Search for Gamma-Ray Spectral Lines from Dark Matter Annihilation up to 100 TeV toward the Galactic Center with MAGIC.

Linelike features in TeV γ rays constitute a "smoking gun" for TeV-scale particle dark matter and new physics. Probing the Galactic Center region with ground-based Cherenkov telescopes enables the search for TeV spectral features in immediate association with a dense dark matter reservoir at a sensitivity out of reach for satellite γ-ray detectors, and direct detection and collider experiments. We report on 223 hours of observations of the Galactic Center region with the MAGIC stereoscopic telescope system reaching γ-ray energies up to 100 TeV. We improved the sensitivity to spectral lines at high energies using large-zenith-angle observations and a novel background modeling method within a maximum-likelihood analysis in the energy domain. No linelike spectral feature is found in our analysis. Therefore, we constrain the cross section for dark matter annihilation into two photons to ⟨σv⟩≲5×10^{-28} cm^{3} s^{-1} at 1 TeV and ⟨σv⟩≲1×10^{-25} cm^{3} s^{-1} at 100 TeV, achieving the best limits to date for a dark matter mass above 20 TeV and a cuspy dark matter profile at the Galactic Center. Finally, we use the derived limits for both cuspy and cored dark matter profiles to constrain supersymmetric wino models.

Modelling the invasion of human small intestinal epithelial-like cells by Salmonella enterica Typhimurium and Listeria monocytogenes using Bayesian inference.

To develop a mechanistic bacterial dose-response model, based on the concept of Key Events Dose-Response Framework (KEDRF), this study aimed to investigate the invasion of intestinal model cells (Caco-2) by Salmonella Typhimurium and Listeria monocytogenes and described the behaviour of both pathogens as a mathematical model using Bayesian inference. Monolayer-cultured Caco-2 cells (approximately 105 cells) were co-cultured with various concentrations (103 -107 colony forming unit [CFU] ml-1 ) of Salm. Typhimurium and L. monocytogenes for up to 9 h to investigate the invasion of the pathogens into the Caco-2 cells. While an exposure of ≥103 CFU ml-1 of Salm. Typhimurium initiated the invasion of Caco-2 cells within 3 h, much less exposure (102 CFU ml-1 ) of L. monocytogenes was sufficient for invasion within the same period. Furthermore, while the maximum number of invading Salm. Typhimurium cells reached by approximately 103 CFU cm-2 for 6-h exposure, the invading maximum numbers of L. monocytogenes cells increased by approximately 106 CFU cm-2 for the same exposure period. The invasion kinetics of both the pathogens was successfully described as an asymptotic exponential mathematical model using Bayesian inference. The developed pathogen invasion model allowed the estimation of probability of Salm. Typhimurium and L. monocytogenes infection, based on the physiological natures of digestion process, which was comparable to the published dose-response relationship. The invasion models developed in the present study will play a key role in the development of an alternative pathogen dose-response model based on KEDRF concept.

Fabrication of Hydrogen Boride Thin Film by Ion Exchange in MgB2.

In this study, hydrogen boride films are fabricated by ion-exchange treatment on magnesium diboride (MgB2) films under ambient temperature and pressure. We prepared oriented MgB2 films on strontium titanate (SrTiO3) substrates using pulsed laser deposition (PLD). Subsequently, these films were treated with ion exchangers in acetonitrile solution. TOF-SIMS analysis evidenced that hydrogen species were introduced into the MgB2 films by using two types of ion exchangers: proton exchange resin and formic acid. According to the HAXPES analysis, negatively charged boron species were preserved in the films after the ion-exchange treatment. In addition, the FT-IR analysis suggested that B-H bonds were formed in the MgB2 films following the ion-exchange treatment. The ion-exchange treatment using formic acid was more efficient compared to the resin treatment; with respect to the amount of hydrogen species introduced into the MgB2 films. These ion-exchanged films exhibited photoinduced hydrogen release as observed in a powder sample. Based on the present study, we expect to be able to control the morphology and hydrogen content of hydrogen boride thin films by optimising the ion-exchange treatment process, which will be useful for further studies and device applications.

