A follow-up on quantitative and qualitative olfactory dysfunction and other symptoms in patients recovering from COVID-19 smell loss.

BACKGROUND: Sudden smell loss is a specific early symptom of COVID-19, which, prior to the emergence of Omicron, had estimated prevalence of ~40% to 75%. Chemosensory impairments affect physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery. The aim of this cohort study was to characterize smell function and recovery up to 11 months post COVID-19 infection. METHODS: This longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial survey (S1) about respiratory symptoms, chemosensory function and COVID-19 diagnosis between April and September 2020, were invited to complete a follow-up survey (S2). Between September 2020 and February 2021, 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness. RESULTS: At follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID illness. The ability to smell during COVID-19 was rated slightly lower by those who did not eventually recover their pre-illness ability to smell at S2. CONCLUSIONS: While smell ability improves for many individuals who lost it during acute COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is associated with broader persistent symptoms of COVID-19, and may last for many months following acute COVID-19. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long-term sequelae; more research into treatment options is strongly warranted given that even conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.

Assessment of the efficacy of intra-articular platelet rich plasma treatment in an ACLT experimental model by dynamic contrast enhancement MRI of knee subchondral bone marrow and MRI T2∗ measurement of articular cartilage.

OBJECTIVE: The vascularization of subchondral bone plays a significant role in the progression of knee osteoarthritis (OA). Treatment with platelet-rich plasma (PRP) has positive effects on cartilage lesions. However, PRP's efficacy for subchondral bone marrow lesions and the relationship of these lesions to cartilage are still undiscovered. Therefore, our aims were first to longitudinally investigate the change in subchondral flow by dynamic contrast enhanced MRI and degeneration of cartilage by MRI T2∗ in an anterior cruciate transection rodent (ACLT) model, and second to examine changes in parameters after intra-articular PRP injection. DESIGN: A 32-week investigation in 18 rats allocated to sham-control, ACLT with normal saline injection (ACLT + NS), and ACLT with PRP injection groups ended with histological evaluation. Another rat was used as a donor of allogenic PRP. RESULTS: Compared to the sham-control group, the ACLT + NS group had higher subchondral blood volume A (0.051, 95% confidence interval: 0.009, 0.092) and lower venous washout kel (-0.030: -0.055, -0.005) from week 4; lower permeability kep from week 18 (-0.954: -1.339, -0.569); higher cartilage T2∗ values (1.803: 1.504, 2.102) reflecting collagen loss beginning at week 10. For the PRP treatment group, subchondral bone marrow A and cartilage T2∗ decreased from week 10. Histological results confirmed and were correlated with the MRI findings. CONCLUSION: Subchondral hyper-perfusion plays a vital role in the pathogenesis of OA and was associated with cartilage degeneration. The efficacy of PRP can be observed from reduced perfusion and MRI T2∗ values.

Clinical effectiveness of house dust mite immunotherapy in mono- versus poly-sensitised patients with allergic rhinitis: a systematic review and meta-analysis.

Selecting an appropriate allergen-specific immunotherapy (AIT) regimen for polysensitised allergic rhinitis (AR) patients is challenging for clinicians. Although previous studies showed comparable effectiveness of single-allergen AIT with house dust mite (HDM) extract between monosensitised and polysensitised AR patients, there is no systematic review and meta-analysis demonstrating the comparable effectiveness of HDM AIT. In this meta-analysis, we analysed nine studies to compare the clinical effectiveness of HDM AIT. The primary outcome was nasal symptom score and secondary outcomes were medication and quality of life scores. The changes in nasal symptom score after HDM AIT did not significantly differ between monosensitised and polysensitised patients. The clinical effectiveness of HDM AIT regarding medication and quality of life score was not significantly different between monosensitised and polysensitised patients). In conclusion, single-allergen AIT with HDM extract showed comparable clinical effectiveness between polysensitised and monosensitised patients with AR.

Safety of acupuncture during pregnancy: a retrospective cohort study in Korea.

