TANGO1 inhibitors reduce collagen secretion and limit tissue scarring.

Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.

MicroRNA signatures differentiate types, grades, and stages of breast invasive ductal carcinoma (IDC): miRNA-target interacting signaling pathways.

BACKGROUND: Invasive ductal carcinoma (IDC) is the most common form of breast cancer which accounts for 85% of all breast cancer diagnoses. Non-invasive and early stages have a better prognosis than late-stage invasive cancer that has spread to lymph nodes. The involvement of microRNAs (miRNAs) in the initiation and progression of breast cancer holds great promise for the development of molecular tools for early diagnosis and prognosis. Therefore, developing a cost effective, quick and robust early detection protocol using miRNAs for breast cancer diagnosis is an imminent need that could strengthen the health care system to tackle this disease around the world. METHODS: We have analyzed putative miRNAs signatures in 100 breast cancer samples using two independent high fidelity array systems. Unique and common miRNA signatures from both array systems were validated using stringent double-blind individual TaqMan assays and their expression pattern was confirmed with tissue microarrays and northern analysis. In silico analysis were carried out to find miRNA targets and were validated with q-PCR and immunoblotting. In addition, functional validation using antibody arrays was also carried out to confirm the oncotargets and their networking in different pathways. Similar profiling was carried out in Brca2/p53 double knock out mice models using rodent miRNA microarrays that revealed common signatures with human arrays which could be used for future in vivo functional validation. RESULTS: Expression profile revealed 85% downregulated and 15% upregulated microRNAs in the patient samples of IDC. Among them, 439 miRNAs were associated with breast cancer, out of which 107 miRNAs qualified to be potential biomarkers for the stratification of different types, grades and stages of IDC after stringent validation. Functional validation of their putative targets revealed extensive miRNA network in different oncogenic pathways thus contributing to epithelial-mesenchymal transition (EMT) and cellular plasticity. CONCLUSION: This study revealed potential biomarkers for the robust classification as well as rapid, cost effective and early detection of IDC of breast cancer. It not only confirmed the role of these miRNAs in cancer development but also revealed the oncogenic pathways involved in different progressive grades and stages thus suggesting a role in EMT and cellular plasticity during breast tumorigenesis per se and IDC in particular. Thus, our findings have provided newer insights into the miRNA signatures for the classification and early detection of IDC.

Correction: Insulated tip/needle-knife endoscopic stricturotomy is safe and effective for treatment of non-traversable anorectal strictures.

[This corrects the article DOI: 10.1055/a-2230-7372.].

Insulated tip/needle-knife endoscopic stricturotomy is safe and effective for treatment of non-traversable anorectal strictures.

Background and study aims The treatment of anorectal strictures is particularly challenging and historically focused on surgical resection and/or diversion. There are a number of endoscopic options, but repeat interventions are common. The use of the needle knife stricturotomy technique as an alternative to surgery in the treatment of a variety of strictures has been described, but its use for the treatment of severe anorectal and anopouch strictures has not been studied. Patients and methods Our Inflammatory Bowel Disease department's records were queried to identify patients with endoscopic non-traversable anorectal/anopouch strictures. Consecutive patients that underwent insulated tip/needle-knife endoscopic stricturotomy treatment were included. Primary outcome was immediate traversability of the treated stricture by the endoscope. Other outcomes included need for reintervention, 30-day post-procedure events, and follow-up period events. Results All strictures were immediately successfully traversed following endoscopic stricturotomy treatment. The mean time to endoscopic reintervention was 5.3 months, with the majority of these patients undergoing repeat stricturotomy. Over a mean follow-up period of 12.8 months, two patients (8%) required surgical intervention (resection with coloanal anastomosis with a colostomy and complete proctectomy) for refractory stricture disease following initial endoscopic stricturotomy. Seven patients (29%) in our study have not required any further reintervention throughout the study period. There were no 30-day post-procedure adverse events and no adverse post-procedure events. Conclusions Endoscopic stricturotomy is safe and effective in treating severe anorectal/anopouch strictures.

Conversion of Failed J Pouch to Kock Pouch: Indications, Contraindications and Outcomes.