Quantum error correction in a solid-state hybrid spin register.

Error correction is important in classical and quantum computation. Decoherence caused by the inevitable interaction of quantum bits with their environment leads to dephasing or even relaxation. Correction of the concomitant errors is therefore a fundamental requirement for scalable quantum computation. Although algorithms for error correction have been known for some time, experimental realizations are scarce. Here we show quantum error correction in a heterogeneous, solid-state spin system. We demonstrate that joint initialization, projective readout and fast local and non-local gate operations can all be achieved in diamond spin systems, even under ambient conditions. High-fidelity initialization of a whole spin register (99 per cent) and single-shot readout of multiple individual nuclear spins are achieved by using the ancillary electron spin of a nitrogen-vacancy defect. Implementation of a novel non-local gate generic to our electron-nuclear quantum register allows the preparation of entangled states of three nuclear spins, with fidelities exceeding 85 per cent. With these techniques, we demonstrate three-qubit phase-flip error correction. Using optimal control, all of the above operations achieve fidelities approaching those needed for fault-tolerant quantum operation, thus paving the way to large-scale quantum computation. Besides their use with diamond spin systems, our techniques can be used to improve scaling of quantum networks relying on phosphorus in silicon, quantum dots, silicon carbide or rare-earth ions in solids.

The effects of teriparatide on acceleration of bone healing following atypical femoral fracture: comparison between daily and weekly administration.

We compared the effectiveness of promoting bone healing between two teriparatide preparations for atypical femoral fracture (AFF). A total of 45 AFFs were included in this study, and we compared the duration of bone union. Teriparatide administered by daily injection enhanced bone union more than weekly administration in complete AFFs. INTRODUCTION: The efficacy of teriparatide for atypical femoral fracture (AFF) has been recently reported. Although two different teriparatide preparations can be used to treat osteoporosis in Japan, daily or weekly injection, all previous reports on the effectiveness of teriparatide for AFF only examined daily injection formulations. Therefore, we compared the promotion of bone healing between the two teriparatide preparations for AFF. METHODS: A total of 45 consecutive AFFs in 43 Japanese patients were included in this study. They received either a daily 20-µg teriparatide injection (daily group; n = 32) or a once-a-week 56.5-µg teriparatide injection (weekly group; n = 13). We compared the clinical background and duration of bone union between these two groups. RESULTS: When all patents were included, the fracture healing time was not significantly different between the two groups. Only patients with complete AFFs had significantly fewer daily bisphosphonate or denosumab injections than the weekly group (P < 0.05). The fracture healing time in the daily group (6.1 ± 4.1 months) was significantly shorter than that in the weekly group (10.1 ± 4.2 months) (P < 0.05). Even if the influence of bisphosphonate or denosumab usage was excluded, a similar significant difference was observed in the fracture healing time (P < 0.05). There was no significant difference between the two groups among patients with incomplete AFFs. CONCLUSIONS: Daily teriparatide injections enhance bone union more than weekly injections in complete AFF patients.

Association between mode of anaesthesia and severe maternal morbidity during admission for scheduled Caesarean delivery: a nationwide population-based study in Japan, 2010-2013.

