The Impact of a Narcotic-Sparing Enhanced Recovery Protocol on Postoperative Narcotic Use Following Colectomy.

BACKGROUND: In the United States, 37% of all opioids are prescribed in the surgical setting, many of which report initial exposure in the postoperative period. OBJECTIVE: This study aimed to assess the impact of a narcotic-sparing enhanced recovery after surgery protocol on postoperative narcotic use by patients and to assess its impact on the narcotic-prescribing practices of physicians. DESIGN: Data regarding consecutive narcotic-naïve patients who underwent a surgical procedure from January 2013 to August 2017 were retrospectively reviewed. SETTINGS: Patients were divided into 2 cohorts: preimplementation (2013-2015) and postimplementation (2015-2017) of the enhanced recovery after surgery protocol. PATIENTS: This study included patients who underwent elective inpatient abdominal colorectal surgery at the University of Florida Health. MAIN OUTCOME MEASURES: The primary outcome measure was 30-day postoperative narcotic use (inpatient and outpatient). Other outcomes measured included pain scores, time to diet institution, length of hospital stay, cost of hospitalization, and postoperative complications. RESULTS: Baseline characteristics were similar between the preprotocol group (n = 537) and postprotocol group (n = 790). Protocol implementation was associated with a decrease in the total 30-day postoperative narcotic amount used by patients (2481 vs 31 morphine milligram equivalents; p = 0.05), inpatient patient-controlled analgesia use (63% vs 0.5%; p < 0.00001; dosage 1254 vs 5 morphine milligram equivalents), inpatient on-demand oral narcotic use (90% vs 32%; p = 0.001; dosage 47 vs 5 morphine milligram equivalents), and outpatient narcotic amount used (46 vs 6 morphine milligram equivalents; p = 0.001). Average pain scores were similar. LIMITATIONS: Retrospective nature of the study and possible underestimation of pre- and postoperative narcotic use. CONCLUSIONS: Implementation of a narcotic-sparing enhanced recovery after surgery protocol was associated with a decrease in both inpatient and 30-day outpatient postoperative narcotic use. Variation in resident physician prescribing practices suggests the need for ongoing education to accompany these protocols. See Video Abstract at http://links.lww.com/DCR/B936 . EL IMPACTO DE UN PROTOCOLO DE RECUPERACIN MEJORADO CON AHORRO DE NARCTICOS EN EL USO POSTOPERATORIO DE NARCTICOS DESPUS DE UNA COLECTOMA: ANTECEDENTES:En los Estados Unidos, el 37 % de todos los opioides se prescriben en el entorno quirúrgico. Entre los adictos a los narcóticos, muchos reportan una exposición inicial en el período posoperatorio.OBJETIVO:Nuestro objetivo fue evaluar el impacto de un protocolo de recuperación mejorada después de la cirugía que ahorra narcóticos en el uso de narcóticos postoperatorios por parte de los pacientes y evaluar su impacto en las prácticas de prescripción de narcóticos de los médicos.DISEÑO:Se revisaron retrospectivamente los datos de pacientes consecutivos sin tratamiento previo con narcóticos que se sometieron a un procedimiento quirúrgico colorrectal abdominal electivo para pacientes hospitalizados desde enero de 2013 hasta agosto de 2017.AJUSTE:Los pacientes se dividieron en 2 cohortes: antes de la implementación (2013-2015) y después de la implementación (2015-2017) del protocolo de recuperación mejorada después de la cirugía.PACIENTES:Pacientes de cirugía colorrectal abdominal electiva para pacientes internados en University of Florida Health.MEDIDAS DE RESULTADO PRINCIPALES:La medida de resultado primaria fue el uso de narcóticos postoperatorios de 30 días (pacientes hospitalizados y ambulatorios). Otros resultados medidos incluyeron puntuaciones de dolor, tiempo hasta la institución de la dieta, duración de la estancia hospitalaria, costo de la hospitalización y complicaciones postoperatorias.RESULTADOS:Las características iniciales fueron similares entre los grupos antes (n = 537) y después del protocolo (n = 790). La implementación del protocolo se asoció con una disminución en la cantidad total de narcóticos postoperatorios de 30 días utilizada por los pacientes (2481 mg frente a 31 mg de equivalentes de morfina, p = 0,05), uso de analgesia controlada por pacientes hospitalizados (63 % frente a 0,5 %, p < 0,00001; dosis 1254 mg frente a 5 mg), uso de narcóticos orales a demanda en pacientes hospitalizados (90 % frente a 32 %, p = 0,001; dosis de 47 mg frente a 5 mg) y cantidad de narcóticos utilizados en pacientes ambulatorios (46 mg frente a 6 mg, p = 0,001). Las puntuaciones medias de dolor fueron similares.LIMITACIONES:La naturaleza retrospectiva del estudio y la posible sub estimación del uso de narcóticos antes y después de la operación fueron limitaciones de los hallazgos del estudio.CONCLUSIÓN:La implementación de un protocolo de recuperación mejorada después de la cirugía que ahorra narcóticos se asoció con una disminución en el uso de narcóticos en el postoperatorio de pacientes hospitalizados y ambulatorios de 30 días. La variación en las prácticas de prescripción de los médicos residentes sugiere la necesidad de una educación continua que acompañe a estos protocolos. Consulte Video Resumen en http://links.lww.com/DCR/B936 . (Traducción-Dr. Mauricio Santamaria ).

