Degenerate oligonucleotide primer MIG-seq: an effective PCR-based method for high-throughput genotyping.

Next-generation sequencing (NGS) library construction often involves using restriction enzymes to decrease genome complexity, enabling versatile polymorphism detection in plants. However, plant leaves frequently contain impurities, such as polyphenols, necessitating DNA purification before enzymatic reactions. To overcome this problem, we developed a PCR-based method for expeditious NGS library preparation, offering flexibility in number of detected polymorphisms. By substituting a segment of the simple sequence repeat sequence in the MIG-seq primer set (MIG-seq being a PCR method enabling library construction with low-quality DNA) with degenerate oligonucleotides, we introduced variability in detectable polymorphisms across various crops. This innovation, named degenerate oligonucleotide primer MIG-seq (dpMIG-seq), enabled a streamlined protocol for constructing dpMIG-seq libraries from unpurified DNA, which was implemented stably in several crop species, including fruit trees. Furthermore, dpMIG-seq facilitated efficient lineage selection in wheat and enabled linkage map construction and quantitative trait loci analysis in tomato, rice, and soybean without necessitating DNA concentration adjustments. These findings underscore the potential of the dpMIG-seq protocol for advancing genetic analyses across diverse plant species.

Targeting apolipoprotein E and N-terminal amyloid ß-protein precursor interaction improves cognition and reduces amyloid pathology in Alzheimer's mice.

Apolipoprotein E (apoE) interaction with amyloid ß-protein precursor (APP) has garnered attention as the therapeutic target for Alzheimer's disease (AD). Having discovered the apoE antagonist (6KApoEp) that blocks apoE binding to N-terminal APP, we tested the therapeutic potential of 6KApoEp on AD-relevant phenotypes in amyloid ß-protein precursor/presenilin 1 (APP/PS1) mice that express each human apoE isoform of apoE2, apoE3, or apoE4 (designated APP/PS1/E2, APP/PS1/E3, or APP/PS1/E4 mice). At 12 months of age, we intraperitoneally administered 6KApoEp (250 µg/kg) or vehicle once daily for 3 months. At 15 months of age, blockage of apoE and N-terminal APP interaction by 6KApoEp treatment improved cognitive impairment in most tests of learning and memory, including novel object recognition and maze tasks in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse line and did not alter behavior in nontransgenic littermates. Moreover, 6KApoEp therapy ameliorated brain parenchymal and cerebral vascular ß-amyloid deposits and decreased abundance of amyloid ß-protein (Aß) in APP/PS1/E2, APP/PS1/E3, and APP/PS1/E4 mice versus each vehicle-treated mouse group. Notably, the highest effect in Aß-lowering by 6KApoEp treatment was observed in APP/PS1/E4 mice versus APP/PS1/E2 or APP/PS1/E3 mice. These effects occured through shifting toward lessened amyloidogenic APP processing due to decreasing APP abundance at the plasma membrane, reducing APP transcription, and inhibiting p44/42 mitogen-activated protein kinase phosphorylation. Our findings provide the preclinical evidence that 6KApoEp therapy aimed at targeting apoE and N-terminal APP interaction is a promising strategy and may be suitable for patients with AD carrying the apoE4 isoform.

Cytological Analysis of the Surgical Field During Transanal Total Mesorectal Excision for Rectal Cancer: A Prospective Study.