BACKGROUND: Although the incidence of maternal mortality during Caesarean delivery remains very low, the rate of severe maternal morbidity is increasing. Improvements in obstetric anaesthetic practice have resulted in a dramatic reduction in the risk of maternal death from general anaesthesia. Less clear is whether the risk of severe maternal morbidity differs according to mode of anaesthesia for women undergoing Caesarean delivery. We analysed the association between the mode of anaesthesia and severe maternal morbidity during Caesarean delivery using a nationally representative inpatient database. METHODS: We identified 89 225 women undergoing scheduled Caesarean delivery from the Diagnosis Procedure Combination database in Japan, 2010-2013. We defined severe maternal morbidity as the presence of any life-threatening complications and identified women with severe maternal morbidity from the database. Propensity score-matched analysis was carried out to compare the odds of severe maternal morbidity between women who underwent general vs neuraxial anaesthesia. RESULTS: Of 89 225 women, 10 058 received general anaesthesia and 79 167 received neuraxial anaesthesia. In the propensity score-matched analysis with 10 046 pairs, a higher incidence of severe maternal morbidity was observed among patients receiving general (2.00%) rather than neuraxial anaesthesia (0.76%). The odds ratio of severe maternal morbidity was 2.68 (95% CI, 1.97-3.64) among women receiving general compared with neuraxial anaesthesia. CONCLUSIONS: For scheduled Caesarean delivery, general anaesthesia compared with neuraxial anaesthesia is associated with greater odds for severe maternal morbidity. However, we should be cautious with interpretation of these findings because they may be explained by confounding indications.

Muscle layer thickness affects the peroral endoscopic myotomy procedure complexity.

Esophageal motility disorders can cause severe dysphagia, regurgitation, and/or noncardiac chest pain due to a lack of coordinated esophageal motility function. However, the clinical significance of esophageal muscle layer thickness remains unclear. The aims of this study are to elucidate the clinical significance of esophageal muscle layer thickness in patients with esophageal motility disorders who undergo peroral endoscopic myotomy (POEM), and to identify predictors of a longer POEM procedure time. Seventy-four consecutive patients with esophageal motility disorders who underwent POEM procedures at Kobe University Hospital from April 2015 to December 2016 were prospectively recruited into this study. First, we investigated the associations between the thickness of the esophageal muscular layer and clinical parameters. There were no significant differences, except in the POEM procedure time, between the patients with esophageal muscle layer thickness values of ≥1.5 mm (group A) and <1.5 mm (group B). However, the relative frequency of a longer POEM procedure time (≥78 min) was significantly higher in group A than in group B (66.7% vs. 19.5, P < 0.0001). Next, independent clinical factors that were related to longer POEM procedures were investigated. Multivariate logistic regression analysis with stepwise selection demonstrated that a thick esophageal muscle layer and the length of myotomy were an independent predictor of a longer POEM procedure (odds ratio: 13.9 and 12.0, respectively). Our results indicate that preoperative endoscopic ultrasonography evaluations can help to predict the technical complexity of POEM procedures.

A Combined test using both cell sediment and supernatant cell-free DNA in pleural effusion shows increased sensitivity in detecting activating EGFR mutation in lung cancer patients.

INTRODUCTION: The aim of this study was to examine whether a combined test using both cell sediment and supernatant cytology cell-free DNA (ccfDNA) is more useful in detecting EGFR mutation than using cell sediment DNA or supernatant ccfDNA alone in pleural effusion of lung cancer patients. METHODS: A total of 74 lung adenocarcinoma patients with paired samples between primary tumour and corresponding metastatic tumour with both cell sediment and supernatant ccfDNA of pleural effusion cytology were enrolled in this study. Cell sediment and supernatant ccfDNA were analysed separately for EGFR mutations by polymerase chain reaction. RESULTS: Out of 45 patients with mutant EGFR in primary tumours, EGFR mutations were detected in 23 cell sediments of corresponding metastases (sensitivity; 51.1%) and 20 supernatant ccfDNA corresponding metastases (sensitivity; 44.4%). By contrast, the combined test detected EGFR mutations in 27 corresponding metastases (sensitivity; 60.0%), and had a higher sensitivity than the cell sediment or the supernatant ccfDNA alone (P < .05). Out of 45 patients with mutant EGFR, 24, three and 18 were cytologically diagnosed as positive, atypical or negative, respectively. The detection rate in the combined test was highest (95.8%) in the positive group, and mutant EGFR was also detected in four of 18 samples (22.2%) in the negative group. CONCLUSIONS: A combined test using both cell sediment DNA and supernatant ccfDNA samples increases the concordance rate of EGFR mutations between primary tumour and corresponding metastases. Our findings indicate that supernatant ccfDNA is useful even in cases where the cytological diagnosis is negative.

