Erratum: Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande [Phys. Rev. Lett. 130, 031802 (2023)].

This corrects the article DOI: 10.1103/PhysRevLett.130.031802.

Search for Cosmic-Ray Boosted Sub-GeV Dark Matter Using Recoil Protons at Super-Kamiokande.

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton×years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross section between 10^{-33}cm^{2} and 10^{-27}cm^{2} for dark matter mass from 1 MeV/c^{2} to 300 MeV/c^{2}.

Dupilumab treatment in patients with atopic dermatitis: a comparative cohort study between the Netherlands and Japan shows a discrepancy in patient-reported outcome measures.

BACKGROUND: Dupilumab was equally effective among all racial subgroups in clinical trials, but a direct comparison in daily practice is lacking. OBJECTIVES: To investigate the effectiveness of dupilumab in patients with atopic dermatitis (AD) in the Netherlands and Japan over 80 weeks of treatment. METHODS: A longitudinal comparative cohort study was conducted in patients with AD who were treated with dupilumab in daily practice. We used linear mixed-effects models to determine changes over time. RESULTS: We found statistically significant differences in sex, disease onset, body mass index and therapeutic history between Dutch (n = 208) and Japanese (n = 153) patients. The baseline Eczema Area and Severity Index (EASI) score was higher in Japanese patients (23·8 vs. 14·8), while baseline Patient-Reported Outcome Measures (PROMs) were higher in Dutch patients. EASI scores decreased quickly to a level indicating 'mild disease' (EASI < 7), and remained low in both countries. However, PROMs showed different trajectories with better scores in Japan. CONCLUSIONS: Dupilumab showed significant, comparable and sustained improvement of EASI scores in Japanese and Dutch patients. However, we found striking differences in the effect on PROMs between the countries, with a better outcome in Japanese patients.

Efficacy and safety of dupilumab in Japanese adults with moderate-to-severe atopic dermatitis: a subanalysis of three clinical trials.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin-4 and interleukin-13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate-to-severe AD. METHODS: We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16-week, phase IIb dose-finding trial (AD-1021; NCT01859988); a 16-week, phase III, placebo-controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52-week, phase III, placebo-controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). RESULTS: Twenty-seven, 106 and 117 Japanese patients were enrolled in AD-1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection-site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation-regulated chemokine and gradual IgE reductions. CONCLUSIONS: Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate-to-severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T-cell activation profiles have been observed. International clinical studies in adults with moderate-to-severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin-4 and interleukin-13, key molecules in type 2 inflammation. The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate-to-severe AD. The effects were comparable with those observed in the overall study population. Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.

Defining and measuring 'eczema control': an international qualitative study to explore the views of those living with and treating atopic eczema.

BACKGROUND: Atopic eczema (also known as eczema) is a chronic, inflammatory skin condition that often afflicts patients' health and well-being. The Harmonising Outcome Measures for Eczema (HOME) initiative recommends that 'long-term control of eczema' is measured in all clinical trials 3 months or longer in duration. However, little has been published on what eczema control means to those living with or treating atopic eczema. OBJECTIVES: To (i) develop understanding of what eczema control means to patients, carers and clinicians and (ii) explore the feasibility and acceptability of different ways of measuring eczema control in the long term. METHODS: Online focus groups explored patients/carers experiences in the UK, the United States, the Netherlands, France, Sweden and Japan, and an international online survey gathered views of clinicians. The framework method was used to analyse the focus groups, and thematic analysis was used to analyse survey data. All findings were integrated into a theoretical framework to create overarching themes that cut across these diverse groups. RESULTS: Eight focus groups with patients (16 years+) and eight groups with carers of children took place (N = 97). Sixty-two people took part in the survey. Eczema control was described as a multifaceted construct involving changes in disease activity, the treatment and management of the condition and psychological, social and physical functioning. Patient/carer measurement allows personal accounts and frequent measurement, whilst clinician measurement was deemed less subjective. The burden on patients/carers and issues for analysing and interpreting data should be considered. CONCLUSIONS: This study formed the basis of judging the content validity and feasibility of measurement instruments/methods to assess control of eczema in clinical trials. This online approach to an international qualitative study is an example of how core outcome set developers with limited resources can engage with multiple stakeholder groups on an international basis to inform consensus meeting discussions.

Staphylococcus pseudintermedius biofilms secrete factors that induce inflammatory reactions in vitro.

