Progress of machine perfusion in managing donor-derived infections in liver transplantation

Introduction

Liver transplantation is the only effective treatment for end-stage liver disease (1). With continuous advances in transplantation techniques, the number of liver transplantations performed worldwide has increased steadily over recent years. Currently, more than 100,000 patients worldwide are registered on liver transplant waiting lists each year, yet fewer than 30% ultimately receive a transplant (2). The annual mortality rate among waitlisted patients remains as high as 15–35%, and a substantial number of patients die while awaiting a donor liver (2). To alleviate the severe shortage of donor organs, increasing attention has been directed toward expanding the utilization of extended criteria donor (ECD), including donors after circulatory death (DCD), steatotic liver grafts, small-for-size grafts, elderly donors, and donors with positive infectious disease markers (3,4).

However, a large proportion of potential donor livers remain unused. According to the 2020 annual report of the Organ Procurement and Transplantation Network (OPTN), among 12,588 potential deceased donors, more than 90% of discarded liver grafts were excluded from transplantation because of donor-related clinical concerns, including complex medical histories, impaired organ function, and anatomical abnormalities. Importantly, infection and potential pathogen exposure also contribute substantially to graft nonutilization. Of the discarded liver grafts, 169 were excluded because of confirmed infection, positive screening for high-risk transmissible diseases, or suspected pathogen exposure. These findings suggest that donor livers with actual or suspected infectious risks are frequently approached with caution and are often discarded in clinical practice (5).

Global epidemiology of donor-derived infections (DDIs)

DDI refers to the transmission of pathogens carried by the donor to the recipient through organ transplantation, resulting in infection with the same pathogen in the recipient (6). Although the overall incidence of unexpected DDI is relatively low, ranging from 0.18% to 1.0% under current donor screening systems, its occurrence can lead to serious consequences, including graft dysfunction, graft loss, and even recipient death (7,8). Studies have shown that following unexpected DDI, graft loss and perioperative mortality rates may reach 15–38%, making DDI an important factor affecting transplant outcomes and the safe utilization of donor organs (8). Western countries have established relatively comprehensive surveillance systems for DDIs. Data from the Disease Transmission Advisory Committee (DTAC) in the United States showed that a total of 2,185 potential donor-derived disease transmission events (PDDTE) were reported between 2008 and 2017. During this period, the number of confirmed or highly probable donor-derived transmission events increased from 17 to 47 cases, demonstrating an overall upward trend (8). These findings suggest that the risk of DDI remains persistent and has attracted increasing attention as the scope of organ utilization continues to expand. In addition, accelerated global population mobility, climate change, and alterations in pathogen ecology have facilitated the emergence and re-emergence of infectious pathogens, rendering the epidemiological characteristics of DDIs increasingly complex. For example, West Nile virus, Dengue virus, and other regionally endemic pathogens have all been documented to be transmitted through organ transplantation, posing new challenges to transplant safety (9).

A wide variety of pathogens can cause DDIs in clinical practice. Viral infections account for approximately one-third of all DDIs, whereas the remaining cases are primarily caused by bacteria, fungi, and parasites (10). Among these pathogens, multidrug-resistant organism (MDRO) have emerged as one of the most concerning infectious threats in the field of transplantation (11). Potential donors admitted to intensive care units frequently require mechanical ventilation, central venous catheterization, and broad-spectrum antibiotic therapy, all of which substantially increase the risk of colonization and infection with resistant pathogens (12-15). A recent multicenter study involving 302 deceased donors and their corresponding solid organ recipients demonstrated that the positivity rate of donor specimens and preservation fluid cultures collected during organ procurement reached 89.4%, with MDRO representing the predominant group of pathogens identified. Among liver transplant recipients receiving organs from MDRO-positive donors, the incidence of DDIs caused by the same resistant organisms reached 19.4% after transplantation (16). Common MDRO encountered in clinical transplantation include vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacterales (CRE), multidrug-resistant Pseudomonas aeruginosa, and Acinetobacter baumannii (11). Among these pathogens, multidrug-resistant Gram-negative bacteria (MDR-GN) have a particularly profound impact on organ utilization, post-transplant infectious complications, and recipient outcomes (17). Notably, carbapenem-resistant Klebsiella pneumoniae (CRKP) has spread rapidly worldwide in recent years and has become one of the most important high-risk pathogens associated with DDIs (18,19).

