IBD], colonic metaplasia using the colonic metaplasia score [CMS], and goblet cell [GC] ratio) in the pouch and AL of patients with UC. A total of 261 pouchoscopies were analyzed. The pouch body had a higher hPDAI (p < 0.001), SIBD (p < 0.001), CMS (p < 0.001), GC ratio (p < 0.001), and ePDAI (p < 0.001) than the AL. The hPDAI was correlated with the SIBD , CMS , and the ePDAI , but not with GC ratio  or the pouch usage duration . The incidence of histological inflammation was higher in specimens showing basal plasmacytosis with severe mononuclear cell infiltration (BP) than in those without BP , BP was commonly found with crypt hyperplasia  and the crypt length correlated with neutrophil infiltration . Histological inflammation, colonic metaplasia, the GC ratio, endoscopic inflammation, and IBD-specific findings were commonly present in the pouch than in the AL. Histological inflammation occurs with IBD-specific findings and colonic metaplasia, and these signify endoscopic inflammation.Why inflammation is common in ileal pouches with ulcerative colitis (UC) is unclear. We therefore clarified the morphological changes in pouches and afferent limbs (AL) of patients with UC and explored the relationship between these findings. We evaluated the morphological findings (histological and endoscopic inflammation as the Pouchitis Disease Activity Index [PDAI] histology subscore [hPDAI] and endoscopy subscore [ePDAI], inflammatory bowel disease [IBD]-specific findings using the IBD score [S Even in the era of biologics, total proctocolectomy is still required by 10–30% of patients with UC2. Since the invention of the ileal pouch3, which recreates a fecal reservoir, many patients have been freed from the ileostomy, which has greatly improved their quality of life (QOL)4.Ulcerative colitis (UC), an inflammatory bowel disease (IBD), has spread worldwide, with an increasing incidence in non-Western countries and remains highly prevalent in Western countries5. Interestingly, this inflammation rarely occurs in the ileostomy of patients with UC or in the ileal pouch of patients with familial adenomatous polyposis (FAP)6. Therefore, fecal stasis in the pouch body and recurrence of IBD are thought to be related to pouchitis; however, the etiology remains unclear. Clinically, the endoscopic and histological morphology of the afferent limbs (AL) and the pouch body  differ in patients with UC, and this difference may help clarify why pouchitis is so common in the UC pouch.Despite these benefits, approximately half of UC patients who received pouch surgery suffer from late complications, such as inflammation of the pouch (pouchitis)7 and endoscopy subscore [ePDAI]7, inflammatory bowel disease [IBD]-specific findings as the IBD score [SIBD]8, colonic metaplasia as the colonic metaplasia score [CMS]9, and goblet cell [GC] ratio as the ratio of goblet cells among epithelial cells) between AL and the pouch body in patients with UC as well as the relationship among these morphological findings.The present study clarified the morphological differences , with the exception of Paneth cell metaplasia. The anal side showed a significantly higher hPDAI , GC ratio , and ePDAI  values in the order DP > PP > AL. The pouch body showed a significantly higher SIBD  and CMS  than the AL. Typical cases of AL, PP and DP are shown in Fig. The morphological differences between AL, PP and DP are shown in Table IBD, CMS, GC ratio, ePDAI, and the duration of pouch usage (Duration) are shown in Table IBD , CMS , and ePDAI , but not with the GC ratio  or Duration . The SIBD was correlated with the CMS  and ePDAI , but not with the GC ratio  or Duration . The CMS was correlated with the ePDAI , but not correlated with the GC ratio  or Duration .Spearman’s correlation coefficients between the hPDAI, Sp < 0.001). In specimens with BP, we frequently found moderate or greater polymorphonuclear leukocyte infiltration , but the villus length was not . In specimens with moderate or greater crypt hyperplasia, we frequently found BP  but not with villus length . The ulceration range showed an inverse correlation with the villus length  but not with the crypt length .The relationship between colonic metaplasia and histological inflammation is shown in Fig. We evaluated a total 142 UC patients, including 261 pouchoscopies. There were significant differences between the pouch body and AL in histological inflammation, IBD-specific findings, colonic metaplasia, the GC ratio, and endoscopic inflammation.11. Various hypotheses regarding the etiology of inflammation of the UC pouch have been proposed, including dysbiosis of the ileal pouch microbiota, deprivation of nutritional short chain fatty acids (SCFAs), recurrence of IBD, mucosal ischemia, genetic predisposition, immune dysregulation12, autophagy13 and apotosis14.Histological inflammation was more common in the pouch body than in the AL, similar to previous reportsClostridium perfringens15, Enterobacteriaceae16, Escherichia coli16, Fusobacterium spp17, Ruminococcus obeum17 has been shown to be associated with pouchitis. Butyrate, a metabolite of butyric acid-producing bacteria, promotes colonic health by reducing oxidative stress, acting as an anti-inflammatory factor18. A reduced butyrate level may therefore result in damage to the intestinal epithelial cell barrier19. These studies suggest that changes in the microbiota and SCFAs are involved in the development of pouchitis. However, it is difficult to explain how such changes themselves are associated with the increased incidence of pouchitis in UC patients.The main differences between the pouch body and the AL may be changes in the microbiota and SCFAs due to fecal stasis. These changes may contribute to pouchitis in many patients, since most cases of pouchitis improve with antibiotics. The increased abundance of 20. Regarding autophagy and apoptosis, the UC pouch without inflammation shows modulation of autophagy markers13 and high levels of pro-apoptotic activity, even in the pouch14. These findings suggest that an unidentified IBD pathogenesis is involved in the inflammation in the UC pouch.Regarding genetic predispositions and immune dysregulation, the NOD2 variant carries an inherent risk of pouchitis and the function of the Nod2 gene is to recognize bacteria, and to stimulate the enteric immune system21, pouchitis may represent the recurrence of underlying IBD within the neorectum22. The IBD-specific findings we reviewed here are those that occur specifically in colonic tissue with IBD, and are consistent with findings in the small intestinal tissue with chronic inflammation in Crohn's disease23. Histological inflammation was strongly associated with BP in this study. BP is an IBD-specific finding that may be involved in the pathogenesis of IBD24. It preceds acute inflammation in non-inflamed areas of UC25 and is also a consensus indicator of UC activity26. Thus, inflammation in the pouch with BP may be IBD-specific pouchitis. Although the etiology of IBD-specific findings is not yet known, IBD-specific findings occur more frequently in specimens with crypt hyperplasia. An increase in crypt length is described as hyperplasia, while a decrease in crypt density is described as atrophy. Since these two changes occur simultaneously, “crypt extension” may be an appropriate term to describe such changes in the crypt morphology. Although the histogenesis of crypt distortion and BP in UC is unclear27, crypt extension may be associated with crypt distortion and BP, as crypt distortion and BP were more frequently observed in cases with a longer crypt length.We newly found that IBD-specific findings are more common in the pouch body than in the AL. Since pouchitis is considerably more common in the patients with UC than in those with FAP (22–50% vs. 0–11%)9. Supporting the finding that colonic metaplasia is related to inflammation independently of the time course, inflammation diminished with time, and colonic metaplasia also diminished in some cases  was not correlated with the ePDAI , or the hPDAI  in our study , which omits the histological assessment, can predict the PDAI scores with high accuracy36. A total of 24% patients who were negative for mPDAI but positive for PDAI had symptoms of pouchitis The present study was associated with three limitations. First, the study included only patients with UC. No report is available on the utility of the IBD score in the small intestine, and it has not been proven that the IBD score is truly an IBD-specific finding even in the small intestine. We are planning a large multicenter study including non-IBD (FAP) patients. Second, over 75% of the patients were asymptomatic (cPDAI = 0). However, the data from this study are valuable because they reflect the whole view of the ileal pouch, since almost all patients with an ileal pouch were regularly evaluated by follow-up pouchoscopy. Third, the histological assessment was not blinded. Therefore, subjective evaluation findings . were objectively evaluated by measuring the number or length.The strength of the study is the detailed evaluation of a large sample of 261 endoscopes and 783 biopsy tissues. As a result, we found not only morphological difference between the pouch and AL, but also the correlation between the findings.In conclusion, (1) histological inflammation, (2) IBD-specific findings, (3) colonic metaplasia, (4) the GC ratio, and (5) endoscopic inflammation were increased in the pouch body in comparison to the AL in patients with UC. Histological inflammation, IBD-specific findings, and colonic metaplasia, occur together and correlate with endoscopic inflammation in the ileal pouch.The study population and materials used are shown in Fig. 38. In brief, for patients whose surgical indications were severe or refractory colitis, stapled ileal pouch-anal anastomosis (IPAA) was performed. Single-stage surgery under hand-assisted laparoscopic proctocolectomy was performed when standby surgery was possible. The other patients received a modified two-stage surgery. For patients whose surgical indication was cancer or dysplasia, hand-assisted laparoscopic proctocolectomy with hand-sewn anastomosis and diverting ileostomy was performed . A 12-cm-long ileal J-pouch was constructed in all patients. The first pouchoscopy was performed at one year after pouch construction, and every two years thereafter as routine clinical practice. Pouchitis was diagnosed by the clinician based on symptoms and the endoscopic findings, and an antibiotic was prescribed.The surgical indications, strategy and procedure are as previously reportedA total of 142 patients and 261 pouchoscopies (until March 2021) were enrolled. The characteristics of the study population are shown in Supplementary Tables S7. Each endoscopic finding was diagnosed by two gastrointestinal surgeons in the IBD center.Segmental evaluation of the anal transitional zone , pouch body (including PP and DP), and AL were performed. The rectal cuff was defined as the area from the dentate line to the anal ileal-pouch anastomosis, DP was defined as the anastomotic site to the anal verge (AV) 10 cm, PP was defined as AV 10 cm to AV 16 cm, and AL was defined as AV 16 cm to 22 cm. Endoscopic inflammation was assessed using ePDAI7.Clinical evaluations were collected using clinical report forms. All patients were surveyed for stool frequency, medication status and clinical symptoms according to the PDAI clinical subscore (cPDAI) at the time of pouchoscopy7. IBD-specific findings were assessed using the IBD Score (SIBD)8. The