BACKGROUND: An unexpectedly large number of patients experienced local recurrence with transanal total mesorectal excision in Norway. This appears to be associated with cancer cell spillage during surgery. OBJECTIVE: To investigate the surgical field cytology during transanal total mesorectal excision. DESIGN: This was a prospective cohort study. SETTINGS: This study was conducted at a single center between June and December 2020. PATIENTS: Forty patients with rectal cancer underwent transanal total mesorectal excision. After irrigation of the surgical field, the water specimens were cytologically evaluated at 6 representative steps. The first sample was used as an initial control. The second, third, fourth, fifth, and sixth samples were collected after the first pursestring suture, rectotomy, the second pursestring suture, specimen resection, and anastomosis, respectively. The clinicopathological features and intraoperative complications of the patients were reviewed. MAIN OUTCOME MEASURES: The primary outcome was to evaluate the presence of cancer cells in washing cytological samples. RESULTS: Of the 40 consecutive patients enrolled in this study, 18 patients underwent neoadjuvant chemoradiotherapy. Incomplete first pursestring suture and rectal perforation were observed in 4 (10.0%) and 3 (7.5%) cases, respectively. In the first sample, 31 patients (77.5%) had malignant cells. Malignant findings were detected in 2 patients (5.0%) from the second to fifth samples. None of the sixth sample exhibited any malignant findings. LIMITATIONS: This single-center study had a small sample size. CONCLUSIONS: Cancer cells were initially detected by cytology, but only a few were observed throughout the procedure; however, cancer cells were not detected in the final surgical field. Further follow-up and novel studies are required to obtain clinically significant findings using cytology during transanal total mesorectal excision. See Video Abstract . ANLISIS CITOLGICO DEL CAMPO QUIRRGICO DURANTE LA ESCISIN TOTAL DEL MESORRECTO TRANSANAL PARA EL CNCER DE RECTO UN ESTUDIO PROSPECTIVO: ANTECEDENTES:Un número inesperadamente grande de pacientes experimentó recurrencia local con la escisión total del mesorrecto transanal en Noruega. Esto parece estar asociado con el derrame de células cancerosas durante la cirugía.OBJETIVO:Investigar la citología del campo quirúrgico durante la escisión total del mesorrecto transanal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Este estudio se realizó en un solo centro entre junio y diciembre de 2020.PACIENTES:Cuarenta pacientes con cáncer de recto se sometieron a escisión total del mesorrecto transanal. Después de la irrigación del campo quirúrgico, las muestras de agua se evaluaron citológicamente en seis pasos representativos. La primera muestra se utilizó como control inicial. La segunda, tercera, cuarta, quinta y sexta muestras se recolectaron después de la primera sutura en bolsa de tabaco, la rectotomía, la segunda sutura en bolsa de tabaco, la resección de la muestra y la anastomosis, respectivamente. Se revisaron las características clínico-patológicas y las complicaciones intraoperatorias de los pacientes.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue evaluar la presencia de células cancerosas en el lavado de muestras citológicas.RESULTADOS:De los 40 pacientes consecutivos inscritos en este estudio, 18 pacientes se sometieron a quimiorradioterapia neoadyuvante. Se observaron la primera sutura en bolsa de tabaco incompleta y perforación rectal en cuatro (10,0%) y tres (7,5%) casos, respectivamente. En la primera muestra, 31 (77,5%) pacientes tenían células malignas. Se detectaron hallazgos malignos en dos pacientes (5,0%) de la segunda a la quinta muestra. Ninguno de la sexta muestra demostraron hallazgos malignos.LIMITACIONES:Este estudio unicéntrico tuvo un tamaño de muestra pequeño.CONCLUSIONES:Inicialmente se detectaron células cancerosas mediante citología, pero solo se observaron unas pocas durante todo el procedimiento; sin embargo, no se detectaron células cancerosas en el campo quirúrgico final. Se requieren más seguimientos y estudios novedosos para obtener hallazgos clínicamente significativos mediante citología durante la escisión total del mesorrecto transanal. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Radiotherapy with or without chemotherapy for locally advanced head and neck cancer in elderly patients: analysis of the Head and Neck Cancer Registry of Japan.