Biofilms, composed of bacterial cells embedded in a secreted polysaccharide and protein matrix, often cause problems such as chronic and refractory infections. Staphylococcus pseudintermedius, which is an important pathogen in veterinary medicine, has a high rate of biofilm production. Although it is considered that S. pseudintermedius biofilms are associated with prolonged inflammatory disorders, there are no reports that S. pseudintermedius biofilm directly regulates inflammatory reactions. In this study, we focused on the metabolites derived from biofilm cultures of S. pseudintermedius and evaluated their inflammatory effects in vitro. Expression levels of interleukin-1 beta and interleukin-6 mRNA significantly increased in RAW264.7 cells that were cultured with biofilm-conditioned medium (BCM). The secreted proteins in BCM were heat resistance and activated a Toll-like receptor (TLR) signalling pathway. Moreover, based on SDS-PAGE analysis, isolates with stronger biofilm-forming capabilities induced more inflammatory reactions and had specific banding patterns compared with those of weak biofilm producers. Collectively, our results suggest that the proteins derived from S. pseudintermedius biofilm induce a host inflammatory response via a TLR pathway. Furthermore, the severity of inflammation depends on the biofilm formation capacity of the S. pseudintermedius strain. SIGNIFICANCE AND IMPACT OF THE STUDY: Staphylococcus pseudintermedius is a biofilm-forming bacterium. We identified some biofilm secreted heat-resistant proteins that induce inflammatory reactions through Toll-like receptor signalling. The expression of the secreted protein varied depending on the potency of biofilm production. Our data suggest that these proteins may be the factors causing biofilm-related inflammation during S. pseudintermedius infections. Identification of these proteins may lead to the development of novel medications to prevent the exacerbation of infections caused by S. pseudintermedius.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.

Clinical Features and Outcomes of Diffuse Alveolar Hemorrhage During Antithrombotic Therapy: A Retrospective Cohort Study.

PURPOSE: Antithrombotic therapy could trigger diffuse alveolar hemorrhage (DAH), and there are several case reports of DAH that occurred during antithrombotic therapy (DAH-AT). However, little is known about the clinical features and outcomes of DAH-AT. The purpose of this study was to clarify the features and mortality of DAH-AT. METHODS: 76 consecutive patients with DAH who were admitted to our hospital between January 2003 and April 2014 were retrospectively reviewed to identify the clinical features and outcomes of DAH-AT. The primary outcome was 90-day mortality. RESULTS: Of the 76 patients with DAH, 39 patients (51 %) had DAH-AT, and 37 patients (49 %) had DAH that occurred with no antithrombotic therapy (DAH-NAT). Of the patients with DAH-AT, 25 (64 %) were taking aspirin, 14 (36 %) were taking warfarin, 5 (13 %) were taking clopidogrel sulfate, and 4 (10 %) were taking cilostazol. Pre-existing cardiac disease was present in 23 (59 %) DAH-AT cases and 5 (14 %) DAH-NAT cases. Logistic regression analysis was used to assess the effect of antithrombotic therapy on the mortality of DAH patients, and no significant difference in survival was seen with antithrombotic therapy (OR 1.18, 95 % CI 0.38-3.78). CONCLUSIONS: Antithrombotic therapies had no effect on the 90-day mortality of DAH patients.

Clinical comparison between arthrocentesis and conventional conservative treatment with maxillomandibular fixation for unilateral high condylar fractures.

This study aimed to compare the effects of arthrocentesis and conventional closed reduction for unilateral mandibular condyle fractures. A total of 30 patients with unilateral condylar fractures were evaluated. Patients with a high condylar fracture and magnetic resonance evidence of joint effusion (JE) were divided into two groups: those treated with intra-articular irrigation and betamethasone injection (group I) and those given conservative treatment and rigid maxillomandibular fixation (MMF) (group II). All patients were assessed for mandibular range of motion (ROM), protrusive movements, lateral excursion movements on the fractured and non-fractured sides, pain in the temporomandibular joint and malocclusion, both before and after treatment. There were no significant differences in regard to protrusion, lateral excursion movement and incidence of malocclusion at 12 months after treatment between the groups (P > 0.05). In group I, ROM and joint pain showed good improvement from the early stages of treatment, and those patients had better outcomes as compared to group II for those parameters at 1 and 3 months after injury. The present findings indicate that arthrocentesis may be more effective and provide faster healing than conventional closed reduction.

Male sexual function after laparoscopic total mesorectal excision.

