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Advances in medical technology provide the modern day field anesthetist with the extra edge to meet the challenges faced in the harsh environment of the battlefield and enhance the survivability of casualties. The tasks of triage, resuscitation, and administration of anesthesia can be facilitated with the use of new airway devices, portable ventilators, and monitoring devices. Before such equipment is used in the field, the anesthetist must carefully weigh the advantages and disadvantages and must be cognizant of the limitations of individual devices in different environmental settings. These devices should ideally be portable, lightweight, rugged in construction, durable, easy to use (requiring minimal training and supervision), readily replaceable, and cost-effective. [ABSTRACT FROM AUTHOR]

Background: As part of a publicly funded initiative to develop genetically engineered Brassicas (cabbage, cauliflower, and canola) expressing Bacillus thuringiensis Crystal (Cry)-encoded insecticidal (Bt) toxin for Indian and Australian farmers, we designed several constructs that drive high-level expression of modified Cry1B and Cry1C genes (referred to as Cry1B M and Cry1C M ; with M indicating modified). The two main motivations for modifying the DNA sequences of these genes were to minimise any licensing cost associated with the commercial cultivation of transgenic crop plants expressing Cry M genes, and to remove or alter sequences that might adversely affect their activity in plants., Results: To assess the insecticidal efficacy of the Cry1B M /Cry1C M genes, constructs were introduced into the model Brassica Arabidopsis thaliana in which Cry1B M /Cry1C M expression was directed from either single (S4/S7) or double (S4S4/S7S7) subterranean clover stunt virus (SCSV) promoters. The resulting transgenic plants displayed a high-level of Cry1B M /Cry1C M expression. Protein accumulation for Cry1C M ranged from 5.18 to 176.88 µg Cry1C M /g dry weight of leaves. Contrary to previous work on stunt promoters, we found no correlation between the use of either single or double stunt promoters and the expression levels of Cry1B M /Cry1C M genes, with a similar range of Cry1C M transcript abundance and protein content observed from both constructs. First instar Diamondback moth (Plutella xylostella) larvae fed on transgenic Arabidopsis leaves expressing the Cry1B M /Cry1C M genes showed 100% mortality, with a mean leaf damage score on a scale of zero to five of 0.125 for transgenic leaves and 4.2 for wild-type leaves., Conclusions: Our work indicates that the modified Cry1 genes are suitable for the development of insect resistant GM crops. Except for the PAT gene in the USA, our assessment of the intellectual property landscape of components presents within the constructs described here suggest that they can be used without the need for further licensing. This has the capacity to significantly reduce the cost of developing and using these Cry1 M genes in GM crop plants in the future., (© 2024. The Author(s).)

Introduction: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers., Methods: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration., Results: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC., Conclusion: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study aimed to investigate the effect of metabolizable energy (ME) levels and exogenous emulsifier supplementation on growth performance, apparent ileal digestibility (AID), body composition, and carcass yield in broilers. The experiment was designed as a 2  ×  2 factorial arrangement with ME levels (control ME vs. reduced 100 kcal/kg ME) and exogenous emulsifier supplementation (0 vs. 0.05 %). A total of 1,000 one-day-old male Cobb 500 broilers were randomly allocated into 4 treatments with 10 replicates and 25 birds per floor pen for 42 d (starter, d 0-14; grower, d 14-28; and finisher, d 28-42). Growth performance was measured biweekly, and AID was evaluated using the indigestible indicator method during d 21 to 28. Body composition was measured at d 35 using Dual-Energy X-Ray Absorptiometry (DXA), and carcass yield was evaluated at d 42. Data were analyzed using the GLM procedure for 2-way ANOVA. Results indicated reduced ME decreased body weight gain and feed intake (P < 0.05). Exogenous emulsifier supplementation improved FCR during the finisher and overall periods (P < 0.05). Reduced ME decreased AID of dry matter (DM), fat, and gross energy (P < 0.05) but increased AID of Val (P = 0.013). Exogenous emulsifier supplementation increased AID of DM, crude protein, His, Ile, Lys, Thr, Val, Pro, Ala, and Tyr (P < 0.05). Reduced ME decreased dressing rate and the relative weight of abdominal fat (P < 0.05). DXA results indicated that reduced ME decreased bone mineral density and fat (P < 0.001) but increased bone mineral contents and muscle (P < 0.05). Therefore, a reduction of 100 kcal/kg ME in the diet had adverse effects on the growth performance and carcass characteristics, but the use of exogenous emulsifier supplementation improved growth performance and nutrient digestibility., Competing Interests: DISCLOSURES There is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the physiological effects of exogenous emulsifiers in broiler chickens that were fed tallow-incorporated reduced-energy diets over 35 days., Methods: A total of 256 Ross 308 one-day-old broilers (42.28±0.16 g) were randomly allocated in a 2×2 factorial arrangement to 32 pens with eight chicks per cage. Birds were fed one of four dietary treatments as follows: i) positive control (PCN; energy sufficient diet); ii) negative control (NCN; energy-deficient diet, -100 ME kcal/kg); iii) PCL (PCN plus 0.05% emulsifier); and iv) NCL (NCN plus 0.05% emulsifier). Growth performance was evaluated weekly whereas assessments for the carcass traits, digestibility, some blood metabolites, ileal morphology, and meat quality were measured on d 21 and d 35., Results: Birds fed the NCL diet had higher (p<0.05) body weights, daily gains, daily feed intake, and improved feed efficiency over the entire 35-day period. Improvements (p<0.05) for the ileal digestibility of crude fat, energy, and dry matter commensurate with longer (p<0.05) villus heights were also observed with emulsifiers in the NCL and PCL diets. For the carcass measurements, only the liver weights were increased (p<0.05) with emulsifiers in the supplemented groups. For blood metabolites, higher (p<0.05) lipase levels were noticed with emulsifiers in the NCL and PCL diets. In addition, marginal reductions (p = 0.076; p = 0.095, respectively) were also noted with emulsifiers for the total cholesterol and triglyceride contents on d 35. Regarding meat quality, breast muscle yellowness was increased (p<0.05) with emulsifier use in supplemented groups., Conclusion: Our results suggest that emulsifier supplementation at 0.05% in diets could potentially improve the growth performance and nutrient digestibility of broilers over 35 days. This could compensate for the lower growth performance that could be recorded with fat-incorporated lower-energy diets.

