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Background. Opioids contribute to more than 60 000 deaths annually in North America. While the expansion of overdose education and naloxone distribution (OEND) programs has been recommended in response to the opioid crisis, their effectiveness remains unclear. Objectives. To conduct an umbrella review of systematic reviews to provide a broad-based conceptual scheme of the effect and feasibility of OEND and to identify areas for possible optimization. Search Methods. We conducted the umbrella review of systematic reviews by searching PubMed, Embase, PsycINFO, Epistemonikos, the Cochrane Database of Systematic Reviews, and the reference lists of relevant articles. Briefly, an academic librarian used a 2-concept search, which included opioid subject headings and relevant keywords with a modified PubMed systematic review filter. Selection Criteria. Eligible systematic reviews described comprehensive search strategies and inclusion and exclusion criteria, evaluated the quality or risk of bias of included studies, were published in English or French, and reported data relevant to either the safety or effectiveness of OEND programs, or optimal strategies for the management of opioid overdose with naloxone in out-of-hospital settings. Data Collection and Analysis. Two reviewers independently extracted study characteristics and the quality of included reviews was assessed in duplicate with AMSTAR-2, a critical appraisal tool for systematic reviews. Review quality was rated critically low, low, moderate, or high based on 7 domains: protocol registration, literature search adequacy, exclusion criteria, risk of bias assessment, meta-analytical methods, result interpretation, and presence of publication bias. Summary tables were constructed, and confidence ratings were provided for each outcome by using a previously modified version of the Royal College of General Practitioners’ clinical guidelines. Main Results. Six systematic reviews containing 87 unique studies were included. We found that OEND programs produce long-term knowledge improvement regarding opioid overdose, improve participants’ attitudes toward naloxone, provide sufficient training for participants to safely and effectively manage overdoses, and effectively reduce opioid-related mortality. High-concentration intranasal naloxone (> 2 mg/mL) was as effective as intramuscular naloxone at the same dose, whereas lower-concentration intranasal naloxone was less effective. Evidence was limited for other naloxone formulations, as well as the need for hospital transport after overdose reversal. The preponderance of evidence pertained persons who use heroin. Author’s Conclusions. Evidence suggests that OEND programs are effective for reducing opioid-related mortality; however, additional high-quality research is required to optimize program delivery. Public Health Implications. Community-based OEND programs should be implemented widely in high-risk populations.

Background: Aerosol therapy is used to deliver medical therapeutics directly to the airways to treat respiratory illnesses. A potential side-effect of this form of treatment is the release of fugitive aerosols into the environment and the exposure of caregivers, other patients, and bystanders to potential viral infections. The aim of this work was to use both flow visualisation and aerosol particle characterisation techniques to study the dispersion, concentrations and size distributions of fugitive aerosols emitted during aerosol therapy delivered via a standard mouthpiece.Methods: Aerosol therapy was delivered via a nebuliser, aerosol holding chamber and mouthpiece to a spontaneously breathing adult patient model that could mimic the release of patient-derived bioaerosol. A combination of laser and Schlieren imaging were used to non-invasively visualise the release and dispersion of fugitive aerosol particles. Time varying aerosol particle number concentrations and size distributions were measured with optical particle sizers at clinically relevant positions. Results: The addition of a capture filter to the expiratory port of the mouthpiece significantly reduced the release and spread of fugitive aerosols. Capture filters were effective in curtailing the release of fugitive aerosols of respirable size, ≤ 5 µm in diameter (P ≤ 0.05). Conclusions: The findings suggest that, where possible, capture filters should be added to the expiratory ports of all aerosol therapy devices to prevent airborne transmission of respiratory illnesses and create safer conditions for healthcare workers and patients.

Advances in the development of anti-tumour drugs and related technologies have resulted in a significant increase in the number of cancer survivors. However, the incidence of chemotherapy-induced cardiotoxicity (CIC) has been rising continuously, threatening their long-term survival. The integration of nanotechnology and biomedicine has brought about an unprecedented technological revolution and has promoted the progress of anti-tumour therapy. In this review, we summarised the possible mechanisms of CIC, evaluated the role of nanoparticles (including liposomes, polymeric micelles, dendrimers, and hydrogels) as drug carriers in preventing cardiotoxicity and proposed five advantages of nanotechnology in reducing cardiotoxicity: Liposomes cannot easily penetrate the heart's endothelial barrier; optimized delivery strategies reduce distribution in important organs, such as the heart; targeting the tumour microenvironment and niche; stimulus-responsive polymer nano-drug carriers rapidly iterate; better economic benefits were obtained. Nanoparticles can effectively deliver chemotherapeutic drugs to tumour tissues, while reducing the toxicity to heart tissues, and break through the dilemma of existing chemotherapy to a certain extent. It is important to explore the interactions between the physicochemical properties of nanoparticles and optimize the highly specific tumour targeting strategy in the future.

Docosahexaenoic acid (DHA) shows anti-inflammatory/proresolution effects in the brain. Higher red blood cell (RBC) DHA in humans is associated with improved cognitive performance and a lower risk for suicide. Here, we hypothesized that binding to the 18 kDa translocator protein (TSPO), a proxy for microglia levels, will be higher in individuals with low DHA relative to high DHA levels. We also postulated that higher TSPO would predict poor cognitive performance and impaired stress resilience.RBC DHA screening was performed in 320 healthy males. [sup11/supC]PBR28 positron emission tomography was used to measure binding to TSPO in 38 and 32 males in the lowest and highest RBC DHA quartiles. Volumes of distribution expressed relative to total plasma ligand concentration (VsubT/sub) was derived using an arterial input function-based kinetic analysis in 14 brain regions.[sup11/supC]PBR28 VsubT/subwas significantly lower (by 12% and 20% in C/T and C/C rs6971 genotypes) in males with low RBC DHA than in males with high RBC DHA. Regional VsubT/subwas correlated positively and negatively with RBC DHA and serum triglycerides, respectively. No relationships between VsubT/suband cognitive performance or stress resilience measures were present.Contrary to our hypothesis, we found lower TSPO binding in low-DHA than in high-DHA subjects. It is unclear as to whether low TSPO binding reflects differences in microglia levels and/or triglyceride metabolism in this study. Future studies with specific targets are necessary to confirm the effect of DHA on microglia. These results underscore the need to consider lipid parameters as a factor when interpreting TSPO positron emission tomography clinical findings.

Background: Colorectal peritoneal carcinomatosis (CRPC) is a primary cause of death in colorectal cancer (CRC) patients. In the past, computed tomography (CT) has been the primary method used to ev...

Background: The Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) is a validated patient-reported outcome measure that evaluates subjective cosmetic and functional complaints. The goa...

