[Advancements in research on para-aortic lymph node dissection in colorectal cancer].

Para-aortic lymph node metastasis from colorectal cancer is relatively rare. Recent studies have shown that curative para-aortic lymph node dissection can lead to similar prognoses as stage III colorectal cancer for selected patients. However, there are still many unresolved debates regarding the appropriate surgical indications, extent of lymph node dissection, and treatment principles for colorectal cancer patients with para-aortic lymph node metastasis. With the continuous improvement of laparoscopic colorectal surgery techniques, the previously complex and high-risk procedure of para-aortic lymph node dissection has now become a safe and feasible approach. However, there are still several challenges that need to be addressed in this field. It is imperative to conduct multicenter clinical studies to demonstrate the survival benefits of this surgical procedure into greater survival benefits. This will help generate more robust evidence in the field of evidence-based medicine.

Cost-effectiveness of virtual reality and wet laboratory cataract surgery simulation.

PURPOSE: To evaluate the cost-effectiveness of phacoemulsification simulation training in virtual reality simulator and wet laboratory on operating theater performance. METHODS: Residents were randomized to a combination of virtual reality and wet laboratory phacoemulsification or wet laboratory phacoemulsification. A reference control group consisted of trainees who had wet laboratory training without phacoemulsification. All trainees were assessed on operating theater performance in 3 sequential cataract patients. International Council of Ophthalmology Surgical Competency Assessment Rubric-phacoemulsification (ICO OSCAR phaco) scores by 2 masked independent graders and cost data were used to determine the incremental cost-effectiveness ratio (ICER). A decision model was constructed to indicate the most cost-effective simulation training strategy based on the willingness to pay (WTP) per ICO OSCAR phaco score gained. RESULTS: Twenty-two trainees who performed phacoemulsification in 66 patients were analyzed. Trainees who had additional virtual reality simulation achieved higher mean ICO OSCAR phaco scores compared with trainees who had wet laboratory phacoemulsification and control (49.5 ± standard deviation [SD] 9.8 vs 39.0 ± 15.8 vs 32.5 ± 12.1, P < .001). Compared with the control group, ICER per ICO OSCAR phaco of wet laboratory phacoemulsification was $13,473 for capital cost and $2209 for recurring cost. Compared with wet laboratory phacoemulsification, ICER per ICO OSCAR phaco of additional virtual reality simulator training was US $23,778 for capital cost and $1879 for recurring cost. The threshold WTP values per ICO OSCAR phaco score for combined virtual reality simulator and wet laboratory phacoemulsification to be most cost-effective was $22,500 for capital cost and $1850 for recurring cost. CONCLUSIONS: Combining virtual reality simulator with wet laboratory phacoemulsification training is effective for skills transfer in the operating theater. Despite of the high capital cost of virtual reality simulator, its relatively low recurring cost is more favorable toward cost-effectiveness.

Chemoenzymatic Synthesis of 13-Oxoverruculogen.

Verruculogens are rare fumitremorgin alkaloids that contain a highly unusual eight-membered endoperoxide. In this paper, we report a concise chemoenzymatic synthesis of 13-oxoverruculogen using enzymatic C-H peroxidation and rhodium-catalyzed C-C bond activation reactions to install the eight-membered endoperoxide and the pentacyclic core of the natural product, respectively. Our strategy involves the use of 13-epi-fumitremorgin B as a substrate analog for endoperoxidation by verruculogen synthase, FtmOx1. The resulting product, 13-epi-verruculogen, is the first unnatural endoperoxide generated by FtmOx1 and is used in the first synthesis of 13-oxoverruculogen. This strategy enables a 10-step synthesis of this natural product from commercially available starting materials and illustrates a hybrid approach utilizing biocatalytic and transition-metal-catalyzed reactions to access challenging alkaloid architectures. Moreover, this work demonstrates the use of native enzyme promiscuity as a viable strategy for the chemoenzymatic synthesis of natural products.

[Clinical application and standardized implementation of intersphincteric resection].