SurePath® LBC improves the diagnostic accuracy of intrahepatic and hilar cholangiocarcinoma.

INTRODUCTION: The current study aimed to compare cytology using SurePath® (SP)-LBC and biliary tissue histology (BTH) for the diagnosis of biliary disease. METHODS: Between January 2014 and December 2016, 57 patients underwent endoscopic retrograde cholangiopancreatography for the diagnosis of biliary disease. Biliary cytological samples were processed using SP-LBC and subsequently BTH was performed. A final diagnosis was confirmed by surgery (23 malignant cases) and clinical follow-up (34 benign and malignant cases): 18 extrahepatic cholangiocarcinoma; 17 intrahepatic/hilar cholangiocarcinoma (intra/H-CC); eight other malignant disease; and 14 benign biliary disease. The diagnoses made using SP-LBC and BTH were classified into four categories: (1) benign; (2) indeterminate; (3) suspicious for malignancy/malignant; and (4) inadequate. In addition, diagnostic accuracy was compared between SP-LBC and BTH. RESULTS: Although 23% (13/57) of BTH samples were classified as inadequate, all SP-LBC cases were classified as adequate. Among 43 malignant cases, 11 normal, four indeterminate and 28 suspicious for malignancy/malignant were found using SP-LBC (26%, 9% and 65%, respectively), in contrast to 10 inadequate, nine normal, 10 indeterminate and 14 suspicious for malignancy/malignant observed using BTH (23%, 21%, 23%, and 33%, respectively). The identification of malignant cells was strikingly different between SP-LBC and BTH. Furthermore, limited to intra/H-CC, accuracy was significantly higher using SP-LBC than using BTH (P < .001). CONCLUSIONS: SP-LBC of the biliary tract is a useful and reliable method for diagnosing biliary malignant disease and has an advantage over BTH for detecting malignant cells and accurately diagnosing intra/H-CC.

Foetal development of the human gluteus maximus muscle with special reference to its fascial insertion.

The human gluteus maximus muscle (GMX) is characterised by its insertion to the iliotibial tract (a lateral thick fascia of the thigh beneath the fascia lata), which plays a critical role in lateral stabilisation of the hip joint during walking. In contrast, in non-human primates, the GMX and biceps femoris muscle provide a flexor complex. According to our observations of 15 human embryos and 11 foetuses at 7-10 weeks of gestation (21-55 mm), the GMX anlage was divided into 1) a superior part that developed earlier and 2) a small inferior part that developed later. The latter was adjacent to, or even continuous with, the biceps femoris. At 8 weeks, both parts inserted into the femur, possibly the future gluteal tuberosity. However, depending on traction by the developing inferior part as well as pressure from the developing major trochanter of the femur, most of the original femoral insertion of the GMX appeared to be detached from the femur. Therefore, at 9-10 weeks, the GMX had a digastric muscle-like appearance with an intermediate band connecting the major superior part to the small inferior mass. This band, most likely corresponding to the initial iliotibial tract, extended laterally and distally far from the muscle fibres. The fascia lata was still thin and the tensor fasciae latae seemed to develop much later. It seems likely that the evolutionary transition from quadripedality to bipedality and a permanently upright posture would require the development of a new GMX complex with the iliotibial tract that differs from that in non-human primates. (Folia Morphol 2018; 77, 1: 144-150).

Tensor fasciae latae muscle in human embryos and foetuses with special reference to its contribution to the development of the iliotibial tract.

