Implementation research was employed to examine rates and contextual factors associated with mothers’ care-seeking for their sick neonates and identify challenges for community-based possible serious bacterial infection (PSBI) services access and implementation during the COVID-19 pandemic.We conducted formative research involving household survey and programmatic qualitative study.This formative study was conducted in Dembecha and Lume woredas of Amhara and Oromia regions.Data were captured from 4262 mothers aged 15–49 years who gave live birth 2–14 months before data collection, and interviews with 18 programme managers and 16 service providers in April to May 2021.A multilevel regression model was employed to identify predictors of maternal care-seeking for PSBI and thematic qualitative analysis to inform strategy development to strengthen PSBI implementation.Overall, 12% (95% CI 11.0% to 12.9%) and 8% (95% CI 7.9% to 9.6%) of mothers reported any newborn illness and severe neonatal infection (PSBI), respectively. More than half of mothers sought formal medical care, 56% (95% CI 50.7% to 60.8%) for PSBI. Women who received postnatal care within 6 weeks (adjusted OR (AOR) 2.08; 95% CI 1.12 to 3.87) and complete antenatal care   had higher odds of care-seeking for PSBI. Conversely, fear of COVID-19  and residing more than 2 hours of walking distance from the health centre  were negatively associated with care-seeking for severe newborn infection. Multiple pre-existing health system bottlenecks were identified from interviews as barriers to PSBI service delivery and exacerbated by the COVID-19 pandemic.We found gaps in and factors associated with care-seeking behaviour of mothers for their sick young infants including fear of COVID-19 and pre-existing health system-level barriers. The findings of the study were used to design and implement strategies to mitigate COVID-19 impacts on management of PSBI. This study employed mixed-methods research to explore the perspectives and experiences of mothers, programme managers, service providers and community volunteers for an in-depth understanding of the limiting factors for the uptake and delivery of community-based management of sick young infants during the COVID-19 pandemic in Ethiopia.The applications of implementation science frameworks offer helped us to systematically explore implementation challenges and design appropriate strategies to mitigate the impact of COVID-19 on the delivery and uptake of community-based management of possible serious bacterial infection (PSBI).All possible barriers affecting the community-based management of the PSBI programme may not be captured as mothers’ views were not included in the qualitative study.Cross-sectional study design may not capture ongoing challenges and impacts due to the dynamic nature of COVID-19 pandemic.While Ethiopia has seen a substantial decline in childhood mortality over the last two decades, the change in neonatal mortality rate (NMR) lagged behind the decrease in postneonatal and child mortality. The NMR in 2019 was 33 per 1000 live births, contributing to approximately 56% of under-five child mortalities.Possible serious bacterial infection (PSBI) is a leading cause of mortality in young infants.In 2012, Ethiopia introduced integrated community case management of childhood illnesses and newborn care in its flagship Health Extension Program (HEP) to improve access to and use of appropriate treatment including for neonatal sepsis in young infants aged 0–59 days when referral is not possible.This formative study was conducted in Dembecha and Lume woredas of Amhara and Oromia regions, respectively. The two woredas comprised 11 health centres, 66 health posts (HP) and an estimated 250 000 people. Details of the study settings and the health system can be found elsewhere.The study is a multiple methods research using the Implementation Research Logic Model (IRLM), a combination of Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) and Consolidated Framework for Implementation Research (CFIR)Data were collected through interview of mothers, programme managers, service providers and community volunteers from 18 April to 24 May 2021. The quantitative component of the study was a cross-sectional population-based study interviewing women who gave live birth 2–14 months before data collection whether their infants were sick during their infancy ages of 0–59 days or not. A structured questionnaire adapted from previous studies was used to capture the data. The questions were translated into local languages (Amharic and Oromiffa). The quantitative component also included HP assessments and self-administered interviews with health extension workers (HEWs), frontline health workers, available on the day of the visit. The HP assessment was conducted using an adapted tool from WHO Service Availability and Readiness Assessment.The survey was used to collect information about household and sociodemographic characteristics of mothers, awareness of PSBI, history of any infection of their infants during the neonatal period (0–59 days), care-seeking for any infection of the infant, knowledge and risk perception of COVID-19, fear of COVID-19 infection to seek care and experiences related to the use of maternal and newborn health services. Prior to data collection, interviewers, supervisors and coordinators were thoroughly trained during a 1-day training on the questionnaire. A pretest of research instruments was also conducted. Survey supervisors and coordinators monitored and supervised the fieldwork and ensured data quality by randomly revisiting selected households to validate responses.The qualitative component employed a programmatic qualitative study using the CFIR as included in the IRLM.Patients and communities were not involved in this study.Our study contains the following assumptions: of 3% estimated annual live birth rate, 5% prevalence of newborn sepsis and 56% of newborn sepsis cases that sought medical care,We recruited all eligible households with children under 15 months of age from updated lists obtained from the Community Health Information System of all 66 HPs, which included information on households with infants under 15 months of age and their unique household identifiers. These records were available at HPs and stored in numerical order. When a complete list of households was not available at HPs, an ad hoc list of households was established by data collectors with the help of the HEWs, Women Development Armies (WDAs) and community volunteers before data collection.For the qualitative component of the study, we conducted 34 IDIs including programme managers (6), development partners (4), service providers (16) and WDA volunteers (8).The dependent variable of interest was the proportion of women who sought medical care from appropriate providers for their sick young infants during the first 2 months of life. Sick young infants were defined as those whose mothers reported symptoms of severe infection, including difficulty breathing, chest indrawing, no longer feeding well, being unusually hot or cold, being less active than usual and/or having convulsions during the first 2 months of life. The independent sociodemographic and obstetric characteristic variables included: maternal education, household wealth index, number of children, distance of residence from a health facility, utilisation of antenatal care (ANC) services, whether complete ANC was received, place of delivery, administrative residence (woreda) and level of fear of COVID-19 and its impact on seeking care.ANC services were considered complete if the mother’s blood pressure (BP) was taken, weight measured and blood and urine tested during the pregnancy of their gest infant. A wealth index score was constructed for each household with the principal component analysis of the household possessions  and household characteristics . Subsequently, households were ranked according to wealth score and then divided into five quintiles using the principal component analysis.xtlogit and xtmelogit Stata commands). The null model, model 1, was fitted without the explanatory variables. In model 2, the intercept model was fitted with level 1 and level 2 variables. In model 3, a cross-level interaction between woreda of residence and distance to the health centres was fitted to reveal any evidence of effect modification of the association between distance to the health centre and PSBI care-seeking by woreda of residence. Explanatory variables were identified based on the CFIR and RE-AIM frameworks included in the models. We present the adjusted ORs (AOR) and CIs at the 95% level.Random intercept logistic models were fitted to estimate associations between the individual and community variables, and the likelihood of seeking care for PSBI. This enabled the probability of PSBI care-seeking to vary randomly across communities based on the assumption that the effects of individual characteristics were the same in each community . Data were iteratively read and subsequently classified into one of the codes.A total of 4262 mothers of children aged 2–14 months were interviewed from the household survey. More than two-thirds of the respondents were 20–34 years old. The majority did not have any education (56%) and most lived 2 hours or more of walking distance from a health centre .In the household survey, we identified 508 sick young infants and 371 severe neonatal infection cases. Twelve per cent (11.6%) (95% CI 9.8% to 13.7%) of mothers reported a history of illness in their youngest child during their neonatal period with 8.4% (95% CI 7.0% to 10.0%) reporting symptoms of severe infection. A little more than half of mothers sought formal medical care, 57.6% (95% CI 47.2% to 67.4%) for any illness and 56.4% (95% CI 45.5% to 66.7%) for severe infection, primarily from health centres .PSBI service registers from the 66 HPs showed a decline in sick young infant HP visits from 1675 cases in 2019 to 538 in 2021. Respondents highlighted several factors that caused low uptake and delivery of PSBI services, including (1) the COVID-19 pandemic, (2) low confidence and competence of HEWs, (3) unavailability of essential drugs, (4) weak support and linkage system and (5) suboptimal functionality of the WDA.The qualitative analysis found that the COVID-19 pandemic had a detrimental impact on care-seeking and delivery of PSBI services. We found that programme managers and service providers perceived that the pandemic generally affected all child health services, including PSBI activities related to generating awareness, or social and behavioural change communication (SBCC) efforts such as interrupted social gatherings, community meetings and community sensitisation programmes, particularly in the first 2–3 months of the pandemic in Ethiopia.The pandemic has affected all activities related to awareness creation or SBCC efforts. It affected advocacy works, community sensitization, pregnant women conferences, and other activities in that it made things very stagnant or not moving forward. (IDI-PM-MoH02)One-third of mothers from the household survey reported fear of getting an infection in seeking maternal and newborn care .Survey was completed in 79 of 117 (68%) HEWs that were available at the time of data collection. We found that only 41% knew all signs of PSBI. This finding was confirmed by programme managers and service providers who also perceived that low competence and confidence levels of HEWs to administer curative services were barriers to quality PSBI services.The Health Extension Workers’ confidence is low… Since they had not practiced the curative services after they received the PSBI training, they are afraid of providing services, they are rather referring cases and not promoting the PSBI service. (IDI-PM-P02)Similar to the facility surveys, informants affirmed that stock-out of drugs was a challenge to providing PSBI treatment services. Understocked HPs could not adequately meet PSBI service delivery requirements due to inaccurate forecasting and planning, insufficient medical supplies, inconsistent supply of drugs, drug expiration, failure to request and refill drug stocks and supplies and stock-outs.Moreover, some essential drugs were not available in the local market, which meant that even when there was no stock in the facility, it was also not possible to procure drugs from local private sector sources. This also led to insufficient or inconsistent medical supplies and stock-outs.Some essential drugs are not available in the local market. For example, amoxicillin dispersible syrups and gentamicin injection 20mg/2ml preparation are not available. (IDI-PM-P02)The HP assessment also demonstrated that on the day of the visit, a significant number of HPs were inadequately stocked with essential commodities. Most lacked gentamicin injection, chlorhexidine gel and ambu bag and mask .Declining mentorship or supervision, lack of training and motivation of HEWs and suboptimal ownership at each level were other factors attributed to weak PSBI programme implementation. Some HEWs had not had any PSBI training, suggesting the need for routine training for new HEWs, as well as refresher training for established workers.There are many HEWs who did not take training and the existing HEWs like me have forgotten the training, so training is needed to enhance the newborn treatment in the health post. In addition to this regular input, supply is needed. (IDI-SP-HEW03)Programme ownership and sustained support from the government were also found to affect PSBI services. Programme support was strong and there was close follow-up when development partners were actively supporting the implementation of PSBI services. When PSBI became integrated with the national service package, PSBI service delivery was slowed due to overall system performance issues, including a lack of resources and competition with other programmes.It (PSBI) is not owned by regions, zones, or woredas. A little bit is better at the ministry level. It is not equally getting focus like EPI and other child health programs. Once the development partners' support phased out, mentorship and supervision activities are quit. (IDI-PM-P01)…the linkages between health post and health center became weaker and to the extent, HEWs are not provided referral slip as before’ (IDI-PM-MoH02).The fragmented referral system was one of the challenges that led to the low uptake of PSBI services. In the referral system, weak linkages between health facilities resulted in insufficient communication, feedback or follow-up on referred cases. ‘Even when PSBI services were available at HPs, inadequate community-level service emerged as an important factor for the low demand and uptake of PSBI services.Community members may not be aware of the availability of newborn care at health post level because HEWs haven’t fully disseminated information though they were directed to do so during PSBI trainings. (IDI-PM-MoH03)The role of WDA is declining over time due to the decline of the program support. ….’ (IDI-PM-MoH01).WDA volunteers carried out community education and mobilisation activities and served as the HEW voice in communities. As a part of the community, they were engaged in early pregnancy identification, birth notification, health promotion, identifying and referring sick newborns and other social support activities. However, various factors contributed to a decline in WDA functionality. These included poor support and supervision, women’s low literacy and negotiation skills, the perception of low commitment and that many had overlapping tasks to manage. ‘It is difficult to manage WDA as it is huge in number…’ (IDI-PM-P01).Ideally, all households would be included in the WDA networks across all kebeles. This, however, made the structure very broad and hard to manage. ‘2=41.25; p<0.01). Model 2, the intercept model, showed that women who received postnatal care (PNC) within 6 weeks and received complete ANC  had higher odds of care-seeking for PSBI. Women who resided in Lume woreda had higher odds of seeking care for PSBI than their counterparts in Dembecha . Furthermore, fear of COVID-19 infection was negatively associated with uptake of care-seeking for PSBI . However, maternal education, household wealth and knowledge of COVID-19 were not significantly associated with mothers’ care-seeking for PSBI.In the null model, the intraclass correlation coefficient showed that 23% of the residual variation in the propensity to uptake PSBI is attributable to unobserved community characteristics. The likelihood ratio test showed that there was strong evidence that the between-community variance was non-zero  and PSBI uptake by woreda of residence. The within-community effect of the administrative woreda in Lume disappeared, while the within-community effect of distance to the health centre on the odds of receiving PSBI was significantly lower for women who resided within 2 hours of walking distance to the health centre as compared with women who resided further away from the health centre  .This study revealed a high prevalence of severe neonatal infection and low care-seeking behaviour of mothers for their sick young infants in rural communities in Lume and Dembecha woredas of Ethiopia. Fear of COVID-19 infection negatively affected care-seeking for sick young infants. Out of 4262 participants, one-third of the mothers reported fear of getting COVID-19 infection in seeking care. Conversely, receiving ANC and PNC consultations and residing more than 2 hours of walking distance to the health centre predicted care-seeking for PSBI. In addition, multiple pre-existing health system factors were identified as barriers to PSBI service delivery.Our results on prevalence are similar to other community-based studies in Ethiopia which identified a prevalence of PSBI ranging from 5% to 14%.This study shows that fear of COVID-19 infection negatively affected care-seeking for their sick young infants in rural settings in Ethiopia. Previous modelling studiesMaternal healthcare uptake and receipt of quality ANC services were significantly associated with care-seeking for PSBI. Evidence from other studies has shown that uptake of the continuum of care services was associated with the uptake of newborn and child health servicesOur cross-interaction model showed that woreda of residence modified the association between distance to health centre and uptake of PSBI care. There was variability in care-seeking for PSBI by residence, and shorter distance to the health centre was positively associated with mothers’ care-seeking for their sick young infants. This suggests the existence of differential geographic access to PSBI, despite the programme being pro-poor, as documented in other studies regarding access to postpartum care in Ethiopia.This study demonstrated the unprecedented challenges posed by the COVID-19 pandemic on PSBI care-seeking during the pandemic in Ethiopia. The following pre-existing conditions proved to be the most formidable barriers and were also identified as challenges in previous studies: poor integration of PSBI in the woreda workstream when partners’ support was phased out, weak support systems, erratic supply and poor logistics management systems, low competence and motivation of HEWs and low community demand.Our study had limitations. Like any survey, responses were potentially influenced by recall and social desirability bias. Thus, to improve reporting, memory aids were used. Though we tried to triangulate data from programme managers, service providers and community volunteers, qualitative data were not collected from women which would limit the findings of this study. Another limitation would be the qualitative findings are subjective and confounded by the individual’s prevailing contexts.Care-seeking for sick young infants is influenced by physical access, antepartum and postpartum care service delivery, health system bottlenecks and fear of COVID-19. Accordingly, there is a need to strengthen the primary health system to be more resilient to provide quality PSBI services during and after the COVID-19 pandemic. Evidence-informed SBCC interventions are pivotal to providing current and comprehensive information on transmission and prevention of COVID-19 in multiple and accessible formats to boost the confidence of clients and mitigate fear of COVID-19 infection. Active engagement of communities to create continuous community awareness activities, actively identify pregnancies, notify births to HEWs, identify sick newborns and link them to the HEP is critical to maintaining service delivery and reducing the negative impacts of COVID-19 on newborn health outcomes.


The purpose was to investigate the diagnostic performance of bimodal optical and radio-guided sentinel node biopsy (SNB) for oral squamous cell carcinoma (OSCC) sub-sites in the anterior oral cavity.Prospective study of 50 consecutive patients with cN0 OSCC scheduled for SNB was injected with the tracer complex Tc99m:ICG:Nacocoll. A near-infrared camera was applied for optical SN detection. Endpoints were modality for intraoperative SN detection and false omission rate at follow-up.In all patients, a SN could be detected. In 12/50 (24%) of cases, the SPECT/CT showed no focus in level 1, but intraoperatively a SN in level 1 was optically detected. In 22/50 cases (44%), an additional SN was identified only due to the optical imaging. At follow-up, the false omission rate was 0%.Optical imaging appears to be an effective tool to allow real-time SN identification comprising level 1 unaffected by possible interference of radiation site from the injection. In early-stage oral cavity cancer with a clinically negative neck (cN0), the risk of subclinical nodal neck disease is 20–30% . SelectiHence, the purpose of this study was to investigate the diagnostic performance of bimodal optical and radio-guided SNB to stage the cN0 neck in early OSCC for tumors localized in the anterior oral cavity. Endpoints were modality for intraoperative SN detection  and false omission rate of SNB based on N-site failures at follow-up.A prospective single-arm clinical study was conducted at Copenhagen University Hospital-Rigshospitalet, a tertiary cancer center in Denmark, between November 2017 and December 2020. Consecutive patients with primary early-stage cT1-T2N0M0 OSCC, scheduled for SNB staging were enrolled. Only patients with biopsy-verified squamous cell carcinoma located in the anterior oral cavity with the following sub-sites were included: FOM, inferior surface of tongue, buccal mucosa, and lower gum. These sub-sites were selected due to a possible higher reported risk of false negative results of SNB caused by the shine-through phenomenon. The nodal neck status prior to surgery was evaluated with clinical examination, ultrasonography, MRI, and/or CT. Exclusion criteria were previous head and neck cancer, previous, radiotherapy or surgery to the neck, and pregnancy or allergy to ICG or iodine. From all patients, a written informed consent to participate was obtained. The study was approved by the Danish Regional Scientific Ethical Committee (H-1-7001881) and conducted in accordance with the Helsinki Declaration (2002).At the day of surgery, or the day before, the patients had a peri-tumoral submucosal injection of the bimodal tracer ICG:Tc99m:Nanocoll. The preparation of the tracer and the imaging protocol has previously been reported in detail . BrieflyThe tumor ablation and the reconstruction were undertaken prior to SNB neck procedure. No free flaps were used in this series. For optical near-infrared fluorescence (NIRF) imaging, one of two available clinically approved optical camera systems, Fluobeam 800  or EleVision  was used. The Fluobeam 800 generated NIRF imaging merged on video recording of the surgical field in gray scale. The camera head was handheld during the procedure, and imaging was presented on a screen on a chart for the surgical team. The EleVision recorded video in color-merged with the NIRF imaging presented in color or signal-intensity graded color. The camera head was mounted on a maneuverable surgical arm attached to chart with a screen. During imaging, surgical lights and headlights were turned away to diminish interference from near-infrared light from external light sources. Prior to incision, the SNs identified on preoperative imaging, were searched with a handheld gamma probe , and the locations were marked on the skin. All patients had an upper submandibular neck incision to allow a super-selective ND of level 1 to be performed. If the tumor involved the midline, both neck sides were entered to access level 1. Depending on the location of the detected SNs on the preoperative imaging, second small incision in the lower part of the neck was needed in some cases to harvest SNs located in levels II–IV. To maintain oncological safety in the assessment of the possible diagnostic benefit of optical navigation for SN detection in level 1, it was decided, that all patients also had a super-selective ND of level 1 performed, instead of an optical exploration only. With this approach, possible subclinical nodal metastasis in level 1, not detected by optical guidance would be removed, and the histological examination of the neck dissection specimen served as reference for the accuracy of optical-guided SN detection. Navigation with a handheld gamma probe directed by the radioactive signal and NIRF imaging for the optical signal was performed in parallel to detect SNs. Specifically, for level 1, the surgical field was initially searched for possible SNs, not detected on preoperative imaging, with NIRF imaging, before the super-selective ND was performed. The anatomical borders of the super-selective ND in level 1b were the preglandular triangle defined by the lower edge of the mandible, the anterior border of the submandibular gland, the anterior belly of the digastric muscle and the mylohyoid muscle medially. The anatomical boundaries for level 1a were the midline space below the mylohyoid muscle between the anterior bellies of the digastric muscles and the hyoid bone inferiorly. Before closure, the surgical field was searched systematically with the gamma probe and the optical camera for any remnant signals. The dissected specimens from level 1 were also searched for radioactive or optical signals ex vivo. A lymph node was denoted a sentinel node if the radioactive count was at least 10% of the count of the hottest lymph node detected . The indHarvested SNs were processed in a standard step-serial sectioning protocol based on H&E and cytokeratin antibody staining, as previously described . Frozen The software SAS Enterprise Version 9.4  was used for data analysis. Survival data was analyzed by use of the Kaplan–Meier method. Overall survival (OS) was defined as time from diagnosis until death of any course or censored at the last known follow-up. Recurrence-free survival (RFS) was defined as time from diagnosis until biopsy-validated recurrence or censored at the last known follow-up. For assessment of a possible association between depth of invasion (DOI) as a continuous variable and presence of a positive SN, a Student’s t test was applied. To access the diagnostic performance of SNB, the primary endpoint was false negative events defined as N-site recurrence in the initially SNB-negative group of patients. False negative rate , false omission rate , and negative predictive value (NPV = 1-FOR) were calculated.A total of 50 patients were enrolled in the study. Demographics and tumor characteristics are depicted in Table p = 0.02).A total of 128 SNs were harvested with a mean of 2.6 SN pr. patient (range 1–5). The drainage patterns of the resected SNs are presented in Table Transcutaneous visualization of one or more SNs by optical imaging prior to the neck incision was possible in the majority of the patients. However, it was not recorded systematically as an endpoint in this study because data from a previous study found transcutaneous NIR-guided SN detection to be inconsistent between patients. Transcutaneous optical visualization was markedly improved if lights in the OR were dimed and if the skin was stretched by positioning of the neck. Also, imaging was improved if the camera head was brought closer to the skin (10–20 cm) and positioned perpendicular to the surface. Twenty-four of the cases were conducted with the Fluobeam system and 26 of the cases with the EleVision system. Both systems demonstrated a high sensitivity for the fluorescent signal from ICG retained in SNs intraoperatively, and in some cases, lymphatic vessels could be clearly visualized. In some cases, when a SN was resected and collecting lymphatic vessels were transected, localized spillage of fluorescent dye could be observed that could be misinterpreted as a possible additional SN located in the surgical field.Of the 6 patients with a positive SNB, 4 patients had completion ND performed where no additional metastasis was found. A total of 8 positive SNs were retrieved, whereas 6 were located in level 1b and 2 were located in level 2a. The tumor deposits consisted of 1 macro-metastasis, 3 micro-metastasis, and 4 isolated tumor cells without signs of extra-nodal extension. In 2 patients, completion ND were waived due to patient frailty and decision of postoperative radiation therapy to T-site-related findings on histology, respectively. In total, 3 patients (6%) had postoperative radiation, whereas 1 patient had radiation upon recurrence. The median follow-up was 30 months (range 2–52 months). Two patients died from causes unrelated to the disease and 1 patient died from OSCC. No N-site recurrences were observed. The 2-year OS and RFS for the entire cohort were 96% and 96%, respectively. Based on the rate of N-site recurrences in the SNB-negative part of the cohort, the diagnostic accuracy of SNB neck staging in conjunction with super-selective level 1 ND was 100%, and the false negative rate and false omission rate were 0%.The results from this study underline the challenge of monomodal radiocolloid-based SNB neck staging of tumors in the anterior oral cavity, which has been described in previous reports as a lower diagnostic accuracy compared to other sub-sites in the oral cavity , 21, 22.Importantly, the primary purpose to explore the level 1, is to detect a possible SN to obtain accurate nodal staging by step-serial sectioning technique and not just clear the level as part of a SND. Direct optical-guided exploration of level 1 to detect possible SNs without subsequent resection of the fibrofatty tissue in anterior level 1b is technically feasible. Such strategy would adhere to the concept of minimal invasiveness of SNB which is one of the major advantages of this procedure. However, in this study, primary exploration followed by a super-selective ND was preferred to maintain high oncological safety in a protocolized setting to evaluate the diagnostic performance of optical SN detection and to collect additional clinical experience with the combined radio- and optical-guided approach.Based on the results from this study, our current clinical practice is to perform combined optical- and radio-guided SNB with transcutaneous and intraoperative optical imaging in level 1 without a super-selective ND.The main advantage of the additional use of optical imaging is that it allows direct real-time visual detection of lymph nodes in high spatial resolution. Lymph nodes imbedded in tissue were also detectable due to relatively high penetration of NIR photons in the range of 1–2 cm. In addition, optical-guided SN detection works independently from the radioactive signal and thereby seems to circumvent the challenge of radiocolloid-mediated shine-through from the injection site in level 1. Also, in this study, SNs located just below the mandible but outside the extent of the performed super-selective ND were detected optically, which exemplifies both the variation in SN drainage patterns and the ability of this technology to detect SNs in less common locations. It could be argued, that a primary optical exploration of level 1 followed by a completion neck dissection in a second procedure, due to a positive SN, would carry an increased risk of damage to the marginal branch of the facial nerve due to scare tissue. In our current experience with the use of optical-guided SN detection, we have not observed issues with nerve damage, but the rate of possible complications should be studied in future clinical studies. Transdermal optical detection of SNs in the neck region appears to be a helpful tool for fast and direct SN localization but deeply located SNs may not be visible . In breaOptical-guided SNB based on ICG has been explored in several types of cancers with reported high SN detection rates and a superior diagnostic performance when compared to blue dye, which previously has been used extensively as a visible lymphatic tracer , 26. In The SNB positivity rate was only 12% in this present study with is markedly lower compared to data form our own and other published series with a positivity rate in the range 20–30% of cN0 in early OSCC , 32. ThiThe drainage patterns described in this cohort support the well-documented involvement of primarily levels 1–3 in early-stage OSCC, with only 3% of harvested SNs outside this region. However, the data also show a substantial variation in the combinations of involved neck levels harboring SNs. Importantly, 40% of the patients had simultaneously combined lymphatic drainage to both level 1 and another neck level, which demonstrates the need to carefully explore the level 1, also if preoperative imaging only suggests drainage outside level 1. These observations very likely explain the mechanism of nodal recurrences in SNB-negative patients in previously reported series where nodal metastases were present upstream from harvested SNs in level 2 or 3 but remained undetected .Apart from optical imaging, other technologies have been explored to overcome the challenge of shine-through to accurately detect SNs in level 1 like portable SPECT or gamma cameras for intraoperative and postoperative imaging , 36. AlsCombined optical and radio-guided SNB in conjunction with a super-selective level 1 ND accurately staged the cN0 neck in patients with OSCC sub-sites in the anterior oral cavity with a false omission rate of 0%. Optical imaging enabled direct intraoperative real-time visualization of SNs, and in 46% of patients, additional SNs in level 1 were detected due to this modality. Exploration of level 1 irrespective of findings on preoperative radio-based imaging is recommended for tumors in FOM and other locations that carry risk of shine-through.


Concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) recording provides information on both intracortical reorganization and networking, and that information could yield new insights into post-stroke neuroplasticity. However, a comprehensive investigation using both concurrent TMS-EEG and motor-evoked potential-based outcomes has not been carried out in patients with chronic stroke. Therefore, this study sought to investigate the intracortical and network neurophysiological features of patients with chronic stroke, using concurrent TMS-EEG and motor-evoked potential-based outcomes.A battery of motor-evoked potential-based measures and concurrent TMS-EEG recording were performed in 23 patients with chronic stroke and 21 age-matched healthy controls.P = 0.002), reduced active motor-evoked potential amplitudes (P = 0.001) and a prolonged cortical silent period (P = 0.007), compared with their contralesional M1. The ipsilesional stimulation also produced a reduction in N100 amplitude of TMS-evoked potentials around the stimulated M1 (P = 0.007), which was significantly correlated with the ipsilesional resting motor threshold (P = 0.011) and motor-evoked potential amplitudes (P = 0.020). In addition, TMS-related oscillatory power was significantly reduced over the ipsilesional midline-prefrontal and parietal regions. Both intra/interhemispheric connectivity and network measures in the theta band were significantly reduced in the ipsilesional hemisphere compared with those in the contralesional hemisphere.The ipsilesional primary motor cortex (M1) of the patients with stroke showed significantly higher resting motor threshold (The ipsilesional M1 demonstrated impaired GABA-B receptor-mediated intracortical inhibition characterized by reduced duration, but reduced magnitude. The N100 of TMS-evoked potentials appears to be a useful biomarker of post-stroke recovery.The online version contains supplementary material available at 10.1186/s12984-023-01223-7. Transcranial magnetic stimulation (TMS) can transsynaptically excite pyramidal neurons by activating the excitatory and inhibitory interneurons located in layers II and III of the brain cortex . A singlUnderstanding post-stroke neurophysiological alteration using many TMS protocols have played an essential role in investigating the correlates of motor recovery with adaptive and maladaptive neurophysiological alteration, predicting prognosis, and guiding non-invasive brain stimulation for stroke. Compelling evidence indicates that corticospinal excitability of the contralesional M1 is comparable with that of healthy counterparts, but such is not the case for the excitability in the ipsilesional M1, which decreases with impaired contralateral motor function. The reduction of ipsilesional M1 excitability can be indexed by increased resting motor threshold (RMT) and decreased resting MEP amplitudes , 3. By mConcurrent TMS and electroencephalography recording (TMS-EEG) is a novel approach that records the summation of postsynaptic excitatory and inhibitory potentials that occur in response to TMS pulses and are termed TMS-evoked potentials (TEPs). This approach enables assessments of local cortical excitability and connectivity between brain regions , and hasA previous study in patients with acute stroke suggested that the absence of the N100 component was an indicator of severe motor impairment . AnotherTo the best of our knowledge, although previous studies with many TMS protocols have provided informative investigation into post-stroke neurophysiology, largely inconsistent findings were reported, particularly in GABA-B receptor-mediated intracortical inhibition. In addition to TEPs characterized by large amplitudes and slow frequencies, ipsilesional stimulation can also produce a TEP pattern similar to that in contralesional stimulation and healthy people, but the characteristics of this TEP pattern in terms of peaks, oscillations, and connectivity are inconclusive. The objective of this study, therefore, was to conduct a comprehensive neurophysiological examination of patients with stroke, using TMS-EEG and MEP-based measures to address previous inconclusive findings in patients with chronic stroke.The study investigated twenty-three patients with a hemiparetic upper extremity due to first-ever unilateral cerebral stroke . The inclusion criteria were patients who were (1) suffering from chronic stroke (time since stroke onset > 6 months); (2) right-handed; (3) and aged between 18 and 75 years. Patients with stroke were excluded if they met any of the following criteria: (1) had any contraindications to TMS ; (2) hadTwenty-one age-matched healthy participants without any known history of neurological or psychiatric diseases  were recruited as healthy controls. This study was conducted following the ethical principles of the Declaration of Helsinki , and wasIn this cross-sectional study, a battery of MEP-based measures and TMS-EEG were administered to both hemispheres of each participant. White noise masking was applied to minimize contamination from auditory-evoked potentials elicited by TMS click sounds . Two conParticipants were seated in a TMS-specific adjustable chair with head and back supports and were kept awake with their eyes open. To maintain consistency throughout the experiment, all TMS procedures were performed over an EEG cap. Biphasic TMS pulses were always delivered to the hotspot of the first dorsal interosseous muscle, using a figure-of-eight cooling coil  connected to a magnetic stimulator . The motor hotspot was defined as the position at which the largest and most reliable MEPs could be obtained from the first dorsal interosseous muscle contralateral to stimulation. The MEPs were recorded from corresponding muscles using disposable Ag-AgCl surface electrodes positioned in a belly-tendon montage, and a ground electrode was placed on the ulnar styloid process. The MRI-less version of a TMS-navigation system  was used to guide the TMS coil positioning, in which a standard magnetic resonance imaging (ICBM152) was warped to match the individual’s brain. To effectively stimulate the M1, the coil was placed on the scalp at approximately 45° away from the midline, with the handle pointed backwards and laterally.RMT was defined as the minimum intensity  that could elicit peak-to-peak MEP amplitudes higher than 50 µV in at least five out of 10 trials. Four MEP-based measures were recorded and analyzed: the cortical silent period (cSP), MEPs, intracortical facilitation (ICF), and SICI. Eight trials were recorded for each protocol, with inter-trial intervals ranging from 4 to 5 s. The intensity of test pulses was fixed at 120% of the RMT for all MEP-based measures. The cSP was the disruption of background electromyogram (EMG) activity by a suprathreshold test pulse while sustaining 30% of the maximal voluntary strength of thumb-index finger contraction. The amplitude of single-pulse MEPs was used to measure corticospinal excitability at rest. The SICI and ICF were obtained by delivering a suprathreshold test pulse after a subthreshold conditioning pulse at 80% of the RMT, with inter-pulse intervals of 2 ms and 10 ms, respectively. When measuring RMT, single-pulse MEP, SICI, and ICF, the participants were instructed to relax their hand muscles, with a background EMG amplitude around 10 µV.The raw signals of MEP-based measures were recorded by a bipolar channel of an EEG system , digitized at 5 kHz, and stored on a laptop for offline analysis.3). To suppress auditory-evoked potentials produced while the coil discharged, all participants wore an inserted earphone, and white noise was played [With referenced to previous studies , 17, TMSs played . To reduThe signals of EMG and EEG were preprocessed offline using EEGLAB 14.1.2 , TESA exIn the temporal domain, we defined five peaks, with reference to the previous literature : P30  was calculated by using dimensionality reduction and state transitions quantification [Where fication .In the time-frequency domain, event-related spectral perturbation (ERSP) was computed by decomposing individual trials using the Morlet wavelet transform  and then averaging across trials. In accordance with a recent study in which patients with slow and local deflections presented with significantly attenuated ERSP at the late stage following TMS pulses , we alsoIn the current study, ipsilesional stimulation induced significantly suppressed ERSP over the midline-frontal and parietal regions of the stimulated hemisphere at the early stage. Therefore, we further investigated functional connectivity and whole brain networks at that early stage. The connectivity measure of interest used in our study was the debiased weighted phase lag index (dwPLI), which was weighted by the magnitude of the imaginary component of cross-spectrum and insensitive to noise and volume conduction . To obtaStatistical analyses were performed using SPSS22  and FieldTrip in MATLAB 2016a. The alpha threshold was set at 0.05 (two-tailed). There was no significant difference on any outcomes between both hemispheres in the healthy controls . Therefore, the left and right hemispheric measures from the healthy controls were averaged to obtain merged values for further between-group comparisons.t-tests. The second set of analyses was between-group comparisons made by independent t-tests. To reduce type I error, Bonferroni correction was applied .The first set of analyses was within-group comparisons using paired P-values < 0.025 were considered to be significantly different. To further elaborate the mechanism of N100 in patients with stroke, first, the local mean field power (LMFP) from 90 to 130 ms surrounding the ipsilesional M1 was averaged across the time window. Second, we explored the Pearson’s correlation coefficients between the LMFPs of the N100, MEP-based measures, and AUCs of transitivity and efficiency.Non-parametric cluster-based permutation tests  with the Monte Carlo method were conducted to address the multiple-comparisons problem in spatial and temporal dimensions when examining the within- and between-group differences in TEPs and TMS-related oscillations . Any posn = 21). Because the ipsilesional MEPs of Pt9 were not recordable, he was not included in the analysis of MEP-based measures (n = 20).Twenty-one of the patients with stroke presented ipsilesional TEPs with quickly changing deflections and complex spatial distribution, whereas the ipsilesional TEPs of the remaining two patients (Pt22 and Pt23) were characterized by large amplitudes, slow frequencies, and stereotypical EEG reactivity. Therefore, those two patients were not included in our subsequent subgroup