Unsatisfactory Outcomes In Patients Research Articles

Can we build better? Challenges with geospatial and financial accessibility in the Caribbean. Illustrative case.

Within the Caribbean, Curaçao provides a neurosurgical hub to other Dutch Caribbean islands. At times, the inefficiency of neurosurgical referrals leads to unsatisfactory patient outcomes in true emergency cases. This article reports an illustrative case of a patient in need of emergency neurosurgical care, who was referred to a tertiary health institution in Curaçao. This case highlights the challenges of timely neurosurgical referrals within the Dutch Caribbean. Highlighting this case may provide a foundation for further discussions that may improve neurosurgical care and access. Limiting long-distance surgical referrals in the acute care setting will aid in saving lives.

Evaluation of the Lebanese Adults' Knowledge Regarding Autism Spectrum Disorder.

The daily functioning and overall well-being of people with ASD depends largely on understanding how the wider public views ASD. Indeed, an increased level of ASD knowledge in the general population may result in earlier diagnosis, earlier intervention, and better overall outcomes. The present study aimed to examine the current state of ASD knowledge, beliefs, and sources of information in a Lebanese general population sample, to identify the factors that could influence this knowledge. A total of 500 participants were involved in this cross-sectional study, which was conducted in Lebanon between May 2022 and August 2022 using the Autism Spectrum Knowledge scale, General Population version (ASKSG). Overall, the participants' understanding of autism spectrum disorder was low, with a mean score of 13.8 (6.69) out of 32, or 43.1%. The highest knowledge score was found for items related to knowledge of the symptoms and associated behaviors (52%). However, the level of knowledge regarding the etiology and prevalence, assessment and diagnosis, treatment, outcomes, and prognosis of the disease was low (29%, 39.2%, 46%, and 43.4%, respectively). Moreover, age, gender, place of residence, sources of information, and ASD case were all statistically significant predictors of ASD knowledge (p < 0.001, p < 0.001, and p = 0.012, p < 0.001, p < 0.001, respectively). The general public in Lebanon perceive a lack of awareness and insufficient knowledge regarding ASD. This results in delayed identification and intervention, leading to unsatisfactory outcomes in patients. Raising awareness about autism among parents, teachers, and healthcare professionals should be a top priority.

Suppression of SMOC2 alleviates myocardial fibrosis via the ILK/p38 pathway.

Fibrosis of the myocardium is one of the main pathological changes of adverse cardiac remodeling, which is associated with unsatisfactory outcomes in patients with heart disease. Further investigations into the precise molecular mechanisms of cardiac fibrosis are urgently required to seek alternative therapeutic strategies for individuals suffering from heart failure. SMOC2 has been shown to be essential to exert key pathophysiological roles in various physiological processes in vivo, possibly contributing to the pathogenesis of fibrosis. A study investigating the relationship between SMOC2 and myocardial fibrosis has yet to be conducted. Mice received a continuous ISO injection subcutaneously to induce cardiac fibrosis, and down-regulation of SMOC2 was achieved by adeno-associated virus-9 (AAV9)-mediated shRNA knockdown. Neonatal fibroblasts were separated and cultured in vitro with TGFβ to trigger fibrosis and infected with either sh-SMOC2 or sh-RNA as a control. The role and mechanisms of SMOC2 in myocardial fibrosis were further examined and analyzed. SMOC2 knockdown partially reversed cardiac functional impairment and cardiac fibrosis in vivo after 21 consecutive days of ISO injection. We further demonstrated that targeting SMOC2 expression effectively slowed down the trans-differentiation and collagen deposition of cardiac fibroblasts stimulated by TGFβ. Mechanistically, targeting SMOC2 expression inhibited the induction of ILK and p38 in vivo and in vitro, and ILK overexpression increased p38 phosphorylation activity and compromised the protective effects of sh-SMOC2-mediated cardiac fibrosis. Therapeutic SMOC2 silencing alleviated cardiac fibrosis through inhibition of the ILK/p38 signaling, providing a preventative and control strategy for cardiac remodeling management in clinical practice.

Biomarkers of Glycocalyx Injury and Endothelial Activation are Associated with Clinical Outcomes in Patients with Sepsis: A Systematic Review and Meta-Analysis.

