Unveiling enigmatic essence of Sphingolipids: A promising avenue for glaucoma treatment.

Treatment of glaucoma, the leading cause of irreversible blindness, remains challenging. The apoptotic loss of retinal ganglion cells (RGCs) in glaucoma is the pathological hallmark. Current treatments often remain suboptimal as they aim to halt RGC loss secondary to reduction of intraocular pressure. The pathophysiological targets for exploring direct neuroprotective approaches, therefore are highly relevant. Sphingolipids have emerged as significant target molecules as they are not only the structural components of various cell constituents, but they also serve as signaling molecules that regulate molecular pathways involved in cell survival and death. Investigations have shown that a critical balance among various sphingolipid species, particularly the ceramide and sphingosine-1-phosphate play a role in deciding the fate of the cell. In this review we briefly discuss the metabolic interconversion of sphingolipid species to get an insight into "sphingolipid rheostat", the dynamic balance among metabolites. Further we highlight the role of sphingolipids in the key pathophysiological mechanisms that lead to glaucomatous loss of RGCs. Lastly, we summarize the potential drug candidates that have been investigated for their neuroprotective effects in glaucoma via their effects on sphingolipid axis.

Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche.

Macrophages are fundamental cells of the innate immune system that support normal haematopoiesis and play roles in both anti-cancer immunity and tumour progression. Here we use a chimeric mouse model of chronic myeloid leukaemia (CML) and human bone marrow (BM) derived macrophages to study the impact of the dysregulated BM microenvironment on bystander macrophages. Utilising single-cell RNA sequencing (scRNA-seq) of Philadelphia chromosome (Ph) negative macrophages we reveal unique subpopulations of immature macrophages residing in the CML BM microenvironment. CML exposed macrophages separate from their normal counterparts by reduced expression of the surface marker CD36, which significantly reduces clearance of apoptotic cells. We uncover aberrant production of CML-secreted factors, including the immune modulatory protein lactotransferrin (LTF), that suppresses efferocytosis, phagocytosis, and CD36 surface expression in BM macrophages, indicating that the elevated secretion of LTF is, at least partially responsible for the supressed clearance function of Ph- macrophages.

Exploring the current use of animal models in glaucoma drug discovery: where are we in 2023?

INTRODUCTION: Animal models are widely used in glaucoma-related research. Since the elevated intraocular pressure (IOP) is a major risk factor underlying the disease pathogenesis, animal models with high IOP are commonly used. However, models are also used to represent the clinical context of glaucomatous changes developing despite a normal IOP. AREAS COVERED: Herein, the authors discuss the various factors that contribute to the quality of studies using animal models based on the evaluation of studies published in 2022. The factors affecting the quality of studies using animal models, such as the animal species, age, and sex, are discussed, along with various methods and outcomes of studies involving different animal models of glaucoma. EXPERT OPINION: Translating animal research data to clinical applications remains challenging. Our observations in this review clearly indicate that many studies lack scientific robustness not only in their experiment conduct but also in data analysis, interpretation, and presentation. In this context, ensuring the internal validity of animal studies is the first step in quality assurance. External validity, however, is more challenging, and steps should be taken to satisfy external validity at least to some extent.

Estimation of Time Since Death Using Biochemical Markers in Synovial Fluid.

ABSTRACT: In the field of forensic medicine, estimating time since death plays an important role in helping the investigative organizations unravel the mystery of crime. Presently, many less reliable subjective parameters are being used to measure it, necessitating the need to have more specific and objective parameters. This cross-sectional comparative study was conducted at the Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Bhopal, India on 60 deceased bodies to determine the correlation between known time since death and biochemical parameters in the synovial fluid specifically sodium, potassium, lactate, and total proteins, analyzed using random access fully automated chemical analyzer (Beckman Coulter Au680) followed by estimation of correlation using Spearman correlation test.All the biochemical parameters that were tested in the synovial fluid except for sodium showed a significant correlation. The potassium and lactate showed a significant positive correlation (P < 0.001), and on the contrary, the total protein level showed a significant negative correlation with time since death (P < 0.001). This study shows usefulness of these markers in estimating the time since death. The smaller sample size and the unavailability of the results of effect of cold storage on these parameters necessitate the need of further similar studies to uncover the real practical application.