BACKGROUND: Whether concurrent chemotherapy with radiotherapy (CRT) is effective for elderly patients with head and neck cancer is a controversial topic. This study aimed to analyze the effectiveness of CRT vs. radiation therapy (RT) among elderly patients in Japan. METHODS: Data from the Head and Neck Cancer Registry of Japan were extracted and analyzed. Patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx who received definitive CRT or RT between 2011 and 2014 were included. RESULTS: CRT was administered to 78% of the 1057 patients aged ≥ 70 years and 67% of the 555 patients aged ≥ 75 years. For the patients aged ≥ 75 years, the overall survival (OS) rate was significantly better in the CRT group than in the RT group (P < 0.05), while the progression-free survival (PFS) rate was not significantly different (P > 0.05). The add-on effect of CRT was significantly poor in elderly patients (P < 0.05), and it was not a significant factor in the multivariate analysis for patients aged ≥ 75 years. After propensity score matching, there were no significant differences in the OS and PFS rates between the patients aged ≥ 70 years and those aged ≥ 75 years (all, P > 0.05). CONCLUSION: Although aggressive CRT is administered to elderly patients in Japan, its effectiveness is uncertain. Further prospective randomized trials are needed to verify whether CRT is superior to RT alone for elderly patients.

Clinical outcome, radiological findings, and genetic features of IDH-mutant brainstem glioma in adults.

BACKGROUND: With the recent advent of genetic testing, IDH-mutant glioma has been found among adult brainstem gliomas. However, the clinical outcome and prognosis of IDH-mutant brainstem gliomas in adults have not been elucidated. This study aimed to investigate the clinical outcome, radiological findings, and genetic features of adult patients with IDH-mutant diffuse brainstem gliomas. METHODS: Data from adult patients with brainstem glioma at Hokkaido University Hospital between 2006 and 2022 were retrospectively analyzed. Patient characteristics, treatment methods, genetic features, and prognosis were evaluated. RESULTS: Of 12 patients with brainstem glioma with proven histopathology, 4 were identified with IDH mutation. All patients underwent local radiotherapy with 54 Gray in 27 fractions combined with chemotherapy with temozolomide. Three patients had IDH1 R132H mutation and one had IDH2 R172G mutation. The median progression-free survival and overall survival were 68.4 months and 85.2 months, respectively, longer than that for IDH-wildtype gliomas (5.6 months and 12.0 months, respectively). At the time of initial onset, contrast-enhanced lesions were observed in two of the four cases in magnetic resonance imaging. CONCLUSION: As some adult brainstem gliomas have IDH mutations, and a clearly different prognosis from those with IDH-wildtype, biopsies are proactively considered to confirm the genotype.

A new predictive parameter for dose-volume metrics in intensity-modulated radiation therapy planning for prostate cancer: Initial phantom study.

BACKGROUND: Organ-at-risk (OAR) sparing is often assessed using an overlap volume-based parameter, defined as the ratio of the volume of OAR that overlaps the planning target volume (PTV) to the whole OAR volume. However, this conventional overlap-based predictive parameter (COPP) does not consider the volume relationship between the PTV and OAR. PURPOSE: We propose a new overlap-based predictive parameter that consider the PTV volume. The effectiveness of proposed overlap-based predictive parameter (POPP) is evaluated compared with COPP. METHODS: We defined as POPP = (overlap volume between OAR and PTV/OAR volume) × (PTV volume/OAR volume). We generated intensity modulated radiation therapy (IMRT) based on step and shoot technique, and volumetric modulated arc therapy (VMAT) plans with the Auto-Planning module of Pinnacle3 treatment planning system (v14.0, Philips Medical Systems, Fitchburg, WI) using the American Association of Physicists in Medicine Task Group (TG119) prostate phantom. The relationship between the position and size of the prostate phantom was systematically modified to simulate various geometric arrangements. The correlation between overlap-based predictive parameters (COPP and POPP) and dose-volume metrics (mean dose, V70Gy, V60Gy, and V37.5 Gy for rectum and bladder) was investigated using linear regression analysis. RESULTS: Our results indicated POPP was better than COPP in predicting intermediate-dose metrics. The bladder results showed a trend similar to that of the rectum. The correlation coefficient of POPP was significantly greater than that of COPP in < 62 Gy (82% of the prescribed dose) region for IMRT and in < 55 Gy (73% of the prescribed dose) region for VMAT regarding the rectum (p < 0.05). CONCLUSIONS: POPP is superior to COPP for creating predictive models at an intermediate-dose level. Because rectal bleeding and bladder toxicity can be associated with intermediate-doses as well as high-doses, it is important to predict dose-volume metrics for various dose levels. POPP is a useful parameter for predicting dose-volume metrics and assisting the generation of treatment plans.