Sepsis is one of the main causes of morbidity and mortality worldwide. Microcirculatory impairment, especially damage to the endothelium and glycocalyx, is often not assessed. The objective of this systematic review and meta-analysis was to summarize the available evidence of the risk of unsatisfactory outcomes in patients with sepsis and elevated glycocalyx injury and endothelial activation biomarkers. A systematic search was carried out on PubMed/MEDLINE, Embase, Cochrane and Google Scholar up to December 31, 2021, including studies in adults and children with sepsis which measured glycocalyx injury and endothelial activation biomarkers within 48 hours of hospital admission. The primary outcome was the risk of mortality from all causes and the secondary outcomes were the risk of developing respiratory failure (RF) and multiple organ dysfunction syndrome (MODS) in patients with elevations of these biomarkers. A total of 17 studies (3,529 patients) were included: 11 evaluated syndecan-1 (n=2,397) and 6 endocan (n=1,132). Syndecan-1 was higher in the group of patients who died than in those who survived [255 ng/mL (IQR: 139-305) vs. 83 ng/mL (IQR:40-111); p=0.014]. Patients with elevated syndecan-1 had a greater risk of death (OR 2.32; 95% CI 1.89, 3.10: p<0.001), MODS (OR 3.3; 95% CI 1.51, 7.25: p=0.003;), or RF (OR 7.53; 95% CI 1.86-30.45: p=0.005). Endocan was higher in patients who died [3.1 ng/mL (IQR 2.3, 3.7) vs. 1.62 ng/mL (IQR 1.2, 5.7); OR 9.53; 95% CI 3.34, 27.3; p<0.001], who had MODS (OR 8.33; 95% CI 2.07, 33.58; p=0.003) and who had RF (OR 9.66; 95% CI 2.26, 43.95; p=0.002). Patients with sepsis and abnormal glycocalyx injury and endothelial activation biomarkers have a greater risk of developing respiratory failure, multiple organ failure, and death. Microcirculatory impairment should be routinely evaluated in patients with sepsis, using biomarkers to stratify risk groups.

Consensus on a standardised treatment pathway algorithm for lumbar spinal stenosis: an international Delphi study.

BackgroundLumbar spinal stenosis (LSS) is a common degenerative spinal condition in older adults associated with disability, diminished quality of life, and substantial healthcare costs. Individual symptoms and needs vary. With sparse and sometimes inconsistent evidence to guide clinical decision-making, variable clinical care may lead to unsatisfactory patient outcomes and inefficient use of healthcare resources.MethodsA three-phase modified Delphi study comprising four consensus rounds was conducted on behalf of the International Taskforce for the Diagnosis and Management of LSS to develop a treatment algorithm based on multi-professional international expert consensus. Participants with expertise in the assessment and management of people with LSS were invited using an international distribution process used for two previous Delphi studies led by the Taskforce. Separate treatment pathways for patients with different symptom types and severity were developed and incorporated into a proposed treatment algorithm through consensus rounds 1 to 3. Agreement with the proposed algorithm was evaluated in the final consensus round.ResultsThe final algorithm combines stratified and stepped approaches. When indicated, immediate investigation and surgery is advocated. Otherwise, a stepped approach is suggested when self-directed care is unsatisfactory. This starts with tailored rehabilitation, then more complex multidisciplinary care, investigations and surgery options if needed. Treatment options in each step depend on clinical phenotype and symptom severity. Treatment response guides pathway entrance and exit points. Of 397 study participants, 86% rated their agreement ≥ 4 for the proposed algorithm on a 0–6 scale, of which 22% completely agreed. Only 7% disagreed. Over 70% of participants felt that the algorithm would be useful for clinicians in public healthcare (both primary care and specialist settings) and in private healthcare settings, and that a simplified version would help patients in shared decision-making.ConclusionsInternational and multi-professional agreement was achieved for a proposed LSS treatment algorithm developed through expert consensus. The algorithm advocates different pathway options depending on clinical indications. It is not intended as a treatment protocol and will require evaluation against current care for clinical and cost-effectiveness. It may, however, serve as a clinical guide until evidence is sufficient to inform a fully stratified care model.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12891-022-05485-5.

