Development of a performance rubric for transanal endoscopic rectal purse-string sutures.

BACKGROUND: Placing a transanal endoscopic rectal purse-string suture (taEPS) is the crucial first component of transanal total mesorectal excision (taTME). However, no structured training is available to improve the procedure-specific skills for taEPS. The aim of this study was to create a performance rubric to improve taEPS skills and provide preliminary evidence for its validity. METHODS: A performance rubric was created based on technical considerations for taEPS, identified by consulting with taTME surgical and performance assessment experts. Ten independent, blinded raters assessed 10 videotaped taEPS procedures of consecutive taTME cases, at National Cancer Center Hospital East (NCCHE), Chiba, Japan, in January 2018-March 2019 using the rubric and the Global Operative Assessment of Laparoscopic Skills (GOALS). Internal consistency and inter-rater reliabilities were calculated. Videotaped taEPS procedures were timed and assessed by the rubric. Correlation between rubric scores and suturing times were analyzed. RESULTS: The rubric consists of four items: loading the needle (LN), atraumatic needle passage (AP), planned suture path (PS), and overall performance (OA). Videotaped performances were graded on a 3-point Likert scale; scores were calculated as sums of the points. Cronbach's α for internal consistency was 0.713. Inter-rater reliabilities were LN: 0.73, AP: 0.76, PS: 0.71, and OA: 0.70. Rubric and GOALS scores were strongly correlated (r = 0.964, p < 0.001). In 112 consecutive taEPS performances, rubric scores were strongly correlated with suturing time (r = - 0.69, p < 0.001). Surgeons' experience with taTME was associated with rubric scores and suturing time. CONCLUSIONS: This study provides preliminary validation for the taEPS skill performance rubric. The rubric's structured training may facilitate skill acquisition by providing trainees with critical clinical considerations.

A novel surgical training simulator for transanal total mesorectal excision.

BACKGROUND: The transanal total mesorectal excision (TaTME) approach for rectal cancer has been gaining popularity. Although TaTME requires specific training, the opportunity to obtain this training is limited. We developed the first dry simulator that includes some important structural landmarks to provide training that includes all the procedural steps of TaTME. METHODS: The model was structured based on a computed tomography scan data. The simulator mimics the rectum and surrounding key anatomical structures. All material components were made of polyvinyl alcohol and stained with various colors to easily identify these anatomical structures while undergoing the training. RESULTS: Our simulator is compact in its size and can be easily packed, stacked, and stored. The materials mimic the real one and the model allows us to perform the entire step-by-step TaTME procedures with genuine clinical devices from the attachment of operative platform to the anastomosis. We have held the course 24 times to date, with more than 200 surgeons participating not only from domestic hospitals but also from other countries. The result of the satisfaction survey from 65 participants, which was rated from 0 to 10 points, was an average score of 8.6 (± 1.4) points. CONCLUSIONS: We present the world's first TaTME simulator and believe that it will play an important role for the safe spread of TaTME surgery.

Highly c-axis orientated superconducting core and large critical current density in Ba0.6Na0.4Fe2As2 powder-in-tube tape.

Improvement of the critical current density (Jc) of superconducting wires/tapes is one of the key issues in the field of superconductivity applications. Here we report the fabrication of a silver-sheathed Ba1-xNaxFe2As2 (BaNa-122) superconducting tape by using a powder-in-tube technique and its superconducting properties, in particular transport Jc, as well as the tape-core texture. The optimally-doped BaNa-122 tape with Na concentration x = 0.4 exhibits the superconducting critical temperature (Tc) of 33.7 K and high transport Jc of 4 × 104 A/cm2 at 4.2 K in a magnetic field of 4 T. Patterns of x-ray diffraction for the superconducting core show that the degree of c-axis orientation is significantly enhanced through the tape fabrication process. The tendency of c-axis orientation is advantageous for achieving higher Jc, suggesting the high potential of BaNa-122 for superconducting wire/tape applications.

Impact of different timing of consuming sweet snack on postprandial glucose excursions in healthy women.