BACKGROUND: The ileal pouch-anal anastomosis has been successful in restoring intestinal continuity and preserving continence in the majority of patients requiring a proctocolectomy. However, a subset of individuals experience significant complications that might result in pouch failure. The conversion of the J pouch to a continent ileostomy pouch represents a significant surgical procedure. In this article, we discuss the indications and contraindications, present the technical principles applied for the conversion, and describe the outcomes of such conversion in the literature. OBJECTIVE: The main objective during the conversion of the J pouch to a continent ileostomy is the creation of a sufficiently sized reservoir with a high-quality valve mechanism while preserving as much small bowel as possible. CONCLUSIONS: The conversion of the J pouch to a continent ileostomy represents a significant surgical procedure. When performed in centers of expertise, it can be a good option for patients who otherwise will require an end ileostomy. Indications for conversion include most cases of J pouch failure, with few important exceptions. See Video.

Application of enzyme-linked immunosorbent assay to detect antimicrobial peptides in human intestinal lumen.

Intestinal transplantation is the definitive treatment for intestinal failure. However, tissue rejection and graft-versus-host disease are relatively common complications, necessitating aggressive immunosuppression that can itself pose further complications. Tracking intraluminal markers in ileal effluent from standard ileostomies may present a noninvasive and sensitive way to detect developing pathology within the intestinal graft. This would be an improvement compared to current assessments, which are limited by poor sensitivity and specificity, contributing to under or over-immunosuppression, respectively, and by the need for invasive biopsies. Herein, we report an approach to reproducibly analyze ileal fluid obtained through stoma sampling for antimicrobial peptide/protein concentrations, reasoning that these molecules may provide an assessment of intestinal homeostasis and levels of intestinal inflammation over time. Concentrations of lysozyme (LYZ), myeloperoxidase (MPO), calprotectin (S100A8/A9) and ß-defensin 2 (DEFB2) were assessed using adaptations of commercially available enzyme-linked immunosorbent assays (ELISAs). The concentration of α-defensin 5 (DEFA5) was assessed using a newly developed sandwich ELISA. Our data support that with proper preparation of ileal effluent specimens, precise and replicable determination of antimicrobial peptide/protein concentrations can be achieved for each of these target molecules via ELISA. This approach may prove to be reliable as a clinically useful assessment of intestinal homeostasis over time for patients with ileostomies.

Role of Microbiome in the Outcomes Following Surgical Repair of Perianal Fistula: Prospective Cohort Study Design and Preliminary Results.

BACKGROUND: Anal fistulae are common, predominantly cryptoglandular, and almost invariably require surgical treatment. Recurrences are common for procedures other than fistulotomy regardless of technique and adequacy of repair. Growing evidence supports the pivotal role of specific intestinal bacteria in anastomotic failures after bowel resection. Anal crypts harbor colonic microbiota suggesting that similar mechanisms to anastomotic healing might prevail after anal fistula repair and hence influence healing. This study aims at assessing the potential role of the intestinal microbiome in the clinical outcomes after surgical repair of cryptoglandular anal fistula. METHODS: This is a pilot prospective cohort study enrolling patients with anal fistula undergoing endoanal advancement flap. For microbiome analysis, stool samples are taken via rectal swab before the procedure; additionally, a portion of the fistula is collected intraoperatively after fistulectomy. Samples from groups with treatment failure are compared to samples from patients who healed after surgical repair. Alpha and beta diversities and differential abundance of microbial taxa are determined and compared between groups with DADA2 analytical pipeline. RESULTS: Five patients have been enrolled to date (one female, four male). At median follow-up of 6 months (2-11), one patient experienced disease recurrence at 3 months. DNA from the 5 rectal swab and tissue samples was extracted, showing increased relative abundance of Enterococcus faecalis in samples from the patient who developed a recurrent fistula but not in those without recurrence. CONCLUSION: These very preliminary data suggest that intestinal microbiome may represent a crucial determinant of the surgical outcomes after anal fistula surgery.

Colonic interposition in esophagectomy: an ACS-NSQIP study.

