Comparative Effectiveness of Long-Acting Injectable Versus Oral Antipsychotics in Patients With Schizophrenia Using the Prevalent New User Design and Subgroup Analyses.

BACKGROUND: We compared the effectiveness of long-acting injectable antipsychotics (LAIs) and oral antipsychotics (OAs) in treating schizophrenia, focusing on whether the benefits of LAIs over OAs are evident even in the prevalent new user design and on effect heterogeneity. METHODS: We conducted a prevalent new user cohort study using 2 administrative claims databases in Japan. We included patients with schizophrenia initiated on LAIs and propensity score-matched patients on OA. We compared the risks of psychiatric hospitalization and treatment discontinuation based on hazard ratios (HRs) using the Cox proportional hazards model. Effect heterogeneity was evaluated using subgroup analyses. RESULTS: In total, 2520 patients using LAI and OA were identified as matched cohorts. Long-acting injectable antipsychotics were associated with a higher psychiatric hospitalization risk than OAs (HR, 1.41; 95% confidence interval [CI], 1.06-1.88) in the entire population; however, LAIs were associated with lower risk in the group with a low proportion of days covered and psychiatric hospitalization history (HR, 0.51; 95% CI, 0.30-0.89). Long-acting injectable antipsychotics were associated with a lower risk of treatment discontinuation than OAs (HR, 0.76; 95% CI, 0.66-0.87) in the entire population; in the subgroup analyses, a consistent trend was observed in all strata (LAIs had a lower risk). CONCLUSIONS: Using a prevalent new user design, this study confirmed that LAIs have an advantage regarding treatment continuity. Long-acting injectable antipsychotics had higher psychiatric hospitalization risk than OAs in the entire population; however, this study suggested the presence of effect heterogeneity due to psychiatric hospitalization history.

Phosphorus(V) Tetraazaporphyrin with an Intense, Broad CT Band in the Near-IR Region.

In phosphorus tetraazaporphyrins (PTAPs), the Q- and charge-transfer (CT) bands appear as a result of configuration interaction between their excited states. On the basis of this concept, a PTAP with an intense, broad CT band in the near-IR region has been rationally designed and realized by introducing eight diphenylaminophenyl (dPAP) groups. The order of the CT and Q-bands in ascending energy was supported by magnetic circular dichroism (MCD) spectroscopy and theoretical calculations. An intense two-photon absorption was also found in the deep near-IR region.

Synthesis of Cross-Chain Bridging Cryptands and Induction of Molecular Chirality.

In this study, we synthesized two cryptands featuring entangled tri- and tetra(ethylene glycol) linkers. The cryptand bearing short linkers was chiral without any asymmetric carbon atoms. After chiral high-performance liquid chromatography was used to separate the enantiomers, the absolute configuration of each cryptand was determined through single-crystal X-ray and circular dichroism analyses. The racemization of the cryptand possessing long linkers proceeded at room temperature.

Synthesis of Peripherally Annulated Phenanthroporphyrins.

Synthesis of unusual phenanthroporphyrins was achieved by a stepwise precursor method. Precursor porphyrins fused with aryl-substituted bicyclo[2.2.2]octadiene afforded the corresponding arylbenzoporphyrins (arylBPs) by a retro Diels-Alder reaction. Unusual phenanthroporphyrins were obtained via the intramolecular Scholl reaction of arylBPs. X-ray crystallographic analysis revealed a distorted, helical porphyrin plane. Red-shifted absorptions of tetraphenanthroporphyrin are observed at ca. 580 nm for the B band and at 700-900 nm for the Q bands. Analysis of magnetic circular dichroism spectra and time-dependent density functional theory calculations was used to explain the optical properties and electronic structures.

Comparative effectiveness of long-acting injectable antipsychotics in patients with schizophrenia in Japan.

