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Background Plasma removal by washing is an effective approach to prevent transfusion reactions by platelet concentrates (PCs). Recently, washed PCs were released by the Japanese Red Cross Society (JRCS). Materials and methods This retrospective multicenter study evaluated the efficacy and safety of released washed PCs (RWPCs) between September 2016 and January 2017 in Japan. The RWPCs were prepared by washing leukoreduced apheresis PCs with the platelet additive solution, BRS-A, using automated cell processors. Results Clinical data were obtained from 91 patients and 1210 RWPC transfusions at 50 institutions. The median number of RWPC transfusions per patient was 8 (range, 1–91). RWPCs were used in 94.5% of the patients with a history of recurrent or severe transfusion reactions for preventing such reactions. Responses of RWPCs were evaluated as complete response (91.6%), partial response (8.2%), no-change (0.2%), and progression (0%) and overall response was equal across subgroups divided by patients’ profiles. The median corrected count increment (CCI) at 1 and 24 h post-transfusion were 13.5 (range, 1.9–35.4) × 109/L and 3.5 (range, −13 to 53.6) × 109/L, respectively, and median CCI at 24 h was 5.5 (range, −13 to 53.6) × 109/L in patients without risk factors associated with platelet transfusion refractoriness. Transfusion reactions to RWPCs were observed in only nine transfusions (0.7%), all of which were mild allergic reactions. Conclusion This study demonstrated that RWPCs were effective and safe in patients with a history of transfusion reactions. Further prospective studies on efficacy together with cost-benefit analysis in RWPCs are needed.

Background Aeromonas spp. are gram‐negative anaerobic rods that are mainly found in water. Respiratory infections due to Aeromonas sp. are rare but have a high mortality rate. Case presentation A 43‐year‐old man fell into a river following an automobile accident and almost drowned. He developed a severe respiratory infection and acute respiratory distress syndrome. Ampicillin/sulbactam was given; however, Aeromonas caviae was detected in his blood culture. Despite treatment with levofloxacin, to which A. caviae was susceptible, his condition failed to improve. However, with additional treatment with cefepime, his blood culture results were negative, and his condition improved. Conclusion When a patient develops a respiratory infection after aspiration of river water, empiric antimicrobial therapy should be given as soon as possible to manage the risk of Aeromonas sp. infection., Aeromonas spp. are gram‐negative anaerobic rods that are mainly found in water. Respiratory infections caused by Aeromonas sp. are rare. A 43‐year‐old man fell into a river and nearly drowned. He developed severe respiratory infections and acute respiratory distress syndrome. Aeromonas caviae was detected in the blood culture. Despite treatment with levofloxacin, to which A. caviae is susceptible, his condition failed to improve. However, with additional treatment with cefepime, the blood culture became negative, and his condition improved.

Hopelessness may be associated with an increased risk of suicide. However, findings regarding the long-term predictive ability of the Beck Hopelessness Scale (BHS) for suicide are inconsistent. This study investigated the long-term predictive ability of BHS scores for subsequent self-harm episodes in individuals admitted to an emergency department after attempting suicide.The BHS was administered to 805 adult patients with a DSM-IV-TR axis I disorder admitted to an emergency department following a suicide attempt. The patients were followed for at least 18 months and up to 5 years. The incidence of the first subsequent suicidal behavior (attempt or dying by suicide) was examined and the numbers per person-year of overall repeat self-harm episodes, suicide attempt episodes, and non-suicidal self-harm episodes were evaluated.The total BHS scores showed significant associations with the overall number of self-harm episodes per person-year (incidence rate ratio [IRR], 1.05; 95% confidence interval [CI], 1.03-1.07; p0.0001), the number of suicide attempt episodes per person-year (IRR, 1.05; 95%CI, 1.03-1.08; p0.0001), and the number of non-suicidal self-harm episodes per person-year (IRR, 1.05; 95%CI, 1.03-1.07; p0.0001).The study excluded children and adolescents. The sample size, while large, was insufficient to ensure generalizability, or to allow subanalyses based on specific disorders.Hopelessness scores assessed in the emergency department after a self-harming episode were associated with a rate of repetition of suicidal behaviors after discharge. Additional strategies to address hopelessness of these patients are warranted.

