Incidence and Risk Factors of Immediate Hypersensitivity Reactions and Immunization Stress-Related Responses With COVID-19 mRNA Vaccine.

BACKGROUND: With the implementation of mass vaccination campaigns against COVID-19, the safety of vaccine needs to be evaluated. OBJECTIVE: We aimed to assess the incidence and risk factors for immediate hypersensitivity reactions (IHSR) and immunization stress-related responses (ISRR) with the Moderna COVID-19 vaccine. METHODS: This nested case-control study included recipients who received the Moderna vaccine at a mass vaccination center, Japan. Recipients with IHSR and ISRR were designated as cases 1 and 2, respectively. Controls 1 and 2 were selected from recipients without IHSR or ISRR and matched (1 case: 4 controls) with cases 1 and cases 2, respectively. Conditional logistic regression analysis was used to identify risk factors associated with IHSR and ISRR. RESULTS: Of the 614,151 vaccine recipients who received 1,201,688 vaccine doses, 306 recipients (cases 1) and 2478 recipients (cases 2) showed 318 events of IHSR and 2558 events of ISRR, respectively. The incidence rates per million doses were estimated as IHSR: 266 cases, ISRR: 2129 cases, anaphylaxis: 2 cases, and vasovagal syncope: 72 cases. Risk factors associated with IHSR included female, asthma, atopic dermatitis, thyroid diseases, and a history of allergy; for ISRR, the risk factors were younger age, female, asthma, thyroid diseases, mental disorders, and a history of allergy and vasovagal reflex. CONCLUSION: In the mass vaccination settings, the Moderna vaccine can be used safely owing to the low incidence rates of IHSR and anaphylaxis. However, providers should be aware of the occurrence of ISRR. Although recipients with risk factors are associated with slightly increased risks of IHSR and ISRR, this is not of sufficient magnitude to warrant special measures regarding their vaccination.

Case report: Unusual coexistence between familial hypercholesterolemia and familial hypobetalipoproteinemia.

Type 1 familial hypobetalipoproteinemia (FHBL1), characterized by low levels of apolipoprotein B (ApoB)-containing lipoproteins, elevation of transaminases, and hepatic steatosis, is a rare disease the prevalence of which is 1 in 3,000 among general population. Here we report an extremely rare family where phenotypes of familial hypercholesterolemia (FH) are canceled by coexistence of FHBL1 caused by an truncating mutation in apolipoprotein B (APOB).

Efficacy of Chest Radiography as a Primary Care Triage Tool in Severe Coronavirus Disease.

Objective Severe acute respiratory syndrome coronavirus 2 has spread globally, and it is important to utilize medical resources properly, especially in critically ill patients. We investigated the validity of chest radiography as a tool for predicting aggravation in coronavirus disease (COVID-19) cases. Methods A total of 104 laboratory-confirmed COVID-19 cases were referred from the cruise ship "Diamond Princess" to the Self-Defense Forces Central Hospital in Japan from February 11 to 25, 2020. Fifty-nine symptomatic patients were selected. Chest radiography was performed upon hospitalization; subsequently, patients were categorized into the positive radiograph (Group A) and negative radiograph (Group B) groups. Radiographic findings were analyzed with a six-point semiquantitative score. Group A was further classified into two additional subgroups: patients who required oxygen therapy during their clinical courses (Group C) and patients who did not (Group D). Clinical records, laboratory data, and radiological findings were collected for an analysis. Results Among 59 patients, 34 were men with a median age of 60 years old. Groups A, B, C, and D consisted of 33, 26, 12, and 21 patients, respectively. The number of patients requiring oxygen administration was significantly larger in Group A than in Group B. The consolidation score on chest radiographs was significantly higher in Group C than in Group D. When chest radiographs showed consolidation in more than two lung fields, the positive likelihood ratio of deterioration was 10.6. Conclusions Chest radiography is a simple and easy-to-use clinic-level triage tool for predicting the severity of COVID-19 and may contribute to the allocation of medical resources.

Clinical characteristics and antibody response to SARS-CoV-2 spike 1 protein using VITROS Anti-SARS-CoV-2 antibody tests in COVID-19 patients in Japan.

