Testicular torsion is the reduction of blood flow to the testis after spermatic cord torsion. For patients, the diagnosis of testicular torsion is controversial and complicated by the fact that ultrasound blood flow signals are not significantly reduced in comparison to the unaffected, healthy, testis, despite persistent symptoms on the affected side. Our study aims to investigate the diagnostic characteristics of high-resolution ultrasonography (US) in pediatric testicular torsion with the preserved flow to increase diagnostic accuracy.Seven pediatric patients aged 49 days to 15 years old, with the preserved blood flow, but surgically diagnosed as testicular torsion, from October 2017 to August 2019, were retrospectively included in the study. The imaging manifestations of high-frequency ultrasonography were evaluated.All cases had preserved testicular blood flow, but the surgical findings showed various degrees of twist, from 90 to 540 degrees. Preoperative ultrasound showed spermatic cord distortion in all cases, and testicular long axis tilting in four cases (4/7 = 57.1%).In some testicular torsion cases, Color Doppler may show normal or increased blood flow signals in the testis. We should further observe the morphology and position of the testes and epididymides, the echo of the testicular parenchyma, and, especially evaluate the “whirlpool sign” in the spermatic cord, to avoid missing testicular torsion with blood flow signals. What is known about the subject: (1) Testicular torsion is a common scrotal emergency, occurring in pediatric patients. (2) Testicular torsion is the reduction of blood flow after spermatic cord torsion.-What this study adds: (1) Preserved intratesticular blood flow may lead to a false negative diagnosis. (2) The “whirlpool sign,” heterogeneous echotexture, appearances of the epididymis are the critical features in patients with the preserved flow.-Testicular torsion is a common scrotal emergency, occurring in 5–25% of pediatric patients –3. The fTesticular torsion is the rotation of the testis with torsion of the spermatic cord. This leads to vascular insult, which results in testicular ischemia and ultimately necrosis. To prevent testicular necrosis, an accurate and quick diagnosis is essential to determine the subsequent treatment . The golThe salvage rate is < 10% if revascularization is surgically corrected after 24 h in patients with testicular torsion –11. TherA testicular ultrasonography (US) is an ideal imaging tool for diagnosing testicular torsion before attempting surgical correction. Using Color Doppler, the vascularity of the testis can be evaluated. The reduction or absence of affected testicular flow has a high diagnostic accuracy with a sensitivity of 86–100%, and a specificity of 97.9–100% –14. ColoSo, the preserved intratesticular flow may lead to a false negative diagnosis , 19. TheA search using the keywords “torsion in scrotal or testicular torsion” was performed throughout the Electronic medical record system from October 2017 to August 2019, to retrieve patients with testicular torsion, who were confirmed by the surgery. Then, searching these testicular images throughout the Picture Archiving and Communication System (PACS), patients with an absence of blood flow to the testis and age over 18 years old were excluded from this study. In addition, testes with the preserved flow were included . We obtaThis is a retrospective study and no patient was involved.All sonograms were obtained with a 5–12 MHz linear transducer . The children were placed in the supine position, and the testes were evaluated in at least 2 planes: longitudinal and transverse. Transverse images were obtained in the superior, mid, and inferior portions of the testes. Longitudinal views were obtained centrally as well as medially and laterally. Each testis was evaluated in its entirety. All the examinations were performed according to the AIUM Practice Guideline for the Performance of Scrotal Ultrasound Examinations .We collected the position, size, morphology, internal echo, and the spermatic cord in the testis, epididymis, and testicular sheath cavity of pediatric patients. The size, echogenicity, and blood flow of each testis and epididymis were compared to the contralateral side. A comparison of the testes was accomplished with a side-by-side transverse image. Color Doppler sonography included at least 1 side-by-side image comparing both testes . TorsionThe statistical method was descriptive due to the small sample size. We used Excel for data description. We reviewed and analyzed case data on age, gender, and clinical manifestations. US findings, such as data on the position, size, morphology, internal echo, and the spermatic cord in the testes, epididymis, and testicular sheath cavity, were collected.In total, fifty seven pediatric ultrasound images with testicular torsion were identified from the PACS. Of these, 50 cases without detectable blood flow were excluded. Therefore, seven cases were included in the final study. All seven pediatric patients received surgery after US examination within 3 h and were surgically confirmed to have testicular torsion.The age of the patients ranged from 49 days to 15 years old. In addition, six patients (6/7 = 85.7%) had scrotal pain and swelling, and one patient (1/7 = 14.3%) who was 49 days old, had scrotal swellings, four (4/7 = 57.1%) on the left side and three (3/7 = 42.8%) on the right side. None of the patients reported a medical history of previous trauma. The demographics and clinical characteristics are summarized in The diseased testicles were enlarged. Furthermore, two of seven (2/7 = 28.6%) cases were inboard bean-shaped, four (4/7 = 57.1%) cases were tilted, and five (5/7 = 71.4%) cases had heterogeneous signals of the parenchyma. Fissure-free echogenic areas were seen around the mediastinum of the testis. Color Doppler showed that the blood flow of the testis parenchyma increased in three cases (3/7 = 42.8%) compared with the opposite side, and no significant difference was found in four cases (4/7 = 57.1%). Additionally, six patients (6/7 = 85.7%) had enlarged epididymis heads and increased blood flow. Testicular hydrocele existed in five cases (5/7 = 71.4%). The spermatic cords were twisted and presented as a “whirlpool sign” in all patients (7/7 = 100%), and the boundary with the epididymis was unclear, forming pseudotumor-like nodules beneath them. The overall results are displayed in All seven cases had unilateral testicular torsion, and all were intrathecal testicular torsions. Furthermore, two cases (2/7 = 28.6%) had a one-quarter twist (90 degrees), two cases (2/7 = 28.6%) had a two-quarter twist (180 degrees), one case (1/7 = 14.3%) had 360 degrees in torsion; and two cases (2/7 = 28.6%) were twisted at 540 degrees. The blood supply was preserved in four testicles (4/7 = 57.1%), and three cases (3/7 = 42.8%) had reversible ischemia. All 7 pediatrics were ended in orchiopexy. The matching surgical results are displayed in Testicular torsion is a time-dependent diagnosis, a true urologic emergency, and early evaluation can assist in urologic intervention to prevent testicular loss. Ultrasound is the ideal imaging modality to evaluate the scrotal contents –24. As tIn the present study, we investigated the ultrasonographic manifestations of testicular torsion with the preserved flow in 7 pediatric patients. The results indicated that the blood flow of the testis parenchyma was not absent, and increased in three cases (3/7 = 42.8%) compared with the opposite side. The present study provided ultrasonographic manifestations of testicular torsion with the preserved flow and indicated the clinicians focus on testicular torsion with preserved for early diagnosis.When twisted, testicles increase in size due to congestion in the parenchyma, presenting a full and spherical shape, which is often misdiagnosed as orchitis. Testicular volumes are easier for comparison to the other side. A difference in the size of the testicles on both sides, with the affected testis larger in volume than the asymptomatic side, is a crucial feature suggestive of testicular torsion , which iThe testes are commonly in an upright position. If the long axis of the testicle is inclined or even horizontal relative to the long axis of the thigh or long axis of the femur, especially if the orientation of the testicular mediastinum changes in the cross-section, it may indicate testicular torsion . In presTesticular torsion can be present with various degrees of twist, thus resulting in the heterogeneous parenchymal echotexture seen in testicular torsion. Assessing echogenicity is useful in predicting the likelihood of testicular salvage on scrotal exploration. The parenchymal echotexture of the affected testis, compared with the contralateral testis, has been used as an indicator for viability. Middleton et al.  demonstrObservation of the epididymis is also essential. Galina et al.  showed tThe epididymis is inevitably involved in torsion, and it is often enlarged. In our study, the epididymides were enlarged to varying degrees, which may be commonly misdiagnosed as epididymitis. An 8-year 3-month-old boy from the current study with a third episode of acute left scrotal pain for 5 days was initially misdiagnosed as epididymitis. In addition, the enlarged epididymis and convoluted spermatic cord are easily entangled together to form pseudo masses . The appThe diagnosis of torsion is based on a lack of blood flow in the testes or a marked reduction in blood flow in the affected testes . In the In the present study, all patients represented cases of intrathecal testicular torsion, which was confirmed by surgery, with various twisting states from 90 to 540 degrees. Taken together, the residual blood flow in all cases may be caused by intermittent or permanent spermatic cord torsion. In this case, the “whirlpool sign” was the crucial feature , which wA meta-analysis  showed tWith regard to the value of operator experience, the sensitivity for visualizing the spermatic cord twist with high-resolution ultrasonography was 81.8% in junior radiologists compared with 97.3% in senior radiologists . The “whIn patients with preserved blood flow, the position of the spermatic cord and other ultrasonic features should be assessed comprehensively, especially evaluate the full length of the spermatic cord.During the follow-up, 2 patients (2/7 = 28.5%) were lost. In addition, three patients (3/7 = 42.8%) underwent testicular ultrasound within 1 month after operation, 1 patient (1/7=14.3%) within 3 months, and 1 patient (1/7 = 14.3%) within 6 months, and ultrasound images indicated there were no complications in these testes at the operating side.This study had some limitations. First, the study has a small sample size. Second, all patients were tested by Color Doppler; however, resistive index (RI) and venous flow were not assessed. Third, we did not recruit normal volunteers as controls, but instead, used the opposite side of the healthy testes as the reference group. Fourth, the quality of a sonogram is dependent on the child's condition and the sonographer's skill, and these factors may have affected the results of this study. In future, prospective, double blind, case-control studies with larger sample sizes should be conducted to confirm our findings.In our retrospective study, 7 cases of testes with preserved flow, we can not diagnose testicular torsion based on Color Doppler. The results showed that testicular torsion was confirmed in all 7 patients after surgery. This gives us a great indicator, when we examine pediatrics with testicular swelling and pain, we should not give a diagnosis of testicular torsion only based on blood flow signals. Testes with Color Doppler flow signals might be obstacles to surgical exploration, with resultant testicular loss in false-negative cases. We should further observe the morphology and position of the testes and epididymis, the echo of the testicular parenchyma, and, especially evaluate the spermatic cord throughout its course, whether there is a “whirlpool sign” or not, so as to avoid missing testicular torsion with preserved flow.