AIMS: Our aim was to evaluate the acute effect of eating sweet snacks at different times of day on glycaemic parameters in young women without diabetes. METHODS: In this randomized controlled three-treatment crossover study, 17 women [(means ± SD) age: 21.2 ± 0.8 years, BMI: 20.7 ± 2.5 kg/m2, HbA1c: 36 ± 2 mmol/mol (5.1 ± 0.2%)] wore flash (continuous) glucose monitoring systems for 7 days. Each participant consumed identical test meals on days 4, 5 and 6, but consumed sweet snacks (baked cake: 498 kcal; 53.6 g of carbohydrate, 8.0 g of protein, 28.0 g of fat) at 12:30 (post-lunch), 15:30 (mid-afternoon) and 19:30 (post-dinner), respectively, on each of those days. Daily glycaemic parameters on those 3 days of snacking at different times of day were compared within-participant. RESULTS: The mean amplitude of glycaemic excursions (3.54 ± 0.32 vs. 2.73 ± 0.20 mmol/L; P < 0.05), standard deviation of glucose (1.20 ± 0.11 vs. 0.92 ± 0.07 mmol/L; P < 0.05), incremental area under the curve (IAUC) for glucose at 12:00-07:00 (986 ± 89 vs. 716 ± 88 mmol/L × min; P < 0.05) and IAUC at 07:00-10:00 the next day (141 ± 17 vs. 104 ± 12 mmol/L × min; P < 0.05) when the snack was eaten post-dinner were all significantly higher than with mid-afternoon snacking. CONCLUSION: Eating sweet snacks post-dinner should be avoided because it worsens glucose excursions as well as postprandial glucose levels after both dinner and the following day's breakfast in young healthy (non-diabetic) women.

CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves.

Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD+ reduction in the hippocampus. Cask expression is responsive to NAD+ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD+ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD+ availability through supplementation of NAD+ intermediates, such as NMN.

Consuming snacks mid-afternoon compared with just after lunch improves mean amplitude of glycaemic excursions in patients with type 2 diabetes: A randomized crossover clinical trial.

AIMS: Our aim was to explore the acute effects of consuming snacks at different times on glucose excursions in patients with type 2 diabetes (T2D). METHODS: Seventeen patients with T2D [means±SD: age 67.4±9.4-years; BMI 23.5±3.1kg/m2; HbA1c 55±6mmol/mol (7.2±1.0%)] were randomly assigned in this crossover study. Each participant wore a continuous glucose monitoring device for 4 days and consumed identical test meals on the second and third days, comprising breakfast at 0700h, lunch at 1200h and dinner at 1900h. Half the participants consumed 75kcal biscuits at 1230h (just after lunch) on the second day and at 1530h (mid-afternoon) on the third day, while the other half consumed snacks at the same times, but vice versa. Each patient's glucose parameters were compared against baseline for the 2days of snacking at different times of day. RESULTS: Consuming snacks in the mid-afternoon led to significantly lower mean amplitudes of glycaemic excursions (mean±SEM: 5.19±0.48 vs. 6.90±0.69mmol/L, P<0.01; standard deviation: 1.75±0.17 vs. 2.16±0.21mmol/L, P<0.01) and incremental areas under the curve for glucose after dinner (479±76 vs. 663±104mmol/L per min, P<0.01) compared with snacking just after lunch, whereas mean glucose levels did not differ over the 2days. CONCLUSION: These results suggest that consuming snacks well separated from lunch may be an effective way to suppress postprandial glucose levels and glycaemic excursions.

Three-day regimen of oseltamivir for postexposure prophylaxis of influenza in wards.

Inpatients who had been in close contact with patients with influenza were given oseltamivir [75mg capsules once daily for adults or 2mg/kg (maximum of 75mg) once daily for children] for three days as postexposure prophylaxis (PEP). The index patients with influenza were prescribed a neuraminidase inhibitor and were discharged immediately or transferred to isolation rooms. The protective efficacy of oseltamivir for three days was 93% overall [95% confidence interval (CI) 53-99%; P=0.023] and 94% for influenza A (95% CI 61-99%; P=0.017), which is comparable to that of seven- to 10-day regimens of oseltamivir as PEP.

Activation of a chondrocyte volume-sensitive Cl(-) conductance prior to macroscopic cartilage lesion formation in the rabbit knee anterior cruciate ligament transection osteoarthritis model.