Activity of Sorafenib Plus Capecitabine in Previously Treated Metastatic Colorectal Cancer.

LESSONS LEARNED: Treatment for patients with metastatic colorectal cancer (mCRC) typically involves multiple lines of therapy with eventual development of treatment resistance. In this single-arm, phase II study involving heavily pretreated patients, the combination of sorafenib and capecitabine yielded a clinically meaningful progression-free survival of 6.2 months with an acceptable toxicity profile. This oral doublet therapy is worthy of continued investigation for clinical use in patients with mCRC. BACKGROUND: Capecitabine (Cape) is an oral prodrug of the antimetabolite 5-fluorouracil. Sorafenib (Sor) inhibits multiple signaling pathways involved in angiogenesis and tumor proliferation. SorCape has been previously studied in metastatic breast cancer. METHODS: This single-arm, phase II study was designed to evaluate the activity of SorCape in refractory metastatic colorectal cancer (mCRC). Patients received Sor (200 mg p.o. b.i.d. max daily) and Cape (1,000 mg/m2 p.o. b.i.d. on days 1-14) on a 21-day treatment cycle. Primary endpoint was progression-free survival (PFS) with preplanned comparison with historical controls. RESULTS: Forty-two patients were treated for a median number of 3.5 cycles (range 1-39). Median PFS was 6.2 (95% confidence interval [CI], 4.3-7.9) months, and overall survival (OS) was 8.8 (95% CI, 4.3-12.2) months. One patient (2.4%) had partial response (PR), and 22 patients (52.4%) had stable disease (SD) for a clinical benefit rate of 54.8% (95% CI, 38.7%-70.2%). Hand-foot syndrome was the most common adverse event seen in 36 patients (85.7%) and was grade ≥ 3 in 16 patients (38.1%). One patient (2.4%) had a grade 4 sepsis, and one patient (2.4%) died while on treatment. CONCLUSION: SorCape in this heavily pretreated population yielded a reasonable PFS with manageable but notable toxicity. The combination should be investigated further.

Rectal cancer patients younger than 50 years lack a survival benefit from NCCN guideline-directed treatment for stage II and III disease.

BACKGROUND: The incidence of rectal cancer in patients younger than 50 years is increasing. To test the hypothesis that the biology in this younger cohort may differ, this study compared survival patterns, stratifying patients according to National Comprehensive Cancer Network (NCCN) guideline-driven care and age. METHODS: The National Cancer Data Base was queried for patients treated with curative-intent transabdominal resections with negative surgical margins for stage I to III rectal cancer between 2004 and 2014. Outcomes and overall survival for patients younger than 50 years and patients 50 years old or older were compared by subgroups based on NCCN guideline-driven care. RESULTS: A total of 43,106 patients were analyzed. Younger patients were more likely to be female and minorities, to be diagnosed at a higher stage, and to have travelled further to be treated at academic/integrated centers. Short- and long-term outcomes were significantly better for patients younger than 50 years, with age-specific survival rates calculated. Younger patients were more likely to receive radiation treatment outside NCCN guidelines for stage I disease. In younger patients, the administration of neoadjuvant chemoradiation for stage II and III disease was not associated with an overall survival benefit. CONCLUSIONS: Age-specific survival data for patients with rectal cancer treated with curative intent do not support an overall survival benefit from NCCN guideline-driven therapy for stage II and III patients younger than 50 years. These data suggest that early-onset disease may differ biologically and in its response to multimodality therapy.