Background: Vitexin is the main bioactive compound of hawthorn (Crataegus pinnatifida), a famous traditional Chinese medicine, and vitexin for injection is currently in phase I clinical trial in China. Objective: This investigation systematically evaluated the metabolism and toxicokinetics of vitexin in rats and dogs. Methods: Rats and beagle dogs were administrated different doses of vitexin, and then the plasma concentration, tissue distribution, excretion, metabolism, pharmacokinetics and plasma protein binding were investigated. Results : The elimination half-life (t1/2) values in rats after a single intravenous dose of 3, 15 and 75 mg/kg were estimated as 43.53±10.82, 22.86±4.23, and 21.17±8.64 min, and the values of the area under the plasma concentration-time curve (AUC0→∞) were 329.34±144.07, 974.79±177.27, and 5251.49±786.98 mg•min/L, respectively. The plasma protein binding rate in rats was determined as about 65% by equilibrium dialysis after 72 hr. After 24 hr of intravenous administration, 16.30%, 3.47% and 9.72% of the given dose were excreted in urine, feces and bile, respectively. The metabolites of the vitexin were hydrolyzed via deglycosylation. The pharmacokinetics of dogs after intravenous administration revealed t1/2, AUC0-∞ and mean residence time (MRT0-∞) values of 20.43±6.37 min, 227.96±26.68 mg•min/L and 17.12±4.33 min, respectively. The no-observed-adverse- effect level (NOAEL) was 50 mg/kg body weight/day. There was no significant accumulation effect at 8 or 20 mg/kg/day in dogs over 92 days of repeated administration. For the 50 mg/kg/- day dose group, the exposure (AUC, Cmax) decreased significantly with prolonged administration. This trend suggests that repeated administration accelerates vitexin metabolism. Conclusion: The absorption of vitexin following routine oral administration was very low. To improve the bioavailability of vitexin, the development of an injectable formulation would be a suitable alternative choice.

Background: Due to the short biological half-life and serious side effects (especially for heart and kidney), the application of Doxorubicin (Dox) in clinical therapy is strictly limited. To overcome these shortcomings, a novel sustained release formulation of doxorubicin-loaded dextran-coated superparamagnetic iron oxide nanoparticles (Dox-DSPIONs) was prepared. Objective: The purpose of this study was to evaluate the intracellular uptake behavior of Dox-DSPIONs and to investigate their pharmacokinetics and biodistribution properties. Method: Confocal laser scanning microscopy was employed to study the intracellular uptake and release properties of Dox from Dox-DSPIONs in SMMC-7721 cells. Simple high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method was established to study the pharmacokinetics and biodistribution properties of Dox-DSPIONs in vivo after intravenous administration and compared with free Dox. Results: Intracellular uptake experiment indicated that Dox could be released sustainedly from Dox-DSPIONs over time. The pharmacokinetics parameters displayed that the T1/2and AUC0-24h of Dox-DSPIONs were higher than those of free Dox, while the Cmax of Dox-DSPIONs was significantly lower than that of free drug. The biodistribution behaviors of the drug were altered by Dox-DSPIONs in mice, which showed obvious liver targeting, and significantly reduced the distribution of the drug in the heart and kidney. Conclusion: Dox-DSPIONs have the sustained-release property in vitro and in vivo, which could significantly prolong blood circulation time, improve bioavailability, and reduce the side effects of Dox. Therefore, the novel formulation of the Dox-DSPIONs has the potential as a promising drug delivery system in cancer therapy.

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4–C6 ( p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC ( p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS ( p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3–C6 ( p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3–C6 correlated with concomitant and 1-year disability ( r = −0.40/–0.62, p < 0.05, corrected). Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability.

Background: Glioma is the most aggressive and lethal tumor of the central nervous system. Due to the cellular heterogeneity, the invasiveness, and blood-brain barrier (BBB), current therapeutic approaches, such as chemotherapy and radiotherapy, are poorly to obtain great anti-tumor efficacy. However, peptides, a novel type of therapeutic agent, displayed excellent ability in the tumor, which becomes a new molecule for glioma treatment. Method: We review the current knowledge on peptides for the treatment of glioma through a PubMed-based literature search. Results: In the treatment of glioma, peptides can be used as (i) decoration on the surface of the delivery system, facilitating the distribution and accumulation of the anti-tumor drug in target site;(ii) anti-tumor active molecules, inhibiting the growth of glioma and reducing solid tumor volume; (iii) immune-stimulating factor, and it activating immune cells in the tumor microenvironment or recruiting immune cells to the tumor for breaking out the immunosuppression by glioma cells. Conclusion: The application of peptides has revolutionized the treatment of glioma, which based on targeting, penetrating, anti-tumor activities and immunostimulatory. Moreover, better outcomes have been discovered in combining different kinds of peptides rather than a single one. Until now, more and more preclinical studies have been developed with multifarious peptides, which shows promising results in vitro or vivo with the model of glioma.

Theranostic visualization of dextran at the nanoscale is beneficial for understanding the bioregulatory mechanisms of this molecule. In this study, we applied structured illumination microscopy (SIM) to capture the distribution of Cy5-Dextran at different incubation periods in living cells. The results showed that Cy5-Dextran could be absorbed by HeLa cells. In addition, we clarified that Cy5-Dextran exhibited differential organelle distribution (lysosomal or mitochondrial) in a time-dependent manner. Moreover, lysosomal Cy5-Dextran localization was found to be independent of the autophagy process, while Cy5-Dextran localized to the mitochondria triggered a pro-apoptotic event, upregulating the levels of reactive oxygen species (ROS) to accelerate mitochondrial fragmentation. This work uses a visualized strategy to reveal the anti-tumor bioactivity of dextran, which was achieved by regulating apoptosis and autophagy.

Micro abstract This large retrospective study using the data from the Surveillance, Epidemiology, and End Results found a similar distribution of 21-gene recurrence score, similar trends of chemotherapy regarding 21-gene recurrence score, and similar prognostic effect of the 21-gene recurrence score between those with Chinese and White American breast cancer. Purpose To compare the distribution, chemotherapy-decision making, and prognosis of the 21-gene recurrence score (RS) between Chinese breast cancer (BC) in the United States and White American (WA) BC. Methods We identified early-stage and estrogen receptor-positive BC patients diagnosed between 2004 and 2015. Multivariate logistic regression, Kaplan-Meier analysis, and multivariate Cox proportional hazards models were used for statistical analyses. Results A total of 67486 patients were identified, including 66215 (98.1%) WA patients and 1271 (1.9%) Chinese patients. Regarding the RS, 38894 (57.6%) had low RS, 23882 (35.4%) had intermediate RS, and 4710 (7.0%) had high RS. A similar distribution of RS was found between WA and Chinese BC (P=0.280). The race was not the predictor associated with high RS. Similar trends of chemotherapy use were found in Chinese and WA BC. In WA BC, there were 4.1%, 31.5%, and 72.2% of patients receiving chemotherapy in low, intermediate, and high RS cohorts, respectively (P Conclusion Our results demonstrate similar distribution, chemotherapy use, and outcome of the 21-gene RS between Chinese and WA BC in the United States.