Intersphincteric resection (ISR) is the ultimate sphincter-preserving surgical technique for low rectal cancer. To promote the standardized implementation of ISR, this review discusses the important issues regarding the clinical application of ISR with reference to the latest Chinese expert consensus on ISR. In terms of ISR-related pelvic anatomy of the rectum/anal canal, hiatal ligament is not identical with the anococcygeal ligament. At the level where the rectourethralis muscle continuously extends to the posteroinferior area of the membranous urethra from the rectum, the neurovascular bundle is identified between the posterior edge of rectourethralis muscle and the anterior edge of the longitudinal muscle of the rectum. This knowledge is crucial to detect the anterior dissection plane during ISR at the levator hiatus level. The indication criteria for ISR included: (1) stage I early low rectal cancer; (2) stage II-III low rectal cancer undergoing neoadjuvant treatment, and supra-anal tumors and juxta-anal tumors of stage ycT3NxM0, or intra-anal tumors of stage ycT2NxM0. However, signet ring cell carcinoma, mucinous adenocarcinoma and undifferentiated carcinoma should be contraindicated to ISR. For locally advanced low rectal cancer (especially anteriorly located tumor), neoadjuvant treatment should be carried out in a standardized manner. However, it should be recognized that neoadjuvant chemoradiotherapy was a risk factor for poor anal function after ISR. For surgical approaches for ISR, including transanal, transabdominal, and transanal transabdominal approaches, the choice should be based on oncological safety and functional consequences. While ensuring the negative margin, maximal preservation of rectal walls and anal canal contributs to better postoperative anorectal function. Careful attention must be paid to complications regarding ISR, with special focus on the anastomotic complications. The incidence of low anterior resection syndrome (LARS) was higher than 40%. However, this issue is often neglected by clinicians. Thus, management and rehabilitation strategies for LARS with longer follow-ups were required.

[Anatomical and histological investigation of the area anterior to the anorectum passing through the levator hiatus].

Objective: To document the anatomical structure of the area anterior to the anorectum passing through the levator hiatus between the levator ani slings bilaterally. Methods: Three male hemipelvises were examined at the Laboratory of Clinical Applied Anatomy, Fujian Medical University. (1) The anatomical assessment was performed in three ways; namely, by abdominal followed by perineal dissection, by examining serial cross-sections, and by examining median sagittal sections. (2) The series was stained with hematoxylin and eosin to enable identification of nerves, vessels, and smooth and striated muscles. Results: (1) It was found that the rectourethralis muscle is closest to the deep transverse perineal muscle where the longitudinal muscle of the rectum extends into the posteroinferior area of the membranous urethra. The communicating branches of the neurovascular bundle (NVB) were identified at the posterior edge of the rectourethralis muscle on both sides. The rectum was found to be fixed to the membranous urethra through the rectourethral muscle, contributing to the anorectal angle of the anterior rectal wall. (2) Serial cross-sections from the anal to the oral side were examined. At the level of the external anal sphincter, the longitudinal muscle of the rectum was found to extend caudally and divide into two muscle bundles on the oral side of the external anal sphincter. One of these muscle bundles angled dorsally and caudally, forming the conjoined longitudinal muscle, which was found to insert into the intersphincteric space (between the internal and external anal sphincters). The other muscle bundle angled ventrally and caudally, filling the gap between the external anal sphincter and the bulbocavernosus muscle, forming the perineal body. At the level of the superficial transverse perineal muscle, this small muscle bundle headed laterally and intertwined with the longitudinal muscle in the region of the perineal body. At the level of the rectourethralis and deep transverse perineal muscle, the external urethral sphincter was found to occupy an almost completely circular space along the membranous part of the urethra. The dorsal part of the external urethral sphincter was found to be thin at the point of attachment of the rectourethralis muscle, the ventral part of the longitudinal muscle of the rectum. We identified a venous plexus from the NVB located close to the oral and ventral side of the deep transverse perineal muscle. Many vascular branches from the NVB were found to be penetrating the longitudinal muscle and the ventral part of rectourethralis muscle at the level of the apex of the prostate. The rectourethral muscle was wrapped ventrally around the membranous urethra and apex of the prostate. The boundary between the longitudinal muscle and prostate gradually became more distinct, being located at the anterior end of the transabdominal dissection plane. (3) Histological examination showed that the dorsal part of the external urethral sphincter (striated muscle) is thin adjacent to the striated muscle fibers from the deep transverse perineal muscle and the NVB dorsally and close by. The rectourethral muscle was found to fill the space created by the internal anal sphincter, deep transverse perineal muscle, and both levator ani muscles. Many tortuous vessels and tiny nerve fibers from the NVB were identified penetrating the muscle fibers of the deep transverse perineal and rectourethral muscles. The structure of the superficial transverse perineal muscle was typical of striated muscle. These findings were reconstructed three-dimensionally. Conclusions: In intersphincteric resection or abdominoperineal resection for very low rectal cancer, the anterior dissection plane behind Denonvilliers' fascia disappears at the level of the apex of the prostate. The prostate and both NVBs should be used as landmarks during transanal dissection of the non-surgical plane. The rectourethralis muscle should be divided near the rectum side unless tumor involvement is suspected. The superficial and deep transverse perineal muscles, as well as their supplied vessels and nerve fibers from the NVB. In addition, the cutting direction should be adjusted according to the anorectal angle to minimize urethral injury.