Objective Preoperative Parameters Predict Difficult Pelvic Dissections and Clinical Outcomes.

BACKGROUND: Objective criteria to predict difficult pelvic dissection with prognostic significance are lacking. Previous studies have focused on predicting intraoperative conversion and not evaluated factors specific to pelvic surgery. We aimed to develop an objective, prognostic, preoperative assessment to predict difficult pelvic dissections and clinical outcomes. Such a model is much needed, may facilitate objective comparisons between rectal cancer centers, or may serve as a stratification variable in clinical trials. MATERIALS AND METHODS: Patients who underwent low anterior resection or abdominoperineal resection for rectal cancer within 10 cm of the anal verge (2009-2014) were retrospectively analyzed. Procedures were categorized into "routine" or "difficult" based on predefined criteria. All patients underwent 14 measurements on preoperative imaging. Outcomes were compared between the two groups. Stepwise multivariate logistic regression was used to develop the prediction model, which was validated in an independent data set. RESULTS: Of the 280 patients analyzed, 80 fulfilled the inclusion criteria. Baseline characteristics were similar except for more males having a "difficult" pelvis. "Difficult" patients were significantly more likely to have a narrower pelvis, smaller pelvic volumes, a longer pelvis, more curved sacrum, and more acute anorectal angle. Difficult cases correlated significantly with higher blood loss, hospital costs, longer operative time, and length of stay. A practical model to predict difficult pelvic dissections was created and included male gender, previous radiation, and length from promontory to pelvic floor > 130 mm. Model validation was performed in 40 patients from an independent data set. CONCLUSIONS: An objective, validated model that predicts a difficult pelvic dissection and associated worse clinical outcome is possible.

A novel method of minimally invasive rectus abdominis muscle flap harvest: Laparoscopic surgeons take note.

The rectus abdominis muscle (RAM) is a workhorse flap to fill or repair abdominal defects. A drawback of an open RAM harvest is donor site morbidity, and minimally invasive techniques for flap harvesting have been previously proposed but involve vertical division of the rectus fascia. We present a case of a 52-year-old woman with a recurrent rectovaginal fistula in a radiated field treated with a laparoscopic low anterior resection with simultaneous RAM flap harvest utilising a single Pfannenstiel incision. Our novel modified laparoscopic-assisted RAM harvest technique prevents longitudinal violation of the anterior and posterior rectus sheaths, thereby promoting a quick recovery, improved cosmesis and decreased post-operative morbidity.

The differential frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117(-)CD127(+)ILC subset in the inflamed terminal ileum of patients with Crohn's disease.

Deregulation of various components of the immune system has been reported in the inflamed gut of Crohn's disease (CD) patients. Innate lymphoid cells (ILCs) are novel innate effector lymphocytes which can rapidly respond to danger signals, from invading pathogens or tissue damage, to maintain homeostasis, especially along the mucosal surfaces. The purpose of this study is to compare composition of the intestinal ILCs subsets of CD patients with differential inflammatory conditions of the terminal ileum, which are marked by distinct histological appearances and mucosal profiles of cytokines. We observed alterations in the frequency of Lineage(-)CRTH2(-)CD45(+)NKp44(-)CD117(-)CD127(+)ILC subset in the inflamed terminal ileum.

Calculating torque, back-EMF, inductance, and unbalanced magnetic force for a hybrid electrical vehicle by in-wheel drive application.