Amaç: Kan dolaşımı enfeksiyonları (KDE), morbidite ve mortalitenin en önemli nedeni sayılmaktadır. Bu çalışmada, kan kültürlerinde üreyen mikroorganizmaların dağılımını ve antimikrobiyal direnç oranlarını incelemek amaçlanmıştır.Yöntem: Yakın Doğu Üniversitesi (YDÜ) Hastanesi, Mikrobiyoloji Laboratuvarı’na Ocak 2016-Aralık 2020 tarihleri arasında gönderilen 7.866 kan kültüründen izole edilen mikroorganizmalar retrospektif olarak değerlendirmeye alınmıştır. Kan kültür şişeleri BACTEC 9120 otomatize sisteminde inkübe edilmiştir. İnkübasyon sırasında pozitif sinyal elde edilmesi halinde, steril enjektörle kan kültür şişelerinin içerisinden örnek alınarak Eosin-Methylene Blue (EMB) ve %5 koyun kanlı agarlara ekimleri yapıldı. Ekimi yapılan kültürler 24-48 saat süresince 35°C’de etüvde inkübasyona bırakıldı. Üreme saptanan kültürlerdeki mikroorganizmaların identifikasyon ve antibiyotik duyarlılık testleri (ADT) için VİTEK 2 (Biomerieux) kompakt otomatize sitemi kullanıldı.Bulgular: Kan kültürlerinin 691 (%8.8)’inde üreme saptanmıştır. İzole edilen mikroorganizmaların 392 (%56.7)’sini gram negatif bakteriler, 295 (%42.7)’ini gram pozitif bakteriler ve 4 (%0.6)’ünü ise Candida türleri oluşturmaktadır. En sık izole edilen bakteriler sırasıyla; Koagülaz negatif stafilokoklar (KNS) (%21.1), E. coli (%15.2), K. pneumoniae (%11.9), Staphylococccus aureus (%11.4) idi. E. coli dağılımına bakıldığı zaman GSBL oranı 2020 yılında artış göstermiştir fakat bunun istatistiksel olarak anlamlı olmadığı anlaşılmıştır (p=0.188). GSBL pozitif K. pneumoniae türleri ise yıllar içerisinde anlamlı derecede artış göstermiş ve 2019 yılında en yüksek (%69.6) seviyeye ulaşmıştır. Pseudomonas aeruginosa için ÇİD (çoklu ilaç dirençli) oranı %13 olarak belirlenmiştir. Acinetobacter baumannii için MDR oranı ise %97 olarak bulunmuştur. Hastalarımız arasındaki metisilin dirençli Staphylococccus aureus (MRSA) oranı %30.4’dür.Sonuç: KDE’dan izole edilen mikroorganizmaların ve duyarlılıklarının en kısa sürede belirlenmesi kritik öneme sahiptir. Ayrıca, aktif sürveyans sistemleri KDE’nın yönetimine yardımcı olmaktadır., Objective: Bloodstream infections (BSI) are considered to be the most important cause of morbidity and mortality. The main purpose of this study is to examine the distribution of microorganisms in blood cultures and the rates of antimicrobial resistance.Method: Microorganisms isolated from 7.866 blood cultures which were sent to our laboratory between January 2016-December 2020 were retrospectively evaluated. Blood culture bottles were incubated in BACTEC 9120 system. Blood samples were taken from the bottles with a sterile syringe and cultured on Eosin-Methylene Blue (EMB) and 5% sheep blood agars if there was a positive signal. The cultivated cultures were left to incubate at 35°C for 24-48 hours. VITEK 2 compact automated system was used for identification and antibiotic susceptibility tests (AST).Results: Reproduction was detected in 691 (8.8%) of blood cultures. There were 56.7% gram-negative, 42.7% gram-positive bacteria and 0.6% Candida species. The most common bacteria isolated are; coagulase negative staphylococci (CNS) (21.1%), Escherichia coli (15.2%), Klebsiella pneumoniae (11.9%) and Staphylococcus aureus (11.4%). The rate of ESBL-Escherichia coli increased in 2020, but this was not statistically significant (p=0.188). ESBL-Klebsiella pneumoniae species showed a significant increase over the years and reached the highest level (69.6%) in 2019. MDR (multi drug resistance) rate for Pseudomonas aeruginosa was determined as 13%. MDR rate for Acinetobacter baumannii was determined as 97%. The rate of methicillin resistant Staphylococcus aureus among patients is 30.4%. Conclusion: It is critical to determine microorganisms and their antibiotic susceptibilities as soon as possible in BSI. Active surveillance systems help manage the BSI.

Introduction Traumatic injury elicits an inflammatory response such as the one occurring during systemic infection. Monocyte distribution width (MDW) has been found to distinguish sepsis in a pool of patients with suspected infection. We hypothesized that an elevated MDW in trauma patients would be associated with the development of multiple organ dysfunction syndrome (MODS) and an increased mortality. Materials and Methods Observational study in a dedicated trauma Intensive Care Unit (ICU) in Madrid during 2019-2020. Patients were classified according to their first MDW value on admission, as greater or lesser than 21 U. Clinical data was obtained and univariate and multivariate analysis were realized, as well as a test performance analysis. Results 354 patients were studied, with a median age of 46 years, 78% male. Half presented with severe trauma ISS > 15, mostly with a blunt mechanism of injury. A MDW ≥ 21 U on admission was found in 17% of cases. These patients were more likely to present with hemodynamic instability and MODS. They had a higher length of stay (3.8 vs 2 days) and higher mortality (21 vs 5%) compared to the low MDW group. These findings remained statistically significant in the multivariate analysis, with an OR 4.6 (IC 95% 1.7-12) for MODS and 3.1 (IC 95% 1.2-8.3) for mortality. Conclusions In trauma patients, a MDW ≥ 21 U on admission was independently associated with a greater risk of MODS, a higher mortality and a higher length of stay. This biomarker could be useful in predicting severity in the initial evaluation of trauma patients.

Human mesenchymal stem cells (hMSCs) were labeled with Dotarem or (Gd-DOTA)2- EM7 (EM7Gd2) via electroporation (EP). Cellular transmission electron microscopy (TEM) reveals free distribution of Gd agents and formation of EM7Gd2 clusters in the cytosol. Cellular magnetic resonance imaging (MRI) reveals that the free Gd agents induce MRI signal enhancement effect due to its fast exocytosis and subsequent interaction with intercellular water molecules. The EM7Gd2 clusters exhibits a longer intracellular retention time and induce a persistent MRI signal reduction effect. The cellular MRI results are interpreted by taking into account both T1 and T2 relaxation rates and their correlation with cellular binding structures of Dotarem and EM7Gd2.