Complement factor D as a predictor of Achilles tendon healing and long‐term patient outcomes

Dense connective tissue healing, such as tendon, is protracted leading to highly variable and unsatisfactory patient outcomes. Biomarkers prognostic of long-term clinical outcomes is, however, unknown. The present study was designed to investigate the proteomic profile of healing, identify potential biomarkers, and assess their association with the patient's long-term outcomes after ATR. Quantitative mass spectrometry analysis demonstrated 1423 proteins in healing and contralateral healthy Achilles tendons of 28 ATR patients. Comparing healing at 2weeks and healthy protein profiles, we identified 821 overlapping, 390 upregulated, and 17 downregulated proteins. Upregulated proteins are related mainly to extracellular matrix organization and metabolism, while downregulated pathways were associated with exocytosis in immune modulation and thrombosis formation. Further proteomic profiling in relation to validated patient outcomes revealed the downregulated pro-inflammatory complement factor D (CFD) as the most reliable predictive biomarker of successful tendon healing. Our finding showed a comprehensive proteomic landscape and bioinformatics on human connective tissue, indicating subtype-specific and shared biological processes and proteins in healing and healthy Achilles tendons, as well as in tendons related to good and poor patient outcomes. Inflammatory protein CFD and serpin family B member 1 were finally identified as potential predictive biomarkers of effective healing outcomes when combined the proteomic profiles with a validated clinical database. Following the future elucidation of the mechanisms associated with the identified biomarkers as predictors of good outcomes, our findings could lead to improved prognostic accuracy and development of targeted treatments, thus improving the long-term healing outcomes for all patients.

Open Reduction &amp; Internal Fixation in Case of Clavicle Fracture &amp; Their Outcomes

Introduction: Clavicle fractures are common, and account for about 2.6 % of all fractures and nearly 44 % of those in the shoulder girdle. Fractures of the middle third of the clavicle are most common (81%). Surgical operation for displaced clavicle fractures is controversial. Traditionally, these fractures have been treated in non-operative ways. This traditional treatment is not without complications, such as shortening, nonunion, deformity and unsatisfactory patient outcomes. In recent days, operative treatment has proven superior results. Aim of the study: Early union &amp; reliable treatment with predictable outcomes. Methods: This is a prospective study, a total of 15 patients were included and analyzed in this study. This study was carried out from January 2016 to June 2020 at Z. H. Sikder Women’s Medical College Hospital &amp; Northern International Medical College and Hospital. The method of fixation of the clavicular fracture was open reduction and internal fixation with a reconstruction plate in twenty patients, a hook plate and T-plate for distal clavicle fracture. Result: In this study, a total of 15 patients were included and analyzed. Table-1 shows the clinical characteristics of the study patients, 8(53.33%) patients were from the age range 31-45, 4(26.67%) patients were from the age range 15-39 and 3(20.00%) patients were from the age range 45-60. The male patients were 12(80%) and the female patients were 3(20%). Figure-1 shows the mean constant shoulder scores of patients. The complication of studying patients was shown in Table-4, 8(53.33%) patients were from unsatisfactory appearance, 4(26.67%) patients were from adhesive capsulitis, 3(30.00%) patients were from both superficial infection and paresthesia over the surgical site and 2(13.33%) patients were from non-union. Conclusion: In conclusion, the conservative treatment remains the treatment of choice for simple clavicle fractures, but for displaced and comminuted fractures surgical intervention ....

Professional quality of life of nurses in critical care units: Influence of demographic characteristics

