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Background: A Th1 predominant immune response has been shown in acute hypersensitivity pneumonitis. Predominance of Th2 appears to favour the development of pulmonary fibrosis through the profibrotic process and has been described as crucial in the progression of idiopathic pulmonary fibrosis. Chronic bird fancier's lung (cBFL) can present with a histological pattern of usual interstitial pneumonia (UIP)-like lesions. Little is known about the Th1/Th2 balance in the pathogenesis of cBFL. Methods: To evaluate the relevance of Th1-type chemokines (interferon-inducible protein, IP-10) and Th2-type chemokines (thymus- and activation-regulated chemokine, TARC) and their receptors (CXCR3 and CCR4) to the histological patterns of cBFL, 40 patients with cBFL who underwent surgical lung biopsies, 12 with acute BFL (aBFL) and 10 healthy volunteers were analysed. IP-10 and TARC levels in serum and bronchoalveolar lavage (BAL) fluid were measured by ELISA. Immunohistochemistry for CXCR3 and CCR4 was performed on surgical lung specimens. Results: The ratio of TARC to P-10 in the serum of patients with UIP-like lesions was significantly higher than in patients with cNSIP/OP-like lesions, aBFL and healthy volunteers. The ratio of CCR4 to CXCR3 in patients with UIP-like lesions was significantly higher than in those with cNSIP/OP-like lesions and cNSIP-like lesions. The ratio of CCR4-positive to CXCR3-positive cells correlated with the ratio of TARC to IP-10 in serum. Conclusions: A Th2 predominant immune response may play an important role in the development of UIP-like lesions, as already observed in idiopathic pulmonary fibrosis. A Th1 predominance may play a role in the development of cNSIP/OP-like lesions in cBFL. [ABSTRACT FROM AUTHOR]

Objective: To investigate the involvement of Tie-1 and Tie-2, receptor tyrosine kinases required for angiogenesis, in synovial proliferation and angiogenesis of rheumatoid arthritis (RA).Methods: Synovial tissues from 10 patients with RA and three control subjects were analysed by double immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR).Results: Expression of Tie-1 and Tie-2 was seen in all synovia, but predominantly in papillary projected portions. In synovial lining cells, Tie-2 was expressed mainly in the basal layer and frequently colocalised with vimentin and proliferating cell nuclear antigen (PCNA), whereas Tie-1 was also expressed in the superficial layer. In stromal cells, Tie-2 immunoreactivity was restricted to vimentin positive fibroblast-but not macrophage derived cells, whereas Tie-1 expression was not dependent on the phenotype. Tie receptors were also highly expressed in the endothelium and surrounding pericytes of capillaries scattered over the papillary proliferated synovium without notable difference in the expression of the two receptors. Furthermore, Tie positive vessels often overexpressed PCNA. In normal synovia, expression of Tie receptors was restricted to the capillary endothelium. RT-PCR confirmed the expression of Tie-1 and Tie-2 in RA synovial tissues and also in the cultured synoviocytes.Conclusion: The results suggest the possible involvement of overexpressed Tie-1 and Tie-2 in synovial lining and stromal cells in the pathophysiology of RA synovitis, probably through distinct mechanisms. Furthermore, expression of Tie receptors in actively growing vasculature may reflect the direct involvement of these receptors in angiogenesis and subsequent vascularisation. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: It has been reported that eradication of Helicobacter pylori improves fold width in H pylori associated enlarged fold gastritis. The aim of this study was to clarify the mechanism of fold thickening in this condition. PATIENTS AND METHODS: In eight patients with enlarged fold gastritis and 13 patients without enlarged folds, the presence of H pylori infection, inflammatory infiltrates, mucosal plasia, and epithelial cell proliferation in the body mucosa were investigated, and production of transforming growth factor alpha (TGF alpha), hepatocyte growth factor (HGF), and interleukin 1 beta (IL 1 beta) was determined by a competitive reverse transcription/polymerase chain reaction method and in vitro short-term culture of biopsy specimens. RESULTS: In the patients with enlarged fold gastritis, inflammatory infiltrates including macrophages increased with H pylori colonisation in the body. Foveolar thickness and proliferating cell nuclear antigen (PCNA) labelling index were increased. Messenger RNA levels of HGF, but not TGF alpha, were increased, and release of HGF and IL 1 beta was increased. HGF release, which was positively correlated with IL 1 beta release and foveolar thickness, decreased in the presence of IL 1 receptor antagonist. After eradication of H pylori, inflammatory infiltrates, IL 1 beta and HGF release decreased with concomitant decreases in PCNA labelling index, foveolar thickness and fold width. CONCLUSIONS: Increased IL 1 beta and HGF production caused by H pylori infection may contribute to fold thickening of the stomach by stimulating epithelial cell proliferation and foveolar hyperplasia in patients with enlarged fold gastritis. [ABSTRACT FROM PUBLISHER]

This study examined the effects of eradication of Helicobacter pylori (H pylori) infection on gastric mucosal morphology and acid secretion. Sixteen H pylori positive patients with enlarged gastric body folds were divided into two groups: (a) patients with moderate enlargement (fold width: 6 to 10 mm, n = 8) and (b) patients with severe enlargement (> 10 mm, n = 8). After successful treatment, gastric body fold width was reduced in both groups (p < 0.01) with an associated decrease in inflammatory infiltrates in the body mucosa (p < 0.01 and p < 0.05). Basal acid output and tetragastrin stimulated maximal acid output (mean (SEM)) in all 16 patients significantly increased from 1.1 (0.5) to 2.9 (0.9) mmol/h (p < 0.05) and from 5.4 (1.3) to 18.7 (2.3) mmol/h (p < 0.01), respectively, with a significant decrease in fasting serum gastrin concentrations, from 127.1 (16.1) to 59.6 (3.8) pg/ml (p < 0.01). The increase in acid secretion after eradication of H pylori was more noticeable in the severe group, who had shown lower acid secretion and higher serum gastrin concentrations (p < 0.05) before eradication, than the increase seen in the moderate group. The decreases in ammonia nitrogen content seen after eradication were significant in basal (from 0.91 (0.17) to 0.37 (0.08) mmol/h, p < 0.05) and stimulated gastric secretions (from 1.57 (0.19) to 0.37 (0.13) mmol/h, p < 0.01), although these changes were too small to explain the increases in basal acid output and maximal acid output. These results suggest that inflammation of the gastric body mucosa caused by H pylori infection is associated with enlarged gastric body folds and inhibition of acid secretion in H pylori positive patients with enlarged gastric body folds. [ABSTRACT FROM PUBLISHER]

This article discusses a case of acute urinary retention caused by periaqueductal grey lesion. Diseases of the central nervous system often cause disturbances in micturition. These diseases include lesions in the spinal cord, pons, cerebellum, hypothalamus, basal ganglia, and cerebrum. In the discussed case, a 31 year old man had sudden voiding difficulty resulting in urinary retention and was referred to a neurologist. Although no particular abnormalities were observed except for an abnormal signal intensity on magnetic resonance imaging in the right dorsal portion of the midbrain, he was suspected to have a demyelinating or inflammatory disease and 30 mg of oral prednisolone daily was prescribed.