OBJECTIVE: To compare the effectiveness of different long-acting injectable antipsychotics (LAIs) (aripiprazole, paliperidone, risperidone, and fluphenazine/haloperidol) in patients with schizophrenia in Japan. METHODS: We conducted a retrospective cohort study using two administrative claims databases. The study population consisted of outpatients with schizophrenia who initiated LAIs between May 1, 2015, and November 30, 2019. We directly compared the risk of psychiatric hospitalization and LAI discontinuation among the LAIs based on hazard ratios (HRs) using Cox proportional hazards regression models. RESULTS: The numbers of eligible patients who initiated aripiprazole, paliperidone, risperidone, and fluphenazine/haloperidol were 303, 124, 73, and 123, respectively. Regarding psychiatric hospitalization, aripiprazole and paliperidone were associated with significantly lower risk compared to fluphenazine/haloperidol (HR of aripiprazole: 0.47, 95 % CI: 0.28-0.78, HR of paliperidone: 0.50, 95 % CI: 0.28-0.89); HR of risperidone showed the same trend as the aripiprazole and paliperidone. Regarding LAI discontinuation, aripiprazole and paliperidone were associated with significantly lower risk of LAI discontinuation compared to fluphenazine/haloperidol (HR of aripiprazole: 0.53, 95 % CI: 95 % CI: 0.35-0.80, HR of paliperidone: 0.57, 95 % CI: 0.35-0.92). Aripiprazole was also associated with a significantly lower risk compared to risperidone (HR: 0.56, 95 % CI: 0.32-0.98). CONCLUSION: Our study suggests that aripiprazole and paliperidone are superior to fluphenazine/haloperidol in the risk of psychiatric hospitalization and LAI discontinuation. Aripiprazole is superior to risperidone in the risk of LAI discontinuation.

Prescription trend and lactic acidosis in patients prescribed metformin before and after the revision of package insert for allowing metformin administration to patients with moderately decreased kidney function based on real-world data from MID-NET® in Japan.

Introduction: This study was conducted to understand the impact of package insert (PI) revision in Japan on 18 June 2019 to allow metformin use for patients with moderately decreased kidney function (30 ≤ estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2). Methods: A new user cohort design was employed to examine the prescription trend and the occurrence of lactic acidosis in patients prescribed metformin before and after PI revision using the Medical Information Database Network (MID-NET®). Results: From 12 May 2016 to 31 March 2020, 5,874 patients (before, n = 4,702; after, n = 1,172) were identified as new metformin users, including 1,145 patients (before, n = 914; after, n = 231) with moderately decreased kidney function. Although no marked changes in metformin prescription were observed before and after PI revision, the daily metformin dose at the first prescription decreased after PI revision. For both before and after PI revision, less than 10 cases of lactic acidosis occurred in all patients prescribed metformin, and no lactic acidosis was observed in patients with moderately decreased kidney function. Conclusion: The results of this study are useful for understanding the safety of metformin use in patients with decreased kidney function and suggest no worse impacts of PI revision in Japan, indicating no further safety concerns on metformin use in patients with moderately decreased kidney function under the situation with careful use and safety monitoring of metformin.

Identification of serum and glucocorticoid-regulated kinase 1 as a regulator of signal transducer and activator of transcription 3 signaling.

Signal transducer and activator of transcription 3 (STAT3) plays key roles in cancer cell proliferation, invasion, and immunosuppression. In many human cancer cells, STAT3 is hyperactivated, which leads to tumor progression and drug resistance, and therefore STAT3 and its modulators are considered effective drug targets. However, the complex regulatory mechanisms of STAT3 have made it difficult to develop potent anticancer drugs that suppress its activity. Here, we report serum and glucocorticoid-regulated kinase 1 (SGK1) as a novel regulator of STAT3 signaling and an effective target for combination therapy with Janus kinase (JAK) inhibitors. We screened small molecules using a gain-of-function mutant of STAT3 resistant to JAK inhibition and found that an SGK1 inhibitor suppressed the constitutive activation of STAT3. Importantly, our results revealed that SGK1 also mediated the activation of wild-type STAT3. Further examination suggested that the tuberous sclerosis complex 2 and mammalian target of rapamycin signaling pathway were involved in STAT3 activation by SGK1. Finally, we demonstrated that SGK1 inhibition enhanced the inhibitory effect of a JAK inhibitor on STAT3 phosphorylation and cancer cell proliferation. Our findings provide new insights into the molecular mechanisms of STAT3 activation and suggest SGK1 as a potential target for STAT3-targeted combination cancer therapy.

Concurrent Takayasu Arteritis and Vascular Ehlers-Danlos Syndrome: A Case Report.

Takayasu arteritis (TAK) is a rare primary systemic inflammatory vasculopathy. It is classified as a large-vessel vasculitis and is known to cause inflammatory aneurysms and vascular stenosis. Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant condition known to cause multiple aneurysms and arterial dissection at a young age owing to a mutation in the gene for type III collagen, COL3A1. Here, we present a case of TAK associated with vEDS with the development of multi-organ infarction of the brain, kidney, and spleen owing to multiple arterial aneurysms and stenosis of the internal carotid artery. The patient was successfully treated using anti-inflammatory agents, glucocorticoids, and tocilizumab with the addition of interventional radiology. In our case, a high inflammatory response led to vasculitis being the main cause of the disease with concurrent vEDS. When patients develop multiple aneurysms, stenosis, and dissections leading to multiple organ infarctions, a systemic differential diagnosis to consider concurrent vasculitis syndrome and non-inflammatory vasculopathy, including hereditary disorders, is important even with time constraints.