Changes in the corrected carotid flow time can predict spinal anesthesia-induced hypotension in patients undergoing cesarean delivery: an observational study.

PURPOSE: Spinal anesthesia is a standard technique for cesarean delivery; however, it possesses a risk of hypotension. We hypothesised that the changes in the corrected flow time induced by the Trendelenburg position could predict the incidence of hypotension after spinal anesthesia for cesarean delivery. METHODS: Patients undergoing elective cesarean delivery under spinal anesthesia were enrolled. Before anesthesia induction, corrected flow time was measured in the supine and Trendelenburg positions (FTc-1 and FTc-2, respectively). Additionally, a percent change in corrected flow time induced by the Trendelenburg position was defined as ΔFTc. The primary endpoint was to investigate the ability of ΔFTc to predict the incidence of spinal anesthesia-induced hypotension until delivery. The receiver operating characteristics curves to assess the ability of FTc-1, FTc-2, and ΔFTc to predict the incidence of hypotension were generated. RESULTS: Finally, 40 patients were included, and of those, 26 (65%) developed spinal anesthesia-induced hypotension. The areas under the curve for FTc-1, FTc-2, and ΔFTc were 0.591 (95% CI: 0.424 to 0.743) (P = 0.380), 0.742 (95% CI: 0.579 to 0.867) (P = 0.004), and 0.882 (95% CI: 0.740 to 0.962) (P < 0.001) respectively, indicating ΔFTc as the best predictor among these three parameters. The best threshold for ΔFTc was 6.4% (sensitivity: 80.8% (95% CI: 53.8 to 96.2), specificity: 85.7% (95% CI: 42.9 to 100.0)). CONCLUSIONS: This study demonstrated that changes in the corrected carotid flow time induced by the Trendelenburg position could serve as a good predictor of spinal anesthesia-induced hypotension for cesarean delivery.

Symmetrized Liouvillian Gap in Markovian Open Quantum Systems.

Markovian open quantum systems display complicated relaxation dynamics. The spectral gap of the Liouvillian characterizes the asymptotic decay rate toward the steady state, but it does not necessarily give a correct estimate of the relaxation time because the crossover time to the asymptotic regime may be too long. We here give a rigorous upper bound on the transient decay of autocorrelation functions in the steady state by introducing the symmetrized Liouvillian gap. The standard Liouvillian gap and the symmetrized one are identical in an equilibrium situation but differ from each other in the absence of the detailed balance condition. It is numerically shown that the symmetrized Liouvillian gap always gives a correct upper bound on the decay of the autocorrelation function, but the standard Liouvillian gap does not.

Intranodal dynamic contrast-enhanced CT lymphangiography and dynamic contrast-enhanced MR lymphangiography in microminipig.

OBJECTIVES: To evaluate the feasibility and image quality of intranodal dynamic contrast-enhanced CT lymphangiography (DCCTL) and dynamic contrast-enhanced MR lymphangiography (DCMRL) in microminipigs. METHODS: Our institution's committee for animal research and welfare provided approval. Three microminipigs underwent DCCTL and DCMRL after inguinal lymph node injection of 0.1 mL/kg contrast media. Mean CT values on DCCTL and signal intensity (SI) on DCMRL were measured at the venous angle and thoracic duct (TD). The contrast enhancement index (CEI; increase in CT values pre- to post-contrast) and signal intensity ratio (SIR; SI of lymph divided by SI of muscle) were evaluated. The morphologic legibility, visibility, and continuity of lymphatics were qualitatively evaluated using a 4-point scale. Two microminipigs underwent DCCTL and DCMRL after lymphatic disruption and the detectability of lymphatic leakage was evaluated. RESULTS: The CEI peaked at 5-10 min in all microminipigs. The SIR peaked at 2-4 min in two microminipigs and at 4-10 min in one microminipig. The peak CEI and SIR values were 235.6 HU and 4.8 for venous angle, 239.4 HU and 2.1 for upper TD, and 387.3 HU and 2.1 for middle TD. The visibility and continuity of upper-middle TD scores were 4.0 and 3.3-3.7 for DCCTL, and 4.0 and 4.0 for DCMRL. In the injured lymphatic model, both DCCTL and DCMRL demonstrated lymphatic leakage. CONCLUSIONS: DCCTL and DCMRL in a microminipig model enabled excellent visualization of central lymphatic ducts and lymphatic leakage, indicating the research and clinical potential of both modalities. KEY POINTS: • Intranodal dynamic contrast-enhanced computed tomography lymphangiography showed a contrast enhancement peak at 5-10 min in all microminipigs. • Intranodal dynamic contrast-enhanced magnetic resonance lymphangiography showed a contrast enhancement peak at 2-4 min in two microminipigs and at 4-10 min in one microminipig. • Both intranodal dynamic contrast-enhanced computed tomography lymphangiography and dynamic contrast-enhanced magnetic resonance lymphangiography demonstrated the central lymphatic ducts and lymphatic leakage.