[Anatomical classification of and laparoscopic surgery for left-sided colorectal cancer with persistent descending mesocolon].

Objective: To investigate anatomical morphology and classification of persistent descending mesocolon (PDM) in patients with left-sided colorectal cancer, as well as the safety of laparoscopic radical surgery for these patients. Methods: This is a descriptive study of case series. Relevant clinical data of 995 patients with left colon and rectal cancer who had undergone radical surgery in Fujian Medical University Union Hospital from July 2021 to September 2022 were extracted from the colorectal surgery database of our institution and retrospectively analyzed. Twenty-four (2.4%) were identified as PDM and their imaging data and intra-operative videos were reviewed. We determined the distribution and morphology of the descending colon and mesocolon, and evaluated the feasibility and complications of laparoscopic surgery. We classified PDM according to its anatomical characteristics as follows: Type 0: PDM combined with malrotation of the midgut or persistent ascending mesocolon; Type 1: unfixed mesocolon at the junction between transverse and descending colon; Type 2: PDM with descending colon shifted medially (Type 2A) or to the right side (Type 2B) of the abdominal aorta at the level of the origin of the inferior mesentery artery (IMA); and Type 3: the mesocolon of the descending-sigmoid junction unfixed and the descending colon shifted medially and caudally to the origin of IMA. Results: The diagnosis of PDM was determined based on preoperative imaging findings in 9 of the 24 patients (37.5%) with left-sided colorectal cancer, while the remaining diagnoses were made during intraoperative assessment. Among 24 patients, 22 were male and 2 were female. The mean age was (63±9) years. We classified PDM as follows: Type 0 accounted for 4.2% (1/24); Type 1 for 8.3% (2/24); Types 2A and 2B for 37.5% (9/24) and 25.0% (6/24), respectively; and Type 3 accounted for 25.0% (6/24). All patients with PDM had adhesions of the mesocolon that required adhesiolysis. Additionally, 20 (83.3%) of them had adhesions between the mesentery of the ileum and colon. Twelve patients (50.0%) required mobilization of the splenic flexure. The inferior mesenteric artery branches had a common trunk in 14 patients (58.3%). Twenty-four patients underwent D3 surgery without conversion to laparotomy; the origin of the IMA being preserved in 22 (91.7%) of them. Proximal colon ischemia occurred intraoperatively in two patients (8.3%) who had undergone high ligation at the origin of the IMA. One of these patients had a juxta-anal low rectal cancer and underwent intersphincteric abdominoperineal resection because of poor preoperative anal function. Laparoscopic subtotal colectomy was considered necessary for the other patient. The duration of surgery was (260±100) minutes and the median estimated blood loss was 50 (20-200) mL. The median number of No. 253 lymph nodes harvested was 3 (0-20), and one patient (4.2%) had No.253 nodal metastases. The median postoperative hospital stay was 8 (4-23) days, and the incidence of complications 16.7% (4/24). There were no instances of postoperative colon ischemia or necrosis observed. One patient (4.2%) with stage IIA rectal cancer developed Grade B (Clavien-Dindo III) anastomotic leak and underwent elective ileostomy. The other complications were Grade I-II. Conclusions: PDM is frequently associated with mesenteric adhesions. Our proposed classification can assist surgeons in identifying the descending colon and mesocolon during adhesion lysis in laparoscopic surgery. It is crucial to protect the colorectal blood supply at the resection margin to minimize the need for unplanned extended colectomy, the Hartmann procedure, or permanent stomas.