Of particular concern, with the widespread adoption of ECD, DCD liver grafts have gradually become an important source for alleviating the shortage of donor livers (20). Although there is currently no definitive evidence demonstrating a higher incidence of DDI in DCD donors compared with donation after brain death (DBD) donors, accumulating evidence suggests that DCD donors may be exposed to greater infection-related risks. The unavoidable warm ischemic injury associated with DCD donation may impair intestinal barrier integrity, enhance inflammatory responses, and increase the risk of pathogen translocation (21). In addition, DCD liver grafts are more susceptible to ischemia-reperfusion injury (IRI) and ischemic cholangiopathy, thereby increasing the risk of biliary tract infections and bacteremia. Several clinical studies have also reported a relatively high prevalence of donor pathogen colonization or infection among DCD donors, which may subsequently result in DDIs in recipients (22,23). Against the background of the persistent burden of DDIs, the increasing prevalence of MDROs, and the widespread utilization of high-risk marginal donors such as DCD donors, strategies aimed at reducing pathogen burden during organ preservation, attenuating IRI, and improving the safe utilization of infection-exposed donor livers have become important research priorities in transplantation. These challenges also provide a strong theoretical rationale for exploring machine perfusion (MP)-based antimicrobial intervention strategies.

Advances in MP for liver graft preservation

Currently, liver graft preservation in clinical practice primarily relies on static cold storage (SCS) and MP. SCS, the traditional method, reduces hepatocellular metabolic activity through hypothermia, thereby limiting lactate accumulation and free radical formation, and delaying ischemic injury. This approach provides basic protection during organ retrieval and implantation. However, with the increasing use of marginal donor livers, SCS shows substantial limitations in controlling IRI, extending preservation duration, enabling real-time functional assessment, and optimizing high-risk grafts (24). The introduction of MP technology has addressed many of the limitations inherent to SCS (25,26). MP maintains continuous perfusion and oxygen delivery under physiological or near-physiological conditions, enabling organ preservation, transportation, viability assessment, and injury repair simultaneously (27). With broader adoption of grafts from elderly donors, steatotic livers, and DCD, MP has increasingly become an integral component of standardized clinical organ preservation (24,28). A typical MP system consists of a perfusion chamber, mechanical pump, arterial and venous circuits, oxygenation module, temperature control unit, pressure monitoring system, and filtration device. Additional ventilation modules may be included depending on the organ type. Among all organs, the technology is most established for the liver, kidney, and lung (25,29,30). In liver perfusion, the choice of perfusion model is mainly determined by two factors: timing (pre-transplant, intra-operative, or post-transplant) and perfusion temperature. Temperature is a critical determinant of metabolic rate and oxygen consumption, directly influencing preservation quality (31,32). For instance, temperatures below 12 °C reduce hepatic metabolic rate by 6–12 fold, whereas normothermic perfusion (35–37 °C) requires continuous high-level metabolic support. Based on perfusion temperature, MP can be categorized into three major modalities (33) in Table 1.

Hypothermic MP (HMP)

HMP is a low-metabolic protective mode. HMP is the earliest MP technology applied to liver preservation. By markedly reducing temperature, it suppresses cellular metabolism, minimizes oxygen consumption and adenosine triphosphate (ATP) depletion, and allows continuous removal of metabolic waste. This maintains cellular homeostasis and effectively attenuates ischemic injury progression. HMP is particularly suitable for severely injured or DCD livers (34,35).

Subnormothermic MP (SNMP)

SNMP is a balanced protection-repair mode. SNMP maintains perfusion temperature between 15–25 °C, achieving a balance between metabolic suppression and preserved enzymatic activity. This temperature range reduces energy demand while allowing partial metabolic and functional recovery, representing a transitional approach between HMP and NMP (36).

Normothermic MP (NMP)

NMP is a physiological metabolic repair mode. NMP operates at physiological temperature (37 °C), replicating an in vivo circulatory environment. It restores full aerobic metabolism, bile production, and detoxification function. As NMP enables simultaneous preservation, repair, and real-time viability assessment, it has become an essential technique for evaluating marginal graft function and excluding non-transplantable livers (37).