Background Professional quality of life, measured as compassion satisfaction, is a prerequisite for nurses working in intensive care units where patients rely on their care. Nurses who experience compassion satisfaction, or good professional quality of life, engage enthusiastically with all work activities and render quality patient care. In contrast, compassion fatigue eventually leads to disengagement from work activities and unsatisfactory patient outcomes. In this study, we described the demographic factors influencing professional quality of life of intensive care nurses working in public hospitals in Gauteng, South Africa (SA), during the first wave of the COVID-19 pandemic. Objectives To describe the demographic factors associated with professional quality of life of critical care nurses working in Gauteng, SA Methods In this cross-sectional study, we used total population sampling and invited all nurses who had worked for at least 1 year in one of the critical care units of three selected public hospitals in Gauteng to participate. One-hundred and fifty-four nurses responded and completed the ProQol-5 tool during the first wave of the COVID-19 pandemic. Data were analysed using descriptive and inferential statistics. Results The nurses’ average age was 45 years, and 59.1% (n=91) had an additional qualification in critical care nursing. Most of the nurses had a diploma (51.3%; n=79), with a mean work experience of 12.56 years. The main demographic variables that influenced professional quality of life were years of work experience (p=0.047), nurses’ education with specific reference to a bachelor’s degree (p=0.006) and nurse-patient ratio (p<0.001). Conclusion Nurses working in critical care units in public hospitals in Gauteng experienced low to moderate compassion satisfaction, moderate to high burnout and secondary traumatic stress, suggesting compassion fatigue. The high workload, which may have been associated with the COVID-19 pandemic, influenced nurses’ professional quality of life. Contributions of the study This study reports on the important problem of compassion fatigue and burnout amongst South African ICU nurses working in the public sector. Associated factors were identified, which should be addressed to improve nurses’ wellbeing.

Effectiveness of Nurse-led Intervention to Improve Quality of life for Family Caregivers of Children with Leukemia: A Quasi-Experimental Study from Karachi Pakistan

Background: Acute lymphoblastic leukemia accounts for 25% of all cancers in children less than 15 years old. The treatment phase of leukemia is lengthy and takes 2-3 years. Due to prolonged treatment, family caregivers often become exhausted, highly distressed with low quality of life and unsatisfactory patient outcomes. Thus, caregivers need interventions such as adaptation strategies and access to support groups that enhance their wellbeing and improves their quality of life (QoL).&#x0D; Objectives: To determine the effectiveness of nurse-led structured educational intervention for family caregivers having a child diagnosed with leukemia and to examine the association between socio-demographic variables and quality of life of leukemia child caregiver.&#x0D; Methodology: A Quasi-Experimental pre-post-test design was applied at the tertiary care hospital of Karachi. A total of 74 family caregivers of leukemia children were recruited from outpatient and inpatient oncology departments using purposive sampling. The data was collected pre-intervention and post-intervention using QoL-FV. Intervention of educational session given in 30-45 minutes for 4 days and after 1month of intervention, posttest done by same questionnaire to estimate the effect of nurse-led education&#x0D; Results: Study findings revealed that mean score of overall QoL improved after one-month of nurse-led educational intervention 95+ 23 and had a significant difference in post-test QOL (&lt;0.001). The sub-dimensions of QoL such as physical wellbeing, psychological wellbeing, and social concern improved significantly in posttest interventions group (P&lt; 0.01). Whereas the spiritual wellbeing was found insignificant after interventions (p&gt;0.080). &#x0D; Conclusion: The study suggests that Nurse-Led education program is helpful to improve family caregivers' quality of life during the treatment journey of their leukemia patient. it must be considered and acknowledged with prime importance and caregivers should be supported by health care professionals.&#x0D; Recommendation: It should be an important aspect to include counseling sessions of families to improve their coping, problem solving and awareness.

Methods for Minimizing Bleeding in Facelift Surgery: An Evidence-based Review.

Introduction:Bleeding and hematoma remain leading causes of postoperative complications and unsatisfactory patient outcomes in facelift surgery. Several methods have been implemented, and continue to be developed, to minimize bleeding in facelift surgery. These methods include perioperative blood pressure management, compression dressings, drains, tissue sealants, wetting solution infiltrate, and tranexamic acid.Methods:An evidence-based review of methods used to minimize bleeding in facelift surgery was conducted using the PubMed database according to PRISMA guidelines. Included studies were evaluated for the effects of implemented methods on bleeding outcomes in facelift surgery. Recommendations for each method evaluated were determined based on the amount, level, and heterogeneity of included studies.Results:Thirty-six studies were included in the evidence-based review. Effective strategies to reduce the time to hemostasis, postoperative drainage volume, and hematoma rate included perioperative blood pressure management, tissue sealants, and tranexamic acid. While the use of drains or wetting solution infiltrate did not demonstrate to significantly influence bleeding outcome measures, these methods may provide other advantages to facelift surgery. Compression dressings have not demonstrated a significant effect on facelift outcome measures.Conclusions:Perioperative medical management of blood pressure, tissue sealants, and tranexamic acid are most effective in facilitating hemostasis and preventing postoperative hematoma in facelift surgery.