Introduction. Serological tests for COVID-19 are important in providing results for surveillance and supporting diagnosis. Investigating the serological response in COVID-19 patients with different disease severity is important for assessing the clinical utility of serological assays.Gap Statement. However, few studies have investigated the clinical utility of antibody assays for COVID-19 or differences in antibody response in association with disease severity.Aim. The study aimed to evaluate the clinical characteristics and clinical utility of VITROS SARS-CoV-2 antibody tests according to COVID-19 severity in patients in Japan.Methodology. We analysed 255 serum specimens from 130 COVID-19 patients and examined clinical records and laboratory data. Presence of total (IgA, IgM, and IgG) and specific IgG antibody for the spike 1 antigen of SARS-CoV-2 was determined using VITROS Anti-SARS-CoV-2 antibody tests.Results. Overall, 98 (75.4 %) and 32 (24.6 %) patients had mild and severe COVID-19, respectively. On admission, 76 (58.5 %) and 45 (34.6 %) patients were positive for total and IgG antibody assays. Among 91 patients at discharge, 90 (98.9 %) and 81 (89.0 %) were positive for total and IgG antibody, respectively. Clinical background and laboratory findings on admission, but not the prevalence or concentration of total or IgG antibody, were associated with disease prognosis. Total and IgG antibody intensities were significantly higher in severe cases than in mild cases in serum collected >11 days after onset, but not within 10 days.Conclusion. VITROS Anti-SARS-CoV-2 total and IgG assays will be useful as supporting diagnostic and surveillance tools and for evaluation of humoral immune response to COVID-19. Optimal prediction of disease prognosis is made from considering both clinical history and laboratory findings.

Antibody response patterns in COVID-19 patients with different levels of disease severity in Japan.

We analyzed antibody response patterns according to the level of disease severity in patients with novel coronavirus disease 2019 (COVID-19) in Japan. We analyzed 611 serum specimens from 231 patients with COVID-19 (mild, 170; severe, 31; critical, 30). Immunoglobulin M (IgM) and IgG antibodies against nucleocapsid protein (N) and spike 1 protein (S1) were detected by enzyme-linked immunosorbent assays. The peaks of fitting curves for the optical density (OD) values of IgM and IgG antibodies against N appeared simultaneously, while those against S1 were delayed compared with N. The OD values of IgM against N and IgG against both N and S1 were significantly higher in the severe and critical cases than in the mild cases at 11 days after symptom onset. The seroconversion rates of IgG were higher than those of IgM against both N and S1 during the clinical course based on the optimal cut-off values defined in this study. The seroconversion rates of IgG and IgM against N and S1 were higher in the severe and critical cases than in the mild cases. Our findings show that a stronger antibody response occurred in COVID-19 patients with greater disease severity and there were low seroconversion rates of antibodies against N and S1 in the mild cases.

Indicators of Acute Kidney Injury as Biomarkers to Differentiate Heatstroke from Coronavirus Disease 2019: A Retrospective Multicenter Analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) and heat-related illness are systemic febrile diseases. These illnesses must be differentiated during a COVID-19 pandemic in summer. However, no studies have compared and distinguished heat-related illness and COVID-19. We compared data from patients with early heat-related illness and those with COVID-19. METHODS: This retrospective observational study included 90 patients with early heat-related illness selected from the Heatstroke STUDY 2017-2019 (nationwide registries of heat-related illness in Japan) and 86 patients with laboratory-confirmed COVID-19 who had fever or fatigue and were admitted to one of two hospitals in Tokyo, Japan. RESULTS: Among vital signs, systolic blood pressure (119 vs. 125 mm Hg, p = 0.02), oxygen saturation (98% vs. 97%, p < 0.001), and body temperature (36.6°C vs. 37.6°C, p<0.001) showed significant between-group differences in the heatstroke and COVID-19 groups, respectively. The numerous intergroup differences in laboratory findings included disparities in white blood cell count (10.8 × 103/µL vs. 5.2 × 103/µL, p<0.001), creatinine (2.2 vs. 0.85 mg/dL, p<0.001), and C-reactive protein (0.2 vs. 2.8 mg/dL, p<0.001), although a logistic regression model achieved an area under the curve (AUC) of 0.966 using these three factors. A Random Forest machine learning model achieved an accuracy, precision, recall, and AUC of 0.908, 0.976, 0.842, and 0.978, respectively. Creatinine was the most important feature of this model. CONCLUSIONS: Acute kidney injury was associated with heat-related illness, which could be essential in distinguishing or evaluating patients with fever in the summer during a COVID-19 pandemic.

Clinical Evaluation of Self-Collected Saliva by Quantitative Reverse Transcription-PCR (RT-qPCR), Direct RT-qPCR, Reverse Transcription-Loop-Mediated Isothermal Amplification, and a Rapid Antigen Test To Diagnose COVID-19.