To use a Hybrid Excitation Synchronous Machine (HESM) in a hybrid electrical vehicle (HEV), its performance indicators such as back-EMF, inductance and unbalanced magnetic force should be computed preferably by an analytical method. First, the back-EMF is calculated by considering alternate-teeth and all-teeth non-overlapping and overlapping windings. The effects of three types of magnetization patterns including the radial, parallel and Halbach magnetizations on the back-EMF waveform have also been investigated. Then, the self-inductance of the stator and rotor windings, the mutual inductance between the stator and rotor windings, and the mutual inductance between the stator phases are computed. Next, the components of the unbalanced magnetic force (UMF) in the direction of the x and y axes and its amplitude are computed. Moreover, the effects of the magnetization patterns on those magnetic pulls are investigated. To minimize the UMFs, symmetry must be implemented in the excitation sources; therefore, first the stator winding then the permanent magnet and rotor winding are modified in such a way that the UMFs are reduced. Increasing the temperature leads to a weakening of the magnet's residual flux density, which strongly affects the performance characteristics of the electric machine such as Back-EMF and UMF. Finally, the ratio of the permanent magnet flux to the rotor flux is determined in such a way that the average torque is maximized. In this section, the effects of three magnetization patterns will be investigated.

Impact of Early Exposure to Robotic Surgery Among Pre-clinical Medical Students on Career Choice and Simulation Skills.

We aimed to assess whether early exposure of medical students to robotic surgery training influences their interest in a surgical career and improves scores on objective simulation tasks. Medical students were invited to participate in robotic online training modules, robotic simulation exercises followed by a hands-on robotic dry-lab session. Pre- and post-simulator scores were recorded. A 29-question anonymous survey was recorded before and after the lab. Seventy percent reported that the training had a positive impact on influencing their decision to pursue a general surgery career. Students showed significantly improved skill and performance on simulation activities post-training. After the training, students felt knowledgeable about robotics, more comfortable operating robotically, and thought that robotic surgery would hold a significant place in the future of surgery. Exposing students to robotic training positively impacts their perception of surgery as a career choice and results in improvement in objective scores on simulation tasks.

Validation of a pelvic surgery difficulty risk model to predict difficult pelvic dissection and poor outcomes.

BACKGROUND: We previously developed the Pelvic Surgery Difficulty Index for predicting intraoperative events and postoperative outcomes associated with rectal mobilization with or without proctectomy ("deep pelvic dissection"). The aim of this study was to validate the scoring system as a prognostic tool for outcomes of pelvic dissection, regardless of the cause of dissection. METHODS: Consecutive patients who underwent elective deep pelvic dissection at our institution from 2009 to 2016 were reviewed. Pelvic Surgery Difficulty Index score (0-3) was calculated from the following parameters: male sex (+1), prior pelvic radiotherapy (+1), and linear distance from sacral promontory to pelvic floor >13 cm (+1). Patient outcomes stratified by Pelvic Surgery Difficulty Index score were compared. The outcomes assessed included operative blood loss, operative time, length of hospital stay, cost, and postoperative complications. RESULTS: A total of 347 patients were included. Higher Pelvic Surgery Difficulty Index scores were associated with significantly more blood loss, operative time, postoperative complications, hospital costs, and hospital stay. The model achieved good discrimination with area under the curve ≥0.7 for most outcomes. CONCLUSION: Preoperative prediction of the morbidity associated with difficult pelvic dissection is possible with an objective, feasible, and validated model. Such a tool may facilitate preoperative preparation and allow for better risk stratification and uniform quality control across centers.

Deciphering the key pathway for triterpenoid biosynthesis in Azadirachta indica A. Juss.: a comprehensive review of omics studies in nature's pharmacy.