Three-Dimensional Engineered Peripheral Nerve: Toward a New Era of Patient-Specific Nerve Repair Solutions.

Reconstruction of peripheral nerve injuries (PNIs) with substance loss remains challenging because of limited treatment solutions and unsatisfactory patient outcomes. Currently, nerve autografting is the first-line management choice for bridging critical-sized nerve defects. The procedure, however, is often complicated by donor site morbidity and paucity of nerve tissue, raising a quest for better alternatives. The application of other treatment surrogates, such as nerve guides, remains questionable, and it is inefficient in irreducible nerve gaps. More importantly, these strategies lack customization for personalized patient therapy, which is a significant drawback of these nerve repair options. This negatively impacts the fascicle-to-fascicle regeneration process, critical to restoring the physiological axonal pathway of the disrupted nerve. Recently, the use of additive manufacturing (AM) technologies has offered major advancements to the bioengineering solutions for PNI therapy. These techniques aim at reinstating the native nerve fascicle pathway using biomimetic approaches, thereby augmenting end-organ innervation. AM-based approaches, such as three-dimensional (3D) bioprinting, are capable of biofabricating 3D-engineered nerve graft scaffolds in a patient-specific manner with high precision. Moreover, realistic in vitro models of peripheral nerve tissues that represent the physiologically and functionally relevant environment of human organs could also be developed. However, the technology is still nascent and faces major translational hurdles. In this review, we spotlighted the clinical burden of PNIs and most up-to-date treatment to address nerve gaps. Next, a summarized illustration of the nerve ultrastructure that guides research solutions is discussed. This is followed by a contrast of the existing bioengineering strategies used to repair peripheral nerve discontinuities. In addition, we elaborated on the most recent advances in 3D printing and biofabrication applications in peripheral nerve modeling and engineering. Finally, the major challenges that limit the evolution of the field along with their possible solutions are also critically analyzed. Impact statement Complex nerve injuries, including critical-sized gaps (>3 cm loss of substance), gaps involving nerve bifurcations, and those associated with ischemic environments, are difficult to manage. A biomimetic, personalized peripheral nerve tissue surrogate to address these injuries is lacking. The peripheral nerve repair market currently represents a multi-billion-dollar industry that is projected to expand. Given the clinical and economical dilemmas posed by this medical condition, it is crucial to devise novel and effective nerve substitutes. In this review article, we discuss progress in three-dimensional printing technologies, including biofabrication and nerve computer-aided design modeling, toward achieving a patient-specific and biomimetic nerve repair solution.

Transcranial Direct Current Stimulation in Patients with Anxiety: Current Perspectives.

Anxiety is one of the most prevalent and debilitating psychiatric conditions worldwide. Pharmaco- and psycho-therapies have been employed in the treatment of human anxiety to date. Yet, either alone or in combination, unsatisfactory patient outcomes are prevalent, resulting in a considerable number of people whose symptoms fail to respond to conventional therapies with symptoms remaining after intervention. The demand for new therapies has given birth to several noninvasive brain stimulation techniques. Transcranial direct current stimulation (tDCS) has arisen as a promising tool and has been proven to be safe and well tolerated for the treatment of many diseases, including chronic pain, depression, and anxiety. Here, reports of the use of tDCS in anxiety disorders in human patients were reviewed and summarized. A literature search was conducted in mid-2019, to identify clinical studies that evaluated the use of tDCS for the treatment of anxiety behavior. The PubMed, Web of Science, and Scielo and PsycInfo databases were explored using the following descriptors: “anxiety”, “anxious behavior”, “tDCS”, and “transcranial direct current stimulation”. Among the selected articles, considerable variability in the type of tDCS treatment applied in interventions was observed. Evidence shows that tDCS may be more effective when used in combination with drugs and cognitive behavioral therapies; however future large-scale clinical trials are recommended to better clarify the real effects of this intervention alone, or in combination with others.