Background Burden of atrial fibrillation (AF), as a continuous measure, is an emerging alternative classification often assumed to increase linearly with progression of disease. Yet there are no descriptions of AF burden distributions across populations. Methods We examined patterns of AF burden (% time in AF) across 3 different cohorts: outpatients with AF undergoing Holter monitoring in a national registry (ORBIT-AF II), routine outpatients undergoing Holter monitoring in a tertiary healthcare system (UHealth), and patients >=65 years with cardiac implantable electronic devices (Merlin.netTM linked to Medicare). Results We included 2,058 ORBIT-AF II patients, 4,537 UHealth patients, and 39,710 from Merlin.netTM. Mean age ranged from 56 to 77 years, sex ranged from 40% to 61% male, and mean CHA2DS2-VASc scores ranged from 2.2 to 4.9. Across all cohorts, AF burden demonstrated skewed frequency towards the extremes, with the vast majority of patients having either very low or very high AF burden. This bimodal distribution was consistent across cohorts, across clinically-documented AF types (paroxysmal vs. persistent), patients with or without a known AF diagnosis, and among patients with different types of cardiac implantable electronic devices. Conclusions Across 3 broad, diverse cohorts with continuous monitoring, distribution of AF burden was consistently skewed towards the extremes without an even, linear distribution or progression. As AF burden is increasingly recognized as a descriptor and potential risk-stratifier, these findings have important implications for future research and patient care.

З метою встановлення особливостей розподілу антигенів HLA-системи, їх внутрішньолокусних і міжлокусних комбінацій при виразковій хворобі дванадцятипалої кишки в дітей всім обстежуваним пацієнтам (n = 120) та особам контрольної групи (n = 100) було проведено HLA-типування генів DRB1, DQA1 і DQB1 методом сиквенс-специфічного зонда, ампліфікації з послідовність-специфічними праймерами (SSP). Виразкова хвороба асоційована зі специфічностями DRB1*11, DRB1*13, алельним варіантом DQB1*0401/02, генотипом DQB1*0301,0302 і гаплотипами DRB1*07/DQA1*0301, DRB1*13/DQA1*0501, DRB1*11/DQB1*0501, DQA1*0102/DQB1*0401/02. Специфічність DRB1*15, алельний варіант DQB1*0201, генотип DQB1*0301,0301 і гаплотипи DRB1*15/DQA1*0101, DRB1*15/DQA1*0102, DRB1*01/DQB1*0201, DRB1*15/DQB1*0301, DQA1*0101/DQB1*0201, DQA1*0201/DQB1*0201 визначають резистентність до виникнення виразкової хвороби.

Biodistribution studies of adenovirus-based vaccines support their clinical development by evaluating their spread and persistence following in vivo administration. AZD1222 (ChAdox1 nCov-19) is a replication-deficient non-human adenovirus-vectored vaccine for coronavirus disease 2019. In this nonclinical study, the biodistribution of AZD1222 was assessed in mice for 29 days following intramuscular injection. Results show that AZD1222 was safe and well tolerated, with a spread that was largely confined to administration sites and the proximal sciatic nerve, with low levels observed in sites that are involved in rapid clearance of particulates by the reticuloendothelial system. Accordingly, levels of AZD1222 decreased from Day 2 to Day 29, indicating clearance. There were no quantifiable levels of AZD1222 in the blood, brain, spinal cord, and reproductive tissue, suggesting a lack of widespread or long-term distribution of AZD1222 vector DNA throughout the body following its administration.

Cisplatin is the most widely used chemotherapeutic agent due to its efficacy in the treatment of a broad range of cancer types; while the side effects and drug resistance of cisplatin limit its clincial application. Combination therapy, which contains several types of free drugs, exhibits promising potential in clinical practice. Nevertheless, current combination chemotherapy cannot accurately deliver different drug components into a single tumor cell at the same time. Herein, we report a triple-action nanoplatinum drug based on artesunate and cantharidin to overcome the influence of pharmacokinetics and distribution variation in different drugs. The results show that the triple action nanoplatinum drug enhances ROS generation, leads to DNA damage, and inhibits DNA repair. Therefore, a high-efficiency killing effect is achieved with a triple-action platinum drug in a single tumor cell.

Introduction/Objective The diffuse axonal injury has a very important place in clinical and forensic aspects of neurotraumatology. A special challenge is proving it in situations of short survival (less than two hours) after a craniocerebral injury. The aim of this study was to determine the efficacy of beta-amyloid precursor protein (?APP) immunohistochemical staining in postmortem diagnosis of axonal injuries in head injury survival shorter than two hours, its expression, and distribution through the brain tissue of the deceased. Methods 36 adult fatalities, both sexes, injured by acceleration-deceleration mechanisms were divided into two groups: died up to two hours and died more than two hours after the injury. Immunostaining of brain tissue samples (frontal parasagittal white mass, genu and splenium of the corpus callosum and rostral pons) was used to register ?APP positivity. Data were processed by methods of descriptive and inferential nonparametric statistics, and p < 0.05 was considered statistically significant. Results The ?APP immunopositivity was shown in 88.9% of cases (82.3% of ? two hours group vs. 94.7% of > two hours group). ?APP expression was enhanced towards the posterior structures of the brain. The shortest survival period with detected ?APP immunopositivity was 20?25 minutes, in three cases. There was an association of ?APP expression in the brainstem and interhemispheric/perimesencephalic subarachnoid hemorrhage (p = 0.035). Conclusion ?APP immunohistochemical staining is effective in proving diffuse axonal injury in casualties that survived less than half an hour. Interhemispheric/perimesencephalic subarachnoid hemorrhage may indicate a more severe form of axonal injury.

KRAS‒PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (KD = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS–PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDEδ interaction.

Background The measurement of plasma concentrations of retinol binding protein is a component of nutritional assessment in neonatal intensive care. However, serial testing in newborns is hampered by the limited amount of blood that can be sampled. Limitations are most severe with preterm infants, for whom close monitoring may be most important. Methods We developed an assay to quantify retinol binding protein using trypsin digestion and liquid chromatography-tandem mass spectrometry, which requires a serum or plasma volume of 5 µl. Additionally, we validated the method according to current recommendations and performed comparison with a standard nephelometry platform in clinical use. Results The assay demonstrated linearity from below 1 mg/dL (0.48 µM) to more than 20 mg/dL (9.7 µM), and an imprecision of 11.8% at 0.43 mg/dL (0.21 µM). The distribution of results observed with the new method was different when compared with nephelometry. Conclusion Liquid chromatography-tandem mass spectrometry facilitated testing a smaller sample volume, thereby increasing the ability to monitor key nutritional markers in premature infants. The differences in results compared with a commercially-available nephelometric assay revealed questionable results for lower concentrations by immunoassay.