A data-driven analysis and optimization of the impact of prescribed fire programs on wildfire risk in different regions of the USA.

In the current century, wildfires have shown an increasing trend, causing a huge amount of direct and indirect losses in society. Different methods and efforts have been employed to reduce the frequency and intensity of the damages, one of which is implementing prescribed fires. Previous works have established that prescribed fires are effective at reducing the damage caused by wildfires. However, the actual impact of prescribed fire programs is dependent on factors such as where and when prescribed fires are conducted. In this paper, we propose a novel data-driven model studying the impact of prescribed fire as a mitigation technique for wildfires to minimize the total costs and losses. This is applied to states in the USA to perform a comparative analysis of the impact of prescribed fires from 2003 to 2017 and to identify the optimal scale of the impactful prescribed fire programs using least-cost optimization. The fifty US states are classified into categories based on impact and risk levels. Measures that could be taken to improve different prescribed fire programs are discussed. Our results show that California and Oregon are the only severe-risk US states to conduct prescribed fire programs that are impactful at reducing wildfire risks, while other southeastern states such as Florida maintain fire-healthy ecosystems with very extensive prescribed fire programs. Our study suggests that states that have impactful prescribed fire programs (like California) should increase their scale of operation, while states that burn prescribed fires with no impact (like Nevada) should change the way prescribed burning is planned and conducted.

Study of Demographics, Clinical Profile and Risk Factors of Inguinal Hernia: A Public Health Problem in Elderly Males.

BACKGROUND: Inguinal hernia repair is the most commonly performed elective surgery in India draining significant healthcare resources. This observational study was conducted at a tertiary-level institute in northern India to look into the demographics, clinical profile and risk factors of inguinal hernia. METHOD:  This study was conducted as an observational study at the tertiary care centre of northern India, including 110 patients who had come to the surgical outpatient department for inguinal hernia repair. After obtaining informed consent from all the participants, demographic details, history and clinical examination were recorded. This was a prospective, single-centre, non-randomized, observational study. RESULTS AND DISCUSSION:  In our study, 43 patients (39%) were >50 years of age. One hundred and seven patients (97.27%) were males, and three (2.72%) were females. Male: Female ratio was 32:1. The preponderance of males was due to their involvement in more strenuous exercises and lifting weights and the anatomical differences between them. The main risk factor in the present study was lifting heavy weights 55%, followed by altered bowel habits 36.36% and respiratory disease (chronic obstructive airway disease). Smoking and diabetes were also associated as risk factors for the hernia. In this study, the most common side of hernia was on the right side, 63%, on the left, 33% and bilateral in 4% of patients. The indirect hernia was the most common type. CONCLUSION: Inguinal hernia is a surgical problem found commonly in the male elderly. Right-sided inguinal hernia is common, with the indirect type being more frequent. Heavy weight lifting and strenuous exercises were commonly found risk factors.

Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.

Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in preclinical studies and clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. In this study, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1. Using genetic approaches, we demonstrate that cotargeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell (LSPC) function and induce differentiation in cell lines and patient-derived cells. Although IRAK1 and IRAK4 are presumed to function primarily downstream of the proximal adapter MyD88, we found that complementary and compensatory IRAK1 and IRAK4 dependencies in MDS/AML occur via noncanonical MyD88-independent pathways. Genomic and proteomic analyses revealed that IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML LSPCs by coordinating a network of pathways, including ones that converge on the polycomb repressive complex 2 complex and JAK-STAT signaling. To translate these findings, we implemented a structure-based design of a potent and selective dual IRAK1 and IRAK4 inhibitor KME-2780. MDS/AML cell lines and patient-derived samples showed significant suppression of LSPCs in xenograft and in vitro studies when treated with KME-2780 as compared with selective IRAK4 inhibitors. Our results provide a mechanistic basis and rationale for cotargeting IRAK1 and IRAK4 for the treatment of cancers, including MDS/AML.