OBJECTIVE: The present study aimed to analyse the Korean National Health Insurance Service (NHIS) cohort data to examine the safety of acupuncture therapy during pregnancy. DESIGN: Retrospective cohort. SETTING: Korea. POPULATION OR SAMPLE: Women with confirmed pregnancy between 2003 and 2012 from the 2002-13 NHIS sample cohort (n = 20 799). METHODS: Women with confirmed pregnancy were identified and divided into acupuncture or control group for comparison of their outcomes. Differences in other factors such as age, and rate of high-risk pregnancy and multiple pregnancy were examined. In the acupuncture group, the most frequent acupuncture diagnosis codes and the timing of treatment were also investigated. MAIN OUTCOME MEASURES: Incidence of full-term delivery, preterm delivery and stillbirth by pregnancy duration and among the high-risk and multiple pregnancy groups. RESULTS: Of 20 799 pregnant women analysed, 1030 (4.95%) and 19 749 were in the acupuncture and control groups, respectively. Both overall (odds ratio [OR] 1.23; 95% CI 0.98-1.54), and in the stratified analysis of high-risk pregnancies (OR 1.09; 95% CI 0.73-1.64), there was no significant difference between acupuncture and control groups in preterm deliveries. No stillbirths occurred in the acupuncture group and 0.035% of pregnancies resulted in stillbirths in the control group. CONCLUSION: No significant difference in delivery outcomes (preterm delivery and stillbirth) was observed between confirmed pregnancies in the acupuncture and control groups. Therefore, in pregnancy, acupuncture therapy may be a safe therapeutic modality for relieving discomfort without an adverse delivery outcome. TWEETABLE ABSTRACT: In pregnancy, acupuncture therapy may be a safe therapeutic modality for relieving discomfort without an adverse outcome.

Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR).

The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejection (AMR) in lung transplantation. Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research. The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report. The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regarding pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

Management of isolated recurrence after surgery for pancreatic adenocarcinoma.

BACKGROUND: Recurrence of pancreatic cancer after primary pancreatectomy occurs in the vast majority of patients. The role of surgical treatment for recurrent pancreatic cancer is not well established. METHODS: Patients who underwent primary pancreatectomy with curative intent from 2000 to 2014 at a single large-volume centre were evaluated retrospectively. CT or PET was used to select patients with an isolated recurrence. The clinicopathological features and survival outcomes were compared according to treatment modalities. RESULTS: Of the 1610 patients with pancreatic cancer who underwent resection, 1346 (83·6 per cent) were diagnosed with recurrent pancreatic cancer. Recurrence was locoregional in 366 patients (27·2 per cent), distant multifocal in 251 (18·6 per cent), distant isolated in 188 (14·0 per cent), locoregional plus distant in 153 (11·4 per cent) and peritoneal seeding in 388 (28·8 per cent). Of the 1346 patients with recurrence, 197 (14·6 per cent) had isolated recurrence; of these, 48 (24·4 per cent of all isolated recurrences; 3·6 per cent of all recurrences) underwent resection. Median survival of the 197 patients after diagnosis of isolated recurrence was 14·7 months; it was longer in patients who underwent surgical resection than among those treated non-surgically (23·5 versus 12·0 months; P = 0·014). Multivariable analysis showed that chemotherapy and resection for recurrence were associated with better prognosis. Median survival after recurrence was longest in the 23 patients with isolated pulmonary recurrence (33·3 months). Survival after recurrence was better in patients who underwent resection of isolated recurrence in the remnant pancreas (median 28·0 versus 12·0 months, P = 0·010) and lung (median 36·5 versus 9·5 months; P = 0·010) than in those who did not undergo resection. CONCLUSION: Surgical resection may be considered an option for treatment of patients with isolated recurrent pancreatic cancer.

The epithelial zinc transporter ZIP10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity.

BACKGROUND: The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. OBJECTIVES: In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis. METHODS: Adult human skin, including skin appendages, were stained with anti-ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10- or HAT-regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. RESULTS: ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT. This decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. CONCLUSIONS: Our study suggests that ZIP10-mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc-dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.

Assessment of liver cirrhosis for patients with Child's A classification before hepatectomy using dynamic contrast-enhanced MRI.