definition of Paneth cell metaplasia in this study was assessed for the presence of Paneth cells in each specimen in order to be closer to the method originally used8. Since Paneth cells are resided in the small intestine, Paneth cell metaplasia in the pouch may not be pathologically appropriate , and we believe that sufficient caution should be exercised in using the term "Paneth cell metaplasia" in the pouch. Colonic metaplasia was assessed using CMS9. The GC ratio was calculated as the average ratio of GCs to epithelial cells in the villus. Findings that required a subjective evaluation were objectively assessed by measuring the number or length, and cutoff values were determined .Biopsies were taken from the most endoscopically inflamed sites in each segment . Hematoxylin and eosin-stained histological sections from biopsy specimens of the AL, PP, and DP were reexamined. Biopsy specimens of the rectal cuff were not reexamined. We evaluated histological inflammation, IBD-specific findings, colonic metaplasia, and the GC ratio for each specimen. Histological inflammation was assessed using hPDAIU test. The relationship between categorical variables were tested using a logistic regression analysis, while those between continuous variables were tested using Spearman’s correlation coefficient. p-values of < 0.05 were considered statistically significant. The Bonferroni method was used when multiple comparisons were conducted.Descriptive statistics were reported as frequencies and percentiles for categorical variables and the median and interquartile range for continuous variables. Differences between categorical variables were tested using chi-squared test, and continuous variables were tested using the Mann–Whitney Statistical analyses were performed using the SPSS software program .This study was performed in accordance with the Declaration of Helsinki and study protocol was approved by the Ethical Advisory Committee of Yokohama City University Graduate School of Medicine (Registration no. B210400067). Informed consent was obtained from all participants.Supplementary Information.


Thanks to the discovery of human eye photoreceptor cells, ipGRC and human nonvisual channels, the nonvisual effects of light have gradually come to our vision and been rationally utilized. Along with this trend, people have expanded their demand for the light environment to both visual and nonvisual needs from only visual needs. With a good natural daylighting, parturients will find their psychological pressure and physiological pain relieved, their rehabilitation rate increased, and they get rehabilitated more quickly. This study was carried out in a representative maternity ward in Harbin based on the latest research results on nonvisual effects at home and abroad. Specifically, the nonvisual effects on the natural light environment in the ward throughout the year were simulated and analyzed from the aspects of equivalent melanopic lux (EML), stimulus frequency (Stim.freq), and circadian effective area (CEA). During the study, natural light in the ward was measured on site, and the evaluation tool and workflow of nonvisual effects were created with the aid of Grasshopper modeling platform, Ladybug+Honeybee, and VB script editor. The results show that the nonvisual effects of natural light on the body of parturients gradually weaken as they further go inside the ward. What is worse, in the most unfavorable all-overcast condition, daylighting on beds far away from the window does not meet the stimulus of human circadian rhythm from April to August. Therefore, additional light is required. The wards have the best nonvisual natural light environment when they are south facing and have a window to floor ratio of 0.3. Natural light is the main light source used by people. Besides its visual functions, people find that it can also have an impact on our circadian rhythm and psychological state, although no scientific explanation demonstrated. Until the retina's third kind of photoreceptor cells—intrinsically photosensitive ganglion cells (ipRGCs)—and nonvisual channels were found in 2002 , a ratioMore and more studies have shown that light's nonvisual effects can directly affect our mood, working efficiency, and physical health , 4. ThisDuring pregnancy, due to their own physiological needs and the needs of fetal growth, the BMR of parturients is 20%~30% higher than that of ordinary people , with flSince the “Two-child Policy” and “Three-child Policy” have been released one after another, the birth rate of newborns is gradually rising. People's demand for maternity hospitals is increasing, and higher requirements and standards are put forward for the hospital environment. As an important part of the hospital physical environment, the impact of light environment on users' physiology and psychology cannot be ignored. Moreover, natural light is of great study significance based on its strengths such as no-cost, complete and continuous spectrum, energy saving, and environmental friendliness.Previous studies on the function of natural light within the building space environment were limited to two aspects: visual effects and efficient utilization of energy. However, in 2012, The Society of Light and Lighting pointed out that natural light's nonvisual effects should also be taken into consideration . AccordiBased on available research background, a double obstetrics ward in Harbin Maternity Hospital is taken as the experimental object. As Harbin is located in a harsh region of China, the winters are cold, dry, and long-lasting, receiving less sunlight, which has a greater impact on maternity and needs to be enhanced to benefit from natural light resources. Therefore, the winter time period was selected, and the ward was firstly analyzed with real measurements of natural light, and then, the dynamic simulation analysis of natural daylighting was carried out with the aid of Grasshopper modeling platform and VB editor. Moreover, the results are presented in Excel. On such a basis, the nonvisual effects of the natural light environment in the ward were evaluated in a scientific and quantitative way. By doing so, this paper will provide effective data support for researches on nonvisual effects of medical space in maternity hospitals and fill the gap in research on light environment in maternity wards in China.Standard for Daylighting Design of Buildings (GB5003-2013) . Finally, two vacant wards on the 9th floor of the inpatient department of Harbin Red Cross Hospital were selected as sample wards  to measure the illuminance at each measuring point. SNDWAYSW-M50 handheld infrared laser rangefinder  was used to measure window size, room depth, and bay net value. At the same time, a tape measure was also used for auxiliary measurement. The ward was measured on January 9-10 (two sunny days) and 12-13 (two completely cloudy days) in 2021. During measurement, the curtains were pulled back, and all indoor lights were turned off, reducing the influence of artificial light on measurement. According to the timetable of sunrise and sunset in Harbin, the illuminance of the measuring points in the two wards is measured from 6 : 00 to 17 : 00 every day. The measurement was performed once every hour for three times at an interval of 5 s. Take the mean value of the three measurements as the final result.In the study, we adopted TES1332A illuminometer  evaluation. Among them, CEA evaluation takes into account the influencing factor of personal photosensitive history for the first time. It is convenient to calculate and has stronger graphical expression ability of the analysis results. Therefore, CEA evaluation is mainly adopted here for simulation analysis and evaluation of nonvisual effects of natural light.The simulation analysis of nonvisual effects mainly includes daylighting simulated calculation and visualization analysis. With the aid of plug-in Honeybee, the annual dynamic natural lighting is simulated, and data are processed with the evaluation tool component produced by the VB editor. Then, the results can be visualized with the combination of Grasshopper's built-in components and Excel. According to the analysis of the measured data, it is found that the illuminance value of the ward facing the north is less sensitive to the weather change, and the illuminance value is low. Therefore, the ward facing the south is taken as the sample ward for computer simulation analysis.(1) Daylighting Simulated Calculation. Based on the wards' measurement data, a 3D model was built in Rhino. The model was converted to the Honeybee Zone that can be identified by Honeybee, and then it was endowed with materials. The color, roughness, highlights, and other factors of materials will exert an impact on the indoor natural daylighting. Honeybee has a calling component of the Radiance material library, through which plastic and glass materials in Radiance are directly available. The reflectivity and transmittance of the indoor materials used in this paper are acquired with field measurements  meeting EML threshold requirements can be obtained. It can be used as the basis for the follow-up analysis of year-round nonvisual effects in these wards. See (2) Visualization Analysis. In this paper, some evaluation components were compiled based on VB and combined with Grasshopper's built-in components for data processing. Then, Excel was used to present data, including the annual equivalent melanopic lux (EML), stimulus frequency (Stim.freq), and percentage of circadian effective area (CEA). The specific simulation process is shown in The analysis chart of whole-year nonvisual illuminance can directly show the nonvisual illumination level of 8760 hours throughout the year, which can be taken as a basis for other analysis indicators. If the EML average of natural light received by a certain point in a certain direction reached 250EML, i.e., the minimal light stimulus standard for nonvisual effects, we deemed that circadian effective (CE) was generated at this measuring point this day. Moreover, in order to quantify the changes of availability of CE stimulus over a period of time , the concept of stimulus frequency (Stim.freq for short) was proposed . AccordiIn order to sustain a healthy circadian rhythm cycle, Konis suggests that at least 5 days of effective physiological rhythmic stimulus within any 7 days are required to avoid upsetting the internal clock of human body . TherefoIn addition to lying supine and leaning against the bed, parturients tend to walk around. For the purpose of evaluating the nonvisual effects of natural light under such a state, it is necessary to evaluate the nonvisual natural light environment in a whole ward. With an available circadian effective area, the dynamic natural light in a building space can be evaluated. In this study, a factor of personal sensitization history is introduced for the first time. With this factor, the nonvisual effects of natural light in a space throughout the year can be analyzed. Hence, a grid at a certain distance from the ground is simulated and calculated in this daylighting simulation. In the nonvisual simulation, the WELL stipulates that the position of 1,500 mm from the ground denotes the height of human eyes when standing, typically the horizontal viewing direction. There are 522 grid measuring 200 mm × 200 mm.As shown in Code for Design of General Hospital (GB51039-2014), the orientation of the ward is not clearly specified. It only requires favorable daylighting, ventilation, and matching with terrain. But