BACKGROUND: The human tensor fasciae latae muscle (TFL) is inserted into the iliotibial tract and plays a critical role in lateral stabilisation of the hip joint. We previously described a candidate of the initial iliotibial tract that originated from the gluteus maximus muscle and extended distally. MATERIALS AND METHODS: This study extended our observations by examining 30 human embryos and foetuses of gestational age (GA) 7-14 weeks (crown-to-rump length 24-108 mm). At GA 7 weeks, the TFL appeared as a small muscle mass floating in the subcutaneous tissue near the origins of the gluteus medius and rectus femoris muscles. RESULTS: Subsequently, the TFL obtained an iliac origin adjacent to the rectus femoris tendon, but the distal end remained a tiny fibrous mass on the vastus lateralis muscle. Until GA 10 weeks, the TFL muscle fibres were inserted into a vastus lateralis fascia that joined the quadriceps tendon distally. The next stage consisted of the TFL muscle belly "connecting" the vastus fascia and the gluteus fascia, including our previous candidate of the initial iliotibial tract. Until GA 14 weeks, the TFL was sandwiched by two laminae of the connecting fascia. CONCLUSIONS: These findings suggested that, when the vastus lateralis fascia separated from the quadriceps tendon to attach to the tibia, possibly after birth, the resulting iliotibial tract would consist of a continuous longitudinal band from the gluteus maximus fascia, via the vastus fascia, to the tibia. Although it is a small muscle, the foetal TFL plays a critical role in the development of the iliotibial tract.

A new insight into the fabella at knee: the foetal development and evolution.

Using longitudinal semiserial sections of 12 lower extremities from 8 human foetuses at 15-18 weeks, we compared foetal morphologies of the knee in specimens with and without fabellae. We also compared the fabella, if present, with the hallucal sesamoid in the same foetus. Cartilaginous fabella, positive for versican and tenascin by immunohistochemistry, was found in 5 of the 8 foetuses. This structure was embedded in a thick and tight lateral fibrous band, providing a common origin of the plantaris muscle and the lateral head of the gastrocnemius muscle. The plantaris was covered by the lateral head of the gastrocnemius, but these 2 muscles were separated by a distinct fascia or space. Notably, the foetal fabella did not attach to the joint capsule. In the 3 specimens without fabellae, the lateral fibrous band was thin, containing a fibrous mass, negative for versican and tenascin, in place of the fabella. The "medial" head of the gastrocnemius faced or covered the plantaris, while the lateral head was continuous with the plantaris. A hallucal cartilaginous sesamoid, positive for versican and tenascin, was present in all 8 specimens. It carried a flat surface facing the joint cavity and was covered by tendons of the short muscles of the foot. Because of the difference in topographical relation of muscles between specimens with or without fabella, rather than mechanical stress to the tendon, fabella development may require a distinct plantaris muscle independent of the gastrocnemius. We discussed about an evolutionary aspect of the fabella and plantaris muscle.

Inter-observer reproducibility of endometrial cytology by the Osaki Study Group method: utilising the Becton Dickinson SurePath™ liquid-based cytology.

OBJECTIVE: The purpose of the present study was to evaluate the reproducibility of the cytological diagnosis of endometrial lesions by the Osaki Study Group (OSG) method of new cytological diagnostic criteria using BD SurePath™ (SP)-liquid-based cytology (LBC). METHODS: This cytological classification using the OSG method consists of six categories: (i) normal endometrium (NE), (ii) endometrial glandular and stromal breakdown (EGBD), (iii) atypical endometrial cells, cannot exclude atypical endometrial hyperplasia or more (ATEC-A), (iv) adenocarcinoma including atypical endometrial hyperplasia or malignant tumour (Malignancy), (v) endometrial hyperplasia without atypia (EH) and (vi) atypical endometrial cells of undetermined significance (ATEC-US). For this study, a total 244 endometrial samplings were classified by two academic cytopathologists as follows: 147 NE cases , 36 EGBD cases , 47 Malignant cases, eight ATEC-A cases, two EH cases and four ATEC-US cases. To confirm the reproducibility of the diagnosis and to study the inter- and intra-observer agreement further, a second review round followed at 3-month intervals, which included three additional cytopathologists. RESULTS: The inter-observer agreement of NE classes improved progressively from 'good to fair' to 'excellent', with values increasing from 0.70 to 0.81. Both EGBD and Malignancy classes improved progressively from 'good to fair' to 'excellent', with values increasing from 0.62-0.63 to 0.84-0.95, respectively. The overall intra-observer agreement between the first and the second rounds was 'good to fair' to 'excellent', with values changing from 0.79 to 0.85. All kappa improvements were significant (P < 0.0001). CONCLUSION: In this study, it seemed that the use of the OSG method as the new diagnostic criteria for SP-LBC preparation, may be a valid method to improve the precision (reproducibility) of endometrial cytology.