AIM: To determine the feasibility of semi-quantitative haemodynamic parameters derived from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to assess liver fibrosis. MATERIALS AND METHODS: Seventy-five patients with Child's A classification (males/females=24/51; average age, 58 years; range, 30-80 years) received DCE-MRI 3 days prior to hepatectomy. Semi-quantitative haemodynamic parameters, including the wash-in slope, wash-out slope, and time-to-peak, were calculated from DCE-MRI data. Liver fibrosis of the resected non-tumour liver was graded pathologically from F0 (no fibrosis) to F6 (cirrhosis) in the regions corresponding to those assessed by DCE-MRI. RESULTS: The wash-out slope showed higher interobserver and intra-observer reliabilities than the wash-in slope and time-to-peak. There was a significant positive correlation between the wash-out slope and pathological grade of fibrosis (Spearman's correlation coefficient: r=0.5331, p<0.0001). The area under the receiver operating characteristic curve was 0.8066 when using the wash-out slope to differentiate cirrhosis (grade F6) from non-cirrhosis (grades F0-5). Using the cut-off point that maximised specificity, the sensitivity was 62.07%, specificity was 91.30%, positive predictive value was 81.81%, negative predictive value was 79.25%, and accuracy was 80%. CONCLUSIONS: The wash-out slope derived from DCE-MRI might be potentially useful in assessing liver cirrhosis in patients with Child's A classification before hepatectomy.

DEPDC5 mutations in familial and sporadic focal epilepsy.

BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized. MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing. RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene. DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

Human periodontal ligament stem cells suppress T-cell proliferation via down-regulation of non-classical major histocompatibility complex-like glycoprotein CD1b on dendritic cells.

BACKGROUND AND OBJECTIVE: Periodontal ligament stem cells (PDLSCs) from the periodontal ligament tissue were recently identified as mesenchymal stem cells (MSCs). The capabilities of PDLSCs in periodontal tissue or bone regeneration have been reported, but their immunomodulatory role in T-cell immune responses via dendritic cells (DCs), known as the most potent antigen-presenting cell, has not been studied. The aim of this study is to understand the immunological function of homogeneous human STRO-1+ CD146+ PDLSCs in DC-mediated T-cell immune responses to modulate the periodontal disease process. MATERIAL AND METHODS: We utilized highly purified (> 95%) human STRO-1+ CD146+ PDLSCs and human bone marrow mesenchymal stem cells (BMSCs). Each stem cell was co-cultured with human monocyte-derived DCs in the presence of lipopolysaccharide isolated from Porphyromonas gingivalis, a major pathogenic bacterium responsible for periodontal disease, in vitro to examine the immunological effect of each stem cell on DCs and DC-mediated T-cell proliferation. RESULTS: We discovered that STRO-1+ CD146+ PDLSCs, as well as BMSCs, significantly decreased the level of non-classical major histocompatibility complex glycoprotein CD1b on DCs, resulting in defective T-cell proliferation, whereas most human leukocyte antigens and the co-stimulatory molecules CD80 and CD86 in/on DCs were not significantly affected by the presence of BMSCs or STRO-1+ CD146+ PDLSCs. CONCLUSIONS: This study unveiled an immunomodulatory role of STRO-1+ CD146+ PDLSCs in negatively regulating DC-mediated T-cell immune responses, demonstrating their potential to be utilized in promising new stem cell therapies.

Improving molecular testing and personalized medicine in non-small-cell lung cancer in Ontario.