in fact, depending on the local climate and direction, the houses in some places are livable even they face east or west. Through software simulation, the nonvisual effects of different orientations of sample wards can be optimized and analyzed, to explore the orientation of hospital wards suitable for cold areas (Harbin).Based on the measurement data, in terms of the ward facing south, the standard was to meet the natural lighting of no less than 190 lx for at least 4 h every day. In sunny days, the light stimulus at each measuring point in the ward could meet parturients' needs for circadian rhythm stimulation. While in all cloudy days, the natural lighting environment near the window was not ideal. In terms of the ward facing north, the standard was natural lighting of no less than 170 lx for at least 4 h every day. Whether cloudy or sunny, natural daylighting in the ward failed to meet parturients' needs for circadian rhythm stimulation. It can thus be seen that although natural light can meet parturients' visual needs in the ward, it still fails to meet their nonvisual, requiring supplementary illumination. In the It can be seen from Figures Through the aforesaid computer simulation, it can be concluded that the natural daylighting having nonvisual effects is problematic at beds away from the window. Especially from April to August, natural light basically cannot meet parturients' needs of circadian rhythm stimulation. This is because the ward is deep inside the war and the solar altitude angle is high from April to August, so the sunlight cannot directly reach the test points. The area near the entrance requires a supplement of high-intensity artificial illumination. Apart from the supplementary artificial illumination, the ward can also be optimized. However, it is quite complicated and demands a huge amount of work to implement optimization methods, such as changes of the ward's plane layout and proportion, or the combination between wards. In comparison, it is more simple and direct to improve the ward's daylighting by changing the ward's window-to-floor ratio.According to Figures Computer simulation has basically the same results with those of the field measurement—natural light's nonvisual effects on people gradually decrease with the increase of depth perpendicular to the ward's lighting surface width. Especially during April-September or on the whole-day cloudy condition, as for parturients away from the window, no matter lying supine or leaning, the natural light basically cannot meet their needs for circadian rhythm stimulation. In that way, supplementary illumination is required. However, during the field measurement, it was found that illuminance values near the window in the ward rose significantly in the morning. If the illuminance value is too high, it is prone to glare and visual fatigue, resulting in physical discomfort. Shading facilities need to be added appropriately to avoid such situationsNatural daylighting of the overall nonvisual effects in the ward can vary significantly with seasonal changes. In summer, nonvisual stimuli received in the area near the window are remarkably better than those near the entrance. While in winter, there are no great changes. Although some areas received a higher value of nonvisual illuminance and a longer duration every day in summer, in terms of meeting the threshold standard and the uniformity, nonvisual natural light environment in the ward is better in winter than that in summerThe change of orientation and window-to-floor ratio has a certain effect on the natural lighting of nonvisual effect in maternity ward. According to the field measurement, the ward facing south has better nonvisual effects than that facing south, which maintain at a higher level. Computer simulation analysis shows that the priority of different directions that wards face in the cold area (Harbin) is as follows: south>east>north>west. When the window-to-floor ratio is 0.3, the nonvisual natural light environment is optimalIn this paper, we adopted WELL standard and CEA evaluation method that were used to quantify nonvisual effects of natural light in wards. According to the study findings, a ward's natural light environment that meets visual needs does not necessarily meet parturients' nonvisual needs. A ward's nonvisual natural light environment has something to do with parturients' behaviors and ward orientation. From the obtained results, the following conclusions can be drawn:


Mycobacterium marinum is a non-tuberculous mycobacteria present in natural and non-chlorinated bodies of water. It is a known fish pathogen but can also cause human disease. It usually causes cutaneous lesions but in rare cases may originate more invasive diseases with the involvement of deep structures. We describe three cases of patients with cutaneous infection by M. marinum evaluated in a tertiary care center, two with confirmed infection and one with a presumptive diagnosis based on clinical and epidemiological features. A brief bibliographic review of M. marinum infections is then presented to support the theme. We aim to alert one to the difficulties in establishing the correct diagnosis of this infection, emphasize the importance of a high degree of suspicion for its identification, and review the therapeutic management options. Mycobacterium marinum is a non-tuberculous mycobacterium (NTM) associated with aquatic environments that can cause human infection [M. marinum is one of the leading causes of extra respiratory human disease worldwide, affecting both immunocompetent and immunocompromised hosts [M. marinum infection can cause deep structure and invasive disease including tenosynovitis, septic arthritis, or osteomyelitis [M. marinum evaluated and treated in a tertiary care hospital in Portugal. Two cases had M. marinum mycobacterial confirmation and one was a presumed diagnosis considering the clinical-pathologic data and epidemiological context.nfection ,2. It isnfection ,4. The pnfection ,2. Humannfection . Fish ennfection ,6. The infection . From thed hosts ,8. Humaned hosts . Lymphaned hosts ,10. In imyelitis ,4. We prCase one M. marinum or Mycobacterium ulcerans genetic material. There were no other microbiologic isolations in bacteriological studies. Although the interferon-gamma release assay (IGRA) was positive, the patient had had no previous tuberculosis diagnosis or known contact with infected individuals, and an active infection was excluded through symptom inquiry and chest radiograph. A diagnosis of cutaneous infection by M. marinum was assumed and combined treatment was started with ethambutol  and rifampin . Gradual improvement occurred over two months and surgical resection of the remaining lesion was posteriorly performed. Another full month of combination therapy was administered afterward  with full resolution and no relapse observed in the 24-month follow-up period.A healthy 58-year-old woman presented with an ulcerated skin lesion on the dorsum of the right hand just above the metacarpophalangeal joint of the right index finger that had appeared 12 months before presentation and never seemed to heal. The patient reported some associated erythema but no pain, pruritus, exudate, or other local symptoms. During this period she never presented any systemic complaints such as fever, malaise, myalgias, weight loss, or hyperhidrosis. She was a kindergarten teacher and had frequent contact with a tropical fish aquarium in the classroom. The lesion was characterized as an erythematous papule with exulceration  and rifampin  was started. There was a progressive reduction in the number and size of lesions over 10 months but some lesions persisted which prompted surgical resection with a posterior skin graft. Two more months of antibiotic treatment were administered . There was complete resolution of the lesions and no documented relapse for a follow-up period of 12 months.A 38-year-old fish farmer with a history of lymphoma , presented with various nodular lesions grouped in the forearm covering an area of 5cm Figure . The firCase threeM. marinum was presumed. The pinch biopsy almost wholly removed the lesion and treatment was completed with a posterior course of antibiotic therapy with ethambutol  and clarithromycin  for two months, with optimal clinical response and resolution and no relapse in the follow-up period of eight months. The choice of clarithromycin instead of rifampin was due to the interaction of rifampin with itraconazole that the patient was taking to treat onychomycosis. In both cases two and three, public health authorities were involved. Adequate aquarium cleaning was recommended. No more secondary cases are known.A 49-year-old fish farmer working in the same fishpond as the patient from case two, presented six months after his colleague with an ulcerated lesion located on the elbow Figure . It had Mycobacterium marinum cutaneous infection is relatively rare and its correct diagnosis can be difficult given its insidious and nonspecific presentation. Frequently, there is a considerable time delay between the symptoms' appearance and the identification of the etiologic agent [ic agent . As descic agent -10.M. marinum are non-pathognomic and thus the combination of both histological analysis of the affected tissue and mycobacterial studies (cultures and molecular tests) are necessary for its correct identification. There are reports of positive cultures in 70% to 80% of cases [M. marirum in cultures is around 30°C , whereas small colonies or no growth is observed at 37°C [Cutaneous lesions caused by of cases , but thiof cases ,4. The o at 37°C . In the M. marinum is always of clinical significance (despite the number of colonies) since it usually does not grow in the laboratory environment or from the uninfected human body [M. marinum and M.ulcerans as these two mycobacteria share 98% of their genome [M. marinum infection [M. marinum shares with Mycobacterium tuberculosis the specific antigens early secreted antigenic target (ESAT)-6 and culture filtrate protein (CFP)-10 that may elicit a positive result in such a test [Isolation of man body . Currentr genome . Althougnfection , they mah a test . M. marinum/M. ulcerans PCR test as well as a positive IGRA test. In the third case, although negative on microbiologic tests, the epidemiological context was decisive for the diagnosis: aquatic environment occupational exposure and a work colleague with confirmed M. marinum infection.In the first two cases, the diagnosis was sustained by mycobacterial growth in culture and a positive M. marinum infection includes other NTM known to cause cutaneous infection , sporotrichosis, and noninfectious diseases such as sarcoidosis, skin tumors, and foreign-body reactions [The differential diagnosis for eactions .M. marinum organisms are susceptible to rifampin, rifabutin, and ethambutol and resistant to isoniazid and pyrazinamide. Isolates are usually also susceptible to clarithromycin and sulfonamides and susceptible or intermediately susceptible to tetracyclines [M. marinum cutaneous infection is usually favorable if it is appropriately treated before deep soft tissue and/or bone involvement [Regarding treatment, as there are no comparative trials of different treatment regimens and there is no consensus for an adequate duration of therapy, the statement endorsed by the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) regarding diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases from 2007  is usefucyclines ,8. The mcyclines ,4. In twolvement . The higM. marinum infections. The high prevalence of mycobacteria infection in ornamental fishes illustrates the importance of the use of adequate individual protective measures such as gloves for fish farmers or aquarium keepers. Establishing a diagnosis of M. marinum infection is not always straightforward given its insidious and nonspecific presentation, long incubation period, and the technical difficulties raised during the microbiological confirmation of the organism. In practice, diagnosis remains largely presumptive based on clinical-histological features and the response to treatment. The clinician should suspect M. marinum infection in the presence of poorly healing wounds, mainly in the upper extremities, and in persons with a history of exposure to aquariums. This three-case report aims to alert clinicians to this infection and difficulties in its diagnostic and therapeutic management, and emphasize the importance of the use of protective measures in individuals at risk.Activities that bring people into contact with fish tanks are increasing in popularity and seem to represent the main risk factors for