AIM Suicide attempters have a high risk of repeated suicide attempts and completed suicide. There is evidence that assertive case management can reduce the incidence of recurrent suicidal behavior among suicide attempters. This study evaluated the effect of an assertive-case-management training program. METHODS This multicenter, before-and-after study was conducted at 10 centers in Japan. Participants were 274 medical personnel. We used Japanese versions of the Attitudes to Suicide Prevention Scale, the Gatekeeper Self-Efficacy Scale, the Suicide Intervention Response Inventory (SIRI), and the Attitudes Toward Suicide Questionnaire. We evaluated the effects with one-sample t-tests, and examined prognosis factors with multivariable analysis. RESULTS There were significant improvements between pre-training and post-training in the Attitudes to Suicide Prevention Scale (mean: -3.07, 95% confidence interval [CI]: -3.57 to -2.57, P

We construct a complete heterotic string field theory that includes both the Neveu-Schwarz and Ramond sectors. We give a construction of general string products, which realizes a cyclic L-infinity structure and thus provides with a gauge-invariant action in the homotopy algebraic formulation. Through a map of the string fields, we also give the Wess-Zumino-Witten-like action in the large Hilbert space, and verify its gauge invariance independently., Comment: 31 pages, 1figure, section for four point amplitudes is inserted; v3 English has been improved; v4 English is improved, Eq(5.16b) is corrected (published as erratum), Eq (A.19) is added

Ionizing radiation produces various types of DNA lesions, such as base damage, single-strand breaks, double-strand breaks (DSBs), and DNA–protein cross-links (DPCs). Of these, DSBs are the most critical lesions underlying the lethal effects of ionizing radiation. With DPCs, proteins covalently trapped in DNA constitute strong roadblocks to replication and transcription machineries, and hence can be lethal to cells. The formation of DPCs by ionizing radiation is promoted in the absence of oxygen, whereas that of DSBs is retarded. Accordingly, the contribution of DPCs to the lethal events in irradiated cells may not be negligible for hypoxic cells, such as those present in tumors. However, the role of DPCs in the lethal effects of ionizing radiation remains largely equivocal. In the present study, normoxic and hypoxic mouse tumors were irradiated with X-rays [low linear energy transfer (LET) radiation] and carbon (C)-ion beams (high LET radiation), and the resulting induction of DPCs and DSBs and their removal from the genome were analyzed. X-rays and C-ion beams produced more DPCs in hypoxic tumors than in normoxic tumors. Interestingly, the yield of DPCs was slightly but statistically significantly greater (1.3- to 1.5-fold) for C-ion beams than for X-rays. Both X-rays and C-ion beams generated two types of DPC that differed according to their rate of removal from the genome. This was also the case for DSBs. The half-lives of the rapidly removed components of DPCs and DSBs were similar (

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER2 inhibitor, S-222611, that selectively inhibited both kinases with IC50 s below 10 nmol/L. S-222611 also inhibited intracellular kinase activity and the growth of EGFR-expressing and HER2-expressing cancer cells. In addition, S-222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. In evaluations with two patient-oriented models, the intrafemoral implantation model and the intracranial implantation model, S-222611 exhibited excellent activity and could be effective against bone and brain metastasis. Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S-222611 showed equivalent or slightly weaker antitumor activity but a safer profile. These results indicated that S-222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses. Considering the safer profile than for irreversible inhibitors, S-222611 could be an important option in future cancer therapy.

Graphene oxide (GO), one of the best transparent substrates for electron microscopy of biological substances, is known to be not very stable to exposure to electron beams (e-beams). We present a me...

Hydroxyapatite (HAp) nanoparticle-coated poly(ϵ-caprolactone) (PCL) microspheres were fabricated via surfactant-free ‘Pickering-type’ emulsion solvent evaporation method in the absence of any molec...

