pain is a major healthcare concern . ChronicThe SARS-CoV-2 virus was first identified at the end of 2019 in China, causing the disease COVID-19. The World Health Organization declared the outbreak of a pandemic on 11 March 2020 . In ordeIn order to identify women with endometriosis at risk of increased analgesics use or misuse during stressful life events, such as the COVID-19 pandemic, we assessed the influence of various demographic, disease-specific, and pandemic-specific factors, as well as mental health, with respect to the increased use of pain medication.The anonymous online questionnaire was accessible between 6th and 27th of April 2020 for members of the Facebook internet platforms of German endometriosis patient support groups. Aside from questions related to demographics  and disease-specific questions , the questionnaire included pandemic parameters , as well as questions regarding anxiety, depression and resilience.C), as well as the pain intensity prior to the implementation of social distancing measures (VASP) [The visual pain scale (VAS) was employed to assess the current pain intensity (VASs (VASP) . Moreoves (VASP) .C) and their pain disability from four weeks prior to the start of social distancing measures (PDIP).Pain-induced disability was assessed with the pain disability index (PDI). Global pain-induced disability is computed by the sum of pain-related disabilities in seven areas of daily life , with each item ranging from 0 (no interference) to 10 . The global pain-induced disability index ranges from 0 to 70 . In thisAnalgesic use, as either OTC or PO analgesic consumption, was assessed using a Likert scale. In order to assess the changes in analgesic use, the variables significantly increased use and increased use, as well as no changes, decreased use and significantly decreased use, were clustered.The Patient Health Questionnaire for Depression and Anxiety (PHQ-4) was used to assess the psychological burden of the study group. Two items of the Patient Health Questionnaire for Depression (PHQ-2) and the Generalized Anxiety Disorder Scale (GAD-2) were combined to form PHQ-4 . PHQ-4 iThe Brief Resilience Scale (BRS) was used to assess how resilience affected the pattern of intake of analgesics. Smith et al. were the first to describe the BRS, which was developed to identify one’s ability to bounce back from stress .2 tests and Mann–Whitney U tests. The statistical dependence between the rankings of two continuous variables expressed as a correlation coefficient ρ was assessed using Spearman correlations.The study population was characterized by using descriptive statistics . Differences between study respondents and non-respondents were examined with χUnivariate analyses were applied to find variables with proper discriminatory values for changes in OTC and PO analgesic use. The various demographic, pandemic-specific and disease-specific variables were used as possible independent predictors in a univariate analysis.p-values less than 0.25 in the univariate regression model [2), p-value, and 95% confidence interval (95% CI).A multivariate regression analysis was performed with backward stepwise selection including the variables with on model ,27. Datap < 0.05. All analyses were carried out with SPSS® software Version 24 .All of the tests were two-tailed, with a significance level of p < 0.001).Our results were based on the data obtained from 278 subjects who answered at least one of the questions regarding changes in their consumption of analgesic self-medication (OTC vs. PO pain medication) during the first wave of the COVID-19 pandemic compared to the period before the pandemic. The sample represented 67.3% (278/413) of subjects who had accessed the web-based survey. The p-values > 0.05)  .p = 0.705) or PO pain medication .Among the investigated pandemic-specific factors, only the degree of reduction in social networks and the perceived reduction in social support were independent predictors of an increased intake of PO pain medication in the univariate analyses . An incrp < 0.25) of increased intake of pain medication during the first wave of the COVID-19 pandemic, were utilized to assess the independence of the predicting variables . To avoid model overfitting and information redundancy, the current global pain-induced disability was included in the multivariate analysis, whereas the previous pain-induced disability or previous pain intensity were not involved. Current pain intensity was not considered in the following analyses because the correlation analyses revealed highly significant positive correlations between current global pain-induced disability and current pain intensity in this study population  and being at higher risk for depressive disorders as measured by PHQ-2 ≥ 3  were found to be independent risk factors for an increased intake of OTC analgesics in women with endometriosis during the first wave of the COVID-19 pandemic. The proposed statistical model illustrated 13.6% of the variance. The model had a sensitivity of 84.4% for predicting an increased intake of OTC analgesics.The multivariate logistic regression model for the prediction of an increased intake of OTC analgesics included 260 women and considered the following possible predictors: age, educational level, duration since diagnosis of endometriosis, duration since pain onset, perceived reduction in social support during pain experience, continuous pain, current global pain-induced disability, PHQ-2 ≥ 3 and GAD-2 ≥ 3. Having a high educational level  was identified as a risk factor for an increased intake of PO pain medication. The final regression model (n = 260) explained 10.9% of the variance and demonstrated a sensitivity of 83.5% for predicting an increased intake of PO analgesics.Educational level, reduction in social network, age at diagnosis of endometriosis, perceived reduction in social support during pain experience, continuous pain, current global pain-induced disability, PHQ-2 ≥ 3 and GAD-2 ≥ 3 were identified as possible predictors of an increased intake of PO analgesics in women with endometriosis. In the multivariate logistic regression model, only current global pain-induced disability  have been recognized as risk factors of an increased intake of OTC analgesics in Spanish adults . A systeWomen with endometriosis often use analgesics as an appropriate adjustment to self-care in times when endocrine therapy is not appropriate or not recommended, e.g., in women wishing to get pregnant, or as an additional therapy to endocrine treatment and other recommended therapeutic options, such as acupressure, physical exercise, TENS units, etc. In order to identify women at risk of increased analgesic use and misuse, we recommend the assessment of pain-induced disability and mental health on a regular basis during treatment and follow-up. Women at risk for increased analgetic use could benefit from additional therapeutic options to relieve pain, such as yoga, physiotherapy and osteopathy . MoreoveThe strengths of this study were the focus on women with endometriosis and the high number of participants who responded to the questions related to changes in their analgesic utilization. Moreover, we were able to assess a large number of potential influencing factors on analgesic consumption in women with endometriosis.We also want to discuss the current findings in the context of some limitations. As the study participants were recruited by Facebook support groups of women with endometriosis, it might be possible that women suffering from more pain-induced disability or depression answered the questions regarding changes in their analgesic use. Nevertheless, according to a recent systematic review, Facebook-recruited samples are similarly representative to study samples recruited via traditional methods . AdditioNext, the instrument used to assess mental health, the PHQ-4 questionnaire, was more of a screening tool, rather than a diagnostic instrument, for core depression and anxiety disorder symptoms in the previous two weeks ,42. NeveThe COVID-19 pandemic changed the healthcare delivery for patients with chronic pain, as many appointments were cancelled or were provided by telemedicine. Women with endometriosis and depressive disorders or those reporting higher pain-induced disability were at a higher risk for an increased intake of analgesics. Understanding the underlying mechanisms of increased analgesic use when facing a stressful life event, such as the COVID-19 pandemic or other stressful life events, may help healthcare practitioners to decide who is at risk of increased analgesic use, misuse and dependency, and whether to see a patient in person and to address possible long-term adverse outcomes due to an analgesic use disorder. The ultra-brief PHQ-4 questionnaire, as well as the PDI questionnaire, could be widely implemented in both the inpatient and outpatient care of women with endometriosis in order to identify those at risk for increased analgesic intake. Longitudinal research is needed to better understand the individual factors associated with the risk for increased analgesic consumption in women with endometriosis.