The thymus gland plays a crucial role in the maturation process of lymphocyte T cells. Developmental disorders of this organ might be caused by genetic diseases, such as the 22q11.2 deletion and DiGeorge syndrome. Other manifestations of this condition are heart defects, a reduced number of T cells, hypocalcemia, and facial dysmorphia.A 13-year-old boy with 22q11 deletion syndrome presented with paresis and paresthesia of the right upper extremity. Magnetic resonance imaging (MRI) revealed a solid mass in the retropharyngeal and prevertebral areas. The lesion was excised and, upon histopathological examination, turned out to be ectopic thymic tissue. A follow-up examination showed no recurrence of the lesion.The ectopic thymus is a rare pathology, especially in 22q11 deletion syndrome patients. In general, thymic tissue can be found anywhere along its normal path of descent. In this case, however, its location cannot be explained solely by its embryological origin, as at no point should the thymus or its histological predecessor be located in the retropharyngeal area. As such, this finding challenges our current understanding of thymic embryological genesis. It plays a significant role in the immune system, providing an appropriate environment for the maturation process of T cells . Embryolsmorphia . One rarIn this study, we aim to highlight the importance of considering the ectopic thymus in the differential diagnosis of neck masses.This article was previously presented as a meeting abstract at the 2022 International Medical Students' Conference on June 3, 2022, in Kraków.+ 1860/µl, Ca2+ 2.45 mmol/l, no heart defects except irrelevant tricuspid incompetence.A 13-year-old boy with 22q11.2 deletion syndrome  was admitted due to numbness of the upper right extremity, dysphagia, and dysarthria that had lasted for four months. Physical examination showed a keeled chest, mild lateral spinal curvature, and winged scapulae. He presented face dysmorphia , height deficiency (−2.0 SD), and low body mass (weight-to-height ratio −20%). No characteristic features of 22q11.2 deletion syndrome were found: lymphocytes T CD3Due to suspicion of Chiari's malformation, he underwent magnetic resonance imaging (MRI) of the craniocervical junction. The T2-weighted coronal and sagittal sequences have revealed a 36 × 45 × 13 mm multilocular contrast-enhancing mass in the retropharyngeal space at the C2-C4 level  AND (“thymus” OR “thymic”) AND (“digeorge” OR “22q11” OR “22q11.2”). This, however, yielded no results for the retropharyngeal location specifically.The human thymus typically stems from the third and possibly fourth pharyngeal pouches ,3. Its pIt is worth noting, however, that this generally accepted theory of thymic embryogenesis does not explain the retropharyngeal location of the pathology presented in this case. As such, two explanations are possible: either the organogenetic process in this patient was somehow adversely affected, which resulted in an aberrant direction of migration of the primordium, or our understanding of the genesis of the thymus is incomplete.However, puzzling this case may be, an ectopic thymus should not be thought of as a first step in the differential diagnosis of retropharyngeal masses. The usual suspects in this kind of lesion most frequently include neoplasms, abscesses, myxedema, spinal trauma, foreign objects, and lymphadenopathies .Under normal circumstances, the thymus is an immunoregulatory organ located in the anterosuperior mediastinum. In rare cases, some parts of its tissue or the entire organ can be found along the normal path of its embryological descent and can manifest in clinically relevant forms as an accessory or ectopic thymus. The regular pathway for thymic descent starts in the third (and possibly fourth) laryngeal pouch and proceeds ventrally and caudally. As such, at no point during its formation should it be found behind the pharynx, in the prevertebral area.The ectopic retropharyngeal thymus, although an unusual finding, let alone in patients diagnosed with 22q11.2 deletion syndrome, needs to be considered as a potential diagnosis for patients presenting with masses located in the retropharyngeal space. Other diagnostic considerations must include such conditions as neoplasms, abscesses, myxedema, spinal trauma, foreign objects, and lymphadenopathies.


Background and Objectives: Saturation diving is a technique used in commercial diving. Decompression sickness (DCS) was the main concern of saturation safety, but procedures have evolved over the last 50 years and DCS has become a rare event. New needs have evolved to evaluate the diving and decompression stress to improve the flexibility of the operations . We monitored this stress in saturation divers during actual operations. Materials and Methods: The monitoring included the detection of vascular gas emboli (VGE) and the changes in the vascular function measured by flow mediated dilatation (FMD) after final decompression to surface. Monitoring was performed onboard a diving support vessel operating in the North Sea at typical storage depths of 120 and 136 msw. A total of 49 divers signed an informed consent form and participated to the study. Data were collected on divers at surface, before the saturation and during the 9 h following the end of the final decompression. Results: VGE were detected in three divers at very low levels (insignificant), confirming the improvements achieved on saturation decompression procedures. As expected, the FMD showed an impairment of vascular function immediately at the end of the saturation in all divers but the divers fully recovered from these vascular changes in the next 9 following hours, regardless of the initial decompression starting depth. Conclusion: These changes suggest an oxidative/inflammatory dimension to the diving/decompression stress during saturation that will require further monitoring investigations even if the vascular impairement is found to recover fast. Saturation diving is a standard technique of divers’ intervention in the North Sea because of its depth (average 100 to 150 msw). Saturation is conducted from large diving support vessel that employs around 80 divers in multiple rotations during a working season. The contractors have developed saturation procedures empirically over the last 40 years and reached a mature level of technology and safety. On the other hand, the need for evaluating the diving and decompression stress to improve flexibility of the operations  arose.“Records show that since 1966 seventy-seven diving personnel tragically have lost their lives in the quest for, depending on your perspective “Black Gold” or “Devil’s excrement” in the North Sea Basin. By nationality: 53 British/Commonwealth subjects, 9 American, 7 Norwegian, 4 Dutch, 3 French, and 1 Italian. Prior to 1971/1974, applicable laws & regulations (if any) required no accurate fatal accident statistics. One can conclude that the actual combined number of deaths is higher. However, it is known that several divers received severe injuries from which they never recovered.”https://the-norwegian.com/north-sea-diving-fatalities (accessed on 20 September 2022))). As a result, the diving companies have the duty to evaluate the performances of their procedures such as the minimal permitted interval between two saturations. This minimum interval has been arbitrarily defined for a long time by industry guidelines or diving regulations but the divers’ recovery between saturations has never been studied scientifically. This recovery period remains important for companies to optimize their crew changes and divers to manage their professional career.Fifty years later, saturation procedures have improved a lot and decompression sickness has become a rare event. Official safety records published in Norway on the Website of the PSA (Petroleum safety Authority) indicate an incidence of less than one case per 2000 exposure over the last 10 years  produced during decompression. Although there is no clear relation between the number of VGE measured and the risk of DCS, it is recognized that the smaller the number of VGE detected, the safer is the decompression . The numThe third dimension covers several biological processes recently identified in the literature . New insThe objective of the study was to define a monitoring package and use it on board a vessel to monitor saturation divers at surface, before the saturation and after exiting saturation (after decompression), in order to evaluate their recovery during the 9 h following the end of their final decompression.A leading diving company provided access to one of their diving support vessels (DSV) operating in the North Sea for this study. Two monitoring sessions were conducted onboard the DSV Deep Arctic  in April and October 2016, during two different projects, one in the Norwegian sector at 121 m of sea water (msw) and the other in the UK sector at 155 msw working depth. The two projects, performed on the same vessel, corresponded to a well intervention on the seabed; the divers used the same breathing gasses, the same diving equipment and performed the same tasks see .The two projects were conducted with saturations according to the Company procedures defined in their diving manuals. However, specific requirements are defined in the Norwegian diving regulations that introduced slight variations.The chambers were initially compressed to 10 msw in 10 min for a 20 min leaks check. Compression then proceeded to the “storage” depth at 1 msw/min.2 at storage depth was controlled at 40 hPa. The storage depth was selected from the working depth using the standard excursion tables . During the bottom phase, divers performed one bell dive of 8 h per day but may sometime skip a dive due to weather conditions or vessel transit. During the dives, the divers’ breathing mixture was Heliox with a PO2 ranging from 60 to 80 hPa.The chamber POThe final decompression can only start after an 8 h period following the last excursion dive.2  until 15 msw and finishes with a chamber oxygen percentage maintained between 23.1 and 23% to limit the fire hazard and optimize inert gas exhalation.The decompression is performed in two phases. It starts with constant chamber PODespite the difference between sectors, the total decompression durations were very similar .The divers were organized in three men teams (two divers and the bellman). Teams