Cost-effectiveness of Direct Transfer to Angiography Suite of Patients With Suspected Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Patients with acute ischemic stroke due to large vessel occlusion (LVO) deemed eligible for endovascular thrombectomy (EVT) are transferred from the emergency room to the angiography suite to undergo the procedure. Recently, the strategy of direct transfer of patients with suspected LVO to the angiography suite (DTAS) has been shown to improve functional outcomes. This study aims to evaluate the cost-effectiveness of the DTAS strategy vs initial transfer of patients with suspected LVO (Rapid Arterial Occlusion Evaluation score >4 and NIH Stroke Scale >10) to the emergency room (ITER). METHODS: A decision-analytic Markov model was developed to estimate the cost-effectiveness of the DTAS strategy vs the ITER strategy from a Dutch health care perspective with a 10-year time horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER) using Dutch thresholds of $59,135 (€50,000) and $94,616 (€80,000) per quality-adjusted life year (QALY). Uncertainty of input parameters was assessed using 1-way sensitivity analysis, scenario analysis, and probabilistic sensitivity analysis. RESULTS: The DTAS strategy yielded 0.65 additional QALYs at an additional $16,089, resulting in an ICER of $24,925/QALY compared with the ITER strategy. The ICER varied from $27,169 to $38,325/QALY across different scenarios. The probabilistic sensitivity analysis showed that the DTAS strategy had a 91.8% and 97.0% likelihood of being cost-effective at a decision threshold of $59,135/QALY and $94,616/QALY, respectively. DISCUSSION: The cost-effectiveness of the DTAS strategy over ITER is robust for patients with suspected LVO. Together with recently published clinical results, this means that implementation of the DTAS strategy may be considered to improve the workflow and outcome of EVT.

The role of EZH2 in ocular diseases: a narrative review.

EZH2, acting as a catalytic subunit of PRC2 to catalyze lysine 27 in histone H3, induces the suppression of gene expression. EZH2 can regulate cell proliferation and differentiation of retinal progenitors, which are required for physiological retinal development. Meanwhile, an abnormal level of EZH2 has been observed in ocular tumors and other pathological tissues. This review summarizes the current knowledge on EZH2 in retinal development and ocular diseases, including inherited retinal diseases, ocular tumors, corneal injury, cataract, glaucoma, diabetic retinopathy and age-related retinal degeneration. We highlight the potential of targeting EZH2 as a precision therapeutic target in ocular diseases.

EZH2 is a protein that helps to regulate the activity of genes in cells. It works as a part of a complex called PRC2 to control a chemical group called lysine 27 in histone H3 and then inhibit the expression of genes. EZH2 is important for the normal development of the retina. Abnormal levels of EZH2 are associated with various eye diseases. This review summarizes the role of EZH2 in different ocular diseases and the potential mechanisms. Targeting EZH2 may be a novel way to treat or prevent ocular diseases.

Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function 692.