This work presents an on-chip analog-to-information conversion technique that utilizes analog hyper-dimensional computing based on reservoir-computing paradigm to process electrocardiograph (ECG) signals locally in-sensor and reduce radio frequency transmission by more than three orders-of-magnitude. Instead of transmitting the naturally sparse ECG signal or extracted features, the on-chip analog-to-information converter analyzes the ECG signal through a nonlinear reservoir kernel followed by an artificial neural network, and transmits the prediction results. The proposed technique is demonstrated for detection of sepsis onset and achieves state-of-the-art accuracy and energy efficiency while reducing sensor power by  As an example, a low-power MedRadio transmitter consumes 2 which is significantly higher than on-chip feature extraction3. While there are several techniques to compress RF transmission9, the compression ratio is typically limited to 6, derivative-based adaptive sampling7, level-crossing sampling8, and adaptive resolution digitization9. The aforementioned techniques have reported compression of transmission data by Radio frequency (RF) transmission is the largest contributor of wireless sensor power, and hence, local in-sensor signal processing is preferred to continuous RF transmission17 to reduce energy consumption of AI circuits use (a) in-memory/near-memory computing (b) reduced precision computations. To address this energy bottleneck in wireless bio-medical sensors, we propose an analog signal processing neural network that directly processes analog ECG samples. The key contribution of this work is design and demonstration of an on-chip analog classifier comprising of a reservoir-computer (RC) followed by a 3-layer artificial neural network (ANN) that process analog ECG segments while reducing energy consumption by 20 to reduce the amount of data that needs to be transmitted off-sensor. To the best of our knowledge, our work presents the first in-sensor AI circuits for analog-to-information conversion for significantly reducing transmission energy in wearable physiological sensors and extend the battery life of such sensors.It is challenging to design in-sensor neural networks with low energy consumption since artificial intelligence (AI) algorithms are computationally intensive. The majority of attemptsFigure The ANN and reservoir test-chips are fabricated separately in 65 nm CMOS, and integrated on printed circuit board level for lab measurement. National Instrument data acquisition (DAQ) module is used to load input data from a computer, and output of the ANN is captured using an oscilloscope and sent to the computer. A Matlab interface is used for communication between the computer, test chips and the NI DAQ. Figure The proposed technique is demonstrated on the publicly available MIMIC–III dataset which comprises of de-identified, comprehensive clinical data of patients admitted to the Beth Israel Deaconess Medical Center in Boston, Massachusetts. The MIMIC–III dataset has 4559 patients with 40.2% sepsis patients and 59.8% non-sepsis patients, male/female split for sepsis and non-sepsis patients of 53.8%/46.2% and 55.8%/44.2% respectively. The dataset is randomly partitioned into 80% training samples and 20% test samples. ECG segments with 6000 samples are used for detection of sepsis 4 h before onset. All methods were carried out in accordance with relevant guidelines and regulations (Declaration of Helsinki).Figure 21, and the ADC for digitizing ECG segment is assumed to consume 5 fJ/conversion-step at 1 kHz and 12-bit resolution22. RC+ANN reduces energy/inference by Figure Table 29. In addition, matching capacitors in switched-capacitor circuits is easier than matching transistors in SRAM cells across large IMC array. However, the trade-off of using switched-capacitor IMC is the lack of re-configurability of ANN weights encoded as capacitor values in switched-capacitor IMC circuits, whereas the ANN weights can be easily re-configured in SRAM array by re-writing new weights into the array.Energy efficiency of traditional AI computing systems are limited by communication costs of bringing together many input activations, and neuron weights, and distributing output activations in von-neumann architectures with separate memory and computing units. Wearable sensors have low energy budget which cannot accommodate conventional AI computing systems. In-memory computing (IMC) can break the von-neumann bottleneck by massively parallelizing computations and drastically reducing communication costs by performing computations using memory units. In this work, we perform analog IMC by using switched-capacitor circuits that store the ANN weights as capacitor values and intermediate results as charge on the circuit nodes. The complete vector matrix multiplications across all the neurons in each layer are performed simultaneously, and the results are stored locally in charge-domain on the shared top-plate of the capacitors. Apart from charge-domain IMC, SRAM based IMC is another popular technique for vector matrix multiplications using CMOS circuits. Compared to SRAM based IMC, switched-capacitor IMC has better linearity for vector matrix multiplications. This is because arithmetic computation through passive charge sharing/redistribution in switched-capacitor IMC is more linear and less sensitive to random variations introduced during chip fabrication than SRAM array since switched-capacitor circuits use ratios of capacitors for computation. In contrast, linearity of vector matrix multiplication using SRAM cells is fundamentally limited by nonlinear relationship between current and voltage on the bitlines where the accumulation happens, and the vector matrix multiplication results are not linear over the full dynamic range30, and a similar AFE in front of our RC+ANN will result in 32 to reduce overall energy consumption of the sensor.In this work, cleaned ECG signal from MIMIC–III dataset has been used to demonstrate the proposed technique of analog-to-information conversion through in-sensor AI. However, in practical at-home monitoring applications, the acquired ECG signal is likely to contain artifacts and will require analog front-end (AFE) with band-pass filtering before the ECG signal is sent to the RC+ANN combination. The AFE will consume additional power that will reduce the energy advantage of the proposed technique over the conventional method of transmitting all the sensor data. As an example, state-of-the-art AFEs for ECG sensor typically consume A circuit level limitation of our work is the lower area efficiency our circuit than state-of-the-art SRAM based AI circuits. This area limitation is fundamentally due to the use of switched-capacitor circuit as building blocks for matrix multiplication which has lower area efficiency than SRAM cell. The area density (in terms of fF/35. In contrast to prior silicon RC, the proposed RC is based on the architecture in36 and does not require large capacitors to realize biological time-constants which is energy-inefficient, and does not require background calibration for analog delay elements or nonlinearity element.Output of the RC with N reservoir neurons can be mathematically expressed asD samples, 36, identity matrix is used for 37 which has shown through systematic investigation that a simple reservoir architecture with sparsely inter-connected reservoir provides comparable accuracy as more complicated reservoir architectures. N are set to 0.6, 0.1 and 63 respectively to optimize prediction accuracy and ensure stability of the reservoir, RC is a well-known computing paradigm that uses static nonlinearity to project the input signal to high-dimensional space, thus allowing easier separation of different input classes. No training is performed in the input or reservoir layers, and the weights are drawn from random distribution. While reservoir computing was invented almost two decades earlier and has been extensively used in the machine-learning literature, hardware implementation of reservoir computing have been mostly on optics/photonics platform with few analog silicon implementationsN virtual neurons by operating the reservoir layer at N-cycle delay in the time-multiplexed feedback path since generation of precise analog delay is difficult in practice. The RC input layer is off-chip for this design to allow testing with different Figure ntg Fig. a. The acmentclass2pt{minimIn contrast to conventional analog design, the circuits components in the RC can be nonlinear since all nonlinearity is absorbed into the reservoir dynamics. Relaxed linearity requirements allow amplifiers in the input layer and RC as well as the ADC to be low bandwidth, which results in increased nonlinearity due to slewing and incomplete settling, but reduces both noise and power. Figure The lower bound on bandwidth of amplifiers in the reservoir layer is set by stability requirements. Since the reservoir is strongly nonlinear, the RC loop has to be linearized around its operating point to theoretically analyze stability. The worst-case scenario from stability perspective occurs when the RC loop has the highest gain, corresponding to the highest gain of the nonlinearity function 38. Stochastic gradient descent is used to optimize the ANN model by minimizing the loss function at each epoch. Once the ANN is fully trained, the model weights are encoded as capacitor values in the SC-CIM. The ANN weights are quantized to 4-bit in the hidden layers, and 6-bit in the output layer. The weight quantization is done during the training iterations to minimize effect of quantization error. A 4fF unit capacitor is used to realize an LSB weight in the SC-CIM without degrading ANN accuracy due to capacitor mismatch.The ANN has 20 neurons in the first hidden layer, and 6 neurons in the second hidden layer. The hidden layers use custom tanh activation function, while the output layer uses a custom softmax activation function. The voltage output of the softmax function is compared with a threshold voltage to generate the ANN decision, i.e., non-sepsis/sepsis. The activation circuits are designed using single-stage, common-source differential amplifiers as shown in Fig.


