Risk factors for bleeding complications in patients undergoing extracorporeal cardiopulmonary resuscitation following out-of-hospital cardiac arrest: a secondary analysis of the SAVE-J II study.

BACKGROUND: Bleeding is the most common complication in out-of-hospital cardiac arrest (OHCA) patients receiving extracorporeal cardiopulmonary resuscitation (ECPR). No studies comprehensively described the incidence rate, timing of onset, risk factors, and treatment of bleeding complications in OHCA patients receiving ECPR in a multicenter setting with a large database. This study aimed to analyze the risk factors of bleeding during the first day of admission and to comprehensively describe details of bleeding during hospitalization in patients with OHCA receiving ECPR in the SAVE-J II study database. METHODS: This study was a secondary analysis of the SAVE-J II study, which is a multicenter retrospective registry study from 36 participating institutions in Japan in 2013-2018. Adult OHCA patients who received ECPR were included. The primary outcome was the risk factor of bleeding complications during the first day of admission. The secondary outcomes were the details of bleeding complications and clinical outcomes. RESULTS: A total of 1,632 patients were included. Among these, 361 patients (22.1%) had bleeding complications during hospital stay, which most commonly occurred in cannulation sites (14.3%), followed by bleeding in the retroperitoneum (2.8%), gastrointestinal tract (2.2%), upper airway (1.2%), and mediastinum (1.1%). These bleeding complications developed within two days of admission, and 21.9% of patients required interventional radiology (IVR) or/and surgical interventions for hemostasis. The survival rate at discharge of the bleeding group was 27.4%, and the rate of favorable neurological outcome at discharge was 14.1%. Multivariable logistic regression analysis showed that the platelet count (< 10 × 104/µL vs > 10 × 104/µL) was significantly associated with bleeding complications during the first day of admission (adjusted odds ratio [OR]: 1.865 [1.252-2.777], p = 0.002). CONCLUSIONS: In a large ECPR registry database in Japan, up to 22.1% of patients experienced bleeding complications requiring blood transfusion, IVR, or surgical intervention for hemostasis. The initial platelet count was a significant risk factor of early bleeding complications. It is necessary to lower the occurrence of bleeding complications from ECPR, and this study provided an additional standard value for future studies to improve its safety.

Dietary Zinc Deficiency Induces Cav3.2-Dependent Nociceptive Hypersensitivity in Mice.

Cav3.2 channels belong to the T-type calcium channel (T-channel) family, i.e., low voltage-activated calcium channels, and are abundantly expressed in the nociceptors, playing a principal role in the development of pathological pain. The channel activity of Cav3.2 is suppressed by zinc under physiological conditions. We thus tested whether dietary zinc deficiency would cause Cav3.2-dependent nociceptive hypersensitivity in mice. In the mice fed with zinc deficient diet for 2 weeks, plasma zinc levels declined by more than half, and mechanical allodynia developed. The dietary zinc deficiency-induced allodynia was restored by T-channel inhibitors or by Cav3.2 gene silencing. These data demonstrate that zinc deficiency induces Cav3.2-dependent nociceptive hypersensitivity in mice, thereby suggesting that pain experienced by patients with diseases accompanied by zinc deficiency (e.g., chronic kidney disease) might involve the increased Cav3.2 activity.

Cav3.2-dependent hyperalgesia/allodynia following intrathecal and intraplantar zinc chelator administration in rodents.

Cav3.2, a T-type calcium channel (T-channel) family member, is expressed in the nociceptors and spinal cord, and its activity is largely suppressed by zinc under physiological conditions. In rats, intrathecal and intraplantar administration of a zinc chelator, TPEN, caused T-channel-dependent mechanical hyperalgesia, and the intraplantar, but not intrathecal, TPEN induced Cav3.2 upregulation in the dorsal root ganglion. In mice, intraplantar TPEN also caused mechanical allodynia, which was abolished by T-channel inhibitors or Cav3.2 gene deletion. Together, spinal and peripheral zinc deficiency appears to enhance Cav3.2 activity in the spinal postsynaptic neurons and nociceptors, respectively, thereby promoting pain.

[A Case of Thrombocytopenia Following Minocycline Administration].

