Report of Two Contrasting Cases of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis: Comparison to Infectious Mononucleosis and Flow Cytometric Analysis of Bone Marrow.

Purpose: This study aims to investigate the characteristics of Epstein-Barr virus associated-hemophagocytic lymphohistiocytosis (EBV-HLH) and HLH caused by a severe form of infectious mononucleosis (IM-HLH) compared to IM by EBV, and thus also to assist in early diagnosis and providing appropriate treatment. Methods: Data for this analysis were collected from patients at the Department of General Medicine, Nara Medical University, between April 1, 2012, and August 1, 2020. EBV infection was diagnosed using clinical presentation and laboratory tests. HLH diagnosis followed the HLH-2004 protocol, supplemented by plasma EBV DNA detection. A range of clinical and laboratory parameters were collected, including age, sex, clinical outcomes, blood cell counts, hemoglobin, platelets, and various serum values. Plasma EBV DNA levels and flow cytometric analysis (FCM) of bone marrow were performed for HLH cases. Results: Among 1850 hospitalized patients, 14 cases were identified, including 2 HLH cases and 12 IM cases. Comparative analysis revealed distinctive features of HLH, including lower lymphocyte and platelet counts and higher levels of ferritin, soluble interleukin 2 receptor (sIL-2R), and D dimer compared to IM. Notably, one HLH case responded well to corticosteroid monotherapy, while the other case did not, resulting in a fatal outcome. Detection of a cluster of CD5-CD7 lymphocytes in bone marrow is a hallmark of EBV-HLH and useful to distinguish from IM-HLH. Conclusion: This study underscores the importance of early differentiation among EBV-HLH, IM-HLH, and IM in adults to guide appropriate treatment strategies. While specific laboratory markers help distinguish HLH from IM, a more detailed analysis of FCM is crucial for precise diagnosis of HLH cases and tailored therapeutic interventions.

Neuro-Behçet's disease with atypical subcortical nodular lesions: A case report and treatment approach.

Neuro-Behçet's disease (NB) is a rare complication of Behçet's disease (BD) characterised by central nervous system involvement. While NB typically presents with brainstem lesions, we report an unusual case of NB in a 27-year-old male with multiple subcortical nodular brain lesions but without brainstem, thalamic, or basal ganglia involvement, making this presentation exceptionally rare. The patient had a prior diagnosis of BD and was HLA-B51 positive. He presented with a sudden loss of consciousness, which was attributed to a seizure. Imaging studies showed low-density areas in the white matter of the bilateral temporal lobes and the right frontoparietal lobe on brain CT. Cerebrospinal fluid examination indicated elevated initial pressure and protein concentration, along with increased interleukin-6. Despite presenting with nodular brain lesions, distinguishing between NB and infectious diseases such as tuberculosis (TB) was challenging, and required brain biopsy revealing vasculitis. However, even with this biopsy result, TB could not be ruled out, so TB was treated at the same time. Treatment with anti-TB drugs and standard steroid therapy initially failed to improve the patient's condition. However, increasing the steroid dosage considering the increased steroid degradation by rifampicin, including pulse therapy with 2 g of methylprednisolone, followed by 18 mg of betamethasone, led to remission of the nodular brain lesions and resolution of the nasopharyngeal ulcer. This case highlights the diagnostic challenge of differentiating between NB and TB based on imaging alone and the potential efficacy of high-dose steroid therapy in cases of steroid-resistant NB with subcortical nodular brain lesions.

Giant Cell Arteritis after COVID-19 Vaccination with Long-Term Follow-Up: A Case Report and Review of the Literature.