A previously developed clinical decision support tool (CDST) identified patients with Crohn’s disease (CD) most likely to respond to vedolizumab. This study evaluated the ability of the CDST to predict real-world healthcare resource utilization (HRU).n = 358; Truven, n = 1445) or an anti-tumor necrosis factor (TNF) agent . Patients were stratified using the 5-variable  and a new modified 3-variable (without laboratory data) CDST. Annualized expenditures and HRU were compared with both CDSTs across response probability groups for a 12-month period.The Optum and Truven healthcare databases were searched for patients with CD treated with vedolizumab . The 5- and 3-variable CDSTs did not consistently identify anti-TNF-treated CD patients with higher HRU. The 3-variable CDST also identified vedolizumab-treated CD patients with higher probability of response and lower probability for surgery or hospitalization in the Truven data set.The 5-variable CDST identified CD patients treated with vedolizumab, but not an anti-TNF agent, at higher risk for HRU. The 3-variable CDST offers similar performance but more flexibility by removing laboratory data requirements for prediction. These validated CDSTs can be integrated into population health monitoring algorithms using real-world data.  Early identification of potential at-risk patients could help direct them to treatment strategies that are proven to reduce the risk of complications, such as treat-to-target monitoring.Vedolizumab is a gut-selective, humanized monoclonal antibody that specifically binds to the α15 Preliminary data suggest that this tool is also able to predict the risk of CD-related surgery.16 Therefore, this CDST has the potential to identify CD patients who remain at risk for disease-related complications while on vedolizumab and who might benefit the most from evolving treatment strategies. However, before broad implementation of this tool, further validation of its ability to predict disease-related complications and healthcare expenditure is needed in the real-world setting. Furthermore, there is a need for real-world assessment of whether this CDST is drug specific or more broadly applicable to other biologic CD treatments such as anti-tumor necrosis factor (TNF) therapy.A clinical decision support tool (CDST) has been developed using data from the vedolizumab GEMINI 2 phase 3 trial and validated using data from the real-world evidence VICTORY consortium to identify CD patients who are most likely to respond to vedolizumab therapy in routine clinical practice.Here, we evaluated the ability of this CDST to predict differences in CD-related hospitalization, surgery, and other HRU in CD patients treated with vedolizumab, and further assessed whether this vedolizumab CDST-predicted outcomes for CD patients treated with an anti-TNF agent, using data from 2 real-world HRU data sets.CD patients treated with vedolizumab or an anti-TNF agent were identified from the Optum database for initial CDST real-world HRU data validation and comparison. Recognizing that the laboratory variables included in the 5-variable CDST may not be routinely available when applying the CDST in clinical practice, a modified 3-variable CDST that does not require laboratory values was assessed in CD patients treated with vedolizumab in the Optum database and then further validated against similar patients in the Truven MarketScan database.Optum I3 Clinformatics Data Mart is an administrative health claims database for members of a large US national managed care company affiliated with Optum. This database includes approximately 15–18 million annual covered lives for a total of roughly 57 million covered lives over a 10-year period (from January 2007 to December 2017). The Truven Health Analytics Database, a part of the IBM MarketScan Databases, is a US nationally representative claims and Medicare supplemental database that consists of medical and pharmacy claims of >150 employers, including 100 health plans, representing approximately 170 million covered lives.Eligible patients were adults who were ≥18 years old on their vedolizumab or anti-TNF agent initiation date and were treated with vedolizumab or an anti-TNF agent between May 1, 2014 and March 31, 2018. Biologic-naive patients and patients that had received prior anti-TNF were included and were not divided by prior anti-TNF exposure. Patients had 2 separate diagnoses of CD 30 days apart after January 1, 2000 and before their vedolizumab or anti-TNF initiation date, and had ≥6 months of pre- and post-index continuous enrollment. The specific codes used to identify the cohorts from both the Optum and Truven data sets are provided in 17 was applied to the Optum data set with available laboratory data . Patients were then stratified into high probability of response , intermediate probability of response , and low probability of response . This stratification was performed for patients treated with vedolizumab or an anti-TNF agent to assess whether the CDST-predicted associations between probability of response and HRU were drug specific.The 5-variable CDSTory data . PatientA modified CDST  based onEvent proportions and event incidence rates of CD-related hospitalization, surgery, and emergency department (ED) visits and annualized per-patient costs of CD-related hospitalization, surgery, and total healthcare expenditures within the first 12 months of vedolizumab or anti-TNF agent initiation were compared across response probability groups. These outcomes were identified in the Optum and Truven databases using prespecified coding criteria.Patients who had any hospitalization claim with a CD-related diagnosis  and who Total healthcare expenditures included the sum of expenditures for hospitalization, surgery, ED visits, office visits, endoscopies, scans, and laboratory tests. Office visits were identified using CPT codes 99211–99215; endoscopies and scans were identified during the 12 months after treatment initiation by the CPT codes listed in The expenditures of each claim were converted to 2017 US dollars ($) using the conversion factors constructed from the average of Consumer Price Index of 12 months for 2015 and 2016, then annualized according to the following rules: actual expenditure in 2017 $ after the treatment initiation date if the interval between the treatment initiation date and the end of continuous insurance eligibility was >12 months; or annualized expenditure in 2017 $ computed as (expenditure in 2017 $)/(end date of insurance eligibility − treatment initiation data + 1) × 365.25 if the interval between the treatment initiation date and the end of continuous insurance eligibility was <12 months.CD patients treated with vedolizumab or an anti-TNF agent in the Optum data set were classified and compared using the full 5-variable and modified 3-variable CDSTs. Patients treated with vedolizumab in the Truven data set were also classified and analyzed using the modified 3-variable CDST to compare for consistency in outcomes in the Optum data set.P values were calculated using Pearson’s χ2-test for categorical variables, and either 1-way analysis of variance among 3 responder groups or 2-sample t-tests between 2 responder groups for continuous variables.Statistical analyses were performed using SAS software. Categorical or binary variables  are reported as proportions or percentages, whereas continuous variables  are reported as mean values (± SD). This study was a retrospective analysis of anonymized administrative claims data from 2 large US healthcare claims databases (Truven and Optum). No specific ethical approval for use of these data was required.n = 179), intermediate (n = 152), and low (n = 27) probabilities of response groups using the Optum data set based on the full CDST, and into high (n = 221) and low (n = 137) probabilities of response groups using the Optum data set based on the modified CDST. Patients were stratified into high (n = 935) and low (n = 510) probabilities of response groups using the Truven database based on the modified CDST.A total of 358 and 1445 CD patients treated with vedolizumab from the Optum and Truven databases, respectively, were included in the study . PatientVedolizumab-treated patients classified as high-probability responders were older among Optum patients, but not among Truven patients; had shorter disease duration; were less likely to have had CD-related hospitalization, surgery, or fistula during the year before vedolizumab initiation; were less likely to have a history of fistulizing disease; and were more likely to be naive for treatment with immunomodulators. Significant differences in baseline characteristics were observed between high- and low-probability vedolizumab response groups .n = 650), intermediate (n = 158), and low (n = 6) probabilities of response groups using the Optum data set based on the full CDST, and into high (n = 726) and low (n = 88) probabilities of response groups using the Optum data set based on the modified CDST. Owing to the small number of low probability patients (n = 6) when using the 5-variable CDST, these patients were not included in the analyses.A total of 814 CD patients treated with an anti-TNF from the Optum database were included in the study . PatientP = .051). Rates of hospitalization and surgery were 2–4 times lower for vedolizumab-treated patients who had a high baseline probability of response compared with those with a low baseline probability of response using both the full CDST  and the modified CDST . Among anti-TNF-treated CD patients, the 5-variable CDST found a significant association between baseline probability of response and surgery or hospitalization but not ED visits; however, the strength of association was less than observed for the 5-variable CDST and vedolizumab-treated patients. For the 3-variable CDST, no association between anti-TNF responsive patients and hospitalization or ED visits was observed, demonstrating inconsistency in prediction in this patient cohort . This pattern was also observed for the 3-variable CDST in the Optum data set , althougt cohort .P = .011) or CD-related surgery  during the 12 months after vedolizumab initiation.HRU for patients treated with vedolizumab in the Truven database demonstrated a similar pattern to that observed with the Optum database patients categorized with the modified 3-variable CDST . A signiP = .017) between the three 5-variable CDST probability of response groups, with a 2- to 3-fold difference between high , intermediate ($17 944.2 [$26 623.0]) and low ($32 391.2 [$49 849.4]) probabilities of response groups, and the lowest costs observed in the high response group. This relationship was also observed using the modified 3-variable CDST . Conversely, among anti-TNF-treated CD patients, there was no significant association between mean healthcare costs and baseline probability of response using either the full 5-variable or modified 3-variable