Drug-induced thrombocytopenia is associated with bleeding tendency and suggests the need for the immediate suspected drug withdrawal. Patients with drug-induced thrombocytopenia usually experience an acute drop in platelet (PLT) levels a week or two after starting a new medication. Thrombocytopenia has both immune and non-immune mechanisms. Minocycline (MINO)-induced thrombocytopenia is rare; thus, there are few studies of this condition. In the present study, intravenous administration of MINO led to thrombocytopenia. The female patient was 80 years old. She was receiving radiation therapy for tongue cancer and medication for pain control. She had fever and aspiration pneumonia and was being treated with an antibacterial drug. Empiric therapy consisting of intravenous administration of tazobactam/piperacillin was performed; however, inflammation and fever did not improve. The bacterial drug was changed to vancomycin and cefmetazole. Sputum culture was positive for Enterobacter cloacae thus, we changed her treatment to MINO. Seven days after starting MINO, PLT levels were low; however, they recovered when treatment was stopped. Our findings suggest that MINO may rarely cause severe thrombocytopenia; thus, it is necessary to observe the patient's blood collection.

Deprescribing as an Opportunity to Facilitate Patient-Centered Care: A Qualitative Study of General Practitioners and Pharmacists in Japan.

Deprescribing has recently been applied to address polypharmacy, particularly among older adults. However, the characteristics of deprescribing that are likely to improve health outcomes have not been well studied. This study explored the experiences and perspectives of general practitioners and pharmacists with regard to deprescribing in older adults with multimorbidity. A qualitative study was conducted involving eight semi-structured focus group interviews with 35 physicians and pharmacists from hospitals, clinics, and community pharmacies. Thematic analysis was applied to identify themes using the theory of planned behavior as a guide. The results illustrated a metacognitive process, as well as influencing factors, through which healthcare providers commit to shared decision making for deprescribing. Healthcare providers acted on the basis of their attitudes and beliefs on deprescribing, the influence of subjective norms, and perceived behavioral control for deprescribing. These processes are influenced by factors such as drug class, prescribers, patients, deprescribing experience, and environment/education. Healthcare providers' attitudes, beliefs, and behavioral control (along with deprescribing strategies) evolve in a dynamic interplay with experience, environment, and education. Our results can serve as a foundation for the development of effective patient-centered deprescribing to improve the safety of pharmaceutical care for older adults.

Association between health literacy and multimorbidity: a nationwide, cross-sectional study of a Japanese population.

OBJECTIVES: To examine the relationship between health literacy and multimorbidity. DESIGN: Nationwide cross-sectional study. SETTING: Community settings across Japan. PARTICIPANTS: Community-dwelling participants aged 20 years or older were selected based on a quota sampling method that adjusted for age, sex and residential area. In total, 3678 participants from the Health Diary Study, with a mean age of 52.3 years (SD, 18.2 years; 1943 (52.8%) female participants), were included. PRIMARY OUTCOME MEASURE: Multimorbidity, the primary outcome measure, was defined as the presence of two or more chronic diseases. RESULTS: Of the 3678 participants, 824 (22.4%) had multimorbidity. The mean functional health literacy (FHL) and communicative and critical health literacy (CCHL) scores were 3.2 (SD, 0.7) and 3.6 (SD, 0.9), respectively. In the univariable analysis, both scores were associated with multimorbidity (p<0.001). However, in the multivariable modified Poisson regression analysis, only the FHL score was significantly associated with multimorbidity (per 1-point increase, 0.91; 95% CI 0.84 to 0.99). CONCLUSIONS: After adjusting for confounding variables, FHL, not CCHL, was significantly related to the presence of multimorbidity. Further longitudinal studies are required to examine the causal relationship between health literacy and multimorbidity.

Caspase-Dependent HMGB1 Release from Macrophages Participates in Peripheral Neuropathy Caused by Bortezomib, a Proteasome-Inhibiting Chemotherapeutic Agent, in Mice.

Given the role of macrophage-derived high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel, we analyzed the role of HMGB1 and macrophages in the CIPN caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent used for the treatment of multiple myeloma. Repeated administration of bortezomib caused CIPN accompanied by early-stage macrophage accumulation in the dorsal root ganglion. This CIPN was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alfa capable of accelerating thrombin-dependent degradation of HMGB1, antagonists of the receptor for advanced glycation end-products (RAGE) and C-X-C motif chemokine receptor 4 (CXCR4), known as HMGB1-targeted membrane receptors, or macrophage depletion with liposomal clodronate, as reported in a CIPN model caused by paclitaxel. In macrophage-like RAW264.7 cells, bortezomib as well as MG132, a well-known proteasome inhibitor, caused HMGB1 release, an effect inhibited by caspase inhibitors but not inhibitors of NF-κB and p38 MAP kinase, known to mediate paclitaxel-induced HMGB1 release from macrophages. Bortezomib increased cleaved products of caspase-8 and caused nuclear fragmentation or condensation in macrophages. Repeated treatment with the caspase inhibitor prevented CIPN caused by bortezomib in mice. Our findings suggest that bortezomib causes caspase-dependent release of HMGB1 from macrophages, leading to the development of CIPN via activation of RAGE and CXCR4.

