Population Pharmacokinetic Model and Dosing Simulation of Meropenem Using Measured Creatinine Clearance for Patients with Sepsis.

PURPOSE: Creatinine clearance (CCr) and pharmacokinetic parameters are markedly affected by pathophysiological changes in patients with sepsis. However, only a few reports have assessed renal function in patients with sepsis using the measured CCr. Furthermore, the administration regimen has not been sufficiently evaluated using a population PK (PPK) model across renal function broad ranges. Therefore, this study was performed to construct a meropenem PPK model for patients with sepsis using the measured CCr and evaluate the optimized meropenem dosing regimen based on the CCr. METHODS: Patients with sepsis who received intravenous meropenem at the Showa University Hospital were enrolled in this prospective observational study. The PPK model was constructed using blood samples and clinical information of patients. The probability of target attainment (PTA) indicates the likelihood of achieving 50% time above the minimum inhibitory concentration (% T > MIC) based on 10,000 virtual patients using Monte Carlo simulations. The PTA for each meropenem regimen was 50% T > MIC based on different renal functions using the Monte Carlo simulation. RESULTS: One hundred samples were collected from 31 patients. The final PPK model incorporating the measured CCr as a covariate in CL displayed the best fit. The recommended dosing regimen to achieve a PTA of 50% T > MIC of 4 mcg/mL was 1 g every 8 hours as a 3-hour prolonged infusion for patients with CCr 85-130 mL/min and 1 g every 8 hours as an 8-hour continuous infusion for patients with CCr ≥ 130 mL/min. CONCLUSIONS: This model precisely predicted meropenem concentrations in patients with sepsis by accurately evaluating renal function using the measured CCr. Extended dosing was demonstrated to be necessary to achieve a PTA of 50% T > MIC for patients with CCr ≥ 85 mL/min. Meropenem effectiveness can be maximized in patients with sepsis by selecting the appropriate dosing regimen based on renal function and the MIC.

Periodontal tissue engineering using an apatite/collagen scaffold obtained by a plasma- and precursor-assisted biomimetic process.

BACKGROUND AND OBJECTIVES: In the treatment of severe periodontal destruction, there is a strong demand for advanced scaffolds that can regenerate periodontal tissues with adequate quality and quantity. Recently, we developed a plasma- and precursor-assisted biomimetic process by which a porous collagen scaffold (CS) could be coated with low-crystalline apatite. The apatite-coated collagen scaffold (Ap-CS) promotes cellular ingrowth within the scaffold compared to CS in rat subcutaneous tissue. In the present study, the osteogenic activity of Ap-CS was characterized by cell culture and rat skull augmentation tests. In addition, the periodontal tissue reconstruction with Ap-CS in a beagle dog was compared to that with CS. METHODS: The plasma- and precursor-assisted biomimetic process was applied to CS to obtain Ap-CS with a low-crystalline apatite coating. The effects of apatite coating on the scaffold characteristics (i.e., surface morphology, water absorption, Ca release, protein adsorption, and enzymatic degradation resistance) were assessed. Cyto-compatibility and the osteogenic properties of Ap-CS and CS were assessed in vitro using preosteoblastic MC3T3-E1 cells. In addition, we performed in vivo studies to evaluate bone augmentation and periodontal tissue reconstruction with Ap-CS and CS in a rat skull and canine furcation lesion, respectively. RESULTS: As previously reported, the plasma- and precursor-assisted biomimetic process generated a low-crystalline apatite layer with a nanoporous structure that uniformly covered the Ap-CS surface. Ap-CS showed significantly higher water absorption, Ca release, lysozyme adsorption, and collagenase resistance than CS. Cell culture experiments revealed that Ap-CS was superior to CS in promoting the osteoblastic differentiation of MC3T3-E1 cells while suppressing their proliferation. Additionally, Ap-CS significantly promoted (compared to CS) the augmentation of the rat skull bone and showed the potential to regenerate alveolar bone in a dog furcation defect. CONCLUSION: Ap-CS fabricated by the plasma- and precursor-assisted biomimetic process provided superior promotion of osteogenic differentiation and bone neoformation compared to CS.