CDST , which was driven by the lower costs incurred for CD-related hospitalization and surgery.Mean healthcare costs followed the same pattern for vedolizumab-treated CD patients in the Truven database, although mean costs were lower compared with the Optum data set . Patient18 clinical prediction models that estimate the probability of a desired outcome can help guide physicians in treatment decisions.20 The full 5-variable vedolizumab CDST, previously developed using data from the phase 3 GEMINI 2 trial and validated using data from the real-world VICTORY consortium, was observed to identify CD patients most likely to respond to 26 weeks of vedolizumab therapy.15 Given that CD patients may require surgery during the course of disease, initial treatment selection, and identification of those patients who are more likely to respond to a specific therapy is important3 and may eventually lead to reduced overall costs of care.With the increasing use of biologic agents for the treatment of IBD over the last decade,In this study, we extended the utility of this CDST to apply clinical trial findings to predict real-world outcomes and inform decisions on patient care. Real-world data were assessed to determine how the full 5-variable CDST can be used in clinical practice and in the prediction of HRU when implemented at the population level. We tested the full 5-variable model versus a modified 3-variable model that does not require laboratory values to help to address the inherent heterogeneity of, and limitations on, data availability associated with real-world data. Both tools showed that patients with a high probability of vedolizumab response had favorable outcomes and less annualized healthcare expenditures. The full 5-variable CDST and the modified 3-variable CDST showed comparable outcomes for patients treated with vedolizumab using the Optum data set, and both tools were better at predicting outcomes for patients treated with vedolizumab than those treated with an anti-TNF. The high-probability vedolizumab response group had significantly lower total healthcare expenditure costs than the low-probability group using both the full 5-variable and the modified 3-variable CDST, while consistent significant differences in healthcare costs were not observed for anti-TNF-treated patients when stratified by the CDST.21 Although there are some common features between the vedolizumab CDST and the ustiknumab CDST, they are not identical and have sufficient differences in variables to mean that each is likely to be selective for the drug for which it was designed.22 Another limitation of the retrospective study was that the data did not allow comparison of treatment patterns within groups. We are unable, for example, to determine if anti-TNF-treated patients with low probability of response might have different outcomes and costs depending on the precise treatment given . Consequently, while this tool can be used to identify at-risk patients and direct clinicians to appropriate treatment strategies, including treat-to-target monitoring, how well the tool predicts the actual outcomes for individual patients may vary depending on the treatment provided. A final limitation is the fact that source administrative data may lack clinical detail, resulting in possible misclassification of patients. Those with mild CD may not have sought medical attention or utilized healthcare resources and hence may have not been identified as part of the data set. However, patients with moderately to severely active CD are expected to have greater burden of disease and hence may account for the majority of the cost of care. Formal cost-effectiveness analyses are recommended to guide clinical decisions further on the relative effectiveness of vedolizumab and other therapeutic options for CD with regard to HRU.This study has some limitations. For example, although the current study has demonstrated the effectiveness of the CDST tool for identifying patients treated with vedolizumab who are at higher risk for HRU, as well as demonstrating relative lack of effectiveness for anti-TNF-treated patients, it does not assess the effectiveness of the tool for other biologics, including ustekinumab. Nonetheless, another CDST designed specifically for ustekinumab has been developed and assessed in patients with CD.This study confirms that our vedolizumab CDST, which was originally developed from clinical trial data sets, can be used to analyze real-world data to predict patient HRU. Both the full 5-variable and the modified 3-variable CDSTs can be used to identify CD patients treated with vedolizumab who are at higher risk for HRU, especially for hospitalization and surgery; our new analysis shows that the tool is effective for vedolizumab-treated patients but cannot be reliably used for patients receiving anti-TNF treatments. These results support integration of the 5- and 3-variable vedolizumab CDSTs into IBD population health monitoring algorithms using real-world data.otac048_suppl_Supplementary_MaterialClick here for additional data file.otac048_suppl_Supplementary_Figure_S1Click here for additional data file.otac048_suppl_Supplementary_Figure_S2Click here for additional data file.


A common secondary complication of oral malignant carcinoma is metastatic cervical lymphadenopathy. The condition is typically treated surgically, with the affected cervical lymph nodes excised, followed by pharmacological treatment. However, additional complications such as asymmetry of facial features, reduced mouth opening, adhesions in sutured tissues, and so on accompany surgical management. This case report describes a case of an adult male who underwent surgery for metastatic cervical lymphadenopathy caused by previous squamous cell carcinoma of buccal mucosa. To address the surgical outcomes that were affecting the patient's quality of life, an integrated physiotherapy management protocol was developed and efficiently followed for three weeks. Improvements in mouth opening, tongue movement, cervical joint movement, chest movement, and the Oral Health Impact Profile quality of life questionnaire were observed at the three-week evaluation, indicating that the intended therapy was effective. Lymph nodes that are irregular in size, consistency, or number are referred to as lymphadenopathy . The lymA middle-aged male was diagnosed with metastatic cervical lymphadenopathy after a history of two recurring squamous cell carcinomas of the buccal mucosa. He was treated surgically and pharmacologically for carcinoma twice, but the rehabilitation component of the post-reconstruction management was ignored each time. Although surgery helps to remove the malignant tumor, it also leaves the patient with structural asymmetry, sutures and scars, edema, a lack of mental and social self-confidence, and other negative effects, which we refer to as surgical aftereffects. The patient’s most recent operation for lymphadenopathy contributed to the prior ones' aftereffects, restricting his mouth opening, tongue movement, and cervical joint mobility. A comprehensive physiotherapy plan was required to counter the effects of the surgeries and enhance his quality of life as much as possible.A 43-year-old male with a known case of squamous cell carcinoma of the right buccal mucosa underwent surgery followed by cardiotoxicity of radiation therapy (CTRT), and now on follow-up, complained of swelling and pain on the left side of the neck area for the last 20 days. On examination, a single left middle jugulodigastric lymph node was palpable, size 4x3 and being roughly oval, hard, fixed, and painful. He received ultrasound sonography-guided fine needle aspiration (USGFNA) for the cytologic investigation of suspicious lymph nodes and 18F-fluorodeoxyglucose (18F-FDG) PET-CT in which PET using 18F-FDG, an analogue of glucose, reveals metabolic abnormalities before morphological changes emerge and precise anatomical location of lesions . Both thThe patient had already undergone two consecutive oral surgeries for well-differentiated squamous cell carcinoma previously. He had wide local excision of the lesion with modified radical neck dissection (MRND) type II and reconstruction with buccal fat in the right oral mucosa at a private hospital 19 months ago. He had a second procedure nine months later at the same clinic, which comprised a large local excision with extended marginal mandibulectomy and repair using a right pectoralis major myocutaneous (PMMC) flap. The patient got 30 fractions of radiation treatment and six rounds of chemotherapy within two months following the second operation. The patient had a habit of chewing tobacco 3-4 times a day for the past 25 years, which he continued after his first carcinoma surgery.2. His vital signs were normal, with an 80-beat-per-minute pulse, an 18-breath-per-minute respiratory rate, and a blood pressure of 120/80 mmHg. During the examination, there was significant asymmetry throughout the face, with an adherent scar on the right side from previous surgery. Edema was present in the right neck region. A 10-cm long suture extended from the thyroid cartilage to the sternocleidomastoid muscle across the neck. The suture site was kept covered with a bandage.The patient was examined post-operatively and found to be mesomorphic with a BMI of 26.78 kg/mPalpation corroborated the observatory findings. The cervical edema was pitting in appearance, with grade II indentation. The patient's mouth opening was reduced to 30 mm (2 and 1/2 finger width approx.) during intra-oral examination, as indicated in Figure Soon after the procedure, physiotherapy treatment began. The objectives were based not just on the recovery from the most recent surgery, but also on the impairments from the previous surgery. The treatment plan was divided into two parts: acute for the first week and progressive for the next two weeks. Table The physiotherapy treatment lasted three weeks throughout the post-operative in-patient period, after which the patient was discharged with a well-explained home exercise programme. The patient was thoroughly examined using outcome measures prior to discharge. Table Lymphadenectomy is the surgical removal of one or more groups of lymph nodes . A 43-yeTissues and scars that had become adhered to the underlying structures post-surgery needed to be released in order to promote mouth opening and improve facial symmetry . The useThis case report provides an integrated detailed week-by-week physiotherapy rehabilitation programme for patients who developed cervical lymphadenopathy following metastatic oral surgery. When the before and after treatment outcomes were compared, the therapy plan provided favorable results, which will help such individuals recover sooner in the future. The commencement of the protocol early after the surgery aids in the patient's recovery from the surgery's secondary effects and allows him to soon regain his social life.