Factors associated with the accomplishment of home death among patients receiving physician-led home healthcare.

AIM: To evaluate unique factors associated with home death in older Asian individuals who received physician-led home healthcare. METHODS: We carried out a case-control study at a single hospital in Japan from February 2018 to December 2019. We included patients who had started receiving physician-led home healthcare and died at home as cases, and those receiving the same type of care but died in the hospital as controls. Multivariable logistic regression was used to evaluate factors associated with home death. RESULTS: A total of 152 patients (mean age 70.3 years [SD 11.2 years]; 86 [56.6%] men) were included, of whom 89 (58.6%) died at home and 63 (41.4%) died in the hospital. Comparing the two groups, the presence of family psychological problems related to care was significantly more common in the hospital death group (home death 49.4%; hospital death 32.3%, P = 0.036). Home death was related to patients aged >85 years compared with patients aged <75 years (adjusted odds ratio 6.47, 95% CI 1.52-27.48) and patients who were in the highest quartile of the number of symptoms (adjusted odds ratio 5.45, 95% CI 1.15-25.95) compared with the lowest. Family members' willingness for the patient to die at home was associated with home death (adjusted odds ratio 7.47, 95% CI 2.13-26.19). CONCLUSIONS: Older age and multiple symptoms were related to accomplishing home death. Patient preference was not associated with the place of death, but family member preference was. These results might reflect family concepts particular to Asia. Geriatr Gerontol Int 2021; 21: 525-531.

Cav3.2 overexpression in L4 dorsal root ganglion neurons after L5 spinal nerve cutting involves Egr-1, USP5 and HMGB1 in rats: An emerging signaling pathway for neuropathic pain.

Overexpression of Cav3.2 T-type Ca2+ channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Cav3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Cav3.2, and ubiquitin-specific protease 5 (USP5) that protects Cav3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Cav3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Cav3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Cav3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Cav3.2 overexpression and neuropathy.

Direct and indirect costs of home healthcare in Japan: A cross-sectional study.

To tackle the rising healthcare expenditure in an ageing society in Japan, home healthcare has been promoted over the past several years. However, there is a dearth of literature on total costs incurring for home healthcare. In this study, we conducted a cross-sectional study among patients, who received home healthcare in the month of May, 2018. Direct healthcare costs and patients' clinical characteristics were collected from medical records and long-term care databases (n = 166). Indirect costs were estimated using a questionnaire survey which obtained information on job absenteeism and care time from the caregiver. A total of 112 patients responded to the survey. The median age was 82 years (interquartile range: 74-88). Total per-person per month home-care costs averaged USD 6,163 with direct costs (USD 2,547) and indirect costs (USD 3,596) accounted for 41.3% and 58.3% of the total costs, respectively. The largest components of direct costs were long-term care costs (48%) and medical costs (47%). Multivariable adjusted model showed that those with heavy healthcare were more likely to incur higher total as well as direct and indirect home healthcare cost (p<.05 for each). Patients aged >75 years (p = .041) were less likely and those who used oxygen at home were more likely to incur direct home healthcare cost (p = .001) than their counterpart. Our study findings show that indirect cost is a major contributor to total home healthcare costs in Japan. Also for patients who need heavy healthcare, both direct and indirect costs are large burden.

Critical role of Cav3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice.

Bortezomib, a first-line agent for treatment of multiple myeloma, exhibits anticancer activity through proteasome inhibition. However, bortezomib-induced peripheral neuropathy (BIPN) is one of the most serious side effects. Since decreased proteasomal degradation of Cav3.2 T-type calcium channels in the primary afferents is involved in persistent pain, we investigated whether BIPN involves increased protein levels of Cav3.2 in mice. Six repeated i.p. administrations of bortezomib for 12 days developed persistent mechanical allodynia. Systemic administration of novel T-type calcium channel blockers, (2R/S)-6-prenylnaringenin and KTt-45, and of TTA-A2, the well-known blocker, reversed the BIPN. Ascorbic acid, known to block Cav3.2, but not Cav3.1 or 3.3, and silencing of Cav3.2 gene also suppressed BIPN. Protein levels of Cav3.2 in the dorsal root ganglion (DRG) at L4-L6 levels increased throughout days 1-21 after the onset of bortezomib treatment. Protein levels of USP5, a deubiquitinating enzyme that specifically inhibits proteasomal degradation of Cav3.2, increased in DRG on days 3-21, but not day 1, in bortezomib-treated mice. In DRG-derived ND7/23 cells, bortezomib increased protein levels of Cav3.2 and T-channel-dependent currents, as assessed by a patch-clamp method, but did not upregulate expression of Cav3.2 mRNA or USP5 protein. MG-132, another proteasome inhibitor, also increased Cav3.2 protein levels in the cultured cells. Given the previous evidence for USP5 induction following nociceptor excitation, our data suggest that BIPN involves the increased protein levels of Cav3.2 in nociceptors through inhibition of proteasomal degradation of Cav3.2 by bortezomib itself and then by USP5 that is upregulated probably in an activity-dependent manner.