BACKGROUND: Although molecular testing has become standard in managing advanced nonsquamous non-small-cell lung cancer (nsclc), most patients undergo minimally invasive procedures, and the diagnostic tumour specimens available for testing are usually limited. A knowledge translation initiative to educate diagnostic specialists about sampling techniques and laboratory processes was undertaken to improve the uptake and application of molecular testing in advanced lung cancer. METHODS: A multidisciplinary panel of physician experts including pathologists, respirologists, interventional thoracic radiologists, thoracic surgeons, medical oncologists, and radiation oncologists developed a specialty-specific education program, adapting international clinical guidelines to the local Ontario context. Expert recommendations from the program are reported here. RESULTS: Panel experts agreed that specialists procuring samples for lung cancer diagnosis should choose biopsy techniques that maximize tumour cellularity, and that conservation strategies to maximize tissue for molecular testing should be used in tissue processing. The timeliness of molecular reporting can be improved by pathologist-initiated reflex testing upon confirmation of nonsquamous nsclc and by prompt transportation of specimens to designated molecular diagnostic centres. To coordinate timely molecular testing and optimal treatment, collaboration and communication between all clinicians involved in diagnosing patients with advanced lung cancer are mandatory. CONCLUSIONS: Knowledge transfer to diagnostic lung cancer specialists could potentially improve molecular testing and treatment for advanced lung cancer patients.

Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs.

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high-dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic-treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad-spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL-1ß and macrophage inflammatory proteins 1α and 1ß at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad-spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.

Chronic infection phenotypes of Pseudomonas aeruginosa are associated with failure of eradication in children with cystic fibrosis.

Early eradication treatment with inhaled tobramycin is successful in the majority of children with cystic fibrosis (CF) with incident Pseudomonas aeruginosa infection. However, in 10-40 % of cases, eradication fails and the reasons for this are poorly understood. The purpose of this study was to determine whether specific microbial characteristics could explain eradication treatment failure. This was a cross-sectional study of CF patients (aged 0-18 years) with incident P. aeruginosa infection from 2011 to 2014 at the Hospital for Sick Children, Toronto, Canada. Phenotypic assays were done on all incident P. aeruginosa isolates, and eradicated and persistent isolates were compared using the Mann-Whitney test or the two-sided Chi-square test. A total of 46 children with CF had 51 incident P. aeruginosa infections. In 72 % (33/46) of the patients, eradication treatment was successful, while 28 % failed eradication therapy. Persistent isolates were less likely to be motile, with significantly less twitch motility (p=0.001), were more likely to be mucoid (p=0.002), and more likely to have a tobramycin minimum inhibitory concentration (MIC) ≥ 128 µg/mL (p=0.02) compared to eradicated isolates. Although biofilm production was similar, there was a trend towards more persistent isolates with deletions in quorum-sensing genes compared with eradicated isolates (p=0.06). Initial acquisition of P. aeruginosa with characteristics of chronic infection is associated with failure of eradication treatment.

Biomarker testing and time to treatment decision in patients with advanced nonsmall-cell lung cancer.

BACKGROUND: Testing for EGFR mutations and ALK rearrangement has become standard in managing advanced nonsmall-cell lung cancer (NSCLC). However, many institutions in Europe, North America and other world regions continue to face a common challenge of facilitating timely molecular testing with rapid result turnaround time. We assessed the prevalence of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. METHODS: We conducted a retrospective chart review of a random sample of one-quarter of all patients with advanced NSCLC referred to the Princess Margaret Cancer Centre from 1 April 2010 to 31 March 2013. RESULTS: Of 300 patients reviewed, 175 seen by medical oncology had nonsquamous NSCLC, 72% of whom had biomarker testing carried out. Patients tested for biomarkers were more likely to be female (47% versus 21%, P = 0.002), Asian (27% versus 6%, P = 0.005) and never smokers (42% versus 8%, P < 0.0001). Only 21% of patients with biomarker testing had results available at their initial oncology consultation. This group had a shorter median time from consultation to treatment decision (0 versus 22 days, P = 0.0008) and time to treatment start (16 versus 29, P = 0.004). Thirteen percent underwent repeat biopsy for molecular testing after the initial consultation. Of those with positive EGFR or ALK results, 19% started chemotherapy before biomarker results became available. CONCLUSIONS: Awaiting biomarker testing results can delay treatment decisions and treatment initiation for patients with advanced NSCLC. This may be avoided by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens to ensure they are sufficient for molecular testing.

Distinct expression patterns of alveolar "alarmins" in subtypes of chronic lung allograft dysfunction.