This study was to explore the differences in the distribution and species diversity of bacteria between hepatocellular carcinoma (HCC) tissues and normal liver tissues. 28 HCC patients treated with surgery were selected as the research objects (HCC group), and 19 healthy volunteers with normal physical examinations were included in the control group (Normal group). The tumor specimens were obtained by intraoperative and biopsy puncture, and a 16S ribosomal ribonucleic acid (rRNA) library was constructed. Based on the sequencing data obtained by the IlluminaHi Seq sequencing platform, the differences of bacteria in the liver tissues of the HCC group and the Normal group were analyzed at the level of phyla, family, and genus. The Ace, Chao1, and Shannon of the two groups were compared. The results showed that IlluminaHi Seq sequencing obtained a total of 11,714,659 valid sequences, with an average of 131,625 sequences per sample. The proportions of Bacteroidetes, Firmicutes, and Proteobacteria in HCC group and Normal group were 48.75% versus 34.16%, 37.44% versus 18.02%, and 10.85% versus 39.26%, respectively. The Bacteroidaceae, Prevotellaceae, Lachnospiraceae, and Ruminococcaceae accounted for 22.49%, 20.62%, 16.54%, and 19.93% in Normal group; while those in the HCC tissues accounted for 26.83%, 14.22%, 11.14%, and 13.18%, respectively. The dominant bacteria at the genus level in HCC group and Normal group were Bacteroides and Prevotella-9, with the proportions of 24.19% versus 26.04% and 14.19% versus 8.44%, respectively. The difference in operational taxonomic unit (OTU) numbers of HCC and Normal group were compared and analyzed, which were 1,266 and 1,082, respectively, and the number of common OTU in the two tissues was 875. The Ace in HCC tissue and normal liver tissue were 1063.8±66.79 and 1003.6±52.19, respectively. The Ace in HCC tissue was greater than that in normal liver tissue (P < 0.05). The Chao1 and Shannon in HCC tissue were 1022.9±67.74 and 5.4269±0.3608, respectively; while those in normal liver tissue were 1003.6±66.79 and 5.2842±0.9714, respectively. The Chao1 and Shannon in HCC tissues were much higher than those in Normal group (P < 0.05). It showed that there was no difference in the types of bacterial species in HCC tissues, but the proportions of their flora at the level of phyla, family, and genus changed greatly, which may be related to the occurrence of HCC. This study could provide a reference for the diagnosis and treatment of HCC.

Lead (Pb) is a well-known neurotoxicant and environmental hazard. Recent experimental evidence has linked Pb exposure with neurological deterioration leading to neurodegenerative diseases, such as Alzheimer’s disease. To understand brain regional distribution of Pb and its interaction with other metal ions, we used synchrotron micro-x-ray fluorescence technique (μ-XRF) to map the metal distribution pattern and to quantify metal concentrations in mouse brains. Lead-exposed mice received oral gavage of Pb acetate once daily for 4 weeks; the control mice received sodium acetate. Brain tissues were cut into slices and subjected for analysis. Synchrotron μ-XRF scans were run on the PETRA III P06 beamline (DESY). Coarse scans of the entire brain were performed to locate the cortex and hippocampus, after which scans with higher resolution were run in these areas. The results showed that: a) the total Pb intensity in Pb-exposed brain slices was significantly higher than in control brain; b) Pb typically deposited in localized particles of

BACKGROUND Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and increased toxicity has been described. This increased toxicity may be related to altered cisplatin distribution and binding in the fat-free body mass of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in patients with HNSCC. METHODS We performed a prospective observational study in patients with HNSCC treated with CRT. Patients received standard-of-care chemotherapy with three cycles of cisplatin at a dose of 100 mg/m2 per cycle. Quantitative data on SMM, measured on computed tomography scans and cisplatin pharmacokinetics (total and ultrafilterable plasma concentrations) were collected, as well as data on toxicity. RESULTS A total of 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose-limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and SMM, weight, fat-free mass and body surface area (p

Background Red ginseng extract boosts immunity against inflammation and cancer in the human body. However, studies on the effects of red ginseng extract on the gut microbiome remain unexplored. Methods In 2019, the positive effects and changes in the gut microbiome after administering 1 pack (3 g) of red ginseng extract per day to 53 adults aged 40 to 75 for 24 weeks were investigated. The gut microbial environment changes were qualitatively and quantitatively analyzed using next-generation sequencing and real-time polymerase chain reaction technology. Results On comparing and analyzing alpha diversity and beta diversity, the microbial pattern showed significant differences (OTUs p = 0.003, chao1 p, Graphical abstract Image 1

The major downside of conventional chemo-therapeutics is their lenient distribution in the body which brings about consequential knock-on to well cells. As out-turn, the concentration of drug extends to the tumor is bring down, ensuring suboptimal therapeutic efficacy. Non-ionic surfactant vesicles (niosome) were drawn up with a point of upgrading the therapeutic presence of the molecules of the drug by shielding the drug. Doxorubicin (DOX), an anti-cancer drug, from the biological environment, results in controlled drug delivery and better availability. Niosome were formulated by the method of conventional thin-film hydration using cholesterol and pluronic P123. Doxorubicin was enclosed in the niosome with an elevated entrapment efficiency of 88%. Their diameter was about 200 nm. The discharged drug by the vesicles was spotted to be managed and sustained for over 24 h at pH 7.4, followed by a Higuchi kinetic release mechanism. In closing, niosome might be an auspicious delivery for DOX with refined targeted drug delivery.

Background It has been observed that gluteal-femoral adipose tissue has a protective effect against risk factors for cardiovascular disease but has not yet been concluded how different evaluation methods of fat distribution affect the results. Methods To test the hypothesis that B-mode ultrasound-measured subcutaneous adipose tissue distribution is associated with cardiovascular risk factors, 326 Japanese unmedicated postmenopausal women aged 50–70 years were analyzed. Subcutaneous adipose tissue thickness at 6 sites (anterior and posterior aspects of trunk, upper-arm, and thigh) and serum total (TC) and high-density lipoprotein cholesterol (HDLC) was measured, and a ratio of HDLC to TC (HDLC/TC) was calculated. We used Bayesian linear regression with 4 separate models with each model predicting HDLC/TC. Results Our first model provided evidence for an inverse correlation (r = –0.23) between ultrasound measured body fat (6 site measurement) and HDLC/TC. The second model noted evidence for an inverse correlation between trunk fat and HDLC/TC and found evidence for the null with respect to the correlation between thigh fat and HDLC/TC. Therefore, we added thigh fat to the null model to produce Distribution Model 2. Within this model, we noted an inverse correlation (r = –0.353) between trunk fat and HDLC/TC. Our last model determined that within the trunk fatness, the abdominal area (anterior trunk) was a larger predictor than the subscapular site (posterior trunk). Conclusion These results support the evidence that ultrasound-measured abdominal subcutaneous adipose tissue thickness is a non-invasive predictor for monitoring the risk for dyslipidemia in postmenopausal women.

The heterogeneous structure that exists in virtually all hydrogels has a significant influence on the resulting strength and toughness. While the internal structure has been observed with electron microscopy, it is difficult to measure the in situ local polymer concentration in the native swollen state. In this study, a modified microelectrode technique (MET) was employed to measure the Donnan potential of a heterogeneous hydrogel with a phase-separated structure. With this method, we succeeded in observing quantitative in situ polymer concentrations ranging from 10.2 mu mol/L to several hundred mmol/L. From the obtained concentration profiles, we could successfully evaluate the internal phase-separated structure with a resolution of less than 0.8 mu m. Using MET, we could estimate the average activity coefficient of the hydrogel, and we found a difference in concentration between the dense and sparse phases. We demonstrate that MET is a powerful method that can locally and quantitatively measure the polyelectrolyte concentration distribution within hydrogels. Furthermore, this method can be applied to cells and organs in vivo due to their similarities with polyelectrolytes. Enabling the in situ determination of the internal structures of biomaterials could have important implications toward the characterization of damaged and diseased tissues on the local scale.