The domain of unknown function 692 (DUF692) is an emerging family of post-translational modification enzymes involved in the biosynthesis of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. Members of this family are multinuclear iron-containing enzymes, and only two members have been functionally characterized to date: MbnB and TglH. Here, we used bioinformatics to select another member of the DUF692 family, ChrH, that is encoded in the genomes of the Chryseobacterium genus along with a partner protein ChrI. We structurally characterized the ChrH reaction product and show that the enzyme complex catalyzes an unprecedented chemical transformation that results in the formation of a macrocycle, an imidazolidinedione heterocycle, two thioaminals, and a thiomethyl group. Based on isotopic labeling studies, we propose a mechanism for the four-electron oxidation and methylation of the substrate peptide. This work identifies the first SAM-dependent reaction catalyzed by a DUF692 enzyme complex, further expanding the repertoire of remarkable reactions catalyzed by these enzymes. Based on the three currently characterized DUF692 family members, we suggest the family be called multinuclear non-heme iron dependent oxidative enzymes (MNIOs).

Flipped Classroom Case Learning vs Traditional Lecture-Based Learning in Medical School Ophthalmology Education: A Randomized Trial.

PURPOSE: To address the problem of teaching noncore specialties, for which there is often limited teaching time and low student engagement, a flipped classroom case learning (FCCL) module was designed and implemented in a compulsory 5-day ophthalmology rotation for undergraduate medical students. The module consisted of a flipped classroom, online gamified clinical cases, and case-based learning. METHOD: Final-year medical students in a 5-day ophthalmology rotation were randomized to the FCCL or a traditional lecture-based (TLB) module. The outcomes of subjective assessments (student-rated anonymous Likert scale questionnaire, scale 1 to 5, and course and teaching evaluation, scale 1 to 6) and objective assessments (end-of-rotation and post-MBChB multiple-choice questions, scale 0 to 60) were compared between the 2 groups. RESULTS: Between May 2021 and June 2022, 216 students (108 in each group) completed the study. Compared with the TLB students, the students in the FCCL group rated various aspects of the course statistically significantly higher, including feeling more enthusiastic and engaged by the course and more encouraged to ask questions and participate in discussions (all P < .001). They also gave higher ratings for the instructional methods, course assignments, course outcomes, and course workload ( P < .001). They gave higher course and teaching evaluation scores to the tutors (5.7 ± 0.6 vs 5.0 ± 1.0, P < .001). The FCCL group scored higher than the TLB group on the end-of-rotation multiple-choice questions (53.6 ± 3.1 vs 51.8 ± 2.8, P < .001). When 32 FCCL students and 36 TLB students were reassessed approximately 20 weeks after the rotation, the FCCL group scored higher (40.3 ± 9.1) than the TLB group (34.3 ± 10.9, P = .018). CONCLUSIONS: Applying the FCCL module in ophthalmology teaching enhanced medical students' satisfaction, examination performance, and knowledge retention. A similar model may be suitable for other specialties.

A remarkable transformation catalyzed by a domain-of-unknown-function 692 during the biosynthesis of a new RiPP natural product.

The domain of unknown function 692 (DUF692) is an emerging family of posttranslational modification enzymes involved in the biosynthesis of ribosomally-synthesized and posttranslationally modified peptide (RiPP) natural products. Members of this family are multinuclear iron-containing enzymes and only two members have been functionally characterized to date: MbnB and TglH. Here, we used bioinformatics to select another member of the DUF692 family, ChrH, that is ubiquitously encoded in the genomes of the Chryseobacterium genus along with a partner protein ChrI. We structurally characterized the ChrH reaction product and show that the enzyme catalyzes an unprecedented chemical transformation that results in the formation of a macrocycle, an imidazolidinedione heterocycle, two thioaminals, and a thiomethylation. Based on isotopic labeling studies, we propose a mechanism for the four-electron oxidation and methylation of the substrate peptide. This work identifies the first SAM-dependent DUF692 enzyme, further expanding the repertoire of remarkable reactions catalyzed by these enzymes.

The endorectal incision level of transanal total mesorectal excision (taTME): An emphasis on the distance from the anterior vs. posterior mesorectal ends to the anal verge.