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Research Ethics Committee of The Second Affiliated Hospital of Wenzhou Medical University. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the National Legislation and the Institutional Requirements.Conception and design: ZX and HL. Administrative support: HL. Provision of study materials or patients: SN and JW. Collection and assembly of data: ZX and JW. Data analysis and interpretation: ZX and SN. Manuscript writing and final approval of manuscript: All authors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


As the coronavirus disease (COVID-19) spread, local governments in China adopted severe lockdown measures to control the pandemic. People were restricted from traveling for leisure, business, education, and medical treatment. Changes were observed in people’s psychological states as a result of COVID-19. This study aimed to construct a Stress Response Questionnaire based on the stress response theory for use with college students, to access their authentic mental health conditions and provide psychological intervention suggestions and countermeasures for the emergency plan formulated by the education department. The questionnaire was used to collect responses from a sample of 16,353 college students from 34 provinces in China. The results showed that anxiety levels varied by sex, current location, and pandemic region, each of which predicted different levels of emotional disturbance. Thus, we highly recommend that the Chinese college administration implement appropriate intervention programs and procedures to help college students maintain their mental health. The COVID-19 pandemic has caused a dramatic loss of human life, posing unprecedented challenges to public health, food systems, and the workplace. More than 500 million laboratory-confirmed cases were documented as of 26 July 2022 . In addiIn the wake of COVID-19, people have experienced significant disruptions to their work and daily lives. Many college students have even experienced stress responses. Additionally, the concept of stress was proposed by Selye, who believed that stress was the sum of an individual’s non-specific responses to external or internal stimuli, accompanied by psychological experiences of tension . Stress The stress response, according to the stress response theory, is a physiology–psychology–behavioral response caused by a combination of stressors and various mediators . The eveThe uncertain factors brought by COVID-19, such as increased employment difficulty, limited learning opportunities, and restricted life, have put college students under a variety of pressures for a long time, which has also had a huge impact on their physical and mental health ,18. MeasAccordingly, college students were selected as the research sample in this study. Based on the stress response theory, we took three important aspects  into consideration, and compiled the Stress Questionnaire for college students in the context of the COVID-19 pandemic. Additionally, using the questionnaire, we investigated the psychological health of college students during the pandemic. The aim is to provide evidence for a thorough understanding of the mental health status of college students during the pandemic. It also provides a reference for Chinese health and education departments to make mental health promotion plans and carry out psychological interventions.www.wjx.cn) [This study is divided into two sub-studies. For Study 1, we created a Stress Response Questionnaire for college students. Its reliability and validity were confirmed. Study 2 examined the mental health of college students during the COVID-19 pandemic in 34 Chinese provinces. The study was also designed in accordance with the principles of the Declaration of Helsinki. It was approved by the ethical authority of the School of Educational Sciences, Huazhong University of Science and Technology. Anonymous codes were assigned to the self-report questionnaires to manage confidentiality. From 29 January to 2 February, information about college students was gathered through an online questionnaire (.wjx.cn) ,26. The Sample 1: We collected questionnaires from 2046 college students. The factors were determined using exploratory factor analysis (EFA). Sample 2: We compiled a Stress Response Questionnaire that was tested by 2030 college students, and the final version of the questionnaire was proven to have good reliability and validity via confirmatory factor analysis (CFA). A total of 247 ineffective questionnaires were removed, possibly because respondents completed the questionnaire within 5 min or answered the same way for eight or more consecutive questions .This study theoretically constructed a Stress Response Questionnaire for college students based on the stress response theory and actual impacts on college students caused by COVID-19. In addition, the questionnaire compilation examined three important aspects: stress response, coping style, and social functioning. During the pandemic, the researchers interviewed college students and administered open-ended questionnaires to assess their mental health. Finally, 32 items were created after clarifying or removing items with unclear expressions or ambiguous contents. In addition, this questionnaire employed a 5-point scale, with 1 representing the least severe and 4 or 5 representing the most severe. The socio-demographic information section included age, sex, educational status, relationship status, and health status (whether or not participants were infected with COVID-19). SPSS 22.0 and AMOS 21.0 were used to conduct exploratory factor analysis and reliability and validity tests on the data.χ2 = 24,502.18, df = 496; p < 0.01), and Bartlett’s test of sphericity were significant, indicating that the data of the questionnaire met the criteria for EFA. Furthermore, combining principal component analysis with the gravel plot test yielded seven factors with eigenvalues greater than 1, and the cumulative variance explanation rate was 55.92%. Considering that the factor loadings ranged from 0.45 to 0.87, the structural validity of this scale was acceptable [The Kaiser–Meyer–Olkin (KMO) value test and Bartlett’s test of sphericity were applied to the prediction data of the questionnaires to confirm the suitability of the data for EFA. In the tests performed, both KMO, which had a value of 0.925 . The meaning of each item is as follows: Q1 , Q2 (I have been scared for no reason for the past week), Q3 (I have been easily upset or panicked in the past week), Q4 (I have been feeling sullen and depressed for the past week), Q5 , T1 (I have felt like I was losing weight for the past week), T2 , X2 (I am still interested in the things that I used to be in the past week), R5 (I think strangers are carrying the COVID-19 virus), J4 (I dare not speak to strangers), X3 , and Y5 . Second, social functioning, which consists of life disturbance, interpersonal disturbance, and emotional disturbance, included seven items . The meaning of each item is as follows: X1 (I have a hard time concentrating on things other than viruses), Y4 , J1 , J2 (I feel distant from or disconnected from crowds), Y2 , Y1 (I feel like I’m getting irritable or short-tempered), and Y3 (I am very troubled by this pandemic).Finally, coping style, which consists of risk coping, protective coping, information coping, stressful coping, and looking for social support, included 12 items . The meaning of each item is as follows: R1 (I think the pandemic is very serious now), R2 (I think I am in danger of COVID-19.), R3 (I think it is very likely that I have COVID-19), F2 (I think village-to-village (community-to-community) isolation is necessary), F1 , we will not be infected), R4 (I think COVID-19 can be cured), G1 , L4 , L1 (The sudden pandemic has made me very stressed), L5 (I feel like I’m becoming suspicious), L2 (I am actively looking for ways to relieve stress), and L3 (I am happy to tell my troubles to those close to me).Internal consistency reliability  and split-half reliability (Spearman–Brown) were employed in this study to test reliability on the basis of 2030 valid data points. The study results indicated that the overall internal consistency coefficient of the questionnaire was 0.872 and its overall split-half reliability was 0.736. These values meant that the questionnaire prepared in this study had positive reliability and could be used as a reliable research measurement tool.2/df = 5.916, CFI = 0.910, GFI = 0.925, NFI = 0.894, and RMSEA = 0.049, and the latent variable model constructed by the 30 items in the EFA had well-fitted data structure.CFA and correlation analysis were used to evaluate the construct validity of the questionnaire. According to the results of the EFA, the factors were named after deleting an item that could not be classified (J3). To adjust the items and factors, we used the stress response theory and the theoretical conception of the questionnaire structure, which allowed us to summarize the 31 items into 11 named factors. Using 2030 valid questionnaires, AMOS was used to perform CFA on the valid questionnaires. The Y3 item was removed during the process of constructing and debugging the model. As shown in An analysis of the correlation between dimensions was used to estimate the construct validity of the questionnaire. In In summary, the Stress