analysis of EEG measures  than their contralesional M1 did, but independent t-tests indicated that neither ipsilesional  nor contralesional  RMT was significantly different from that of healthy controls  and in the M1 of the healthy controls , but the active MEP amplitude in the contralesional M1 of the patients with stroke did not significantly differ from that in the M1 of the healthy controls . Likewise, there was a slight reduction of the ipsilesional MEP amplitude compared with that in the contralesional M1 , but the difference was not significant after Bonferroni correction. Neither the ipsilesional  nor the contralesional  MEP amplitude was significantly different from that of healthy controls. The contralesional ICF was significantly lower than that of healthy controls , but that of the ipsilesional M1 was not significant after Bonferroni correction ; in addition, the ICF comparison between the bilateral M1 was not significant  in the patients with stroke. The comparison of the SICI values did not yield any significant differences . An unambiguous cSP was identified in all of the healthy controls and 12 out of 20 patients with stroke in the ipsilesional M1. However, the remaining eight patients presented low-level of EMG activity during the silent period . Nevertheless, the ipsilesional cSP was significantly prolonged compared with the contralesional cSP  and the cSP of the healthy controls . A correlation analysis between the bilateral difference in RMT and the bilateral difference in cSP was carried out, and a nonsignificant correlation was found , thus ruling out the possibility that the prolonged cSP was related to an increase in the intensity of stimulation.In the patients with stroke, the ipsilesional M1 had a significantly larger RMT , whereas larger amplitudes were found over the central and prefrontal regions of the nonstimulated hemisphere (P = 0.012), thus suggesting that the N100 amplitude over the ipsilesional hemisphere was always lower than that of the contralesional hemisphere, irrespective of the hemispherical sides of stimulation. In addition, reversed differences between the above two stimulation conditions were found at roughly 340 ms to 370 ms post-TMS pulses. Regarding the comparison between populations, cluster-based permutation tests (independent t-tests) failed to show any significant difference in TEP amplitudes. The PCI-st of the brain responses to TMS pulses applied to both hemispheres of the patients with stroke were comparable , and they did not significantly differ from healthy controls . The LMFP of the ipsilesional N100 was significantly associated with RMT  and MEPs , but it was not significantly associated with active MEPs, ICF, SICI or cSP .As shown in Fig. P < 0.001), alpha (P = 0.003), and beta-1 (P = 0.005) frequency bands compared with ERSP produced by contralesional stimulation  and alpha (P = 0.013) frequency bands at the early stage over the stimulated hemisphere. The comparisons of TMS-related oscillations at the late stage (150–350 ms) did not yield any significant differences (data not shown).Cluster-based permutation tests revealed that at the early stage (15–150 ms), ipsilesional stimulation induced significantly suppressed broadband ERSP in the theta  and that of the contralesional hemisphere . Similarly, significantly lower connectivity was also found in the beta-2 band . For the connectivity between the ipsilesional M1 and the parietal region in the theta band, it was significantly lower that that of the contralesional hemisphere  and that of the healthy controls . Ipsilesional M1 stimulation produced lower M1–M1 connectivity than that of the healthy controls , but it was not significant after Bonferroni correction.At the early stage following TMS pulses, the connectivity in the theta band between the patients’ ipsilesional M1 and prefrontal region was significantly lower than that of the healthy controls , and tended to be lower than that of the healthy controls . Similarly, the AUC of weighted transitivity in the beta-2 band produced by ipsilesional stimulation tended to be lower than that produced by contralesional stimulation . In addition, ipsilesional stimulation produced a significantly lower AUC of weighted efficiency in the theta band in the patients with stroke than contralesional stimulation did  and than that of the healthy controls . However, no significant difference in the AUC of weighted efficiency in the beta-2 band  was found. Pearson’s correlation analysis showed that the LMFP of N100 was significantly correlated with the AUC of weighted transitivity , but it was not significantly correlated with the AUC of weighted efficiency in the theta band .Furthermore, network analysis showed that the AUC of weighted transitivity in the theta band produced by ipsilesional stimulation was significantly lower than that produced by contralesional stimulation . Brain oscillations reflect the transmission and processing of endogenous information within a network through synchronization in specific frequency bands. For instance, long-range synchronization in the theta band mediates the connectivity between the prefrontal cortex and the posterior parietal cortex within the frontoparietal network . RosanovFrom the perspective of network topology, a brain network with small-world characteristics supports the efficient transformation of information. A previous study showed bilaterally decreased small-world characteristics in the delta band in patients at the acute stage of stroke , and theSeveral limitations should be acknowledged. First, there is no consensus on how to analyze the duration of cSP, therefore, the approach of extracting the time from TMS pulse onset to returned EMG bursts, was used in the current study, which might limit the comparability with previous studies. Second, suprathreshold intensity was used for TMS-EEG, which may produce somatosensory-evoked potentials due to the re-afferent feedback from peripheral muscle twitches . AlthougThe present study extends our understanding of the neurophysiological state of patients with chronic stroke, especially those with quick-frequency TEP waveforms. We concluded that patients with chronic stroke with mild motor impairment showed a reduction in the cortical excitability of the ipsilesional M1 and an impairment of intra/interhemispheric connectivity. Moreover, the intracortical inhibition after stroke is complex, characterized by long duration, but low magnitude, and its clinical significance related to motor functions is awaiting more studies. The N100 of TEPs is associated with both excitatory and inhibitory functioning, as well as with certain network features, which indicate that it could be a potential biomarker in post-stroke motor recovery. MEP-based measures are limited to the investigation of the corticospinal tract, while concurrent TMS-EEG extends the utility of TMS to the investigation of underlying post-stroke intra and intercortical networks.Below is the link to the electronic supplementary material.Additional File 1: Intracortical and intercortical networks in patients after stroke: A concurrent TMS-EEG study


Nuclear lamins are the main components of the nuclear lamina in many eukaryotes. They are members of the intermediate filament (IF) protein family. Lamins differ from cytoplasmic IF proteins by the presence of a nuclear localisation sequence (NLS) and a C-terminal tetrapeptide, the CaaX motif. The CaaX motif is target of post-translational modifications including isoprenylation, proteolytic processing, and carboxyl-methylation. These modifications, in conjunction with the NLS, direct lamins to the inner nuclear membrane where they assemble into filaments. Lamins lacking a CaaX motif are unable to associate independently with nuclear membranes and remain in the nucleoplasm. So far, three species have been reported to exclusively express CaaX-less lamins. All three belong to the lophotrochozoan lineage. To find out whether they represent rare exceptions, we analysed lamins of representatives of 17 lophotrochozoan phyla. Here we report that all four clades of Rotifera as well as individual taxa of Mollusca and Annelida lack CaaX-lamins, but express lamins with alternative C-termini. Of note, the respective mollusc and annelid groups occupy very different phylogenetic ranks. Most of these alternative C-termini are rich in aromatic residues. A possible function of these residues in membrane association is discussed. Alternative splicing of terebellid lamin transcripts gives rise to two lamin variants, one with a CaaX motif and one with an alternative C-terminus. A similar situation is found in Arenicolidae, Opheliidae, Capitellidae, and Echiura. This points a way, how the switch from lamins carrying a CaaX motif to lamins with alternative C-termini may have occurred.The online version contains supplementary material available at 10.1007/s00709-022-01809-3. The nuclear lamina is an integral part of the nuclear skeleton in eukaryotic cells. The lamina is made up of a network of filaments that are closely attached to the nuclear aspect of the inner nuclear membrane. Lamin proteins constitute the major components of the lamina. Together with lamina-associated polypeptides and lamin-binding proteins, they contribute to a wealth of cellular functions. The lamina is involved in nuclear mechanics and nuclear positioning, in the spatial organization of interphase chromatin and DNA replication, and it contributes to transcription and regulatory functions (Burke and Stewart Lamin proteins are members of the intermediate filament (IF) protein family  and by a CaaX isoprenylation motif at the C-terminus  ; the downstream gene contains a CaaX-encoding lamin (PTSG_10008); however, the last exon encoding the CaaX motif is located on a separate genomic contig (ACSY01003084) and therefore probably remained undiscovered so far , those with several hundred species , and the Monoplacophora, for which only 32 species have been described to date WlFW*   Corpet . We idenown Fig. . The codown Fig. . Eight oown Fig.   and up to four in the Decapodiformes , Dosidicus gigas (3), Euprymna tasmanica (2), Octopoteuthis deletron (3), Onychoteuthis banksii (2), Pterygioteuthis hoylei (2), Sepia esculenta (2), Sepia pharaonis (2), Sepioloidea lineolata (4), Vampyroteuthis infernalis (3), Watasenia scintillans (3)). These variants result from alternative splicing of the additional one, respectively two exons, which are located between exon 10 and the two terminal exons  are the structural components of the plant lamina. They are considered to be the analogs of lamins in plants Below is the link to the electronic supplementary material.