worked in shifts (12:00 p.m. to midnight and midnight to 12:00 p.m.). Each team was involved in one bell excursion dive per day during their shift. The divers’ in-water time was limited to 6 h with a mandatory break at mid-excursion.The study group consisted of volunteer, male, certified commercial saturation divers. These divers were declared fit for the saturation by the vessel hyperbaric nurse after a mandatory pre-dive medical examination.All experimental procedures were conducted in accordance with the Declaration of Helsinki  and wereA total of 49 divers accepted to participate to the study.The group anthropometric parameters were obtained after a confidential interview in the vessel hospital. See .As expected from saturation divers, all were very experienced divers with a long diving career. See .Part of the group freely took of antioxidant supplements  before and during the saturation. See .Saturation divers generally spend a lot of time maintaining a high level of physical fitness and are involved in all sorts of sports. Every diver in the group except one had a daily or at least weekly physical activity when at home. See .The participants were divided as follows: 37 divers in saturation in the Norwegian project (75%) and 12 divers in saturation in the UK project (25%). The saturation duration depended on the sector regulations. It is 14 days maximum bottom time in Norway and 28 days total saturation time in the UK. The mean saturation duration was 19.70 ± 6.5 days  see .The voluntary divers were first involved in the study in the few hours after arriving onboard, after their pre-saturation medical examination, just before entering the saturation chambers. Baseline (control) measurements (FMD and Questionnaires) were recorded. The group of divers were then monitored during the next 12 h following the end of the decompression to surface.The questionnaires and measurements were run in the vessel hospital room that warranted confidentiality.It is admitted that after the decompression, due to operational constraints, it was difficult to “catch” the divers at regular times and some subjects (30%) only performed one or two sessions of the four initially planned see .FMD, an established measure of the endothelium-dependent vasodilation mediated by nitric oxide (NO) , was useAll ultrasound assessments were performed by an experienced operator, with more than 100 scans/year, which is recommended to maintain competency with the FMD method .When the images were chosen for analysis, the boundaries for diameter measurement were identified manually with an electronic caliper (provided by the ultrasonography proprietary software) in a threefold repetition pattern to calculate the mean value. In our laboratory, the mean intra observer variability for FMD measurement for the operator recorded the same day, on the same site and on the same subject was 1.2 ± 0.2%.FMD were calculated as the percent increase in arterial diameter from the resting state to maximal dilation.The echocardiographic VGE signals over the 1 min recording were evaluated by frame-based bubble counting as described by Germonpré et al. , but alsEchocardiography was performed with a M-Turbo portable echocardiograph  used in a medical clinic included in the vessel while the patient was comfortably lying in a medical bed ; four chamber view echocardiography loops were recorded on hard disk for offline analysis by three blinded evaluators. VGE numbers were counted at 30 min and 60 min post saturation decompression.Evaluation of decompression stress and of the potential benefit of preventive measures has been done historically based on the presence or absence of clinical symptoms of DCS. However, for obvious ethical reasons, this is not acceptable in the field of recreational or professional diving . AlthougThe normality of data was performed by means of Shapiro–Wilk or D’Agostino-Pearson tests.When a Gaussian distribution was assumed, and when comparisons were limited to two samples, paired or non-paired t-test were applied. If the Gaussian distribution was not assumed, the analysis was performed by means of a non-parametric Mann-Whitney U test or, a Wilcoxon paired test. Taking the baseline measures as 100%, percentage changes were calculated for each diver, allowing for an appreciation of the magnitude of change rather than the absolute values (one sample t-test). All statistical tests were performed using a standard computer statistical package, GraphPad Prism version 5.00 for Windows .p < 0.05 was considered statistically significant. All data are presented as mean ± standard deviation (SD).A threshold of Sample size was calculated setting the power of the study at 95%, and assuming that variables associated with diving would have been affected to a similar extent as that observed in our previous studies ,17,18 ouThe linear regression line was performed using the least squares method and the lateral bands represented are in the 95% predictivity range.A very low number of bubbles were found in the participants after their decompression during their “bend-watch” period (the first 9 h).n = 49), only three showed circulating gas emboli according to the EB scale that represented 0.2 ± 0.05 (mean ± SD) bubbles per heartbeat, which represents less than grade 1 on the EB grading scale in three divers. This is extremely low and doesn’t allow statistical analysis. To allow the reader to compare with other diving situations this grading is 10 times lower than an average number of bubbles after a simple dive of 25 min at 25 m considered within safety limits [Among all divers (y limits .p < 0.0001) during the first two hours after decompression and quickly recovers reaching 98.75 ± 0.91 (p < 0.0001) in the last two hours (6–8 h after decompression)  see .Our data suggest that total vascular function recovery has not yet reached 8 h after the end of decompression. We then computed a best fit equation to extrapolate the time needed to achieve recovery. The linear regression line and the equation are shown in Few scientific studies have been performed in real commercial saturation conditions during the last ten years. These studies are difficult because of the offshore constraints and project planning that do not allow much time for scientific testin—not to mention the cost of accommodating the scientific team onboard. Available studies are related to the subjective evaluation of saturation operations by the divers themselves . More adOur goal in this experiment was to document vascular recovery post saturation diving (after decompression). Vascular gas emboli are probably involved in the post dive reduction of FMD. Nevertheless, the available literature refrains us to draw a direct link between FMD reduction and VGE, since micro and macro vascularization react differently , and difIn a recent experiment, a similar reduction in FMD was found in a setting excluding bubble formation, but a significant change in FMD was demonstrated depending on the oxygen partial pressure of the breathed gas .Moreover, in this experimental setting, we only saw minimal levels of bubbles allowing for neglecting this stressor in such saturation decompression procedures. Decompression bubbles are very likely not to be found post decompression after saturation diving. Further investigations are needed to monitor bubbles production after excursions while being in saturation or during the decompression phase.A nitric oxide (NO) mediated change in the surface properties of the vascular endothelium favoring the elimination of gas micronuclei has previously been suggested to explain this protection against bubble formation . It was It appears that FMD seems more linked to oxygen partial pressure changes during diving, whereas VGE are more depending on preexisting gas micronuclei population ,34 in thFMD is a marker of endothelial function and is reduced in the brachial artery of healthy divers after single or repetitive dives ,35. ThisDecreased nitroglycerin-mediated dilation after diving highlights dysfunction in vascular smooth-muscle cells as possible etiology of those results .Very recent data show that the FMD reduction encountered after a single dive without the presence of VGE, is comparable to the reduction found with the presence of VGE .The divers that volunteered in our saturation experiment were taking some antioxidant “medication” see  as a proA recent manuscript  shows veOur data are in tune with the NOx returning to baseline, since FMD is closely related to the availability of nitric oxide (NO), and we can see from our results that FMD almost fully recovers after 8 h. If we apply the formula extracted from our data the mean time needed to reach 100% recovery would be around 540 min (9 h) and in the least predictive range (−95%) around 600 min (10 h) would be needed to fully recover, which is confirmed by Mrakic-Sposta et al. (2020) results. In fact, their results show that 24 h post saturation, the ROS (Reactive Oxygen Species) are still significantly higher than baseline, but concomitantly TAC  is also still high. From our results we can consider that the vascular dysfunction has already recovered and that the balance between antioxydants and prooxydants is clearly efficient and therefore fostering recovery. Another parameter measured by Mrakic-Sposta et al.  was IL-6-This study builds on established modern methods of evaluation of decompression stress including vascular function and current theories of VGE generation.-As there is possible large inter-individual variation for VGE and FMD effects after diving, the subjects served as their own controls.-The measured effects are consistent with the theoretical rationale and do not require complicated new hypotheses.-The equipment used for these experiments is readily available and reliable, inviting other research groups to repeat the study.-The study was performed in real operational activities.-A large number of divers volunteered for the study (never a saturation diving study addressed so many participants).Strengths:-The subjects were not homogenous or necessarily similar in body composition .-Operational constraints sometimes altered the planning of the measurements.-Gender balance was impossible to reach.Weaknesses:This monitoring session has no equivalent in the commercial diving industry because of its duration (6 month), conditions (a working diving support vessel) and the large number of divers who volunteered for the study. It was the first time that the possibility for assessing onsite the vascular function of divers was offered during actual saturation diving operations. The study not only confirmed the role of inflammation and oxidative stress in saturation diving but it also permitted to obtain an estimation of the recovery time needed.The lessons learnt from this experiment were that (1) scientific studies are possible even on a diving support vessel during operations under extreme environmental conditions. (2) Both national safety rules seem to provide health of the divers. (3) The equipment selected for the study was too heavy to be easily mobilized, and it could only work at ambient pressure and required a specific expertise. The future monitoring sessions, if any, should aim at using simpler equipment, which could be operated by the divers themselves inside the chamber, under pressure. Future experiments should include pressure resistance bubble measuring devices such as the O’Dive system tool to ascertain a minimal bubble number in the sub-clavian vein during excursion dives and during decompression .