OBJECTIVE: The anterior cruciate ligament transection (ACLT) rabbit osteoarthritis (OA) model confers permanent knee instability and induces joint degeneration. The degeneration process is complex, but includes chondrocyte apoptosis and OA-like loss of cartilage integrity. Previously, we reported that activation of a volume-sensitive Cl(-) current (ICl,vol) can mediate cell shrinkage and apoptosis in rabbit articular chondrocytes. Our objective was therefore to investigate whether ICl,vol was activated in the early stages of the rabbit ACLT OA model. DESIGN: Adult Rabbits underwent unilateral ACLT and contralateral arthrotomy (sham) surgery. Rabbits were euthanized at 2 or 4 weeks. Samples were analyzed histologically and with assays of cell volume, apoptosis and electrophysiological characterization of ICl,vol. RESULTS: At 2 and 4 weeks post ACLT cartilage appeared histologically normal, nevertheless cell swelling and caspase 3/7 activity were both significantly increased compared to sham controls. In cell-volume experiments, exposure of chondrocytes to hypotonic solution led to a greater increase in cell size in ACLT compared to controls. Caspase-3/7 activity, an indicator of apoptosis, was elevated in both ACLT 2wk and 4wk. Whole-cell currents were recorded with patch clamp of chondrocytes in iso-osmotic and hypo-osmotic external solutions under conditions where Na(+), K(+) and Ca(2+) currents were minimized. ACLT treatment resulted in a large increase in hypotonic-activated chloride conductance. CONCLUSION: Changes in chondrocyte ion channels take place prior to the onset of apparent cartilage loss in the ACLT rabbit model of OA. Further studies are needed to investigate if pharmacological inhibition of ICl,vol decreases progression of OA in animal models.

Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain.

OBJECTIVE: To assess the functional changes of Transient receptor potential vanilloid 1 (TRPV1) receptor and to clarify its mechanism in a rat mono-iodoacetate (MIA)-induced joint pain model (MIA rats), which has joint degeneration with cartilage loss similar to osteoarthritis. METHODS: Sensitization of TRPV1 in MIA rats was assessed by transient spontaneous pain behavior induced by capsaicin injection in knee joints and electrophysiological changes of dorsal root ganglion (DRG) neurons innervating knee joints in response to capsaicin. Mechanisms of TRPV1 sensitization were analyzed by a newly developed sandwich enzyme-linked immunosorbent assay that detects phosphorylated TRPV1, followed by functional and expression analyses of protein kinase C (PKC) in vivo and in vitro, which involves TRPV1 phosphorylation. RESULTS: Pain-related behavior induced by intra-articular injection of capsaicin was significantly increased in MIA rats compared with sham rats. In addition, capsaicin sensitivity, evaluated by capsaicin-induced inward currents, was significantly increased in DRG neurons of MIA rats. Protein levels of TRPV1 remained unchanged, but phosphorylated TRPV1 at Ser800 increased in DRG neurons of MIA rats. Phosphorylated-PKCɛ (p-PKCɛ) increased and co-localized with TRPV1 in DRG neurons of MIA rats. Capsaicin-induced pain-related behavior in MIA rats was inhibited by intra-articular pretreatment of the PKC inhibitor bisindolylmaleimide I. In addition, intra-articular injection of the PKC activator phorbol 12-myristate 13-acetate increased capsaicin-induced pain-related behavior in normal rats. CONCLUSION: TRPV1 was sensitized at the knee joint and at DRG neurons of MIA rats through PKC activation. Thus, TRPV1 sensitization might be involved in chronic pain caused by osteoarthritis.

Arthrodesis of the ankle using an anterior sliding tibial graft for osteoarthritis secondary to osteonecrosis of the talus: A comparison of vascularised non-vascularised grafts.

AIMS: This retrospective cohort study compared the results of vascularised and non-vascularised anterior sliding tibial grafts for the treatment of osteoarthritis (OA)of the ankle secondary to osteonecrosis of the talus. PATIENTS AND METHODS: We reviewed the clinical and radiological outcomes of 27 patients who underwent arthrodesis with either vascularised or non-vascularised (conventional) grafts, comparing the outcomes (clinical scores, proportion with successful union and time to union) between the two groups. The clinical outcome was assessed using the Mazur and American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scores. The mean follow-up was 35 months (24 to 68). RESULTS: The mean outcome scores increased significantly in both groups. In the vascularised graft group, the mean Mazur score improved from 36.9 to 74.6 and the mean AOFAS scale improved from 49.6 to 80.1. In the conventional arthrodesis group, the mean Mazur score improved from 35.5 to 65 and the mean AOFAS scale from 49.2 to 67.6. Complete fusion was achieved in 13 patients (76%) in the vascularised group, but only four (40%) in the conventional group. The clinical outcomes and proportion achieving union were significantly better in the vascularised group compared with the conventional arthrodesis group, although time to union was similar in the two groups. TAKE HOME MESSAGE: Vascularised sliding tibial grafts may be used to achieve arthrodesis in patients with OA of the ankle secondary to osteonecrosis of the talus.