The long-term success of lung transplantation is limited by chronic lung allograft dysfunction (CLAD). The purpose of this study was to investigate the alveolar alarmin profiles in CLAD subtypes, restrictive allograft syndrome (RAS) and bronchiolitis obliterans syndrome (BOS). Bronchoalveolar lavage (BAL) samples were collected from 53 recipients who underwent double lung or heart-lung transplantation, including patients with RAS (n = 10), BOS (n = 18) and No CLAD (n = 25). Protein levels of alarmins such as S100A8, S100A9, S100A8/A9, S100A12, S100P, high-mobility group box 1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in BAL fluid were measured. RAS and BOS showed higher expressions of S100A8, S100A8/A9 and S100A12 compared with No CLAD (p < 0.0001, p < 0.0001, p < 0.0001 in RAS vs. No CLAD, p = 0.0006, p = 0.0044, p = 0.0086 in BOS vs. No CLAD, respectively). Moreover, RAS showed greater up-regulation of S100A9, S100A8/A9, S100A12, S100P and HMGB1 compared with BOS (p = 0.0094, p = 0.038, p = 0.041, p = 0.035 and p = 0.010, respectively). sRAGE did not show significant difference among the three groups (p = 0.174). Our results demonstrate distinct expression patterns of alveolar alarmins in RAS and BOS, suggesting that RAS and BOS may represent biologically different subtypes. Further refinements in biologic profiling will lead to a better understanding of CLAD.

Lentivirus IL-10 gene therapy down-regulates IL-17 and attenuates mouse orthotopic lung allograft rejection.

The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation.

The association between UGT1A1 polymorphisms and treatment toxicities of liposomal irinotecan.

BACKGROUND: Initial dose adjustment is recommended for patients with known UGT1A1∗28 homozygosity for both conventional irinotecan and liposomal irinotecan (nal-IRI). A recent population pharmacokinetic (PK) study showed that Asian patients had a lower prevalence of UGT1A1∗28 homozygosity but a significantly higher maximum blood concentration of SN-38 (SN-38 Cmax) and a higher incidence of grade ≥3 neutropenia after nal-IRI administration than Caucasian patients. The current study investigated the association of UGT1A1 polymorphisms, including the Asian prevalent UGT1A1∗6, PK and toxicities of nal-IRI-based therapy in the Asian population. PATIENTS AND METHODS: A total of 162 patients with nal-IRI-based therapy and available UGT1A1∗6 and UGT1A1∗28 genotyping were included, with 82 Asian patients from six previous phase I or II studies of nal-IRI (cohort 1) and another 80 patients with nal-IRI + 5-fluorouracil/leucovorin every 2 weeks as real-world practice in a single institute in Taiwan (cohort 2). RESULTS: The frequency of UGT1A1∗6 or UGT1A1∗28 homozygosity/compound heterozygosity was 9.3%, with UGT1A1∗6/∗6 in 2.5%, UGT1A1∗28/∗28 in 1.9% and UGT1A1∗6/∗28 in 4.9%. Among the 53 patients in cohort 1 with available PK data, all 7 patients with homozygosity/compound heterozygosity harbored UGT1A1∗6 and had a significantly higher level of median dose-normalized area under the concentration-time curve (AUC) and Cmax of SN-38 than those with single heterozygosity/wild type. Of the entire study population, the incidence of grade ≥3 neutropenia and diarrhea was significantly higher in patients with homozygosity/compound heterozygosity than in those with single heterozygosity/wild type, 73.3% versus 38.1% (P = 0.012, Fisher's exact test) and 33.3% versus 9.5% (P = 0.018, Fisher's exact test), respectively. CONCLUSION: The results suggest that the recommendation of a lower starting dose of nal-IRI for patients with UGT1A1∗28 homozygosity should be extended to include patients with UGT1A1∗6 homozygosity/compound heterozygosity.

A retroviral vector suitable for ultrasound image-guided gene delivery to mouse brain.