Injury prevention is one of the most important and urgent issue in children health since the primary cause of death of children is unintentional injuries. Developing safety measures based on injury data are essential for preventing childhood injuries. Passive approach, namely Injury prevention approach by product modification is strongly needed. The risk assessment is one of the most fundamental methods to design safety products. However, the conventional risk assessment has been carried out subjectively because product makers have poor data on injuries. Developing methodology quantitative risk assessment for injury prevention is required by product makers. This paper proposes a new system for risk assessment by integrating biomechanical simulation, sensory observation data on how children's use products, and hospital-based injury surveillance data. The system allows a product designer for foreseeing how children use a product and which types of injuries occur due to the product in daily environment. To prove the effectiveness of the proposed system, this paper describes the application of the system to risk analysis of the swing in a park. In order to obtain children's behaviour data around the swing, video cameras were installed in the park. The camera image of behaviour data was analysed by image processing. As for injury data, authors used detailed injury data collected in hospitals using the body graphic information system developed by authors. The developed system can search the candidate of possible situation resulting in serious injuries using sensory data and injury data, and evaluate risk quantitatively in terms of head injury criteria (HIC) using biomechanical simulation. [ABSTRACT FROM PUBLISHER]

Objective: To investigate the early detection of pulmonary non-tuberculous mycobacterial (PNTM) disease by CT before the initiation of molecular-targeted therapeutic drugs in patients with rheumatoid arthritis (RA) and the efficacy and safety of combined treatment with antibiotics., Methods: Patients with RA underwent chest CT before the introduction of molecular-targeted therapies in the Further Improvement of Rheumatoid arthritis Treatment registry. The primary endpoint was the number of patients who were detected by CT as having PNTM disease, complicating RA., Results: Of 4447 patients with RA who underwent chest CT, 107 had suspected PNTM disease, and 33 diagnoses were confirmed by culture. In 14 of the 33 patients, plain radiographs showed no abnormalities; PNTM disease was only observed on CT scans. The prevalence of PNTM disease in patients with RA requiring molecular-targeted treatment was six times higher than that in healthy individuals. 31 patients initiated molecular-targeted therapeutic drugs in combination with anti-NTM treatment, and 28 were followed up for 24 months. No significant difference was observed in the retention rate and RA disease activity at 24 months between the PNTM and non-PNTM groups. Coexisting PNTM disease did not affect treatment discontinuation. None of the 28 patients in the PNTM group experienced exacerbation of PNTM disease., Conclusion: CT screening before the initiation of molecular-targeted treatment enabled the detection of asymptomatic PNTM that was undetectable on plain radiographs. This study showed that molecular-targeted therapeutic drugs in combination with anti-NTM treatment could control the disease activity of both PNTM and RA., Competing Interests: Competing interests: YM has received consulting fees, speaking fees and honoraria from Eli Lilly and has received research grants from GlaxoSmithKline. KS received speaking fees from Chugai, Lilly, Astellas and Taisho, and a research grant from UCB Japan. SN has received consulting fees, lecture fees and honoraria from Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, AbbVie, Astellas, Asahi-kasei, Sanofi, Chugai, Eisai, Gilead Sciences and Boehringer-Ingelheim and has received research grants from Mitsubishi-Tanabe. YT has received speaking fees and honoraria from Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe and GlaxoSmithKline and research grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo and Behringer-Ingelheim., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objective: To investigate sustained remission following the discontinuation of tofacitinib in patients with rheumatoid arthritis., Methods: Patients who had an inadequate response to methotrexate (MTX) with or without biological disease-modifying antirheumatic drugs were randomly divided into two groups at baseline, and tofacitinib treatment in combination