A new form of surgical treatment for patients with avascular necrosis of the talus and secondary osteoarthritis of the ankle.

A new method of vascularised tibial grafting has been developed for the treatment of avascular necrosis (AVN) of the talus and secondary osteoarthritis (OA) of the ankle. We used 40 cadavers to identify the vascular anatomy of the distal tibia in order to establish how to elevate a vascularised tibial graft safely. Between 2008 and 2012, eight patients (three male, five female, mean age 50 years; 26 to 68) with isolated AVN of the talus and 12 patients (four male, eight female, mean age 58 years; 23 to 76) with secondary OA underwent vascularised bone grafting from the distal tibia either to revascularise the talus or for arthrodesis. The radiological and clinical outcomes were evaluated at a mean follow-up of 31 months (24 to 62). The peri-malleolar arterial arch was confirmed in the cadaveric study. A vascularised bone graft could be elevated safely using the peri-malleolar pedicle. The clinical outcomes for the group with AVN of the talus assessed with the mean Mazur ankle grading scores, improved significantly from 39 points (21 to 48) pre-operatively to 81 points (73 to 90) at the final follow-up (p = 0.01). In all eight revascularisations, bone healing was obtained without progression to talar collapse, and union was established in 11 of 12 vascularised arthrodeses at a mean follow-up of 34 months (24 to 58). MRI showed revascularisation of the talus in all patients. We conclude that a vascularised tibial graft can be used both for revascularisation of the talus and for the arthrodesis of the ankle in patients with OA secondary to AVN of the talus.

The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing.

Ageing is associated with a variety of pathophysiological changes, including development of insulin resistance, progressive decline in ß-cell function and chronic inflammation, all of which affect metabolic homeostasis in response to nutritional and environmental stimuli. SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD biosynthetic enzyme, together comprise a novel systemic regulatory network, named the 'NAD World', that orchestrates physiological responses to internal and external perturbations and maintains the robustness of the physiological system in mammals. In the past decade, an accumulating body of evidence has demonstrated that SIRT1 and NAMPT, two essential components in the NAD World, play a critical role in regulating insulin sensitivity and insulin secretion throughout the body. In this article, we will summarize the physiological significance of SIRT1 and NAMPT-mediated NAD biosynthesis in metabolic regulation and discuss the ideas of functional hierarchy and frailty in determining the robustness of the system. We will also discuss the potential of key NAD intermediates as effective nutriceuticals for the prevention and the treatment of age-associated metabolic complications, such as type 2 diabetes.

High-resolution computed tomography and health-related quality of life in Mycobacterium avium complex disease.

SETTING: Kyoto, Japan. OBJECTIVE: To validate the St George's Respiratory Questionnaire (SGRQ) in pulmonary Mycobacterium avium-intracellulare complex disease and to analyse the significance of high-resolution computed tomography (HRCT) findings as determinants of health-related quality of life (HRQoL) after adjusting for clinical and physiological parameters. DESIGN: Eighty-five patients completed the SGRQ, pulmonary function tests and other patient-reported measurements. HRCT findings were assessed using an established computed tomography (CT) scoring method. RESULTS: The SGRQ was validated with good internal consistency, test-retest reliability and significant correlations with most physiological variables and other patient-reported measurements. White blood cell counts, C-reactive protein levels, sputum culture results, treatment history, total CT scores, and consolidation, cavity and lobar volume-decrease CT component scores were significantly correlated with the SGRQ total and component scores. Stepwise multiple regression analyses revealed that the consolidation, cavity and lobar volume-decrease component scores were correlated with the SGRQ total and/or component scores. The total CT scores had the strongest relationships with the SGRQ total scores among the various clinical parameters tested, including microbiological, radiological, physiological and laboratory findings (32.8% of variance). CONCLUSION: HRCT findings, particularly consolidation, cavity and lobar volume-decreases, were the most significant clinical parameters related to patient HRQoL.