The clinical performances of six molecular diagnostic tests and a rapid antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were clinically evaluated for the diagnosis of coronavirus disease 2019 (COVID-19) in self-collected saliva. Saliva samples from 103 patients with laboratory-confirmed COVID-19 (15 asymptomatic and 88 symptomatic) were collected on the day of hospital admission. SARS-CoV-2 RNA in saliva was detected using a quantitative reverse transcription-PCR (RT-qPCR) laboratory-developed test (LDT), a cobas SARS-CoV-2 high-throughput system, three direct RT-qPCR kits, and reverse transcription-loop-mediated isothermal amplification (RT-LAMP). The viral antigen was detected by a rapid antigen immunochromatographic assay. Of the 103 samples, viral RNA was detected in 50.5 to 81.6% of the specimens by molecular diagnostic tests, and an antigen was detected in 11.7% of the specimens by the rapid antigen test. Viral RNA was detected at significantly higher percentages (65.6 to 93.4%) in specimens collected within 9 days of symptom onset than in specimens collected after at least 10 days of symptoms (22.2 to 66.7%) and in specimens collected from asymptomatic patients (40.0 to 66.7%). Self-collected saliva is an alternative specimen option for diagnosing COVID-19. The RT-qPCR LDT, a cobas SARS-CoV-2 high-throughput system, direct RT-qPCR kits (except for one commercial kit), and RT-LAMP showed sufficient sensitivities in clinical use to be selectively used in clinical settings and facilities. The rapid antigen test alone is not recommended for an initial COVID-19 diagnosis because of its low sensitivity.

The influence of a noisy environment on hearing impairment and tinnitus: The hearing outcomes of 50-year-old male Japan ground self-defense force personnel.

OBJECTIVES: Hearing loss is one of the biggest health problems in the world and occupational noise-induced hearing loss is recognized as the most common work-related illness. However, many factors that result in hearing loss make it difficult to define the specific factor that induces noise-induced hearing loss. To access the exact effect of occupational noise exposure on hearing, we conducted a cross-sectional cohort study of the relationship between noise exposure and hearing impairment in 50-year-old male Japanese Self-Defense Force (JSDF) personnel who work in a noisy environment. This population is ideal for the detection of noise-induced hearing impairments due to the homogeneity of genetic and social backgrounds. METHODS: The data utilized in this study were collected from a "50-year-old milestone health examination" of the JSDF from July 2013 to October 2015. One thousand sixty-seven male personnel were enrolled in the study. Pure-tone audiometry was conducted with an audiometer. A survey questionnaire asked participants to self-report occupational noise exposure. RESULTS: This cohort revealed that noise-exposed personnel had a higher hearing threshold and a higher odds ratio in 1) the average threshold of 4 frequencies (500 + 1000 + 2000 + 4000 Hz / 4), 2) the average threshold of higher 3 frequencies (2000 + 4000 + 8000 Hz / 3), and 3) the threshold of 4 kHz compared to no noise-exposed control personnel. The prevalence of tinnitus was also significantly higher in the noise-exposed group. CONCLUSIONS: This study provides specific evidence for the relationship between noise exposure and noise-induced hearing impairments.

Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis.

BACKGROUND: The ongoing COVID-19 pandemic is a global threat. Identification of markers for symptom onset and disease progression is a pressing issue. We described the clinical features of people infected on board the Diamond Princess cruise ship who were diagnosed with asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or mild or severe COVID-19, on admission to the Self-Defense Forces Central Hospital (Tokyo, Japan) and at the end of observation. METHODS: This retrospective, single-centre study included participants with laboratory-detected SARS-CoV-2 infection who were admitted to the Self-Defense Forces Central Hospital from Feb 11 to Feb 25, 2020. Clinical records, laboratory data, and radiological findings were analysed. Clinical outcomes were followed up until discharge or Feb 26, 2020, whichever came first. We defined asymptomatic infection as SARS-CoV-2 infection with no history of clinical signs and symptoms, severe COVID-19 as clinical symptoms of pneumonia (dyspnoea, tachypnoea, peripheral capillary oxygen saturation <93%, and need for oxygen therapy), and mild COVID-19 as all other symptoms. Clinical features on admission were compared among patients with different disease severity, including asymptomatic infection, at the end of observation. We used univariable analysis to identify factors associated with symptomatic illness among asymptomatic people infected with SARS-CoV-2 and disease progression in patients with COVID-19. FINDINGS: Among the 104 participants included in the final analysis, the median age was 68 years (IQR 47-75) and 54 (52%) were male. On admission, 43 (41%) participants were classified as asymptomatic, 41 (39%) as having mild COVID-10, and 20 (19%) as having severe COVID-19. At the end of observation, 33 (32%) participants were confirmed as being asymptomatic, 43 (41%) as having mild COVID-19, and 28 (27%) as having severe COVID-19. Serum lactate hydrogenase concentrations were significantly higher in the ten participants who were asymptomatic on admission but developed symptomatic COVID-19 compared with the 33 participants who remained asymptomatic throughout the observation period (five [50%] vs four [12%] participants; odds ratio 7·25, 95% CI 1·43-36·70; p=0·020). Compared with patients with mild disease at the end of observation, patients with severe COVID-19 were older (median age 73 years [IQR 55-77] vs 60 years [40-71]; p=0·028) and had more frequent consolidation on chest CT (13 [46%] of 28 vs nine [21%] of 43; p=0·035) and lymphopenia (16 [57%] vs ten [23%]; p=0·0055) on admission. INTERPRETATION: Older age, consolidation on chest CT images, and lymphopenia might be risk factors for disease progression of COVID-19 and contribute to improved clinical management. FUNDING: None.