with MTX was administered to both groups. Either MTX or tofacitinib was then withdrawn if patients achieved Clinical Disease Activity Index remission at week 52. The primary outcome was the proportion of patients who sustained clinical remission at week 104., Results: A total of 113 patients participated in this study. Among them, a total of 48 patients achieved remission at week 52. After discontinuation of tofacitinib, only 29.2% (7/24) of patients remained remission, while 50.0% (10/20) of patients, which was numerically higher but not statistically significant, sustained remission after MTX discontinuation. A greater proportion of bio-naïve patients achieved remission at week 52 and sustained low disease activity with tofacitinib discontinuation at week 104. Additionally, the patients who were able to discontinue tofacitinib without flares had lower rheumatoid factor (p=0.04) and lower anti-cyclic citrullinated peptide antibody (p=0.051) before discontinuation of tofacitinib. No severe adverse events were recorded after discontinuation of tofacitinib or MTX. In patients who relapsed after tofacitinib discontinuation, 71.4% achieved remission with resumption of tofacitinib., Conclusions: This study implies that a blanket cessation of tofacitinib may not be suitable for all patients, given that 58% of the participants experienced relapse. However, the withdrawal of tofacitinib is unlikely to result in the acquisition of treatment-resistance., Competing Interests: Competing interests: SK has received consulting fees, speaking fees and/or honoraria from Eli Lilly, Bristol-Myers, GlaxoSmithKline and research grants from Daiichi-Sankyo, Abbvie, Boehringer Ingelheim and Astellas. YM has received consulting fees, speaking fees and/or honoraria from Eli Lilly and has received research grants from GlaxoSmithKline. KA has received research grants from Asahi-Kasei Pharma and speaking fees from Abbvie GK, Chugai Pharmaceutical Co, Eisai, Eli Lilly and Pfizer Japan. KM has received research grants from Asahi-Kasei Pharma and Chugai. HK has received speaking fees and/or honoraria from AbbVie, Asahi-Kasei, Bristol-Myers, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Pfizer and UCB, and received research grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Mitsubishi-Tanabe and Taisho. SN has received consulting fees, speaking fees and/or honoraria from Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, Sanofi, Abbvie, Eisai, Chugai, Gilead, Boehringer Ingelheim and has received research grants from Mitsubishi-Tanabe. YK has received consulting fees, speaking fees and/or honoraria from Abbvie, Asahi Kasei, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Novartis, Pfizer, Boehringer Ingelheim, Asahi-Kasei, Eli Lilly, GlaxoSmithKline, UCB, and has received research grants from Mitsubishi-Tanabe, Chugai and Abbvie. KY has received consulting fees, speaking fees and/or honoraria from Pfizer, Chugai Pharma, Takeda Industrial Pharma, Astellas Pharma, Abbvie, Bristol-Myers Squibb, Mitsubishi-Tanabe Pharma, GlaxoSmithKline, Eli Lilly, Janssen Pharma, Eisai Pharma, Actelion Pharmaceuticals Japan, Asahi Kasei Pharma Corp, Ono Pharma, Otsuka Pharma, Nippon Shinyaku, Gilead G.K, Daiichi Sankyo, Boehringer Ingelheim Japan, Japan Tobacco, Hisamitsu Pharma, MSD, Sanofi, AYUMI Pharma, Nippon Kayaku. YTanaka has received speaking fees and/or honoraria from Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, received research grants from Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Manipulation of tablets or capsules is frequently carried out in pharmacies to regulate doses for personalised therapy. We proposed the use of reconstructed granules as a suitable, flexible dosage form and developed an on-site granulation method using a compounding mixer. The aim of this study was to demonstrate the feasibility of small-scale preparation of granules in a pharmacy setting. Rifampicin capsules were used as a model medicine because of the associated need for drug desensitisation therapy., Methods: The contents of a rifampicin capsule were granulated using a compounding mixer, and small ointment containers (12 mL) with filling rates of 4%, 8%, 12%, and 16% were used as granulation vessels. The obtained granules were examined for particle size distribution, yield, crystal transition, drug dissolution profile, storage stability, and weight loss during dosing., Results: The yields increased by >95%, and the span of the particle size distribution decreased to 1.0, as the filling rate increased. The smallest batch size was found to be 0.8 g in a 12 mL vessel. Examination