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.

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.

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.

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.

Tocilizumab monotherapy for large vessel vasculitis: results of 104-week treatment of a prospective, single-centre, open study.

OBJECTIVE: To evaluate the efficacy and safety of tocilizumab (TCZ) monotherapy for large vessel vasculitides (LVV), including Takayasu arteritis (TAK) and GCA. METHODS: Twelve patients with a newly diagnosed LVV (eight GCA, four TAK) were enrolled. One TAK patient withdrew consent, so 11 (eight GCA, three TAK) were analysed in a prospective, open-label study. TCZ (8 mg/kg) monotherapy, without glucocorticoids or immunosuppressants, was administered every 2 weeks for 2 months and then every 4 weeks for 10 months. Patients were followed for 1 year after the final TCZ dose. Complete and partial responses were defined as disappearance or improvement of all clinical symptoms and normalization of CRP. Relapse was defined as the worsening or recurrence of clinical symptoms, increase in CRP attributable to vasculitis, and/or the need for initiation of glucocorticoids and/or immunosuppressants. Poor clinical response described patients who did not fit the definition of complete response or partial response. RESULTS: Complete and partial responses rates were 75/66% and 25/0% in GCA/TAK patients, respectively, at week 24 and week 52. Five GCA patients and one TAK patient remained disease-free for 1 year after therapy. One GCA patient required TCZ discontinuation due to heart failure at week 24. CONCLUSION: TCZ monotherapy showed a high response rate for newly diagnosed LVV patients, and the majority of patients did not relapse for 1 year after TCZ cessation. Result of this study could help us to understand the crucial role of IL-6 in the pathogenesis of LVV.

Assessing the Efficacy of Very Early Motor Rehabilitation in Children with Down Syndrome.

Among children with Down syndrome, the frequency of motor rehabilitation intervention and the age at the start of this intervention are independently related to the age at onset of independent walking. Early motor rehabilitation, before age 6 months, may be effective in reducing motor delay in children with Down syndrome.

Risk of colorectal cancer for fecal immunochemistry test-positive, average-risk patients after a colonoscopy.

BACKGROUND AND AIM: Because the risk of colorectal cancer has not been well examined in fecal immunochemistry test (FIT)-positive patients who previously underwent colonoscopy, this study aimed to investigate this topic. METHODS: This was a single-center, observational study of prospectively collected data in Japan. FIT-positive, average-risk patients who underwent colonoscopy were divided into groups as follows: those who never underwent colonoscopy in the past (no colonoscopy group), those with a history of colonoscopy between 6 months and 5 years (0.5- to 5-year colonoscopy group), and those with a history of colonoscopy more than 5 years ago (> 5-year colonoscopy group). We investigated the prevalence of advanced neoplasia and invasive cancer among these groups using multiple logistic regression analysis. RESULTS: Detection rates of advanced neoplasia in the no colonoscopy group, 0.5- to 5-year colonoscopy group, and > 5-year colonoscopy group were 14.8% (240/1626), 3.9% (13/330), and 6.9% (17/248), respectively. Detection rates of invasive cancer in each aforementioned group were 5.7% (92/1,626), 0.3% (1/330), and 1.2% (3/248), respectively. Odds ratios of advanced neoplasia in the 0.5- to 5-year colonoscopy group and > 5-year colonoscopy were 0.23 (95% confidence interval [CI]: 0.13-0.42) and 0.40 (95% CI: 0.24-0.68), respectively, in multivariate analysis. The odds ratios of invasive cancer in each aforementioned group were 0.05 (95% CI: 0.01-0.37) and 0.19 (95% CI: 0.06-0.61), respectively. CONCLUSION: Re-screening with the FIT should not be recommended for at least 5 years for average-risk patients after colonoscopy without high-risk neoplasms, because the risks of colorectal cancer are low in such patients.