Aim: The present study aimed to investigate the construct structure behind the psychosocial response, behavioral response, prenatal depression, and post-traumatic stress disorder (PTSD) in pregnant women during the COVID-19 pandemic in China., Method: The validated Chinese version of the Edinburgh Postnatal Depression Scale (EPDS), PTSD CheckList (PCL)-6, and two newly established scales for COVID-19-related psychological and behavioral responses were used. Structural equation modeling (SEM) analysis was applied to evaluate the structural relationships of psychological and behavioral responses during the COVID-19 pandemic., Results: Of the 1,908 mothers who completed the questionnaires, 1,099 met the criteria for perinatal depression, and 287 were positively screened for PTSD, where 264 women exceed the cut-off points for both. Pregnant women with full-time or part-time jobs tended to have the lowest scores of EPDS (10.07 ± 5.11, P < 0.001) and stress levels (23.85 ± 7.96, P = 0.004), yet they were more likely to change their behavior in accordance with the COVID-19 outbreak (13.35 ± 3.42, P = 0.025). The structural model fit the data (χ 2 = 43.260, p < 0.001) and resulted in satisfactory fit indices (CFI = 0.984, TLI = 0.959, RMSEA = 0.072, and χ 2 /d f = 10.815), all path loadings were significant ( p < 0.05). The SEM indicates that the level of QoL was attributable to the occurrence of PND, leading to PTSD, and COVID-19 related behavioral and psychological responses., Conclusion: The inter-relationships between the COVID-19-related psychosocial and behavioral responses have been assessed, indicating that the pandemic increased the burden of perinatal depression. Psychoeducation, as well as other psychological interventions, may be needed to alleviate the COVID-19-based anxiety and increase their engagement in protective behaviors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Chiu, Lin, Akinwunmi, Wong, Zhang and Ming.)

Background: Total knee replacement (TKR) surgery is a treatment option for advanced hemophilic arthropathy. Due to its rarity and complexity, previous reports could only demonstrate the results of single-site studies including few cases. This population-based study aimed to investigate the major epidemiological characteristics, mean consumption of coagulation factors, length of hospital stays, complications, and failure rate of primary TKR for severe hemophilia patients in Taiwan., Methods: A cohort of 996 hemophilia patients registered between 1995 and 2011 was included, and 103 primary TKRs were performed on 75 patients. Unilateral TKR was performed on 47 patients and bilateral TKRs on the remaining 28 patients, including 12 simultaneous and 16 staged surgeries. The mean age at surgery was 32.3 years (range, 17.3-55.7), and the mean follow-up duration was 77.9 months (range, 2.3-176.8)., Results: Failure was noted in 8 patients (8.5%) at mean 32.8 months (range, 2.3-95) after surgery. Four patients revealed aseptic loosening, whereas infection in 4. The 10-year prosthesis survivorship was 88.6%. For patients receiving unilateral TKR, the mean length of hospital stay was 15 days (range, 7-32). The mean cost of factor supplement was United States Dollar (USD) 43 543 with a mean 4-unit packed red blood cells transfusion (range, 0-38). The total admission cost was USD 48 326 (range, USD 4165-262 619)., Conclusion: The prevalence of TKA for hemophilia patients was 7.5% in Taiwan. The mean hospital stay was 14 days, and the 10-year prosthesis survivorship was 88.6%. The mean daily factor usage was decreased from 235.7 units preoperatively to 202.1 units postoperatively. In comparison with the staged-bilateral TKRs, the simultaneous procedures significantly reduced the mean total cost from USD 101 923 to USD 61 587 (p = 0.023). Therefore, in terms of cost-effectiveness, bilateral simultaneous TKR is more preferable than staged procedures., Competing Interests: Conflicts of interest: Dr. Hui-Chi Hsu, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Introduction: Concurrent anthracycline and taxane is an effective and efficient way to deliver neoadjuvant chemotherapy for HER2-negative breast cancers. Data on efficacy and tolerance to 6 cycles of concurrent docetaxel, epirubicin, and cyclophosphamide (TEC) is limited., Method: All patients with HER2-negative breast cancers who received neoadjuvant TEC from January 2013 to December 2019 were reviewed., Results: A total of 71 patients [57 luminal B disease; 14 triple negative breast cancer (TNBC)] received neoadjuvant TEC with prophylactic granulocyte colony-stimulating factor (G-CSF). The pathological complete response (pCR) rate was 26.3% and 28.6% for luminal B and TNBC, respectively. With median follow-up of 48.9 months, 3 years disease-free survival was 85.9%, and 3 years overall survival was 89.6%. Non-hematological toxicities were common but the majority was grade 1 or 2. The most common grade 3 or 4 toxicity were hematological, including neutropenia (26.8%) and anemia (15.5%). There was no cardiotoxicity observed. Half of the patients had at least one dose reduction but all patients completed the planned 6 cycles and had breast surgery done., Conclusion: Six cycles of TEC with prophylactic G-CSF is an effective and tolerable neoadjuvant regime for HER2-negative breast cancers. Hematological toxicities were the most common toxicities. Although many patients required dose reduction, all patients completed treatment and there was no observed cardiotoxicity., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background and Aims: There are no prospective data on stereotactic body radiation therapy (SBRT) as a bridge to liver transplantation for HCC. This study aimed to evaluate the efficacy and safety of SBRT as bridging therapy, with comparison with transarterial chemoembolization (TACE) and high-intensity focused ultrasound (HIFU)., Approach and Results: Patients were prospectively enrolled for SBRT under a standardized protocol from July 2015 and compared with a retrospective cohort of patients who underwent TACE or HIFU from 2010. The primary endpoint was tumor control rate at 1 year after bridging therapy. Secondary endpoints included cumulative incidence of dropout, toxicity, and posttransplant survival. During the study period, 150 patients were evaluated (SBRT, n = 40; TACE, n = 59; HIFU, n = 51). The tumor control rate at 1 year was significantly higher after SBRT compared with TACE and HIFU (92.3%, 43.5%, and 33.3%, respectively; P = 0.02). With competing risk analysis, the cumulative incidence of dropout at 1 and 3 years after listing was lower after SBRT (15.1% and 23.3%) compared with TACE (28.9% and 45.8%; P = 0.034) and HIFU (33.3% and 45.1%; P = 0.032). Time-to-progression at 1 and 3 years was also superior after SBRT (10.8%, 18.5% in SBRT, 45%, 54.9% in TACE, and 47.6%, 62.8% in HIFU; P < 0.001). The periprocedural toxicity was similar, without any difference in perioperative complications and patient and recurrence-free survival rates after transplant. Pathological complete response was more frequent after SBRT compared with TACE and HIFU (48.1% vs. 25% vs. 17.9%, respectively; P = 0.037). In multivariable analysis, tumor size <3 cm, listing alpha-fetoprotein <200 ng/mL, Child A, and SBRT significantly reduced the risk of dropout., Conclusions: SBRT was safe, with a significantly higher tumor control rate, reduced the risk of waitlist dropout, and should be used as an alternative to conventional bridging therapies., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Objective: The relationship between autoimmune rheumatic diseases, inflammatory bowel diseases, and carpal tunnel syndrome is unclear. We aimed to survey the occurrence and characteristics of carpal tunnel syndrome in autoimmune rheumatic diseases and inflammatory bowel diseases, compared with the general population., Methods: We used the Longitudinal Health Insurance Database 2015 from Taiwan's National Health Insurance Research Database. Patients diagnosed with autoimmune rheumatic diseases/inflammatory bowel diseases were identified. The incidence rates and surgical rates of carpal tunnel syndrome among individual diseases were calculated. The hazard ratios when compared with age and sex matched, and 1:1 ratio control groups were surveyed., Results: A total of 2591 women and 701 men were identified. The incidence rate of carpal tunnel syndrome was highest in Crohn disease (1001 per 100,000 person-years, 95% confidence interval = 0-2747), followed by scleroderma and Sjögren syndrome. The incidence rate in the control group was 571 per 100,000 person-years (95% confidence interval = 314-829). Significantly increased adjusted hazard ratios were seen in Sjögren syndrome (1.44, 95% confidence interval = 1.09-1.90) and rheumatic arthritis (1.33, 95% confidence interval = 1.05-1.70). The overall surgical rate was 0.2% in patients with autoimmune rheumatic diseases/inflammatory bowel diseases and 0.3% in the control group, without a significant difference (P = 0.85)., Conclusions: Patients with Sjögren syndrome and rheumatic arthritis are susceptible to carpal tunnel syndrome. Patients with autoimmune rheumatic diseases/inflammatory bowel diseases have similar surgical rates as general population., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Previous recommendations suggested living donor liver transplantation (LDLT) should not be considered for patients with Model for End-Stage Liver Disease (MELD) > 25 and hepatorenal syndrome (HRS)., Approach and Results: Patients who were listed with MELD > 25 from 2008 to 2017 were analyzed with intention-to-treat (ITT) basis retrospectively. Patients who had a potential live donor were analyzed as ITT-LDLT, whereas those who had none belonged to ITT-deceased donor liver transplantation (DDLT) group. ITT-overall survival (OS) was analyzed from the time of listing. Three hundred twenty-five patients were listed (ITT-LDLT n = 212, ITT-DDLT n = 113). The risk of delist/death was lower in the ITT-LDLT group (43.4% vs. 19.8%, P < 0.001), whereas the transplant rate was higher in the ITT-LDLT group (78.3% vs. 52.2%, P < 0.001). The 5-year ITT-OS was superior in the ITT-LDLT group (72.6% vs. 49.5%, P < 0.001) for patients with MELD > 25 and patients with both MELD > 25 and HRS (56% vs. 33.8%, P < 0.001). Waitlist mortality was the highest early after listing, and the distinct alteration of slope at survival curve showed that the benefits of ITT-LDLT occurred within the first month after listing. Perioperative outcomes and 5-year patient survival were comparable for patients with MELD > 25 (88% vs. 85.4%, P = 0.279) and patients with both MELD > 25 and HRS (77% vs. 76.4%, P = 0.701) after LDLT and DDLT, respectively. The LDLT group has a higher rate of renal recovery by 1 month (77.4% vs. 59.1%, P = 0.003) and 3 months (86.1% vs, 74.5%, P = 0.029), whereas the long-term estimated glomerular filtration rate (eGFR) was similar between the 2 groups. ITT-LDLT reduced the hazard of mortality (hazard ratio = 0.387-0.552) across all MELD strata., Conclusions: The ITT-LDLT reduced waitlist mortality and allowed an earlier access to transplant. LDLT in patients with high MELD/HRS was feasible, and they had similar perioperative outcomes and better renal recovery, whereas the long-term survival and eGFR were comparable with DDLT. LDLT should be considered for patients with high MELD/HRS, and the application of LDLT should not be restricted with a MELD cutoff., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Interleukin-1α (IL-1α) is a major alarmin cytokine which triggers and boosts the inflammatory responses. Since its discovery in the 1940s, the structure and bioactivity of IL-1α has been extensively studied and emerged as a vital regulator in inflammation and hematopoiesis. IL-1α is translated as a pro-form with minor bioactivity. The pro-IL-1α can be cleaved by several proteases to generate the N terminal and C terminal form of IL-1α. The C terminal form of IL-1α (mature form) has several folds higher bioactivity compared with its pro-form. IL-1α is a unique cytokine which could localize in the cytosol, membrane, nucleus, as well as being secreted out of the cell. However, the processing mechanism and physiological significance of these differentially localized IL-1α are still largely unknown. Accumulating evidence suggests IL-1α is involved in cancer pathogenesis. The role of IL-1α in cancer development is controversial as it exerts both pro- and anti-tumor roles in different cancer types. Here, we review the recent development in the processing and signaling of IL-1α and summarize the functions of IL-1α in cancer development.