Background: A wide range of techniques has been developed over the past decades to characterize amyloid-β (Aβ) pathology in mice. Until now, no method has been established to quantify spatial changes in Aβ plaque deposition due to targeted delivery of substances using ALZET® pumps. Objective: Development of a methodology to quantify the local distribution of Aβ plaques after intracerebral infusion of compounds. Methods: We have developed a toolbox to quantify Aβ plaques in relation to intracerebral injection channels using Zeiss AxioVision® and Microsoft Excel® software. For the proof of concept, intracerebral stereotactic surgery was performed in 50-day-old APP-transgenic mice injected with PBS. At the age of 100 days, brains were collected for immunhistological analysis. Results: The toolbox can be used to analyze and evaluate Aβ plaques (number, size, and coverage) in specific brain areas based on their location relative to the point of the injection or the injection channel. The tool provides classification of Aβ plaques in pre-defined distance groups using two different approaches. Conclusion: This new analytic toolbox facilitates the analysis of long-term continuous intracerebral experimental compound infusions using ALZET® pumps. This method generates reliable data for Aβ deposition characterization in relation to the distribution of experimental compounds.

Background: The HIV-1 pandemic is undoubtedly the major public-health crisis of our time. The extensive research on HIV has deepened our understanding of its pathogenesis and transmission dynamics. Some new entity molecules have been approved by the FDA for HIV treatment but till now protective vaccine remains elusive. Scientists are targeting many important proteins of HIV-1; gp41, gp120, CCR5 coreceptor, integrase, reverse transcriptase and protease. Few compounds are used as nucleotide analogues to stop HIV replication. Altogether, these compounds and their derivatives specifically block HIV entry and DNA replication. Using ADMET studies, people are working on these compounds to reduce toxicity and increase potency. Objective: Our main aim is to discuss the Pharmacokinetics properties of 23 important FDA antiretroviral drugs used for the treatment of HIV-1 infections. Methods: We have searched literature related to pharmacokinetics properties in PubMed, Google Scholar search engine. Conclusion: Here, we have reviewed the pharmacokinetic properties such as absorption, bioavailability, distribution, metabolism, and excretion, of important 23 FDA approved drugs. The drugs namely Fuzeon, Selzentry, Complera, Epivir, Retrovir, Emtriva, Ziagen, Edurant, Intelence, Pifeltro, Sustiva, Viramune, Isentress, Genvoya, Tivicay, Reyataz, Prezista, Lexiva, Invirase, Aptivus etc. are classified into five major classes: fusion inhibitors, Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Integrase Strand transfer inhibitors (INSTIs) and Protease inhibitors (PIs). This Review may helpful for the future development of potent antiretroviral drugs with improved pharmacokinetic properties.

Photodynamic therapy (PDT) has garnered immense research interest. PDT can directly kill the cells via a combination of photosensitizer, light, and molecular oxygen. It has emerged as a promising therapeutic option for cancer treatment owing to its advantages such as minimized systemic toxicity, minimal invasiveness, high therapeutic efficacy, and potential for developing antitumor immunity. The novel photosensitizer 32-(4-methoxyphenyl)-152-aspartyl-chlorin e6 (DYSP-C34) was synthesized by introducing a 32-aryl substitution and amino acid substituent of the Chenghai chlorin (CHC). Briefly, 32-(4-methoxyphenyl) substitution was achieved via olefin metathesis reactions. The aspartic acid side chain was introduced regioselectively at C-152, followed by hydrolysis to yield the target DYSP-C34. CHC with the same chemical structure as chlorin e6 was prepared from chlorophyll a, which was extracted from Spirulina powders derived from Chenghai Lake in the Yunnan province of China. This strategy successfully endowed the resultant photosensitizer with better cellular permeability and increased water solubility. In addition, the photodynamic antitumor effects of PDT largely depend on the dose of photosensitizer used, time between photosensitizer administration and light exposure, and possibly other still poorly known variables. Determination of optimal conditions for PDT requires a coordinated interdisciplinary effort. Therefore, the pharmacokinetics and tissue distribution of DYSP-C34 in vivo are critical for the efficacy and safety of PDT. Herein, a high performance liquid chromatography-ultraviolet (HPLC-UV) detection method was established for the determination of the new photosensitizer DYSP-C34 in rat plasma. The sample preparation involved a protein-precipitation and liquid-liquid extraction method. Methanol was used to precipitate proteins and chloroform was used to extract chlorins. Then, DYSP-C34 was separated on a Unitary C18 column (250 mm×4.6 mm, 5 μm) with a mobile phase comprising methanol and 5 mmol/L tetrabutylammonium phosphate buffer solution (70∶30, v/v). The flow rate was 1.0 mL/min with UV detection using a wavelength of 400 nm at 40 ℃. Results showed that DYSP-C34 and chlorin e6 trimethyl ester (IS) were well separated under these conditions. The method was sensitive and sufficiently precise with a good linear relationship (determination coefficient (r2)=0.9941) over the range of 1-200 μg/mL in rat plasma. At three spiked levels (8, 40, and 120 μg/mL), the average recoveries were 74.39%, 69.71%, and 65.89%, respectively. The intra-day and inter-day relative standard deviations (RSDs) were lower than 5%. The precision met the requirements of biological sample determination. Furthermore, DYSP-C34 was stable in rat plasma under various storage conditions at room temperature, three freeze-thaw cycles, and long-term cryopreservation. The validated method was successfully applied to the pharmacokinetic study of DYSP-C34 after intravenous injection of a single dose in rat plasma. The pharmacokinetic parameters after intravenous injection of DYSP-C34 (16 mg/kg) were calculated. The plasma half-life (t1/2z) was 6.98 h, the area under the plasma concentration-time curve AUC(0-∞) was 1025.01 h·mg/L and the mean retention time MRT(0-∞) was 9.19 h. In addition, the results of DYSP-C34 distribution in tumor-bearing mice showed that DYSP-C34 could accumulate in tumor tissues, with higher concentrations in liver and kidney tissues, and lower concentrations in heart, spleen, and lung tissues. In summary, a specific, simple, and accurate HPLC-UV method was developed and validated for the determination of DYSP-C34 in rat plasma and tumor-bearing mouse tissues. The pharmacokinetics of DYSP-C34 after intravenous administration in rats and the tissue distribution characteristics of tumor-bearing mice were clarified for the first time. It is significant for clinical rational drug use and pharmacodynamic research. Therefore, choosing an appropriate time for light treatment time can achieve the best photodynamic effect. The results of pharmacokinetics and tissue distribution of DYSP-C34 provide vital guidance for subsequent pharmacodynamic research and further clinical trials in terms of dosage, light time, light toxicity and side effects.