Evaluation of factors associated with relapse in telaprevir-based triple therapy for chronic hepatitis C.

BACKGROUND AND RATIONALE: Most patients with chronic hepatitis C show virological response to telaprevir-based triple therapy, and achieve an end-of-treatment response (ETR). However, some patients showing ETR develop virological relapse. This study was carried out to evaluate factors associated with relapse after triple therapy. MATERIALS AND METHODS: A prospective, multicentric study was conducted in chronic hepatitis C patients who received telaprevir-based triple therapy. We evaluated independent variables such as age, with or without cirrhosis, prior treatment response to interferon (IFN) therapy, IL28B genotype, core amino acid (aa) 70 mutation, drug adherence, white blood cell counts, hemoglobin level, and serum low-density lipoprotein (LDL) cholesterol level. The characteristics of the patients who relapsed after achieving ETR were compared with those who did not. RESULTS: Among 168 patients, 157 patients achieved ETR (93.5%) and 11 discontinued. Of these 157 patients, relapse occurred in 21 patients (13.4%). Nineteen patients (90.5%) of 21 relapsed patients had the IL28B non-TT genotype (P = 1.79 × 10 -9 ). Multivariate analysis identified core amino acid 70 [P = 0.018, crude odds ratio (OR): 6.927] and the IL28B genotype (P = 3.758 × 10 -5 , crude OR: 39.311) as significantly independent factors that influenced the relapse-related variables. Among the 49 patients with the IL28B non-TT, 18 patients had core aa70 mutation and 31 patients had core aa70 wild-type. In addition, 66.7% (12/18) of those with core aa70 mutation and 22.6% (7/31) of those with core aa70 wild-type developed relapse (P = 0.005). DISCUSSION: Core aa70 mutation and the IL28B non-TT genotype were identified as independent factors that influenced relapse after achievement of ETR for telaprevir-based triple therapy.

Oblique cord (chorda obliqua) of the forearm and muscle-associated fibrous tissues at and around the elbow joint: a study of human foetal specimens.

In adults, the oblique cord or chorda obliqua separates the origins of the flexor pollicis longus (FPL) and flexor digitorum profundus (FDP) muscles from the supinator muscle and elbow joint. This study examined the topographic anatomy of the oblique cord and related muscles in foetuses. Semiserial sections of five mid-term foetuses of gestational age (GA) 14-16 weeks and 12 late-stage foetuses of GA 28-30 weeks were histologically examined and three forearms at GA 30 weeks were macroscopically evaluated. Late-stage foetuses showed a fascial structure between the supinator and FDP muscles. The latter extended proximally to the elbow joint and the muscle origin thickened the distal, ulnar part of the capsule. The FPL origin also extended proximally but did not reach the joint capsule. These morphologies were consistent with macroscopic examinations. The brachialis muscle was widely inserted into the proximal, anterior part of the capsule. In addition, the medial collateral ligament was not covered by the pronator-flexor muscles but by the triceps brachii muscle. The oblique cord apparently did not form prenatally. After birth, the proximal parts of the FDP and FPL muscles were likely replaced by collagenous tissues, providing a specific type of intermuscular septum i.e., the oblique cord. This type of muscle-ligament transition was observed in the annular ligament of the radius. The foetal elbow joint was characterised by strong support by the FDP, brachialis and triceps brachii muscles. Therefore, the foetal elbow is not a miniature version of the adult elbow.