Since ancient times, Azadirachta indica, or Neem, has been a well-known species of plant that produces a broad range of bioactive terpenoid chemicals that are involved in a variety of biological functions. Understanding the molecular mechanisms that are responsible for the biosynthesis and control of terpenoid synthesis is majorly dependent on successfully identifying the genes that are involved in their production. This review provides an overview of the recent developments concerning the identification of genes in A. indica that are responsible for the production of terpenoids. Numerous candidate genes encoding enzymes that are involved in the terpenoid biosynthesis pathway have been found through the use of transcriptomic and genomic techniques. These candidate genes include those that are responsible for the precursor synthesis, cyclization, and modification of terpenoid molecules. In addition, cutting-edge omics technologies, such as metabolomics and proteomics, have helped to shed light on the intricate regulatory networks that govern terpenoid biosynthesis. These networks are responsible for the production of terpenoids. The identification and characterization of genes involved in terpenoid biosynthesis in A. indica presents potential opportunities for genetic engineering and metabolic engineering strategies targeted at boosting terpenoid production as well as discovering novel bioactive chemicals.

A novel hybrid methodology to secure GOOSE messages against cyberattacks in smart grids.

IEC 61850 is emerging as a popular communication standard for smart grids. Standardized communication in smart grids has an unwanted consequence of higher vulnerability to cyber-attacks. Attackers exploit the standardized semantics of the communication protocols to launch different types of attacks such as false data injection (FDI) attacks. Hence, there is a need to develop a cybersecurity testbed and novel mitigation strategies to study the impact of attacks and mitigate them. This paper presents a testbed and methodology to simulate FDI attacks on IEC 61850 standard compliant Generic Object-Oriented Substation Events (GOOSE) protocol using real time digital simulator (RTDS) together with open-source tools such as Snort and Wireshark. Furthermore, a novel hybrid cybersecurity solution by the name of sequence content resolver is proposed to counter such attacks on the GOOSE protocol in smart grids. Utilizing the developed testbed FDI attacks in the form of replay and masquerade attacks on are launched and the impact of attacks on electrical side is studied. Finally, the proposed hybrid cybersecurity solution is implemented with the developed testbed and its effectiveness is demonstrated.

A Comprehensive Review of Randomized Clinical Trials Shaping the Landscape of Rectal Cancer Therapy.

Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one third of newly diagnosed cases. Surgery remains the cornerstone of curative therapy, with total mesorectal excision being the standard of care. Although minimally invasive procedures might be appropriate for a subset of patients with early-stage, superficial tumors, the standard of care for medically operable patients with nonmetastatic rectal cancer includes a comprehensive multimodality approach of neoadjuvant chemoradiotherapy, surgery with total mesorectal excision, and systemic chemotherapy. However, the morbidity and mortality related to both local and distant organ relapse have remained challenging. In the present review, we have discussed the trial-level evidence that has shaped the current clinical practice patterns in the treatment of curable, nonmetastatic rectal cancer. In addition, we have discussed the anticipated results of ongoing clinical trials and outlined pragmatic opportunities for future investigation to optimize the current status quo and, hopefully, provide prospective validation of novel approaches in the treatment of rectal cancer.

Utility of Restaging MRI Following Neoadjuvant Chemoradiotherapy for Stage II-III Rectal Adenocarcinoma.

Background Magnetic resonance imaging (MRI) is currently utilized for the pretreatment staging of locally advanced rectal cancer; however, there is no consensus regarding the utility of repeat MRI for restaging following neoadjuvant chemoradiotherapy (CRT). In this study, we aimed to investigate the clinical utility of restaging MRI after CRT in patients with clinical stage II-III rectal cancer. Methodology We performed a retrospective observational study at a tertiary care hospital. Our study population included patients with clinical stage II-III rectal cancer treated with neoadjuvant CRT who underwent both pre- and post-CRT MRI followed by surgical resection from 2012 to 2017. MRIs were reviewed by radiologists with an interest in rectal cancer MRI imaging using a standardized template. The utility of post-CRT MRI was evaluated by assessing its impact on change in surgical planning, concordance with pathologic staging, and prediction of surgical margins. Results A total of 30 patients were included in the study; 67% had clinical stage III and 33% had stage II disease based on pre-CRT MRI. Post-CRT MRI findings did not lead to a change in the originally outlined surgical plan in any patient. Compared to pre-CRT MRI, post-CRT MRI was not significantly more accurate in predicting T stage (k = 0.483), N stage (k = 0.268), or positive surgical margins (k = 0.839). Conclusions Due to poor concordance with pathologic staging, inability to more accurately predict surgical margin status and the absence of a demonstrable change in surgical treatment, post-CRT restaging with MRI, in its current form, appears to be of limited clinical utility.