INTRODUCTION: For patients with cancer or injury of the esophagus, esophagectomy with reconstruction using the stomach (gastric pull-up, GPU) or colon (colonic interposition, CI) can restore function but is associated with high morbidity. We sought to describe the differences in outcomes between the two replacement organs using a national database. METHODS: From ACS-NSQIP, patients who underwent GPU or CI between 2006 and 2020 were identified. Univariate analyses were performed on length of stay, complications, reoperation, readmission, and mortality. Variables with P ≤ 0.2 were included in the multivariate regression. Primary outcomes were 30-day reoperation, readmission, and mortality. Data were assessed using Chi-squared tests and logistic regression. RESULTS: There were 12,545 GPU and 502 CI patients. GPU patients were older with higher BMI, and more likely to be male (80.3% versus 70.3%, P < 0.0001) and white (77.8% versus 69.1%, P < 0.0001). More GPU patients had independent functional status and underlying bleeding disorders, but fewer other preoperative comorbidities than CI patients. On univariate analysis, CI patients had longer hospital stays (13 versus 10 days, P < 0.0001); more reoperations (23.9% versus 14.5%, P < 0.0001); a lower rate of discharge to home (70.9% versus 82.1%, P < 0.0001); and a higher mortality rate (6.2% versus 2.9%, P < 0.0001). On multivariate analysis, CI was associated with increased risk of reoperation but not with readmission or mortality. Reoperation was associated with CI, smoking, chronic wound, hypertension, higher ASA class, contaminated or dirty wound class, and longer operative time. Readmission was associated with female gender, hypertension, and longer operative time. Mortality was associated with age, metastatic cancer, preoperative sepsis, preoperative renal failure, malignant esophageal disease, higher ASA class, incomplete closure, and longer operative time. CONCLUSION: Colonic interposition, although a more difficult option with traditionally worse outcomes, should still be considered for patients requiring esophagectomy if the stomach cannot be used to restore continuity, as differences in outcomes appear to be due to underlying frailty of patients rather than the procedure.

Self-adherence to post-colonoscopy consults in patients undergoing diagnostic colonoscopy: Findings from a cross-sectional, quantitative survey at a South African quaternary hospital.

Post-colonoscopy consults empower patients to make informed decisions around their subsequent treatment, and non-compliance with these consults ("no-shows") hinders disease management. There is a paucity in the literature regarding self-adherence to post-colonoscopy consults in resource-limited settings such as South Africa. An understanding of self-adherence to post-colonoscopy consults in this setting is required to establish whether improved interventions are needed, and what specific elements of self-adherence should be addressed with these interventions. The objective of this hypothesis-generating, cross-sectional, quantitative survey was to conduct a baseline assessment of cognitive, motivational, social, and behavioural variables related to self-adherence to post-colonoscopy consults in patients who underwent diagnostic colonoscopy at a South African quaternary hospital. The Adherence Determinants Questionnaire (ADQ) was administered in 47 patients to establish a baseline assessment of elements related to self-adherence to post-colonoscopy consults, including interpersonal aspects of care, perceived utility, severity, susceptibility, subjective norms, intentions, and supports/barriers. ADQ scores were transformed to a percentage of the maximum score for each element (100.0%). The overall mean transformed ADQ score was 57.8%. The mean transformed scores for specific ADQ components were as follows: subjective norms (40.8%), perceived severity (55.4%), perceived utility (56.6%), intentions (59.4%), supports/barriers (59.9%), interpersonal aspects (62.2%), and perceived susceptibility (65.9%). There were no statistically significant differences in overall mean transformed ADQ scores and individual ADQ elements across categories of participant age (p-values ranging between 0.180 and 0.949 when compared between participants ≤40 years and >40 years old), gender (p-values ranging between 0.071 and 0.946 when compared between males and females), and race (p-values ranging between 0.119 and 0.774 when compared between Black Africans and non-Black Africans). Our findings suggest a general need for appropriate interventions to improve self-adherence to post-colonoscopy consults in our setting.

A Transcriptome-Based Precision Oncology Platform for Patient-Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies.

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. SIGNIFICANCE: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials. This article is highlighted in the In This Issue feature, p. 1275.

Patient's attitudes and perceptions around attending oncology consultations following surgery for colorectal cancer: A qualitative study.

Background: The oncology consultation following surgery for colorectal cancer (CRC) is usually the first step in the receipt of chemotherapy. Non-compliance with this consultation results in non-receipt of recommended chemotherapy, when appropriate, and worse clinical outcomes. This study sought to explore South African patients' attitudes and perceptions around attending scheduled oncology consultations following their CRC surgery. Methods: Semi-structured qualitative interviews were conducted with patients who had surgery for CRC at a quaternary South African hospital and who had to decide whether they would return for an oncology consultation. The "Model of health services use" informed the design of the interview guide, which included questions on factors that impact health seeking behavior. Demographics of participants, CRC disease stage, and compliance with scheduled oncology consultations were also collected. Descriptive statistics were used to analyse the quantitative data, while deductive thematic analysis was used to analyse the qualitative data. Results: Seven participants were interviewed. The median age was 60.0 years and four participants (57.1%) were female. Black African, White, and Asian participants accounted for 85.7% of the study sample. Most participants had stage III CRC (71.4%). The oncology consultation no-show rate was 14.3%. Participant's knowledge and beliefs around CRC proved to be an important predisposing factor that influenced follow-up decisions. Family support and religion were cited as important enabling factors. Travel costs to the hospital and frustrations related to the clinic appointment booking/scheduling process were cited as important disabling factors. Lastly, the participant's self-perceived need for additional oncology care also appeared to influence their decision to return for ongoing oncology consultation after the initial surgery. Conclusion: Several contextual factors can potentially influence a patient's compliance with a scheduled oncology consultation following CRC surgery. A multipronged approach which addresses these factors is required to improve compliance with oncology consultations.