Inactivation of p53 provides a competitive advantage to del(5q) myelodysplastic syndrome hematopoietic stem cells during inflammation.

Inflammation is associated with the pathogenesis of myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPC) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPC remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPC as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPC exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPC exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPC upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPC due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone.

Comparison of Postoperative Chronic Groin Pain After Repair of Inguinal Hernia Using Nonabsorbable Versus Absorbable Sutures for Mesh Fixation.

BACKGROUND: Inguinal hernia repair is one of the most common operations performed in general surgery. Lichtenstein mesh hernioplasty is a commonly practiced technique for open inguinal hernia repair. Out of many other complications postoperatively, chronic groin pain is one of the patients' most common postoperative complaints. There is no direct evidence to explain the cause of post-mesh hernioplasty pain. Only a few studies have been done to judge the effect of suture material used for mesh fixation on chronic groin pain. AIMS AND OBJECTIVES: To compare the postoperative groin pain level in mesh hernioplasty using nonabsorbable versus absorbable sutures for mesh fixation at predetermined intervals using a visual analog scale (VAS) score. METHODS:  A prospective, single-center, non-randomized, observational study was conducted. All patients per inclusion and exclusion criteria of inguinal hernia planned for surgery were admitted electively on the day of surgery and were operated on in minor OT under local anesthesia for open mesh hernioplasty. The VAS score assessed the postoperative pain level. RESULTS:  This observational study was done to look for any difference in postoperative chronic groin pain after mesh fixation with either nonabsorbable, prolene sutures (PS) or absorbable vicryl sutures (VS). One hundred and ten patients fulfilling the department of general surgery inclusion criteria were admitted to the study. In our study, postoperatively, the incidence of chronic groin pain was assessed and followed up to six months. After six months, 25%of patients had pain. Of this 25%, the majority (70%) of patients had mild pain, 15% had moderate pain, and 15% had severe pain. There was no statistically significant difference between the two groups of mesh fixation by nonabsorbable versus absorbable sutures. CONCLUSION: Inguinal hernia is one of the most typical conditions seen in general surgery clinics with male predominance. Definitive management of inguinal hernia is surgery. There is no difference in postoperative chronic groin pain with either type of suture material i.e., nonabsorbable or absorbable (prolene vs vicryl) sutures. To conclude, fixation material for mesh does not influence chronic inguinodynia. However, further studies are required for the same.

Comparison Between Closed and Open Methods for Creating Pneumoperitoneum in Laparoscopic Cholecystectomy.

Background: To study the efficacy of closed and open methods for creating pneumoperitoneum in laparoscopic cholecystectomy by comparing the two in terms of their outcome and complication. Study Design: Single-centre, prospective, observational study. Materials and study: Purposive sampling method where the inclusion criteria were all patients with cholelithiasis who were advised and consented to laparoscopic cholecystectomy of age 18-70 years were included in the study group. Exclusion criteria include patients with a paraumbilical hernia, a history of upper abdominal surgery, uncontrolled systemic illness, and local skin infection. Sixty cases of cholelithiasis satisfying exclusion and inclusion criteria who underwent elective cholecystectomy during the study period were included. Thirty-one of these cases underwent the closed method, while in the remaining 29 patients open method was adopted. Cases in which pneumoperitoneum created by closed technique were grouped as group A and those by open technique as group B. Parameters comparing the safety and efficacy of the two methods were studied. The parameters were access time, gas leak, visceral injury, vascular injury, need for conversion, umbilical port site hematoma, umbilical port site infection, and hernia. Patients were assessed on the first postoperative day, the seventh postoperative day, and then two months after surgery. Some follow-ups were done telephonically. Results: Out of 60 patients, 31 underwent the closed method, while 29 underwent the open method. Minor complications like gas leak during the procedure was observed more in the open method. The mean access time in the open-method group was less than in the closed-method group. Other complications like visceral injury, vascular injury, need for conversion, umbilical port site hematoma, umbilical port site infection, and hernia were not observed in either group during the allocated follow-up period in the study. Conclusion: Open technique for pneumoperitoneum is as safe and effective as the closed technique.

Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling.

Fms-like tyrosine kinase 3 (Flt3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, indicating persistence of leukemia stem cells (LSC). Here utilizing a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model we determined that FLT3-ITD AML LSC were enriched within the primitive ST-HSC population. FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12-abundant reticular (CAR) cells were increased in Flt3-ITD AML marrow. CXCL12 deletion from the microenvironment enhanced targeting of AML cells by Flt3-TKI plus chemotherapy treatment, including enhanced LSC targeting. Both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling in AML cells and further reduction was seen after treatment in CXCL12 deleted mice. p38 inhibition reduced CXCL12-dependent and -independent maintenance of both murine and human Flt3-ITD AML LSC by MSC and enhanced their sensitivity to treatment. p38 inhibition in combination with chemotherapy plus TKI treatment leads to greater depletion of Flt3-ITD AML LSC compared with CXCL12 deletion. Our studies support roles for CXCL12 and p38 signaling in microenvironmental protection of AML LSC and provide a rationale for inhibiting p38 signaling to enhance Flt3-ITD AML targeting.

Neuroprotective effects of exogenous brain-derived neurotrophic factor on amyloid-beta 1-40-induced retinal degeneration.

Amyloid-beta (Aß)-related alterations, similar to those found in the brains of patients with Alzheimer's disease, have been observed in the retina of patients with glaucoma. Decreased levels of brain-derived neurotrophic factor (BDNF) are believed to be associated with the neurotoxic effects of Aß peptide. To investigate the mechanism underlying the neuroprotective effects of BDNF on Aß1-40-induced retinal injury in Sprague-Dawley rats, we treated rats by intravitreal administration of phosphate-buffered saline (control), Aß1-40 (5 nM), or Aß1-40 (5 nM) combined with BDNF (1 µg/mL). We found that intravitreal administration of Aß1-40 induced retinal ganglion cell apoptosis. Fluoro-Gold staining showed a significantly lower number of retinal ganglion cells in the Aß1-40 group than in the control and BDNF groups. In the Aß1-40 group, low number of RGCs was associated with increased caspase-3 expression and reduced TrkB and ERK1/2 expression. BDNF abolished Aß1-40-induced increase in the expression of caspase-3 at the gene and protein levels in the retina and upregulated TrkB and ERK1/2 expression. These findings suggest that treatment with BDNF prevents RGC apoptosis induced by Aß1-40 by activating the BDNF-TrkB signaling pathway in rats.

Itch in Hidradenitis Suppurativa/Acne Inversa: A Systematic Review.

Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory disease of the pilosebaceous unit leading to formation of painful, inflammatory nodules, abscesses and tunnels in apocrine gland-bearing areas of the skin. Pain and drainage are the most important symptoms associated with reduction of quality of life in HS. On the other hand, an overlooked symptom in quality of life studies is itch, despite the fact that several studies have reported its importance. Various theories have tried to explain the pathogenesis of itch in HS, such as the presence of mast cells in the cell infiltrates and elevated Ig E levels in the lesional skin. Smoking and advanced stage of disease have been found to be associated with increased intensity of itch. A PUBMED search was conducted to perform a systematic literature review using the term "hidradenitis suppurativa" [all fields], the keywords "pruritus", "itching", "itch" [all fields] and with "AND" as operator. Mast cells and mTor signaling were found to be raised in both lesional and perilesional skin. Itch as a presenting symptom has been found in 35-82.6% of patients across multiple studies. It often co-presents with pain and may be misinterpreted as burning, stinging, tickling, tweaking, prickling, etc. The presence of itch is associated with reduced quality of life, depression and impairment of social life. Brodalumab, a monoclonal antibody against IL-17A receptor, produced significant improvements in itch, pain, QoL and depression in patients with moderate to severe HS. Statins have shown some reduction in itch intensity score. Further studies are required to gain a better understanding of the etiopathogenesis and optimal therapeutic modalities for itch in HS that will allow clinicians to better address issue and reduce its impact on quality of life.