Response Questionnaire for college students developed in this study consisted of three dimensions , with a total of 30 items. Among them, stress response consisted of emotional, somatic and behavioral responses, and included 11 items. Coping styles consisted of risk coping, protection coping, informational coping, stressful coping, and social support, and included 12 items. Social functioning consisted of life disturbance, interpersonal disturbance, and emotional disturbance, and included seven items. The indicators of the scale satisfy the psychometric requirements, with good reliability and validity, and can be used as a measurement tool for subsequent related research. The final version of the Stress Response Questionnaire for college students during the pandemic was used. As a result, 16,353 effective questionnaires were collected from college students from 34 provinces and autonomous regions of China (Hong Kong and Macao) between 29 January and 2 February 2020. Overall, 7850 females and 8503 males participated in the survey. The participants consisted of 13,084 undergraduates, 219 graduate students, 42 PhD students, and 3008 vocational students. Their average age varied from 19.79 ± 1.96 years. Ultimately, the investigations resulted in an effective response rate of 98.5%.t-test.SPSS 22.0 was used to perform descriptive statistics and an independent samples The results of the descriptive statistics showed that 48.4% of students were located in Wuhan , while 51.6% were located elsewhere in China. In addition, 40.89% of the questionnaires returned were from students living in cities near Wuhan, thus suggesting that nearly half of the students lived in Hubei province, the epicenter of the pandemic. Furthermore, 54.2% of all students came from townships  and 45.8% from cities (urban areas); additionally, 48% of the questionnaire respondents were females, while males comprised 52%. A total of 78.8% of all college students were single, 20.8% were in a relationship, and only 0.4% were married.Based on descriptive statistics, it was determined that the mean scores for emotional responses, physical responses, behavioral responses, life distress, interpersonal distress, and emotional distress were all lower than the theoretical mean (M = 2.41), thus indicating that college students showed weaker stress responses to the pandemic. The students had strong protective factors against the pandemic and were able to adopt protective measures effectively, as the average scores of risk coping, protective coping, stress coping, and seeking social support all exceeded the theoretical mean. The information coping rating was below the hypothetical average, which may be related to college students’ excessive attention to pandemic-related information.t-tests were conducted to test the significance of differences in the three demographic variables of sex, current location, and region for each dimension of psychological stress during the pandemic among college students  and behavioral response  than males, and preferred to adopt risk coping , protective coping  and stress coping  when encountering stress, whereas males preferred informational coping . However, females tended to seek social support, contrary to males , who seemed to meet more interpersonal disturbances than females  according to the data results. There were no significant sex differences in somatic response, life disturbances, and emotional disturbances.The results in t = 7.82, p < 0.001) and somatic responses  rather than emotional responses  , informational coping , stress coping , and in seeking social support . However, students who were inside Hubei province faced more life disturbances  and emotional disturbances  compared to those outside.The survey revealed that students who were inside Hubei province showed more behavioral responses ( < 0.05) . We alsot = −5.10, p < 0.001) and somatic responses , whereas they chose to take behavioral responses  in responding to the pandemic. Students in rural areas reported more protective coping  and informational coping  but less seeking of social support . There is also a significant difference in social functioning, since students in urban areas reported fewer life disturbances  and interpersonal disturbances .Regarding the dimension of the current region , students who came from rural areas reported fewer emotional  emotional response, (b) physical response, and (c) behavioral response. The factors mediating the relationship between stress and stimuli were also considered. Coping style may be regarded as an example of a mediating variable, which is essential in understanding the consequences of life distress . Risk coIn terms of sex, females had a more robust stress reaction to the pandemic than males ,33 and uMeanwhile, males were more likely to respond rationally to the pandemic, and they reached the goal of protecting themselves by paying close attention to the information. Tracing the evolutionary roots of sex differences, male resources and status are closely tied to mate choice in order to better survive and reproduce . Males wIn the course of the massive pandemic, regional differences existed in the psychological health of the general public . In HubeHigher emotional and physical stress responses were observed in urban students than in rural students. This difference may be due to the urban population density. The main routes of transmission of the virus are airborne droplet transmission and close contact transmission. Since cities have a larger population base and a higher likelihood of infection with the virus, the urban residents showed a higher emotional and somatic response. However, in the countryside, transportation, networks, and other facilities were not as reliable as in cities, resulting in a reduced flow of information, increased behavioral reactions, and a more significant impact on interpersonal relations for students. In addition, due to the lack of internet access in rural areas, people’s interactions relied more on face-to-face interactions. The pandemic made it necessary to maintain a certain distance from others in human interactions, which, in turn, exacerbated the life distress and interpersonal distress of rural residents and had a more significant impact on students’ interpersonal relationships.By investigating the mental health status of Chinese college students after the COVID-19 outbreak, it was found that female students had a stronger stress response than male students. The emotional response of college students in areas outside the pandemic center was slightly higher than that of students in the pandemic center, and they used social media to track the development of the pandemic more. In addition, students in rural areas had fewer emotional and somatic responses than those in urban areas because the countryside is far away from densely populated areas, where the pandemic was not easily developed. The government and university workers need to attach great importance to the mental health development of students and make timely interventions. It should be noted that although the data in this study came from the early stage of the pandemic, it is still relevant to comprehensively grasp the mental health status of college students and carry out targeted psychological counseling and educational guidance work at a time when the pandemic is normalized.Effective interventions can change people’s mindsets about stress . ResearcEducators can take several approaches to help students manage their stress. First, licensed mental health teachers can conduct cognitive enhancement practices to make students recognize why stress management is significant to their long-term health conditions  and their later generations. Second, courses related to mental health and effective thinking are also necessary. As a result of widespread misleading information, effective thinking courses would help students identify false and true information. When citizens cannot think critically and independently, they are easy prey for dogmatists, film artists, and those who offer simple solutions to complex problems . MoreoveIn general, a social support system is the most significant resource for emotional recovery from a catastrophe , and strFirst, the mental and physical health of students should be thoroughly assessed in schools by supporting the students, staff, and faculty. Second, the school administration should engage psychological counselors to gather basic information, conduct hierarchical screening, provide accurate assistance, and intervene promptly . Third, This study also has some limitations. First, the cross-sectional design of the study showed the correlation between the pandemic and the psychological state of college students. However, researchers should examine the extent of the pandemic’s impact on the mental health of college students in future longitudinal or interventional studies. Second, all the questionnaires we received were anonymous, and one limitation of the questionnaire is its subjectivity. Respondents may still be affected by social desirability, that is, showing behaviors that society hopes for, expects, and accepts. China is a country that particularly emphasizes collectivism , nationa