Are the kind of medications and patient's background associated with improving polypharmacy in elderly?

BACKGROUND: Polypharmacy is associated with negative outcomes in older population. Managing polypharmacy is important but there is no definite method for regulating it. Our aim was to evaluate what medications and patient's background are associated with reducing polypharmacy. METHODS: A prospective, single-center, cohort study was conducted from June to October in 2016. Participants were 65 and older hospitalized patients. We evaluated the difference between the numbers of medications used at the time of admission and discharge for individual drug class. Univariate analyses using paired t tests were applied to evaluate reduction in prescription medications, and logistic regression was used to evaluate factors for any reduction of prescription medications used at discharge. RESULTS: There were 494 subjects, and the mean of age was 79.6 ± 7.8 years. The mean number of medications used at admission was 6.9 ± 4.7 and that at discharge was 6.8 ± 4.3. The types of medications that reduced between admission and discharge were drugs for functional gastrointestinal disorders and agents acting on the renin-angiotensin system, etc. Individual components that were strongly associated with a reduction of the number of medications used were only length of hospital stay (OR 0.99, 95% CI, 0.99-1.0), while the number of medications on admission was related to increasing medication during hospitalization (OR 1.05, 95% CI, 1.01-1.06). CONCLUSIONS: Most of the kinds and the number of medications prescribed might not be changed during hospitalization despite those were probably the causes of admission. The factor associated with improvements in polypharmacy was length of hospital stay.

Zinc deficiency promotes cystitis-related bladder pain by enhancing function and expression of Cav3.2 in mice.

Cav3.2 T-type Ca2+ channel activity is suppressed by zinc that binds to the extracellular histidine-191 of Cav3.2, and enhanced by H2S that interacts with zinc. Cav3.2 in nociceptors is upregulated in an activity-dependent manner. The enhanced Cav3.2 activity by H2S formed by the upregulated cystathionine-γ-lyase (CSE) is involved in the cyclophosphamide (CPA)-induced cystitis-related bladder pain in mice. We thus asked if zinc deficiency affects the cystitis-related bladder pain in mice by altering Cav3.2 function and/or expression. Dietary zinc deficiency for 2 weeks greatly decreased zinc concentrations in the plasma but not bladder tissue, and enhanced the bladder pain/referred hyperalgesia (BP/RH) following CPA at 200mg/kg, a subeffective dose, but not 400mg/kg, a maximal dose, an effect abolished by pharmacological blockade or gene silencing of Cav3.2. Acute zinc deficiency caused by systemic N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylendiamine (TPEN), a zinc chelator, mimicked the dietary zinc deficiency-induced Cav3.2-dependent promotion of BP/RH following CPA at 200mg/kg. CPA at 400mg/kg alone or TPEN plus CPA at 200mg/kg caused Cav3.2 overexpression accompanied by upregulation of Egr-1 and USP5, known to promote transcriptional expression and reduce proteasomal degradation of Cav3.2, respectively, in the dorsal root ganglia (DRG). The CSE inhibitor, ß-cyano-l-alanine, prevented the BP/RH and upregulation of Cav3.2, Egr-1 and USP5 in DRG following TPEN plus CPA at 200mg/kg. Together, zinc deficiency promotes bladder pain accompanying CPA-induced cystitis by enhancing function and expression of Cav3.2 in nociceptors, suggesting a novel therapeutic avenue for treatment of bladder pain, such as zinc supplementation.

Enhanced Hyperthermic Responses to Lipopolysaccharide in Mice Exposed to Repeated Cold Stress.