In summary, MP improves graft preservation by optimizing metabolic conditions, enhancing oxygen delivery, reducing IRI, and enabling dynamic functional monitoring. Collectively, these advantages significantly improve graft quality, post-transplant outcomes, and overall organ utilization.

Major advantages of MP over SCS in liver graft preservation

Significant attenuation of IRI and improved graft functional recovery

IRI is a central mechanism underlying early allograft dysfunction after liver transplantation and is closely associated with acute and chronic rejection, hepatic fibrosis, and tumor recurrence, all of which markedly influence long-term outcomes (38-40). Although SCS reduces metabolic activity through hypothermia, complete cessation of circulation still leads to cellular edema, energy depletion, acidosis, accumulation of metabolic byproducts, and mitochondrial dysfunction. These changes, upon reperfusion, trigger amplification of oxidative stress and inflammatory cascades (41).

By contrast, MP provides continuous oxygenated, nutrient-rich perfusate during preservation, maintaining partial or near-physiological microcirculatory flow. This dynamic perfusion reduces metabolic derangements and cellular injury resulting from ischemia. Continuous washout of lactate and reactive oxygen species, along with preserved ATP generation and ionic homeostasis, mitigates IRI at its source (42,43). Consequently, livers preserved using MP exhibit faster functional recovery after implantation and show a markedly lower risk of early allograft dysfunction.

Substantial extension of safe preservation duration, enabling broader organ distribution

The safe preservation window of SCS is typically limited to 6–12 hours (44), restricting transportation distance and confining allocation largely to regional networks. This narrow time frame reduces flexibility in matching donors and recipients and contributes to unnecessary graft discard. MP stabilizes hepatic metabolism and preserves cellular integrity, enabling preservation times far beyond those achievable with SCS. Whether using HMP, SNMP, or NMP perfusion, MP extends preservation from several hours to more than 10 hours—and in some platforms to even longer durations (26). This prolonged functional window supports long-distance and international sharing of donor livers, greatly improving allocation efficiency and making broader organ-sharing networks feasible.

Real-time dynamic functional assessment enhances graft safety

Under SCS, livers are maintained in a static, hypothermic state without any means for functional evaluation. Pre-transplant assessment relies mainly on donor history and macroscopic examination, which inherently carries uncertainty and increases the risk of implanting nonviable grafts and subsequent postoperative complications. MP allows continuous real-time monitoring of key physiological parameters during preservation (45), including hemodynamic indicators—perfusion flow, arterial and portal pressure; metabolic metrics—lactate clearance, glucose consumption, bile production; cellular injury markers—aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and others. These dynamic data points enable reliable assessment of graft viability and prediction of post-transplant function, thereby reducing the risk of transplanting unsuitable grafts and improving patient safety (46-48).

Enhanced preservation quality of marginal grafts, improving overall organ utilization

Marginal livers—including steatotic grafts, grafts from elderly donors, and donation after DCD livers—are particularly vulnerable to ischemia and susceptible to irreversible injury under SCS, contributing to low utilization rates. MP delivers continuous oxygenation, nutrient supply, and metabolic waste clearance, enabling partial repair of mildly to moderately damaged marginal grafts. It improves mitochondrial function, restores energy metabolism, and alleviates microcirculatory disturbances, effectively converting a proportion of previously discardable grafts into transplantable organs. This capacity to rescue marginal livers is pivotal for addressing the persistent global donor shortage (49-51).