Giant cell arteritis (GCA) is a chronic vasculitis that primarily affects the elderly, and can cause visual impairment, requiring prompt diagnosis and treatment. The global impact of the coronavirus disease 2019 (COVID-19) pandemic has been substantial. Although vaccination programs have been a key defense strategy, concerns have arisen regarding post-vaccination immune-mediated disorders and related risks. We present a case of GCA after COVID-19 vaccination with 2 years of follow-up. A 69-year-old woman experienced fever, headaches, and local muscle pain two days after receiving the COVID-19 vaccine. Elevated inflammatory markers were observed, and positron emission tomography (PET) revealed abnormal uptake in the major arteries, including the aorta and subclavian and iliac arteries. Temporal artery biopsy confirmed the diagnosis of GCA. Treatment consisted of pulse therapy with methylprednisolone, followed by prednisolone (PSL) and tocilizumab. Immediately after the initiation of treatment, the fever and headaches disappeared, and the inflammation markers normalized. The PSL dosage was gradually reduced, and one year later, a PET scan showed that the inflammation had resolved. After two years, the PSL dosage was reduced to 3 mg. Fourteen reported cases of GCA after COVID-19 vaccination was reviewed to reveal a diverse clinical picture and treatment response. The time from onset of symptoms to GCA diagnosis varied from two weeks to four months, highlighting the challenge of early detection. The effectiveness of treatment varied, but was generally effective similarly to that of conventional GCA. This report emphasizes the need for clinical vigilance and encourages further data collection in post-vaccination GCA cases.

The Combination of the Lactate Dehydrogenase/Hemoglobin Ratio with the PLASMIC Score Facilitates Differentiation of TTP from Septic DIC Without Identification of Schistocytes.

In some cases, differentiating thrombotic thrombocytopenic purpura (TTP) from septic disseminated intravascular coagulation (DIC) without measuring ADAMTS13 activity is critical for urgent lifesaving plasma exchange. To investigate whether PLASMIC score without identifying the presence of schistocytes, D-dimer, fibrin/fibrinogen degradation products (FDP), FDP/D-dimer ratio, prothrombin time-international normalized ratio (PT-INR), lactate dehydrogenase (LD), hemoglobin (Hb), and LD/Hb ratio are useful in differentiating patients with TTP from those with septic DIC. Retrospective analysis was conducted on the medical records of the patients with septic DIC (32 patients) or TTP (16 patients). The PLASMIC score and other laboratory measurements all were helpful in differentiating TTP from septic DIC. When dichotomized between high risk (scores 6-7) and intermediate-low risk (scores 0-5), the PLASMIC score predicted TTP with a sensitivity of 75.0% and a specificity of 100%. However, 4 of 16 patients with TTP and 19 of 32 patients with septic DIC showed comparable PLASMIC scores of 4 or 5, making it difficult to distinguish between the two by PLASMIC score alone. Among the measurements examined, the LDH/Hb ratio was the most useful for differentiation. Receiver operating characteristic analysis of the LD/Hb ratio for predicting TTP revealed a cutoff of 53.7 (IU/10 g) (sensitivity 0.94, specificity 0.91). If the LD/Hb ratio was less than 53.7, it was unlikely that the patient had TTP. A combination of the LD/Hb ratio and the PLASMIC score may be useful for distinguishing between TTP and DIC and identifying patients who need rapid plasma exchange or caplacizumab administration.

Regulation of von Willebrand factor by ADAMTS13 ameliorates lipopolysaccharide-induced lung injury in mice.

The relationship between von Willebrand factor (VWF) and inflammation has attracted considerable attention in recent years. VWF, which is stored in the Weibel-Palade bodies (WPBs) of endothelial cells (ECs), is released from WPBs in response to inflammatory stimuli and is thought to contribute to inflammation by promoting leukocyte extravasation. In this study, lung injury model mice were produced by intratracheal injection with lipopolysaccharides. The severity of lung inflammation was evaluated in mice with different genotypes (wild-type, Vwf-/-, Adamts13-/-) and mice treated with drugs that inhibit VWF function. Lung inflammation was significantly ameliorated in Vwf-/- mice compared with wild-type mice. Furthermore, inflammation was significantly suppressed in wild-type mice treated with anti-VWF A1 antibody or recombinant human ADAMTS13 compared with the untreated control group. The underlying mechanism appears to be an increased VWF/ADAMTS13 ratio at the site of inflammation and the interaction between blood cell components, such as leukocytes and platelets, and the VWF A1 domain, which promotes leukocyte infiltration into the lung. This study suggested that ADAMTS13 protein and other VWF-targeting agents may be a novel therapeutic option for treatment of pulmonary inflammatory diseases.