Pain and depression frequently co-occur. Due to its antidepressant and analgesic properties, ketamine has been used for the management of treatment-resistant depression and pain. This systematic review examined the literature on the efficacy of sub-anesthetic doses of ketamine in individuals experiencing comorbid depression and chronic pain (CDCP), as well as comorbid depression and acute pain (CDAP). A secondary objective was to provide an assessment of dosage, route, and adverse effects of ketamine treatment for CDCP and CDAP. A literature search was conducted on MEDLINE, PsycINFO, and Embase databases, coupled with a manual screening of the bibliography sections of included articles. In addition, registered ongoing and planned trials were searched on Clinicaltrials.gov. The end date of the search was April 9th, 2022. Included studies assessed changes in depression and pain in patients receiving at least one sub-anesthetic dose of ketamine. Assessment of quality was conducted using the GRADE checklist. Of the 7 CDCP clinical trials, 3 reported a reduction in depression and pain, 3 reported a reduction in depression or pain only, and 1 reported no improvement in either comorbidity. Among the 7 CDAP clinical trials, 4 studies found improvements in depression and pain while the remaining 3 reported improvements in only one parameter. Ten of the 12 case studies and 2 of the 3 observational studies assessing CDCP and CDAP found improvements in pain and depression scores post-treatment with effects of variable duration. The planned methodologies of the registered clinical trials are in line with those of the published research. Preliminary evidence supports the efficacy of ketamine in treating CDCP and CDAP. However, the current review identified a small number of heterogeneous studies with mixed results, preventing comprehensive conclusions. More longitudinal placebo-controlled studies are needed to identify the effects of ketamine for patients with CDCP and CDAP. DepressThe prevalence of pain symptoms in patients with depression and of depression symptoms in patients with chronic pain is higher than the prevalence rates of both conditions alone , 8. ApprOf similar concern is the presence of acute pain, which also commonly co-occurs with depression . Acute pain differs from chronic pain in its duration - in particular, acute pain is present for less than 6 months . PreviouKetamine has been used as an anesthetic agent for over 50 years. More recently, sub-anesthetic doses of ketamine have been shown to exert antidepressant and analgesic properties in the management of treatment-resistant depression (TRD) , 15 and A number of systematic reviews and meta-analyses have examined the role of sub-anesthetic doses of ketamine in the treatment of depression –29 and hAlthough ketamine has not been formally approved by the North American federal agencies  as a treatment modality for pain, it has been used to treat post-operative pain, chronic pain, complex regional pain syndrome, phantom limb pain, and other neuropathic conditions requiring analgesia . In systDespite previous efforts to systematically review the role of ketamine in the treatment of depression or pain  individually , 31, 33,2.This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The com2.1.2.1.1.(depression OR mood disorders OR major depressive disorder OR depress* OR affective disorders) AND  AND [ketamine(mh) OR S-Ketamine OR Esketamine]. The complete search strategy is provided in the Relevant studies published before April 9, 2022 were identified using the MEDLINE, PsycINFO, and Embase OVID databases. The search strategy was based on a combination of Medical Subject Headings terms including “ketamine”, “S-ketamine”, as well as indexed terms related to depression and pain: 2.1.2.https://clinicaltrials.gov/) using the terms: ketamine AND (depression OR postpartum depression) AND (pain OR cancer OR surgery), with no restrictions on the status of the study in the search. The complete search strategy is provided in the A search of past and ongoing clinical trials was conducted using Clinicaltrials.gov  clinical trials captured participants with depression, studies were excluded if the inclusion criteria did not require participants to have a depression diagnosis or symptoms as indicated by a valid rating scale.Articles that were excluded were animal studies, review articles, and papers written in a language other than English. In addition, duplicate results were removed. There were no restrictions on participant characteristics, such as sex/gender or age. Inclusion criteria for this review were either studies that had participants diagnosed with MDD by a psychiatrist according to the 2.3.The following information was extracted from each published study by two independent reviewers (A.B. and F.A.) using a standardized format: first author, year of publication, clinical diagnosis, participant characteristics , as well as sample size and study design. In regard to the administration of treatment, the following data were extracted: administration route , dose, and treatment duration. The data on outcome parameters related to measurement of depression and pain, treatment response, and remission rate, as well as adverse effects and study limitations were also extracted. In addition, data regarding sample size, clinical diagnosis, study design, treatment route and dose, as well as start, registration, and completion dates were extracted from the registered  clinical trials.2.4.The quality of the studies was assessed according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) checklist , 38, whiSelected placebo-controlled clinical trials were assessed to have a low risk for selection and performance biases, since 93% of them –50 used 3.3.1.The initial search yielded 1096 published papers and 28 registered  trials. Of these, 496 published articles were removed based on the exclusion criteria. This resulted in a total of 628 studies  that were examined for their titles and abstracts, as well as the full text, depending on their potential eligibility. Five additional studies were qualified based on the manual search of the references within eligible studies. At the full-text level, 599 studies  did not meet the inclusion criteria. This resulted in the final number of 29 published studies included in the present review  assessed CDCP and 12 (35%) assessed CDAP .3.2.1.When looking at the distribution of study types among those concerning CDCP, 7 out of 22 (32%) were published clinical trials, 2 out of 22 (9%) were observational studies, 11 out of 22 (50%) were case studies, and 2 out of 22 (9%) were registered clinical trials.3.2.2.When looking at the distribution of study types among those concerning CDAP, 7 out of 12 (59%) were published clinical trials, 1 out of 12 (8%) was an observational study, 1 out of 12 (8%) was a case study, and 3 out of 12 (25%) were registered clinical trials. The distribution of study types between CDCP and CDAP is illustrated in 3.3.N = 16 to N = 654 : specifically, ten studies had sample sizes over 100  published studies reported administering intravenous ketamine infusions.3.4.1.Of the seven clinical trials conducted among patients suffering from chronic pain symptoms and depression, three (43%) , 45, 46 3.4.2.via patient-controlled intravenous analgesia  (N = 6) (N = 5) (N = 4) (N = 11) (N = 7)  (N = 6) , 52, 65  (N = 6) , 54, 67. (N = 5) , 50, 55  (N = 4) , 56, 67.(N = 11) , followe (N = 7) –55, 66.  (N = 7) –62, 64 r3.5.1.Studies assessing CDCP used the following scales to measure depression scores: HADS, HDRS, Beck Depression Inventory (BDI), MADRS, State-Trait Anxiety Depression Inventory (STADI), and Center for Epidemiological Studies Depression-Revised (CESD-R). The following scales were used to measure pain scores: VAS, NRS, Brief Pain Inventory (BPI), Comparative Pain Scale (CPS), Neuropathic Pain Symptom Inventory (NPSI), McGill Pain Questionnaire (MPQ) and Edmonton Symptom Assessment System (ESAS).3.5.2.Depression scores in studies assessing CDAP were measured with the following: EPDS, BDI, Brief Edinburgh Depression Scale, Patient Health Questionnaire-9 (PHQ-9), HDRS, and MADRS. Pain was assessed with the following: VAS, NRS, and MPQ. More information about the frequencies of the measures across the published studies can be found in 3.6.3.6.1.The findings of the 14 clinical trials  , 69, 72 3.6.4.1.N = 4 and N = 80. The origins of the chronic pain were associated with cancer or chronic visceral pain. The ketamine treatments ranged from a dose of 0.125–0.5 mg/kg esketamine given intravenously to an oral 1.0 mg/kg administration given once a day for 12 weeks. Pain outcomes were assessed with the VAS while depression scores were assessed with the HADS, HDRS, and Quick Inventory of Depressive Symptomatology-Self Rated 16-item. More detailed information can be found in Two (40%) , 71 clin3.6.4.2.N = 45 and N = 564, while treatment doses ranged from 0.2 to 0.5 mg/kg administered intravenously. Pain outcomes were assessed with a rating scale such as the NRS while depression scores were assessed with the MADRS and HADS. More detailed information can be found in the Of the five registered trials, three (60%) looked at CDAP , 69, 72.3.7.There were a variety of acute adverse effects related to ketamine administration that were reported across the included published studies. Common adverse effects included nausea, vomiting, dizziness, and headache. Six out of 29 published studies , 59, 65 4.4.1.This paper systematically reviewed the literature examining the effects of ketamine administration on CDCP and CDAP symptomatology. Pain and depression symptoms commonly co-occur; for example, patients with depression are more likely to experience back pain while patients with back pain are more likely to experience depression , 8. TherExamination of the published literature identified a mixture of studies looking at ketamine efficacy for CDCP as well as CDAP. Therefore, the current review opted to include studies that investigated the effects of ketamine on depression and pain of various aetiologies and types . Across all studies investigating CDCP and CDAP, treatment protocols and findings were variable. However, reported adverse effects of ketamine administration were similar across studies looking at both CDCP and CDAP. There were only five registered (ongoing and planned) clinical trials to date: three assessing CDAP and two assessing CDCP.Forty-three percent of published clinical trials investigating CDCP found significant decreases in pain and depression scores, while the remaining reported conflicting results . One observational study found decreases in chronic pain and depression scores , while aAmong the published clinical trials investigating CDAP, the results also varied: trials concluded that reductions were found in either acute pain only (29%), depression symptoms only (14%), or both (57%). One observational study reported reductions in depression and pain . SimilarDue to heterogeneity in pain conditions, outcome measures, and treatment protocols across the included published studies, a meta-analysis was not considered feasible. This is based on guidelines suggesting that meta-analyses should only be conducted when studies are homogenous in terms of participants, design, and outcomes .4.2.4.2.1.Across published trials, ketamine was found to be efficacious at reducing pain and depression scores in CDCP. The open-label study  and two Surprisingly, one RCT found orally administered ketamine to be no more effective than placebo at mitigating symptoms of CDCP, including neuropathic pain in cancer . The aut4.2.2.The two observational CDCP studies that were included in the review make it difficult to establish a consensus in terms of findings. Corriger and colleagues  employedOverall, CDCP case studies reported a relatively fast treatment response and remarkable reductions in pain and depression symptoms, with variable durations of ketamine effect . This follows from various treatment regimens, including intravenous, intramuscular, and orally administered ketamine, suggesting that ketamine was generally effective. However, the bioavailability of oral ketamine is low, limiting its clinical use. Oral ketamine has extensive first-pass metabolism with only 17%–24% of oral racemic ketamine