Gene transfer to the early-stage embryonic brain using the ultrasound image-guided gene delivery (UIGD) technique has proven to be valuable for investigating brain development. Thus far, this technology has been restricted to the study of embryonic neurogenesis. When this technique is designed to be employed for the study in adult animals, a long-term stable gene expression will be required. We attempted to develop a retroviral vector suitable for expressing exogenous genes in the brains of postnatal and adult mice in the context of the UIGD technique. Retroviral vectors containing four different long terminal repeats (LTRs) (each from Moloney murine leukemia virus (MoMLV), murine stem cell virus (MSCV), myeloproliferative sarcoma virus (MPSV) and spleen focus-forming virus (SFFV)) were compared using the well-known CE vector having the EF1α internal promoter as a control. The MS vector containing MSCV LTR produced a higher viral titer and a higher level of gene expression than other vectors including CE. The MS vector drove the gene expression in cultured neural stem cells for 3 weeks. Furthermore, the MS vector could efficiently deliver the gene to the mouse central nervous system, as transgene expression was found in various regions of the brains and spinal cords as well as in all major neural cell types. The data from an in vivo luciferase imaging analysis showed that the gene expression from the MS vector was sustainable for almost 3 months. Our data suggested that the MS vector would be suitable to construct mice containing the transgene expressed in the brain or spinal cord in a quick and cost-effective manner.

Effect of pre-exposure to sevoflurane on the bispectral index in women undergoing Caesarean delivery under general anaesthesia.

BACKGROUND: Patients undergoing Caesarean delivery under inhalation anaesthesia are at a high risk of awareness, especially in the period before delivery. We assessed the effects of pre-exposure to sevoflurane on the bispectral index (BIS) in the interval before delivery. METHODS: Sixty-four patients undergoing elective Caesarean delivery were randomly assigned to receive 1.0-1.1 vol% (control 1) or 1.2-1.3 vol% (control 2) end-tidal sevoflurane, or the same concentrations of end-tidal sevoflurane combined with pre-exposure to 1 vol% sevoflurane for the last 1 min of the preoxygenation period (the preSevo 1 and preSevo 2 groups, respectively). We assessed BIS values, arterial pressure, and heart rate at the time of induction; before intubation; and upon skin incision, uterine incision, and delivery. We also determined the maternal incidence of intraoperative awareness and the neonatal Apgar scores, and conducted umbilical blood gas analysis. RESULTS: At skin incision, BIS values were significantly lower in the preSevo 1 group than in the control 1 group [50 (13) vs 72 (8), P<0.001] and in the preSevo 2 group than in the control 2 group [44 (11) vs 67 (10), P<0.001]. The mean BIS values in the preSevo 1 and 2 groups were maintained below 60 in the period before delivery. No other parameter differed among groups, and no patient exhibited intraoperative awareness. CONCLUSIONS: Pre-exposure to low concentrations of sevoflurane reduced BIS values in the interval before delivery, suggesting that this approach may reduce the risk of maternal awareness. Clinical Research Information Service (code KCT0000069, http://cris.cdc.go.kr).

Effects of the mixing ratio of the CaAl12O19:mn and Zn2SiO4:mn color-conversion layer on the color tunable emissions of white organic light-emitting devices.

The optical properties of white organic light-emitting devices (WOLEDs) fabricated utilizing a CaAl12O19:Mn and Zn2SiO4:Mn phosphor layer were investigated. X-ray diffraction patterns for CaAl12O19:Mn and Zn2SiO4:Mn phosphors showed that Mn ions in the CaAl12O19:Mn phosphors were completely substituted into Ca ions and that Mn ions in the Zn2SiO4:Mn phosphors were completely substituted into Zn ions. Field emission scanning electron microscopy images showed that the size of the CaAl12O19:Mn phosphor was approximately between 0.1 and 3 microm, and that the size of the Zn2SiO4:Mn phosphor was smaller than 7 microm. The color coordinates of the electroluminescence spectra for WOLEDs with phosphor thicknesses of 0.25 and 0.35 mm shifted to the white emission side because the generated blue light from the blue OLEDs combined with the red and green lights was converted by the CaAl12O19:Mn and the Zn2SiO4:Mn phosphor down-conversion layers.