Net reclassification index in comparison of prognostic value of disseminated intravascular coagulation diagnostic criteria by Japanese Society on Thrombosis and Hemostasis and International Society on Thrombosis and Haemostasis: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of the Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria with that of the International Society on Thrombosis and Haemostasis (ISTH) DIC diagnostic criteria for 28-day in-hospital mortality. METHODS: We conducted a multicenter prospective cohort study involving two hematology departments, four emergency departments, and one general medicine department in Japan between August 2017 and July 2021. We assessed three ISTH DIC diagnostic criteria categories using low cutoff levels of D-dimer (low D-dimer), high cutoff levels of D-dimer (high D-dimer), and fibrinogen/fibrin degradation products (FDP) as fibrin-related markers. The main outcome was diagnosis-based category additive net reclassification index (NRI). RESULTS: A total of 222 patients were included: 82 with hematopoietic disorders, 86 with infections, and 54 with other diseases. The 28-day in-hospital mortality rate was 14% (n = 31). The DIC rates diagnosed by the JSTH, ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were 52.7%, 47.3%, 42.8%, and 27.0%, respectively. The overall category additive NRI by JSTH DIC diagnosis vs. ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were - 10 (95% confidence interval [CI]: -28 to 8, p = 0.282), - 7.8 (95% CI: -26 to 10, p = 0.401), and - 11 (95% CI: -26 to 3, p = 0.131), respectively. CONCLUSIONS: JSTH criterion showed the highest sensitivity for DIC diagnosis that did not improve but reflected the same prognostic value for mortality evaluated using ISTH DIC diagnosis criteria. This finding may help clinicians to use JSTH DIC criterion as an early intervention strategy in patients with coagulopathy.

The efficacy and safety of caplacizumab in Japanese patients with immune-mediated thrombotic thrombocytopenic purpura: an open-label phase 2/3 study.

Caplacizumab is an anti-von Willebrand factor humanized single-variable-domain immunoglobulin fragment whose efficacy and safety in immune-mediated thrombotic thrombocytopenia purpura (iTTP) have been demonstrated in international studies. This prospective, open-label phase 2/3 study evaluated caplacizumab 10 mg administered daily during plasma exchange and for 30 days afterward, in combination with immunosuppressive treatment, in Japanese adults with a clinical diagnosis of iTTP (new or recurrent). The primary endpoint was prevention of iTTP recurrence; key secondary endpoints included time to platelet count response, time to organ damage normalization, and safety. Among 21 treated patients, 1 of 15 (6.7%) evaluable patients developed iTTP recurrence. Median time to normalization was 2.79 days for platelet count and 2.65 days for organ damage markers (n = 15). Treatment-emergent adverse events (TEAEs) were mostly mild to moderate in severity; the most frequently reported caplacizumab-related TEAEs were increased alanine aminotransferase, epistaxis, and gastrointestinal hemorrhage (all in 9.5% of patients). At least one bleeding event was reported in 7 of 21 patients (33%). Caplacizumab was effective in Japanese patients with iTTP, with a low rate of iTTP recurrence, rapid normalization of platelet counts and organ damage markers, and no unexpected TEAEs. Trial registration: ClinicalTrials.gov identifier, NCT04074187.

A Case of Mycoplasma Infection with an Atypical Presentation of Abducens Nerve Palsy, Erythema Multiforme and Polyarthritis without Respiratory Manifestations.