Objectives: To evaluate whether the therapeutic effect of ultrasound-guided injections with 10 mg or 40 mg triamcinolone acetonide (TA) was dose-dependent in patients with idiopathic mild to moderate carpal tunnel syndrome (CTS)., Design: Prospective, double-blind, randomized controlled study with 12 weeks of follow-up., Setting: Rehabilitation outpatient clinic of a single medical center., Participants: Patients with CTS (N=56)., Intervention: Participants were randomly assigned to 2 treatment groups for injection: (A) 40 mg TA+2% lidocaine hydrochloride or (B) 10 mg TA+2% lidocaine hydrochloride., Main Outcome Measures: Participants were evaluated using visual analog scale (VAS) and Boston Carpal Tunnel Questionnaire (BCTQ, including Symptom Severity Scale [SSS] and Functional Status Scale [FSS]) at baseline and 6 and 12 weeks after injection). Nerve conduction studies, including parameters of distal motor latency, amplitude of compound motor action potential, amplitude of sensory nerve action potential and sensory nerve conduction velocity of median nerve, and the patient's subjective impression of improvement, were recorded before injection and 6 and 12 weeks after injection., Results: No significant differences were observed in baseline demographic characteristics and clinical evaluations. The parameters in group A and B at baseline, 6 weeks, and 12 weeks were (1) SSS: 2.17±0.14, 1.19±0.04, and 1.34±0.09 and 1.87±0.11, 1.21±0.07, and 1.26±0.04; (2) FSS: 1.63±0.07, 1.27±0.06, and 1.33±0.08 and 1.50±0.10, 1.18±0.05, and 1.26±0.05; (3) VAS: 6.4±0.3, 2.2±0.3, and 3.0±0.1 and 6.7±0.3, 2.0±0.3, and 3.1±0.3, respectively, and significantly decreased after 6 and 12 weeks in both treatment groups (P<.05). All parameters of nerve conduction studies improved in both groups after 12 weeks (P<.05). VAS, BCTQ, and nerve conduction studies did not show significant intergroup differences after 6 and 12 weeks., Conclusion: In patients with idiopathic mild to moderate CTS, ultrasound-guided injection with 10 and 40 mg TA yield similar improvements in BCTQ, VAS, and nerve conduction studies at the 12-week follow-up., (Copyright © 2020 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

A novel pneumonia-like coronavirus disease (COVID-19) caused by a novel coronavirus named SARS-CoV-2 has swept across China and the world. Public health measures that were effective in previous infection outbreaks (eg, wearing a face mask, quarantining) were implemented in this outbreak. Available multidimensional social network data that take advantage of the recent rapid development of information and communication technologies allow for an exploration of disease spread and control via a modernized epidemiological approach. By using spatiotemporal data and real-time information, we can provide more accurate estimates of disease spread patterns related to human activities and enable more efficient responses to the outbreak. Two real cases during the COVID-19 outbreak demonstrated the application of emerging technologies and digital data in monitoring human movements related to disease spread. Although the ethical issues related to using digital epidemiology are still under debate, the cases reported in this article may enable the identification of more effective public health measures, as well as future applications of such digitally directed epidemiological approaches in controlling infectious disease outbreaks, which offer an alternative and modern outlook on addressing the long-standing challenges in population health., (©Zonglin He, Casper J P Zhang, Jian Huang, Jingyan Zhai, Shuang Zhou, Joyce Wai-Ting Chiu, Jie Sheng, Winghei Tsang, Babatunde O Akinwunmi, Wai-Kit Ming. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 17.09.2020.)

Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6-15 months in HR + HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR + HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR + HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.

Here's what's known about the safety of these sweeteners and their effect on weight, appetite, and the risk for type 2 diabetes.

Background & Aims: The impact of hepatitis B core antibody (anti-HBc) positive liver grafts on survival and the risk of de novo hepatitis B virus (HBV) infection after liver transplantation (LT) remain controversial. Therefore, we aimed to analyze this risk and the associated outcomes in a large cohort of patients., Methods: This was a retrospective study that included all adults who underwent LT at Queen Mary Hospital, Hong Kong, between 2000 and 2015. Data were retrieved from a prospectively collected database. Antiviral monotherapy prophylaxis was given for patients receiving grafts from anti-HBc positive donors., Results: A total of 964 LTs were performed during the study period, with 416 (43.2%) anti-HBc positive and 548 (56.8%) anti-HBc negative donors. The median follow-up time was 7.8 years. Perioperative outcomes (hospital mortality, complications, primary nonfunction and delayed graft function) were similar between the 2 groups. The 1-, 5- and 10-year graft survival rates were comparable in anti-HBc positive (93.3%, 85.3% and 76.8%) and anti-HBc negative groups (92.5%, 82.9% and 78.4%, p = 0.944). The 1-, 5- and 10-year patient survival rates in anti-HBc positive group were 94.2%, 87% and 79% and were similar to the anti-HBc negative group (93.5%, 84% and 79.7%, p = 0.712). One-hundred and eight HBsAg negative recipients received anti-HBc positive grafts, of whom 64 received lamivudine and 44 entecavir monotherapy prophylaxis. The risk of de novo HBV was 3/108 (2.8%) and all occurred in the lamivudine era. There were 659 HBsAg-positive patients and 308 (46.7%) received anti-HBc positive grafts. The risk of HBV recurrence was similar between the 2 groups. Donor anti-HBc status did not impact on long-term patient and graft survival, or the risk of hepatocellular carcinoma recurrence after LT., Conclusions: De novo HBV was exceedingly rare especially with entecavir prophylaxis. Anti-HBc positive grafts did not impact on perioperative and long-term outcomes after transplant., Lay Summary: The risk of de novo hepatitis B infection after liver transplantation was rare when using hepatitis B core positive liver grafts with entecavir monotherapy prophylaxis. Hepatitis B core antibody status did not impact on perioperative and long-term outcomes after liver transplantation. This provides support for the clinical use of hepatitis B core positive liver grafts when required., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Urinary tract infection (UTI) is the most frequent complication in patients who have spinal cord injury (SCI). The occurrence rate of UTI in this type of hospitalized patients was correlated to seasonality, age, and gender., Methods: Patients hospitalized during the 4-year study period with underlying SCI were identified from Taiwan's National Health Insurance Research Database. Patients with a discharge diagnosis of UTI were identified as those with SCI and UTI; they were divided into the following four age groups: <18 years, 18 to 44 years, 45 to 64 years, and ≥65 years. The gender, monthly number of cases, major complication rate, seasonal differences, and odds ratios (ORs) of associated factors were analyzed., Results: Data of 30 149 hospitalized patients diagnosed with SCI were retrieved. SCI and UTI were diagnosed in 3405 (11.3%) patients, of them 2296 were males (67.4%) and 1109 were females (32.6%). The UTI occurrence rate in hospitalized SCI patients was higher in males (11.8%) than in females (10.4%) (OR: 1.24; 95% CI: 1.15-1.34); it was highest in the ≥65-year-old age group (12.8%) and lowest in the <18-year-old age group (5.8%) (OR: 2.51; 95% CI: 1.83-3.44). The UTI occurrence rate varied from 7% to 18%, and it was highest in the summer (13.0% ± 2.6%) and lowest in the winter (10.2% ± 1.9%) (OR: 1.27; 95% CI: 1.15-1.40). Acute pyelonephritis was the most common complication in SCI and UTI cases., Conclusion: The mean occurrence rate of UTI in hospitalized SCI patients was 11.3%; it was higher in males, in patients aged ≥65 years, and in the summer. Therefore, physicians should pay attention to the occurrence of UTI in aged male patients with SCI, especially in the summer.

Background: Over the last 10 years, there has been a major treatment revolution for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to explore the outcome of different neoadjuvant chemotherapy in a tertiary breast cancer centre with early HER2-positive breast cancer as well as factors associated with pathological complete response (pCR) and recurrence-free survival (RFS). The pattern of recurrence was also studied., Methods: This retrospective study analysed the outcome of neoadjuvant chemotherapy during the period 2005 to 2016 in a tertiary referral centre in Hong Kong. Patients were divided into three groups according to the neoadjuvant chemotherapy they received: chemotherapy only (Chemo), chemotherapy plus trastuzumab (Chemo-H) and chemotherapy plus double anti-HER2 therapy (Chemo-DH)., Results: There were 226 cases analysed during the study period. The rate of pCR was 5%, 26% and 60% in Chemo, Chemo-H and Chemo-DH groups, respectively (Chemo vs pooled Chemo-H/DH: p<0.0001; Chemo-H vs Chemo-DH: p<0.0001). This was accompanied by a trend of increased rate of breast conservation therapy in Chemo-DH cohort (p=0.046). Use of double anti-HER2 therapy, older age (>50 years) and hormone receptor negativity were associated with more pCR. pCR was associated with better RFS. Among those with recurrence, the proportion of patients with brain as the only site of recurrence increased remarkably with more efficacious anti-HER2 treatment (0% in Chemo, 8% in Chemo-H, 67% in Chemo-DH)., Conclusion: pCR remains an important predictive factor for improved RFS. In the era of dual anti-HER2 neoadjuvant therapy, brain-only recurrence poses a challenge to disease surveillance and treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The health-related quality of life (HRQoL) was affected in children and adolescents with scoliosis. However, there was lack of study to compare the HRQoL among patients with different types of scoliosis. We aimed to investigate whether the HRQoL differs among patients with idiopathic, congenital, neuromuscular, and syndromic scoliosis., Methods: Children and adolescents with scoliosis were recruited from a single tertiary hospital. The HRQoL, as assessed by the child health questionnaire 50-item parent form, was compared with a reference health sample group using the effect size (ES). Intergroup differences related to scoliosis subtype and severity were explored., Results: A total of 67 participants with scoliosis (24 idiopathic, 15 congenital, 15 neuromuscular, and 13 syndromic) were analyzed. The HRQoL in patients with neuromuscular scoliosis was affected the most, in both physical (ES range: 0.97-2.4) and psychosocial domains (ES range: 0.92-2.58). To a lesser extent, the physical (ES range: 0.99-1.13) and psychosocial (ES range: 0.8-1.18) domains were also affected in patients with syndromic scoliosis. The domains of family activities (ES = 1.1), role/social-emotional/behavioral (ES = 0.99), general health perception (ES = 0.94), and self-esteem (ES = 0.87) were affected in patients with idiopathic scoliosis. In contrast, only the general health perception domain (ES = 1.27) was affected in patients with congenital scoliosis. Scoliosis severity correlated with scores in the physical domains and some psychosocial domains, while treatment type correlated with scores in the physical domains only. Scoliosis subtype and severity both affected the physical and psychosocial domains, with a stronger impact for subtype., Conclusion: Differences in the HRQoL exist among scoliosis subtypes, with neuromuscular scoliosis being most affected. Although the scoliosis subtype and severity both affect the HRQoL, the subtype is more influential than severity.