Humans interact with virus-infected animal hosts, travel globally, and maintain social networks that allow for novel viruses to emerge and develop pandemic potential. There are key lessons-learned from the coronavirus diseases 2019 (COVID-19) pandemic that blood operators can apply to the next pandemic. Warning signals to the COVID-19 pandemic included outbreaks of Severe acute respiratory syndrome-related coronavirus-1 (SARS-CoV-1) and Middle East respiratory syndrome-related coronavirus (MERS-CoV) in the prior two decades. It will be critical to quickly determine whether there is a risk of blood-borne transmission of a new pandemic virus. Prior to the next pandemic blood operators should be prepared for changes in activities, policies, and procedures at all levels of the organization. Blood operators can utilize “Plan-Do-Study-Act” cycles spanning from: vigilance for emerging viruses, surveillance activities and studies, operational continuity, donor engagement and trust, and laboratory testing if required. Occupational health and donor safety issues will be key areas of focus even if the next pandemic virus is not transfusion transmitted. Blood operators may also be requested to engage in new activities such as the development of therapeutics or supporting public health surveillance activities. Activities such as scenario development, tabletop exercises, and drills will allow blood operators to prepare for the unknowns of the next pandemic.  The COVID-19 pandemic originated in late 2019 as the result of the emergence and transmission of the Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus from an animal host to humans , influenHumans knowingly and unknowingly interact with or encroach on virus-infected animal hosts . We alsoThis manuscript will focus on the lessons learned from the COVID-19 pandemic and provide suggestions for how blood operators can prepare for the emergence of novel viruses that may cause the next viral pandemic.In this manuscript we will define an emerging pathogen “as an infectious agent whose incidence is increasing following its first introduction into a new host population.” In contrast, a “re-emerging pathogen is one whose incidence is increasing in an existing host population as a result of long-term changes in its underlying epidemiology” . A priorConsidering these trends, during the period prior to the emergence of SARS-CoV-2, Canadian Blood Services maintained a spreadsheet of emerging pathogen events and routinely scanned the peer-reviewed and grey literature for patterns of zoonotic disease emergence or re-emergence . In the Emerging and re-emerging pathogens are a risk to society because their pathophysiology may not be understood , individEarly in 2020, there was a significant amount of work undertaken to determine whether there was a risk of blood-borne transmission of SARS-CoV-2. The blood banking community concluded that it was unlikely that SARS-CoV-2 was transfusion-transmissible ,42,57,58The next pandemic will require an early understanding of (1) whether the virus has a viremic phase in humans ,42; (2) Viruses can be most easily described as delivery systems for nucleic acid coded information that is under constant evolutionary pressure to change or mutate . MutatioChanges in the dominant SARS-CoV-2 variants of concern over time meant that blood operators needed to review policies focussed on enhancing staff safety and reducing transmission in the workplace ,37 Tabl. We alsoEven if the next pandemic is not blood-borne and/or transfusion-transmitted blood operators may face business pressures that will require agility and creativity. Early in the COVID-19 pandemic, there were no COVID-19 vaccines nor COVID-19 specific antiviral agents available to reduce severe outcomes in infected individuals . This leEarly in the pandemic, Canadian Blood Services became engaged with public health surveillance activities focussed on generating SARS-CoV-2 seroprevalence data and undertaking an analysis of humoral correlates of immunity . These aPractically, this means that blood operators need to be prepared for changes in activities, policies, and procedures during a pandemic.Viral evolution could theoretically change the pathophysiology of the virus, and this may change the potential for transfusion transmission and blood operators may need to decide if and when they should use laboratory tests to test blood products .Blood operator policies focussed on staff vaccination requirements will need to stay current to viral evolution that changes the effectiveness of vaccines when available .Although SARS-CoV-2 was not transfusion-transmitted, there was an initial concern whether clinical tests would be consistently able to detect the virus ,70. If tThe Agency for Healthcare Research and Quality Identifies a “Model for Improvement” (MFI) that can be used to generate a framework to organize improvement work. For pandemic planning, four MFI steps can be generated; (1) What is our pandemic preparedness goal or objective? to the Model for Improvement, (2) Determine how to measure the effectiveness of a pandemic preparedness change, (3) Determine the pandemic preparedness changes that will help us achieve our goal or objective, (4) Undertake small tests of using Plan-Do-Study-Act (PDSA) cycles  71]..71].vigilance for emerging virusessurveillance, donor studies and risk assessments for novel viruses that have emergedensuring that operations continuedonor engagement and trustinitiation of laboratory testing for emerged virusDuring the development of a pandemic, blood operators need to take a structured approach to planning for all stages from emergence of a novel virus to an active pandemic period. Blood operators must face these issues when undertaking all facets of operations. In addition to these concerns, blood operators may be faced with a question as to whether the emerging or re-emerging agent is blood-borne and capable of being transmitted by the transfusion of blood products ,57. A vaPrior to the COVID-19 pandemic, there were a variety of influenza pandemic plans focussed on the health services sector that were developed at national and international levels ,75,76. EThe SARS-CoV-2 pandemic as well as the prior Influenza a H1N1 (pdm09) pandemic presented with multiple waves of activity ,81. GeneDepending on the mode of transmission of the next pandemic virus, blood operators will need to undertake activities, policies, and procedures to ensure the safety of staff and donors at donations sites as well as operational facilities. Blood donor deferrals were created not only as an extremely precautionary approach to prevent transfusion-transmission but also to prevent respiratory transmission of SARS-CoV-2 in donor centers . A surveA variety of pathogens may be candidate agents of the next pandemic. Although a novel agent may emerge there are several existing candidates that may cause the next pandemic. This could be due to changes in fitness, transmission dynamics or infection control failures. Existing agents could include Ebola virus or an avian influenza A virus strain ,98. ViruRiboviria, Kingdom Orthornaviria, Order Nidovirales, Family Coronaviridae, Genus Betacoronavirus, Subgenus Sarbecovirus, Species Severe acute respiratory syndrome-related coronavirus. It shares the same species with Severe acute respiratory syndrome-related coronavirus-1 (SARS-CoV-1) [Merbecovirus sits the species Middle East respiratory syndrome-related coronavirus (MERS-CoV). Nearby in the same genus within the Subgenus Embecovirus sits the seasonally circulating Human coronavirus HKU1 [Coronaviridae , the last major coronavirus emerging events or crises have involved viruses within the genus Betacoronavirus. Coronaviruses have large genomes that exhibit a high level of plasticity and are prone to recombination. This makes them prone to spread between animal hosts [Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is a single stranded positive sense RNA virus within the Realm S-CoV-1) . Within rus HKU1 ,100. Theal hosts .The pathophysiology of coronavirus even within a genus may vary and newly discovered betacoronaviruses that emerged around the time of SARS-CoV-2 may not bind to angiotensin-converting enzyme 2 (ACE-2) due to genetic deletion in two regions of their receptor-binding motifs . With chBoth the COVID-19 pandemic and the recent spillover of Monkeypox virus, an Orthopox virus, into non-endemic countries in 2022 raises questions about how blood operators can remain vigilant and prepared for the next emerging virus threat that could lead to a pandemic . CurrentPlanning for worst case scenarios will allow for blood operators to think about warning signals suggesting transfusion transmission of a new emerging virus with pandemic potential. There are multiple factors that could impact on whether an emerging betacoronavirus might be transfusion transmitted. They could include factors such as; reproductive number, transmissibility, disease severity, host cell receptor, and vaccine effectiveness . One sceBlood operators are key members of the health care system and often play an underappreciated public health role . Strengt