Rationale and significance of combining antibiotics with MP

For decades, international efforts have explored the addition of antibiotics to organ preservation solutions in attempts to reduce donor-derived bacterial contamination and improve the usability of infection-prone marginal grafts (52,53). However, these early attempts yielded limited benefit due to the narrow antibiotic spectrum available at the time, insufficient drug purity, and suboptimal bactericidal activity. In recent years, rapid advancements in antibiotic development have produced agents with broader antimicrobial coverage, improved stability, and substantially enhanced bactericidal potency, thereby revitalizing interest in integrating antibiotics into organ preservation strategies. Emerging evidence indicates that supplementing preservation solutions with appropriate antibiotic concentrations can effectively suppress bacterial proliferation, maintain a more sterile preservation environment, and ultimately enhance the viability and utilization of marginal donor livers (54). However, the impact of the preservation environment on microbial growth dynamics differs fundamentally among organ preservation techniques. In conventional SCS and HMP, organs are maintained at an extremely low temperature of 0–4 °C. Even when microorganisms are present, their metabolic activity and cellular replication are markedly suppressed, making explosive microbial proliferation during preservation unlikely. In contrast, the emergence of NMP has substantially amplified and accelerated infection-related risks while more closely replicating physiological conditions. NMP is performed at a physiological temperature of 35–37 °C and commonly utilizes perfusates containing red blood cells and high concentrations of nutrients. Such conditions effectively provide an ideal incubating environment for pathogens that may be latent within donor organs. Clinical studies have demonstrated that during prolonged NMP, in the absence of effective antimicrobial agents, more than 50% of perfusate samples exhibit extensive logarithmic-phase bacterial or fungal proliferation within a few hours (55). Therefore, maintaining stable antimicrobial activity within the perfusion circuit is of critical pathophysiological importance for mitigating tissue injury and inflammatory responses induced by microbial contamination. The routine and optimized incorporation of highly effective antibiotics into NMP systems is not only intended to control DDIs but also represents a prerequisite for the safe and reliable operation of NMP technology itself.

By optimizing antibiotic selection, dosing, and duration of perfusion exposure, it becomes feasible to establish a robust “anti-infective barrier”, providing a safer reperfusion microenvironment for marginal livers—particularly those with documented bacterial contamination or high infection risk. This strategy represents a conceptual shift in organ preservation—from purely physical protection to an integrated model combining physical support with targeted pharmacologic intervention. The approach significantly expands the clinical potential of MP in managing high-risk, infection-exposed donor livers.

Mechanisms underlying the combined use of antibiotics and MP

Optimization of antibiotic delivery efficiency by MP

MP maintains continuous arterial and portal venous flow, enabling far more efficient antibiotic delivery compared with SCS. Continuous perfusion not only improves microvascular circulation but also facilitates antibiotic transendothelial transport, thereby increasing drug concentrations within key hepatic cell populations, including hepatocytes, cholangiocytes, and Kupffer cells (56,57). Evidence indicates that local antibiotic concentrations during MP may increase several-fold relative to SCS (53). Moreover, MP restores perfusion uniformity, reduces microcirculatory obstruction and “low-flow regions”, and allows more homogeneous antibiotic distribution within the parenchyma. This is particularly beneficial for donor livers with focal infection or bacterial contamination, enabling more precise and targeted delivery. Perfusion parameters such as flow rate and pressure can be dynamically adjusted based on infectious burden and organ condition, improving the hemodynamic environment for antibiotic distribution. In contrast to systemic administration, antibiotic delivery via MP risks significantly less systemic toxicity, as drug exposure is concentrated within the organ rather than the entire circulation. This reduces the likelihood of nephrotoxicity, neurotoxicity, and other adverse effects, offering a distinct advantage for the utilization of marginal donor livers.

Synergistic protective effects between antibiotics and MP

Beyond serving as a drug delivery platform, MP also exerts inherent biological protective effects that act synergistically with antibiotic therapy to enhance graft quality.

Dual benefits: infection control and attenuation of IRI. MP improves mitochondrial function, reduces intracellular calcium overload, mitigates oxidative stress, and preserves central metabolic pathways, thereby substantially reducing IRI (58,59). Antibiotics eliminate residual pathogens within the graft and reduce innate immune activation triggered by bacterial components such as LPS, leading to decreased production of inflammatory mediators including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and consequently further alleviating IRI (60).

Promotion of metabolic stability and reduction of drug accumulation toxicity. MP maintains aerobic metabolism, allowing drug metabolites to be continuously cleared through the perfusion circuit, preventing their accumulation in tissues and reducing the risk of toxicity (61). This is particularly important for polymyxins, which have known cytotoxic potential.