Monitoring Misinformation on Twitter During Crisis Events: A Machine Learning Approach.

Social media has been increasingly utilized to spread breaking news and risk communications during disasters of all magnitudes. Unfortunately, due to the unmoderated nature of social media platforms such as Twitter, rumors and misinformation are able to propagate widely. Given this, a surfeit of research has studied false rumor diffusion on Twitter, especially during natural disasters. Within this domain, studies have also focused on the misinformation control efforts from government organizations and other major agencies. A prodigious gap in research exists in studying the monitoring of misinformation on social media platforms in times of disasters and other crisis events. Such studies would offer organizations and agencies new tools and ideologies to monitor misinformation on platforms such as Twitter, and make informed decisions on whether or not to use their resources in order to debunk. In this work, we fill the research gap by developing a machine learning framework to predict the veracity of tweets that are spread during crisis events. The tweets are tracked based on the veracity of their content as either true, false, or neutral. We conduct four separate studies, and the results suggest that our framework is capable of tracking multiple cases of misinformation simultaneously, with F 1 $F_1$ scores exceeding 87%. In the case of tracking a single case of misinformation, our framework reaches an F 1 $F_1$ score of 83%. We collect and drive the algorithms with 15,952 misinformation-related tweets from the Boston Marathon bombing (2013), Manchester Arena bombing (2017), Hurricane Harvey (2017), Hurricane Irma (2017), and the Hawaii ballistic missile false alert (2018). This article provides novel insights on how to efficiently monitor misinformation that is spread during disasters.

Treatment of a Refractory Case of Chronic Bullous Disease of Childhood in a Five Year Old Child with Rituximab.

Patients with chronic bullous disease of childhood (CBDC) generally respond well to treatment with drugs like Dapsone and oral and topical steroids. Refractory cases are additionally treated with immunosuppressants like azathioprine, methotrexate, ciclosporin, colchicine, tetracycline, and IVIG (Intravenous Immunoglobulin). However, there are few patients who fail to respond to these therapies and pose a challenge both to the patient and the treating physician. Rituximab has been used widely to treat pemphigus cases in adults, but its use in children has not been much reported. We hereby report a case of a 5-year-old child with CBDC, refractory to other treatments, who responded favorably to Rituximab.

Tackling retinal ganglion cell apoptosis in glaucoma: role of adenosine receptors.

INTRODUCTION: The role of adenosine receptors as therapeutic targets for neuroprotection is now widely recognized. Their role, however, in protection against retinal ganglion cell (RGC) apoptosis in glaucoma needs further investigation. Hence, in this review, we look into the possibility of adenosine receptors as potential therapeutic targets by exploring their role in modulating various pathophysiological mechanisms underlying glaucomatous RGC loss. AREAS COVERED: This review presents a summary of the adenosine receptor distribution in retina and the cellular functions mediated by them. The major pathophysiological mechanisms such as excitotoxicity, vascular dysregulation, loss of neurotrophic signaling, and inflammatory responses involved in glaucomatous RGC loss are discussed. The literature showing the role of adenosine receptors in modulating these pathophysiological mechanisms is discussed. The literature search was conducted using Pubmed search engine using key words such as 'RGC apoptosis,' 'adenosine,' adenosine receptors' 'retina' 'excitotoxicity,' 'neurotrophins,' 'ischemia', and 'cytokines' individually and in various combinations. EXPERT OPINION: Use of adenosine receptor agonists and antagonists, for preservation of the RGCs in glaucomatous eyes independent of the level of intraocular pressure seems a very useful strategy. Future application of this strategy would require appropriate designing of drug formulation for tissue and disease-specific receptor targeting. Furthermore, the modulation of physiological functions and potential adverse effects need further investigations.