Background: The way postpartum parents’ COVID-19-related concerns are associated with the family environment, support resources and depressive symptoms areunder-investigated. Methods: Two hundred and forty-three new parents  completed self-report questionnaires within an 8-week period after birth. Parental concerns for COVID-19-related life changes were assessed with the COVID-19 Questionnaire, perceived social support with the Multidimensional Scale of Perceived Social Support, perceived family functioning with the Family Adaptability and Cohesion Evaluation Scales IV Package, dyadic coping behaviors with the Dyadic Coping Inventory and maternal/paternal postnatal depression with the Edinburgh Postnatal Depression Scale. Results: (a) Higher levels of COVID-19-related concerns about daily life were associated with lower levels of family communication, satisfaction and increased depressive symptomatology in both parents, and with lower levels of family functioning in mothers; (b) Maternal health care COVID-19-related concerns were linked with lower levels of family communication, lower perceived social support and with an increase in maternal depressive symptoms; and (c) COVID-19-related concerns about neonate hospitalization were associated with increased maternal depressive symptoms. Conclusion: Τhese findings suggest that COVID-19-related concerns had a common negative effect on both postpartum mothers’ and fathers’ mental health and on certain aspects of family functioning. The COVID-19 pandemic constitutes a global health crisis and, at the same time, a worldwide traumatic experience . In GreeA growing public health concern is the potential impact of the SARS-CoV-2 pandemic on high-risk populations, such as pregnant and postpartum women ,9,10,11.Restricted evidence from studies in different regions on the way the COVID-19 pandemic affected parentsin the perinatal period (pregnancy to 12 months postpartum) indicatedthat: (a) In the US, women’s worries about their infant contracting SARS-CoV-2were connected with concern aboutthemselvesor their partners contracting the virus ; (b) In Sociodemographic factors, such as parental age, educational level and occupational status, have been associated with parental mental health ,23,24. FLimited research in Greece indicates that the overall levels of parents’  depression were lower than the rates in the literature. Similarly to other regions, the mixed picture of the pandemic impact on family relationships and the proportionately larger negative pandemic effect on mothers compared to fathers is confirmed ,30.The impact of the pandemic on individual mental health and relational functioning may be explained through the Circumplex Model of Marital and Family Systems ,32,33 anAccording to Bodenmann’s Systemic-Transactional Model ,35, the Τhis study sought to contribute to a growing body of knowledge by investigating the relationship between COVID-19-related concerns, thefamily environment, dyadic coping, perceived social support and depressive symptoms of postpartum parents in Greece. The family environment may affect the interaction of negative emotions among its members under a crisis condition . Support(a)Describe and compare postpartum mothers’ and fathers’ COVID-19-related concerns, perceived family environment, dyadic coping, perceived social support and depressive symptoms.(b)Examine the association between dimensions of family functioning, dyadic coping, perceived social support and depressive symptoms for mothers and fathers in the pandemic period.(c)Identify the association between maternal/paternal pandemic-related concerns and aspects of family functioning, dyadic coping, perceived social support and postpartum depression,(d)Investigate the independent contribution of each dimension of parental COVID-19-related concerns on the four outcomes  after taking into account a variety of potential confounding variables.The objectives of this study were the following:Participants were recruited through the Department of Neonatology/Neonatal Intensive Care Unit of the University Hospital of Heraklion, and the Department of Obstetric-Gynecology of the General Hospital of Chania in Crete, Greece. Data collection was carried out during the third and fourth pandemic waves (February–September 2021). The infection rate of the fourth wave was 144 times larger than the first wave .InclusioParticipants completed scales in the following order: sociodemographic and socioeconomic data, the COVID-19 Questionnaire, the Multidimensional Scale of Perceived Social Support, the Family Adaptability and Cohesion Evaluation Scale, the Dyadic Coping Inventory and the Edinburgh Postnatal Depression Scale.Permission for the use of each psychometric scale was granted by the research team who translated and adapted the instruments in the Greek population. Before every series of questions, a short introduction informing the participants about the questionnaire’s scope was provided. Participants were asked to complete a number where applicable, or tick the box or circle corresponding to their chosen answer. Questionnaires were completedbefore new mothers’hospital discharge, or within an 8-week period after giving birth.This study received approvals both from the Institutional Review Board and the Scientific Councils of the above hospitals . All participants were informed about the aim and the procedure of the study and gave their written consent. Participation was anonymous, voluntarily and not compensated.Parental concerns for COVID-19-related life changes were measured according to a 14-item questionnaire which was developed for this study. Participants were asked specifically about COVID-19-related concerns regarding: (a) daily life, such as personal/family health, economic and employment status, lack of social services, changes in eating habits, concentration problems and deterioration of previous health problems (7 items); (b) maternal health care during pregnancy, such as the impact of the pandemic on maternal care services and on the possibility of feeling fear as a result of restrictions in paternal presence during visitation to the obstetrician (2 items); and (c) neonate hospitalization (if applicable), such as the implications the pandemic had on neonate care in the course of delivery/birth, on parental visitation to NICU, the impact of visitation restrictions on maternal mental health before and after birth, and on breastfeeding (5 items). Responses for all items ranged from ‘never’ (=1) to ‘very often’ (=5). In this study, Cronbach’s alpha coefficient for the three factors ranged from 0.59 to 0.73. The Greek version of the Multidimensional Scale of Perceived Social Support ,41,42  were examined through multivariate linear regression models. Potential confounders  were included a priori in the multivariable models. Estimated associations are described in terms of β-coefficients and their 95% confidence intervals (CI). All hypothesis testing was conducted assuming a 0.05 significance level and a two-sided alternative hypothesis. The statistical data analysis was performed by statistical package IBM SPSS Statistics (version 26).All FACES dimensions were positively correlated between each other in both mothers and fathers. Furthermore, all FACES-IV dimensions were positively associated with dyadic coping and social support in both parents. In addition, cohesion was negatively correlated with depressive symptoms only in mothers. Communication was negatively correlated with depressive symptoms only in fathers. The other three dimensions—flexibility, total family functioning and communication—were negatively associated with depressive symptoms in both parents. Dyadic coping was significantly associated with social support and depressive symptoms in both parents. Social support and depressive symptoms were significantly correlated in fathers, but not in mothers.According to The results from the multivariate analysis are presented in The current study aimed to provide a comprehensive examination of the relationship between COVID-19-related concerns, the family environment, social support, dyadic coping and postnatal depression of postpartum mothers and fathers in Crete, Greece. We showed that maternal and paternal COVID-19-related concerns were in the midrange. Our evidence is not in accordance withfindings coming from Italy, which show that parents were very worried about the COVID-19-related situation  and to tWe showed that mothers reported higher postnatal depressive symptoms compared to fathers. This confirms relevant findings showing higher levels of maternal versus paternal postpartum depression during the pandemic . This fiCOVID-19-related concerns about personal/family health and employment/economic status were negatively correlated only with maternal, reports on cohesion, flexibility and total family functioning, and were positively related with maternal depressive symptoms. This finding confirms the evidence showing that the higher perceived threat from COVID-19 has been associated with increased odds of depression of women in the perinatal period ,57. GendMoreover, higher levels of COVID-19-related life changes were associated with lower levels of family communication and satisfaction in both parents. This finding is consistent with evidence showing that postpartum mothers’ and fathers’ health concerns and COVID-19-related restrictive measures contributed to relationship difficulties . This maCOVID-19-related concerns of postpartum mothers about their health care were linked with lower levels of family communication, lower perceived social support and with an increase in maternal depressive symptoms. This is in accordance with evidence showing that women in the perinatal period reported decreased social support during the COVID-19 pandemic which was associated with poorer mental health . TherelaMaternal concerns for COVID-19-related restrictions associated with neonate hospitalization (including breastfeeding concerns) were positively associated with maternal depressive symptoms. Τhis confirms evidence showing that mothers with hospitalized neonates in the NICU are more likely to screen positive for postpartum depression . This fiThis study contributes to a much-needed area of research. Given the methodological concerns of online data collection of previous studies , the curThe findings of the present study suggest that COVID-19-related concerns had a common negative effect on both postpartum mothers’ and fathers’ mental health and on certain aspects of family functioning. The current findings can inform interventions to promote new mothers’ and fathers’ well-being in a timely fashion and improve social support. Health professionals need to be trained to assist in coping with the “spill-over” effects, such as family stress due to financial instability, in future health crisis situations ,19,21,71Note: The Department of Neonatology and the Neonatal Intensive Care Unit (NICU) of the General University Hospital of Heraklion hospitalizes neonates born in Crete and the islands of the South Aegean.