Hydroxyapatite (HAp) nanoparticle-armored poly(ε-caprolactone) (PCL) microspheres were fabricated via a "Pickering-type" emulsion solvent evaporation method in the absence of any molecular surfactants. It was clarified that the interaction between carbonyl/carboxylic acid groups of PCL and the HAp nanoparticles at an oil-water interface played a crucial role in the preparation of the stable Pickering-type emulsions and the HAp nanoparticle-armored microspheres. The HAp nanoparticle-armored PCL microspheres were characterized in terms of size, size distribution, morphology, and chemical compositions using scanning electron microscopy, laser diffraction, energy dispersive X-ray microanalysis, and thermogravimetric analysis. The presence of HAp nanoparticles at the surface of the microspheres was confirmed by scanning electron microscopy and energy dispersive X-ray microanalysis. Pyrolysis of the PCL cores led to the formation of the corresponding HAp hollow microcapsules.

A phase modulation of an optical frequency comb has been applied to measure a fine spectrum in the 1.5 μm wavelength range by the optical heterodyne-detection method. The measurement frequency range covered 25 GHz, which satisfies the frequency interval of the optical frequency comb, with a spectral resolution of 1 MHz.

Background: Percutaneous vertebroplasty (PVP) is a technique that structurally stabilizes a fractured vertebral body. However, some patients return to the hospital due to recurrent back pain following PVP, and such pain is sometimes caused by new compression fractures. Purpose: To investigate whether the apparent diffusion coefficient (ADC) of adjacent vertebral bodies as assessed by diffusion-weighted imaging before PVP could predict the onset of new compression fractures following PVP. Material and Methods: 25 patients with osteoporotic compression fractures who underwent PVP were enrolled in this study. ADC was measured for 49 vertebral bodies immediately above and below each vertebral body injected with bone cement before and after PVP. By measuring ADC for each adjacent vertebral body, ADC was compared between vertebral bodies with a new compression fracture within 1 month and those without new compression fractures. In addition, the mean ADC of adjacent vertebral bodies per patient was calculated. Results: Mean preoperative ADC for the six adjacent vertebral bodies with new compression fractures was 0.55×10−3 mm2/s (range 0.36–1.01×10−3 mm2/s), and for the 43 adjacent vertebral bodies without new compression fractures 0.20×10−3 mm2/s (range 0–0.98×10−3 mm2/s) ( P−3 mm2/s (range 0.21–1.01×10−3 mm2/s), and that for the 19 patients without new compression fractures 0.17×10−3 mm2/s (range 0.01–0.43×10−3 mm2/s) ( P Conclusion: The ADC of adjacent vertebral bodies as assessed by diffusion-weighted imaging before PVP might be one of the predictors for new compression fractures following PVP.

We propose high-resolution spectroscopy based on laser light frequency sweeping using an optical single-sideband modulator. It has been confirmed experimentally that the frequency stability of the light source and high-speed scanning are critical for obtaining high resolutions of up to 1 MHz.

The electrochemical treatment of activated carbon electrodes has been investigated as a novel method enhancing the capacitance of electric double layer capacitor (EDLC) electrodes. The treatment at 0.7 V floating in a week at 70°C can be applied to EDLC with aqueous electrolytes. In 30 wt% H2SO4/H2O electrolyte, the treatment causes a capacitance increase in a low voltage region: 0–0.4 V. On the other hand, in 3.5 M NaBr/H2O electrolyte, it results in a remarkable capacitance increase of 2.4 times in a high voltage region: 0.4–1.0 V. These results suggest that the treatment mechanisms in the above electrolyte systems should be different. We report herein the origins and mechanisms of these capacitance increases.

Disconnection in the frontal-thalamic-cerebellar circuit is thought to be associated with cognitive abnormality in patients with schizophrenia. The superior cerebellar peduncle is involved in neural connectivity in the circuit. Because diffusion tensor imaging (DTI) can detect neural disconnection, we investigated whether there was neural disruption in the superior cerebellar peduncle in patients with schizophrenia. DTI was performed in 21 schizophrenic subjects and 21 age- and sex-matched healthy subjects. Cognitive cluster scores were attained by using the Positive and Negative Syndrome Scale (PANSS). Schizophrenic subjects had significantly lower fractional anisotropy (FA) in the right and left superior cerebellar peduncles than healthy subjects. Higher FA in the left superior cerebellar peduncle was associated with worse cognitive function in patients with schizophrenia. These findings suggest that there is neural disruption in the superior cerebellar peduncle in patients with schizophrenia, which may be involved in the cognitive abnormalities found in schizophrenia.