BACKGROUND: There is no intraluminal guidance to ensure complete inclusion of the mesorectum in transanal total mesorectal excision (taTME). This study aimed to assess the distance difference between the anterior and posterior mesorectal terminal ends and the anal verge as a potential risk for residual mesorectum after resection. METHODS: Forty-four surgical specimens of extra-levator abdominoperineal excision (ELAPE) and 28 mid-sagittal cadaveric specimens were included to this study. The distance between the mesorectum terminal end (T) and the endoluminal landmarks (dentate line (D)/anal verge (A)) was measured and compared between men and women. Furthermore, 66 MRI images from The Cancer Imaging Archive (TCIA) were used to validate the same concept in a non-Asian population. RESULTS: The mesorectal terminal end was found to be aligned along with the levator hiatus. From the midsagittal view, the ELAPE specimens showed that the distance between T and A anteriorly was significantly longer than the same distance posteriorly (34.74±7.79mm vs 23.74±4.24mm, P<0.001). Similarly, the distance measured in the cadaveric specimens was significantly longer anteriorly than posteriorly (P<0.001). The validation cohort of non-Asian MRI image has confirmed the same (56.68±14.17mm vs. 38.18 ±10.42mm, P<0.001(. There was no significant difference between men and women. CONCLUSIONS: Because of the remarkable distance difference between the anterior and posterior mesorectal terminal ends away from the anal verge, the taTME proctectomy level may not meet the required mesorectal end. Thus, if TME is planned, aligning the proctectomy level around the levator hiatus would be the best place that can ensure complete TME.

Surveillance, Diversity and Vegetative Compatibility Groups of Fusarium oxysporum f. sp. vasinfectum Collected in Cotton Fields in Australia (2017 to 2022)

Cotton (Gossypium hirsutum) is a billion-dollar crop in regional New South Wales (NSW) and Queensland, Australia. Fusarium wilt (FW) caused by Fusarium oxysporum f. sp. vasinfectum (Fov) is an economically important disease. Initial disease losses of up to 90% when the disease was first detected resulted in fields being taken out of cotton production. The disease is now well-managed due to the adoption of highly resistant varieties. However, annual disease surveys recently revealed that the disease dynamic has changed in the past few seasons. With relatively mild and wet weather conditions during the 2021/22 growing season, FW was detected in eight surveyed valleys in NSW and Queensland, with the disease incidence as high as 44.5% and 98.5% in individual fields in early and late seasons, respectively. Fov is genetically distinct and evolved from local Fusarium oxysporum strains. Additionally, the pathogen was reported to evolve rapidly under continuous cotton cropping pressure. However, our knowledge of the genetic composition of the prevailing population is limited. Sequences of the translation elongation factor alpha 1 (TEF1) revealed that 94% of Fusarium isolates recovered from FW-infected cotton were clustered together with known Australian Fov and relatively distant related to overseas Fov races. All these isolates, except for nine, were further confirmed positive with a specific marker based on the Secreted in Xylem 6 (SIX6) effector gene. Vegetative compatibility group (VCG) analyses of 166 arbitrarily selected isolates revealed a predominance of VCG01111. There was only one detection of VCG01112 in the Border Rivers valley where it was first described. In this study, the exotic Californian Fov race 4 strain was not detected using a specific marker based on the unique Tfo1 insertion in the phosphate (PHO) gene. This study indicated that the prevalence and abundance of Fov across NSW and Queensland in the past five seasons was probably independent of its genetic diversity.

[Historical evolution and ultimate goal of minimally invasive surgery for colorectal cancer].

Minimally invasive colorectal surgery has been an entity for just over 30 years. Compared with traditional open surgery, minimally invasive surgery has the advantages of less trauma, more delicate operation and faster postoperative recovery. At present, minimally invasive surgery for colorectal tumor shows a diversified trend in terms of surgical approach, surgical platform or surgical methods. Besides, standardized comprehensive treatment and immunotherapy have had far-reaching impacts on the development of minimally invasive surgery. The diagnosis and treatment of perioperative complications is still another important topic in the research of minimally invasive surgery in the future. In addition to the short-term outcomes, the most important thing that patients truly require and emphasize is the permanence of the curative effect, that is, long-term survival and good defecation, urination and sexual function. Thus, permanence is the ultimate goal of minimally invasive surgery. To achieve this, we should strive to correct improper treatment methods, rationally select applicable groups of emerging surgical approaches and surgical platforms, pay more attention to comprehensive tumor diagnosis and treatment, and prudently carry out new technology research on the basis of the basic concept of patient safety.