[Japanese Guideline for Traumatic Intracranial Hypotension:Interpretation and Current Situation].

Since the 2000s, "intracranial hypotension syndrome associated with trauma" has become a social problem in relation to litigation and compensation issues in Japan. To address this problem, guidelines for correct diagnosis have been developed. The basic pathogenesis of this disease is cerebrospinal fluid leakage caused by fragile tissue injury due to trauma. In order to improve the treatment outcome of this disease, it is important to prove the CSF leakage directly, using diagnostic imaging based on the guidelines, rather than diagnosing it based on clinical manifestations alone. For management, an epidural blood patch(EBP)should be used only after careful consideration. As such, rest and adequate fluid replacement should generally be given first. However, in cases with concomitant subdural hematoma, the order of hematoma irrigation and EBP should be determined according to the condition and urgency of each patient. In addition, it is necessary to standardize the formal name of this condition in papers to ensure rigorous academic discussion.

Pharmacokinetics and lung distribution of macrolide antibiotics in sepsis model rats.

Recent studies have shown azithromycin-specific clinical efficacy against macrolide-resistant strains of Streptococcus pneumoniae, despite the low susceptibility of the bacteria in vitro. This discrepancy complicates dosing and selection for treatment of macrolide-resistant strains. Although phagocyte delivery of azithromycin to inflamed tissues is considered a possible factor for clinical efficacy, there is a lack of sufficient evidence, and other pharmacokinetic factors under systemic inflammation may contribute.The concentrations of azithromycin, clarithromycin and erythromycin in the plasma and buffy coat were determined in normal and sepsis model rats. Furthermore, we compared the transport of the drug into the lung.The levels of all three macrolides in the buffy coat were higher than the levels in the plasma, and lower leukocyte counts in plasma were observed in septic rats, suggesting accumulation of the drugs per leukocyte was increased. The concentrations in the lung tissue of septic rats at each sampling time were the same as those in normal rats, and azithromycin-specific long-term stasis in the lung was evident.These results suggest that both the phagocyte delivery and the stasis of azithromycin in the lung could contribute to its clinical efficacy in treating infections caused by macrolide-resistant strains.

[Quality Control of Medical Instruments and Cleaning Water].

PURPOSE: Herein we aimed to investigate the degradation of surgical instruments in our hospital and how water quality affects the rate of metal corrosion. MATERIALS AND METHODS: We observed 279 stainless steel instruments, and determined the presence of damage like metal corrosion or scale formation. We also measured the concentrations of chloride(Cl-)and silicate(SiO44-)ions in the water used for cleaning in our operating rooms, including tap water from the city water supply and reverse-osmosis(RO)filtered water. RESULT: Pitting corrosion was observed on 71% of the instruments we investigated. The concentration of Cl- was 0.7mg/L in tap water and 0.1mg/L in RO water, while the concentration of SiO44- was 0.3mg/L in both the tap and RO water. DISCUSSION: Of the dissolved ions Cl- and SiO44-, Cl- is more of a concern, as it causes pitting corrosion over time, while SiO44- causes scale formation. Considering the typical water quality in the operating-room environment, degradation must be monitored for the general maintenance of metal surgical instruments.

Non-Markovian Quantum-Classical Ratchet for Ultrafast Long-Range Electron-Hole Separation in Condensed Phases.

In organic photovoltaic systems, a photogenerated molecular exciton in the donor domain dissociates into a hole and an electron at the donor-acceptor heterojunction, and subsequently separates into free charge carriers that can be extracted as photocurrents. The recombination of the once-separated electron and hole is a major loss mechanism in photovoltaic systems, which controls their performance. Hence, efficient photovoltaic systems need built-in ratchet mechanisms, namely, ultrafast charge separation and retarded charge recombination. In order to obtain insight into the internal working of the experimentally observed ultrafast long-range charge separation and protection against charge recombination, we theoretically investigate a potential ratchet mechanism arising from the combination of quantum delocalization and its destruction by performing numerically accurate quantum-dynamics calculations on a model system. We demonstrate that the non-Markovian effect originating from the slow polaron formation strongly suppresses the electron-transfer reaction back to the interfacial charge-transfer state stabilized at the donor-accepter interface and that it plays a critical role in maintaining the long-range electron-hole separation.