Nucleotide sequences of mouse parvovirus (MPV) isolate, named MPV/UT, and mouse minute virus (MMV) were analyzed and used for expressing recombinant proteins in E. coli. ELISA tests using recombinant major capsid protein (rVP2) and recombinant major non-structural protein (rNS1) as antigens were developed and their performance in serologic detection of rodent parvovirus infection was assessed. MPV-rVP2 and MMV-rVP2 ELISAs reacted specifically with anti-MPV and anti-MMV mouse sera, respectively. MMV-rNS1 antigen had a wide reaction range with antisera to rodent parvoviruses including MPV, MMV, Kilham rat virus (KRV) and H-1 virus. All mice oronasally infected with MPV were seropositive at 4 weeks post-infection in screening by ELISAs using MPV-rVP2 and MMV-rNS1 antigens, but were negative by conventional ELISA using whole MMV antigen. A contact transmission experiment revealed that transmission of MPV occurred up to 4 weeks post-infection, and all cage mates were seropositive in screening with MPV-rVP2 and MMV-rNS1 ELISAs. These results indicate that MPV-rVP2 and MMV-rVP2 are specific ELISA antigens which distinguish between MPV and MVM infection, while MMV-rNS1 antigen can be used in generic ELISA for a variety of rodent parvoviruses. The higher sensitivity of MPV-rVP2 ELISA than conventional ELISA for detecting seroconversion to MPV in oronasally infected mice as well as in cage mates suggests the usefulness of MPV-rVP2 ELISA in quarantine and microbiological monitoring of MPV infection in laboratory mice.

Recent evidence from neuroimaging studies suggests that neural dysfunction is involved in the pathophysiology of schizophrenia. Diffusion tensor imaging (DTI) is a technique that has the potential to detect subtle disruptions of neural connectivity. Fractional anisotropy (FA), which is measured by DTI, is a measure of the directionality of diffusion anisotropy. Decrease in FA indicates abnormalities of white matter due to increased water diffusion accompanied by an increase in extracellular space. In the literature, previous studies reported that patients with schizophrenia showed widespread lower FA in the white matter. These findings suggest that patients with schizophrenia have microstructural lesions in the cerebral white matter. We used DTI to determine whether neural connectivity was disturbed in the middle cerebellar peduncles in schizophrenic subjects. We found a significant FA reduction in the middle cerebellar peduncle in patients with schizophrenia. Therefore, neural disconnectivity between the cerebellum and cerebrum was considered present in patients with schizophrenia and may be involved in the pathology of schizophrenia. This review provides current findings regarding DTI study on the cerebellar peduncle in patients with schizophrenia.

To examine volumetric abnormality, the caudate nucleus was measured in patients with schizophrenia and healthy subjects using magnetic resonance imaging. The absolute and relative volumes of white matter in the caudate nucleus were found to be significantly smaller in patients with schizophrenia compared to those in healthy subjects. There were significant correlations between dosages of neuroleptics during the previous year and absolute gray matter volumes of the caudate nucleus as well as relative white matter volumes in patients with schizophrenia. These findings suggest that reduced white matter volume of the caudate nucleus may be a factor affecting the abnormal connectivity of the corticostriatal loop, and that neuroleptic medication would be related to white matter alteration in patients with schizophrenia. Our result replicates a previous study reporting that there is a lack of negative correlation between age and caudate nucleus volume. We also suggest that the disease process of schizophrenia might interfere with normal aging.

Diffusion tensor imaging (DTI) was used to investigate subtle disruption in the middle cerebellar peduncles in patients with schizophrenia. Fractional anisotropy (FA) was measured in 25 patients with schizophrenia and 21 healthy subjects using DTI. The FA of the right and left middle cerebellar peduncles was significantly lower in the schizophrenic patients compared to healthy subjects. FA in the left middle cerebellar peduncles was significantly correlated with the dosage of neuroleptics in patients with schizophrenia. There were no significant differences of mean diffusivity in the right and left middle cerebellar peduncles between patients with schizophrenia and healthy subjects. The findings of the study suggest that antipsychotics may improve the subtle disruption in the middle cerebellar peduncles in patients with schizophrenia.