Predictors of unsatisfactory patient outcomes in primary reverse total shoulder arthroplasty

Despite favorable clinical and functional results for reverse total shoulder arthroplasty (RSA), there remains a group of patients without postoperative complications who demonstrate poor improvement and overall outcome. Using a single surgeon shoulder arthroplasty registry, we identified patients who underwent RSA from 2013 to 2016 with minimum of 2-year postoperative follow-up. Patients with intra- and postoperative complications were excluded. Poor postoperative clinical outcome was defined as those patients within the bottom 30th percentile for American Shoulder and Elbow Surgeons (ASES) score. Poor postoperative improvement was defined as the bottom 30th percentile of ASES improvement, measured preoperatively to the 2-year postoperative mark. Multivariate logistic regression modeling was used to determine preoperative characteristics (e.g., demographics, comorbidities, preoperative ASES score) associated with poor outcome. A total of 137 patients met the inclusion and exclusion criteria. Multivariable logistic regression modeling found that prior shoulder surgery, the majority (75%) of which were arthroscopic, was the only independent factor associated with both poor improvement (adjusted odds ratio, 2.46 [1.03-5.83]) and outcome (adjusted odds ratio, 4.92 [1.74-14.96]). Preoperative opioid use was associated with poor outcomes only, whereas the high preoperative ASES score was associated with poor postoperative improvement. Prior ipsilateral shoulder surgery was strongly associated with poor clinical improvement and outcome after RSA. No other factors correlated with both poor improvement and outcome. This association is important to decision making for any shoulder surgery, given the long-term implications.

GPAA1 promotes gastric cancer progression via upregulation of GPI-anchored protein and enhancement of ERBB signalling pathway

BackgroundGastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. However, existing therapies are insufficient to meet patients’ needs; thus, the identification of additional therapeutic targets and exploration of the underlying mechanism are urgently needed. GPAA1 is the subunit of the GPI transamidase that transfers the GPI anchor to proteins within the ER. The functional impacts of increased expression levels of GPAA1 in human cancers are not well understood.MethodsData mining was performed to determine the pattern of GPAA1 expression and the reason for its overexpression in tumour and adjacent normal tissues. In vitro and in vivo experiments evaluating proliferation and metastasis were performed using cells with stable deletion or overexpression of GPAA1. A tissue microarray established by the Ren Ji Hospital was utilized to analyse the expression profile of GPAA1 and its correlation with prognosis. Western blotting, an in situ proximity ligation assay, and co-immunoprecipitation (co-IP) were performed to reveal the mechanism of GPAA1 in gastric cancer.ResultsGPAA1 was a markedly upregulated oncogene in gastric cancer due to chromosomal amplification. GPAA1 overexpression was confirmed in specimens from the Ren Ji cohort and was associated with ERBB2 expression, predicting unsatisfactory patient outcomes. Aberrantly upregulated GPAA1 dramatically contributed to cancer growth and metastasis in in vitro and in vivo studies. Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling.ConclusionsGPAA1 facilitates the expression of cancer-related GPI-anchored proteins and supplies a more robust platform—the lipid raft—to promote EGFR-ERBB2 dimerization, which further contributes to tumour growth and metastasis and to cancer progression. GPAA1 could be a promising diagnostic biomarker and therapeutic target for gastric cancer.