and 8%–11% of oral esketamine reaching systemic circulation . In contIn 50% of the case studies (including one CDAP report) –62, 64, 4.2.3.The analysis of registered clinical trials for ketamine treatment of CDCP provides insight into the direction wherein this field of research is moving. Though the search results were limited, the two included registered clinical trials were characterized by variability in terms of treatment protocols and patient populations. This is in line with the already published literature and may lead to obstacles when attempting to synthesize the results of the registered trials in prospective reviews. Like the majority of the published trials on the use of ketamine for CDCP, both registered trials were RCTs. Inconsistent with the published literature, ketamine was equally planned to be administered intravenously and orally. Dosages planned to be used in the registered clinical trials were in line with those of the published literature . While the published clinical trials and observational studies typically employed sample sizes over 100, the two registered trials opted for fewer participants. Taken together, these results suggest that the methodology of upcoming research on the use of ketamine for treatment of CDCP will, for the most part, be similar to that of existing research.4.3.4.3.1.A significant finding across the examined RCTs is the fast-acting, yet short-lived, effects of ketamine in attenuating depression symptoms and/or acute pain. Six of the seven RCTs reported rapid clinical reductions in acute pain following ketamine administration, with effects being observed within eight hours  to five Another key observation amongst these studies is the high variability of duration and onset of ketamine efficacy in reducing both (or either) acute pain and depression symptoms in comparison to one another. For example, one study  reportedFurthermore, the RCTs varied in the samples' characteristics, particularly in regard to the severity of their medical conditions: some samples consisted of pregnant women undergoing a caesarean section, while others involved intensive surgeries or life-threatening conditions . Therefore, it's difficult to deduce whether ketamine was equally effective in reducing depression and pain symptoms in each of these populations who varied in the severity of their condition. For example, the sample in Kudoh et al.  consiste4.3.2.In line with most RCTs, a single retrospective observational study by Wang et al.  determinIn contrast, a single case report by Nichols and colleagues  investig4.3.3.Consistent with the designs of the CDAP published studies, the three registered trials plan to utilize similar pain and depression scales  to measure the efficacy of ketamine in treating acute pain and depression symptoms in post-operative patients. In addition, the registered trials follow a randomized study protocol, which is consistent with the published RCTs. Moreover, the administration route of ketamine in the registered trials is parallel to that of the published trials, as ketamine will be administered intravenously with varied dosing regimens. Given these similarities, the effects of ketamine on CDAP can be better understood by examining a greater number of RCTs that are similar in study design, and therefore, more likely to produce more interpretable and conclusive results.4.4.A strength of the current systematic review is that it included both published and registered clinical trials to provide an up-to-date assessment of research that has been conducted in the field. Furthermore, this review examined research concerning depression co-occurring with acute and chronic pain to gain an understanding of how ketamine may be used to treat comorbid depression and pain of varying aetiologies and durations.The current review also has a number of limitations. First and foremost, the designs of the included studies were highly heterogeneous: there was a significant variation in inclusion and exclusion criteria of participants, presence of a control group, treatment protocol, primary and secondary measures, and length and frequency of follow-up, which makes it difficult to rule out possible confounding variables. Moreover, some of the studies in the present review  were of limited reliability, validity, and generalizability due to their lack of randomization and/or limited utilization of objective measures. The absence of randomization poses a risk for systematic bias caused by participants' expectations towards the treatment effects. Another important limitation is the high variability in terms of demographics of patient populations, which makes it difficult to hone in on which populations ketamine works most efficiently for. Lastly, another important confounder to consider is various aetiologies of pain included in the various selected studies. Given the diversity in the origins of pain including cancer-related chronic pain, neuropathic pain, or post-operative acute pain, it is difficult to determine whether ketamine is equally efficacious across different pain conditions.4.5.Across case studies, ketamine was most commonly found to reduce pain and depression symptoms of CDCP. The results of the included published clinical trials and observational studies are mixed, however, as they most commonly suggest that ketamine is effective at reducing both chronic pain and depression or only one of the two comorbidities. Similar to the CDCP literature, research on CDAP suggests that ketamine is effective at reducing both pain and depression, or either parameter individually. Further, the planned methodology of the registered clinical trials for depression and comorbid pain are in line with that of the published research, as they examine pain from various aetiologies with varied dosing regimens across studies. Longer follow-up periods are needed to better understand the long-term effects of ketamine and, in particular, possible changes in the course of CDCP or CDAP, including relapse and remission. Another future avenue for research would be to explore the effects of individual enantiomers on pain and depression. When comparing racemic and esketamine, the reviewed literature found esketamine to be more efficacious in reducing pain; however, one of its limitations was its potential to lead to psychotomimetic side effects. Existing literature suggests that arketamine may be a reasonable alternative with a better side effect profile and longer lasting anti-depressant effects. Future studies should compare esketamine, arketamine, and racemic ketamine at different doses to explore the efficacy of each enantiomer for the treatment of CDCP and CDAP. Studies should also examine whether increasing doses can potentiate effects and produce comparable results between enantiomers, as well as compare the range of side effects in different dose ranges.


To observe the efficacy of TKI inhibitor combined with PD-1 treatment in patients with early recurrence after radical resection of HCC, and to analyze the factors that affect the efficacy.The baseline demographic and clinical data of 58 patients with early recurrence after radical resection of HCC  were collected. Recurrence and metastasis were classified into early (< or =2 years) and late phase (>2 years). After systemic drug treatment , the efficacy was evaluated based on the RECIST 1.1 standard. COX regression model was used to analyze the factors affecting PFS and OS in HCC patients. Survival curves were drawn by Kaplan-Meier method.The study finally included 58 patients who underwent radical resection of HCC, of which 39 were in the TKIs group and 19 were in the TKIs + ICIs combined treatment group. There was no statistical difference in the baseline data of the two groups in HB, PLT, Child-Pugh score and other indicators. Efficacy evaluation results showed that in the 39 TKIs group, 7 patients were PD and 9 patients were PR; while in the 19 TKIs combined with PD-1 group, 2 patients were PD and 6 patients were PR. The median PFS of the TKIs group was 6.2 months, while the median PFS of the TKIs combined PD-1 group was 14.0 months . The median OS of the TKIs group was 18.0 months, while the median OS of the TKIs combined with PD-1 group was 35.8 months, an extension of 17.8 months .In the first-line treatment of patients with early recurrence after radical resection of HCC, patients treated with TKIs combined with PD-1 therapy has a survival advantage over those treated with TKIs alone. Ascites, HBV DNA positivity, and high levels of AFP often indicate poor efficacy of systemic drug therapy, suggesting that such patients should be closely monitored after surgery and that comprehensive systemic treatment should be administrated in time to improve the prognosis. Primary liver cancer has become the 4th common malignant tumor and the 3rd cause of tumor death in China . The maiAlthough surgical resection is the best treatment for HCC, the postoperative prognosis of patients is not ideal. Recurrence occurs in most patients with early HCC after radical operations such as surgical resection, liver transplantation. At present, HCC patients who relapse after radical surgery are mainly administrated with systemic treatment drugs for advanced liver cancer, including etiological treatment, chemotherapy, targeted drug therapy, checkpoint inhibitors (ICIs) and liver protection therapy. Agents targeting epidermal growth factor receptor (EGFR), mainly including tyrosine kinase inhibitors (TKIs), such as sorafenib or lenvatinib, have been approved as first-line drugs for the treatment of advanced liver cancer –6.The mechanisms of early recurrence and late recurrence after radical resection of HCC are completely different. Patients with early recurrence of HCC (within 2 years) may be related to vascular invasion and residual neoplastci foci , 8. AlthThe subjects of the study were patients with recurrence of intrahepatic tumors after radical operation  of HBV-related HCC at Nanjing Jinling Hospital and Shanghai Changzheng Hospital between March 2018 and September 2020. The cohort study design was adopted. Patients involved in this study were regularly followed up, and information of postoperative diagnosis and treatment were collected. The research protocol complies with the ethical code of the 2008 Declaration of Helsinki, and all the research subjects signed an informed consent form.The inclusion criteria include: a. Patients pathologically diagnosed with HCC; b. Radical operation of HCC, including patients after resection or liver transplantation; c. Recurrence within 2 years after surgery; d. Age ≥18 years; e. Informed consent.The exclusion criteria include: a. Other pathological types of HCC, including intrahepatic cholangiocarcinoma and mixed liver cancer; b. Patients who