A 3.06 µm Single-Photon Avalanche Diode Pixel with Embedded Metal Contact and Power Grid on Deep Trench Pixel Isolation for High-Resolution Photon Counting.

In this study, a 3.06 µm pitch single-photon avalanche diode (SPAD) pixel with an embedded metal contact and power grid on two-step deep trench isolation in the pixel is presented. The embedded metal contact can suppress edge breakdown and reduce the dark count rate to 15.8 cps with the optimized potential design. The embedded metal for the contact is also used as an optical shield and a low crosstalk probability of 0.4% is achieved, while the photon detection efficiency is as high as 57%. In addition, the integration of a power grid and the polysilicon resistor on SPAD pixels can help to reduce the voltage drop in anode power supply and reduce the power consumption with SPAD multiplication, respectively, in a large SPAD pixel array for a high-resolution photon-counting image sensor.

Evaluation of a Previously Developed Predictive Model for Infective Endocarditis in 320 Patients Presenting with Fever at 4 Centers in Japan Between January 2018 and December 2020.

BACKGROUND In our previous single-center study, we developed an infective endocarditis (IE) prediction model among patients with undiagnosed fever (UF) based on 5 factors that can be obtained on admission: ambulance transfer, presence of cardiac murmur or pleural effusion, blood neutrophil percentage, and platelet count. The present study aimed to retrospectively evaluate the prediction model for IE in 320 patients presenting with fever at 4 university hospitals in Japan from January 2018 to December 2020. MATERIAL AND METHODS Patients aged ≥20 years admitted to 4 hospitals with I-330 (IE) or R-50-9 (UF) according to the International Statistical Classification of Diseases and Related Health Problems-10 were enrolled. More than 2 physicians at each hospital reviewed the patient diagnoses using the modified Duke criteria, allocating "definite IE" to IE group (n=119) and "non-definite IE" to UF group (n=201). Five factors on admission were analyzed by multivariate logistic regression. The discriminative ability and calibration of the model were evaluated using the area under the curve (AUC) and the shrinkage coefficient, respectively. RESULTS A total of 320 patients were enrolled. The odds ratios (95% confidence intervals) were as follows: ambulance transfer 1.81 (0.91-3.55); cardiac murmur 13.13 (6.69-27.36); pleural effusion 2.34 (0.62-2.42); blood neutrophil percentage 1.09 (1.06-1.14); and platelet count 0.96 (0.93-0.99). The AUC was 0.783 (0.732-0.834) with a shrinkage coefficient of 0.961. CONCLUSIONS The IE prediction model is useful to estimate the probability of IE immediately after admission for fever in patients aged ≥20 years.

[Haploidentical stem cell transplantation for acute myeloid leukemia associated with adult-onset Shwachman-Diamond syndrome].

A 21-year-old man presented with bone marrow failure, short stature, fatty degeneration of the pancreas on CT images, and Shwachman-Bodian-Diamond syndrome (SBDS) gene abnormalities (exon 2: c.258+2T>C and deletion of exon 3). Thus, the patient was diagnosed with Shwachman-Diamond syndrome (SDS). In the clinical course, the patient developed acute myeloid leukemia (AML). Hematopoietic stem cell transplantation from the human-leukocytic-antigen-haploidentical father of the patient was performed. The patient was conditioned with 150 mg/m2 fludarabine, 6.4 mg/kg busulfan, and 4 Gy total body irradiation. Graft-versus-host disease prophylaxis included tacrolimus, micophenolate mofetil, and posttransplant cyclophosphamide. Although the patient achieved a complete remission on day 21, AML relapsed on day 434 after the transplantation. He died of sepsis. The prognosis of patients with SDS and AML is poor. Adult-onset cases must be recognized, and transplantation should be performed during bone marrow failure.

Relapsing Infectious Mononucleosis-Like Symptoms Associated with Liver Insufficiency in a Chronic Hepatitis B Patient with Common Variable Immunodeficiency.

BACKGROUND Common variable immunodeficiency (CVID) is a rare disease. Infectious mononucleosis-like symptoms due to Epstein-Barr virus reactivation in adulthood are also rare. Here, we aimed to report a case of Epstein-Barr virus reactivation presenting with relapsing infectious mononucleosis-like symptoms with liver failure in common variable immunodeficiency with chronic hepatitis B virus infection. CASE REPORT A 36-year-old Japanese woman with chronic hepatitis B virus infection developed relapsing fever, lymphadenopathy with marked splenomegaly, and ascites 6 months after treatment with propagermanium, a nonspecific immune modulator, and subsequent treatment with entecavir and pegylated interferon sequential therapy. Although the hepatitis B virus load was controlled, Epstein-Barr virus deoxyribose nucleic acid was detected in her serum. Seven months later, her symptoms improved following corticosteroid treatment. Prior to sequential therapy, she developed pneumonia 4 times in 2 months and exhibited consistent hypoimmunoglobulinemia before corticosteroid treatment. Further examinations showed low amounts of switched memory B cells, and absence or barely detectable levels of isohemagglutinins. Subsequently, she was diagnosed with common variable immunodeficiency. CONCLUSIONS Epstein-Barr virus reactivation with relapsing infectious mononucleosis-like symptoms can occur following immune modulation therapy in patients with common variable immunodeficiency, and this can affect the patient's primary disease. Therefore, immunoglobulin screening along with the consideration of CVID in all patients is required before immune modulation therapy is planned.