To establish an early diagnosis of Alzheimer’s disease (AD), we evaluated brain spatial dynamics and cognitive function in mild AD. Seventeen patients with the diagnosis of mild AD and 17 age-matched controls were examined for Ω (global complexity), Σ (total power) and Φ (generalized frequency) by 19-channel electroencephalography (EEG). As a result, the mild AD group showed significantly higher Ω values than the control group. The Φ values were highly correlated with the Mini-Mental State Examination scores and the full IQ and performance IQ scores of the Japanese Wechsler Adult Intelligence Scale Revised. These results indicate an increase in spatial complexity of the brain electric field in mild AD, as well as a close relationship between slowing of the global frequency of field changes and the cognitive decline in mild AD.

A user data capacity of more than 23 Gbytes (GB) is required for the next-generation optical disks to store HDTV signals for over 2 hours. To achieve such recording capacity, mastering recorders must have higher resolution performance than present ones. Therefore we have been developing an electron beam recorder (EBR) (Y. Kojima et al, Joint MORIS/ISOM 1997 Tech. Dig., Th-L-06, 1997). Previously we reported the high-resolution performance of the EBR using an electron beam (EB) resist (ZEP-520). At the same time we confirmed the performance of read-only memory (ROM) disks (M. Katsumura et al, ISOM 2000 Tech. Dig., We-C-02, 2000; Y. Wada et al, Jpn. J. Appl. Phys. vol. 40, pp. 1653-1660, 2001). We acquired sufficient process quality for next generation optical disks, but the recording speed in this process is not sufficient for mass production. Accordingly it is necessary to raise the recording speed in EB mastering. Although there are several proposals for high-speed recording, we propose a chemically amplified resist (CAR) method for the improvement of mass production. In this paper, we report the application of the CAR to high-speed EB recording and the reproduction performance of the 25 GB CAR disks.

Brain electrophysiological characteristics of Alzheimer's disease (AD) were investigated by global field power (GFP) and low-resolution electromagnetic tomography (LORETA). GFP measures the energy of the brain electric field. LORETA computes for the smoothest of all possible source configurations throughout the brain volume by minimizing the total source strengths. The study population included a total of 29 AD patients and 15 age-matched controls. Clinical stages were based on the functional assessment staging (FAST). Mild-AD consists of 18 patients with a diagnosis of moderate cognitive decline (Stage 4). Advanced-AD consists of 11 patients with a diagnosis of severe cognitive decline (Stages 5, 6 and 7). Nineteen-channel eye-closed EEG was recorded using Cz reference and artifact-free 20 s were picked up and recomputed vs. average reference. Mild-AD showed lower power at Beta-2 and Beta-3 bands than control, and remarkably, advanced-AD showed lower power at the higher band of Alpha-1 than control. The t-scores of the current density of mild-AD were more reduced in the right frontal and temporal areas than the control at the beta bands, and of advanced-AD, reduced in low temporal area at alpha bands and reduced in temporal and parietal area at beta bands. This result clearly demonstrates the physiological characteristics of the clinical stages in Alzheimer's disease.

The purpose of this study is to develop the compact auxiliary water heater using tubular flame for home CHP (combined heat and power). The tubular-flame water-heater consists of the tubular flame burner, the coiled tube heat exchanger and the inserted tube installed at the center of the coiled tube as an additional heat exchanger. The tubular flame is formed in a rotating flow field by injecting the air-fuel mixture tangentially into the cylindrical chamber. The swirling flow of the combustion gas flows through the gap between the coiled tube and inserted tube. The high heat transfer performance can be achieved on these heat exchangers without the expanded heat transfer surface due to the swirling flow. Thus, the compact water heater can be constructed by using the tubular flame burner. At the first stage of the development, the maximum thermal efficiency achieves 81 % at the combustion rate of 15 kW. The heat transfer characteristics on the coiled tube and the inserted tube is investigated under the combustion and non-combustion conditions. Heat transfer coefficient on the coiled tube has about 5.6 times higher than that under the no-swirling flow condition at the same flow rate. Nusselt number on the coiled tube heat exchanger and the inserted tube can be estimated by Dhir's correlation equation for the swirling flow, which was provided as a function of the ratio between tangential momentum and axial momentum. The heat transfer characteristics on not only the coiled tube but the inserted tube was dominated by the swirling convection flow.