have not undergone radical operation of HCC in the past, or have distant metastases; c. Patients with poor general conditions after radical operation, or not suitable for systemic treatment for other reasons; d. Patients who relapse more than 2 years after surgery; e. Patients who refuse to participate in this study.After inclusion and exclusion stated above, 58 patients were finally enrolled in the final analysis Figure 1For the patients enrolled in this study, in addition to the clinical information after the previous radical operations of HCC in the medical records, information on the subsequent systemic treatment was also collected. The systemic drug treatments involved in this study include 1) oral sorafenib treatment, 400mg, 2/day; 2) oral lenvatinib treatment, body weight ≥60kg, 12mg, 1/day; body weight <60kg, 8mg, 1/day; 3) nivolumab, ivgtt, 3 mg/kg, every 2 weeks; 4) pembrolizumab, ivgtt, 200 mg, every 3 weeks; or 5) toripalimab, ivgtt, 3 mg/kg, every 2 weeks. After the above-mentioned standardized systemic drug treatment, the RECIST 1.1 standard was referred to evaluate the changes in the target lesions in the liver every two months, including disease progression (PD), stable (SD), and partial remission (PR). In addition, follow-up information is fully recorded. All collected patient-related information is accurately entered into computer for subsequent statistical analysis.Data are all sorted and analyzed using SPSS 18.0 software. COX regression model was conducted to analyze the influence of subgroup factors on PFS and OS in HCC patients, and multivariate analysis was conducted to determine independent risk factors. The survival curve was drawn using the Kaplan-Meier method. The impact of risk factors on the disease outcome was evaluated by HR (hazard ratio). A two-tailed P value less than 0.05 was considered to be statistically significant.This study finally included 58 patients with HCC recurrence after radical operation, including 39 patients in the TKIs group and 19 patients in the TKIs + ICIs combined treatment group. In the TKIs group, 16 patients were under 50 years old, 19 patients were 50 to 60 years old, and 4 patients were over 60 years old. In the TKIs + ICIs combined treatment group, the above three groups were 5, 4, and 10 cases, which is statistically different from the TKIs group (P=0.002). There were more males in the TKIs group compared with the TKIs + ICIs combined treatment group . There was no statistically significant difference in HB, PLT and other indicators between the two groups. The two groups were comparable at the baseline level Table 1.In the TKIs group, the efficacy evaluation showed that there were 7 patients with PD, 9 patients with PR, and the remaining 23 patients with SD. In the TKIs + ICIs combined treatment group, the efficacy evaluation showed that 2 patients were with PD, 6 patients were with PR, and the remaining 11 patients were with SD. On the whole, after TKIs combined with PD-1 treatment, HCC in the TKIs + ICIs combined treatment is more efficient than TKIs alone Figure 2Univariate COX regression analysis was conducted to determine the effect of treatment group on PFS and OS. The median PFS of the TKIs treatment group and TKIs + ICIs combined treatment group were 6.2 months and 14.0 months . The median OS of the TKIs treatment group and TKIs + ICIs combined treatment group were 18.0 and 35.8 months, respectively  Figure 3Furthermore, the impact of the above-mentioned baseline biochemical and virological indicators on the OS was analyzed. The results of univariate COX regression analysis showed that patients with ascites had poorer OS than those without ascites, HR (95% CI): 2.611 (1.157-5.892) (P=0.021); patients with positive HBV DNA also had poorer OS than those without, HR (95% CI): 3.451 (1.309-9.102) (P=0.012); patients with high AFP expression, HR (95% CI): 3.631 (1.449-9.097) (P=0.006) Table 2.The prognosis of advanced HCC is poor, with high recurrence and mortality rate. Early HCC is often treated with radical operations including surgical resection, liver transplantation, and radical TACE , 12. At In recent years, the research of molecular targeted drugs in the treatment of HCC has gradually received attention, and multi-kinase inhibitor drugs represented by sorafenib have been widely used in clinical practice. As PD-1/PD-L1 pathway inhibitors were approved by the FDA, immunotherapy targeting immune checkpoints has attracted widespread attention as a new choice for HCC patients. For example, in September 23, 2017, based on the results of the CheckMate 040 trial, the U.S. FDA accelerated the conditional approval of nivolumab as a second-line treatment for HCC, which marked that HCC immunotherapy had advanced to a new stage . In addiCompared with the research of similar drugs abroad, the underlie disease of the research participants in our country is more complicated. For example, the proportion of patients with HBV infection was higher (83.9%), the proportion of subjects with BCLC stage C was as high as 94.9%, the proportion of subjects with extrahepatic metastasis was 81.6%, and patients with AFP≥400ng/mL accounted for 51.2%. The results of this study showed that the median PFS of the TKIs treatment group was 6.2 months, while the median PFS of the TKIs combined with PD-1 treatment group was 14.0 months. The median OS of the TKIs treatment group was 18.0 months, and the median OS of the TKIs combined with PD-1 treatment group was 35.8 months. This is probably attributed to chronic HBV infection, with severe general condition and poor prognosis after recurrence .This study observes and analyzes the efficacy of systemic treatment in patients after radical resection of HCC. Several limitations should be addressed: (1) This is an observational study, in which grouping cannot be randomized. Patients were enrolled from a single center, which made it impossible to avoid some potential confounding biases. (2) The sample size of this study is limited. To some extent, the reliability of the results of the study remained to be improved. (3) The treatment of patients cannot be basically consistent as in clinical drug registration trials. This study is non-interventional, which may lead to bias in the results. This study has preliminarily obtained the curative effect of systemic treatment after radical resection of HCC. Based on the above-mentioned research limitations, it is hoped that follow-up research can overcome the above limitations and obtain more comprehensive research conclusions.In summary, systemic treatment after liver cancer surgery can positively and effectively improve the survival of patients. Specific populations can choose TKIs combined with PD-1 therapy as the first-line treatment to improve the prognosis of HCC recurrence.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Medical Ethics Committee of Nanjing Jinling Hospital. The patients/participants provided their written informed consent to participate in this study.XC and YZ conceived of and designed the study. ZL, NH, and XR performed the literature search, generated the figures and tables, and wrote the manuscript. ZL, NH, and XR collected and analyzed the data, and critically reviewed the manuscript. XC and YZ supervised the study and reviewed the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by Natural Science Foundation of Jiangsu Province (BK20200275), and “Pyramid Talent Project”, a three-year action plan for talent development of Second Affiliated Hospital of Naval Medical University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: This study aims to evaluate the diagnostic performance of Deep Learning (DL) machine for the detection of adenomyosis on uterine ultrasonographic images and compare it to intermediate ultrasound skilled trainees. Methods: Prospective observational study were conducted between 1 and 30 April 2022. Transvaginal ultrasound (TVUS) diagnosis of adenomyosis was investigated by an experienced sonographer on 100 fertile-age patients. Videoclips of the uterine corpus were recorded and sequential ultrasound images were extracted. Intermediate ultrasound-skilled trainees and DL machine were asked to make a diagnosis reviewing uterine images. We evaluated and compared the accuracy, sensitivity, positive predictive value, F1-score, specificity and negative predictive value of the DL model and the trainees for adenomyosis diagnosis. Results: Accuracy of DL and intermediate ultrasound-skilled trainees for the diagnosis of adenomyosis were 0.51  and 0.70 , respectively. Sensitivity, specificity and F1-score of DL were 0.43 , 0.82  and 0.46 (0.42–0.50), respectively, whereas intermediate ultrasound-skilled trainees had sensitivity of 0.72 , specificity of 0.69  and F1-score of 0.55 . Conclusions: In this preliminary study DL model showed a lower accuracy but a higher specificity in diagnosing adenomyosis on ultrasonographic images compared to intermediate-skilled trainees. Adenomyosis is a benign gynecological disease described by the presence of endometrial glands and stroma within the myometrium, as well as reactive hyperplasia and hypertrophy of the muscular layer . AdenomyPathological examination of myometrial specimen remains the gold standard for the diagnosis of adenomyosis and its estimated prevalence ranges from 21% to 36% among hysterectomized women. However, only a small, selected percentage of symptomatic women with adenomyosis undergoes hysterectomy, and the real prevalence of the disease is underestimated ,8,9.Transvaginal ultrasound (TVUS) represents the method of choice for the non-invasive diagnosis of adenomyosis with adequate sensitivity and specificity ,11,12. SDespite being low cost and easily accessible, TVUS has some limitations for the diagnosis of adenomyosis. It is an operator-dependent technique with adequate diagnostic performance and inter-operator reproducibility only if performed by expert sonographers ,14,15. IRecently, the need to improve efficiency in all clinical settings using technological advances led to the development of powerful instruments such as artificial intelligence (AI) . AI is dAI applicability for healthcare purposes has already been partially investigated and has shown promising results in several medical fields, including gynecology. In particular, AI in gynecological studies was tested for several tasks on medical images, including discriminating malignancy or benignity of ovarian masses, diagnosing cervical cancer, staging endometrial cancer, or diagnosing rectosigmoid endometriosis ,19,20.To the best of our knowledge, no study has ever assessed the accuracy of DL in the diagnosis of adenomyosis using TVUS. Therefore, the aims of this study are to first evaluate the diagnostic performance of DL in the diagnosis of adenomyosis