Breast cancer is currently one of the cancers with a higher mortality rate in the world. The biological research on anti-breast cancer drugs focuses on the activity of estrogen receptors alpha  to topologically enhance the molecular representation of candidate drugs. By constructing atom-level graphs through atomic descriptors for each distinct compound, ABCD-GGNN can topologically learn both the implicit structure and substructure characteristics of a candidate drug and then integrate the representation with explicit discrete molecular descriptors to generate a molecule-level representation. As a result, the representation of ABCD-GGNN can inductively predict the ERExtensive experiments conducted on our collected anti-breast cancer candidate drug dataset demonstrate that our proposed method outperform all the other representative methods in the tasks of predicting ERIn this paper, we propose the ABCD-GGNN representation method to efficiently integrate the topological structure and substructure features of the molecules with the discrete molecular descriptors. With a ranking operator applied, the predicted properties efficiently facilitate the candidate drug selection against breast cancer.The online version contains supplementary material available at 10.1186/s12859-022-04913-6. Breast cancer is currently one of the most common cancers in the world with a higher fatality rate. According to the related statistics, more than 2 million new cases of breast cancer were diagnosed, where 0.6 million cases died. It accounted for about 15% of all cancer deaths among women worldwide [The research on breast cancer is closely related to estrogen receptors , 4. Studt cancer .In order for a compound to be a candidate drug, in addition to having good biological activity, it also needs to have good pharmacokinetic properties and safety in the human body, collectively known as ADMET  properties . Among tAt present, in the field of drug research, regarding time and cost consuming , 10, QuaWith the development of the field of bioinformatics, diverse machine learning based methods have been proposed and applied into QSAR/QSPR modeling for drug property prediction –14. The Recently, the popularity of graph neural networks in the bioinformatics community brings potential to further enhance the molecular representation, which is the third stage of QSAR/QSPR modeling –30. GrapAlthough many variants of graph neural networks have been developed for molecular representation and ADMET prediction, limitations of existing methods still exist. First, existing graph-based methods only map the descriptors into a global molecule-level strucrure, which means that they may fail to mine the intrinsic knowledge implicit in the key chemical substructures of the molecules. The significance of biological substructure within a compound is neglected. Second, compared with feature engineering-based machine learning models, GNN models are generally less sensitive to the source of atomic descriptors , 41, whiWe propose an Anti-Breast Cancer Drug selection method utilizing Gated Graph Neural Networks (ABCD-GGNN), which topologically learns both the implicit structure and substructure characteristics of a candidate drug, and integrates with explicit discrete molecular descriptors to better generate a molecular-level representation. As a result, activity, property, and toxicity of the candidate drugs can all be inductively predicted.We design a whole framework of anti-breast cancer drug selection based on ABCD-GGNN to automatically assist researchers with a decision-support setting. To our best knowledge, this is the first work aiming to deal with anti-breast cancer drug development via graph-based deep learning method.Extensive experiments conducted on our collected anti-breast cancer candidate drug dataset demonstrate the outstanding performance of our proposed ABCD-GGNN representation method and the rationality of our designed framework for candidate drug selection.Inspired by the recent progress claimed above, in this paper, we propose the ABCD-GGNN representation method to topologically realize QSAR/QSPR model for ERIn this section, we first introduce the candidate drug dataset we collect. Then, we illustrate the implementation of our anti-breast cancer drug selection method based on ABCD-GGNN step by step. As the pipeline shown in Fig. To evaluate the efficiency of our proposed method, we collect a dataset containing 1974 organic compounds that may be the candidate drugs of anti-breast cancer. The dataset provides the simplified molecular input line entry system (SMILES) and 729 molecular descriptors of each organic compound. The 729 molecular descriptors include diverse descriptions on the characteristics of molecule in two-dimension and three-dimension. The dataset labels the ERIn the stage of topological molecular graph representation, graph neural networks are adopted to atomically model the structure of a drug so as to learn the topological molecular features three-dimensionally for the final representation of ABCD-GGNN. With the atom node information globally interacted in the graph structure, both topological structure and substructure features can be well represented and integrated. We first illustrate the implementation of the topological structure representation. Then we illustrate how topological substructure representations are generated and integrate with the topological structure feature to enhance the topological molecular representation. The whole framework of the topological molecular graph representation based on ABCD-GGNN is shown in Fig. E is the set of graph edges. In terms of atom-level graph construction for candidate drugs. V denotes the atom set in a molecule and E denotes the chemical bond set in a molecule.Graph construction is the kernel stage for the topological graph representation. Given that a graph is denoted as In terms of the feature initialization for each atom node, here we summarize 8 atomic descriptors from the corresponding SMILES and 729 molecular descriptors, which are atom type, number of bonds, formal charge, chirality, hydrogen bound number, hybridization, aromaticity, and atom mass. The detailed descriptions on the 8 atomic descriptors are listed in Table A, e.g., In terms of edge construction for each molecular graph, we construct an adjacent matrix t increased and can finally achieve global information interaction of the whole topological structure. In this way, we can finally get a topological structure representation for a candidate drug. Detailed interaction functions are listed as follow:W, U, and b are trainable weights and biases. Getting the molecular graph constructed, we then employ GGNN  to realiWith the topological structure representation of the distinct molecule updated, we then aggregate the atom-level representations into a molecule-level representation in the readout stage. The readout functions are designed as follow:The readout functions are designed as above with the intention to reflect the truth that all atom node representations contribute to the information aggregation by getting through averaging function and a max-pooling function, while only part of atom nodes with higher weights distributed by attention mechanism contribute more . ConsequSubgraphs are believed to imply significant attribute characteristics that may further extract and enhance the original graph representation , especiaG. Then, we construct the atom-level subgraphs and get through the global interaction via GGNN and representation readout operations as the original graph does. Consequently, we get a substructure-level representation set Therefore, we additionally extract the substructures from SMILES of the molecules via the SMILES pair encoding algorithm. Given c, W, and b are trainable parameters to be learned. Consequently, here we finally get the topological molecular graph representation h that deeply integrate the structure and substructure characteristics of the molecule.Considering that the contributions different substructures make to the molecular representation are uneven, here we adopt an attention mechanism to dynamically adjust the weights of the original graph and each subgraph. In this way, both molecular graph representation and diverse substructure graph representations get deeply integrated. In other words, the topological graph representations of the candidate drugs are strongly enhanced. Detailed formulas of the attention mechanism and the feature integration is shown below:Molecular descriptors are the discrete expression of a molecule which may imply the potential chemical properties as a candidate drug. Given that the anti-breast cancer candidate drug dataset provides 729 molecular descriptors of all the candidate drugs, which is a quite large number. Here we first employ XGBoost algorithm to select the descriptors that count more. Then, we further reduce the dimensionality of the integrated molecular descriptor representation to realize the molecular descriptor representation readout.Considering the redundancy and sparsity of the raw molecular descriptors, we believe it is necessary to select the more property-related descriptors with the help of machine learning method. Therefore, here we apply XGBoost, a decision-tree-based ensemble Machine Learning algorithm that uses a gradient boosting framework, to select the top 50 property-related descriptors for further feature integration and readout.In terms of the implementation of XGBoost, we first set the objective function, i.e., the loss function as below:To make each sample on a leaf node, the node score is defined as Based on the topological graph representation and the molecular descriptor representation, a final representation of anti-breast candidate drug can be integrated to predict both the ERTo adaptively adjust the contribution the topological graph representation and molecular descriptor representation make to the prediction result, we design the hyper parameter In this stage, we can claim that the molecular representation based on ABCD-GGNN is completed.W, b denote trainable parameters, m denotes the batch size, and We treat the prediction of ERW, b denote trainable parameters and In terms of ADMET properties prediction, the representation To comprehensively consider both the two types of attributes when evaluating the potential of the candidate drugs, here we design a ranking operator consisting of feature binning and scorecard. By scoring each candidate drug, a ranking list can be generated, which can efficiently facilitate the research on anti-breast cancer drug selection.Since the ADMET properties are binary while the ERTo set up the scorecard for the candidate drug ranking, we first calculate the corresponding score of the attribute as below:Finally, the calculation formula of the scorecard is defined as below to get the scores of the candidate drugs.In this section, 1) we first evaluate the performance of our proposed ABCD-GGNN on our collected anti-breast cancer candidate drug dataset and compare them with other representative models. 