Associations of coprescribed medications for chronic comorbid conditions in very old adults with clinical dementia: a retrospective cohort study using insurance claims data.

OBJECTIVE: To assess the association of coprescribed medications for chronic comorbid conditions with clinical dementia in older adults, as indicated by the initiation of a new prescription of antidementia medication (NPADM). DESIGN: Retrospective enumeration cohort study. SETTING: A Japanese city in Tokyo Metropolitan Area. PARTICIPANTS: A total of 42 024 adults aged ≥77 years residing in Kashiwa City, a suburban city of Tokyo Metropolitan Area, who did not have any prscription of antidementia medication from 1 April to 30 June 2012. MAIN OUTCOME MEASURE: The primary outcome was NPADM during follow-up period until 31 March 2015 (35 months). Subjects were categorised into four age groups: group 1 (77-81 years), group 2 (82-86 years), group 3 (87-91 years) and group 4 (≥92 years). In addition to age and sex, 14 sets of medications prescribed during the initial background period (from 1 April 2012 and 31 June 2012) were used as covariates in a Cox proportional hazard model. RESULTS: In a follow-up period of 1 345 457 person-months (mean=32.0±7.5 months, median 35 months), NPADM occurred in 2365 subjects. NPADM incidence at 12 months was 1.9%±0.1% (group 1: 0.9%±0.1%, group 2: 2.1%±0.1%, group 3: 3.2%±0.2% and group 4: 3.6%±0.3%; p<0.0001). In addition to older age and female sex, use of the following medications was significantly associated with NPADM: statins (HR: 0.82, 95% CI 0.73 to 0.92; p=0.001), antihypertensives (HR: 0.80, 95% CI 0.71 to 0.85; p<0.0001), non-steroidal bronchodilators (HR: 0.72, 95% CI 0.58 to 0.88; p=0.002), antidepressants (HR: 1.79, 95% CI 1.47 to 2.18; p<0.0001), poststroke medications (HR: 1.45, 95% CI 1.16 to 1.82; p=0.002), insulin (HR: 1.34, 95% CI 1.01 to 1.78; p=0.046) and antineoplastics (HR: 1.12, 95% CI 1.01 to 1.24; p=0.035). CONCLUSIONS: This retrospective cohort study identified the associations of coprescribed medications for chronic comorbid conditions with NPADM in older adults. These findings would be helpful in understanding the current clinical practice for dementia in real-world setting and potentially contribute to healthcare policymaking. TRIAL REGISTRATION NUMBER: UMIN000039040.

Designation Products: Boron Neutron Capture Therapy for Head and Neck Carcinoma.

The Japanese Ministry of Health, Labour and Welfare approved a drug called borofalan (10 B), a treatment system, and a dose calculation program for boron neutron capture therapy (BNCT) in March 2020. The application pertaining to the products submitted to the Pharmaceuticals and Medical Devices Agency was supported by a Japanese, open-label, uncontrolled trial (Study 002) in patients with unresectable, locally recurrent head and neck squamous cell carcinoma after chemoradiotherapy or radiotherapy, or in those with unresectable locally advanced or locally recurrent (LA/LR) head and neck nonsquamous cell carcinoma. The drug was administered as a single intravenous dose using infusion rates of 200 mg/kg per hour for the first 2 hours after the start of administration and 100 mg/kg per hour during irradiation. Neutron irradiation was performed using the devices at a single dose of 12 Gy-equivalent for oral, pharyngeal, or laryngeal mucosa for up to 60 minutes from 2 hours after the start of drug administration. The primary endpoint was the overall response rate (ORR). The results of Study 002 showed that the ORR based on an assessment of the Independent Central Review Committee per RECIST version 1.1 was 71.4% (90% confidence interval [CI], 51.3%-86.8%). The lower limit of the 90% CI exceeded the prespecified threshold for ORR. When BNCT is applied to patients with unresectable LA/LR head and neck cancer, precautions should be taken, and patients should be monitored for possible onset of dysphagia, brain abscess, skin disorder, crystal urine, cataract, and/or carotid hemorrhage. IMPLICATIONS FOR PRACTICE: Borofalan (10 B), a treatment system and a dose calculation program for boron neutron capture therapy (BNCT), demonstrated significant efficacy in an open-label, uncontrolled trial in which overall response rate was the primary endpoint for patients with unresectable locally advanced or locally recurrent head and neck cancer. Although no information about survival benefits was obtained, BNCT will become an effective treatment option that is expected to manage local lesions that are intractable with any standard therapy. In addition, BNCT is expected to maintain quality of life of the intended patient population, on account of its high tumor selectivity and low invasiveness.