of the resultant granules revealed that granulation did not affect the crystal polymorphism, dissolution profile, or storage stability of rifampicin. Furthermore, the weight loss of the granules during the dosing process was significantly lower than that of the capsule powder content., Conclusions: We demonstrated that granules with sufficient quality for clinical use could be extemporaneously prepared using a compounding mixer in pharmacies. This improved the usability of the medicine, preventing weight loss, and making it a suitable alternative formulation for precise personalised pharmacotherapy., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To study the pathophysiological differences of EGPA and IgG 4 -related disease (RD) by clarifying their clinical, pathological and immunological features., Methods: Clinical and pathological findings were compared in patients with EGPA and IgG 4 -RD. Peripheral blood mononuclear cells were used for comprehensive flow cytometric analysis., Results: An elevation of the IgG4 level was found in all EGPA cases, with the accompanying pathological findings of lymphocytic infiltration and fibrosis observed in 30.8% patients, and the elevation of IgG 4 /IgG ratio in 61.5% patients. However, actual IgG 4 levels, as well as the degree of the infiltration of IgG 4 -positive plasma cells, were still higher in patients with IgG 4 -RD than patients with EGPA. Examination by ACR/EULAR classification criteria showed only 13.6% of the EGPA patients met entry criteria, while all of them met the exclusion criteria. In regard to the immunophenotyping, EGPA patients had increases in activated CD4 and CD8 T cells compared with the healthy controls. However, no such similar changes occurred in IgG 4 -RD patients. On the other hand, both the EGPA and IgG 4 -RD patient groups had correlated increased plasmablasts and Tfh. These results indicate the presence of two axes: namely, the activation of T cells and that of B cells. Both axes are present in EGPA, but the T cell activation axis was not observed in IgG 4 -RD., Conclusions: The elevation of serum IgG 4 as well as pathological IgG 4 infiltration are not specific. Meanwhile, EGPA and IgG4-RD differ in immunological phenotypes, indicating the possible importance of the predominant activation of T cells in the development of vasculitis., Competing Interests: Competing interests: YM has received consulting fees, speaking fees, and/or honoraria from Eli Lilly and has received research grants from Glaxo Smith Kline. SN has received consulting fees, speaking fees, and/or honoraria from Bristol-Myers, Pfizer, GlaxoSmithKline, Sanofi, Astellas, Asahi-kasei, Boehringer Ingelheim and has received research grants from Mitsubishi-Tanabe and Novartis. YT has received consulting fees, speaking fees, and/or honoraria from Abbvie, Daiichi-Sankyo, Chugai, Takeda, Mitsubishi-Tanabe, Bristol-Myers, Astellas, Eisai, Janssen, Pfizer, Asahi-kasei, Eli Lilly, GlaxoSmithKline, UCB, Teijin, MSD and Santen, and also research grants from Mitsubishi-Tanabe, Takeda, Chugai, Astellas, Eisai, Taisho-Toyama, Kyowa-Kirin, Abbvie, and Bristol-Myers., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Several studies have reported that cilostazol (CLS) may reduce in-stent restenosis (ISR) after carotid artery stenting (CAS). However, it is not known for how long CLS must be continued to prevent ISR., Methods: We retrospectively reviewed a prospectively collected database of patients who underwent elective CAS and follow-up angiography at 3 months and 1 year after the procedure. ISR was defined as stenosis of 50% or greater on digital subtraction angiography. The cumulative incidence rates of angiographic ISR were compared between the three groups, divided according to duration of CLS use : (1) patients who were maintained on CLS for 12 months or more after CAS (12M CLS group, n=70), (2) patients who were treated with CLS for the first 3 months after CAS (3M CLS group, n=23), and (3) patients who did not receive CLS (no CLS group, n=136)., Results: A total of 229 lesions in 199 patients were included in our analysis. During a median follow-up of 365 days, ISR was detected in 15 lesions. The cumulative ISR rates overall and in the 12M CLS, 3M CLS, and no CLS groups were 5.6%, 0%, 5.0%, and 8.4%, respectively, at 1 year, and the log rank test showed that there was a significant difference between the three groups (p<0.05). Cox regression analysis demonstrated that the 12M CLS group had a significantly lower risk of ISR than the 3M CLS group (adjusted relative risk (aRR) 3.06e-10, 95% CI 0 to 