The Pivot Mandu is an innovative device featuring a leak-tight adjustable 3D balloon spacer, incorporating inner mesh support, an outer e-PTFE layer, and a compliant balloon in the middle layer with a specialized detachable system. To assess its feasibility, proof of concept was rigorously evaluated through bench testing and survival porcine animal experiments. The results demonstrated successful remote inflation of the balloon system, with the balloon spacer exhibiting sustained patent and functional integrity over an extended observation period of up to 6 months. A noteworthy feature of the newly designed 3D balloon spacer is its capability for easy size adjustment during procedures, enhancing its adaptability and practicality in clinical settings. This three-layered 3D balloon spacer, with its established long-term patency, exhibits highly encouraging outcomes that hold promise in overcoming the current limitations of spacer devices for heart valve diseases. Given the compelling results from preclinical investigations, the translation of the Pivot Mandu into human trials is strongly warranted. The rapid advancement of cardiovascular therapeutic devices has shifted the focus from vascular diseases to valvular diseases, commonly referred to as structural heart diseases. Building upon the remarkable success of transcatheter aortic valve replacement (TAVR) in aortic valve diseases , there hAmong these spacer devices, such as FORMA , MitraSpHowever, it is important to acknowledge that the benefits associated with the open cavity structure are counterbalanced by the potential disadvantage of an increased susceptibility to clot formation due to stagnant blood flow within the cavity. In this study, our objective was to devise an innovative spacer design that effectively addresses the limitations associated with current spacers, while preserving the advantages of the Pivot-TR system . To achiThe Pivot Mandu device, developed by TAU MEDICAL Inc. , features a unique and innovative 3D balloon spacer configuration. This device builds on the same conceptual design as the previously introduced Pivot-TR device ). A total of 16 healthy Yorkshire farm pigs (weight 40.63 ± 2.30 kg) were used in this study. All the surviving animals were administered rivaroxaban 20 mg daily and other medicines during the survival period. All the animals were euthanized at the time of termination. These 16 pigs were used in one or more tests to evaluate the efficiency and safety parameters.n = 20). We inflated the 3D balloon spacer in a saline solution at the average human body temperature. The diameter of the 3D balloon spacer, the maximum degree of swelling, and resulting changes in the physical properties were observed according to the amount of fluid injected.Expansion evaluation was performed at the bench level to confirm the expansion performance of the 3D balloon spacer  reduction comparable to the previous design, the TR grade was evaluated following the induction of TR through the destruction of the valve structure in two randomly selected pigs from each survival period . Destrucn = 1, 2, 4, 3, 1, and 5, respectively) was performed for all the subjects. Of these 16 pigs, four were excluded from the safety assessment because they showed procedure-related infection , and multiple contaminants at the time of device manufacturing, as confirmed by the histological findings , or fulminant right heart failure owing to severe valve damage resulting from the tricuspid regurgitation modeling .Long-term follow-up at various time points . An independent and experienced pathologist at the Pusan National University Hospital examined the specimens.p-value of <0.05 was considered statistically significant.Statistical analysis of the 3D balloon spacer patency was performed using a linear mixed-effects model. Pairwise comparisons of patency at different time points were adjusted using the Bonferroni correction. All statistical computations were executed using the R statistical software package . Additionally, the R packages ‘nlme’ and ‘multcomp’ were employed for the linear mixed-effects model and multiple comparison procedures, respectively. A A performance evaluation of the Pivot Mandu device was conducted through bench and preclinical testing. All the devices were found to be 100% detachable, and it was confirmed that they expanded to the desired size.An experiment was conducted in a water tank set at 36.5 °C to construct the same environmental conditions as the human body . When a In the 16 pigs, 3D balloon spacers were expanded with the injection of saline and contrast agents to measure the changes in the outer diameter (OD) within the saline injection.The operator could freely adjust the size of the 3D balloon spacer by adjusting the amount of fluid injected into the 3D balloon spacer during the procedure. The OD of the 3D balloon spacer varied depending on the amount of fluid injected, and the diameter increased to a maximum of 22.6 mm . The adjp-value < 0.05) in the first week, and there were no significant changes after 1 week to 8 weeks , it was stabilized and maintained for 24 weeks . This OD reduction had no significant effect on the TR reduction.After implantation, we evaluated the patency of the 3D balloon spacer over a survival period of 8 weeks in 16 pigs. The average OD was decreased by 10.19% (After inducing the tricuspid regurgitation (TR) via structural damage to the tricuspid valve in two randomly selected pigs with survival periods of 4 and 24 weeks, the TR reduction in the 3D balloon spacer was verified. As shown in Among the 12 pigs subjected to the safety evaluation and pathological examination, no instances of thrombus formation, valve interaction, or other abnormal symptoms were observed. Endothelial formation was observed in the pigs implanted with the Pivot Mandu device eight weeks after implantation. The tricuspid leaflets exhibited increased thickness, which was attributed to fibrosis and histiocytic reactions. A neointimal membrane formed on both the inner and outer surfaces of the e-PTFE, covering the 3D balloon spacer, with a more significant thickening observed on the outer surface . Any kinIn this study, we have demonstrated that the new design of the Pivot Mandu system meets the crucial criteria of being a “permanent implantable” device similar to a balloon-like spacer while also offering the advantage of “size adjustability”. This design enhancement was specifically aimed at making the previously reported Pivot-TR system more suitable for long-term implantation.In the previous study, we proposed a tricuspid regurgitation (TR) reduction device with a new concept of vertically traversing spacer through the tricuspid valve. The device, a Pivot-TR system, has the 3D leaflet as a coaptation enhancer. Several spacer-based devices have been developed for the treatment of tricuspid regurgitation (TR), including the Edwards Forma , CoramazBut, despite the outstanding functionality of the Pivot-TR spacer, it has come to our attention that approximately 10% of animal cases experienced complications related to thrombus formation . These cOur innovative ‘detachable fluid filling system’  effectivIn our Pivot-Mandu system, we found that the silicone valve alone might not be sufficient to maintain a leak-tight seal of the balloon over a long-term period . To addrThe adjustable balloon system in our Pivot-Mandu system offers a significant advantage in terms of tailoring the balloon size to meet each patient’s specific anatomical requirements. This customization capability ensures that the balloon can be optimally sized and positioned for maximum efficacy and safety. In our adjustable balloon system, we utilized a polyurethane membrane as the main balloon skin. It was made based on the suitability of polyurethane in compliant balloon systems. Polyurethane is known for its flexibility and elasticity, allowing the balloon to expand and contract effectively while maintaining structural integrity ,17. ThisThe augmented expandability of e-PTFE (expanded polytetrafluoroethylene) in body fluid, as discovered in our study , is indeThe catheter retrieval of the Pivot-Mandu using a snare remains feasible, similar to the open cavity Pivot-TR system. However, it is important to note that the process of rupturing the balloon of the Pivot-Mandu with a needle should be added to the process of device retrieval.In summary, our novel design of the Pivot-TR (Pivot-Mandu) system represents a significant advancement in the concept of long-term implantable balloon-like spacers. This design incorporates several key features, including the use of an inner self-expandable mesh support within the compliant balloon structure to ensure a leak-tight system. Additionally, the inclusion of a dual-layer balloon skin consisting of an inner polyurethane layer and an outer e-PTFE layer enhances long-term stability.The previously reported Pivot-TR system, which features an open cavity design, is currently undergoing early clinical trials in Korea for short-term implantation (within 1 week) to establish the proof of concept in patients with severe tricuspid regurgitation (TR). Subsequent clinical trials of the Pivot-Mandu system will follow, aiming to demonstrate its long-term efficacy and safety in patients requiring prolonged implantation. These clinical trials will provide crucial insights into the real-world performance and potential benefits of the Pivot-Mandu system as a viable treatment option for patients with TR.This study had several limitations.In pig models, anatomical structure from the pulmonary artery through IVC is somewhat different from humans. The most prominent difference is that the cavotricuspid isthmus of the RA is almost negligible in pigs while humans have very prominent cavotricuspid isthmus . The device and system are designed for human application. It may not be suitable for individual pigs, and we need to further study real human applications.TR severity was estimated by only the visual evaluation of echocardiographic specialists without any objective parameter. In pig models, echocardiographic evaluation had several limitations coming from the difficulty of imaging acquisition in diverse angles.The 3D balloon spacer newly designed in this study can easily adjust size during the procedure, has a detachable fluid filling system, and is designed with a leak-tight structure to maintain its shape for long-term implantation. Therefore, this novel three-layered 3D balloon spacer with proven long-term patency is expected to be a breakthrough for intracardiac implantable devices such as various valve-related diseases and alternatives to the existing filler-type spacer.


At present, the COVID-19 pandemic is still ongoing globally and the virus is constantly mutating. The herd immunity barrier established by past infections or vaccinations is gradually weakening and reinfections are occurring. To evaluate the pandemic fatigue and vaccine hesitancy among people who have recovered from COVID-19 in the post-pandemic era, we conducted an anonymous cross-sectional survey study in China from 4 July to 11 August 2023, nearly 6 months after the last large-scale nationwide infection. Basic sociodemographic characteristics, health-related factors , COVID-19 vaccination history, and self-reported long COVID were obtained as potential covariates. A series of logistic regression models were performed to examine the association between pandemic fatigue and vaccine hesitancy toward the next dose of COVID-19 vaccines via crude relative risks (cORs) and adjusted relative risks (aORs) with 95% CIs. According to our results, of the 2942 participants, 1242 (42.2%) were hesitant (unwilling or not sure) to receive the next dose of COVID-19 vaccines. The average score on the Pandemic Fatigue Scale was 21.67 ± 8.86, in which the scores of all items in the vaccine-hesitant group were significantly higher than those in the vaccine-accepting group. Additionally, the higher the pandemic fatigue level among people who have recovered from COVID-19, the more likely they were to be hesitant to receive the next dose of the COVID-19 vaccines . Overall, more than 40% of the recovered participants were unwilling or uncertain about the next vaccine dose, with varying degrees of pandemic fatigue. Pandemic fatigue is a potentially relevant factor for vaccine hesitancy and may hinder the translation of vaccination intention into behavior. Considering the ongoing reinfection situation, implementing a health education plan to reduce pandemic fatigue and prioritizing vaccination issues for people who have recovered from COVID-19 may be key to promoting the reduction of the COVID-19 disease burden and ensuring the health and well-being of the population. The coronavirus disease 2019 (COVID-19) has been raging continuously for three years, indicating a great threat to human health ,4. From Vaccination, a vital weapon to actively prevent infectious diseases, is a milestone development in the history of human civilization ,7. BuildAs the 4-year mark is approaching since the commencement of the COVID-19 pandemic November 2019), during which a “waxing and waning” battle trajectory has been observed almost globally and affected most aspects of human life, the concept of “pandemic fatigue” has become widely recognized in both academic and popular discourse . Pandemi19, durinAt present, the COVID-19 pandemic is still ongoing globally and the virus is constantly mutating ,11. TherTo evaluate pandemic fatigue and vaccine hesitancy among people who have recovered from COVID-19 in the post-pandemic era, we conducted an anonymous cross-sectional survey in China from 4 July to 11 August 2023, nearly 6 months after the last large-scale nationwide SARS-CoV-2 infection . It can Seventh National Census to allocate a total sample size of 3000 people. The predetermined sample size was obtained using a random sampling method in each province. After excluding unqualified replies and verifying the sufficient power of the test under α as 0.05 and the confidence interval width as 0.1 p (p = hesitancy rate in this study), 2942 participants with COVID-19 infection history were ultimately included in our analysis  is a subjective questionnaire that has been used as a tool to measure subjects’ fatigue from the COVID-19 pandemic, which has been used cross-culturally with good validity and internal consistency ,24. AfteTo determine the attitude of participants with a history of COVID-19 infection towards receiving the next dose of COVID-19 vaccines, we set a question as “Are you willing to receive the next dose of COVID-19 vaccine if available?”