Usefulness of the GLIM criteria to predict recovery of activities of daily living in older adults with post-acute stroke.

OBJECTIVES: The usefulness of malnutrition diagnosed using the Global Leadership Initiative on Malnutrition (GLIM) criteria as a predictor of recovery of activities of daily living is unclear. This study aimed to investigate whether baseline malnutrition diagnosed using the GLIM criteria was predictive of recovery of activities of daily living in older patients with post-acute stroke. MATERIALS AND METHODS: A retrospective cohort study was conducted in patients aged ≥70 years with post-acute stroke. The outcome was activities of daily living measured using the motor domain of the Functional Independence Measure (FIM-motor) score at discharge. Participants were classified as malnourished or non-malnourished according to the GLIM criteria. Multivariate linear regression analyses were performed to determine whether baseline malnutrition diagnosed using the GLIM criteria was predictive of the FIM-motor score at discharge. The analysis was adjusted for clinically relevant covariates associated with rehabilitation outcomes after stroke. RESULTS: A total of 236 patients (mean age, 80.0 years; female, 54.2%) were included in the analysis. On admission, 83 (35.2%) patients were diagnosed with malnutrition. Multivariate linear regression analyses showed that malnutrition diagnosed using the GLIM criteria was predictive of the FIM-motor score at discharge (ß = -0.347, P < 0.001). CONCLUSIONS: Identifying malnutrition using the GLIM criteria is useful for predicting recovery of activities of daily living in older patients with post-acute stroke.

Deep breathing alleviates propofol-induced pain: a prospective, randomized, single-blind study.

PURPOSE: Propofol is commonly used to induce general anesthesia; however, the pain caused during propofol injection is a disadvantage. This study aimed to assess whether deep breathing attenuates propofol injection pain. METHODS: This prospective, single-blind, randomized controlled study included 200 patients who were scheduled to undergo elective surgery under general anesthesia and randomly and equally divided them into group D and group C. The observers were not blinded to the pain-relieving modality, but each patient was blinded. Group D patients were requested to repeatedly take deep breaths throughout general anesthesia induction with propofol. Group C patients were requested to breathe in the usual manner. The intensity of propofol injection pain was evaluated using the visual analog scale (VAS). Furthermore, we recorded the patients' pain expressions, including grimace or hand-withdrawal, and the recalled pain measured using a VAS in the post-anesthetic care units (PACU). RESULTS: Compared with patients in group C, those in group D showed significantly reduced VAS scores for propofol injection pain (20 [interquartile range (IQR): 0-48] vs. 37 [IQR 9-65], P = 0.017) and recalled pain in the PACU (16 [IQR 0-32] vs. 26 [IQR 0.5-51], P = 0.031). Further, the grimace incidence was significantly lower in group D (18%) than in group C (45%) (P < 0.001). There was no significant difference in the incidence of pain at induction, recalled pain, or hand-withdrawal. CONCLUSIONS: Deep breathing could be an easy, safe, and inexpensive method for reducing pain during propofol injection.