Switching dynamics and linear response spectra of a driven one-dimensional nonlinear lattice containing an intrinsic localized mode.

An intrinsic localized mode (ILM) represents a localized vibrational excitation in a nonlinear lattice. Such a mode will stay in resonance as the driver frequency is changed adiabatically until a bifurcation point is reached, at which point the ILM switches and disappears. The dynamics behind switching in such a many body system is examined here through experimental measurements and numerical simulations. Linear response spectra of a driven micromechanical array containing an ILM were measured in the frequency region between two fundamentally different kinds of bifurcation points that separate the large amplitude ILM state from the two low amplitude vibrational states. Just as a natural frequency can be associated with a driven harmonic oscillator, a similar natural frequency has been found for a driven ILM via the beat frequency between it and a weak, tunable probe. This finding has been confirmed using numerical simulations. The behavior of this nonlinear natural frequency plays important but different roles as the two bifurcation points are approached. At the upper transition its frequency coalesces with the driver and the resulting bifurcation is very similar to the saddle-node bifurcation of a single driven Duffing oscillator, which is treated in an Appendix. The lower transition occurs when the four-wave mixing partner of the natural frequency of the ILM intersects the topmost extended band mode of the same symmetry. The properties of linear local modes associated with the driven ILM are also identified experimentally for the first time and numerically but play no role in these transitions.

Genetic relatedness of Mycobacterium avium-intracellulare complex isolates from patients with pulmonary MAC disease and their residential soils.

Mycobacterium avium-intracellulare complex (MAC) strains were recovered from 48.9% of residential soil samples (agricultural farms (n = 7), residential yards (n = 79), and planting pots (n = 49)) of 100 pulmonary MAC patients and 35 non-infected control patients. The frequency of MAC recovery did not differ among soil types or among patients regardless of the presence of pulmonary MAC disease, infecting MAC species or period of soil exposure. Variable numbers of tandem repeats (VNTR) analysis for MAC clinical and soil isolates revealed 78 different patterns in 47 M. avium clinical isolates and 41 soil isolates, and 53 different patterns in 18 M. intracellulare clinical isolates and 37 soil isolates. Six clinical and corresponding soil isolate pairs with an identical VNTR genotype were from case patients with high soil exposure (≥2 h per week, 37.5% (6/16) with high exposure compared with 0.0% (0/19) with low or no exposure, p <0.01), suggesting that residential soils are a likely source of pulmonary MAC infection.

Gene cloning and characterization of the protein encoded by the Neospora caninum bradyzoite-specific antigen gene BAG1.

Neospora caninum is an Apicomplexan parasite that causes repeated abortion and stillbirth in cattle. The aim of this study was to clone the gene encoding the N. caninum orthologue (NcBAG1) of the Toxoplasma gondii bradyzoite-specific protein TgBAG1 and characterize its expression pattern in the parasite. Isolation of the full-length 684-bp gene revealed that it shared 78.3% sequence similarity with TgBAG1. NcBAG1 encodes a predicted protein of 227 amino acids with 80.3% similarity to TgBAG1. A putative signal peptide sequence and an invariant GVL motif characteristic of small heat-shock proteins were identified in the predicted N. caninum amino acid sequence. We expressed the NcBAG1 gene as a recombinant glutathione S-transferase fusion protein (rNcBAG1) in Escherichia coli and used the purified 60 kDa protein to obtain a monoclonal antibody (Mab). rNcBAG1 reacted to Mabs specific for NcBAG1 and TgBAG1. No reaction between the NcBAG1 Mab and N. caninum tachyzoites was observed. Although the predicted molecular mass of NcBAG1 is 25 kDa, Western blot analysis of parasite lysates using the NcBAG1 Mab revealed a cross-reactive protein of approximately 30 kDa. Additionally, immunofluorescence assays using the tachyzoite-specific Mab for NcSAG1 and the bradyzoite-specific Mab for TgBAG1 or NcSAG4 revealed NcBAG1-specific expression in bradyzoites in cultures exposed to sodium nitroprusside, a reagent that increases the frequency of bradyzoites. Interestingly, the NcBAG1 protein was identified in the cytoplasm of the bradyzoite-stage parasites. This preliminary analysis of the NcBAG1 gene will assist investigations into the role of this protein in N. caninum .