Objective: The aim of this study was to investigate the feasibility of using subdural strip electrodes, placed just rostral to the surgical field, to record sensory evoked potentials (SEPs) from the lumbosacral sensory nerves and define the most inferior functional portion of the conus medullaris during detethering surgery for spinal dysraphism and/or tethered cord syndrome (TCS)., Methods: Six patients, 2 boys and 4 girls, aged 0.5 to 16 years, were enrolled in this study. One patient had lipomyelomeningocele-related, 4 had myelomeningocele-related, and 1 had diastematomyelia and lipomyelomeningocele-related TCS. In addition to the routine preparations that are needed for performing functional mapping and monitoring during surgery for spinal dysraphism and TCS, the patients had a 1 × 4 strip of electrodes placed rostral to the surgical field, where it was secured by a surgeon after opening the dura. With the patient under total intravenous anesthesia, the sensory nerves and conus medullaris were stimulated with a concentric bipolar electrode over the surgical field while SEPs were recorded with the strip electrodes to identify any possible sensory roots with remaining function and the most inferior functional portion of the conus medullaris., Results: The SEP amplitudes that were recorded with the subdural strip electrodes ranged from 4 to 400 μV, and the responses to sensory nerve stimulation were frequently much larger than were those to conus stimulation. Use of the SEP recordings for sensory mapping along with the routine mapping and monitoring techniques allowed detethering to be completed such that none of the patients sustained any new functional deficit after surgery., Conclusions: Recording SEPs from the functional sensory nerves and conus medullaris through subdural strip electrodes proved to be a feasible and valuable tool during detethering surgery in young patients. This approach may help surgeons achieve maximal detethering while preserving important sensory functions, consequently retaining the patient's quality of life.

Introduction: The sonographic changes of the median nerve after steroid injection for carpal tunnel syndrome (CTS) still require investigation., Methods: Sixty-two patients with CTS were included. The Boston Carpal Tunnel Questionnaire was administered, and ultrasonographic examinations were performed before and at 2, 6, and 12 weeks after steroid injection. At 12 weeks, general improvement was scored on a 6-point Likert scale., Results: After treatment, the cross-sectional area (CSA) of the median nerve was significantly reduced at 2-, 6-, and 12-week follow-ups (for each, P < 0.001, analysis of variance). The "significant improvement" group (n = 39) had a significantly greater reduction in the CSA at the carpal tunnel inlet (P = 0.014) and CSA in the proximal carpal tunnel (P = 0.003) compared with the "little/no improvement" group (n = 23)., Discussion: Sonographic measurement of CSA may be considered complementary to the standard clinical evaluation in monitoring of treatment response in patients with CTS. Muscle Nerve 58: 402-406, 2018., (© 2018 Wiley Periodicals, Inc.)

Purpose: This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals., Methods: This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants., Findings: Single-dose elbasvir and grazoprevir median T max were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC 0-∞ and C max increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84-1.01] and 0.98 [0.86-1.09], respectively), whereas grazoprevir AUC 0-∞ and C max increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27-1.57] and 1.96 [1.64-2.29]). After repeated administration, the accumulation ratios for AUC 0-24 , 24-hour concentration, and C max were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median T max after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC 0-24 (Chinese/white participants) were 1.58 (1.03-2.42) and 1.21 (0.76-1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated., Implications: In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-8742 PN022., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)

Background: Molecular aberrations in KRAS, NRAS, BRAF, and PIK3CA have been well-described in advanced colorectal cancer. The incidences of other mutations are less known. We report results of molecular profiling of advanced colorectal cancer in an academic cancer center., Patients and Methods: Patients with advanced colorectal were enrolled in an institution-wide molecular profiling program. Profiling was performed on formalin-fixed paraffin embedded archival tissues using a customized MassArray panel (23 genes, 279 mutations) or the Illumina MiSeq TruSeq Cancer Panel (48 genes, 212 amplicons, ≥ 500× coverage) in a Clinical Laboratory Improvement Amendments-certified laboratory. PTEN was determined by immunohistochemistry., Results: From March 2012 to April 2014, 245 patients were enrolled. At least one mutation was found in 54% (97/178) and 91% (61/67) of patients using MassArray or MiSeq platforms, respectively (P < .01). Of all patients, KRAS G12/13 mutation was identified in 39%, and non-G12/13 KRAS, BRAF, or NRAS mutations were present in 9%, 6%, and 4%, respectively. Other common mutations included TP53 (68.7%), APC (41.8%), and PIK3CA (13.5%). Co-mutation with KRAS, NRAS, or BRAF was found in 75% of patients with PIK3CA mutation. Of 106 patients with known PTEN immunohistochemistry status, 16% were negative. A higher average number of mutations were observed in right versus left colorectal cancer (P < .01), with 13 of 14 BRAF mutations located in right colon cancer., Conclusion: Mutations are common in advanced colorectal cancer. Right colon cancers harbor more genetic aberrations than left colon or rectal cancers. These aberrations may contribute to differential outcomes to anti-epidermal growth factor receptor therapy among patients with right colon, left colon, or rectal cancers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Congenital or early-onset brain structural lesions often cause contralateral hemiparesis, cognitive deficits, developmental delays, and seizures. Seizure is the most debilitating condition, as it greatly impairs quality of life in both the affected individuals and their caregivers and prevents them from active social participation., Case Description: A 34-year-old man with hemiparesis and early-onset seizures since childhood owing to a congenital brain lesion developed intractable seizures in the last 2 years and was subsequently admitted for resective epileptic surgery. During the operation, we employed an innovative intraoperative neurophysiologic monitoring technique. In contrast to routine application for transcranial stimulation, we recorded compound muscle action potentials over the bilateral limb muscles simultaneously, instead of over the contralateral muscles only, to determine the patterns of the corticospinal projections. Transcranial stimulation over the bilateral hemispheres was applied before craniotomy, and direct cortical stimulation over the lesioned hemisphere was applied after craniotomy. By integrating both approaches, we could first identify the pattern of corticospinal projections before craniotomy and then accurately define the noneloquent area, which guided the resection to successfully accomplish the surgical goal., Conclusions: This technique is simple because no patient participation is required. We believe that it has the potential to replace conventional preoperative functional magnetic resonance imaging and transcranial magnetic stimulation in resective epilepsy surgery, particularly for young patients. Not only can it improve the safety of surgical procedures, but also it can help predict functional outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Long-term antiviral prophylaxis is required to prevent hepatitis B recurrence for patients with chronic hepatitis B after liver transplantation. We determined the long-term outcome of 265 consecutive chronic hepatitis B liver transplant recipients treated with entecavir monotherapy without hepatitis B immune globulin. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up. The median duration of follow-up was 59 months. The cumulative rates of hepatitis B surface antigen (HBsAg) seroclearance were 90% and 95% at 1 and 5 years, respectively. At 1, 3, 5, and 8 years, 85%, 88%, 87.0%, and 92% were negative for HBsAg, respectively, and 95%, 99%, 100%, and 100% had undetectable hepatitis B virus (HBV) DNA, respectively. Fourteen patients remained persistently positive for HBsAg, all of whom had undetectable HBV DNA. There was no significant difference in liver stiffness for those who remained HBsAg-positive compared to those who achieved HBsAg seroclearance (5.5 versus 5.2 kPa, respectively; P = 0.52). The overall 9-year survival was 85%. There were 37 deaths during the follow-up period, of which none were due to hepatitis B recurrence., Conclusion: Long-term entecavir monotherapy is highly effective at preventing HBV reactivation after liver transplantation for chronic hepatitis B, with a durable HBsAg seroclearance rate of 92%, an undetectable HBV DNA rate of 100% at 8 years, and excellent long-term survival of 85% at 9 years. (Hepatology 2017;66:1036-1044)., (© 2017 by the American Association for the Study of Liver Diseases.)