Quantum heat current under non-perturbative and non-Markovian conditions: Applications to heat machines.

We consider a quantum system strongly coupled to multiple heat baths at different temperatures. Quantum heat transport phenomena in this system are investigated using two definitions of the heat current: one in terms of the system energy and the other in terms of the bath energy. When we consider correlations among system-bath interactions (CASBIs)-which have a purely quantum mechanical origin-the definition in terms of the bath energy becomes different. We found that CASBIs are necessary to maintain the consistency of the heat current with thermodynamic laws in the case of strong system-bath coupling. However, within the context of the quantum master equation approach, both of these definitions are identical. Through a numerical investigation, we demonstrate this point for a non-equilibrium spin-boson model and a three-level heat engine model using the reduced hierarchal equations of motion approach under the strongly coupled and non-Markovian conditions. We observe the cyclic behavior of the heat currents and the work performed by the heat engine, and we find that their phases depend on the system-bath coupling strength. Through consideration of the bath heat current, we show that the efficiency of the heat engine decreases as the strength of the system-bath coupling increases, due to the CASBI contribution. In the case of a large system-bath coupling, the efficiency decreases further if the bath temperature is increased, even if the ratio of the bath temperatures is fixed, due to the discretized nature of energy eigenstates. This is also considered to be a unique feature of quantum heat engines.

[A Patient with Sinking Skin Flap Syndrome who Underwent Perfusion MRI before and after Cranioplasty].

Background:Sinking skin flap syndrome(SSFS)manifests as subjective symptoms, such as headache, dizziness, and undue fatigability, in addition to neurologic symptoms, such as hemiplegia, aphasia, and perceived failure, when the skin over a bone defect sinks in the weeks or months following a decompressive craniectomy. Indeed, these symptoms can improve after a cranioplasty. Case presentation:A 58-year-old woman presented with a disturbance of consciousness. She was found to have a subarachnoid hemorrhage due to a ruptured right middle cerebral artery aneurysm. She underwent a craniotomy with clipping of the affected artery and a decompressive craniectomy on the same day. Post-operatively, the disturbance of consciousness improved, but the left-sided paralysis persisted. She complained of intractable headaches, was disoriented, and a lack of spontaneity emerged as the skin over the bone defect sank. She underwent cranioplasty on the 43rd day after admission, and the symptoms resolved promptly after surgery. Rehabilitation was canceled at the onset of symptoms, but resumed after the symptoms improved. Based on perfusion MRI, the cerebral blood flow(CBF):cerebral blood volume(CBV)ratio of the affected side increased before and after surgery compared with the healthy side. A lumboperitoneal shunt was placed on the 52nd day after admission to manage the hydrocephalus. She was discharged from the hospital with higher brain dysfunction and a mild state of paralysis. Conclusion:The timing of cranioplasty in patients with SSFS has not yet been established, but surgery should be performed before symptoms appear because SSFS impairs rehabilitative efforts.

Quantum heat transport of a two-qubit system: Interplay between system-bath coherence and qubit-qubit coherence.

We consider a system consisting of two interacting qubits that are individually coupled to separate heat baths at different temperatures. The quantum effects in heat transport are investigated in a numerically rigorous manner with a hierarchial equations of motion (HEOM) approach for non-perturbative and non-Markovian system-bath coupling cases under non-equilibrium steady-state conditions. For a weak interqubit interaction, the total system is regarded as two individually thermostatted systems, whereas for a strong interqubit interaction, the two-qubit system is regarded as a single system coupled to two baths. The roles of quantum coherence (or entanglement) between the two qubits (q-q coherence) and between the qubit and bath (q-b coherence) are studied through the heat current calculated for various strengths of the system-bath coupling and interqubit coupling for high and low temperatures. The same current is also studied using the time convolutionless (TCL) Redfield equation and using an expression derived from the Fermi golden rule (FGR). We find that the HEOM results exhibit turnover behavior of the heat current as a function of the system-bath coupling strength for all values of the interqubit coupling strength, while the results obtained with the TCL and FGR approaches do not exhibit such behavior, because they do not possess the capability of treating the q-b and q-q coherences. The maximum current is obtained in the case that the q-q coherence and q-b coherence are balanced in such a manner that coherence of the entire heat transport process is realized. We also find that the heat current does not follow Fourier's law when the temperature difference is very large, due to the non-perturbative system-bath interactions.