Clinical evaluation of an immunochromatographic IgM/IgG antibody assay and chest computed tomography for the diagnosis of COVID-19.

BACKGROUND: We evaluated the clinical performance of an immunochromatographic (IC) IgM/IgG antibody assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and chest computed tomography (CT) for the diagnosis of Coronavirus disease 2019 (COVID-19). METHODS: We examined 139 serum specimens collected from 112 patients with COVID-19 and 48 serum specimens collected from 48 non-COVID-19 patients. The presence of IgM/IgG antibody for SARS-COV2 was determined using the One Step Novel Coronavirus (COVID-19) IgM/IgG Antibody Test. Chest CT was performed in COVID-19 patients on admission. FINDINGS: Of the139 COVID-19 serum specimens, IgM was detected in 27.8 %, 48.0 %, and 95.8 % of the specimens collected within 1 week, 1-2 weeks, and >2 weeks after symptom onset and IgG was detected in 3.3 %, 8.0 %, and 62.5 %, respectively. Among the 48 non-COVID-19 serum specimens, 1 generated a false-positive result for IgM. Thirty-eight of the 112 COVID-19 patients were asymptomatic, of whom 15 were positive for IgM, and 74 were symptomatic, of whom 22 were positive for IgM and 7 were positive for IgG. The diagnostic sensitivity of CT scan alone and in combination with the IC assay was 57.9 % (22/38) and 68.4 % (26/38) for the asymptomatic patients and 74.3 % (55/74) and 82.4 % (61/74) for the symptomatic patients, respectively. CONCLUSION: The IC assay had low sensitivity during the early phase of infection, and thus IC assay alone is not recommended for initial diagnostic testing for COVID-19. If RT-qPCR is not available, the combination of chest CT and IC assay may be useful for diagnosing COVID-19.

Idiopathic Multicentric Castleman Disease with Autoimmune Hemolytic Anemia and Production of Anti-drug Antibody against Tocilizumab.

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder, and only a few cases have been reported to be complicated with autoimmune hemolytic anemia (AIHA). A 43-year-old man who presented with multiple swollen lymph nodes was diagnosed with iMCD. He was also diagnosed with AIHA based on laboratory findings, including the results of a bone marrow aspiration study. The patient was treated with tocilizumab; however, the effect was limited, probably due to anti-drug antibodies. Tocilizumab was therefore switched to rituximab, and his anemia was improved. Complication with AIHA should be carefully considered when iMCD patients present with severe anemia.

Disseminated Cryptococcosis with Adrenal Insufficiency and Meningitis in an Immunocompetent Individual.

We present a case of cryptococcosis with adrenal insufficiency and meningitis in a healthy host without any risk factors. Antifungal therapy did not reduce the cryptococcal antigen titers of the cerebrospinal fluid and serum or the bilateral adrenal gland enlargement. It was suggested that the adrenal glands were the focus of persistent fungemia. Removal of both adrenal glands brought about a response to antifungal therapy. We conclude that if antifungal therapy is ineffective, bilateral adrenalectomy is an effective measure for treatment of such patients. Cryptococcosis is a possible cause of primary adrenal insufficiency in immunocompetent patients.

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

OBJECTIVE: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. METHODS: Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. RESULTS: In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10-8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). CONCLUSIONS: Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

Usefulness of urinary glucose excretion after oral glucose tolerance testing to detect insulin secretion failure before the onset of diabetes mellitus.