. The answer was progressively set on a 5-point Likert scale . We defined vaccine hesitancy as reluctance or uncertainty about receiving the next dose of COVID-19 vaccines, and then further asked for specific reasons for hesitancy.Sociodemographic characteristics , health-related factors , and COVID-19 vaccination history were obtained as potential covariates. Risk perception items of COVID-19 reinfection were adapted from the Health Belief Model and involved two parts: perceived susceptibility and perceived severity . Particit-test to compare the group differences among basic characteristics of vaccine hesitancy and pandemic fatigue. A series of logistic regression models were performed to examine the association between pandemic fatigue and vaccine hesitancy via crude relative risks (cORs) and adjusted relative risks (aORs) with 95% CIs. Model A was unadjusted. We controlled sociodemographic factors  in model B, and then plus health factors (drinking and chronic disease history) in model C. Risk perception factors (perceived susceptibility and perceived severity) were additionally added to model D. Model E adjusted for all covariates that were significantly unequally distributed across three pandemic fatigue levels. On the basis of Model E, subgroup analyses were performed among participants with different characteristics. All statistical analyses were conducted by Software SPSS 26.0 , and we set the significance level at a two-sided p value of <0.05.Statistical descriptions of all quantitative variables were reported as frequencies, percentages, means (M), and standard deviations (SD). We used the Chi-square test and Of the 2942 participants who have recovered from COVID-19 , 1185 (4p < 0.05), including three information fatigue items and three behavioral fatigue items. The scores of six items in the vaccine-hesitant group were all significantly higher than those in the vaccine-accepting group.As is shown in p < 0.05). As the level of pandemic fatigue increased among the population, vaccine hesitancy also increased significantly. There was no significant difference in vaccination intention among people grouped by sex, age, location, education, drinking habits, chronic disease history, and perceived susceptibility to COVID-19 reinfection.The associations between pandemic fatigue and hesitancy toward the next dose of COVID-19 vaccines among people who have recovered from COVID-19 remained stable in a series of models . In modep for interaction > 0.05), except for people stratified by education and smoking history. The association between pandemic fatigue and vaccine hesitancy weakened gradually with increasing education levels but remained significant. In the subgroup with the lowest education level, people who perceived high pandemic fatigue were 10.97 times more likely to be vaccine-hesitant than those with low pandemic fatigue, while it decreased to 3.88 times in the Master’s degree subgroup. Furthermore, the impact of pandemic fatigue on vaccination intention was more pronounced in the smoking subgroup  than in the non-smoking subgroup .Subgroup analyses were exhibited in China experienced a nationwide Omicron variant outbreak from late 2022 to early 2023 . To our In contrast to high COVID-19 vaccine acceptance in the general population, our findings found that 42.2% of the 2942 participants were hesitant to receive the next dose of COVID-19 vaccines ,31,32. AThe direct and indirect effects of COVID-19 have caused great stress to the population and led to poor mental health outcomes . AccordiAcross a range of models, pandemic fatigue was consistently positively associated with vaccine hesitation rates among those recovering from COVID-19, which became more significant with increasing adjustment. Previous studies in different populations have also reached similar conclusions ,37. Ali-This is a nationwide study encompassing all provinces in mainland China, which is representative and statistically efficacious. However, as described in the Methods section, this is a cross-sectional study and caution is needed when making causal inferences. Second, only those with access to the Internet were able to participate in this survey, which to some extent ignores the remaining portion of the population and may lead to selection bias. Third, we did not adjust for social media use, income, occupation, and vaccine production information when analyzing the association between pandemic fatigue and vaccine hesitancy, and there is a possibility that the level of association was misestimated. Additionally, it is important to note that this study was conducted only in patients who had recovered from COVID-19, so the levels of pandemic fatigue and vaccine hesitancy in this study were not representative of the general population. Future studies with longitudinal or experimental designs are encouraged to confirm our findings and elucidate potential mechanisms and interventions to reduce pandemic fatigue and vaccine hesitancy.In this study, 42.2% of participants with a history of COVID-19 were hesitant to receive the next dose of COVID-19 vaccines, and only 40.7% of respondents reported a low level of pandemic fatigue. People with higher levels of pandemic fatigue were more likely to be hesitant to receive the next dose of COVID-19 vaccines. Therefore, given the ongoing reinfections, implementing a health education plan to reduce pandemic fatigue and prioritizing vaccination issues for people with a history of COVID-19 may be vital in promoting the reduction of the COVID-19 disease burden and ensuring the health and well-being of the population.


Identifying Human Epithelial Type 2 (HEp-2) mitotic cells is a crucial procedure in anti-nuclear antibodies (ANAs) testing, which is the standard protocol for detecting connective tissue diseases (CTD). Due to the low throughput and labor-subjectivity of the ANAs’ manual screening test, there is a need to develop a reliable HEp-2 computer-aided diagnosis (CAD) system. The automatic detection of mitotic cells from the microscopic HEp-2 specimen images is an essential step to support the diagnosis process and enhance the throughput of this test. This work proposes a deep active learning (DAL) approach to overcoming the cell labeling challenge. Moreover, deep learning detectors are tailored to automatically identify the mitotic cells directly in the entire microscopic HEp-2 specimen images, avoiding the segmentation step. The proposed framework is validated using the I3A Task-2 dataset over 5-fold cross-validation trials. Using the YOLO predictor, promising mitotic cell prediction results are achieved with an average of 90.011% recall, 88.307% precision, and 81.531% mAP. Whereas, average scores of 86.986% recall, 85.282% precision, and 78.506% mAP are obtained using the Faster R-CNN predictor. Employing the DAL method over four labeling rounds effectively enhances the accuracy of the data annotation, and hence, improves the prediction performance. The proposed framework could be practically applicable to support medical personnel in making rapid and accurate decisions about the mitotic cells’ existence. Connective tissue diseases (CTD) are autoimmune disorders initiated by generating abnormal autoantibodies that act against nuclear and cytoplasmic antigens and so-called anti-nuclear antibodies (ANAs). ANAs affect body tissues, causing chronic inflammatory disorders such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjögren’s syndrome, and idiopathic inflammatory myopathies . DiagnosIn the IIF HEp-2 protocol, several ANAs appear as distinct HEp-2 cell fluorescence patterns, and each one is associated with a particular disorder ,4. The IHEp-2 cell patterns could be classified based on the cell cycle phases into two broad categories, i.e., mitotic patterns (cell under division phase) and interphase patterns (non-mitotic phase). The HEp-2 cells undergo the mitotic phase through 10∼15% of their entire lifecycle, causing their appearance in the HEp-2 specimen images to be very rare compared to the interphase cell patterns . During HEp-2 mitotic cell detection using HEp-2 specimen images has barely been studied in the literature of HEp-2 image analysis . TypicalAn end-to-end deep learning framework is proposed to accurately and rapidly detect multiple mitotic cells from the entire HEp-2 specimen images within seven different classes of the I3A dataset: Centromere, Golgi, Homogeneous, Nuclear Membrane, Speckled, Nucleolar, and Mitotic Spindle. This is the first work that proposes detecting mitotic cells from the microscopic specimen image regardless of its class type, which provides a practical framework that could be integrated with a microscopic imaging system to support instant and direct detection of the mitotic cell from the captured specimen images.A deep active learning (DAL) strategy is involved to automatically annotate the mitotic cells for the detection task by adjusting the bounding boxes to surround each mitotic cell in the specimen images. Providing such annotation data could initiate further studies for developing mitotic cell detection approaches that could be applied to whole HEp-2 specimen images.A pre-processing step via contrast-limited adaptive histogram equalization (CLAHE) is employed to enhance the specimen image quality leading to improve detection performance.A comprehensive detection study is conducted by adopting two well-performed deep learning detectors  labeling iteratively during training. The main contributions of this work are further highlighted as follows:The rest of this paper is organized as follows. A review of contemporary literature relevant to this study is presented in Automatic detection of mitotic cells from various staining patterns of the entire HEp2 specimen images is challenging for building any CAD system for autoimmune disease ,13,17. TUnlike the HEp-2 cell interphase patterns classification, a few research works have been conducted to solve the task of mitotic pattern detection from microscopic medical images for various diseases ,13. TherAlmost all existing works in the literature on HEp-2 mitotic cell detection attempted to address this task as a binary classification between mitotic and interphase cell-level images. Because the mitotic cells are a minority in all available datasets, most existing works proposed using conventional learning approaches for solving the unbalancing problem. For instance, Foggia et al.  manuallyRecently, this task was studied using various deep learning-based approaches. In , Gupta eUnlike the cell-level scenario, the specimen-level scenario performs the prediction task over the entire HEp-2 specimen images . A few wHowever, to the best of our knowledge, the recent work presented by Gupta et al.  is the oRecently, increasing research has been conducted to study the use of GANs for different medical imaging applications involving detection tasks ,47. For Alternatively, a limited number of studies that used GANs