Analysis of Outcomes in Adolescents and Young Adults With Pilonidal Disease.

Purpose: Numerous definitive surgical techniques exist for the treatment of pilonidal disease with varied recurrence rates and wound complications. Due to the wide array of techniques and lack of consensus on the best approach, we proposed to study our experience treating pilonidal disease in adolescents and young adults. Methods: A retrospective analysis was conducted of patients 10-24 years old treated at a tertiary medical center from 2011 to 2016. Data including demographics, management, and outcomes were collected and analyzed. Primary outcome was recurrence of disease. Results: One hundred and thirty three patients with pilonidal disease underwent operative management. Fifty one percent underwent primary closure and 49% healed by secondary intention with no significant difference in recurrence rates (primary 18%, secondary 11%; p = 0.3245). Secondary healing patients had significantly lower wound complication rates (primary 51%, secondary 23%; p = 0.0012). After accounting for sex, race, weight, and operative technique, age was predictive of disease recurrence with an adjusted odds ratio (OR) of 0.706 (0.560-0.888; p = 0.003). Age and sex were both predictive of wound complications. Older patients had decreased risk of wound complication (adjusted OR 0.806, 95% CI 0.684-0.951; p = 0.0105), and male patients had increased risk of wound complication (adjusted OR 2.902, 95% CI 1.001-8.409; p = 0.0497). Conclusion: In summary, there is no significant difference in the recurrence rates between operative techniques for pilonidal disease. Older patients have decreased risk of recurrence following intervention. Wound complication rates are lower in patients undergoing secondary healing, though this may be better explained by differences in age and sex. Additional research investigating newer, minimally-invasive techniques needs to be pursued.

Effects of Patient and Surgery Characteristics on Persistent Postoperative Pain: A Mediation Analysis.

OBJECTIVE: Acute postoperative pain intensity is associated with persistent postsurgical pain (PPP) risk. However, it remains unclear whether acute postoperative pain intensity mediates the relationship between clinical factors and persistent pain. MATERIALS AND METHODS: Participants from a mixed surgical population completed the Brief Pain Inventory and Pain Catastrophizing Scale before surgery, and the Brief Pain Inventory daily after surgery for 7 days and at 30 and 90 days after surgery. We considered mediation models using the mean of the worst pain intensities collected daily on each of postoperative days (PODs) 1 to 7 against outcomes of worst pain intensity at the surgical site endpoints reflecting PPP (POD 90) and subacute pain (POD 30). RESULTS: The analyzed cohort included 284 participants for the POD 90 outcome. For every unit increase of maximum acute postoperative pain intensity through PODs 1 to 7, there was a statistically significant increase of mean POD 90 pain intensity by 0.287 after controlling for confounding effects. The effects of female versus male sex (m=0.212, P=0.034), pancreatic/biliary versus colorectal surgery (m=0.459, P=0.012), thoracic cardiovascular versus colorectal surgery (m=0.31, P=0.038), every minute increase of anesthesia time (m=0.001, P=0.038), every unit increase of preoperative average pain score (m=0.012, P=0.015), and every unit increase of catastrophizing (m=0.044, P=0.042) on POD 90 pain intensity were mediated through acute PODs 1 to 7 postoperative pain intensity. DISCUSSION: Our results suggest the mediating relationship of acute postoperative pain on PPP may be predicated on select patient and surgical factors.

Comprehensive literature review of randomized clinical trials examining novel treatment advances in patients with colon cancer.