2) Then, we make extensive characteristics analysis and ablation study to demonstrate the effectiveness and contribution each stage makes for the ABCD-GGNN representation. 3) Finally, we demonstrate the biological rationality of applying the ABCD-GGNN prediction results into the ranking operator for candidate drug selection.Linear Regression a representative supervised learning method. Based on one or more independent variables, linear regression can model a best-fitting relationship for regression problem.Random Forest an ensemble learning method that constructs decision trees during training. It can realize prediction on the mean prediction of trees for regression tasks by utilizing random subspace method and bagging during tree construction.SVM a traditional supervised learning method. By maximizing the margin between data samples, SVM can perform well on both regression and classification problem.Bi-LSTM a representative sequential deep learning method which consists of two LSTMs: one forward and the other backwards direction. Bi-LSTM effectively capture the contextual information in time dimension.Graph-CNN one of the most representative graph neural network method. By combining CNN with spectral theory, Graph-CNN is more advantageous in dealing with the discriminative feature extraction of signals in the discrete spatial domain and can better describe the intrinsic relationship between different nodes of the graph.To better reflect the performance of the compared models, in the ERKeeping track of the representation methods applied in the study on drug prediction, we compare the representation performance of ABCD-GGNN with those of representative baseline models, which can be categorized into two types: 1) traditional machine learning methods, for example, Linear Regression and Random Forest for ERIn terms of the detailed dataset setting, we keep the ratio of positive samples and negative samples close to 1:1 for each property. In addition, we utilize ten-fold cross-validation to evaluate the performance of all the compared methods. Positive and negative samples are kept balanced in each fold. We divide the dataset in a ratio of 8:1:1 as training set, validation set, and test set, respectively. The hyperparameters were tuned according to the performance on the validation set. Empirically, we set the learning rate as 0.01 with Adam optimizer and the dropout rate as 0.5. The interaction step of GGNN is set as 2. The hyper parameter The performance of the compared models on the prediction of ERentclass1pt{minimaWe conduct the experiments to calculate the mean runtime of ABCD-GGNN and other compared baselines on both ERTo demonstrate the effectiveness of both representation readout: discrete descriptor representation and topological graph representation, we take ablation study on the ABMET prediction task. The results are shown in Table In addition, since our designed hyper parameter We designed fusion strategy in the readout stage of ABCD-GGNN, which utilizes both average pooling and max pooling operations to better represent each compound. To demonstrate the effectiveness of the fusion of the two pooling operations, we take the ablation study in terms of the pooling operation selection as is shown in Table Interaction step is the key parameter which controls the global information interaction of molecular graph representation. Therefore, we coduct the ablation study to seek the optimal number of interaction step for anti-breast cancer candidate drug selection. Figure In the stage of discrete molecular descriptor representation, a XGBoost is adopted to select the top 50 molecular descriptors, which is intended to reduce the redundancy of the original 729 molecular descriptors. To demonstrate the effectiveness of the XGBoost, we conduct analysis on the 50 molecular descriptors from the XGBoost. The scores of and the heatmap of the selected 50 molecular descriptors are shown in Fig. We also conduct result analysis to demonstrate the biological rationality of the ranking operator for the final candidate drug selection. We first comprehensively consider the predicted value of the model’s biological activity value and the classification value of the ADMET property, and perform a cluster analysis on it, as shown in Fig. We evaluated the effectiveness of ABCD-GGNN in predicting ERThe experimental results of our method ABCD-GGNN confirm two perspectives to improve the performance of methods for predicting the properties of molecular compounds. From a computational perspective, advanced artificial intelligence methods such as graph neural networks can be utilized to construct a better representation of molecular compound properties based on the structure and substructure of molecules. From a biological perspective, effective integration of structural and substructural features of molecules and other characteristics that reflect the properties of molecules  can better model the characteristic expression of molecular compounds and help researchers understand the biological mechanisms involved. Conclusions above are based on the facts that 1) molecular descriptors can determine the biological activity of compounds as independent variables; 2) graph neural networks enable global feature extraction to further enhance the molecular representation; and 3) as illustrated in Table If a large number of molecular descriptor classes are available, we suggest using a regression model to evaluate the correlation of descriptors with compound properties and the coupling between descriptors , so as to reduce the redundancy and sparsity of the original molecular descriptors. We analyzed the original 729 molecular descriptors using the XGBoost model, and the results are shown in Table For the selection of anti-breast cancer drugs, we suggest a ranking operator consisting of feature binning and scorecard to select the appropriate anti-breast cancer drugs statistically. Figure In summary, in this paper, we give full consideration to the high correlation between ERIn this paper, we propose the ABCD-GGNN representation method aiming at topologically representing the features of anti-breast cancer candidate drugs and predicting the ERAdditional file 1. Descriptions of components of the feature initialization for the atomic nodes.


Structured review of video laryngoscopy recordings from physician team prehospital rapid sequence intubations (RSIs) may provide new insights into why prehospital intubations are difficult. The aim was to use laryngoscope video recordings to give information on timings, observed features of the airway, laryngoscopy technique, and laryngoscope performance. This was to both describe prehospital airways and to investigate which factors were associated with increased time taken to intubate.Sydney Helicopter Emergency Medical Service  has a database recording all intubations. The database comprises free-text case detail, airway dataset, scanned case sheet, and uploaded laryngoscope video. The teams of critical care paramedic and doctor use protocol-led intubations with a C-MAC Macintosh size four laryngoscope and intubation adjunct. First-pass intubation rate is approximately 97%. Available video recordings and their database entries were retrospectively analyzed for pre-specified qualitative and quantitative factors.Prehospital RSI video recordings were available for 385 cases from January 2018 through July 2020. Timings revealed a median of 58 seconds of apnea from laryngoscope entering mouth to ventilations. Median time to intubate  was 35 seconds, interquartile range 28-46 seconds. Suction was required prior to intubation in 29% of prehospital RSIs. Fogging of the camera lens at time of laryngoscopy occurred in 28%. Logistic regression revealed longer time to intubate was associated with airway soiling, Cormack-Lehane Grade 2 or 3, multiple bougie passes, or change of bougie.Video recordings averaging 35 seconds for first-pass success prehospital RSI with an adjunct give bed-side “definitions of difficulty” of 30 seconds for no glottic view, 45 seconds for no bougie placement, and 60 seconds for no endotracheal tube placement. Awareness of apnea duration can help guide decision making for oxygenation. All emergency intubators need to be cognizant of the need for suctioning. Improving the management of bloodied airways and bougie usage may reduce laryngoscopy duration and be a focus for training. Video screen fogging and missed recordings from some patients may be something manufacturers can address in the future. These reviews of airway registries of intubations performed with direct laryngoscopy Macintosh blades have identified factors such as expertise of operator, blood and/or vomitus in the airway, restricted jaw or neck movement, limited surrounding space, and in some studies, facial trauma, short neck, and obesity as associated with failed first-pass intubation and Cormack-Lehane Grade 3-4.Prehospital intubation is known to be challenging. Database studies internationally have investigated factors associated with this difficulty. First-pass success is desirable as it is associated with decreased complications in the critically ill. It is not known what airway factors are associated with difficult prehospital intubation with video laryngoscopy. If it is known why and how prehospital intubations are challenging, training and protocols can be tailored to address these challenges.With the introduction of video laryngoscopy, many services have seen their first-pass rates improve.Video laryngoscopy recordings provide new perspectives on the challenges in prehospital intubation. Recordings can show timing of events and record the actual airway encountered by the laryngoscopist. This is an advantage to databases reliant on clinician memory alone. Whether duration of laryngoscopy attempt is important to patient outcome is unknown. Duration of laryngoscopy measured from video laryngoscopy recordings was used as a marker of difficulty.The aim was to investigate the relationship between duration of laryngoscopy and airway challenges identified from both video and airway database. The hypothesis was that airway anatomy and pathology, laryngoscopy technique, and laryngoscope function could all impact duration of laryngoscopy. Reasons behind longer intubations and a time dependent definition of difficult intubation are proposed.Ethical approval [6457- 2020/ETH00981] for this retrospective observational analysis of routinely collected data was granted by Western Sydney Local Health District Human Research Ethics Committee . This manuscript follows STROBE guidelines.Sydney Helicopter Emergency Medical Service  performs approximately 260-300 prehospital rapid sequence intubations (RSIs) per year, predominantly for traumatic injury, with a 97% first-pass success rate. Operating from three bases in New South Wales, Australia, critical care doctor and paramedic teams are dispatched by road, helicopter, and fixed wing, attending approximately 3,000 cases each year. The doctors are consultants or senior trainees from anesthesia, emergency medicine, and intensive care. advocates a team approach to optimize first-pass success. This process and checklist