Mycoplasma pneumoniae is a self-propagating microorganism that commonly causes respiratory tract infections. It can also cause a variety of extrapulmonary symptoms with or independently of respiratory symptoms, such as skin lesions, arthralgia, myalgia, hemolysis, cardiac lesions, gastrointestinal symptoms, and central nervous system lesions, which are rare manifestations reported in approximately 0.1% of cases. In this study, we present a unique case of Mycoplasma-related abducens nerve palsy, polyarthritis, and erythema multiforme without respiratory disease. The patient was a 69-year-old woman who presented to our hospital with a skin rash, fever, arthralgia, and diplopia without respiratory symptoms. Brain magnetic resonance imaging showed optic neuritis on the right side, suggesting the diplopia was caused by right abducens nerve palsy. However, the etiologies of abducens nerve palsy were not revealed by the physical examination, blood biochemistry tests, or bacteriological examinations, including the cerebrospinal fluid examination obtained at admission. Mycoplasma infection was suspected from erythema multiforme revealed by a skin biopsy and polyarthralgia, and it was finally diagnosed according to elevated Mycoplasma particle agglutination (PA) antibodies in paired serum. Though minocycline did not improve her diplopia, the daily administration of 30 mg of prednisolone gradually improved her symptoms, and the Mycoplasma PA antibody titer, which was regularly measured in the clinical course, also decreased, suggesting a relationship between Mycoplasma infection and abducens nerve palsy. This is the first case of isolated abducens nerve palsy, which was reported as the only central neurological symptom in an adult patient with Mycoplasma infection. The mechanism or pathogenesis of CNS manifestations caused by Mycoplasma pneumoniae remains to be elucidated, and further investigation is needed. Hence, Mycoplasma infection is a common disease. Clinicians should be aware of the diverse manifestations, including abducens nerve palsy, of Mycoplasma infection and should consider Mycoplasma infection even in the absence of typical respiratory symptoms.

Sensitivity and specificity analyses of COVID-19 screening protocol for emergency medical services: A STARD-compliant population-based retrospective study.

During the novel coronavirus disease (COVID-19) pandemic, emergency medical services (EMS) has borne a huge burden in transporting emergency patients. However, the protocol's effect on identifying emergency patients who are likely to have COVID-19 is unknown. We aimed to evaluate the diagnostic accuracy of a prehospital COVID-19 screening protocol for EMS. We conducted this population-based retrospective study in Nara Prefecture, Japan. The Nara Prefectural Government implemented a screening protocol for COVID-19 comprising the following symptom criteria (fever, cough, sore throat, headache, malaise, dysgeusia, or anosmia) and epidemiological criteria (contact history with confirmed COVID-19 cases or people with upper respiratory symptoms, or travel to areas with high infection rate). A patient meeting at least one criterion of each class was considered positive. We evaluated all 51,351 patients from the regional EMS database of the Nara Prefecture (emergency Medical Alliance for Total Coordination of Healthcare) who were registered from June 15, 2020 to May 31, 2021 and had results of COVID-19 reverse transcription polymerase chain reaction (RT-PCR) tests. We assessed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this protocol. We also assessed how these outcomes changed by adding vital signs and conducted a 10-fold and 100-fold prevalence simulation. The screening protocol was used for 246/51351 patients (0.5%). Among them, 31 tested positive after EMS transportation. This protocol's sensitivity, specificity, PPV, and NPV were 40.8%, 99.6%, 12.6%, and 99.9%, respectively. With the addition of ≥2 vital signs (body temperature ≥37.5 °C, respiratory rate ≥20 breaths/minute, and oxygen saturation <90%), sensitivity and PPV changed to 61.8% and 1.0%, respectively, while NPV remained 99.9%. With a 10-fold and 100-fold increase in disease, the protocol PPV would be 59.0% and 94.3%, and NPV would be 99.1% and 90.7%, respectively, and with additional vital signs, PPV would be 8.9% and 53.1%, and NPV would be 99.4% and 93.2%, respectively. This COVID-19 screening protocol helped enable EMS transport for patients with COVID-19 with a PPV of 12.6%. Adding other vital sign variables may improve its diagnostic value if the prevalence rate increases.