Surgery for Crohn's disease: upfront or last resort?

Crohn's disease (CD) can involve the entire gastrointestinal tract from the mouth to the anus and can lead to a constellation of symptoms. With the advancement of effective medical treatments for CD, a tendency has emerged to consider surgical treatment as a last resort. This potentially has the disadvantage of delaying surgery and if it fails might leave patients sicker, less well nourished, and with more severe complications. As with most non-malignant diseases, the choice of surgery vs medical treatment is a patient's personal preference under the guidance of the treating physician, except in extreme situations where surgery might be the only option. In this article, we will discuss the available evidence regarding the optimal timing of surgery in CD, focusing on whether early surgery can bring benefits in terms of disease control, symptom relief, and quality of life.

Overview of Common Complications in Inflammatory Bowel Disease Surgery.

The complication rate after surgery in patients with inflammatory bowel disease is high owing to chronic inflammatory and suboptimal physiologic state, the effect of steroids and immunosuppressive medication, and the inherent complexity of the surgical procedures. Although some of the complications after surgery are similar for Crohn disease and ulcerative colitis, others are specific to the diagnosis. Complications are divided into early postoperative and late complications. Specific complications are related to more extensive surgery such as a proctocolectomy or reoperative procedures or with complex reconstructive procedures such as the ileoanal pouch and continent ileostomy.

Construction of and Conversion to Continent Ileostomy: A Systematic Review.

BACKGROUND: Continent ileostomy was first introduced by Nils Kock in 1969 as Kock pouch (K-pouch). Its most characteristic feature, the nipple valve that offers continence' was a later addition. Even though today's continent ileostomy is sidelined by ileal pouch-anal anastomosis as the gold standard of restorative procedures for colectomy patients, it remains an excellent option for select patients, offering an alternative to end-ileostomy or a poorly functioning ileoanal pouch. OBJECTIVE: The study aimed to summarize principles and techniques behind K-pouch construction, both de novo and as "J to K" conversion, as well as examine surgical outcomes following the procedure in the modern era regardless of indication. DATA SOURCES: Data sources included PubMed and the Cochrane Library up to July 2021. STUDY SELECTION: The study selection materials included articles reviewing continent ileostomy procedures and outcomes between 2000-2021. Case reports and series <15 were excluded. RESULTS: Fifteen articles were selected for review, describing 958 patients with a K-pouch, 510 patients who had undergone a Barnett continent intestinal reservoir, and 40 who had undergone construction of a T-pouch. CONCLUSION: Continent ileostomies carried out in specialized centers by experienced surgeons can be a great option for patients who would otherwise be confined by an end ileostomy. High pouch survival rates with higher quality-of-life scores than end ileostomy and comparable with IPAA make continent ileostomy a great option, even if we consider the less than ideal reoperation and complication rates. However, it is of paramount importance that patients are carefully selected, thoroughly educated, highly motivated, and engaged in their care. Specifically, for patients with Crohn's disease, further research is needed to help elucidate factors that affect pouch survival and candidacy for K-pouch creation. Finally, continuous surgical technique modifications and refinements can allow even more patients to be considered suitable for the procedure.

Vaccination-based immunotherapy to target profibrotic cells in liver and lung.

Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.

Management of pouch neoplasia: consensus guidelines from the International Ileal Pouch Consortium.

Surveillance pouchoscopy is recommended for patients with restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis or familial adenomatous polyposis, with the surveillance interval depending on the risk of neoplasia. Neoplasia in patients with ileal pouches mainly have a glandular source and less often are of squamous cell origin. Various grades of neoplasia can occur in the prepouch ileum, pouch body, rectal cuff, anal transition zone, anus, or perianal skin. The main treatment modalities are endoscopic polypectomy, endoscopic ablation, endoscopic mucosal resection, endoscopic submucosal dissection, surgical local excision, surgical circumferential resection and re-anastomosis, and pouch excision. The choice of the treatment modality is determined by the grade, location, size, and features of neoplastic lesions, along with patients' risk of neoplasia and comorbidities, and local endoscopic and surgical expertise.