New Insights Into the Substorm Initiation Sequence From the Spatio-Temporal Development of Auroral Electrojets.

In the present study we examine three substorm events, Events 1-3, focusing on the spatio-temporal development of auroral electrojets (AEJs) before auroral breakup. In Events 1 and 2, auroral breakup was preceded by the equatorward motion of an auroral form, and the ground magnetic field changed northward and southward in the west and east of the expected equatorward flow, respectively. Provided that these magnetic disturbances were caused by local ionospheric Hall currents, this feature suggests that the equatorward flow turned both eastward and westward as it reached the equatorward part of the auroral oval. The auroral breakup took place at the eastward-turning and westward-turning branches in Events 1 and 2, respectively, and after the auroral breakup, the westward AEJ enhanced only on the same side of the flow demarcation meridian. The zonal flow divergence is considered as an ionospheric manifestation of the braking of an earthward flow burst in the near-Earth plasma sheet and subsequent dawnward and duskward turning. Therefore, in Events 1 and 2, the auroral breakup presumably mapped to the dawnward and duskward flow branches, respectively. Moreover, for Event 3, we do not find any pre-onset auroral or magnetic features that can be associated with an equatorward flow. These findings suggest that the braking of a pre-onset earthward flow burst itself is not the direct cause of substorm onset, and therefore, the wedge current system that forms at substorm onset is distinct from the one that is considered to form as a consequence of the flow braking.

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas.

In a cross-continental research initiative, including researchers working in Australia and Denmark, and based on joint external funding by a 3-year grant from the Novo Nordisk Foundation, we have used DNA sequencing, extensive chemical profiling and molecular networking analyses across the entire Eremophila genus to provide new knowledge on the presence of natural products and their bioactivities using polypharmocological screens. Sesquiterpenoids, diterpenoids and dimers of branched-chain fatty acids with previously unknown chemical structures were identified. The collection of plant material from the Eremophila genus was carried out according to a 'bioprospecting agreement' with the Government of Western Australia. We recognize that several Eremophila species hold immense cultural significance to Australia's First Peoples. In spite of our best intentions to ensure that new knowledge gained about the genus Eremophila and any potential future benefits are shared in an equitable manner, in accordance with the Nagoya Protocol, we encounter serious dilemmas and potential conflicts in making benefit sharing with Australia's First Peoples a reality.

Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma.

BACKGROUND: Ripretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study. PATIENTS AND METHODS: Patients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit. RESULTS: A total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs. CONCLUSIONS: In this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients.

[Delayed gastric emptying after surgery for transverse colon cancer: diagnosis, management and prevention].

Delayed gastric emptying is a syndrome of gastric motility disorder with slow gastric emptying as the main sign, provided that mechanical factors such as intestinal obstruction and anastomotic stricture are excluded. The incidence of delayed gastric emptying after colon cancer surgery is 1.4%, mainly after transverse colon cancer surgery. Most of the studies on delayed gastric emptying are case reports, lacking systematic studies. The diagnoses and treatments can be draw on the experience of delayed gastric emptying after pancreatic surgery. Our retrospective study indicated that the incidence of delayed gastric emptying after surgery for transverse colon cancer was 4.0%, higher than that for other colon cancer. Patients who underwent gastrocolic ligament lymph node dissection were at higher risk than those who did not (3.6% vs. 0.8%). Gastrocolic ligament lymph node dissection and stress are causative factors for delayed gastric emptying after surgery for transverse colon cancer. We add the gastrografin test upon the diagnostic criteria of the International Study Group for Pancreatic Surgery, which is simple and practical. Nasogastric tube decompression, enteral nutrition combined with parenteral nutrition, glucocorticoids, and prokinetic agents can cure most patients with postoperative delayed gastric emptying. All the patients with postoperative delayed gastric emptying were cured in our studies. Strict indications for gastrocolic ligament lymph node dissection (patients with cT3-4 and cN+) may decrease the occurrence of delayed gastric emptying after surgery for transverse colon cancer.