Periodontal tissue regeneration by recombinant human collagen peptide granules applied with ß-tricalcium phosphate fine particles.

OBJECTIVES: Recombinant human collagen peptide (RCP) is a recombinantly created xeno-free biomaterial enriched in arginine-glycine-aspartic acid sequences with good processability whose use for regenerative medicine applications is under investigation. The biocompatibility and osteogenic ability of RCP granules combined with ß-tricalcium phosphate (TCP) submicron particles (ß-TCP/RCP) were recently demonstrated. In the present study, ß-TCP/RCP was implanted into experimental periodontal tissue defects created in beagles to investigate its regenerative effects. METHODS: An RCP solution was lyophilized, granulated, and thermally cross-linked into particles approximately 1 mm in diameter. ß-TCP dispersion (1 wt%; 500 µL) was added to 100 mg of RCP granules to form ß-TCP/RCP. A three-walled intrabony defect (5 mm × 3 mm × 4 mm) was created on the mesial side of the mandibular first molar and filled with ß-TCP/RCP. RESULTS: A micro-computed tomography image analysis performed at 8 weeks postoperative showed a significantly greater amount of new bone after ß-TCP/RCP grafting (2.2-fold, P < 0.05) than after no grafting. Histological findings showed that the transplanted ß-TCP/RCP induced active bone-like tissue formation including tartaric acid-resistant acid phosphatase- and OCN-positive cells as well as bioabsorbability. Ankylosis did not occur, and periostin-positive periodontal ligament-like tissue formation was observed. Histological measurements performed at 8 weeks postoperative revealed that ß-TCP/RCP implantation formed 1.7-fold more bone-like tissue and 2.1-fold more periodontal ligament-like tissue than the control condition and significantly suppressed gingival recession and epithelial downgrowth (P < 0.05). CONCLUSIONS: ß-TCP/RCP implantation promoted bone-like and periodontal ligament-like tissue formation, suggesting its efficacy as a periodontal tissue regenerative material.

Single-photon emission computed tomography (SPECT) predicted neurological prognosis in heat stroke: A case report.

Heat stroke may cause multi-organ dysfunction and death. Some patients with neurological abnormalities in the acute phase have neurological sequelae, particularly cerebellar ataxia, in the recovery phase. However, there is no method to predict the neurological prognosis, and the usefulness of imaging has not yet been established. We report the case of an 86-year-old woman with dementia brought to our emergency department in a coma and hyperthermia. The patient was diagnosed with heat stroke and promptly treated in the ICU but remained unconscious. The patient gained consciousness on day 19, but difficulty with stillness associated with cerebellar ataxia in her right upper extremity became apparent. On day 1, head magnetic resonance imaging (MRI) showed no obvious abnormality. However, on day 6, high-signal areas, suggestive of edema, were seen in the bilateral cerebellar hemispheres. Single-photon emission computed tomography (SPECT) on day 9 revealed significant hypoperfusion in the right cerebellum. These changes improved at the time of hospital discharge. This was a case of persistent cerebellar ataxia due to heat stroke, in which imaging findings improved over time. In most cases, MRI findings do not match clinical symptoms. However, the low cerebral blood flow in the early SPECT images was consistent with the clinical symptoms. MRI may not be a prognostic indicator; however, SPECT images may be useful for predicting sequelae.

Benign noninfectious subcutaneous emphysema with minor injury: A case report.