Prognostic value of serum high mobility group box 1 protein and histone H3 levels in patients with disseminated intravascular coagulation: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of serum high mobility group box 1 protein (HMGB1) and histone H3 levels with the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scores for 28-day in-hospital mortality in patients with DIC caused by various underlying diseases. METHODS: We conducted a multicenter prospective cohort study including two hematology departments, four emergency departments, and one general medicine department in Japan, between August 2017 and July 2021. We included patients diagnosed with DIC by the ISTH DIC scoring system. RESULTS: Overall, 104 patients were included: 50 with hematopoietic disorders, 41 with infections, and 13 with the other diseases. The 28-day in-hospital mortality rate was 21%. The receiver operator characteristic (ROC) curve showed that a DIC score of 6 points, serum HMGB1 level of 8 ng/mL, and serum histone H3 level of 2 ng/mL were the optimal cutoff points. The odds ratios of more than these optimal cutoff points of the DIC score, serum HMGB1, and histone H3 levels were 1.58 (95% confidence interval [CI]: 0.60 to 4.17, p = 0.36), 5.47 (95% CI: 1.70 to 17.6, p = 0.004), and 9.07 (95% CI: 2.00 to 41.3, p = 0.004), respectively. The area under the ROC curve of HMGB1 (0.74, 95% CI: 0.63 to 0.85) was better than that of the ISTH DIC scores (0.55, 95% CI: 0.43 to 0.67, p = 0.03), whereas that of histone H3 was not (0.71, 95% CI: 0.60 to 0.82, p = 0.07). Calibration and net reclassification plots of HMGB1 identified some high-risk patients, whereas the ISTH DIC scores and histone H3 did not. The category-free net reclassification improvement of HMGB1 was 0.45 (95% CI: 0.01 to 0.90, p = 0.04) and that of histone H3 was 0.37 (95% CI: - 0.05 to 0.78, p = 0.08). CONCLUSIONS: Serum HMGB1 levels have a prognostic value for mortality in patients with DIC. This finding may help physicians develop treatment strategies.

Assessment of global coagulation function under treatment with emicizumab concomitantly with bypassing agents in haemophilia A with inhibitor (UNEBI Study): multicentre open-label non-randomised clinical trial.

INTRODUCTION: Subcutaneous emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (PwHA) and factor VIII inhibitor. However, thrombotic events occurred in some PwHA with inhibitor who had received high cumulative doses of activated prothrombin complex concentrates at their breakthrough bleeds, when they were also given prophylactic emicizumab. After that, although the recommended guidance was proposed for bypassing agents (BPAs) therapy under emicizumab prophylaxis for haemostatic management, detailed investigation(s) is(are) required to elucidate the safe and appropriate dose of BPAs to use concomitantly with emicizumab prophylaxis. METHODS AND ANALYSIS: In the UNEBI Study, 60 PwHA with inhibitor will be enrolled for a maximum duration of 3 years, and samples of 20 events following concomitant use of BPAs with emicizumab will be collected. An 'event' is defined as obtaining blood samples before and after administration of BPA when a breakthrough bleed or a surgical procedure occurs. The coagulation potential in the obtained samples will be measured by global coagulation assays. The primary endpoint is the degree of improvement in the maximum coagulation rate by clot waveform analysis (CWA) before and after administration of fixed-dose BPAs. This parameter obtained from CWA, which is triggered with an optimally diluted mixture of prothrombin time/activated partial thromboplastin time-reagents, is reported to be an excellent marker for assessing the degree of improvement in coagulation potential in emicizumab-treated plasma. ETHICS AND DISSEMINATION: The UNEBI Study was approved by the Japan Certified Review Board of Nara Medical University. The results of the study will be communicated through publication in international scientific journals and presentations at (inter)national conferences. TRIAL REGISTRATION NUMBER: jRCTs051190119.

The balance of comprehensive coagulation and fibrinolytic potential is disrupted in patients with moderate to severe COVID-19.