Background & aims Increased intrapancreatic fat is associated with pancreatic diseases; however, there are no established objective diagnostic criteria for fatty pancreas. On non-contrast computed tomography (CT), adipose tissue shows negative Hounsfield Unit (HU) attenuations (−150 to −30 HU). Using whole organ segmentation on non-contrast CT, we aimed to describe whole gland pancreatic attenuation and establish 5th and 10th percentile thresholds across a spectrum of age and sex. Subsequently, we aimed to evaluate the association between low pancreatic HU and risk of pancreatic ductal adenocarcinoma (PDAC). Methods The whole pancreas was segmented in 19,456 images from 469 non-contrast CT scans. A convolutional neural network was trained to assist pancreas segmentation. Mean pancreatic HU, volume, and body composition metrics were calculated. The lower 5th and 10th percentile for mean pancreatic HU were identified, examining the association with age and sex. Pre-diagnostic CT scans from patients who later developed PDAC were compared to cancer-free controls. Results Less than 5th percentile mean pancreatic HU was significantly associated with increase in BMI (OR 1.07; 1.03–1.11), visceral fat (OR 1.37; 1.15–1.64), total abdominal fat (OR 1.12; 1.03–1.22), and diabetes mellitus type 1 (OR 6.76; 1.68–27.28). Compared to controls, pre-diagnostic scans in PDAC cases had lower mean whole gland pancreatic HU (−0.2 vs 7.8, p = 0.026). Conclusion In this study, we report age and sex-specific distribution of pancreatic whole-gland CT attenuation. Compared to controls, mean whole gland pancreatic HU is significantly lower in the pre-diagnostic phase of PDAC.

Objective To clarify the effects of cellular self-aggregation of adipose-derived stem cells (ADSCs) on erectile function (EF). Methods A model of neurogenic erectile dysfunction was performed using bilateral cavernous nerve crush injury in rats. ADSCs suspensions (1 × 106/0.2 ml), were administered via intracavernous injection (ICI) after being allowed to shelve for 0 minute (ICI 0) or 60 minutes (ICI 60) in vitro, as well as cell aggregates isolated from ICI 60 (ICI A). The caudal vein injection group (CVI 60) was used to evaluate whether cell self-aggregation was beneficial to EF when introduced into the peripheral circulation. One day after the transplantation, the distribution of cells was observed. EF and histopathological changes were evaluated after 4 weeks. Results Approximately 85% of ADSCs self-aggregated into cell clusters at 60 minutes. The ICI 60 had more significant improvements in EF and more visualized ADSCs retained in the corpus cavernosum (CC) than ICI 0 and CVI 60 (P Conclusion ADSCs self-aggregation before ICI may be an influential factor in the treatment of neurogenic erectile dysfunction. Its potential mechanism may be through improving cell retention in the CC.

PURPOSE OF THE REPORT The aim of this study was to evaluate the distribution of hypoxia using 18F-EF5 as a hypoxia tracer in cervical cancer patients with PET/MRI. We investigated the association between this 18F-EF5-PET tracer and the immunohistochemical expression of endogenous hypoxia markers: HIF1α, CAIX, and GLUT1. PATIENTS AND METHODS Nine patients with biopsy-proven primary squamous cell cervix carcinoma (FIGO 2018 radiological stages IB1-IIIC2r) were imaged with dual tracers 18F-EF5 and 18F-FDG using PET/MRI (Int J Gynaecol Obstet. 2019;145:129-135). 18F-EF5 images were analyzed by calculating the tumor-to-muscle ratio to determine the hypoxic tissue (T/M ratio >1.5) and further hypoxic subvolume (HSV) and percentage hypoxic area. These 18F-EF5 hypoxic parameters were correlated with the size and localization of tumors in 18F-FDG PET/MRI and the results of hypoxia immunohistochemistry. RESULTS All primary tumors were clearly 18F-FDG and 18F-EF5 PET positive and heterogeneously hypoxic with multiple 18F-EF5-avid areas in locally advanced cancer and single areas in clinically stage I tumors. The location of hypoxia was detected mainly in the periphery of tumor. Hypoxia parameters 18F-EF5 max T/M ratio and HSV in primary tumors correlated independently with the advanced stage (P = 0.036 and P = 0.040, respectively), and HSV correlated with the tumor size (P = 0.027). The location of hypoxia in 18F-EF5 imaging was confirmed with a higher hypoxic marker expression HIF1α and CAIX in tumor fresh biopsies. CONCLUSIONS The 18F-EF5 imaging has promising potential in detecting areas of tumor hypoxia in cervical cancer.

Sclareol is a labdane diterpene which carries on a broad range of biological activities. However, its poor water solubility and bioavailability are the foremost drawbacks that limit its application in therapeutics. The purpose of this investigation was to develop a natural nanoformulation made up of a biopolymer i.e. zein and sclareol in order to address this issue and to enhance the pharmacological efficacy of the drug. The sclarein nanoparticles (sclareol-loaded zein nanosystems) showed a typical monomodal pattern, characterized by a mean diameter of ~120 nm, a narrow size distribution and a surface charge of ~−30 mV. The evaluation of the entrapment efficiency and the drug-loading capacity of the nanosystems demonstrated the noteworthy ability of the protein matrix to hold sclareol while allowing a gradual release of the compound over time. The nanosystems increased the cytotoxicity of sclareol at a drug concentration of ≥5 μM with respect to the free compound after just 24 h incubation against various cancer cell lines. Indeed, the interaction of tritiated sclarein formulations with cells showed a time-dependent cell uptake of the nanosystems commencing as early as 1 h from the onset of incubation, favouring a significant decrease of the efficacious concentration of the drug.

Background The aim of the current study is to investigate the variations of anatomical (LVRem%) and functional remnant volumes (fLVRem%) and the dynamic uptake of Technetium-Mebrofinate (FRLF) measured from 99m Technetium-Mebrofinate SPECT-CT scan (TMSCT) in patients at high risk of post-hepatectomy liver failure (PHLF). Methods Variations in the measures of LVRem% and fLVRem% were assessed. The predictive accuracies of LVRem%, fLVRem% and FRLF with respect to PHLF were reported. Results From the N = 92 scans performed, LVRem% and fLVRem% returned identical results in 15% of cases, and ±10 percentage points in 79% of cases. Some patients had larger discrepancies, with difference of >10 percentage points in 21% of cases. The difference was significant in those with primary liver cancers (−4.4 ± 9.2, p = 0.002). For the N = 29 patients that underwent surgery as planned on TMSCT, FRLF was a strong predictor of PHLF, with an AUROC of 0.83 (p = 0.005). Conclusion TMSCT is emerging as a useful modality in pre-operative assessment of patients undergoing major liver resection. For those with primary liver cancer, there is a significant variation in the anatomical and functional distributions that needs considered in surgical planning. Reduced FRLF, measured as the dynamic uptake in the future liver remnant, is a strong predictor of PHLF.