Effects of medical service fee revision on reducing irrational psychotropic polypharmacy in Japan: an interrupted time-series analysis.

PURPOSE: According to the revised Japanese medical service fees aimed at reducing irrational psychotropic polypharmacy, medical service fees are reduced if the number of simultaneously prescribed psychotropic drugs exceeds the standard. This study primarily aims to examine the effect of the 2018 revision. METHODS: Using a large Japanese administrative claims database, we retrospectively identified five groups (April 2013-September 2018) prescribed at least one drug from the following drug groups: anxiolytics, hypnotics, sum of anxiolytics and hypnotics, antipsychotics, and antidepressants (study population in each group: 547,511, 406,524, 759,137, 112,929, and 201,046, respectively). We used an interrupted time-series design to evaluate changes in the proportion of patients prescribed more than the standard number of drugs. RESULTS: After the 2018 revision, the proportion of patients prescribed more than the standard number of drugs significantly decreased only for the sum of anxiolytics and hypnotics; estimated changes in level and trend were - 0.60% [- 0.69%, - 0.52%] and - 0.04% [- 0.06%, - 0.02%] per month, respectively. The proportion of patients exhibiting a decrease in the number of prescribed drugs from more than the standard to within the standard increased when the revision was enforced (April 2018); this proportion in April 2018 was 36.3%, while all other proportions were in the range of 12.1-22.3%. CONCLUSION: The 2018 revision promoted a reduction in the number of prescribed drugs, which served as an important factor in the decrease in the proportion of patients prescribed more than the standard number of drugs for the sum of anxiolytics and hypnotics.

Synthesis of Non- or Antiaromatic Dicarbaamethyrin: [24]Diazulihexaphyrin(0.1.0.0.1.0).

A "3+3" condensation reaction of 1,3-di(2-pyrrolyl)azulene with aryl aldehyde followed by an oxidative aromatization afforded diazuliamethyrin, [24]diazulihexaphyrin(0.1.0.0.1.0). X-ray diffraction analysis revealed a relatively planar structure of diprotonated diazuliamethyrin with a mean plane deviation of 0.37 Å. A 24π non- or antiaromatic character was confirmed by 1H NMR, absorption, MCD spectra, and TD-DFT calculations that included the NICS values and ACID plots.

Risk for Colorectal Cancer in Patients with Serially Positive Fecal Immunochemistry Test in an Annual Screening Program.

OBJECTIVES: There are patients who do not undergo colonoscopy even if the fecal immunochemistry test (FIT) results are positive and even with repeated positive test results the following year. We aimed to investigate colorectal cancer (CRC) risk in examinees with positive FIT results in our annual screening program. METHODS: We analyzed patients who underwent initial colonoscopy from April 2010 to March 2017 because of positive FIT results using an endoscopy database in our hospital. We investigated the difference in the risk of advanced colorectal neoplasia as a surrogate marker of CRC between those who had an initial positive test and those who had repeated positive tests. RESULTS: A total of 748 patients were included in this analysis. The advanced neoplasia detection rates were 7.6% (50/656) and 18.5% (17/92) for the initial and repeated positive test groups, respectively. Subgroup analysis of those with repeated positive tests revealed that the detection rates in examinees with positive tests 1-2 and >2 years ago were 16.7% (6/36) and 19.6% (11/56), respectively. The odds ratios for advanced neoplasia detection in patients with positive tests 1-2 and >2 years ago compared with those in the initial positive test group were 2.72 (95% confidence interval [CI], 1.04-7.10) and 3.09 (95% CI, 1.47-6.48), respectively. CONCLUSIONS: The risk of CRC appears more than doubled in patients with a repeated positive FIT result. Prompt colonoscopy is recommended for FIT-positive cases.

Potential Triggers for Thrombocytopenia and/or Hemorrhage by the BNT162b2 Vaccine, Pfizer-BioNTech.