Serological Testing Reveals the Hidden COVID-19 Burden among Health Care Workers Experiencing a SARS-CoV-2 Nosocomial Outbreak.

We describe the results of testing health care workers, from a tertiary care hospital in Japan that had experienced a coronavirus disease 2019 (COVID-19) outbreak during the first peak of the pandemic, for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody seroconversion. Using two chemiluminescent immunoassays and a confirmatory surrogate virus neutralization test, serological testing revealed that a surprising 42% of overlooked COVID-19 diagnoses (27/64 cases) occurred when case detection relied solely on SARS-CoV-2 nucleic acid amplification testing (NAAT). Our results suggest that the NAAT-positive population is only the tip of the iceberg and the portion left undetected might potentially have led to silent transmissions and triggered the spread. A questionnaire-based risk assessment was further indicative of exposures to specific aerosol-generating procedures (i.e., noninvasive ventilation and airway suctioning) having mediated transmission and served as the origins of the outbreak. Our observations are supportive of a multitiered testing approach, including the use of serological diagnostics, in order to accomplish exhaustive case detection along the whole COVID-19 spectrum. IMPORTANCE We describe the results of testing frontline health care workers, from a hospital in Japan that had experienced a COVID-19 outbreak, for SARS-CoV-2-specific antibodies. Antibody testing revealed that a surprising 42% of overlooked COVID-19 diagnoses occurred when case detection relied solely on PCR-based viral detection. COVID-19 clusters have been continuously striking the health care system around the globe. Our findings illustrate that such clusters are lined with hidden infections eluding detection with diagnostic PCR and that the cluster burden in total is more immense than actually recognized. The mainstays of diagnosing infectious diseases, including COVID-19, generally consist of two approaches, one aiming to detect molecular fragments of the invading pathogen and the other to measure immune responses of the host. Considering antibody testing as one trustworthy option to test our way through the pandemic can aid in the exhaustive case detection of COVID-19 patients with variable presentations.

Necrotizing fasciitis following primary peritonitis caused by Streptococcus pyogenes with covS mutation in a healthy woman: a case report.

BACKGROUND: Primary peritonitis due to Streptococcus pyogenes (S. pyogenes) is uncommon in patients without comorbid conditions such as immunosuppression, nephritic disease, or liver cirrhosis. Furthermore, it does not cause another infection at the same time in a healthy person. However, several S. pyogenes mutants have been reported, and some of them exhibit strong virulence. Mutation of the control of virulence (cov) S gene of Streptococcus enhances bacterium survival by repressing negative regulators of virulence, which causes bacterial invasion of aseptic tissues, such as the parenteral space. We report a case of primary peritonitis and subsequent necrotizing fasciitis by the same S. pyogenes species with mutated covS in a previously healthy woman. CASE PRESENTATION: We present the case of a 55-year-old woman admitted to the hospital due to abdominal pain and nausea. She was treated for peritonitis. A few days later, she became hypotensive and tachycardic and was transferred to the intensive care unit (ICU) for the treatment of septic shock with primary peritonitis. On the second day of her ICU stay, both of her forearms developed swelling and redness around the peripheral injection site. The patient had developed necrotizing fasciitis. Since her skin symptoms spread rapidly, urgent debridement was performed. Her condition improved with antibiotic treatment and multiple episodes of debridement. S. pyogenes was detected in cultures of the patient's blood, ascites, and skin. The identified strain was emm89 genotype and had a genetic mutation of covS. CONCLUSIONS: S. pyogenes with covS mutation may spread from a portal, such as the upper respiratory tract or digestive system, to all organs immediately, causing septic shock. Infection with S. pyogenes with mutated genes should be considered in the differential diagnosis of gastrointestinal symptoms, even in a previously healthy patient.

General Anesthetic Management of a Patient With Hypertrophic Cardiomyopathy for Oral Surgery: Did Digitalis Contribute to Bradycardia?