Coagulation and fibrinolytic mechanisms are enhanced in patients with coronavirus (COVID-19), but disturbances in the balance of both functions in COVID-19 patients remain unclear. We assessed global coagulation and fibrinolysis in plasma from 167 COVID-19 patients (mild/moderate/severe: 62/88/17, respectively) on admission using clot-fibrinolysis waveform analysis (CFWA). Maximum coagulation velocity (|min1|) and maximum fibrinolysis velocity (|FL-min1|) were expressed as ratios relative to normal plasma. Ten patients (6.0%) developed thrombosis, 5 (3.0%) had bleeding tendency, and 13 (7.8%) died during admission. FDP levels increased with severity of COVID-19 symptoms (mild/moderate/severe; median 2.7/4.9/9.9 µg/mL, respectively). The |min1| ratios were elevated in all categories (1.27/1.61/1.58) in keeping with enhanced coagulation potential, with significant differences between mild cases and moderate to severe cases. The |FL-min1| ratios were also elevated in all groups (1.19/1.39/1.40), reflecting enhanced fibrinolytic potential. These data identified coagulation dominance in moderate to severe cases, but balanced coagulation and fibrinolysis in mild cases. There were significant differences in FDP and TAT, but no significant differences in |min1| or |FL-min1| ratios, between patients with and without thrombosis. CFWA monitoring of coagulation and fibrinolysis dynamics could provide valuable data for understanding hemostatic changes and disease status in COVID-19 patients.

Surgical risk assessment for super-elderly patients.

AIM: Super-elderly patients are often frail and the decision on surgical indications remains a difficult issue. The purpose of this study was to provide a certain preoperative surgical risk assessment tool for super-elderly people. METHODS: We selected 112 individuals who were super-elderly patients aged >90 years who had surgeries under general anesthesia in our department. Based on the quality of the postoperative outcome of each case, we categorized these patients into two groups: good and poor groups. We evaluated the fundamental examination items, such as American Society of Anesthesiologists physical status, skeletal muscle mass index and so on, and a couple of the well-known risk score systems represented by Estimation of Physiology Ability and Surgical Stress. RESULTS: A total of 85 of the 112 patients belonged to the good group and the rest belonged to the poor group. The quality of postoperative outcome is well characterized by Estimation of Physiology Ability and Surgical Stress (P = 0.001). Receiver operating characteristic analysis of Estimation of Physiology Ability and Surgical Stress for the quality of postoperative outcome shows sensitivity of 0.83 and specificity of 0.61. Multivariate logistic regression analysis showed that skeletal muscle mass index and American Society of Anesthesiologists physical status are prominent as the risk determinants affecting the quality of postoperative outcome. A scoring system based on the skeletal muscle mass index, which is a good index of sarcopenia, and American Society of Anesthesiologists physical status, named the "SAP score" has the following characteristics. P-value <0.001, sensitivity 0.76 and specificity 0.91. CONCLUSIONS: Informed consent based on the risk score might be able to reduce the regrettable situation where it would have been better to have had surgery or not to have had surgery. Geriatr Gerontol Int 2022; 22: 271-277.

Development of alternative gene transfer techniques for ex vivo and in vivo gene therapy in a canine model.