AIM: The aim of this prospective study was to clarify the frequency of male sexual dysfunction after laparoscopic total mesorectal excision (LTME) and to examine the relationship between pelvic autonomic nerve (PAN) preservation status and functional outcomes. METHOD: Candidates for LTME were included in this study. PAN preservation status after LTME was examined in detail by video review. Patients completed a functional questionnaire (the International Index of Erectile Function) before and 3, 6 and 12 months after the operation. RESULTS: Twenty-six patients who underwent LTME were assessable. Detailed video reviews identified inadvertent PAN damage during surgery. PAN injury was observed in 11 cases (41%), including eight cases (32%) of inadvertent PAN damage (incomplete preservation group). There was a trend toward increasing inadvertent PAN injury rate in patients with high body mass index and large tumours. The results from all patients who underwent LTME showed no deterioration in total International Index of Erectile Function or its domain scores 12 months after surgery. In the incomplete preservation group, these scores temporarily decreased (3 and 6 months after surgery), but such deterioration was not observed in the complete preservation group. Most of the 12 patients with potentially active erectile function before the operation recovered this function, and only one patient (7%) with PAN injury was still judged as inactive 12 months after surgery. CONCLUSION: The proportion of patients with sexual dysfunction after LTME is low. With the enhanced visibility of the laparoscope, inadvertent PAN injury was detected in a significant number of cases and associated with transient deterioration of sexual function.

A prevalent founder mutation and genotype-phenotype correlations of OTOF in Japanese patients with auditory neuropathy.

Auditory neuropathy is a hearing disorder characterized by normal outer hair cell function and abnormal neural conduction of the auditory pathway. Aetiology and clinical presentation of congenital or early-onset auditory neuropathy are heterogeneous, and their correlations are not well understood. Genetic backgrounds and associated phenotypes of congenital or early-onset auditory neuropathy were investigated by systematically screening a cohort of 23 patients from unrelated Japanese families. Of the 23 patients, 13 (56.5%) had biallelic mutations in OTOF, whereas little or no association was detected with GJB2 or PJVK, respectively. Nine different mutations of OTOF were detected, and seven of them were novel. p.R1939Q, which was previously reported in one family in the United States, was found in 13 of the 23 patients (56.5%), and a founder effect was determined for this mutation. p.R1939Q homozygotes and compound heterozygotes of p.R1939Q and truncating mutations or a putative splice site mutation presented with stable, and severe-to-profound hearing loss with a flat or gently sloping audiogram, whereas patients who had non-truncating mutations except for p.R1939Q presented with moderate hearing loss with a steeply sloping, gently sloping or flat audiogram, or temperature-sensitive auditory neuropathy. These results support the clinical significance of comprehensive mutation screening for auditory neuropathy.

Possible spin singlet quadrumerization in Pb2Re2O(7-δ).

A single crystal of pyrochlore Pb(2)Re(2)O(6.75) was prepared by hydrothermal synthesis, and its magnetic and transport properties were investigated. Pb(2)Re(2)O(6.75) shows the metallic conduction with an anomalous second-order structural phase transition at T(s)=294 K, in which the magnetization and the structure change similarly to that at 200 K of the superconductor Cd(2)Re(2)O(7). A three-dimensional Ising-like order parameter probed by the atomic displacement suggests that an unconventional spin singlet state is possibly realized in the ground state of Pb(2)Re(2)O(6.75), in which four spins make a quadrumer in order to remove the spin frustration of the pyrochlore lattice.

Potential role for S100A4 in the disruption of the blood-brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammation of the joints. RA has been shown to increase the morbidity of and mortality due to cardiovascular and cerebrovascular diseases. We recently reported that cerebrovascular permeability was increased in mice with collagen-induced arthritis (CIA), an animal model of RA. S100A4, a member of the S100 family, is up-regulated in synovial fluid and plasma from RA patients. This study was aimed at evaluating a role of S100A4 in the mediation of blood-brain barrier (BBB) dysfunction in CIA mice. CIA was induced by immunization with type II collagen in mice. Cerebrovascular permeability was assessed by measurement of sodium fluorescein (Na-F) levels in the brains of control and CIA mice. Serum S100A4 concentrations in control and CIA mice were measured by enzyme-linked immunosorbent assays (ELISA). Accumulation of Na-F in the brain and serum levels of S100A4 were increased in CIA mice. Increased S100A4 levels in the serum are closely correlated with hyperpermeability of the cerebrovascular endothelium to Na-F. We investigated whether S100A4 induces BBB dysfunction using mouse brain capillary endothelial cells (MBECs). S100A4 decreased the transendothelial electrical resistance and increased Na-F permeability in the MBECs. S100A4 reduced the expression of occludin, a tight junction protein, and stimulated p53 expression in MBECs. These findings suggest that S100A4 increases paracellular permeability of MBECs by decreasing expression levels of occludin, at least in part, via p53. The present study highlights a potential role for S100A4 in BBB dysfunction underlying cerebrovascular diseases in patients with RA.