The treatment of colon cancer has had numerous recent advances, in terms of surgical approach, adjuvant therapies, and more. In this review, the authors examine randomized clinical trials comparing open surgery to laparoscopic surgery (including total mesocolic excision), and also examine the role of robotic surgery. Novel surgical techniques including the no-touch technique, side-to-side anastomosis, suture technique, complete mesocolic excision (CME) with central vascular ligation (CVL), and natural orifice transluminal endoscopic surgery (NOTES) are outlined. The role of placing endoscopic self-expandable metal stents (SEMS) for colonic obstruction is compared and contrasted with the surgical approach, and the effect that the anti-VEGF inhibitor bevacizumab may have on this side effect profile is further explored. The role of the resection of the primary tumor in the setting of metastatic disease is examined with respect to survival benefit. Pathways of perioperative care which can accelerate post-surgical recovery, including enhanced recovery after surgery (ERAS) are examined. The role of adjuvant chemotherapy in patients with high-risk stage II and patients with stage III disease is examined, along with the role on circulating tumor DNA (ctDNA) as well as with the biologic targeted agents cetuximab and bevacizumab. Lastly, the authors detail the postoperative surveillance schedules after surgical resection with respect to survival outcomes.

ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper.

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.

Selective harmonics elimination in multilevel inverter by a derivative-free iterative method under varying voltage condition.

Selective Harmonics Elimination Pulse width modulation (SHE PWM) presents an alternative modulation technique to operate medium voltage medium and high power converters as it reduces the switching losses. SHE PWM generates high-quality output waveform at the low switching frequency. Its application to multilevel converters furthers leads to improvement in output waveforms with lower switching losses, lesser dv/dt and lowers switching devices ratings. In this Paper SHE PWM for an asymmetrical cascaded H-bridge multilevel inverter under unequal DC voltage condition for fundamental and multiple switching cases are investigated. More harmonics can be eliminated by considering multiple switching's. The Solution of the Nonlinear transcendental SHE equation is obtained using an advanced derivative free numerical technique which. The method is simple in implementation with fast calculations per iteration as it avoids the evaluation of Jacobian and its matrix. Also the need for precise initial guess in the proximity of actual solution is not needed as an identity matrix of the size of designed variable serves the purpose. Different inequality in the dc voltages is taken to eliminate the lower order harmonics from the output. Only exact solutions for the switching angles which ensure the complete elimination of targeted harmonics are reported. Simulation and Hardware results are presented to confirm the validity of the proposed technique.

STAT3 Genotypic Variant rs744166 and Increased Tyrosine Phosphorylation of STAT3 in IL-23 Responsive Innate Lymphoid Cells during Pathogenesis of Crohn's Disease.

Crohn's disease (CD) results from dysregulated immune responses to gut microbiota in genetically susceptible individuals, affecting multiple areas of the gastrointestinal tract. Innate lymphoid cells (ILCs) are tissue-resident innate effector lymphocytes which play crucial roles in mucosal immune defense, tissue repair, and maintenance of homeostasis. The accumulation of IFN-γ-producing ILC1s and increased level of proinflammatory cytokines produced by ILCs has been observed in the inflamed terminal ileum of CD patients. To date, the precise mechanisms of ILC plasticity and gene regulatory pathways in ILCs remain unclear. Signal transducer and activator of transcription 3 (STAT3) regulates gene expression in a cell-specific, cytokine-dependent manner, involving multiple immune responses. This study proposes the positive correlation between the prevalence of STAT3 rs744166 risky allele "A" with the severity of disease in a cohort of 94 CD patients. In addition, the results suggest an increased STAT3 activity in the inflamed ileum of CD patients, compared to unaffected ileum sections. Notably, IL-23 triggers the differentiation of CD117+NKp44- ILC3s and induces the activation of STAT3 in both CD117+NKp44- and CD117-NKp44- ILC subsets, implying the involvement of STAT3 in the initiation of ILC plasticity. Moreover, carriage of STAT3 "A" risk allele exhibited a higher basal level of STAT3 tyrosine phosphorylation, and an increased IL-23 triggered the pSTAT3 level. We also demonstrated that there was no delayed dephosphorylation of STAT3 in ILCs of both A/A and G/G donors. Overall, the results of this study suggest that IL-23-induced activation of STAT3 in the CD117-NKp44- ILC1s involves in ILC1-to-ILC3 plasticity and a potential regulatory role of ILC1 function. Those genetically susceptible individuals carried STAT3 rs744166 risky allele appear to have higher basal and cytokine-stimulated activation of STAT3 signal, leading to prolonged inflammation and chronic relapse.