Heating Rates under Fast Periodic Driving beyond Linear Response.

Heating under periodic driving is a generic nonequilibrium phenomenon, and it is a challenging problem in nonequilibrium statistical physics to derive a quantitatively accurate heating rate. In this work, we provide a simple formula on the heating rate under fast and strong periodic driving in classical and quantum many-body systems. The key idea behind the formula is constructing a time-dependent dressed Hamiltonian by moving to a rotating frame, which is found by a truncation of the high-frequency expansion of the micromotion operator, and applying the linear-response theory. It is confirmed for specific classical and quantum models that the second-order truncation of the high-frequency expansion yields quantitatively accurate heating rates beyond the linear-response regime. Our result implies that the information on heating dynamics is encoded in the first few terms of the high-frequency expansion, although heating is often associated with an asymptotically divergent behavior of the high-frequency expansion.

Validation of Continuous Noninvasive Blood Pressure Monitoring Using Error Grid Analysis.

BACKGROUND: Error grid analysis was recently proposed to compare blood pressure obtained by 2 measurement methods. This study aimed to compare continuous noninvasive blood pressure (CNBP) with invasive blood pressure (IBP) using the error grid analysis and investigate the confounding risk factors attributable to the differences between CNBP and IBP. METHODS: Sixty adult patients undergoing general anesthesia were prospectively enrolled. Simultaneous comparative data regarding CNBP and IBP were collected. The Bland-Altman analysis was conducted to compare CNBP and IBP for systolic blood pressure (SBP) and mean blood pressure (MBP; acceptable accuracy: mean bias <5 mm Hg; standard deviation <8 mm Hg). The clinical relevance of the discrepancies between CNBP and IBP was evaluated by the error grid analysis, which classifies the differences into 5 zones from "no risk" (A) to "dangerous risk" (E). Additionally, an ordinal logistic regression analysis was performed to evaluate the relationship between the risk zones for MBP, classified by the error grid analysis and covariates of interest. RESULTS: A total of 10,663 pairs of CNBP/IBP were finally analyzed. The Bland-Altman analysis showed an acceptable accuracy with a bias of -3.3 ± 5.6 mm Hg for MBP but a poor accuracy with a bias of 5.4 ± 10.5 mm Hg for SBP. The error grid analysis showed the proportions of zones A to E as 96.7%, 3.2%, 0.1%, 0%, and 0% for SBP, respectively, and 72.0%, 27.9%, 0.1%, 0%, and 0% for MBP, respectively. The finger cuff missed 23.9% of epochs when SBP <90 mm Hg and 55.3% of epochs when MBP <65 mm Hg. The ordinal logistic regression analysis revealed that older age (adjusted odds ratio for decade: 1.54, 95% confidence interval [CI], 1.15-2.08; P = .004) and length of time from the initiation of finger cuff inflation (adjusted odds ratio for 60 minutes: 1.40, 95% CI, 1.13-1.73; P = .002) were significant factors of being in a more dangerous zone of the error grid. CONCLUSIONS: The error grid analysis revealed the larger clinical discrepancy between CNBP and IBP in MBP compared with that in SBP. Old age and longer finger cuff inflation time were significant factors of being in a more dangerous zone of the error grid, which could affect the hemodynamic management during surgery.

A frameshift variant in the EXT1 gene in a feline leukemia virus-negative cat with osteochondromatosis.

Osteochondromatosis is a benign proliferative disorder characterized by cartilage-capped bony protuberances. In humans and most mammals, variants in the EXT1 or EXT2 gene are strongly correlated with the etiology of osteochondromatosis. However, in cats, osteochondromatosis has only been associated with feline leukemia virus infection. In this study, to explore other factors involved in the etiology of feline osteochondromatosis, we examined the EXT1 and EXT2 genes in a feline leukemia virus-negative cat with osteochondromatosis. Genetic analysis revealed a heterozygous single base pair duplication in exon 6 of the EXT1 gene (XM_023248762.2:c.1468dupC), leading to a premature stop codon in the EXT1 protein. Notably, this frameshift variant is recognized as one of the most common pathogenic variants in human osteochondromatosis. Our data suggest for the first time that genetic variants can have etiologic roles in osteochondromatosis in cats, as in humans and other animals.