Identification of Tipifarnib Sensitivity Biomarkers in T-Cell Tumor Cell Lines

BackgroundT-cell leukemia and lymphoma (TCL) is a very aggressive and heterogeneous group of hematological malignancies with poor prognosis and inadequate response to current therapies. The standard first-line treatments have resulted in unsatisfactory patient outcomes and unfortunately, targeted treatments are still at a preliminary phase. The RAS/MAPK pathway is crucial for TCR signaling of T-cells and it is deregulated in TCL. We aimed to determine the therapeutic value of farnesyl transferase inhibitor (FTIs) tipifarnib in TCL cell lines. Effects on cell viability, apoptosis, cell cycle and gene expression were evaluated. Tipifarnib blocks the localization of some farnesylated proteins, including some RAS family members, to cellular membranes, thereby inhibiting their activation. Tipifarnib is a potent and specific FTI with prominent anti-proliferative effects.MethodsWe tested tipifarnib in 18 T-cell leukemia and 4 T-cell lymphoma cell lines for in vitro sensitivity and for biomarker discovery, both genomic and immunohistochemical. We selected cell lines with available genomic data from COSMIC, CCLE or generated by our group. The MAPK, NFAT, NFKB and JAK/STAT pathways were tested by immunohistochemistry analysis under basal conditions. The range of drug concentrations to perform IC50 analysis was established between 0-10,000 nM (ten points), using CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, Madison, WI, USA) following manufacturer´s instructions at 0h, 48h and 96h. All experiments were done in sextuplet and all numerical data were expressed as the average of the values ± the standard error of the mean. IC50 analyses were performed with GraphPad Prism v5. Clinically-relevant drug sensitivity was defined as IC50 <100nM at 96h (defined as sensitive). RNAseq was performed in 4 sensitive cell lines with tipifarnib and DMSO (vehicle) in three biological replicates at 72h. Differential gene expression (DE) analysis was carried out under these two conditions. Pathway analysis was done using Gene Set Enrichment Analysis (GSEA). Induction of apoptosis and cell viability were tested by flow cytometry in sensitive cell lines.Results59.1% (n=13) of cell lines were sensitive to tipifarnib at concentrations which are readily achievable in the clinic. RAS, RAS-guanine nucleotide exchange factors (GEFs) and RAS-GTPase activating proteins (GAPs) genes were mutated in 45.5%, 50% and 27.3%, of cell lines respectively, but their mutational status was not associated with drug sensitivity. We found TP53 and DNMT3 mutated in 80% and 33.3% in sensitive cell lines respectively, and in 63.6% and 0% in resistant cell lines. The mutational state of NOTCH1 was associated with tipifarnib sensitivity; 66.7% in sensitive cell lines versus 9.1% in resistant cell lines (p=0.005). ERK activation (MAPK pathway) was significantly associated with drug sensitivity (p=0.046). Conversely, RelB (NFκB pathway) was associated with drug resistance (p=0.007). GSEA analysis showed that tipifarnib downregulated cell cycle, protein localization to membranes, metabolism, and ribosome and mitochondrial activity. The effect of tipifarnib on cell cycle progression and apoptosis was validated by flow cytometry assays. Tipifarnib decreased cellular viability, increased apoptosis and blocked cell cycle progression in G1 phase. GSEA of molecular pathways regulated by tipifarnib identified downregulation of MYC targets and mTOR and MAPK pathways. MYC is a target of NOTCH1, mutated in sensitive cases and associated with tipifarnib sensitivity.ConclusionsIn vitro response to tipifarnib in T-cell lymphoma and leukemia cell lines can be predicted using several biomarkers. The mutational NOTCH1 status, together with p-ERK (MAPK activation) were associated with increased sensitivity while RelB expression was associated with resistance. DisclosuresGualberto:Kura Oncology: Employment, Equity Ownership. Piris:Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Kura: Honoraria.

Stereotactic Lesioning of the Thalamic Vo Nucleus for the Treatment of Writer's Cramp (Focal Hand Dystonia).

Writer's cramp (focal hand dystonia) is a sporadic focal dystonia that affects a specific part of the upper limb causing excessive co-contraction of antagonistic muscles. It usually presents as a task-specific dystonia, including, among others, writing of a character or playing a musical instrument. Although treatments for writer's cramp exist, medical therapy often results in unsatisfactory outcomes in patients with this type of dystonia. However, accumulating evidence suggests that long-term and complete remission of various types of focal hand dystonia can be achieved with stereotactic ablation or deep brain stimulation of the thalamic ventral-oralis complex (Vo) nucleus, which includes both the ventralis oralis posterior and anterior nuclei of the thalamus. Following the striking therapeutic success of Vo thalamotomy in patients with medically-refractory writer's cramp, we here introduce the use of stereotactic lesioning of the thalamic Vo nucleus for the treatment of this focal type of dystonia. Our findings identified patients with disabling writer's cramp (i.e., it prevents their success in their professional careers) to be good candidates for positive outcome with this surgical technique.