Positional changes in tendon insertions from bone to fascia: development of the pes anserinus and semimembranosus muscle insertion in human foetuses.

Development of a long muscle belly in foetal extremities generally requires a definite bony insertion of the long tendon. However, in adults, the pes anserinus and the semimembranosus tendon (SMT) are inserted into fasciae. Development of fascial insertions in foetuses was investigated by examining serial histological sections obtained from 7 foetuses at 8-9 weeks and 8 foetuses at 14-16 weeks. The presence of matrix substances and macrophages was also examined by immunohistochemistry. At 8 weeks, the tendons of the semitendinosus, gracilis, sartorius and semimembranosus muscles were straight and inserted into the initial shaft-like proximal end of the tibia on the proximal side of the popliteus muscle. At 9 weeks, however, the medially extending popliteus muscle appeared to push the pes anserinus tendons superficially, with a loss of cartilage insertions. The SMT obtained an attachment to the popliteus muscle. At 14-16 weeks, the SMT divided into thick and thin bundles: the former contained abundant macrophages and inserted into the tenascin-positive perichondrium of the enlarged proximal tibia, while the later without macrophages ended at the joint capsule. The pes anserinus tendons, negative for both versican and tenascin-c, took highly tortuous courses toward the fascia cruris. Because the medial extension of the popliteus muscle was associated with the enlargement of the proximal tibia, the topographical relationship of the popliteus muscle with these 4 tendons changed drastically, resulting in a loss of cartilage insertion of the pes anserinus tendons as well as the division and reconstruction of the SMT.

Ribavirin dose reduction during telaprevir/ribavirin/peg-interferon therapy overcomes the effect of the ITPA gene polymorphism.

Treatment success of chronic hepatitis C virus genotype 1 infection has improved with the advent of telaprevir plus peg-interferon/ribavirin triple combination therapy. However, the effect of inosine triphosphatase (ITPA) polymorphism on dose reduction during triple therapy, especially during the postmarketing phase, has not been sufficiently evaluated. We analysed 273 patients with genotype 1 infection who were treated with triple therapy and assessed the effect of the ITPA polymorphism on dose reduction. ITPA and IFNL4 SNP genotypes were determined by the Invader assay. A stepwise multivariate regression analysis was performed to identify factors associated with outcome of the therapy. The overall sustained viral response (SVR) rate 12 weeks after the end of therapy was 80.2% (219/273). Decline of haemoglobin was significantly faster, and ribavirin was more extensively reduced in patients with ITPA SNP rs1127354 genotype CC than CA/AA. Extensive reduction of ribavirin resulted in mild reduction of telaprevir and peg-interferon, but no significant increase in viral breakthrough. Although the amount of telaprevir given was slightly higher in CA/AA patients, the total dose of peg-interferon and the SVR rate did not differ between the two groups. Multivariate analysis showed that IFNL4 but not ITPA SNP genotype, platelet count and peg-interferon adherence were significantly associated with outcome of therapy. Postmarketing-phase triple therapy resulted in a high SVR rate in spite of extensive ribavirin dose reduction in a diverse patient population, indicating the importance of treatment continuation and appropriate management of adverse events.

Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1.