Immune thrombocytopenia is an autoimmune disease that can cause bleeding in severe cases. Although available published data do not associate the BNT162b2 vaccine (Pfizer-BioNTech) with the risk of developing thrombocytopenia, the ChAdOx1 nCov-19 vaccine has raised concerns about its potential link with thrombosis and thrombocytopenia. We would like to clarify whether the BNT162b2 vaccine administration may interfere with pre-existing conditions and whether it may cause a risk of thrombocytopenia. Herein, we report three cases of post-vaccine thrombocytopenia among patients with rheumatoid arthritis (RA); one case in which a causal relationship cannot be ruled out with the BNT162b2 vaccine was officially announced. Furthermore, we reviewed reports of adverse events and death cases with a focus on thrombocytopenia and hemorrhages, following vaccination with BNT162b2 in Japan between February 17, 2021 and July 16, 2021, as reported by the Ministry of Health, Labour, and Welfare within the general population. The three cases in this report share the common features of old age, RA, chronic renal failure or hypertension, and pre-existing mild thrombocytopenia at baseline. A total of 746 death cases were reported during this time period, with death by bleeding accounting for 8.8% of the total deaths, of which 84.8% were cranial and statistically higher in young women than among elderly women. The risk-benefit ratio of the vaccine needs to be reconsidered based on high- and low-risk population types and ethnicity. To do so, the expansion of the pharmacovigilance system for BNT162b2 vaccination is urgently required worldwide.

Structures of ions accommodated in salty ice Ih crystals.

Frozen aqueous electrolytes are ubiquitous and involved in various phenomena occurring in the natural environment. Although salts are expelled from ice during freezing of aqueous solutions, minor amounts of the constituent ions are accommodated in the crystal lattice of ice. This phenomenon was associated with the generation of the Workman-Reynolds freezing potential. Molecular simulations also confirmed the ion incorporation in the crystal lattice of ice Ih upon freezing of aqueous electrolytes and identified possible local structures of the ions. However, no experimental information is available on the structure of ions accommodated in the crystal lattice of ice Ih. In this work, we use X-ray absorption fine structure (XAFS) to study the local structures of K+ and Cl- accommodated in ice Ih single crystals. Previous molecular simulations predicted that ions are trapped in the hexagonal cavities of the ice structure or replace two water molecules in the crystal lattice. Four possible configurations are considered and optimized by the calculations using ONIOM (QM/QM/QM). The results are evaluated in terms of the agreement between the experimental XAFS spectra and those simulated from the optimized structures. The spectra are most reasonably interpreted by assuming that K+ replaces one water molecule in the ice crystal lattice and is accommodated in a tetrahedral coordination cage. Similarly, Cl- probably adopts the same configuration, because it explains the coordination number better than other structures, such as that assuming the replacement of two water molecules belonging to the same hexagonal planes.

Phenanthroline-Fused Phthalocyanine Analogues Having a Monovalent Corrole Inner Perimeter and 4nπ Nonaromatic Properties.

Condensation of 4,5-bis(4-tert-butyl-2,6-dimethylphenoxy)phthalonitrile with 2,9-diamino-1,10-phenanthroline in the presence of M(OAc)2 (M = Ni, Pd, Zn) afforded a series of phenanthroline-fused phthalocyanine analogues with a 16 π-electron skeleton. While the arrangement of elements along the inner perimeter of these macrocycles is the same as that of the hitherto reported trivalent corroles, they represent the first example of porphyrinoids possessing a monovalent corrole inner perimeter and nonaromatic characteristics as revealed by their spectroscopic data and theoretical studies.

Simultaneous Discordant B-Lymphoblastic Lymphoma and Follicular Lymphoma.

OBJECTIVES: We report a rare case of B-lymphoblastic lymphoma (B-LBL) and low-grade follicular lymphoma (FL) identified concurrently in biopsies from different sites at the initial diagnosis in a 39-year-old man. The clonal relationship between the 2 histologic subtypes was investigated. METHODS: A diagnosis of FL grade 1/2 (low grade) was made by bone marrow (BM) biopsy. B-LBL was identified in biopsies from the testis and pancreas. Cytogenetic and molecular analyses were performed to investigate their clonal relationship. RESULTS: Interphase fluorescence in situ hybridization analyses and G-banding karyotype analyses identified the BCL2-IGH and MYC-IGH translocation in tumor cells from both the BM and testis. The tumor cells from the BM and testis shared the same IGH VDJ usage and a high degree of somatic mutations. These findings suggest that acquisition of MYC gene rearrangement is a critical event for lymphoblastic transformation of FL. Of note, the presence of intraclonal diversity in the B-LBL sample further suggests an earlier or concurrent event of MYC translocation than the somatic IGH mutation in the germinal center and the dedifferentiation of lymphoma cells to a precursor stage of B-cell development. CONCLUSIONS: B-lymphoblastic transformation of FL can occur with MYC gene rearrangement.