Posttraumatic subcutaneous emphysema, which can be benign and noninfectious, is associated with necrotizing fasciitis. Rarely, extensive emphysema occurs after a minor traumatic injury. A 23-year-old man came to our hospital with extensive emphysema, ranging from the left hand to the axilla, after a minor injury. Necrotizing fasciitis was suspected. Based on the blood and imaging tests, necrotizing fasciitis was not actively suspected. He was admitted and observed for one day, and he was discharged the following day. The mechanism by which air can enter through a small injury is unclear, but the one-way ball-valve mechanism is the most commonly proposed explanation. The nontraumatic causes of non-infectious subcutaneous emphysema include insect bites, skin biopsies, and the use of shock absorbers. Since it developed from a minor wound, other mechanisms, aside from the one-way ball-valve, were possibly involved. Based on the imaging results of this case, the air was predominantly distributed in the subcutaneous tissue along the neurovascular bundle. The relatively sparse tissue likely caused the extensive subcutaneous emphysema. While evaluating post-traumatic subcutaneous emphysema, benign and noninfectious cases should be differentiated to prevent unnecessary therapeutic intervention.

Antibiotic Impregnation, Release, Activity, and Interaction With Porous Hydroxyapatite for Infectious Control in Neurotrauma Surgery.

We demonstrated the antibiotic impregnation and release properties of four porous hydroxyapatite (HAp) materials with 40% or 50% porosity and different pore structures for infectious control in neurotrauma surgery. The antibiotics used were meropenem (MEPM), ceftriaxone sodium hydrate (CTRX), gentamicin sulfate (GM), and linezolid (LZD). Greater amounts of antibiotics could be impregnated into each HAp material by increasing the volume of the antibiotics using a simple impregnation method for 15 min at atmospheric pressure. Each material showed two antibiotic release patterns based on the type of antibiotic and their interaction with the material. The first was non-reactive release of MEPM and LZD, which plateaued on day 2 after an initial burst; the second was reactive release of CTRX and GM, which showed a two-phase release comprising an initial burst followed by sustained release from day 2. Almost all eluates showed antibacterial activity against Staphylococcus aureus, suggesting that any combination of materials and antibiotics examined can be used to prevent intraoperative infection during surgery. Notably, CTRX and GM, which showed sustained release for several days, may also be useful for infected cases, including control of wound infection around 48 h postoperatively.

Repeated hypocalcemia in a patient with "Hikikomori" following veganism.

Calcium absorption; Vitamin D deficiency; Lack of sunlight; Hikikomori; Vegan.

Ultrasonic irrigation of periodontal pocket with surface pre-reacted glass-ionomer (S-PRG) nanofiller dispersion improves periodontal parameters in beagle dogs.

OBJECTIVES: Surface pre-reacted glass-ionomer (S-PRG) nanofiller, an antibacterial ion-releasing bioactive glass, has been shown to adhere to tooth surfaces and reported to improve inflammatory parameters in experimental periodontitis. In this study, cementum substrate was irrigated ultrasonically with dispersion to examine in-vitro nanofiller adhesion and antibacterial activity. Moreover, periodontal pockets in a beagle dog were ultrasonically irrigated with dispersion to assess periodontal healing. METHODS: The morphology of human cementum irrigated with S-PRG nanofiller dispersion was examined by scanning electron microscopy and energy dispersive X-ray spectrometry. The antibacterial activity of the treated cementum was tested using Actinomyces naeslundii. In addition, experimentally formed periodontal pockets in beagle dog were ultrasonically irrigated with S-PRG nanofiller dispersion. Periodontal parameters (gingival index, bleeding on probing, probing pocket depth, and clinical attachment level) were measured from baseline (0 weeks) through 12 weeks. Moreover, the effects of irrigation with S-PRG nanofiller on changes in periodontal microflora and bone healing were analyzed. RESULTS: After ultrasonic irrigation, S-PRG nanofiller adhered to the cementum and exhibited antibacterial activity. The periodontal parameters were shown to improve following ultrasonic irrigation with S-PRG nanofiller dispersion. Analysis by next-generation sequencing revealed that the ratio of red-complex species decreased in the pockets irrigated with S-PRG nanofiller dispersion. In addition, the S-PRG nanofiller showed the potential to promote bone healing. CONCLUSIONS: Ultrasonic irrigation with S-PRG nanofiller dispersion using an ultrasonic scaler system permitted delivery of the S-PRG nanofiller to the root surface, providing improved parameters in experimental periodontitis and modifying the composition of subgingival periodontal microflora.