are rehearsed at three monthly currencies. “30-second drills” are practiced when encountering difficulty with laryngoscopy. These cover re-checking patient positioning, use of external laryngeal manipulation or occipital lift, suctioning, attempting direct lift of epiglottis with blade, use of video laryngoscopy view, and a “deep midline lift and withdraw” technique before changing operator. “30-second drills” are so named because they can be accomplished within 30 seconds. The Sydney HEMS preferred technique is to use direct laryngoscopy with video screen confirmation by assistant, with the availability of video laryngoscopy at team discretion. The protocol allows for clinician discretion in whether a patient is preoxygenated (denitrogenated) by spontaneous breathing or assisted breaths. Oxygenation is via bag-valve-mask (BVM) fitted with variable PEEP valve held tightly against the face and nasal cannula. The protocol recommends assisting ventilations and the physician performing intubation when saturations do not reach 98% with this preoxygenation. All intubations are reviewed in quality assurance activities.The Sydney HEMS clinical practice standard for prehospital RSIThe C-MAC Pocket Monitor devices  with reusable metal Macintosh size four blades were introduced at the end of 2017. All teams are encouraged to try to video their laryngoscopies.The service carries two bougies, a blue hollow Frova intubating catheter  and a white solid plastic bougie . During the course of this study, the Frova bougie changed from packaged straight to manufactured curved.After a mission, the physician completes a cloud-based database . It is a combination of free-text entry fields, selection boxes, and a detailed airway registry. Uploading of hand-written clinical notes and CMAC videos is expected. Further detail is available on the Sydney HEMS website.Video laryngoscopy recordings were identified from the database from January 2018 until end of July 2020. Inclusion criteria were RSI (defined as an intubation with muscle relaxant in a patient with signs of life) in a prehospital setting.Key timepoints for video laryngoscope recordings were decided on before commencement of study, timed to the nearest second. Time zero was taken as laryngoscope passed between lips. Key timepoints were: optimized view of larynx accepted for placing bougie, bougie first seen on screen, bougie passing cords, tracheal tube passing cords, cuff inflation, and ventilations seen on the video as fogging in tracheal tube. Timings were taken from video laryngoscope recordings and not cross referenced with capnograph waveform, although successful intubation is judged by both visual confirmation of placement and end tidal carbon dioxide. In the event of an interrupted attempt, time to laryngoscope passing lips upon removal was measured. Time to intubation was therefore time from laryngoscope passing lips to tracheal tube passing glottis and was selected for the main analysis.Descriptive factors noted from the videos were: laryngoscopy blade initially inserted into vallecula or lifting epiglottis; airway soiling with blood; suctioning required; grossly abnormal airway anatomy; which bougie or stylet used, number of bougie attempts; fogging of camera lens; video screen “whiteout” from white bougie; and presence of foreign bodies.To determine if the video cohort were representative of the entire service prehospital RSI practice, comparison was made between the cases with videos and the overall caseload for that period from Air Maestro.Data from Air Maestro were extracted by two retrieval physicians. Data to be abstracted were defined before data collection commenced. In addition to the timings and observations described above, patient detail and airway registry detail were also taken from the database.Database information used for the analysis were patient age; night time; difficult airway predictor tick boxes ; intubated by doctor or critical care paramedic; grade of intubation; percentage of glottic opening; critical physiology before RSI drugs given .The data collection form was trialed and adjusted before use by both extractors (HG & CHB). For any discrepancies, collective agreement was reached. To confirm interrater reliability and consistency of data, collection was confirmed by funnel plot of variables. Database and chart review was conducted in accordance with good practice.Data were collected on RedCap software . Exploratory analysis was performed using statistical computing software . Descriptive statistics utilized parametric and non-parametric tests as appropriate. P <.05 was defined as statistical significance.A regression analysis was planned to investigate associations between airway factors and time to intubation. First-pass intubations time to intubate was selected as the outcome variable. Factors from both the airway registry and video analysis were then entered as independent variables as identified by relevant existing literature and clinical experience. As this was an exploratory analysis, a stepwise process was planned. Final model residuals would be examined for normality using the Shapiro-Wilk test and qq plot, and for heteroscedasticity using the Breusch-Pagan test to satisfy the assumptions and hence appropriateness of a linear regression before proceeding.Cases with missing variables for any of the airway factors examined have to be excluded from a linear regression .A total of 385 videos of prehospital RSIs were uploaded on the database Figure . The groFigure Second or subsequent laryngoscopy was required in 12 cases (3.1 %). First attempt was abandoned at 63 seconds (57-84) median (IQR). Reasons were given in medical notes for interrupting 11 of the 12 abandoned attempts and included: inadequate relaxation (1); desaturation (4); readjusting blade by same operator (2); change of operator (3); and BVM ventilation awaiting smaller tube (1).The following rates of equipment and patient challenges were noted. In 25% of cases 98/385), the anatomical landmarks were not clearly seen. Suctioning of blood and/or secretions was seen in 113/385 videos (29%). Glottic structures appeared significantly swollen or abnormal in 34 (8.8%) videos and one video revealed a foreign object . The video suffered “whiteout” with a temporary loss of view of glottis during insertion of the white bougie in 12 of 135 cases (9%).The time between the bougie appearing on the video and it passing the cords was a median (IQR [range]) of two (1-5 [0-70]) seconds. For 10% of first-pass intubations, the bougie was being manipulated on screen for over 15 seconds. The number of bougie passes towards the cords seen during this time was median two (IQR 2-3) but with a range of two to eleven.A small number of outlier observations n = 26) were omitted from the final model which did not change the regression results. Time to intubate was median 35 seconds with interquartile range 28-46 seconds with range 16 and 111 seconds, as given in Table 6 were omTable Checkbox criteria for difficult airway predictors identified by the team before laryngoscopy were indicated for 201 of 367 intubations 54.8%), as shown in Table .8%, as sThe average time from start of laryngoscopy until ventilations seen was 58 seconds. Many practitioners were not aware that laryngoscopy and intubation takes one minute on average. This could guide decision making on oxygenation. The choice to hand ventilate before laryngoscopy may be based on the perceived risk of desaturation – which needs to take into account both the time taken waiting for paralysis before laryngoscopy and the further minute for laryngoscopy before ventilations occur. to troubleshoot difficult views, so named because they can be completed within 30 seconds. This study suggests they be started at 30 seconds also.From the videos, the following definitions of difficult intubation for prehospital systems utilizing CMAC Macintosh laryngoscopes with bougies is proposed. Difficult laryngoscopy would be a view of the glottis not achieved within 30 seconds . Difficult bougie placement would be not passed by 45 seconds . Difficult intubation would be those taking longer than 60 seconds for tracheal tube to pass cord (33 of 368 [9.0%] took longer than 60 seconds). Teams use “30-second drills” and is reflected in this dataset where one in three cases needed suctioning. Together with screen fogging and bougie whiteout, the risk of camera soiling highlights the need for maintaining skills in direct laryngoscopy for prehospital providers. Training for airway soiling events seems warranted.The soiled airway is well-known to prehospital practitionersThe need for multiple bougie passes may reflect a challenging laryngoscopy, room for skill improvement, or a combination. Within this cohort of 97% first-pass intubations, 10% of those intubations took longer than 15 seconds to place a bougie after gaining a view of the glottis. Whether changing bougie equipment, its storage, or bougie skills training could reduce the number of bougie passes remains unknown.None of the bed-side difficult airway predictors from the airway registry  showed as a relationship with first-pass time to intubate. Whilst it is tempting the dismiss these historical predictors as not useful, it may be that the approach used effectively mitigates for these well-known factors.Only 385 videos from 694 prehospital RSI intubations were studied, although the characteristics of the video group marry those of the overall workload. Challenges to videoing are both inherent in the device and human in nature. Hopefully technology will provide some solutions in the future.Statistical analysis dependent on assumptions of the linear model often requires certain compromises, such as excluding extreme outliers. This reduces the number of cases available to the analysis. Fortunately, sensitivity analysis showed that the removal of outlier values did not alter the results and conclusions from the regression.The C-MAC images are only one small part appreciating the challenges in prehospital intubation. The image does not capture the entire pharyngeal space. There are of course challenges outside of the mouth – eyewear fogging, reduced manual dexterity in the cold, and equipment failures, to name a few. The video recordings are a valuable part of quality assurance process and can be seen on the Sydney HEMS website.Future work could investigate the relationship with patient outcomes such as desaturation, regurgitation, or airway trauma for prolonged attempts, and whether they are desirable to multiple attempts.Knowledge of average timings could aid decision making on value of continuing or interrupting a laryngoscopy attempt. Linear regression identified a soiled airway and multiple attempts to pass a bougie are associated with increased time to intubate. In analyzing timings, it is impossible to distinguish between operator, equipment, context, and patient and one should be cautious in interpretation. Bloody airways and bougie technique would be a worthwhile focus for future training. The CMAC screen fogging and difficulty recording are areas for future technological advance.