Comparative outcomes of vascular access in patients older than 70 years with end-stage renal disease

ObjectiveThe advantage of arteriovenous fistulas (AVFs) in older patients requiring dialysis is controversial. We reviewed our vascular access experience in patients ≥70 years of age (older group) compared with younger patients. MethodsWe analyzed consecutive patients who underwent access surgery between 2013 and 2016. Primary success (PS) and primary patency (PP) data were analyzed between the older and younger groups before and after propensity score matching of the patients' characteristics and access composition. PS was defined as the achievement of access function that was amenable to two sessions of successful cannulation without early occlusion or maturation failure requiring revision. PP was defined as the time with uninterrupted patency without intervention. ResultsA total of 594 consecutive accesses were created among 563 patients, of whom 119 were allocated into each group after propensity score matching. In the whole cohort, 193 accesses (32.5%) were performed in older patients. AVFs were performed in 130 (67.4%) older patients and 293 (73.1%) younger patients. Regarding AVFs, the PS rate (83.6% in the older group vs 94.3% in the younger group; P = .001) and the overall PP at 6 and 12 months (73.1% and 57.1%, respectively, in the older group vs 86.7% and 77.7%, respectively, in the younger group; P = .009) were lower in the older group than in the younger group. However, no differences were found in the PS and PP rates for arteriovenous grafts between groups. Regarding the AVF location, the PS rate for forearm AVFs was significantly lower in the older group than in the younger group (76% vs 93%; P < .001); however, the PS rate of the upper arm was not different between the groups (94% vs 97%; P = .425). In the patients with PS, the PP rate of AVFs was similar between the two groups. In the older group with forearm AVFs, the median diameter of the radial artery was larger in the patients with PS than in the patients without PS (2.20 mm with PS vs 2.00 mm without PS; P = .008). The propensity score matching results demonstrated similar trends for the whole cohort, with lower PS (P = .042) and PP rates (P = .023) for AVF in the older group. ConclusionsThe outcomes after AVF were poorer in the older group than in the younger group, which was primarily due to unsatisfactory outcomes in patients with forearm AVFs. Thus, stricter criteria, especially regarding the radial artery diameter, should be applied for forearm AVFs in older patients, and additional research is necessary to delineate the risk factors for primary failure.

Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer

Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways.

Therapeutic options in peripheral T cell lymphoma.

Peripheral T cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphomas with a very poor prognosis. The standard first-line treatments have resulted in unsatisfactory patient outcomes. With the exception of low-risk anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), the majority of patients relapse rapidly; the current 5-year overall survival rates are only 10–30 %. Novel targeted therapies and combination chemotherapies are required for the treatment of patients with PTCL. In recent years, some retrospective and prospective studies have been performed concerning PTCL. Consequently, a number of novel agents and their relevant combination therapies have been identified, including histone deacetylase inhibitors, immunoconjugates, antifolates, monoclonal antibodies, immunomodulatory agents, nucleoside analogs, proteasome inhibitors, kinase inhibitors, bendamustine, l-asparaginase, and other targeted agents. It is hoped that these innovative approaches will finally improve outcomes in patients with PTCL. This review summarizes the currently available approaches for the treatment of PTCL with an emphasis on potential new agents, including the role of stem cell transplantation.

Investigation of Nasal Mobility in Asians and its Change After Alloplastic Augmentation

Augmentation rhinoplasty is one of the most popular cosmetic surgeries in Asia, and both dorsal augmentation and mobile nose modifications are emphasized for the characters of the Asian nose and for Asians who are fond of the Western nasal shape. The goal in rhinoplasty is to create a balanced and natural appearance. Therefore, the cosmetic aspects, postoperative complications, and functional aspects should be regarded as a whole. In fact, the first 2 aspects had been widely reported in a large number of literatures. However, the functional aspects about mobility have been ignored by most surgeons. A sample method was used in this article to investigate the range of mobility of normal nasal tip in Asians and analyze the correlations of the nasal mobility and alloplastic materials. A total of 170 healthy adult subjects aged from 18 to 35 were included and were classified into 3 groups standing for normal nose and rhinoplasty with L-shaped silicon implants with e-PTFE implants. A 3D raster surface scanner was used to capture the images of the subjects accurately and rapidly in this detailed anatomical study. The range of nasal mobility (to right or left) in Asian normal women was 35.53 ± 4.84 degrees, and the length of mobile part was 16.62 ± 1.94 mm, which accounts for 40% ± 5% of nasal length. The L-shaped alloplastic implants would reduce the nasal mobility, and there had been differences among the changes caused by different implants, which might cause unsatisfactory outcomes in patients. Results of the study indicated that augmentation rhinoplasty should be performed as well as augmented mammaplasty which attaches importance not only to the static and dynamic appearance of the nasal tip but also to the feeling when it is touched.