TGF-ß-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche.

Hematopoietic stem and progenitor cells (HSPCs) reside in the supportive stromal niche in bone marrow (BM); when needed, however, they are rapidly mobilized into the circulation, suggesting that HSPCs are intrinsically highly motile but usually stay in the niche. We questioned what determines the motility of HSPCs. Here, we show that transforming growth factor (TGF)-ß-induced intracellular plasminogen activator inhibitor (PAI)-1 activation is responsible for keeping HSPCs in the BM niche. We found that the expression of PAI-1, a downstream target of TGF-ß signaling, was selectively augmented in niche-residing HSPCs. Functional inhibition of the TGF-ß-PAI-1 signal increased MT1-MMP-dependent cellular motility, causing a detachment of HSPCs from the TGF-ß-expressing niche cells, such as megakaryocytes. Furthermore, consistently high motility in PAI-1-deficient HSPCs was demonstrated by both a transwell migration assay and reciprocal transplantation experiments, indicating that intracellular, not extracellular, PAI-1 suppresses the motility of HSPCs, thereby causing them to stay in the niche. Mechanistically, intracellular PAI-1 inhibited the proteolytic activity of proprotein convertase Furin, diminishing MT1-MMP activity. This reduced expression of MT1-MMP in turn affected the expression levels of several adhesion/deadhesion molecules for determination of HSPC localization, such as CD44, VLA-4, and CXCR4, which then promoted the retention of HSPCs in the niche. Our findings open up a new field for the study of intracellular proteolysis as a regulatory mechanism of stem cell fate, which has the potential to improve clinical HSPC mobilization and transplantation protocols.

Antipsychotic medication and cognitive function in schizophrenia.

Antipsychotic polypharmacy and excessive dosing still prevail worldwide in the treatment of schizophrenia, while their possible association with cognitive function has not well been examined. We examined whether the "non-standard" use of antipsychotics (defined as antipsychotic polypharmacy or dosage >1,000 mg/day of chlorpromazine equivalents) is associated with cognitive function. Furthermore, we compared cognitive function between patients taking only atypical antipsychotics and those taking only conventionals. Neurocognitive functions were assessed in 67 patients with chronic schizophrenia and 92 controls using the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Wisconsin Card Sorting Test (WCST), and the Advanced Trail Making Test (ATMT). Patients showed markedly poorer performance than controls on all these tests. Patients on non-standard antipsychotic medication demonstrated poorer performance than those on standard medication on visual memory, delayed recall, performance IQ, and executive function. Patients taking atypical antipsychotics showed better performance than those taking conventionals on visual memory, delayed recall, and executive function. Clinical characteristics such as duration of medication, number of hospitalizations, and concomitant antiparkinsonian drugs were different between the treatment groups (both dichotomies of standard/non-standard and conventional/atypical). These results provide evidence for an association between antipsychotic medication and cognitive function. This association between antipsychotic medication and cognitive function may be due to differential illness severity (e.g., non-standard treatment for severely ill patients who have severe cognitive impairment). Alternatively, poorer cognitive function may be due in part to polypharmacy or excessive dosing. Further investigations are required to draw any conclusions.

Isoform-specific effect of apolipoprotein E on endocytosis of beta-amyloid in cultures of neuroblastoma cells.

Investigation of the interactions of nerve cells with human apolipoprotein E (apoE), beta-amyloid (Abeta), and their complex, which are known to be included in senile plaques, is necessary to clarify the functional role of apoE in the pathogenesis of Alzheimer's disease. Using flow cytometric analysis, we investigated the isoform-specific effects of apoE on the endocytosis of Abeta in cultured neuroblastoma cells. The level of internalized Abeta within the cells was dependent on the culture time and the kind of apoE isoform present. Both apoE3 and apoE4 enhanced the internalization of Abeta; however, no difference was observed between their effects. The internalized Abeta was hardly catabolized at all in the presence of apoE4, while rapid clearance of Abeta was observed in the presence of apoE3. Unlike apoE3 and apoE4, apoE2 had no effect on Abeta clearance from the media. The isoform-specific effects of apoE on the endocytosis of Abeta may be implicated in the development of Alzheimer's disease, and if so, each isoform of apoE would induce a different incidence of that disease.