Massage-related nerve injury is an uncommon, rarely reported complication. We report an unusual case of radial nerve neuropathy at the spiral groove in a 58-year-old woman that resulted from a single episode of deep tissue massage. Although the spiral groove is known as the most common site implicated in radial nerve neuropathy, to our knowledge, there have not previously been any reports of massage-related spiral groove radial nerve neuropathy. Electrodiagnostic and ultrasound examinations were used to localize the nerve lesion at the spiral groove and also to provide prognostic evaluation. Serial follow-ups demonstrated concomitant improvement in clinical symptoms and electrodiagnostic parameters. A near-total recovery was achieved after 6 months. This case presentation aims to increase awareness and early recognition of massage-related nerve injuries., Level of Evidence: V., (Copyright © 2017 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

The precise placement of recording electrodes at the relevant myotome is mandatory while performing pedicle screw stimulation (PSS) during spine surgery; however, their placement at trunk muscles is challenging. This study aimed to determine whether ultrasound guidance is useful for trunk muscle localization for PSS during spine surgery. A retrospective clinical study was conducted from a prospective database. Eighty-four patients eligible for spine surgery were recruited. Ultrasound was used to localize the intercostal, rectus abdominis, and internal oblique and psoas muscles if pedicle screw placement was performed at T3 to L1. After the operation, patients were examined for any new neurological deficits related to this procedure, and computed tomography was performed to check screw position if indicated. Four to 22 pedicle screws were used for spinal fixation. The threshold of stimulus to obtain a compound muscle action potential ranged from 1.29 to >20mA during PSS. Six of our patients sustained new postoperative deficits, and only one case was related directly to pedicel screw misplacement. Loss of motor evoked potential (MEP) over both the lower limbs was noted during pedicle screw placement, and the stimulus threshold during PSS were 1.29mA at the left T9 and 3.8mA at the right T5 level. MEP remained absent at the end of surgery despite removal of those two screws. The patient woke with significant weakness in both lower limbs (muscle power 0/0) and voiding difficulty. Fortunately, he regained walking ability 4.5months later after intensive rehabilitation therapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To compare the effectiveness of local steroid injection plus splinting with that of local steroid injection alone using clinical and electrophysiological parameters in patients with carpal tunnel syndrome (CTS)., Design: Randomized controlled study with 12 weeks of follow-up., Setting: Tertiary care center., Participants: Volunteer sample of patients (N=52) diagnosed with CTS., Interventions: Participants were randomly assigned to the steroid injection group (n=26) or the steroid injection-plus-splinting group (n=26). Patients of both groups received ultrasound-guided steroid injection with 1mL of 10mg (10mg/mL) triamcinolone acetonide (Shincort) and 1mL of 2% lidocaine hydrochloride (Xylocaine). Participants in the second group also wore a volar splint in the neutral position while sleeping and also during daytime whenever possible for the 12-week intervention period., Main Outcome Measures: Participants were evaluated before the treatment and at 6 and 12 weeks after the onset of treatment. The primary outcome measure was Boston Carpal Tunnel Questionnaire scores. The secondary outcome measures were as follows: scores on the visual analog scale for pain; electrophysiological parameters, including median nerve distal motor latency, sensory nerve conduction velocity (SNCV), and compound muscle action potential and sensory nerve action potential (SNAP) amplitudes; and patient's subjective impression of improvement., Results: At 12-week follow-up, improvements in symptom severity and functional status scores on the Boston Carpal Tunnel Questionnaire as well as SNCV and SNAP amplitudes were greater in the group that received steroid injection combined with splinting than in the group that received steroid injection alone. The between-group difference was .48 points (95% confidence interval [CI], .09-.88 points; P=.032) in the Symptom Severity Scale score, .37 points (95% CI, .06-.67 points; P=.019) in the Functional Status Scale score, 3.38m/s (95% CI, 0.54-6.22m/s; P=.015) in the SNCV amplitude, and 3.21μV (95% CI, 0.00-6.46μV; P=.025) in the SNAP amplitude., Conclusions: In people with CTS, steroid injection combined with splinting resulted in modestly greater reduction of symptoms, superior functional recovery, and greater improvement in nerve function at 12-week follow-up as compared with steroid injection alone. However, these small differences are of unclear clinical significance., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The programmed cell death protein 1 (PD1) is one of the checkpoints that regulates the immune response. Ligation of PD1 with its ligands PDL1 and PDL2 results in transduction of negative signals to T-cells. PD1 expression is an important mechanism contributing to the exhausted effector T-cell phenotype. The expression of PD1 on effector T-cells and PDL1 on neoplastic cells enables tumor cells to evade anti-tumor immunity. Blockade of PD1 is an important immunotherapeutic strategy for cancers. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD1 antibody that has been extensively investigated in numerous malignancies. In melanoma refractory to targeted therapy, pembrolizumab induced overall response rates (ORRs) of 21-34%. It was superior to another immune checkpoint inhibitor ipilimumab (Yervoy) in stage III/IV unresectable melanoma. In refractory non-small cell lung cancer (NSCLC), pembrolizumab induced ORRs of 19-25%. Based on these results, pembrolizumab was approved by the USA FDA for the treatment of advanced melanoma and NSCLC. Tumor cell PDL1 expression may be a valid response predictor. Molecular analysis also showed that tumors with high gene mutation burdens, which might result in the formation of more tumor-related neo-antigens, had better responses to pembrolizumab. In malignancies including lymphomas and other solid tumors, preliminary data showed that ORRs of around 20-50 % could be achieved. Adverse events occurred in up to 60% of patients, but grade 3/4 toxicities were observed in <10% of cases. Immune-related adverse events including thyroid dysfunction, hepatitis and pneumonitis are more serious and may lead to cessation of treatment.

Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.

Background: There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity., Methods: Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2., Results: Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment., Conclusions: The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.

Objectives: To investigate the effects of ultrasound-guided injections of hyaluronic acid (HA) versus steroid for trigger fingers in adults., Design: Prospective, double-blinded, randomized controlled study., Setting: Tertiary care center., Participants: Subjects with a diagnosis of trigger finger (N=36; 39 affected digits) received treatment and were evaluated., Interventions: Subjects were randomly assigned to HA and steroid injection groups. Both study medications were injected separately via ultrasound guidance with 1 injection., Main Outcome Measures: The classification of trigger grading, pain, functional disability, and patient satisfaction were evaluated before the injection and 3 weeks and 3 months after the injection., Results: At 3 months, 12 patients (66.7%) in the HA group and 17 patients (89.5%) in the steroid group exhibited no triggering of the affected fingers (P=.124). The treatment results at 3 weeks and 3 months showed similar changes in the Quinnell scale (P=.057 and .931, respectively). A statistically significant interaction effect between group and time was found for visual analog scale (VAS) and Michigan Hand Outcome Questionnaire (MHQ) evaluation (P<.05). The steroid group had a lower VAS at 3 months after injection (steroid 0.5±1.1 vs HA 2.7±2.4; P<.001). The HA group demonstrated continuing significant improvement in MHQ at 3 months (change from 3wk: steroid -2.6±14.1 vs HA 19.1±37.0; P=.023; d=.78)., Conclusions: Ultrasound-guided injection of HA demonstrated promising results for the treatment of trigger fingers. The optimal frequency, dosage, and molecular weight of HA injections for trigger fingers deserve further investigation for future clinical applications., (Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Dacomitinib is an irreversible oral pan-HER tyrosine kinase inhibitor with antitumor activity demonstrated in patients with recurrent/metastatic (RM) SCCHN. A Phase I trial of dacomitinib with standard therapy in LA SCCHN is ongoing (NCT01737008). As enteral feeding is needed for many SCCHN patients, this study investigated the PK properties of dacomitinib when administered via GT (NCT01484847). Since patients with GT are difficult to recruit, this study also determined the feasibility of PK assessments using a unique design in LA SCCHN patients with GT, by giving a single dose of drug during their radiotherapy (co-administration with chemotherapy avoided)., Methods: Eligible patients were given a single dose of crushed dacomitinib at 45 mg in water suspension via GT. All doses were administered in fasting state and supine position. PK samples were drawn prior to dose (t = 0), 30 min and 1, 2, 3, 4, 6, 12, 24, 48, 72, 96, 144, 168, 192 and 216 hrs post-dose, and analyzed by HPLC-MS/MS. PK parameters (mean [CV%]) of this study were compared with those of dacomitinib given orally using Student t test., Results: Six patients with LA SCCHN patients were enrolled. The median age of patients was 54 years. Two different types of GT were used: 14 F Cope-loop tube (n = 3), 20 F PEG/disc retention tube (n = 3). PK study showed t1/2 of 58 h, Cmax of 17 ng/ml, Tmax of 8 h, AUC0-inf of 1185 ng*hr/ml, Vd/F of 3310 L and CL/F of 41 L/hr., Conclusion: Compared with oral dosing of intact immediate release (IR) tablets, GT administration resulted in 34 % reduction in Cmax and 33-44 % decrease in AUC (all p <0.05) (Jänne et al., Clin Cancer Res 2011). Such differences were not detected when compared with the PK properties of dacomitinib administered orally in aqueous suspension (Bello et al., Cancer Chemother Pharm 2013). These differences may be attributed to aqueous suspension of dacomitinib. Caution should be taken with GT administration of orally active small molecule targeted therapy. This study also demonstrated that PK trials in GT patients are feasible using novel designs.

During surgical removal of tumors of the skull base or cerebellopontine angle with brainstem compression, the vagus nerve is at a high risk for injury that can result in permanent or transient swallowing and speech dysfunction. Intramuscular recording of cricothyroid muscle can be used for vagal nerve mapping during intraoperative neurophysiologic monitoring so as to prevent the above complications. However, it is a small muscle that lies beneath the strap muscles over the anterior neck and is not easily accessible by a blind approach. Here, we present a case in which cricothyroid muscle was identified for precise electrode placement under ultrasound guidance during preparation for intraoperative monitoring. We concluded that localization of the cricothyroid muscle by ultrasonography proved to be a feasible and easy technique, and the compound muscle action potential recorded by this approach is clearly recognizable during intraoperative vagal nerve mapping., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The progress in the development of systemic treatment for advanced pancreatic cancer (APC) has been slow. The mainstream treatment remains using chemotherapy including gemcitabine, FOLFIRINOX, and nab-paclitaxel. Erlotinib is the only approved biological therapy with marginal benefit. Studies of agents targeting epidermal growth factor receptor, angiogenesis, and RAS signaling have not been satisfying, and the usefulness of targeted therapy in APC is uncertain. Understanding in molecular processes and tumor biology has opened the door for new treatment strategies such as targeting insulin-like growth factor 1 receptor, transforming growth factor β, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Notch pathway. New directions also include the upcoming immunotherapy and many novel agents that act on the microenvironment. The practice of personalized medicine using predictive biomarkers and pharmacogenomics signatures may also enhance the effectiveness of existing treatment. Future treatment approaches may involve comprehensive genomic assessment of tumor and integrated combinations of multiple agents to overcome treatment resistance., (©AlphaMed Press.)

Purpose: The purpose of the study is to determine corticospinal organization using intraoperative neurophysiologic monitoring (IONM) during resective epilepsy surgery for patients with congenital hemiparesis and intractable epilepsy., Methods: Ten patients, aged 3-17, with intractable epilepsy underwent resective surgery. Transcranial stimulation (TCS) was achieved using a pair of cork screws at Cz and C3/C4, respectively. A 1 × 4 stimulating electrode strip was placed on the presumed motor cortex of the affected hemisphere for direct cortical stimulation (DCS) after craniotomy. Multipulse TCS and DCS train stimulation was delivered, with simultaneous recordings from bilateral abductor pollicis brevis and abductor halluces, to determine the corticospinal projection pattern of the paretic limbs., Results: The above mapping techniques revealed ipsilateral corticospinal projections from the contralesional hemisphere to target muscles in the paretic limbs in three patients, projections from both hemispheres to target muscles in three, and preserved crossed projections from the affected hemisphere in four. Nine patients were seizure free after surgery. Five had unchanged postoperative functional status, and three showed minimally improved use of the paretic hand. Two developed new motor deficits after surgery, which may have been due to a premotor syndrome in one patient, since it completely resolved within 2 weeks. The other experienced increased weakness of the paretic lower limb because a small part of the eloquent cortex was removed for better seizure control., Conclusions: Using IONM to define the corticospinal projection pattern is a valuable technique that can potentially replace preoperative fMRI and transcranial magnetic stimulation in resective epilepsy surgery, particularly for younger patients.