Sodium-glucose cotransporter 2 inhibitors are commonly used to promote urinary glucose excretion (UGE). However, it remains unclear how UGE reflects glucose metabolism in the natural history of diabetes. Thus, we retrospectively reviewed the prediabetes medical records of 64 patients who had undergone 75-g oral glucose tolerance testing (OGTT) with measurements of UGE at 0 min, 60 min, and 120 min. The mean age and glycated hemoglobin levels were 46 ± 10 years and 5.6 ± 0.3%, respectively. The median UGE (60 min + 120 min) value was 16.8 mg ([interquartile range]: [10.5-150.0 mg]). Thus, we categorized 16 patients as having high UGE (≥150.0 mg) and 48 patients as having low UGE (<150.0 mg). As compared with the low UGE group, the high UGE group exhibited a significantly lower median insulinogenic index (0.23 [0.12-0.35] vs. 0.56 [0.31-1.06], p = 0.001) and homeostasis model assessment of ß-cell function value (46 [26-67] vs. 66 [41-85], p = 0.028). The log-transformed insulinogenic index exhibited a significant inverse association with log-transformed UGE (60 min + 120 min) (r = -0.50, p < 0.001). The association between higher UGE and lower insulinogenic index was also observed in a subgroup analysis of patients with plasma glucose levels of ≥160 mg/dL during the OGTT. Therefore, UGE measurements after OGTT may provide a useful clinical marker for detecting insulin secretion failure and advancing preventive and therapeutic interventions among populations with a high risk of developing diabetes.

Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.

OBJECTIVE: Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. METHODS: A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. RESULTS: Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion). CONCLUSIONS: Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload.

Gout is a common disease which results from hyperuricemia. We have reported that the dysfunction of urate exporter ABCG2 is the major cause of renal overload (ROL) hyperuricemia, but its involvement in renal underexcretion (RUE) hyperuricemia, the most prevalent subtype, is not clearly explained so far. In this study, the association analysis with 644 hyperuricemia patients and 1,623 controls in male Japanese revealed that ABCG2 dysfunction significantly increased the risk of RUE hyperuricemia as well as overall and ROL hyperuricemia, according to the severity of impairment. ABCG2 dysfunction caused renal urate underexcretion and induced hyperuricemia even if the renal urate overload was not remarkable. These results show that ABCG2 plays physiologically important roles in both renal and extra-renal urate excretion mechanisms. Our findings indicate the importance of ABCG2 as a promising therapeutic and screening target of hyperuricemia and gout.

Oxygen diffusion and nonstoichiometry in BiFeO3.

Leakage current is a serious problem for the use of ferroelectricity in room-temperature multiferroics BiFeO3, and oxygen nonstoichiometry is considered as one of its principal origins. In order to establish a method to control oxygen content in the compound, we investigated the annealing process of stoichiometric BiFeO3 grains in air and revealed that oxygen diffusion occurs in two steps: (1) the weight of the sample decreases in a short time, which originates from the generation of oxygen deficiency near the surface of the grains; and then (2) it increases gradually and slowly, which originates from oxygen diffusion toward equilibrium in the inner part of the grains, introducing excess oxygen there. Step 1 causes the leakage current, and step 2 tends to cause inhomogeneity of oxygen content as well as the leakage current. Steps 1 and 2 are related to oxygen deficiency and excess oxygen often observed in thin films and bulk crystals, respectively. For the synthesis of homogeneous and highly insulating bulk sample, it is important to avoid these annealing processes, and it is a good way to grow a crystal with stoichiometric oxygen content by the control of atmospheric oxygen partial pressure and taking out its inner part.

Effect of doping on the magnetostructural ordered phase of iron arsenides: a comparative study of the resistivity anisotropy in doped BaFe2As2 with doping into three different sites.

To unravel the role of doping in iron-based superconductors, we investigated the in-plane resistivity of BaFe(2)As(2) doped at one of the three different lattice sites, Ba(Fe(1-x)Co(x))(2)As(2), BaFe(2)(As(1-x)P(x))(2), and Ba(1-x)K(x)Fe(2)As(2), focusing on the doping effect in the low-temperature antiferromagnetic/orthorhombic (AFO) phase. A major role of doping in the high-temperature paramagnetic/tetragonal (PT) phase is known to change the Fermi surface by supplying charge carriers or exerting chemical pressure. In the AFO phase, we found a clear correlation between the magnitude of the residual resistivity and the resistivity anisotropy. This indicates that the resistivity anisotropy originates from anisotropic impurity scattering due to dopant atoms. The magnitude of the residual resistivity was also found to be a parameter controlling the suppression rate of the AFO ordering temperature. Therefore, the dominant role of doping in the AFO phase is to introduce disorder to the system, distinct from that in the PT phase.