Feasibility and Safety of Ambulatory Surgery as the Next Management Paradigm in Colorectal Resection Surgery.

BACKGROUND: Current clinical dogma favors universal inpatient admission after colorectal resection particularly in the presence of an anastomosis. OBJECTIVE: We evaluate the feasibility and safety of ambulatory surgery in carefully selected patients undergoing colorectal resection/anastomosis. METHODS: Between October 2020 and October 2021, all patients undergoing colorectal resection/anastomosis meeting specific criteria {no major comorbidity [American Society of Anesthesiologist (ASA) <4], not on therapeutic anticoagulation, compliant patient/family} were counseled preoperatively for ambulatory surgery (discharge <24 h postsurgery). Complicated surgery (ileoanal pouch, enterocutaneous fistula repair, reoperative pelvic surgery, multiple resections) and/or ostomy creation (loop/end ileostomy, Hartmann's, abdominoperineal resection) were exclusions. Discharge was at 6 to 8 hours postoperatively if all predetermined factors (no ostomy teaching needed, ambulating comfortably, tolerating diet, stable vitals, and blood-work) were met and patients were willing, or was postponed to the next day at patient request. All discharged patients received phone checks the next day with the option also given for voluntary readmission if inpatient care was preferred by patient. Patients discharged <24 hours postop (AmbC) were compared to those staying on as inpatients admitted (InpC) and also to a comparable historical (October 2019-October 2020) group when ambulatory surgery was not offered (HistC). RESULTS: Of 184 abdominal colorectal surgery patients, 97 had complicated colorectal resection and/or ostomy. Of the remaining 87, 29 (33.3%) were discharged <24 hours postoperatively [7 (24%) patients at 8 h]. Of these 29 AmbC patients, 4 were readmitted <30 days (ileus: 1, rectal bleeding: 2, nausea/vomiting: 1), 1 readmission was on first postdischarge day, none were voluntary post phone-check. AmbC and InpC (n=58) had similar age, sex, race, body mass index, and comorbidity. InpC had greater estimated blood loss (109 vs 34 mL, P <0.001) while length of stay was expectedly significantly longer (109 vs 17 hours, P <0.001). There was no mortality in either group. AmbC and InpC had similar readmission, reoperation, anastomotic leak, ileus, and surgical site infection. Mean length of stay for HistC was 83 hours. AmbC and HistC had similar age, sex, race, body mass index, and ASA class. Complications including readmission, reoperation, anastomotic leak, ileus, and surgical site infection were also similar for AmbC and HistC. CONCLUSIONS: With careful patient selection, preoperative education, perioperative management, and postoperative follow-up, ambulatory surgery is feasible in up to a third of patients undergoing colorectal resection/anastomosis and can be performed with comparable safety to the time-honored practice of routine inpatient hospitalization. Refinements in inclusion/exclusion criteria and postoperative outpatient follow-up will allow a paradigm shift in how such patients are managed, which has huge implications for patient experience, care-giver workload and health care finances.

A Pathfinding Algorithm for Lowering Infection Exposure of Healthcare Personnel Working in Makeshift Hospitals.

Due to the recent COVID-19 outbreak, makeshift (MS) hospitals have become an important feature in healthcare systems worldwide. Healthcare personnel (HCP) need to be able to navigate quickly, effectively, and safely to help patients, while still maintaining their own well-being. In this study, a pathfinding algorithm to help HCP navigate through a hospital safely and effectively is developed and verified. Tests are run using a discretized 2D grid as a representation of an MS hospital plan, and total distance traveled and total exposure to disease are measured. The influence of the size of the 2D grid units, the shape of these units, and degrees of freedom in the potential movement of the HCP are investigated. The algorithms developed are designed to be used in MS hospitals where airborne illness is prevalent and could greatly reduce the risk of illness in HCP. In this study, it was found that the quantum-based algorithm would generate paths that accrued 50-66% less total disease quantum than the shortest path algorithm with also about a 33-50% increase in total distance traveled. It was also found that the mixed path algorithm-generated paths accrued 33-50% less quantum, but only increased total distance traveled by 10-20%.