Introduction: Refilling intrathecal baclofen (ITB) pumps can be difficult because many patients gain excessive weight after implantation due to their reduced expenditure of energy on muscle spasticity., Methods: We report a case of a 12-year-old girl with spastic quadriplegia who gained 20 lbs after pump implantation. It was necessary to identify the access port of her pump by ultrasonography during drug refilling so as to avoid multiple needle punctures., Results: The access port of the pump was readily visible by ultrasonography and stood out from other parts of the pump., Conclusion: Localisation of the access ports of ITB pumps by ultrasonography proved to be a feasible and easy technique for refilling the drug reservoir in patients with excessive weight gain and abundant subcutaneous fat after ITB therapy.

We present the case of a 47-yr-old gentleman with cervical cord injury after he received massage in the neck area. Magnetic resonance imaging of the cervical spine showed a herniation of the nucleus pulposus and compressive myelopathy. The patient required surgical intervention and rehabilitation. Despite 6 mos of rehabilitation, residual hand dysfunction and minor ambulation problems persisted. Although massage has many benefits, this case reminds us that there is potential danger in performing neck massage.

Subdiffusion is an important physical phenomenon observed in many systems. However, numerical techniques to study it, especially when coupled to reactions, are lacking. In this paper, we develop an efficient Monte Carlo algorithm based on the Gillespie algorithm and the continuous-time random walk to simulate reaction-subdiffusion systems. Using this algorithm, we investigate Turing pattern formation in the Schnakenberg model with subdiffusion. First, we show that, as the system becomes more subdiffusive, the homogeneous state becomes more difficult to destablize and Turing patterns form less easily. Second, we show that, as the number of particles in the system decreases, the magnitude of fluctuations increases and again the Turing patterns form less easily. Third, we show that, as the system becomes more subdiffusive, the ratio between the two diffusive constants must be higher in order to observe Turing patterns. Finally, we also carry out linear stability analysis to validate the results obtained from our algorithm.

Introduction: Etoricoxib is a second generation cyclooxygenase-2 inhibitor with a rapid-onset time and a long duration of action. It is ideal for providing pre-emptive analgesia for ambulatory surgeries. We hypothesised that pre-operative etoricoxib can decrease the use of fentanyl post-operatively, when compared with placebo in patients undergoing termination of pregnancy. We also compared their pain scores, time to discharge, side effects and satisfaction with analgesia post-operatively., Methods: After approval by the hospital research ethics committee and receipt of informed written consent, we recruited 40 American Society of Anesthesiologists Physical Status Classification I and II patients scheduled for elective first trimester termination of pregnancy. Patients were randomly allocated to receive either oral etoricoxib 120 mg (Group E, n=20) or placebo tablet (Group P, n=20) pre-operatively. A blinded observer evaluated the post-operative pain scores, need for supplementary analgesia, side effects and satisfaction scores. Sample size was calculated (power of 0.8 and alpha=0.05) to detect a 20 percent difference in fentanyl usage. Amount of fentanyl used, pain scores and satisfaction scores were analysed using non-parametric tests. The incidence of side effects was analysed using chi-squared test., Results: Etoricoxib 120 mg significantly decreased the amount of fentanyl required after termination of pregnancy compared to placebo (0 microg/patient, interquartile range [IQR] 0-25 versus 50 microg/patient, IQR 0-50, p-value is less than 0.05). Patients who received etoricoxib 120 mg also had significantly lower pain scores than the placebo group at time of discharge (8 +/- 11 versus 1 +/- 3, p-value is less than 0.05) and at six hours post operation (8 +/- 12 versus 0 +/- 0, p-value is less than 0.01). There was no difference in their side effects, and time to discharge and overall satisfaction were similar in both groups., Conclusion: Pre-operative administration of oral etoricoxib 120 mg decreased the use of fentanyl and pain scores after minor gynaecological surgery without significant side effects.

Background: This randomized, double-blinded, controlled trial of 40 patients in early labor was conducted to determine whether a reduction in the total amount of intrathecal levobupivacaine and fentanyl would reduce the incidence of motor blockade and pruritus, respectively., Material/methods: Combined spinal epidural (CSE) analgesia was instituted. Group A (n=20) received 2.5 mg levobupivacaine with 25 microg fentanyl intrathecally while group B (n=20) received half that dose., Results: The duration and quality of spinal analgesia were comparable in the 2 groups. There was a reduced incidence of motor blockade in patients from Group B (P<0.01). This was apparent 5 minutes after the spinal injection and persisted throughout the next 30 minutes. However, there were also 2 parturients from this group who required epidural supplementation as a result of partial analgesia. Other side effects were not different between the 2 groups., Conclusions: A reduction in the intrathecal dose of 2.5 mg levobupivacaine with 25 microg fentanyl by half is an option for CSE in labor because it can reduce the incidence of motor impairment. Although the reduced dose does not differ significantly from the full dose with respect to onset, duration, and quality of analgesia for the majority of parturients, it must be highlighted that insufficient labor analgesia may occur in certain individuals. In this respect, further studies related to dosage of intrathecal levobupivacaine in obstetric labor analgesia will be beneficial in substantiating this point.

Advances in medical technology provide the modern day field anesthetist with the extra edge to meet the challenges faced in the harsh environment of the battlefield and enhance the survivability of casualties. The tasks of triage, resuscitation, and administration of anesthesia can be facilitated with the use of new airway devices, portable ventilators, and monitoring devices. Before such equipment is used in the field, the anesthetist must carefully weigh the advantages and disadvantages and must be cognizant of the limitations of individual devices in different environmental settings. These devices should ideally be portable, lightweight, rugged in construction, durable, easy to use (requiring minimal training and supervision), readily replaceable, and cost-effective.

Background: Postpartum haemorrhage due to retained placenta is one of the commonest life-threatening conditions during the third stage of labour. Uterine relaxation is usually required to facilitate placental removal. 'Full-stomach' obstetric patients (which includes those who delivered within 48 h), parturients with a history of antepartum or recurrent postpartum hemorrhage, grand multiparity, twin pregnancy, and those with cardiac abnormalities may benefit from an alternative to volatile-based general anaesthesia for uterine relaxation to avoid complications associated with the technique (e.g. aspiration pneumonitis and cardiovascular compromise)., Case Report: A 34-year-old gravida 4, para 3 parturient with rheumatic valvular heart disease presented with retained placenta and postpartum haemorrhage on two consecutive deliveries and had the placenta removed manually by the same surgeon under two different anaesthetic techniques. On the first occasion, general anaesthesia was administered whereas only i.v. fentanyl and nitro-glycerine were used on the second occasion. The postoperative course was uneventful on both occasions., Conclusions: The use of nitro-glycerine was found to be efficacious for manual removal of placenta with minimal haemodynamic perturbations, avoiding the use (and associated risks) of general anaesthesia for uterine relaxation. The ability of nitro-glycerine to reduce spontaneous uterine activity, induce uterine relaxation, coupled with its short duration of action and high efficacy, may render it a safe alternative to general anaesthesia for facilitating intrauterine manoeuvres. Nitro-glycerine may be useful especially in patients with associated co-morbid chronic cardiac conditions, e.g. rheumatic heart disease, which is characterised by impaired haemodynamics and cardiac reserves.