A case of polyangiitis overlap syndrome of giant cell arteritis and granulomatosis with polyangiitis successfully treated with rituximab.

We report a case of polyangiitis overlap syndrome of giant cell arteritis (GCA) and granulomatosis with polyangiitis (GPA) and conduct a literature review of polyangiitis overlap syndrome. The patient was 73-year-old male who developed cranial-type GCA and GPA simultaneously and was successfully treated with rituximab. Rituximab might be effective for not only GPA but also GCA.

Recent Progress in Optically-Active Phthalocyanines and Their Related Azamacrocycles.

Optically-active phthalocyanines (Pcs) and related macrocycles reported in the 2010-2020 period are introduced in this review. They are grouped into several categories: (1) chiral binaphthyl-containing Pcs, (2) optically active alkyl chain-containing Pcs, (3) chiral axial ligand- coordinated or -linked Pcs, (4) chiral subphthalocyanines (SubPcs), and (5) related azamacrocycles. For each compound, the structure and important characteristics are summarized.

Significance of fecal hemoglobin concentration for predicting risk of colorectal cancer after colonoscopy.

BACKGROUND AND AIM: As the significance of the quantitative fecal immunochemical test (FIT) in patients who previously underwent a colonoscopy is unknown, this study aimed at investigating the association between fecal hemoglobin concentration and the risk of colorectal cancer (CRC). METHODS AND RESULTS: We retrospectively analyzed FIT-positive patients who underwent a colonoscopy through our opportunistic annual screening program from April 2010 to March 2017 at the Kyoto Second Red Cross Hospital. We stratified them into no colonoscopy and past colonoscopy (>5 years or ≤5 years) groups based on whether they had a history of undergoing a colonoscopy and analyzed the correlation between fecal hemoglobin concentration and advanced neoplasia or invasive cancer detection in each group. We analyzed 1248 patients with positive FIT results. There were 748 (59.9%), 198 (15.9%), and 302 (24.2%) patients in the no colonoscopy, past colonoscopy (>5 years), and past colonoscopy (≤5 years) groups, respectively. In the no colonoscopy group, the advanced neoplasia detection rate significantly increased with the fecal hemoglobin concentration (P < 0.001). However, no significant trend was observed in the past colonoscopy (both >5 years and ≤5 years) group (P = 0.982). No invasive cancer was detected in the past colonoscopy (≤5 years) group. CONCLUSION: The risk of CRC might be low even if fecal hemoglobin concentration was high, especially in those who underwent colonoscopy within 5 years.

Aptamer-Based Sensing of Small Organic Molecules by Measuring Levitation Coordinate of Single Microsphere in Combined Acoustic-Gravitational Field.

We present aptamer-based sensing using a coupled acoustic-gravitational (CAG) field, which transduces a change in the density of a microparticle (MP) to a change in the levitation coordinate. A large density of the MP is initially induced by the binding of gold nanoparticles (AuNPs) on the MP through sandwich hybridization with aptamer DNA molecules. Targets added to the system interact with the aptamer DNA molecules to form complexes, and the duplex between the aptamer and the probe DNA molecules is dissociated. This leads to the release of AuNPs from the MP and a decrease in its density. As the target concentration increases, the levitation coordinate of the MP increases. From the levitation coordinate shift, we can determine the target concentration. The detection limits for adenosine triphosphate, dopamine, and ampicillin as test targets are 9.8 nM, 17 nM, and 160 pM, respectively. The dissociation constants for the aptamer-target complexes are quantitatively determined from the dependence of the levitation coordinate on the target concentration. This scheme is a useful analytical tool not only for the trace analyses of targets but also for the evaluation of aptamer-target interactions.

Kawasaki Disease Following Severe Sunburn Injury.

Background: Although an etiology of Kawasaki disease (KD) is unknown, an aberrant innate immune system in predisposed individuals has been proposed to play a key role in the development of KD vasculitis. Various etiological pathogens have been proposed as the trigger of KD and a scaled injury preceding symptom onset has been reported as one of them. Here, we report a 17-month-old Japanese female who was hospitalized due to high fever lasting for 4 days with infection ruled out as a cause. On admission, she displayed severe sunburn all over her body following a prolonged period of outdoor play 5 days ago. On the 5 day of illness, she developed complete KD. Serum levels of high mobility group box 1, a representative for damage-associated molecular patterns (DAMPs), were elevated during acute phase and continued to decrease during subacute phase. This unique course suggested the inflammatory process of KD involving innate immunity via DAMPs.