High failure rate of the dissolution tests for 500-mg amoxicillin capsules sold in Cambodia: is it because of the product or the test method?

OBJECTIVES: During the survey of substandard medicines in Cambodia in 2007, it was found that more than 90% of 500-mg amoxicillin (AMPC) capsules failed the United States Pharmacopeia (USP) 30 TEST 1 dissolution test. In the USP, several monographs provide multiple methods for performing the dissolution test. By using the 500-mg AMPC capsule as an example, we aimed to identify the problems and implications of the USP methods adopted for the dissolution test as a global standard. METHODS: All AMPC samples were collected from the Cambodian market in 2007. For the quantitative test, we referred to USP 30. We performed the USP 28 and USP 30 TEST 2 dissolution tests and compared these results with those of the USP 30 TEST 1. RESULTS: All 500-mg AMPC capsules used for the comparison passed the quantitative test. Samples that passed the USP 28 and USP 30 TEST 2 dissolution tests were identical, and the pass rate was 97.1% (34/35), whereas the pass rate with the USP 30 TEST 1 was 8.6% (3/35). The difference in the dissolution results between the three methods was significant (P<0.0001). CONCLUSION: This study revealed that many users would select the most stringent method when multiple methods exist in the USP. This may lead to a high failure rate of the tests. Because USP is a global standard, we recommend that it take into consideration the developing countries and create a more detailed user-friendly manual for selection for appropriate methods.

The characteristics of in vitro biological activity of titanium surfaces anodically oxidized in chloride solutions.

Photo-functionalized radical reactions on TiO(2) have been correlated with adsorption of organic impurities and decreasing hydrophilicity of titanium-based biomaterials. Such reactive oxygen species (ROS) spontaneously generated on oxidized titanium surfaces may also have important roles against time-dependent degradation of biological ability and adherent micro-organisms. This study examined in vitro biological ability as a function of time and antimicrobial activity on oxidized titanium surfaces without photo-functionalization. Mechanically polished titanium and thermally oxidized titanium surfaces that had been stored for 4 wks showed adsorbed organic impurities with decreased surface hydrophilicity. Even after the storage period, anodically oxidized titanium surfaces enabled super-hydrophilicity without adsorption of organic impurities, because of the ROS and the hydrophilic functional groups generated on the surfaces. The osteogenic gene expressions of osteoblasts cultured on anodically oxidized titanium surfaces with or without storage were significantly higher than those on thermally oxidized titanium and polished titanium surfaces. Titanium surfaces anodically oxidized in a solution with chloride achieved antimicrobial activity against an oral microorganism due to the amount of ROS generated on the surface. Thus, titanium anodically oxidized in solution with chloride may have potential use for titanium-based internal fixation devices.

Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines.

BACKGROUND: The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to HER2-targeted agents in naturally derived breast cancer cells. MATERIALS AND METHODS: We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR). RESULTS: Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 microg/ml trastuzumab: 58% versus 92%; P = 0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1 microM CL-387,785: 21% versus 77%; P = 0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype. CONCLUSIONS: PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.

Expression of inflammatory mediators in the otitis media induced by Helicobacter pylori antigen in mice.

Helicobacter pylori is a Gram-negative bacterium that is recognized as one of the key factors in gastric diseases such as gastritis, peptic ulcer and gastric cancer. Recent studies have shown relationships between H. pylori and extra-digestive diseases, and the presence of H. pylori in the middle ear and upper respiratory tract has been reported. However, the role of H. pylori in middle ear disease remains unclear. The present study demonstrated that H. pylori whole-cell protein directly induces macrophage migration inhibitory factor, macrophage inflammatory protein 2, interleukin 1 beta and tumor necrosis factor alpha in middle ear epithelium in mice, and severe proliferation of inflammatory cells was observed in middle ear cavity inoculated with H. pylori whole-cell protein. In addition, trans-tympanic injection of macrophage migration inhibitory factor up-regulated expression of macrophage inflammatory protein 2 in the middle ear. These findings indicate that H. pylori infection causes immunological inflammation in middle ear epithelium, and H. pylori may play a significant role in otitis media.