Maintenance of stable drug concentrations to reduce resistance development. MP enables sustained and controllable antibiotic concentrations, exposing microorganisms to a stable bactericidal environment and decreasing the likelihood of resistance associated with subinhibitory concentrations (54). Such concentration stability is difficult to achieve with SCS.

Collectively, the combined use of MP and antibiotics provides “structural protection, metabolic support and infection control”, offering a comprehensive strategy to improve the quality of high-risk donor livers.

Differential antibiotic effects under various MP modalities

Studies comparing different temperature-based MP modalities—including HMP and NMP—have shown no significant difference in the bactericidal efficacy of antibiotics, suggesting that temperature has minimal impact on their direct antimicrobial activity (53). This indicates that antibiotics maintain robust activity across a wide temperature range (4–37 °C), allowing flexible use in different perfusion settings. These studies also assessed short-term safety when organs were exposed to high-dose antibiotics. Results showed no histological damage in kidneys subjected to high concentrations of these agents.

However, systematic evaluation of hepatic safety under high-dose antibiotic exposure during MP remains lacking. Given the liver’s central role in drug metabolism, its sensitivity, metabolic load, and cytotoxicity thresholds may differ significantly from those of the kidney. Therefore, dedicated toxicological studies are necessary to fully establish hepatic safety in this context.

Limitations and challenges of combining antibiotics with MP

Limitations in translating animal evidence to clinical practice

Current evidence supporting the use of “antibiotic-assisted MP for infected donor livers” is derived primarily from rodent models, particularly rats. Although these models are valuable for mechanistic research, their translational relevance remains limited. First, rat livers are much smaller and anatomically different from human livers; their perfusion dynamics, metabolic rates, and drug absorption, distribution, and clearance characteristics differ substantially from those in humans. Second, existing studies typically involve very small sample sizes with limited statistical power, making it difficult to generate clinically actionable evidence. Moreover, the pathogen spectrum used in rodent infection models does not fully reflect the complexity of contamination encountered in clinical donor livers, particularly in cases involving multidrug resistance (MDR)/extensively drug resistance (XDR) pathogens. Consequently, current animal data are insufficient to directly guide clinical decision-making and represent a major barrier to clinical translation.

Clinical challenges intrinsic to MP technology

Although MP has been shown globally to improve the quality of marginal donor livers, several practical challenges still hinder its widespread clinical adoption (62).

Lack of standardized operating protocols; reliance on operator experience. Whether using HMP or NMP, perfusion pressure, flow rate, temperature, and oxygen delivery must be adjusted in real time according to graft characteristics. No universally accepted standardized operating parameters currently exist, and perfusion management still largely depends on operator experience. This raises technical complexity and increases the risk of perfusion failure.

Absence of unified viability assessment criteria. Criteria for determining whether a perfused liver is suitable for transplantation remain inconsistent. Although parameters such as lactate clearance, bile production, and metabolic indicators (e.g., ATP content) have been proposed, none have achieved consensus or been incorporated into standardized guidelines. This leads to significant variability across centers and affects organ utilization rates.

High cost and operational complexity (63). MP requires expensive equipment, disposable supplies, specialized perfusates, and ongoing technical maintenance, all of which far exceed the costs of SCS. When NMP is initiated at the donor hospital, the procurement team must establish a complete perfusion setup on site, substantially increasing logistical and financial burden. Additionally, MP requires trained personnel to monitor perfusion stability in real time, which limits adoption in resource-constrained regions.

Risk of adverse events from perfusion failure. Equipment malfunction, unstable circulation, or insufficient perfusion can prolong warm ischemia time and exacerbate graft injury. Thus, inherent uncertainties associated with MP limit its routine use in high-risk scenarios such as infected donor livers.

Challenges related to clinical adaptation of antibiotic use

Despite strong theoretical advantages, the application of antibiotics during MP faces multiple challenges related to antimicrobial selection, dosage optimization, and safety validation.

Delayed microbiological results and difficulty in antibiotic selection. Conventional microbiological testing (e.g., culture and susceptibility) typically requires 24–48 hours, whereas organ transplantation must be completed within approximately 6–12 hours (64,65). This mismatch makes it difficult to select perfusion antibiotics based on pathogen-directed therapy, increasing the risk of mismatched antimicrobial coverage. Although rapid diagnostic tools such as metagenomic next-generation sequencing (mNGS) and polymerase chain reaction (PCR) panels can shorten turnaround time, they are not widely available and may not detect all resistance genes or uncommon pathogens.