Colorectal cancer is the third most common form of cancer in the United States, and up to 60% of these patients develop liver metastasis. While hepatic resection is the curative treatment of choice, only 20% of patients are candidates at the time of diagnosis. While percutaneous thermal ablation (PTA) has demonstrated 24%–51% overall 5-year survival rates, assurance of sufficient ablation margin delivery (5 mm) can be challenging, with current methods of 2D distance measurement not ensuring 3D minimum margin. We hypothesized that biomechanical model-based deformable image registration (DIR) can reduce spatial uncertainties and differentiate local tumor progression (LTP) patients from LTP-free patients.We retrospectively acquired 30 patients (16 LTP and 14 LTP-free) at our institution who had undergone PTA and had a contrast-enhanced pre-treatment and post-ablation CT scan. Liver, disease, and ablation zone were manually segmented. Biomechanical model-based DIR between the pre-treatment and post-ablation CT mapped the gross tumor volume onto the ablation zone and measured 3D minimum delivered margin (MDM). An in-house cone-tracing algorithm determined if progression qualitatively collocated with insufficient 5 mm margin achieved.p < 0.01) in MDM from the LTP and LTP-free groups. A total of 93% (13/14) of patients with LTP had a correlation between progression and missing 5 mm of margin volume.Mann–Whitney U test showed a significant difference (Biomechanical DIR is able to reduce spatial uncertainty and allow measurement of delivered 3D MDM. This minimum margin can help ensure sufficient ablation delivery, and our workflow can provide valuable information in a clinically useful timeframe. For the remaining patients, systemic treatment or other forms of loco-regional therapy such as thermal liver ablation are offered.9 Liver ablation has demonstrated 5-year overall survival rates from 24% to 51%,12 and significantly longer overall survival when combined with systemic chemotherapy compared with chemotherapy alone.13Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide18 with minimum margins of 5–10 mm suggested to achieve optimal local control.20 Despite its criticality, ensuring a sufficient ablation margin can be challenging for several reasons. First, tumor visualization is limited on the intraprocedural noncontrast-enhanced computed tomography (CT) or ultrasound images for tumor targeting and probe guidance. Second, it is nearly impossible to distinguish between disease and ablated tissue in the post-treatment contrast-enhanced CT scan for hypoenhancing disease, preventing accurate measurement of delivered margin. Finally, accurate 3-dimensional (3D) assessment of ablation margin is difficult as rigid registration can be insufficient due to liver deformation throughout the procedure, and to the inherent inability to effectively assess ablation zone on a constrained intraprocedural time period without the aid of high-level computational analysis.Minimal radiographic ablation margins have been described as one of the most relevant factors associated with improved local tumor control following thermal liver ablation,22 Rigid registrations can suffer in the presence of large deformation, and one recently published workflow has been shown to terminate when target registration errors greater than 3 mm are present,22 which commonly occur given liver deformations associated with patient’s breathing and changes in position,23 and post-ablation volumetric changes. While promising work leveraging a nonrigid intensity-based registration has been previously shown,25 “good” or “perfect” registration was achieved on only 62% of cases because of difference in liver position, difference in breathing phase, or artifacts in the image.Current methods of ablation assessment often rely on 2D distance measurement to visible landmarks on the post-treatment imaging, do not ensure 3D minimum margin, or rely strictly on rigid registration.29 We also propose a method for establishing the relationship between the minimum ablation margin and the recurrence.We hypothesized that the minimum ablation margin, calculated following the use of a biomechanical model-based deformable image registration (DIR), will differentiate patients with local tumor progression and those receiving sufficient ablation delivery. The biomechanical model-based registration proposed has demonstrated accuracy in the presence of liver position and breathing phase and is unaffected by artifacts as long as the liver boundary can be obtained.2 |Data from 30 patients whose liver metastasis from colorectal cancer had been treated with local PTA at XXX were retrospectively evaluated under a prospectively maintained liver ablation registry approved by the institutional review board. Patients were included if they had a contrast-enhanced pre-treatment CT image within 45 days of PTA procedure, post-treatment contrast-enhanced portal-venous phase immediately performed at the end of PTA procedure, and follow-up imaging confirming freedom from local progression (mean 660 days) or evidence of local progression. The cohort comprised 14 patients with post-ablation local tumor progression (LTP) and 16 without LTP. Patient characteristics are listed in 2.1 |Tri-phasic  CT images  were obtained with iodinated intravenous contrast injection prior and after to the ablation procedure for tumor identification and ablation zone assessment, respectively. Patients with biopsy-confirmed local progression also had their tri-phasic CT images at the time of recurrence diagnosis obtained.All imaging data were uploaded into the FDA-approved radiation therapy treatment planning system . The liver was manually segmented on all portal-venous pre-treatment, intraprocedural guidance, post-treatment, and recurrence CT images. The venous phase of the pre-treatment tri-phasic CT was used to delineate the gross tumor volume (GTV) region of interest (ROI), as the contrast between normal tissue and disease was greatest in this phase. The post-treatment venous-phase CT image was used to define the ablation zone. The tumor recurrence was defined on the venous-phase CT. Segmentations of the GTV, ablation zone, and recurrent disease were performed under the guidance of a radiology-trained physician fellow and approved by a board-certified diagnostic and interventional radiologist with 11 years of experience in interventional oncology , 2.2.2 |30 Morfeus has been shown to have an accuracy on the order of the image voxel size when registering liver images for image-guided radiation therapy applications.31Two different registration techniques were performed to map the disease onto the post-treatment image to enable the calculation of the minimal ablation margin. First, rigid registration was performed between pre-treatment and post-treatment CTs using an automated gray-level cross correlation of the liver volume ROIs. Second, the biomechanical model-based DIR Morfeus, which is integrated with the RayStation system, was performed.32 between the generated triangular mesh and the manually defined slice-based contours on a patient-by-patient basis.Morfeus creates triangular surface meshes of the liver, which define the relationship between pre-treatment and post-treatment image sets. The optimization of two mesh creation parameters in RayStation was investigated in this study, the smoothing radius and triangular-mesh edge length. We investigated triangular-mesh edge values of 3, 6, 9, and 12 mm (default 6 mm) and smoothing radii of 1, 3, and 5 mm (default 1 mm). The metric of success for our selection of these parameters was the Dice similarity coefficient (DSC)Morfeus then assigns Young’s modulus of 1000 Pa and Poisson’s ratio of 0.45, values which represent stiffness and compressibility, respectively, in a linear elastic material model. The correspondence of the generated triangular mesh determined the boundary conditions for the finite element analysis. The finite element analysis resulted in a dense deformation vector field, which was resampled to the ROI of the liver contour. The ablation zone was then propagated from the post-to pre-treatment image set using the results of the rigid registration only and the deformation vector field .2.3 |With the disease contour mapped onto the registered post-treatment imaging, a 3D minimum distance to agreement (DTA) was computed between the GTV and ablation zone following rigid registration alone and rigid registration combined with biomechanical registration .Regions in which the ablation zone contour entirely encompassed the GTV were considered to have positive ablation margins, and regions where the GTV and ablation zone contour overlapped had a margin of 0 mm. To remove the bias of minimum margin assessment when the GTV was on a subcapsular location, the ablation zone contour was expanded by 10 mm everywhere outside of the liver. This ensured that the minimum margin is accurately recorded as the minimum margin within the liver.U test,33 as the data are not paired and not continuous since the minimum DTA has a close limit of 0 mm.Comparison of rigid registration to deformable registration to distinguish locally