It has been believed that the crystal structure of alumina influences the surface flashover voltage. Residual stress is one of numerical indicators reflecting crystal structure of the material. In this experiment, residual stresses before flashover, after one flashover and after 200 flashovers were measured. For a non annealed alumina, measured values of residual stresses were -90.8 MPa (compressive stress, before flashover), -75.1 MPa (after one flashover), and 108 MPa (tensile stress, after 200 flashovers). For an annealed (1400°C in air, 4 hours) alumina, these were 52.4 MPa (tensile stress, before flashover), 16.5 MPa (after one flashover), and 10.4 MPa (after 200 flashovers).

Miso (fermented soybean paste) is a traditional Japanese fermented food, and is now used worldwide. The solid-state culture of filamentous fungus, Aspergillus oryzae, grown on rice is known as rice-koji, and is important as a starter for miso fermentation because of its prominent hydrolytic enzyme activities. Recently, commercial miso products have been supplemented with purinic ribonucleotides, such as inosine monophosphate (IMP) and guanine monophosphate, to enhance the characteristic umami taste of glutamate in miso. Because the purinic ribonucleotides are degraded by enzymes such as acid phosphatases in miso, heat inactivation is required prior to the addition of these flavorings. However, heat treatment is a costly process and reduces the quality of miso. Therefore, an approach to lower acid phosphatase activities in koji culture is necessary. Transcriptional analysis using an A. oryzae KBN8048 rice-koji culture showed that eight of the 13 acid phosphatase (aph) genes were significantly down-regulated by the addition of phosphoric acid in the preparation of the culture in a concentration-dependent manner, while aphC expression was markedly up-regulated under the same conditions. The eight down-regulated genes might be under the control of the functional counterpart of the Saccharomyces cerevisiae transcriptional activator Pho4, which specifically regulates phosphatase genes in response to the ambient phosphate availability. However, the regulatory mechanism of aphC was not clear. The IMP dephosphorylation activities in rice-koji cultures of KBN8048 and the aphC deletion mutant (ΔaphC) were reduced by up to 30% and 70%, respectively, in cultures with phosphoric acid, while protease and amylase activity, which is important for miso fermentation, was minimally affected. The miso products fermented using the rice-koji cultures of KBN8048 and ΔaphC prepared with phosphoric acid had reductions in IMP dephosphorylation activity of 80% and 90%, respectively, without any adverse effects on amylase and protease activities. Thus, preparing the A. oryzae rice-koji culture under phosphate-sufficient conditions preferentially produces a fermentation starter of miso exhibiting low purinic ribonucleotide dephosphorylation activity. Moreover, aphC is a potential breeding target to reduce purinic ribonucleotide degradation activity further in commercial miso products.

This case report describes a successful outcome of mirtazapine treatment in a patient with difficult post-thoracotomy pain. A 63-year-old man received thoracotomy for the resection of esophageal tumor. The pain continued 2 years after the operation. Allodynia was present in the region of the intercostal nerves from the surgical wound. Remedies such as clonazepam, amitriptyline, gabapentin, and acetaminophen were not effective, and epidural block effect was only temporal. The patient experienced a reduction in shooting pain after taking pregabalin; however, he still suffered from persistent pain and, mirtazapine was additionally administrated. One month after this, shooting and persistent pain was reduced, and the patient's appetite was improved, which had been present since the thoracotomy. Since then, his weight slightly increased and the administration of mirtazapine was stopped in accordance with the patient's request. The pain became worse again. Therefore, mirtazapine, commonly used as an antidepressant agent, was considered to be beneficial for neuropathic pain as an analgesic adjuvant.

Two-faced character in a film: Soft "Janus" two-dimensional colloidal crystal films were made using polystyrene (PS) particles, on an air-water interface as a mold for a flexible polypyrrole layer. By removing the PS particles, an array of femtoliter-sized cups was produced. These two-dimensional colloidal crystal films can also be transferred onto substrates with curvature.

Indirect electroreductive transformations of α,β-epoxy carbonyl compounds 1 mediated by diphenyl diselenide ((PhSe)2) as a recyclable reagent to their β-hydroxy derivatives 2 in 80–90% yields were ...