Challenges in dose optimization and potential toxicity. Animal data suggest that short-term exposure to high-dose antibiotics during perfusion does not cause renal injury, but systematic evaluation of hepatic toxicity remains lacking. Human donor livers vary widely in metabolic capacity, and livers from elderly donors, steatotic donors, or donors with prior drug exposure may be more susceptible to antibiotic-induced injury. Thus, high-concentration antibiotics during MP may increase the risk of hepatocyte or cholangiocyte damage. Ideally, dose adjustments should rely on therapeutic drug monitoring (TDM), but current TDM reflects only plasma levels, requires substantial turnaround time, and does not measure intra-organ tissue concentrations. This limits precise intra-perfusate dose regulation.

Reduced activity of some antibiotics and urgent need for new agents. While studies have verified the efficacy of polymyxins during perfusion, their activity against complex MDR/XDR strains—such as New Delhi metallo-beta-lactamase (NDM), Klebsiella pneumoniae carbapenemase (KPC), or oxacillinase-48 (OXA-48)-producing organisms—is inconsistent. The bactericidal potency of many clinically used antibiotics against target pathogens has declined significantly. As antimicrobial resistance continues to evolve, relying solely on existing antibiotics is inadequate to address increasingly complex DDIs. There is an urgent need to develop new antimicrobial agents specifically suited for use in perfusion environments.

Future directions and clinical implications of MP for infected donor livers

MP technology has provided a novel strategy for the safe utilization of infection-exposed donor livers. In addition to improving organ preservation quality and enhancing the assessment of graft viability, MP also creates unique opportunities for ex vivo antimicrobial intervention. Emerging evidence has demonstrated that the administration of antimicrobial agents during MP can effectively reduce pathogen burden within donor organs, decrease the risk of DDI transmission, and potentially improve the utilization of infection-exposed liver grafts. However, current evidence is still largely derived from animal studies and small-scale clinical investigations. Moreover, standardized protocols regarding perfusion modalities, antimicrobial regimens, and outcome assessment systems remain lacking, and the long-term efficacy and safety of these approaches require further validation.

Future research should focus on establishing standardized MP systems for infection-exposed donor livers. Key priorities include the development of large-animal models and the generation of high-quality clinical evidence, optimization of antimicrobial strategies against different pathogens, particularly MDRO, and the integration of advanced diagnostic technologies, such as metagenomic sequencing, rapid PCR-based detection, and antimicrobial resistance gene analysis, to enable rapid pathogen identification and precision intervention. In addition, further investigations are warranted to evaluate the potential applications of novel antimicrobial agents, antimicrobial peptides, bacteriophages, and other innovative anti-infective approaches within MP platforms. Continuous improvements in perfusion device performance, including greater intelligence, automation, and cost-effectiveness, should also be pursued.

Taken together, with ongoing advances in pathogen detection technologies, anti-infective strategies, and MP platforms, precision antimicrobial management based on MP may enable infection-exposed donor livers to transition from traditionally high-risk grafts to donor resources that are assessable, amenable to intervention, and safe for clinical utilization. Such developments may ultimately provide a novel clinical pathway for improving recipient outcomes while maximizing the utilization of scarce donor organs.

Conclusions

In summary, DDI remains a key limitation in liver transplantation, especially with increasing multidrug-resistant pathogens, leading to graft discard and poor outcomes. MP overcomes the limitations of SCS by enabling functional preservation, real-time viability assessment, and improved graft quality. Importantly, MP combined with antibiotics provides a promising strategy for ex vivo infection control and graft reconditioning. However, issues such as lack of standardization, uncertainty in antimicrobial use, and safety concerns still need to be addressed before widespread clinical application.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0051/prf

Funding: This work was supported by the National Key Research and Development Program of China (No. 2024YFA1109002) and the Liaoning Province Science and Technology Program Joint Plan (No. 2025-BSLH-399).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0051/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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