to approach the HEp-2 cell image analysis tasks are found in the literature. For example, Li et al.  used a UThe end-to-end scenario of the proposed AI-based mitotic cell detection framework is depicted in https://hep2.unisa.it/dbtools.html (accessed on 20 March 2023)) [To achieve the goal of this work, the publicly available I3A Task-2 HEp-2 specimen dataset is used (Download link for the I3A dataset: h 2023)) . This daEach specimen slide  should contain a few cells in the mitotic phase to validate the test preparation process. Thus, there is a need to manually annotate the mitotic cells across all specimen images to develop the proposed detection framework. As mentioned earlier, HEp-2 cells undergo the mitotic phase in a small portion of their lifecycle, making their appearance in the specimen images very rare. Moreover, depending on the staining patterns of the specimen, the associated mitotic cells can manifest in different fluorescence patterns, as illustrated in As it is known that the positive HEp-2 specimen images can be acquired with low contrast quality . To imprEfficient Use of Labeling Resources: Labeling large datasets can be time-consuming and expensive. DAL can significantly reduce the manually labeled data needed to achieve high performance in a deep learning model, saving significant labeling resources.Improved Model Performance: DAL can lead to more accurate deep learning models. By selecting the most informative samples to label, the model can learn from high-quality data and improve its performance faster than it would with random sampling.Active Learning: DAL incorporates active learning, which is an approach that seeks to optimize the learning process by selecting the most informative samples to label. This can lead to faster convergence of the model and better generalization performance.Human-in-the-Loop: DAL can also incorporate human feedback into the labeling process. This can further improve the performance of the model by taking advantage of human expertise and intuition.Deep active learning (DAL) is an emerging approach that automatically annotates unlabeled data to fine-tune the supervised learning algorithms accurately ,68. The To detect the mitotic cells among all other cells in the same HEp-2 specimen image, the machine should learn the different patterns of mitotic cells of all the seven classes based on the ground truth (GT) labels. For the object detection task, the GT is the bounding box that surrounds the whole target object  inside the HEp-2 specimen image. To automatically generate the GT labels for all HEp-2 specimen images, the DAL procedure includes the following strategies: initialization strategy, deep learning model selection, query strategy, and stopping criterion. For the initialization strategy, a sub-set of HEp-2 specimen images from all seven classes is carefully selected and manually annotated with the support of the GT binary DAPI masks shown in Three experts are involved in verifying the mitotic cell appearance in the specimen images to generate trustable GT labels. Two state-of-the-art deep learning detectors  are selected for the model selection as they are well-known and reliably used for detection tasks in the medical imaging domain ,65,69,70We enlarged the size of the training dataset via various augmentation strategies to improve the prediction accuracy, avoid the over-fitting that may occur during the training time, and also to minimize the class imbalance problem . We applThe detection of mitotic cells from the microscopic HEp-2 specimen images is achieved using robust deep learning detectors of YOLO  , width (w), and height (h). Concurrently, the confidence score representing the probability of object existence is estimated for each box using the neural network layers. For each prediction output, a specific node in the network is responsible for optimizing and finding the best solution. At the end, all predictors are stored in the tensor of prediction, as shown in Faster Region-CNN (Faster-RCNN)  is an efFaster R-CNN deep architecture is composed of a backbone pre-trained network (CNN), region proposal network (RPN), region of interest (RoI) pooling, and head network. First, the backbone pre-trained CNN extracts the most representative deep feature maps from the input HEp-2 specimen images. This network takes the input images and yields their corresponding feature maps. Different CNN architecture could be employed as a feature generation component of the Faster R-CNN. In this work, we use a backbone of the ResNet-50 network , which iThe region of interest (RoI) pooling layer uses the feature maps generated by the backbone network to extract features relevant to each proposed bounding box and resize them to a fixed size . Finally, the head network is a simple two fully connected layers used for final object classification and refinement of bounding boxes’ coordinates. Deep learning components of the Faster R-CNN are trained using the labeled specimen images that provide the bounding boxes’ coordinates for each mitotic cell inside the microscopic HEp-2 image. The abstract diagram of the deep learning Faster R-CNN architecture is depicted in A multi-scale strategy is used during training to learn the mitotic cell prediction via multiple image spatial resolutions ,75. The For the YOLO detector, a mini-batch size of 32 with 100 epochs is selected to fine-tune the AI models. For optimization, the stochastic gradient descent (SGD) optimizer is selected with the initial learning rate (LR) of 0.01, the final one-cycle learning rate of 0.1, the momentum of 0.937, weight decay of Precision: measures the ratio of the predicted true positives (TP) to all positive predictions (TP + FP):Recall: measures the ratio of the predicted true positive (TP) to the total positive (TP + FN):i. AP represents a weighted average of precision at different recall values, and is calculated as follows:Mean Average Precision (mAP): measures the performance of object detection models by calculating the mean of average precision (AP) values over different recall values at a specific IoU threshold:The proposed deep learning detection framework is evaluated using a 5-fold cross-validation strategy using the testing sets. For each fold, the quantitative evaluation results of precision, recall, and mean average precession (mAP@0.5) are derived and reported, which are defined as follows:Each evaluation metric is monitored during the training process to show the detection improvement over the training time. In addition, the training and validation bounding boxes regression and detection loss curves are also reported. Meanwhile, some qualitative results of the predicted mitotic cells on the entire HEp-2 specimen images are visually presented to show the potential predicted bounding boxes with their confidence probability scores.The experimental study is executed via a PC with a CPU of Intel(R) Core(TM) i7-10700KF @ 3.80 GHz, 32.0 GB RAM, six CPUs, and one GPU of NVIDIA GeForce RTX 3060.The training and validation bounding box regression and object detection loss functions are recorded for each epoch during the fine-tuning optimization process of the deep learning models. This is to evaluate the deep learning parameter optimization progress during the training process. For labeling HEp-2 mitotic cell bounding boxes, the DAL cycle is iteratively repeated four times. At each cycle, the evaluation of both detectors is checked and recorded. For the first DAL cycle, the subset of 200 HEp-2 specimen images is manually annotated by three experts as mentioned in For the YOLO detector, the validation performance in terms of precision, recall, and mAP increased from 77.01%, 78.56%, and 72.98% in the first round into 90.26%, 89.53%, and 86.35% in the fourth round, respectively. Similarly, the validation performance of the Faster R-CNN during the DAL rounds increased from 70.15%, 69.89%, and 65.89% in the first round into 88.85%, 87.98%, and 85.61% in the fourth round in terms of precision, recall, and mAP, respectively. It is clearly shown that the YOLO detector could achieve a better detection evaluation over all DAL training cycles, as shown in The quantitative detection evaluation results using YOLO and Faster R-CNN detectors are summarized in t-test is used to statistically examine the significance of the differences between the results of both detectors. The null hypothesis (Ho) is that there are no significant differences between the results of both detectors, while the alternative hypothesis (Ha) is that their results are significantly different. Using a confidence level of t-test analysis demonstrated significant differences between the effects of YOLO and Faster R-CNN with p-values of t-test analysis, the YOLO detector performed better than the Faster R-CNN on HEp-2 mitotic cell detection from the microscopic specimen images.Moreover, a paired Both detectors demonstrate accurate cell object detection and bounding box coordinate prediction for the mitotic cells, as shown in the example depicted in The pre-processed step for the HEp-2 specimen images using the CLAHE technique for contrast stretching improves the detection performance . SpecifiThe recent work of Gupta et al.  detects The execution time comparison for a single image detection is reported in Research studies for HEp-2 mitotic cell detection are limited in the literature. To the best of our knowledge, this is the first deep learning study to detect multiple mitotic cells directly from the microscopic HEp-2 specimen images of different HEp-2 interphase-type staining classes. As mentioned above, Gupta et al.  used theOn the other hand, all previous works that addressed the mitotic-interphase classification task were proposed on cell-level images. In particular, a small subset of carefully cropped mitotic cells was classified against another set of interphase cell images as provided in the I3A Task-3 dataset . AccordiThe limitations of this work are associated with the scarcity of medical annotated datasets for models’ training, which imposes the use of the DAL mechanism for automatic data annotation. As known, the DAL procedure requires intensive labor work, especially from the experts who are responsible for verifying and confirming the automatic labels of the machine. The similarity among the mitotic cells with some interphase cells confuses the deep learning detectors in some sense predicting FP and FN cases. Even so, we experimentally optimized the training parameters of both detectors to achieve the best detection performance and minimize the falsely detected cases. It is required to improve this framework to make detection for all cell types to develop a comprehensive one-shot HEp-2 cell detection framework, which is challenging due to the lack of an accurate annotation for all individual cell objects in each specimen image.A prospective future extension of this work is to extend the annotation task to include the interphase cell patterns of the HEp-2 specimen images to develop an end-to-end trainable framework for simultaneously classifying mitotic and interphase cell types directly from the microscopic HEp-2 specimen images. In contrast to recent related works such as that of Xie et al. , which aInspired by the recent success of using GANs for medical data augmentation , a potenMoreover, due to the high variability of different HEp-2 cell patterns and the limitation of accurately annotating a large number of microscopic images, it is significant to provide an uncertainty quantification (UQ) measure for the DL detectors’ predictions for a robust diagnosis ,83. ImprMitotic cell detection from the whole HEp-2 specimen images is a mandatory procedure to approve the correctness of the ANAs slide preparation and to support accurate classification for other interphase cell patterns. This paper presents an automatic deep learning framework to detect the mitotic cells directly from the microscopic HEp-2 specimen images. Due to the scarcity of the labeled dataset, the deep active learning (DAL) approach is involved in annotating the mitotic cells supporting the supervised deep learning models to achieve better detection performance. The experimental results demonstrated the superiority of the YOLO-based framework over the Faster R-CNN counterpart in this task. Data pre-processing via CLAHE improved the prediction performance of both YOLO and Faster R-CNN detectors by mAP of 4% and 7%, respectively. Moreover, the employed data augmentation techniques boosted the detection performance of the proposed HEp-2 mitotic cell detection framework by mAP of 7.5% and 8.3% for YOLO and Faster R-CNN, respectively. The proposed framework shows its capability and reliability to automatically detect multiple mitotic cells from diverse types of HEp-2 specimen images.