Daclatasvir (DCV) and asunaprevir (ASV) are NS5A and NS3 protease-targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (HCV) infection. We analysed the relationship between pre-existing drug-resistant variants and clinical outcome of the combination treatment with DCV and ASV. Ten patients with HCV genotype 1b were orally treated with a combination of ASV and DCV for 24 weeks. The frequencies of amino acid (aa) variants at NS3 aa positions 155, 156 and 168 and at NS5A aa31 and 93 before and after treatment were analysed by ultra-deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (SVR) was achieved in 8 out of 10 patients (80%), and relapse of HCV RNA after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre-existing DCV-resistant variants (L31V/M and/or Y93H; 0.9-99.4%) were detected in three out of eight patients who achieved SVR. Pre-existing DCV-resistant variants were detected in a relapsed patient (L31M, Y93H) and in a patient with viral breakthrough (Y93H); however, no ASV-resistant variants were detected. In these patients, HCV RNA rebounded with ASV- and DCV- double resistant variants (NS3 D168A/V plus NS5A L31M and Y93H). While pre-existing DCV-resistant variants might contribute to viral breakthrough in DCV and ASV combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra-deep sequence analysis of pre-existing resistant variants appears limited.

Positional cloning of the sex-linked giant egg (Ge) locus in the silkworm, Bombyx mori.

The giant egg (Ge) locus is a Z-linked mutation that leads to the production of large eggs. Cytological observations suggest that an unusual translocation of a large fragment of the W chromosome bearing a putative egg size-determining gene, Esd, gave rise to giant egg mutants. However, there is currently no molecular evidence confirming either a W-Z translocation or the presence of Esd on the W chromosome. To elucidate the origin of giant egg mutants, we performed positional cloning. We observed that the Bombyx mori. orthologue of the human Phytanoyl-CoA dioxygenase domain containing 1 gene (PHYHD1) is disrupted in giant egg mutants. PHYHD1 is highly conserved in eukaryotes and is predicted to be a Fe(II) and 2-oxoglutarate-dependent oxygenase. Exon skipping in one of the two available Ge mutants is probably caused by the insertion of a non-long terminal repeat transposon into intron 4 in the vicinity of the 5' splice site. Segmental duplication in Ge(2) , an independent allele, was caused by unequal recombination between short interspersed elements inserted into introns 3 and 5. Our results indicate that (1) Bombyx PHYHD1 is responsible for the Ge mutants and that (2) the Ge locus is unrelated to the W-linked putative Esd. To our knowledge, this is the first report describing the phenotypic defects caused by mutations in PHYHD1 orthologues.

Cytological nuclear atypia classification can predict prognosis in patients with endometrial cancer.

OBJECTIVE: Endometrial cancer is one of the leading causes of malignancy in females. Nuclear findings are important for patients with cancer, and can provide valuable information to treating oncologists. We investigated whether nuclear findings were a useful prognostic factor in patients with endometrial cancer. METHOD: We investigated 71 cases of endometrial carcinoma with paired histology and cytology at Kurume University Hospital. We classified endometrial endometrioid adenocarcinoma (EEC) G1 and G2 as type I carcinomas, and uterine papillary serous carcinoma (UPSC), clear cell carcinoma (CC) and EEC G3 as type II carcinomas. For the establishment of the cytological nuclear atypia classification, we examined the following nuclear factors on the cytological smears: mitotic figures, prominent nucleoli, nuclear area and anisonucleosis. RESULTS: There was a significant difference in mitotic figures (P < 0.001) and anisonucleosis (P = 0.026) in cytological smears between type I and type II carcinomas. Based on these findings, we categorized cytological nuclear atypia into three groups, nuclear atypia-1 (57.7%), nuclear atypia-2 (19.7%) and nuclear atypia-3 (22.5%), and this classification system correlated well with prognosis in patients with endometrial cancer (P < 0.001). Furthermore, this classification system was able to extract patients with a good prognosis from those with high-grade carcinomas, such as UPSC+CC+EEC G3, and patients with a poor prognosis from those with EEC G1. CONCLUSIONS: Our system of cytological nuclear atypia classification based on endometrial cytology can predict patient prognosis. Cytological nuclear atypia classification and histological typing may be useful for the treatment and follow-up of patients with endometrial cancer, and should be routinely incorporated into cytological reports.