on uterine ultrasonographic images and compare it to that of intermediate ultrasound skilled trainees.This was a proof-of-concept, monocentric, observational, cross-sectional study, conducted in a tertiary academic centre. The whole study followed an a priori protocol previously drawn up according to STROBE guidelines and checklist .Exclusion criteria were as follows: age less than 18 years old, virgo intacta status, ongoing or recent (less than 6 months) pregnancy, suspicion of gynecological malignancy, previous hysterectomy, menopausal status, coexistence of adenomyosis and fibroids at TVUS. From 1 to 30 April 2022, all eligible consecutive women referring to our tertiary gynecological ultrasound clinic were consecutively asked to participate to the study.Accuracy was used as the primary evaluation metric for the diagnostic performance of DL machine in the diagnosis of adenomyosis at 2D gray scale mode TVUS images. Accuracy is a statistical measure of how well a binary classification test correctly identifies or excludes a condition, that is, the proportion of correct predictions (both true positives and true negatives) among the total number of patients examined.Other metrics used to measure accuracy from different perspectives were the following: recall (sensitivity), precision , F1-score , specificity and negative predictive value (NPV). The same metrics were used to assess the performance of intermediate skilled trainees for the diagnosis of adenomyosis and were informally compared with those obtained with DL machine.Secondarily, all the measures listed above were calculated using the diagnoses of fibrosis and homogeneous echogenicity as reference.For each patient, anamnestic and clinical data were acquired as follows: age, body mass index (BMI), parity, history of infertility, previous endometriosis surgery, moderate-to-severe pain symptoms defined as numerical rating scale (NRS) equal or superior to 5 , heavy mVoluson E8 ultrasound machine  with a 4–9 MHz volumetric vaginal probe was used for all acquisitions. Ultrasound scans were obtained with patients in a modified lithotomic position. During the 2D gray scale mode TVUS examination, an expert sonographer classified uteruses in three groups: homogenous myometrial echogenicity, fibroids or adenomyosis.Adenomyosis was diagnosed when two or more of the following sonographic criteria were present: globular uterus appearance, asymmetrical thickening, hypoechogenic myometrial cysts, hyperechoic islands, fan-shaped shadowing, echogenic subendometrial lines and buds, junctional zone irregolarities ,3,8. OthFor each patient, presence of deep endometriotic lesions and endometrioma was also investigated according to IDEA consensus ,26.An end-to-end DL model was developed for the classification of uterine images. Sequential ultrasound images including uterine corpus and cervix were extracted from ultrasound video clips by an automatic system. Manual segmentation was performed by the experienced sonographer. Uterine boundaries were manually traced in the sagittal scan including a region of interest (ROI) that clearly highlighted ultrasound features of adenomyosis or fibroids, according to literature. These ultrasound images were used for the construction, validation and testing of the DL system. n = 30), validation (n = 30) and testing set (n = 40). The training set was used to train the network by teaching it the parameters of the models. Two architectures were considered: ResNet and Vgg. Among these, Vgg13, Vgg19, ResNet 18 and ResNet 34 models were used.The available dataset of 100 ultrasound video clips was divided in a random and balanced way into three parts: training  was used as a sampler and Successive Halving Pruner (SHP) as a pruner. To reduce over-fitting, data augmentation was also applied, which generates additional training models using random image transformations. To this end, the captured images were extracted with the resolution reduced from 300 × 300 pixels to 224 × 224 pixels, random horizontal flips and vertical flips were employed and Gaussian blur was applied.The test set was used to independently assess the generalization error for the final models chosen.Diagnostic performance of each DL models was acquired.For each patient, uterine images were acquired for storage using short video clips (8–10 s). The uterus (cervix and corpus) was filmed in a sagittal plane and with a lateral left-to-right movement of the probe, using a grayscale mode. Videoclips were downloaded in Mp4 format from the hospital image database system and then de-identified prior to being reanalyzed by three intermediate ultrasound skilled trainees. These trainees were 4th year residents in O&G with intermediate ultrasound skills (consisting of more than 500 gynecologic ultrasound cases) doing their postgraduate studies in endometriosis management . The traNumerical variables were summarized as mean ± SD or median (95% CI); categorical variables were summarized as counts and percentages. Chi-squared test, Fisher’s exact test and variance analysis were used for comparison of categorical and numerical variables, where appropriate.To compare the performance of the best DL model with that of the best trainee in diagnosing adenomyosis, accuracy, sensitivity, positive predictive value (PPV), F1-score , specificity and negative predictive value (NPV) were calculated.Analyses were conducted using Stata 15 software . The significance level was set at 5%.The study protocol received approval by the local Ethics Committee (114/2022/Oss/AOUBo). All patients signed an informed consent before entering the study, and all data were anonymized.During the study period, 100 eligible patients were enrolled. Ultrasound diagnosis by expert operator were as follows: 45 patients with homogeneous echogenicity of the myometrium, 30 with fibroids and 25 women with adenomyosis.2, respectively. There was no significant difference in terms of baseline data among the three study groups, except for age, rate of spontaneous delivery and heavy menstrual bleeding, which were higher in the fibroids group, while previous surgery for endometriosis was more frequent in the adenomyosis group.Baseline and clinical characteristics are summarized in Sonographic signs suggestive for adenomyosis in the “adenomyosis group” diagnosed by expert operator are reported in -n = 1645 homogeneous echogenicity, n = 1071 fibroids, n = 836 adenomyosis;Training set: -n = 481 homogeneous echogenicity, n = 336 fibroids, n = 252 adenomyosis;Validation set: -n = 495 homogeneous echogenicity, n = 359 fibroids, n = 336 adenomyosis.Testing set: After the application of data augmentation, number of uterine images were as follows:Confusion matrix of the DL for the testing set is shown in As reported in Regarding fibroids diagnosis, DL model reached sensitivity, specificity and F1-score of 0.57 , 0.73  and 0.52 (0.48–0.56), respectively, with an accuracy of 0.68 . Intermediate ultrasound skilled trainees had sensitivity of 0.63 , specificity of 0.82 , F1-score of 0.61  and accuracy of 0.77 . Positive predictive value and negative predictive value for the diagnosis of fibroids were 0.47 (0.42–0.52) and 0.80 (0.77–0.83) for DL, and 0.61 (0.43–0.76) and 0.84 (0.74–0.91) for trainees, respectively.Despite AI recently gaining popularity in the field of medical imaging and has experienced increased its applications in gynecology, no study has ever used this tool in the diagnosis of uterine adenomyosis. Therefore, this study can be considered a proof-of-concept for this issue.Recently, DL based on artificial neural networks with representation learning has been adopted to help operators to untangle among differential diagnoses.In the present study, the DL model showed a low accuracy in the diagnosis of uterine adenomyosis (51%). This observation may reflect the complexity of the disease. Indeed, adenomyosis is a heterogeneous disease that can have several phenotypes, varying per extension  and location  within the myometrium ,11.As secondary finding, the accuracy of intermediate ultrasound-skilled trainees (70%) resulted higher than that of the DL. Moreover, these trainees showed a higher sensitivity (72%) but a lower specificity (69%) compared to those of the DL. This over-diagnosis could be explained by the tertiary center setting in which frequency of adenomyosis is estimated higher than general population and the offline assessment of uterine images instead of personal execution of TVUS. Conversely, the DL model showed a higher specificity, being more effective in identifying healthy uteruses, with low false positive values. Indeed, the DL model could be a useful tool to exclude adenomyosis where it is not present and disprove the over diagnosis of less experienced operators, avoiding unnecessary second-level examinations or over treatment cases.Limitations of our study are the small sample size and the monocentric design, reducing the generalizability of our results. Larger multicentric studies are needed to better evaluate the potential clinical aid of AI in the diagnosis of adenomyosis. Although the lack of histological confirmation of adenomyosis may be considered another limitation of the study, pathological examination is unethical in patients without any indication for surgery. On the other hand, to date, an experienced sonographer must be considered an adequate alternative to histological diagnosis in women who are asymptomatic or have not completed their reproductive plan.The impossibility to fully investigate the JZ by using 3D-TVUS examination and to evaluate translesional vascularity through Power Doppler mode may have influenced the diagnostic performance of the expert sonographer firstly and then that of the trainees and the DL machine.In order to improve the diagnostic performance of the DL in diagnosing adenomyosis, future research can be focused to specific training of the DL machine on the recognition of each of ultrasound criteria suggestive for adenomyosis. Moreover, more studies are needed to evaluate any improvement of DL performance, adding other sonographic signs  and/or clinical data .In this proof-of-concept study, the DL model achieved a low diagnostic performance for the detection of adenomyosis with accuracy of 51%, lower than that of intermediate skilled trainees. Sensitivity and F1-score of the intermediate skilled trainees were higher than those of DL as well. However, DL model showed potential for excluding adenomyotic uteri, with higher specificity and NPV than those of intermediate skilled trainees.Larger multicentric studies with adjuvant investigation of JZ by 3D-TVUS and translesional vascularity through Power Doppler are needed to better evaluate the potential clinical application of AI in the diagnosis of adenomyosis.