recurring from nonlocally recurring patients was performed using a Mann–Whitney 2.4 |To quantify the correlation of 3D minimum margin with the location of tumor progression, registration between the post-ablation image and the recurrence image (obtained months later) is required, where physical changes in ablation cavity size challenge registration algorithms. Our data showed an average decrease of 37% in ablation cavity volume from post-treatment to recurrence images, likely due to dehydration of the tissue after thermal ablation and autophagy of the treated tissue.A rigid registration, instead of a deformable registration, was performed to avoid the potential introduction of unknown errors, as there is no validated deformable registration available to account for ablation zone shrinkage.A cone-tracing algorithm using spherical coordinates was used to assess correspondence of the recurrence to the 3D minimum ablation margin. Comparison of spherical coordinates requires that the ablation zone in both post-treatment and recurrence imaging be correctly registered translationally and rotationally. We developed a workflow to perform this focused rigid registration of the ablation CT and follow-up CT based on the identification and registration of vasculature in the normal liver within close proximity of the ablation region. While asymmetric shrinkage of the ablation zone in areas proximal to large vessels is assumed, our rigid registration is driven by similarities in the vessels to be robust to deviations in ablation zone recovery.34 on the post-treatment CT and the recurrence CT. A sphere of interest with a radius of 5cm, 7.5cm, and 10cm was defined on both images, centered on the ablation zone in the post-treatment CT and the recurrence CT. The rigid registration was then performed based solely on the vasculature within these spheres of interest. The 7.5-cm radius was chosen on the basis of visual inspection of the completed registration for all patients.Liver vasculature was automatically segmented using an in-house vesselness algorithmIf sufficient vasculature could not be identified, manual registration was performed to best align the ablation zones on the post-treatment and recurrence images under the guidance of a trained interventional radiologist. To reduce bias, the radiologist was unaware of where the predicted minimum margin was located.To create a quantitative metric of the relationship between the identified minimum margin on the post-treatment CT and the recurrence identified on the follow-up CT, we developed a 3D cone-tracing algorithm to determine if the spherical coordinates of the recurrence and the minimum ablation margin matched. For visualization purposes, this cone was then mapped onto the centroid of the ablation zone on the post-treatment image. If the mapped cone overlapped with the minimum margin, the recurrence was considered to have occurred in the same relative region that the minimum margin existed. If the mapped cone did not overlap with the identified margin, the recurrence was considered to be unrelated to the minimum margin.3 |3.1 |Rigid and deformable registrations between the pre-treatment images and both the intraprocedural and post-treatment images were successfully completed for all 30 patients.U test revealed a significant (p < 0.01) difference between the two groups based on 3D minimum distance to agreement  minimum ablation margin around the GTV for patients without local recurrence was 3.19 mm , compared to patients diagnosed with local recurrence 1.14 mm . Only three patients in the local recurrence group had margins greater than 2 mm. A Mann–Whitney greement . A receiRigid registration resulted in considerable errors in the mapping of disease, where the mapped disease was shown to overlap within normal liver tissue. As the disease and ablation zone will appear hypoenhancing on portal-venous phase imaging, little to no amount of GTV volume mapped from the pre-treatment should be present outside of the ablation zone . We show the distribution of percentage GTV volume mapped outside of the ablation zone (should be 0) for both the rigid and deformable registrations . The mea3.2 |In two cases, the contrast enhancement was insufficient to identify nearby vasculature, so manual rigid registration was performed focused on the ablation area. Of the 14 patients who experienced a recurrence, 13 (93%) had an overlap between the recurrence and the 5 mm expansion of disease outside of the ablation zone. That is, the recurrence occurred in the region where the ablation did not cover the intended 5 mm margin around the tumor. The median volume overlap between the projected cone and the minimum margin was 0.34 cc  .Despite the fact that the volume of overlap can be very small, the consensus among our reviewing physicians is that the location of 5 mm expansion coincides with actual recurrence .For patient #7, which did not have overlap, the definition of the ablation zone post-treatment was not very clear, with the scan appearing to be in the arterial phase, not the portal-venous .4 |U test (p < 0.01). We observed overlap between future recurrence and the minimum ablation margin in 86% of patients, and we believe this indicates that the minimum ablation margin is informative of where recurrence might develop. Our study demonstrated that the mean difference in minimum ablation margin between the group of patients who experienced local recurrence and the group who did not was large  and statistically significant (p < 0.01).The efficacy of the proposed workflow was shown by distinguishing between the retrospectively obtained patients who experienced local recurrence from those who did not with high statistical significance using a Mann–Whitney Rigid registration alone was not sufficient to properly identify the minimum ablation margin. In many cases, the disease was mapped outside of the ablation zone entirely when rigid registration was used Panel A, . Most no35 The process is fully automated after receiving segmentations of the GTV, ablation zone, and liver, with run times of approximately 5 min. The result returns the ablation margin on the pre-treatment image and an image showing the distribution of the ablation zone. This distribution can assist the physician in identifying where further ablation may be desired during the procedure. Previous work has shown that ablation assessment can reduce local progression rates, but required a secondary ablation procedure.36The proposed workflow has the potential to improve local control rates in patients, by assessing the minimum DTA immediately following ablation even in cases of deformation >1cm. The development of deep learning for liver segmentation has removed the previous challenges in clinical implementation introduced by manual segmentation.In addition to determining the ablation margins, the algorithms proposed in this research can also be employed to ensure accurate placement of the probe into the tumor, especially in cases where contrast is no longer present in the image and artifacts from ablation probes impair tumor visibility. This would require a CT scan of the entire liver once the probe is inserted to perform biomechanical model-based DIR to map the tumor onto the image with the probe to evaluate the accuracy of placement.Our work is primarily limited by the paucity of patients presenting with CLM who also had contrast-enhanced CT scans performed up to 45 days before treatment and post-treatment scans on the day of treatment. The amount of volume overlap between recurrence and volume of tissue within the 5 mm margin that was not covered by the ablation region also was small, less than 0.5 cc for 61% (8/13) of the patients in whom overlap was present. However, it is important to note that we expect that the overall volume of tissue that should have been included in the 5 mm ablation margin volume, but was not (i.e. area of missed ablation) would be very small, and therefore any overlap would also be small. However, it also demonstrates the potential importance of achieving a complete 5 mm ablation margin volume around the tumor.Furthermore, our work is limited by the inherent variability in the segmentation of CLM and ablation zones. Under-estimation of the disease could lead to the belief of sufficient ablation delivery, while over-estimation of disease could lead to unnecessary ablation of normal tissues. This should also be considered for the use of this technology prospectively. Our results in the spatial overlap between the identified minimum margin and recurrence rely on the assumption that vessels near the recovering ablation zone are not distorted by relative differences in tissue regrowth during recovery.5 |Our work demonstrates the potential utility of a biomechanical model-based DIR to aid in determining if sufficient ablation margin has been achieved and correlating the location of the recurrence to the minimum ablation area. For ease of use, we have created a GUI built into our treatment planning system which automates a majority of the process.The clinical impact of these tools is currently being evaluated in a randomized phase II clinical trial.Supplementary Table