INTRODUCTION: Gene therapy have recently attracted much attention as a curative therapeutic option for inherited single gene disorders such as hemophilia. Hemophilia is a hereditary bleeding disorder caused by the deficiency of clotting activity of factor VIII (FVIII) or factor IX (FIX), and gene therapy for hemophilia using viral vector have been vigorously investigated worldwide. Toward further advancement of gene therapy for hemophilia, we have previously developed and validated the efficacy of novel two types of gene transfer technologies using a mouse model of hemophilia A. Here we investigated the efficacy and safety of the technologies in canine model. Especially, validations of technical procedures of the gene transfers for dogs were focused. METHODS: Green fluorescence protein (GFP) gene were transduced into normal beagle dogs by ex vivo and in vivo gene transfer techniques. For ex vivo gene transfer, blood outgrowth endothelial cells (BOECs) derived from peripheral blood of normal dogs were transduced with GFP gene using lentivirus vector, propagated, fabricated as cell sheets, then implanted onto the omentum of the same dogs. For in vivo gene transfer, normal dogs were subjected to GFP gene transduction with non-viral piggyBac vector by liver-targeted hydrodynamic injections. RESULTS: No major adverse events were observed during the gene transfers in both gene transfer systems. As for ex vivo gene transfer, histological findings from the omental biopsy performed 4 weeks after implantation revealed the tube formation by implanted GFP-positive BOECs in the sub-adipose tissue layer without any inflammatory findings, and the detected GFP signals were maintained over 6 months. Regarding in vivo gene transfer, analyses of liver biopsy samples revealed more than 90% of liver cells were positive for GFP signals in the injected liver lobes 1 week after gene transfers, then the signals gradually declined overtime. CONCLUSIONS: Two types of gene transfer techniques were successfully applied to a canine model, and the transduced gene expressions persisted for a long term. Toward clinical application for hemophilia patients, practical assessments of therapeutic efficacy of these techniques will need to be performed using a dog model of hemophilia and FVIII (or FIX) gene.

Hot-water bathing before bedtime and shorter sleep onset latency are accompanied by a higher distal-proximal skin temperature gradient in older adults.

STUDY OBJECTIVES: Passive body heating in controlled settings could shorten sleep onset latency (SOL). The hypothesized mechanism is vasodilation-induced heat loss before bedtime. However, this evidence is based on small sample-sized studies in specific populations. Thus, we analyzed the association of hot-water bathing and its before-bedtime timing with SOL and heat loss in a large study population of older adults. METHODS: We conducted a longitudinal analysis using repeated measurements of hot-water bathing and sleep among 1,094 older adults (mean age, 72.0 years). SOL was recorded using actigraphy and self-reported sleep estimates and was categorized into conditions (intervals of 1-60, 61-120, 121-180, and > 181 minutes between hot bath and bedtime) and compared with the control condition of no bathing. The heat-loss indicator, distal-proximal skin temperature gradient, was examined in the same categorization. RESULTS: Mixed-effects linear regression models suggested that the bathing conditions of 61-120 minutes and 121-180 minutes showed significantly shorter log-transformed actigraphic SOL by 0.23 log-minutes (95% confidence interval (CI), 0.03-0.42) and 0.32 log-minutes (95% CI, 0.09-0.56), shorter self-reported SOL by 0.16 log-minutes (95% CI, 0.02-0.30) and 0.18 log-minutes (95% CI, 0.01-0.35), and higher distal-proximal skin temperature gradient for 30 minutes before bedtime by 0.49°C (95% CI, 0.22-0.75) and 0.51°C (95% CI, 0.20-0.83), respectively, independent of potential confounders. CONCLUSIONS: Hot-water bathing before bedtime is significantly associated with shorter SOL and higher distal-proximal skin temperature gradient among the large-scale older population. This finding could enhance the generalizability of hot-water bathing habits for ameliorating sleep initiation difficulty.

Complete Resolution of a Case of TAFRO Syndrome Accompanied by Mediastinal Panniculitis, Adrenal Lesion, and Liver Damage with Hyperbilirubinemia.

TAFRO syndrome is a systemic inflammatory, lymphoproliferative disorder, but the pathophysiology of the disease is unknown. It is typically characterized by thrombocytopenia, anasarca, a fever, reticulin fibrosis, renal dysfunction, and organomegaly. However, other manifestations have been also reported. We encountered a 43-year-old man with TAFRO syndrome who showed mediastinal panniculitis, liver damage, and adrenal lesions in addition to the core signs. He achieved complete remission with combination therapy of corticosteroids, tocilizumab, and cyclosporin, and remission was maintained even after drug discontinuation at 15 months. Atypical manifestations and complete remission of TAFRO syndrome were remarkable features of our case.