Corrigendum to "Repeated hypocalcemia in a patient with "Hikikomori" following veganism" [Heliyon 8 (6), (July 2022), Article e09563].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09563.].

Sustained antibacterial coating with graphene oxide ultrathin film combined with cationic surface-active agents in a wet environment.

Antimicrobial surfactants contained in mouthrinse have excellent efficacy, but are not retained on the tooth surface (are rinsed away) due to their low water resistance and thus do not exhibit sustained antibacterial activity. We have developed a new coating method using graphene oxide (GO) that retains the surfactant on the tooth surface even after rinsing with water, thus providing a sustained antibacterial effect. Ultra-thin films of GO and an antimicrobial agent were prepared by (1) applying GO to the substrate surface, drying, and thoroughly rinsing with water to remove excess GO to form an ultrathin film (almost a monolayer, transparent) on the substrate surface, then (2) applying antimicrobial cationic surface active agents (CSAAs) on the GO film to form a composite coating film (GO/CSAA). GO/CSAA formation was verified by scanning electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and ζ-potential and contact angle measurements. GO/CSAA was effective at inhibiting the growth of oral pathogens for up to 7 days of storage in water, and antibacterial activity was recovered by reapplication of the CSAA. Antibacterial GO/CSAA films were also formed on a tooth substrate. The results suggest that GO/CSAA coatings are effective in preventing oral infections.

High-throughput identification and determination of aminoglycoside antibiotics in human plasma using UPLC-Q-ToF-MS.

Aminoglycosides are a class of broad-spectrum antibiotics with several clinical uses. Owing to the ototoxicity and nephrotoxicity of aminoglycosides, therapeutic drug monitoring is required. This study aimed to devise a high-throughput method for identification and quantitative determination of aminoglycoside antibiotics in human plasma samples using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q-ToF-MS). Plasma samples (100 µL) spiked with five aminoglycosides (streptomycin, spectinomycin, amikacin, kanamycin, and gentamycin) and an internal standard (ribostamycin) were diluted and centrifuged in aqueous formic acid and acetonitrile. The clear supernatant extract was evaporated and reconstituted in the mobile phase, of which 4 µL was subjected to UPLC-Q-ToF-MS. Prominent peaks were observed for the drugs within 3 min. The recoveries of five aminoglycosides from plasma samples were 92.6-120%. The regression equations showed excellent linearity (0.9999 ≥ r2 ≥ 0.9987) within the range of 1.0-100 µg/mL, and detection limits of 0.5-2.0 µg/mL. The coefficients of the intra- and inter-day variations for five drugs were less than 11.8%, while the accuracy of quantitation was in the range of 89-111%. In this study, a novel method was presented for identification and determination of aminoglycosides in human plasma samples using UPLC-Q-ToF-MS analysis. This method can be applied to high-throughput analysis used for clinical and environmental purposes.

Atmospheric impregnation behavior of calcium phosphate materials for antibiotic therapy in neurotrauma surgery.

As part of a verification model of antibiotic therapy in cranioplasty, we evaluated the impregnation efficiency of interporous calcium phosphate materials with saline under atmospheric pressure and compared it to the efficiency of using the decompression method established by the Japanese Industrial Standard, under which pressure is reduced by 10 kPa. Five types of material formed in 1 mL cubes were selected as test samples: two consisting of hydroxyapatite (HAp) with 85% and 55% porosity and three of ß-tricalcium phosphate (ß-TCP) with 75%, 67%, and 57% porosity. All test samples showed an impregnation ratio of more than 70%, except for the HAp sample with 55% porosity, which had a ratio of approximately 50%. These high ratios were achieved at only 15 min. The impregnation effects were likely dependent on porosity and were independent of base material, either HAp or ß-TCP. Obtaining sufficient impregnation and antimicrobial efficacy in materials with low porosity, which are commonly used in cranioplasty, would require an increased volume of antibiotics rather than increased duration of impregnation. Our findings will enable the simple preparation of drug-impregnated calcium phosphate materials, even in operating rooms not equipped with a large decompression device.