Validation of a novel virtual reality simulation system with the focus on training for surgical dissection during laparoscopic sigmoid colectomy.

BACKGROUND: Mastery of technical skills is one of the fundamental goals of surgical training for novices. Meanwhile, performing laparoscopic procedures requires exceptional surgical skills compared to open surgery. However, it is often difficult for trainees to learn through observation and practice only. Virtual reality (VR)-based surgical simulation is expanding and rapidly advancing. A major obstacle for laparoscopic trainees is the difficulty of well-performed dissection. Therefore, we developed a new VR simulation system, Lap-PASS LP-100, which focuses on training to create proper tension on the tissue in laparoscopic sigmoid colectomy dissection. This study aimed to validate this new VR simulation system. METHODS: A total of 50 participants were asked to perform medial dissection of the meso-sigmoid colon on the VR simulator. Forty-four surgeons and six non-medical professionals working in the National Cancer Center Hospital East, Japan, were enrolled in this study. The surgeons were: laparoscopic surgery experts with > 100 laparoscopic surgeries (LS), 21 were novices with experience < 100 LS, and five without previous experience in LS. The participants' surgical performance was evaluated by three blinded raters using Global Operative Assessment of Laparoscopic Skills (GOALS). RESULTS: There were significant differences (P-values < 0.044) in all GOALS items between the non-medical professionals and surgeons. The experts were significantly superior to the novices in one item of GOALS: efficiency ([4(4-5) vs. 4(3-4)], with a 95% confidence interval, p = 0.042). However, both bimanual dexterity and total score in the experts were not statistically different but tended to be higher than in the novices. CONCLUSIONS: Our study demonstrated a full validation of our new system. This could detect the surgeons' ability to perform surgical dissection and suggest that this VR simulator could be an effective training tool. This surgical VR simulator might have tremendous potential to enhance training for surgeons.

Changes in corrected carotid flow time induced by recruitment maneuver predict fluid responsiveness in patients undergoing general anesthesia.

Non-invasive methods to assess patients' fluid responsiveness during lung-protective ventilation are needed. We hypothesized changes in the corrected carotid flow time induced by the recruitment maneuver predict fluid responsiveness under general anesthesia. Thirty patients undergoing general anesthesia in the supine position were prospectively enrolled. The study protocol was conducted when the patient was hemodynamically stable during surgery. Flow time was measured on Doppler images of the common carotid artery. Carotid flow time, heart rate, stroke volume, stroke volume variation, and pulse pressure variation were recorded before and after a recruitment maneuver at a continuous airway pressure of 30 cmH2O for 30 s, and before and after volume expansion with 250 mL for 10 min. Patients were defined as fluid responders if the increase in stroke volume was > 10% after volume expansion. Twenty patients (67%) were fluid responders. All Doppler images for carotid flow time were obtained within 30 s. Changes in the corrected flow time accurately predicted fluid responsiveness (area under the curve: 0.82, 95% confidence interval [CI] 0.64-0.94, p = 0.002). The optimal threshold for changes in the corrected flow time was - 11.7% with a sensitivity of 95.0% (95% CI 75.1-99.9%) and a specificity of 80.0% (95% CI 44.4-97.5%). The gray-zone of changes in the corrected flow time was from - 25.1 to - 12.2% and included 12 patients (40%). Changes in the corrected carotid flow time were a useful, technically easy-to-perform, and non-invasive method to predict fluid responsiveness without a need for hemodynamic monitoring or arterial cannulation.

Combined Hypofractionated Radiotherapy and Chemotherapy Versus Hypofractionated Radiotherapy Alone for Cats with Localized Sinonasal Lymphoma.