0.51, p<0.05) and the no CLS group (aRR 1.41e-10, 95% CI 0 to 0.15, p<0.001), whereas no difference was found between the 3M CLS group and the no CLS group., Conclusions: An overall cumulative ISR rate of 5.6% was documented angiographically at 1 year after CAS. Continuous daily use of CLS (for at least 1 year) may have a beneficial effect on long term prevention of ISR., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: There is a growing body of evidence demonstrating that deep brain stimulation (DBS) of globus pallidus internus (GPi DBS) and subthalamic nucleus (STN DBS) are effective treatment for patients with Parkinson's disease (PD). However, it remains controversial whether the best stimulation target for a PD patient is GPi or STN., Methods: A computer literature search of PubMed was carried out. We included randomised studies with direct comparison between targets. The outcome of unified PD rating scale (UPDRS) III was expressed as the standardised mean difference (SMD) between targets in baseline to endpoint change. Pooled risk ratio (RR) between targets was also used to assess adverse events., Results: Four studies, comprising a total sample size of 502 PD patients (254 GPi DBS, 248 STN DBS), were included in this meta-analysis. The overall effect of GPi DBS on UPDRS III was not significantly different from STN DBS (SMD=0.19, 95% CI -0.2 to 0.58, p=0.34, four studies, n=448). This result was heterogeneous (p=0.03, I(2)=66%). In terms of adverse events, depression was significantly less frequent in patients with GPi DBS than STN DBS with homogeneous studies (pooled RR=0.53, 95% CI 0.31 to 0.90, p=0.02, three studies, n=479, I(2)=48%)., Conclusions: The effect of GPi DBS was similar to STN DBS except for depression, however, only three studies described depression as adverse events. We need additional randomised trials with direct comparison between targets based on unified scoring of adverse events., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: The transfemoral approach has been a common technique for carotid artery stenting (CAS). When aortic or peripheral arterial conditions limit the transfemoral approach, the transbrachial approach may be used as an alternative. The purpose of our study was to report initial experiences of CAS with a novel sheath guide specifically designed for transbrachial carotid cannulation., Methods: Patients who underwent transbrachial CAS with a novel sheath guide between May 2011 and July 2012 were analyzed. The sheath guide has an internal diameter of 6 Fr (2.24 mm, 0.088 inch) and is 90 cm long with a soft distal part and a particular distal shape like a modified Simmons catheter., Results: Sixty-two patients underwent transbrachial CAS with the sheath guide. Transbrachial carotid cannulation was easy and successful and CAS procedures were performed easily through the sheath guide in every case. No sheath-related periprocedural complications occurred., Conclusions: The sheath guide specifically designed for transbrachial carotid cannulation is useful for transbrachial CAS.

Background: A study was undertaken to investigate the feasibility, safety and effectiveness of emergency carotid artery stenting (eCAS) for a high-grade carotid stenosis with intraluminal thrombus (ILT) with or without proximal flow control (PFC)., Methods: Patients with acute ischemic stroke included in the analysis were those who were admitted between 2001 and 2010 with serious neurological symptoms, without a large high-intensity area of diffusion-weighted images and who underwent eCAS for a high-grade carotid stenosis with ILT. Patients underwent eCAS without PFC until 2004 (group C) and under PFC after 2004 (group P). The National Institutes of Health Stroke Scale (NIHSS) score on admission, just before CAS and 7 days after CAS as well as the 3-month modified Rankin Scale were investigated., Results: Fifty-six patients underwent eCAS, eight of whom had a high-grade stenosis with ILT. Four of the eight patients were in group C and four were in group P. Probable distal embolism associated with eCAS occurred in two cases in group C and in none in group P. In groups C and P the median 7-day NIHSS scores were 15 and 5, respectively (p<0.05) and the median 3-month modified Rankin Scale scores were 4 and 2, respectively (p<0.05), but there were no significant differences between the two groups in the NIHSS scores on admission and just before CAS., Conclusion: In stroke patients with a high-grade carotid stenosis with ILT, eCAS under PFC is safer and more effective in achieving a favorable clinical outcome than eCAS without PFC.