Purpose: To investigate the effectiveness and safety of negative-pressure wound therapy (NPWT) in treating primary spinal infections. Methods: Patients who underwent surgical treatment for primary spinal infection between January 2018 and June 2021 were retrospectively evaluated. They were divided into two groups based on the type of surgery: one that underwent negative-pressure wound therapy (NPWT) and another that underwent conventional surgery . The two groups were compared in terms of the total operation time, total blood loss, total postoperative drainage, postoperative pain score, time for the postoperative erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to return to normal, postoperative complications, treatment time, and recurrence rate. Results: A total of 43 cases of spinal infection were evaluated, with 19 in the NPWT group and 24 in the CVSG group. The NPWT group had a superior postoperative drainage volume, antibiotic use time, erythrocyte sedimentation rate and CRP recovery times, VAS score at 3 months after the operation, and cure rate at 3 months after operation compared with the CVSG group. There were no significant variations in the total hospital stay and intraoperative blood loss between the two groups. Conclusions: This study supports the use of negative pressure in the treatment of a primary spinal infection and indicates that it has a notably better short-term clinical effect than conventional surgery. Additionally, its mid-term cure rate and recurrence rate are more desirable than those of conventional treatments. The number of spinal infections is gradually increasing . FortunaOwing to the difficulty of achieving complete debridement with minimally invasive spine surgery, open debridement and internal fixation remain the standard surgical treatments for spinal infections. Conventional open surgery, however, causes increased trauma, a longer operation time, and more blood loss, which may be too much for patients in a poor condition to tolerate. Single open spinal fusion surgery for spinal infections carries a greater risk of recurrence, thus necessitating the development of a minimally invasive spinal surgery method with complete debridement for the surgical treatment of spinal infections.Negative-pressure wound therapy (NPWT) has been widely recognized for its therapeutic benefits to soft tissue infections, limb bone infections, and chronic refractory wounds since its introduction in the 1990s. Numerous studies have been conducted to assess the efficacy of NPWT in the treatment of bone and soft tissue infections. Luo et al. reported the successful treatment of 12 patients with sacroiliac joint tuberculosis (TB) using NPWT, with an improved hospital stay and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) decrease rates compared with conventional treatments . AdditioA retrospective study was conducted to evaluate the efficacy and safety of negative-pressure wound therapy (NPWT) as an adjunct to surgical debridement in spinal infections, and the results were compared with those of a control group of patients who underwent conventional surgery and open packing during the same period.This study included patients who were admitted between 1 January 2018 and 31 June 2021, and had been clinically diagnosed with lumbar infection without spinal cord injury. Post-surgery, a single type of drainage  was applied. The Ethics Committee of the 960th Hospital of the PLA approved this investigation . Exclusion criteria included receiving both negative-pressure drainage and traditional drainage, having concomitant spinal deformity, being diagnosed with sepsis, and having a postoperative observation of less than one year.In this retrospective study, the grouping method was based on staged negative-pressure drainage (NPWT) or traditional primary debridement and bone graft fusion internal fixation (CVSG). A comparison of gender, age, data related to the surgery, and postoperative monitoring indicators was conducted on two groups of patients who had all received surgical treatment and were observed for more than a year .This study included a total of 43 individuals, consisting of 26 males and 17 females, with an average age of 57.33 years. A total of 19 patients tested positive for bacterial cultures in the two groups, all of whom were administered antibiotics sensitive to their disease, with the traditional drainage group having 3 cases of Staphylococcus aureus, 2 cases of coagulase-negative staphylococcus, 1 case of tuberculosis bacillus, 1 case of Escherichia coli, 1 case of Klebsiella pneumoniae, and 1 case of an unidentified Gram-negative bacillus. Meanwhile, the negative pressure drainage group had 1 case of Staphylococcus aureus, 2 cases of coagulase-negative staphylococcus, 1 case of Escherichia coli, 1 case of Klebsiella pneumoniae, 2 cases of Streptococcus vivostreus, and 3 cases of an unidentified Gram-negative bacillus.We selected the most effective antibiotics to use based on drug sensitivity tests. If this was not feasible, then antibiotics with a wide spectrum of activity were utilized. Intravenous therapy was used during hospitalization, then changed to oral medication after discharge until clinical recovery. The clinical treatment criteria included the following: symptoms, body temperature, and erythrocyte sedimentation gradually returning to normal; lower-back pain symptoms significantly improving; imaging showing that the abscess had disappeared, intervertebral calcification, resorption of dead bone, fibrosis or ossification, and bone bridge formation; and MRI revealing that the inflammatory changes had disappeared and the signals of the vertebral body and surrounding tissues were normal. It was expected that the patient would be able to maintain the aforementioned standards while living and working as normal for a period of six months.The surgical methods in the NPWT group were: a one-stage debridement with negative-pressure drainage and internal fixation, and a two-stage iliac bone grafting. The negative-pressure sponge  should bThe total operation time, intraoperative blood loss, postoperative drainage volume, duration of hospitalization, and visual analog scale (VAS) were all documented for each patient in both groups. Additionally, CRP, ESR, and blood routine were regularly monitored during the hospital stay. Upon discharge, the patients were followed up on a bi-weekly basis for the same indicators. Follow-up continued after the patients left the hospital, with outpatient visits conducted on the 1st, 3rd, 6th, and 12th months post-surgery. This enabled the medical team to analyze data such as the time of antibiotic use and when the ESR and CRP returned to normal, and to assess the patient’s overall condition.t-test and Pearson’s chi-squared analysis were conducted for the continuous and categorical variables, respectively. Statistical significance was set at an alpha level of less than 0.05.The SPSS 22.0 software package was utilized to analyze the data, which were expressed as the mean ± standard deviation. Student’s The average duration of follow-up was 33.28 ± 11.86 months, with the range being between 16 and 56 months. The NPWT group consisted of 19 patients, 12 males and 7 females, with an average age of 59.00 ± 9.68 years. The infection sites included 3 cases of thoracic spine, 1 case of thoracolumbar spine, and 15 cases of lumbar spine. The CVSG group was made up of 24 patients, 14 males and 10 females, with an average age of 56.00 ± 16.30 years. The infection sites were 3 cases of thoracic spine, 1 case of thoracolumbar spine, and 20 cases of lumbar spine see . There wp < 0.05).The results of the comparison between the NPWT and CVSG groups in terms of surgical outcomes are presented in The NPWT group showed significantly better results than the CVSG group in terms of the antibiotic usage duration (4.13 ± 1.38 months vs. 5.60 ± 2.28 months), time for ESR to return to normal (53.11 ± 33.57 days vs. 91.64 ± 50.07 days), time for CRP to return to normal (47.11 ± 30.67 days vs. 74.23 ± 45.87 days), VAS score at 3 months after surgery (1.47 ± 0.77 points vs. 2.50 ± 1.38 points), and cure rate at 3 months after surgery (13 cases vs. 0 cases). Moreover, the NPWT group had a significantly higher mid-term cure rate and lower recurrence rate 12 months after surgery than the CVSG group .The prevalence of spinal infections is on the rise due to the accelerated aging process, improved diagnosis, and larger susceptible population. Drug-resistant strains are two and a half times more common than in the general population . TreatmeNWPT is effective in extracting exudate, pus, and other substances through the application of negative pressure. Furthermore, NPWT is able to break down large, soft tissues and secretions into smaller particles, which can then be aspirated. An even suction pressure is applied to the surface of polyvinyl alcohol (PVA), forming a drainage system that extends in all directions. Sequestrum, pus, and bloodless tissues are known to have the lowest concentrations of drugs in the bloodstream, making them more susceptible to the development of drug-resistant bacteria and bacterial biofilms, which are major contributors to recurrent infections ,19,20. PPresently, the traditional surgical approach to spinal infection is debridement, drainage, and bone grafting and internal fixation for patients with spinal instability. However, this type of operation can be lengthy and cause a great deal of trauma and bleeding, as well as potentially not completely debriding the area. Additionally, individuals with preexisting medical issues have a significantly higher rate of severe complications and mortality following the procedure compared with individuals without preexisting conditions ,23. In aThe treatment of spinal infection involves two distinct processes: controlling the infection and repairing the tissue defect at the site of infection, which includes bone and soft tissue repair. Conventional methods typically address these two processes concurrently. However, the use of negative-pressure wound therapy (NPWT) temporally separates infection control and tissue repair, allowing for tissue repair to occur after the infection has been cleared. This technique has been shown to increase the cure rate and decrease the recurrence rate of spinal infections. Additionally, NPWT reduces local edema and bacterial loads, destroys the local biofilm, and attracts pus and small necrotic tissue out of the body, improving local blood circulation and blood concentration at the site of infection. As such, NPWT is superior to conventional surgical techniques for treating primary spinal infections, and the use of a second-stage iliac bone transplant further reduces the surgical difficulty and danger of anesthesia.This study reveals that NPWT technology has a notably better short-term clinical effect than conventional surgery, and its mid-term cure rate and recurrence rate are more desirable than those of conventional treatments. The efficacy of NPWT in treating spinal infections in the short and medium terms is clear, and its use is expected to become commonplace in clinical settings. This research is limited by the need to include a larger sample size and to conduct a study across multiple sites.