BACKGROUND: Colonoscopy does miss some lesions that may be later diagnosed as post-colonoscopy colorectal cancers (PCCRCs). We evaluated the rate of PCCRCs in a cohort of our patients. METHODS: The data of patients diagnosed with first primary colorectal cancers (CRCs) between July 2014 and June 2017 were analyzed. Colorectal cancers were considered to be missed if they occurred among patients who have had an index colonoscopy between 7 and 36 months prior to their diagnosis. The incidence of missed lesions and the distribution of such lesions in the large bowel are presented. RESULTS: In the study, 399 of the total 541 patients whose CRCs were diagnosed by colonoscopy were included. The median age of the patients (213 males and 186 females) was 75.3 (32.4-82.1) years. Seven patients with diagnosis of primary CRCs had undergone index colonoscopy between 7 and 36 months prior to their diagnostic colonoscopy. Therefore, the PCCRC rate in this cohort was 1.8% (7/399 × 100). The mean time interval between the false negative colonoscopy (index colonoscopy) and diagnostic colonoscopy was 18.7 (9.1-34.9) months. Missed CRCs were located in the ascending (2), transverse (1), descending (1), and sigmoid colon (2) and in the rectum (1). CONCLUSION: Our PCCRC rate was 1.8%, which is lower than the usually reported rate.

Busulfan (Bu) is a bifunctional alkylating agent that is widely used prior to hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (pop PK) model for Bu in Chinese pediatric patients. A systemic external evaluation of eleven published pop PK models was conducted in Chinese HSCT pediatric patients. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE% (MDPE), median absolute PE%, and percentage of PE% within ±20% (F20 ) and ±30% (F30 ) were calculated in prediction-based diagnostics. Simulation-based diagnostics were conducted through a prediction- and variability-corrected visual predictive check (pvcVPC) and the normalized prediction distribution error (NPDE). The relative individual prediction error (IPE%) was calculated using Bayesian forecasting with 1-3 concentration points. The one-compartment open linear pop PK model, which was built by Su-jin Rhee et al. (model H), incorporating patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other pop PK models. In prediction-based diagnostics, the MDPE, F20 , and F30 of model H were 8.48%, 45.35%, and 59.56%, respectively. The NPDE of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model, that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients. This article is protected by copyright. All rights reserved.

PURPOSE To appropriately adopt the organ preservation approach, including subsequent chemoradiotherapy (CRT) in patients who respond to neoadjuvant chemotherapy (NAC), the distribution of residual disease, including pathological lymph nodes (LNs) and recurrence site, needs to be recognized preoperatively. This study was designed to evaluate whether endoscopic response evaluation can predict residual tumor distribution. METHODS Patients with esophageal squamous cell carcinoma who underwent transthoracic esophagectomy (TTE) were retrospectively reviewed. Endoscopic responder (ER) to NAC was defined according to primary tumor endoscopic findings. Recurrence-free survival (RFS), overall survival (OS), and residual tumor patterns were compared between groups. RESULTS Of 193 patients, 40 (20%) were classified as ER. ERs showed significantly better RFS and OS. The pN location was found within the primary tumor and cN field in 88% of ERs, which was significantly higher than non-ERs at 63% (p = 0.004). Furthermore, the postoperative recurrence incidence in the distant organ was significantly lower in the ERs than the non-ERs (8%, 32%, respectively, p = 0.002). Residual disease, including postoperative initial recurrence, existed within the same field as the primary tumor and cN in 88% of ERs, significantly higher than 42% in the non-ERs (p < 0.001). CONCLUSIONS Endoscopic response evaluation can preoperatively predict distribution of residual tumors after NAC, which could help radiation field selection in subsequent definitive CRT when patients prefer to omit TTE. Along with improvements in NAC response rate, this could facilitate organ preservation in patients who respond to NAC.

Background Endolymphatic hydrops (ELH), which is a pathological feature of Meniere's disease (MD), is characterized by an extended endolymphatic space (ELS). Aims/objectives We aimed to perform a quantitative volumetric analysis of inner-ear ELH in patients with unilateral MD (uMD). Material and methods This study included 97 patients with definite uMD and 49 control subjects (CS). The ELS/total fluid space (TFS) volume ratio (%) and the distribution rate of the inner-ear components in the ELS (%) were measured using 3D magnetic resonance imaging and compared between patients with uMD and CS. Results Compared to CS, patients with uMD had significantly higher mean ELS/TFS volume ratios for inner-ear components. The mean distribution rate of the inner-ear components in the ELS was not significantly different between the two groups. Conclusions and significance In patients with uMD, ELH was noted to be spread throughout the entire inner ear and the endolymph was evenly distributed in the total ELS. These findings should be useful as a standard reference for further research.

Background. One of the most important cells in local immunity in lung are mast cells. They are involved in both innate and adaptive immune responses to inhaled allergens. The question of distribution of these both cell types in guinea pig lung in case of experimental allergic inflammation in most aspects remains open. Objective. The aim of this research is to study the distribution and quantitative changes of mast cells in lung of guinea pigs in ovalbumin-induced allergic inflammation. Methods. the lungs of 48 male guinea pigs have been studied using histological, morphometric and statistical methods in cases of experimental ovalbumin-induced allergic inflammation. The total number of mucosa related must cells and perivascular mast cells in guinea pig lungs were counted. Results. It has been established that mucosa related mast cells are normally more abundant in guinea pigs lung than perivascular ones. Maximum increase in a number of mucosa related mast cells was revealed in the early period of allergic inflammation, as evidenced by maximum increase coefficient of 1.4 in the 1st experimental group, compare to the control (P*/**

Extensive studies have been conducted to elucidate the effects of such parameters as molecular weight, polydispersity, and composition on the controlled release properties of poly(d,l-lactic

This study aimed to determine the bioavailability and pharmacokinetic parameters of sulfadiazine (SDZ) in channel catfish (Ictalurus punctatus) following oral gavage and intravenous injection. The healthy channel catfish were orally and intravenously administrated with SDZ solution at doses of 50 and 5 mg/kg, respectively. Plasma samples were determined by ultra-performance liquid chromatography with an ultraviolet detector. The results demonstrated that the concentration-time profile of SDZ after oral dosing was best described by a one-compartmental open model with first-order absorption. The absorption half-life (t1/2Kα ), the elimination half-life (t1/2Ke ), and the area under concentration-time profile (AUC0-∞ ) were estimated to be 0.87 h, 29.04 h, and 1311.72 mg.h/L, respectively. After intravenous administration, the concentration-time curve of SDZ conformed to a two-compartmental open model without absorption. The distribution half-life (t1/2α ), the elimination half-life (t1/2β ), the apparent distribution volume (Vss ), the total clearance (CL), and AUC0-∞ were calculated to be 0.19 h, 14.24 h, 0.36 L/kg, 0.018 L/h/kg, and 277.12 mg.h/L, respectively. Finally, the bioavailability was estimated to be 47.33%. This study will provide some useful information for the modification of the dosage form of SDZ in aquaculture, and is partly beneficial for appropriate use of SDZ in the future.

WHAT IS KNOWN AND OBJECTIVES Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, is characterized by large inter-individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo-HSCT recipients and to identify covariates influencing CsA pharmacokinetics. METHODS A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS AND DISCUSSION The results showed that the daily CsA dose, haematocrit, total bile acid, C-reactive protein (CRP) and co-administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8 L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340 L. Bioavailability was 67.2% with an inter-individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. WHAT IS NEW AND CONCLUSION CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo-HSCT recipients.