Chronic Kidney Disease-Associated Pruritus.

Pruritus is a distressing condition associated with end-stage renal disease (ESRD), advanced chronic kidney disease (CKD), as well as maintenance dialysis and adversely affects the quality of life (QOL) of these patients. It has been reported to range from 20% to as high as 90%. The mechanism of CKD-associated pruritus (CKD-aP) has not been clearly identified, and many theories have been proposed to explain it. Many risk factors have been found to be associated with CKD-aP. The pruritus in CKD presents with diverse clinical features, and there are no set features to diagnose it.The patients with CKD-aP are mainly treated by nephrologists, primary care doctors, and dermatologists. Many treatments have been tried but nothing has been effective. The search of literature included peer-reviewed articles, including clinical trials and scientific reviews. Literature was identified through March 2021, and references of respective articles and only articles published in the English language were included.

TNF-α-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling.

Chronic myeloid leukemia (CML) is propagated by leukemia stem cells (LSCs) that are not eradicated by tyrosine kinase inhibitor (TKI) treatment and persist as a source of disease recurrence. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) and LSC maintenance. Using a murine CML model, we examine leukemia-induced alterations in mesenchymal cell populations. We show that 6C3+ stromal progenitors expand in CML BM and exhibit increased LSC but reduced HSC supportive capacity. Tumor necrosis factor alpha (TNF-α) signaling mediates expansion and higher expression of CXCL1 in CML BM 6C3+ cells and higher expression of the CXCL1 receptor CXCR2 in LSCs. CXCL1 enhances LSC proliferation and self-renewal, whereas CXCR2 inhibition reduces LSC growth and enhances LSC targeting in combination with tyrosine kinase inhibitors (TKIs). We find that TNF-α-mediated alterations in CML BM stromal niches enhance support of LSC maintenance and growth via CXCL1-CXCR2 signaling and that CXCR2 inhibition effectively depletes CML LSCs.

A Two-Stage Data-Driven Spatiotemporal Analysis to Predict Failure Risk of Urban Sewer Systems Leveraging Machine Learning Algorithms.

Risk-informed asset management is key to maintaining optimal performance and efficiency of urban sewer systems. Although sewer system failures are spatiotemporal in nature, previous studies analyzed failure risk from a unidimensional aspect (either spatial or temporal), not accounting for bidimensional spatiotemporal complexities. This is owing to the insufficiency of good-quality data, which ultimately leads to under-/overestimation of failure risk. Here, we propose a generalized methodology/framework to facilitate a robust spatiotemporal analysis of urban sewer system failure risk, overcoming the intrinsic challenges of data imperfections-e.g., missing data, outliers, and imbalanced information. The framework includes a two-stage data-driven modeling technique that efficiently models the highly right-skewed sewer system failure data to predict the failure risk, leveraging a bidimensional space-time approach. We implemented our analysis for Bogotá, the capital city of Colombia. We train, test, and validate a battery of machine learning algorithms-logistic regression, decision trees, random forests, and XGBoost-and select the best model in terms of goodness-of-fit and predictive accuracy. Finally, we illustrate the applicability of the framework in planning/scheduling sewer system maintenance operations using state-of-the-art optimization techniques. Our proposed framework can help stakeholders to analyze the failure-risk models' performance under different discrimination thresholds, and provide managerial insights on the model's adequate spatial resolution and appropriateness of decentralized management for sewer system maintenance.