The Requirements for Additional Strength Biowaivers for Immediate Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

In relation to the registration of generic products, waivers of in vivo bioequivalence studies (biowaivers) are considered in three main cases: certain dosage forms for which bioequivalence is self-evident (e.g. intravenous solutions), biowaivers based on the Biopharmaceutics Classification System and biowaivers for additional strengths with respect to the strength for which in vivo bioequivalence has been shown. The objective of this article is to describe the differences and commonalities in biowaivers for additional strengths of immediate release solid oral dosage forms between the participating members of the International Pharmaceutical Regulators Program (IPRP). The requirements are based on five main aspects; the pharmacokinetics of the drug substance, the manufacturing process, the qualitative and quantitative composition of the different strengths, and the comparative dissolution profiles. For the pharmacokinetic aspects, many regulators/agencies have the same requirements. All strengths must be manufactured with the same process, although a few regulators/agencies accept small differences. In relation to the formulation aspects, the data required breaks down into three major approaches based initially on one of those of the EU, the USA or Japan, but there are some differences in these three major approaches with some country specific interpretations. Most regulators/agencies also have the same requirements for the dissolution data, though there are some notable exceptions.

A Survey of the Regulatory Requirements for the Acceptance of Foreign Comparator Products by Participating Regulators and Organizations of the International Generic Drug Regulators Programme.

The acceptance of foreign comparator products is the most limiting factor for the development and regulatory assessment of generic medicines marketed globally. Bioequivalence studies have to be repeated with the local comparator products of each jurisdiction because it is unknown if the comparators of the different countries are the same product, with the consequent duplication of efforts by regulators and industry alike. The regulatory requirements on the acceptability of foreign comparator products of oral dosage forms differ between countries participating in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme. Brazil, Colombia, the European Union member States, Japan, Mexico, South Korea and the United States only accept bioequivalence studies with their local comparator. In contrast, Australia, Canada, New Zealand, Singapore, South Africa, Switzerland and Taiwan accept studies with foreign comparators under certain conditions. Canada limits its use to highly soluble drugs with a wide therapeutic range in immediate release products. Australia requires a comparison of the quantitative composition. In contrast, there are fewer restrictions on the acceptance of foreign comparators in New Zealand, Singapore, South Africa, Switzerland and Taiwan. For the WHO Prequalification of Medicines and for developing generics of the essential medicines the WHO lists comparators from different countries. In conclusion, there is currently no consensus amongst regulators on the acceptability of foreign comparator products.

[Cooperation between Clinics and Hospitals Using a Critical Path for G-CSF Prophylaxis in Cancer Chemotherapy].

BACKGROUND: Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011. METHODS: We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital. RESULTS: Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%). CONCLUSION: Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.

A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme.

PURPOSE: The Biopharmaceutics Classification System (BCS) based biowaiver is a scientific model which enables the substitution of in vivo bioequivalence studies with in vitro data as evidence of therapeutic equivalence subject to certain conditions. Despite being based on the same principles, BCS-based biowaivers are interpreted and regulated differently among international regulatory agencies. In this survey, the Bioequivalence Working Group (BEWG) of the International Generic Drug Regulators Programme (IGDRP) compared the criteria for BCS-based biowaivers applied by the participating regulators and organisations. METHODS: Differences and similarities regarding solubility, permeability, dissolution, excipients and fixed-dose combination products, were identified and compared in a detailed survey of each participant's criteria for BCS-based biowaivers. These criteria were determined based upon the participants' respective regulatory guidance documents, policies and practices. RESULTS: This review has, with the exception of two participants who do not accept BCS-based biowaivers, revealed that most IGDRP participants interpret the BCS principles and conditions similarly but notable differences exist in the application of these principles.  Conclusion: Although many similarities exist, this review identifies several opportunities for greater convergence of regulatory requirements amongst the surveyed jurisdictions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

A prospective study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in malignant lymphoma patients following highly emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a troublesome issue in chemotherapy for cancer patients. A second-generation 5HT3 receptor antagonist (5HT3RA), palonosetron, is effective and safe for the prevention of CINV in breast cancer patients treated with cyclophosphamide and anthracycline, but there is little data for malignant lymphoma. We conducted a prospective phase 2 study at a single institution to clarify the efficacy and safety of palonosetron in lymphoma patients. METHODS: Chemotherapy-naïve lymphoma patients who were treated with highly emetogenic chemotherapy (HEC) received a single intravenous bolus of palonosetron, 0.75 mg/body, before chemotherapy on day 1 during the first course of chemotherapy. The occurrence of CINV was assessed using the Multinational Association for Supportive Care in Cancer (MASCC) antiemesis tool, which was recorded by patients during the first course of chemotherapy. RESULTS: A total of 59 patients were enrolled, and 49 patients were eligible and evaluated. The complete response (CR) rate was 93.9% (95% confidence interval 83.1-98.7%) at 0-120 h post-chemotherapy. The proportion of patients who developed nausea of any grade and vomiting at 0-120 h post-chemotherapy was 34.7 and 6.1%, respectively. Although treatment-related adverse events were observed in 36 (73.5%) patients, these were mild and they recovered by the next cycle of chemotherapy. CONCLUSION: The present study demonstrated that a single dose of palonosetron was highly effective and safe for the prevention of CINV in lymphoma patients.

Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis.

OBJECTIVES: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. METHODS: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 - erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. RESULTS: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. CONCLUSION: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

Examination time as a quality indicator of screening upper gastrointestinal endoscopy for asymptomatic examinees.

BACKGROUND AND AIM: The significance of examination time of esophagogastroduodenoscopy (EGD) for asymptomatic examinees is yet to be established. We aimed to clarify whether endoscopists who allot more examination time can detect higher numbers of neoplastic lesions among asymptomatic examinees. METHODS: We reviewed a database of consecutive examinees who underwent EGD in our hospital from April 2010 to September 2015. Staff endoscopists were classified into fast, moderate, and slow groups based on the mean examination time of EGD without a biopsy. Neoplastic lesion detection rate among these groups was compared using multiple logistic regression. RESULTS: Of the 55 786 consecutive examinees who underwent EGD, 15 763 asymptomatic examinees who were screened by staff doctors were analyzed. Mean examination time of 13 661 EGD without biopsy was 6.2 min (range, 2-18 min). When cut-off times of 5 and 7 min were used, four endoscopists were classified into the fast (mean duration, 4.4 ± 1.0 min), 12 into the moderate (6.1 ± 1.4 min), and four into the slow (7.8 ± 1.9 min) groups. Neoplastic lesion detection rates in the fast, moderate, and slow groups were 0.57% (13/2288), 0.97% (99/10 180), and 0.94% (31/3295), respectively. Compared with that in the fast group, odds ratios for the neoplastic lesion detection rate in the moderate and slow groups were 1.90 (95% confidence interval [CI], 1.06-3.40) and 1.89 (95% CI, 0.98-3.64), respectively. CONCLUSION: Endoscopists who do not allot adequate examination time may overlook neoplastic lesions in the upper gastrointestinal tract.

Multiple small intestinal ulcers associated with protein-losing enteropathy secondary to cholesterol crystal embolism:a case report.

A 78-year-old man with hypertension, nephrosclerosis, and angina pectoris visited his family doctor with a history of fatigue and leg edema. He had a history of percutaneous coronary intervention 5 years prior, and was taking low-dose aspirin. Blood tests revealed hypoalbuminemia, gastrointestinal 99mTc-HSA scintigraphy was positive, and alpha-1 antitrypsin clearance was high;therefore, the hypoalbuminemia was thought to be secondary to a protein-losing enteropathy. A small bowel series revealed multiple, ring-shaped, longitudinal ulcers in the ileum. Balloon-assisted enteroscopy from the anus showed severe stenosis with an ileal ulcer. Since we were not able to diagnose the ulcers, mesalazine and supplemental nutritional care were provided. Four years after the hypoalbuminemia had been diagnosed, the patient died because of pulmonary congestion secondary to renal failure. An autopsy revealed severe atherosclerosis in his aorta and multiple cholesterol embolisms in his small intestine, kidney, stomach, colon, liver, and spleen. The multiple ulcers in the small intestine were thought to be caused by cholesterol crystal embolism, which should be considered in the differential diagnosis of small intestinal ulcers in elderly men or patients after cardiovascular intervention.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine in healthy adults: a phase II, open-label, uncontrolled trial in Japan.