Stabilization of circulatory dynamics is a critical issue in the anesthetic management of patients with hypertrophic cardiomyopathy (HCM). In this report, we managed general anesthesia for a 74-year-old male patient with nonobstructive HCM who developed circulatory instability intraoperatively. Severe bradycardia measuring 35 beats/min and hypotension measuring 78 mm Hg systolic were observed during surgery. Using stroke volume variation and stroke volume from the FloTrac as indices, successful circulatory management was performed with dopamine. The hypotension and bradycardia were thought to be the result of methyldigoxin and possibly associated with our perioperative management. Cardiology consult should have been obtained. We demonstrated that the FloTrac can be beneficial in diagnosing and managing cardiovascular instability and administration of dopamine in the anesthetic management of nonobstructive HCM patients.

Efficacy of Recombinant Human Soluble Thrombomodulin in Treating Disseminated Intravascular Coagulation Complicating Allogeneic Hematopoietic Stem Cell Transplantation.

The prognosis for patients who experience hemostatic complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor. However, no report has investigated disseminated intravascular coagulation (DIC) caused by the complications of allo-HSCT without infection. Recombinant human soluble thrombomodulin (rhTM) was used to treat 12 episodes of DIC (n = 10; group 1) caused by allo-HSCT complications such as acute graft-versus-host disease (aGVHD) or thrombotic microangiopathy (TMA), and the clinical outcomes were compared with those of historical controls (n = 9; group 2) treated for DIC without rhTM. In group 1, the mean DIC score was significantly improved after using rhTM. Fibrinogen degeneration product (FDP), C-reactive protein (CRP), and the inflammatory cytokine high-mobility group box 1 (HMGB1) were also significantly decreased. Serial changes from the baseline values of platelet counts and levels of FDP were significantly better in group 1 than in group 2. The recovery rate from DIC was significantly higher in group 1 than in group 2. These findings suggest that rhTM is effective against both DIC and systemic inflammatory complications after allo-HSCT.

Severe de novo Hepatitis B Recovered from Late-Onset Liver Insufficiency with Prolonged Ascites and Hypoalbuminemia due to Hepatitis B Virus Genotype Bj with Precore Mutation.

De novo hepatitis B is associated with a high risk of hepatic failure often resulting in fatal fulminant hepatitis even when nucleotide analogues are administered. A 77-year-old female developed de novo hepatitis B after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) treatment for diffuse large B-cell lymphoma. Hepatitis B virus (HBV) isolated from the patient was of genotype Bj, with a precore mutation (G1896A) exhibiting an extremely high viral load at the onset of hepatitis. She showed markedly high levels of transaminase with mild jaundice on admission and rapid decrease of prothrombin activity after admission. Although acute liver failure was averted by the administration of entecavir and corticosteroid pulse therapy, liver volume decreased to 860 ml, and marked hypoalbuminemia accompanying massive ascites occurred 2 months after the onset of hepatitis and persisted for 3 months with high levels of HBV DNA and mild abnormal alanine aminotransferase levels. Frequent infusions of albumin solution, nutrition support, and alleviation therapy showed limited effect. However, overall improvement along with HBV DNA reduction was observed after increasing the dose of entecavir and completion of prednisolone that was administered with a minimum dose for adrenal insufficiency. An immediate and sufficient suppression of virus replication with potent antiviral therapy is critical, particularly in patients infected with HBV precore mutation (G1896A) and/or Bj genotype, which may have a high viral replication and direct hepatocellular damage.

Delayed Viral Clearance after 6-Week Treatment with Peginterferon Plus Ribavirin in a Patient with Chronic Hepatitis C Virus Genotype 1b.

Following interferon-based therapy for chronic hepatitis C, the negativity of hepatitis C virus RNA is essential to achieve viral clearance at the end of treatment. We report a case of clearance of chronic hepatitis C virus infection following early discontinuation (at 6 weeks) of peginterferon plus ribavirin therapy, without negativity for hepatitis C virus RNA during the treatment period. The patient was a 76-year-old Japanese male infected with hepatitis C virus genotype 1b and TT of IL28B rs8099917. Hepatitis C virus RNA remained positive at persistently low levels for more than 2 months after the cessation of therapy and became negative at 7 months after the discontinuation of therapy. Spontaneous clearance of hepatitis C virus RNA can occur following antiviral failure in patients with persistently low viral loads, and virological follow-up is therefore necessary in chronic hepatitis C virus infection, even after antiviral failure.

Evaluation of care for leukemia and lymphoma patients during their last hospitalization from the perspective of the bereaved family.

We aimed to evaluate care for leukemia and lymphoma patients during their last hospitalization from the perspective of the bereaved family. Questionnaires were sent to the bereaved family members of adult leukemia and lymphoma patients. We used the Care Evaluation Scale (CES) and asked the bereaved family members about care satisfaction and "good death" factors during the patient's last week of life or last admission period. We distributed 177 questionnaires and were able to analyze 103 (58.2%) responses. Compared with the results of a previous study of palliative care units in Japan, the CES scores were significantly lower in 9 out of 10 domains. Assessment of the "good death" components revealed that only 33% of respondents agreed that the patient had been relieved as far as possible of pain and physical distress during the last week of life. Only 21.4% of respondents agreed that the patient had been relieved as far as possible of psychological distress, and 57% of caregivers were not satisfied with the level of care. During the last hospitalizations of leukemia or lymphoma patients, their care was insufficient and a good death was not often achieved. Improvement of end-of-life care for leukemia and lymphoma patients is needed.