Despite considering hypofractionated radiotherapy (HRT) a useful treatment option for feline localized sinonasal lymphoma (stage I), the benefits of additional chemotherapy remain controversial. This retrospective cohort study evaluated the efficacy of the early initiation of chemotherapy in combination with HRT (HRTC) to prolong the progression-free survival (PFS) and overall survival (OS) in cats with localized sinonasal lymphoma compared with HRT alone. While 24 eligible cats received HRT alone (HRT group), 18 received HRTC (HRTC group). The total median administered dose was 35 Gy, with one fraction per week, for a median of five fractions. In the HRTC group, the chemotherapy protocol was cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based and cyclophosphamide, vincristine, and prednisolone (COP)-based in 14 (78%) and 4 cats (22%), respectively. Cats in the HRTC group had significantly longer PFS (677 versus 104 days; P = .04) and OS (983 versus 263 days; P = .04) than those in the HRT group. Considering the poor outcome in the HRT group despite the cats having received rescue chemotherapy for progressive disease, the early initiation of additional chemotherapy along with HRT may be recommended for feline localized sinonasal lymphoma.

Outcome of Localized Bile Duct Carcinoma in Six Dogs Treated with Liver Lobectomy.

The prognosis for bile duct carcinoma in dogs is generally believed to be poor. However, only a few studies have evaluated the postoperative outcomes in such cases. The objective of this case series was to describe the postoperative outcomes of localized intrahepatic bile duct carcinoma in dogs. The electronic medical records of 16 dogs with bile duct carcinoma were reviewed, and 6 dogs were included in the study. All cases were diagnosed as bile duct carcinoma using postoperative pathology, and five of them had already been diagnosed using preoperative core biopsy. The tumors in all of the dogs were confirmed as completely resected on histopathological examination. Two dogs received toceranib following the surgery. The median follow-up time was 693 days (range, 420-1386 days), with a median survival time of 894 days (range, 420-1386 days). Local recurrence or distant metastases were detected in two of the six dogs (33%) on 354 and 398 days following surgery, respectively. The median progression-free survival was 492 days (range, 354-1386 days). In conclusion, dogs with localized intrahepatic bile duct carcinoma had a good prognosis following complete surgical resection.

Familial adenomatous polyposis in dogs: hereditary gastrointestinal polyposis in Jack Russell Terriers with germline APC mutations.

Many hereditary disorders in dogs have equivalents in humans and thus attract attention as natural animal models. Breed predisposition to certain diseases often provides promising clues to explore novel hereditary disorders in dogs. Recently, cases of gastrointestinal (GI) polyps in Jack Russell Terriers (JRTs) have increased in Japan. In 21 affected JRTs, polyps were found in either or both the stomach and colorectum, with a predilection for the gastric antrum and rectum. Multiple polyps were found in 13 of 21 examined dogs, including 5 dogs with both gastric and colorectal polyps. Some dogs were found to have GI polyps at an early age, with the youngest case being 2.3 years old. Histopathologically, 43 of 46 GI polyps (93.5%) were diagnosed as adenomas or adenocarcinomas. Immunohistochemical analysis revealed cytoplasmic and nuclear accumulation of ß-catenin in the tumor cells. As in the case of human patients with familial adenomatous polyposis, all examined JRTs with GI polyps (n = 21) harbored the identical heterozygous germline APC mutations, represented by a 2-bp substitution (c.[462A>T; 463A>T]). The latter substitution was a non-sense mutation (p.K155X) resulting in a truncated APC protein, thus suggesting a strong association with this cancer-prone disorder. Somatic mutation and loss of the wild-type APC allele were detected in the GI tumors of JRTs, suggesting that biallelic APC inactivation was involved in tumor development. This study demonstrated that despite differences in the disease conditions between human and dog diseases, germline APC mutation confers a predisposition to GI neoplastic polyps in both dogs and humans.

Gallic acid is a dual α/ß-secretase modulator that reverses cognitive impairment and remediates pathology in Alzheimer mice.

Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid ß-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular ß-amyloid deposits, and decreased cerebral amyloid ß-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates α- and reduces ß-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits ß-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA. We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.