[Anatomical observation and clinical significance of the prostatic part of neurovascular bundle in total mesorectal excision].

Objective: To observe the anatomical architecture of the prostatic part of the neurovascular bundle (NVB) in total mesorectal excision (TME). Methods: A descriptive cohort study and an anatomical observation study were carried out. A total of 38 male patients with rectal cancer who underwent TME in the Department of Colorectal Surgery at the affiliated Union hospital of Fujian Medical University between November 2013 and March 2015 were included. A total of 4 hemipelvis were examined at the Laboratory of Clinical Applied Anatomy, Fujian Medical University. The following outcomes were observed: 1) the clinical significance of bleeding of the prostatic part of NVB: surgical videos were reviewed and the incidence of bleeding was recorded. The urogenital function was assessed using the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) score. The correlation between prostatic part bleeding and postoperative urogenital function was evaluated. 2) anatomical observation: the vessels, nerve fibers, as well as their surrounding fatty tissue from the prostatic part were treated as a whole, namely, the fat pad of the prostatic part. The anatomical architecture of the prostatic part in the surgical videos was reviewed and interpreted with the cadaveric findings. Categorical variables were compared between groups using a Fisher exact probability. while continuous variables with skewed distribution were compared between groups using the Mann-Whiteny U test. Results: The median age of the included 38 patients was 57 years (range, 31-75), and the median tumor distance to the anal verge was 6 cm (range, 1-8). Of them, a total number of 21 (55.3%) patients had bleeding of the prostatic part of NVB (bleeding group), while the rest had not (17 cases, 44.7%, non-bleeding group). 1) the clinical significance of bleeding of the prostatic part of NVB. The urinary function significantly decreased in patients in the bleeding group according to IPSS score after the 3rd month and the 6rd month of the surgery [7 (0-16) vs. 2 (0-3), Z=-1.787, P=0.088; 2 (0-15) vs. 0 (0-2), Z=-2.270, P=0.028]. There was no difference regarding the IPSS score between the two groups after 1 year of the surgery (P>0.05). With a total of 23 patients with normal preoperative sexual activity included, 87.5% (7/8) of patients in the non-bleeding group can expect to return to their preoperative baseline, this incidence was significantly higher than that of only 40% (6/15) in the bleeding group (P=0.029). 2) anatomical observation: for cadaveric observation, the prostatic part of NVB was located in the narrow triangular space composed of anterolateral walls of the rectum, the posterolateral surface of the prostate and the medial surface of the levator ani musculature. The tiny vascular branches and nerve fibers from the prostatic part were hard to identify. The cavernosal nerves cannot reliably be distinguished from the neural supply to the prostate, rectum and levator ani. In the cross-section of levels of prostatic base and mid-prostate in cadaveric hemipelvis specimens, the boundary of the prostatic part fat pad was partly overlapped and merged with the boundary of the mesorectum. Intraoperative observation showed that the areas of overlap referred to the rectal branches from the prostatic part piercing the proper fascia to supply the mesorectum, which carried the largest tension and high risk of bleeding during circumferential dissection toward the perirectal plane. The ultrasonic scalpel was required to pre-coagulate the rectal branches at the point close to the proper fascia of the rectum to prevent bleeding. In the cross-section of the prostatic apex level, the prostatic part approached ventrally and its boundary was away from the boundary of the mesorectum. Conclusions: NVB prostatic part injury is one of the causes of urogenital dysfunction after TME. The nerve fibers from the prostatic part were tiny, and its functional zones cannot be distinguished during operation. Therein, the fat pad of the prostatic part should be protected as a whole. Understanding the morphology of the fat pad of the prostatic part provides invaluable surgical guidance to dissect this critical area. When dissecting around the anterolateral rectal wall, appropriate anti-traction tension should be maintained and the rectal branches from the prostatic part should be coagulated with an ultrasonic scalpel to prevent bleeding.