Dimethylaminopyridine-supported graft polymer catalyst and its flow system.

A new heterogeneous organocatalyst, graft polymer supported dimethylaminopyridine (g-DMAP), is developed. This catalyst has a flexible structure and comprises DMAP anchored to the polyethylene-graft-polyacrylic acid (PE-g-PAA). It exhibits higher activity than DMAP supported on polystyrene cross-linked with divinylbenzene and can be recovered in batch mode acetylation. The activity and stability of this catalyst allow its application in continuous flow systems. Continuous acetylation proceeds with excellent conversion, and a turnover number of 560 can be achieved using g-DMAP. Parallel fixed bed reactors were used to scale up the synthesis of this continuous flow system. Eight parallel fixed bed reactors displayed excellent conversion.

Pure red cell aplasia associated with autoimmune hepatitis successfully treated with cyclosporine A.

A 47-year-old female with a 17-year history of autoimmune hepatitis had been treated with prednisolone, azathioprine, and ursodeoxycholic acid. Although her alanine aminotransferase level occasionally showed mild abnormality, the prednisolone dose could not be increased because she had developed cataract during the course of her illness. In May 2012, she developed severe normochromic normocytic anemia without hemorrhage, and azathioprine was discontinued because it was suspected of being the cause. However, anemia recurred frequently even after discontinuation, necessitating repeated blood transfusions. Bone marrow analysis revealed selective erythroblastopenia, thus leading to a diagnosis of pure red cell aplasia. Cyclosporine A was administered, which led to a dramatic recovery from anemia, and stabilized her alanine aminotransferase levels. Furthermore, the prednisolone dose could be gradually tapered. Pure red cell aplasia associated with autoimmune hepatitis is extremely rare. The present case shows that patients with autoimmune hepatitis refractory to the standard treatment regimen and those with concomitant pure red cell aplasia may be treated with cyclosporine A.

Prognosis of patients with core binding factor acute myeloid leukemia after first relapse.

Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse.

Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myelogenous leukemia in first complete remission.

The benefits of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myelogenous leukemia (AML) in first complete remission (CR1) have mostly been evaluated in younger patients. Although favorable outcomes of allo-HCT over chemotherapy have been reported with the use of reduced-intensity conditioning (RIC) regimens in elderly patients with AML in CR1, information is still limited, especially on the effects of cytogenetic risks and donor sources. We collected data from AML patients aged 50 to 70 years who achieved CR1, and compared the outcome in 152 patients who underwent allo-HCT in CR1 (HCT group) to that in 884 patients who were treated with chemotherapy (CTx group). The cumulative incidence of relapse in the HCT group was significantly lower than that in the CTx group (22% versus 62%). Both overall survival (OS) and relapse-free survival (RFS) were significantly improved in the HCT group (OS: 62% versus 51%, P = .012), not only in the whole population, but also in the intermediate-risk group. Among patients who had a suitable related donor, the outcomes in the HCT group were significantly better than those in the CTx group. The introduction of appropriate treatment strategies that include allo-HCT may improve the outcome in elderly patients with AML in CR1.

[Acquired hemophilia complicated with hemorrhage induced acute renal failure].

A 63-year-old woman, without a family history of hemophilia, was admitted to our hospital because of subcutaneous bleeding, intramuscular and intra-articular hematoma, and macroscopic hematuria. On routine blood analysis, a prolonged activated partial thromboplastin time, decreased concentration of factor VIII to less than 1%, and a markedly elevated level of factor VIII inhibitor to 14.1 BU/ml were revealed. Diagnosis of acquired hemophilia was made and she was treated with prednisolone and recombinant activated factor VII (rFVIIa). On day 9 of rFVIIa therapy, she was complicated by acute renal failure (ARF) with increasing macroscopic hematuria. Computed tomography revealed bilateral swelling of the kidneys with bleeding and dilatation of the left renal pelvis. Activated prothrombin complex concentrates (aPCC) was administrated in combination with steroid pulse therapy and hydration. The bleeding tendency, including ARF, was improved with aPCC, and she was treated with prednisolone and cyclophosphamide. She is currently in good health and attending an outpatients' clinic. Acquired hemophilia is associated with various underlying conditions, but our patient did not show any previous history. ARF is a rare complication in acquired hemophilia, requiring a non-invasive treatment combination with early induction of immunosuppressive therapy.