Two antigenically distinct B strain lineages of influenza virus have co-circulated since the mid-1980s; however, inactivated trivalent influenza vaccines contain only one B lineage. The mismatch between the circulating and vaccine lineages has been a worldwide issue. In this study, an inactivated quadrivalent influenza vaccine (QIV) candidate containing two B lineages was manufactured and its immunogenicity and safety evaluated in an open-label, uncontrolled trial. In this phase II trial, 50 subjects aged 20-64 years received two doses of QIV s.c. 1 to 4 weeks apart. Sera were collected pre- and post-vaccination and safety assessed from the first vaccination to 21 ± 7 days after the second vaccination. After the first vaccination, hemagglutination inhibition titers against each strain increased markedly; the seroconversion rate, geometric mean titer ratio and seroprotection rate being 94.0%, 24.93, and 100.0%, respectively, for the A/H1N1pdm09 strain; 94.0%, 12.47, and 98.0%, respectively, for the A/H3N2 strain; 54.0%, 4.99, and 66.0%, respectively, for B/Yamagata strain, and 72.0%, 6.23 and 80.0%, respectively, for the B/Victoria strain, thus fulfilling the criteria of the European Medical Agency's Committee for Medicinal Products for Human Use. Also, the QIV induced sufficient single radial hemolysis and neutralizing antibodies against all four vaccine strains. No noteworthy adverse events were noted. The results of this trial demonstrate that QIV is well tolerated and immunogenic for each strain, suggesting that QIV potentially improves protection against influenza B by resolving the issue of B lineage mismatch.

Pregnane X receptor and hepatocyte nuclear factor 4α polymorphisms are cooperatively associated with carbamazepine autoinduction.

OBJECTIVE: We attempted to clarify the influence of polymorphisms of nuclear receptors on carbamazepine therapy. PARTICIPANTS AND METHODS: The common polymorphisms of nuclear receptors--a tentative pregnane X receptor (PXR)*1B, hepatocyte nuclear factor 4α (HNF4α) rs2071197 (c.115+308G>A), and cytochrome P450 3A5*3 polymorphisms--were genotyped in 168 Japanese patients with epilepsy. The associations of these polymorphisms with the disposition, clinical efficacy, and incidence of adverse effects of carbamazepine treatment were retrospectively investigated in 104 patients treated with carbamazepine alone. The associations with disposition were also assessed in 64 patients treated with carbamazepine and other antiepileptic drugs, which constituted the internal replication group, and in the combined 168 patients. RESULTS: Neither polymorphism alone affected the carbamazepine disposition, but a significant interactive effect of PXR*1B and HNF4α rs2071197 polymorphisms on the concentration-to-dose (C/D) ratios was observed (P=0.027). The C/D ratios among patients with the HNF4α G/G genotype were higher in PXR*1B carriers than in PXR*1B noncarriers, which was confirmed in the internal replication and combined groups. In patients with the HNF4α G/G genotype, the rate of freedom from seizures until 3 months after starting carbamazepine therapy was significantly greater and the time required to reach the dose required for seizure freedom was shorter in PXR*1B carriers than in PXR*1B noncarriers. CONCLUSION: These results suggest that PXR*1B, in combination with HNF4α rs2071197, might be associated with the C/D ratios and the duration to reach the maintenance dose of carbamazepine therapy, thus indicating an influence upon the autoinduction of the carbamazepine metabolism.

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.

Risk of neutropenia in psoriasis patients prescribed anti-IL-23 antibody in comparison with anti-IL-17 antibody or adalimumab based on real-world data from the MID-NET® in Japan.

BACKGROUND: To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. METHOD: We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/µL) or grade 3 (neutrophil count < 1,000/µL) neutropenia. RESULTS: Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia. CONCLUSION: No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.

Characterization of the plastidic phosphate translocators in the inducible crassulacean acid metabolism plant Mesembryanthemum crystallinum.

In plant Mesembryanthemum crystallinum, which has the inducible crassulacean acid metabolism (CAM), isoforms of plastidic phosphate translocators (pPTs) are categorized into three subfamilies: the triose phosphate/phosphate translocator (McTPT1), the phosphoenolpyruvate/phosphate translocator (McPPT1), and the glucose 6-phosphate/phosphate translocator (McGPT1 and McGPT2). In order to elucidate the physiological roles of these pPTs in M. crystallinum, we determined the substrate specificity of each pPT isoform. The substrate specificities of McTPT1, McPPT1, and McGPT1 showed overall similarities to those of orthologs that have been characterized. In contrast, for glucose 6-phosphate, McGPT2 showed higher selectivity than McGPT1 and other GPT orthologs. Because the expression of McGTP2 is specific to CAM while that of McGTP1 is constitutively expressed in both the C3- and the CAM-state in M. crystallinum, we propose that McGPT2 functions as a CAM system-specific GPT in this plant.