Lipopolysaccharide (LPS) induces hyperthermia accompanied by various other systemic inflammatory symptoms. The rodents exposed to repeated cold (RC) stress according to a specific schedule are useful as experimental models for autonomic imbalance or fibromyalgia. It is now proven that RC-stressed mice exhibit tolerance to LPS, we examined thermal responses to LPS challenge in RC-stressed mice by monitoring core temperature using the telemetry system. Systemic administration of LPS caused bimodal hyperthermic responses in RC-stressed and unstressed mice. The magnitude of the LPS-induced hyperthermia was greater in RC-stressed mice than in unstressed mice. The RC stress-induced enhancement of hyperthermic responses to LPS was abolished by pretreatment with diclofenac, which is a cyclooxygenase (COX) inhibitor. LPS did not significantly increase COX-2 protein levels in the lung or hypothalamus of RC-stressed or unstressed mice. RC stress did not alter baseline serum corticosterone levels or their increases in response to LPS challenge. These results suggest that RC stress enhances the susceptibility of mice to LPS challenge, leading to greater prostanoid-dependent hyperthermia, which might contribute to tolerance to LPS in RC-stressed mice.

Therapeutic potential of RQ-00311651, a novel T-type Ca2+ channel blocker, in distinct rodent models for neuropathic and visceral pain.

T-type Ca channels (T channels), particularly Cav3.2 among the 3 isoforms, play a role in neuropathic and visceral pain. We thus characterized the effects of RQ-00311651 (RQ), a novel T-channel blocker, in HEK293 cells transfected with human Cav3.1 or Cav3.2 by electrophysiological and fluorescent Ca signaling assays, and also evaluated the antiallodynic/antihyperalgesic activity of RQ in somatic, visceral, and neuropathic pain models in rodents. RQ-00311651 strongly suppressed T currents when tested at holding potentials of -65 ∼ -60 mV, but not -80 mV, in the Cav3.1- or Cav3.2-expressing cells. RQ-00311651 also inhibited high K-induced Ca signaling in those cells. In mice, RQ, administered intraperitoneally (i.p.) at 5 to 20 mg/kg or orally at 20 to 40 mg/kg, significantly suppressed the somatic hyperalgesia and visceral pain-like nociceptive behavior/referred hyperalgesia caused by intraplantar and intracolonic administration of NaHS or Na2S, H2S donors, respectively, which involve the enhanced activity of Cav3.2 channels. RQ-00311651, given i.p. at 5 to 20 mg/kg, exhibited antiallodynic or antihyperalgesic activity in rats with spinal nerve injury-induced neuropathy or in rats and mice with paclitaxel-induced neuropathy. Oral and i.p. RQ at 10 to 20 mg/kg also suppressed the visceral nociceptive behavior and/or referred hyperalgesia accompanying cerulein-induced acute pancreatitis and cyclophosphamide-induced cystitis in mice. The analgesic and antihyperalgesic/antiallodynic doses of oral and i.p. RQ did not significantly affect the locomotor activity and motor coordination. Together, RQ is considered a state-dependent blocker of Cav3.1/Cav3.2 T channels and may serve as an orally available analgesic for treatment of neuropathic and inflammatory pain including distinct visceral pain with minimum central side effects.

Mechanisms for proteinase-activated receptor 1-triggered prostaglandin E2 generation in mouse osteoblastic MC3T3-E1 cells.

We analyzed signaling mechanisms for prostaglandin E2 (PGE2) production following activation of proteinase-activated receptor-1 (PAR1), a thrombin receptor, in preosteoblastic MC3T3-E1 cells. PAR1 stimulation caused PGE2 release, an effect suppressed by inhibitors of COX-1, COX-2, iPLA2, cPLA2, MAP kinases (MAPKs), Src, EGF receptor (EGFR) tyrosine kinase (EGFR-TK) and matrix metalloproteinase (MMP), but not by an intracellular Ca2+ chelator or inhibitors of PI3 kinase, protein kinase C (PKC) and NF-κB. PAR1 activation induced phosphorylation of MAPKs and upregulation of COX-2. The phosphorylation of p38 MAPK was suppressed by inhibitors of Src and EGFR-TK. The COX-2 upregulation was dependent on ERK, p38, EGFR-TK, Src, and COX-2 itself. PAR1 activation also induced MEK-dependent phosphorylation of cAMP response element binding protein (CREB). All inhibitors of EP1, EP2, EP3 and EP4 receptors suppressed the PAR1-triggered PGE2 release. Exogenously applied PGE2 facilitated PAR1-triggered COX-2 upregulation, but it alone had no effect. Together, the PAR1-mediated PGE2 production in MC3T3-E1 cells appears to involve iPLA2 and cPLA2 for arachidonic acid release, and the MEK/ERK/CREB and Src/MMP/EGFR/p38 pathways for COX-2 upregulation, which is facilitated by endogenous PGE2 formed by COX-2. These signaling mechanisms might underlie the role of the thrombin/PAR1/PGE2 system in the early stage of the bone healing.