2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Diverticulitis in Adults and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for diagnostic imaging of suspected acute diverticulitis. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment in Adults and Children.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides a recommendation for risk stratification according to severity of illness score. The panel's recommendation is based upon evidence derived from systematic literature reviews and adheres to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Utility of Intra-abdominal Fluid Cultures in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for obtaining cultures of intra-abdominal fluid in patients with known or suspected intra-abdominal infection. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Intra-abdominal Abscess in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for diagnostic imaging of suspected acute intra-abdominal abscess. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Appendicitis in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for diagnostic imaging of suspected acute appendicitis. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Cholecystitis and Acute Cholangitis in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for diagnostic imaging of suspected acute cholecystitis or acute cholangitis. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Utility of Blood Cultures in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for obtaining blood cultures in patients with known or suspected intra-abdominal infection. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment, Diagnostic Imaging, and Microbiological Evaluation in Adults, Children, and Pregnant People.

As the first part of an update to the clinical practice guideline on the diagnosis and management of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America, the panel presents twenty-one updated recommendations. These recommendations span risk assessment, diagnostic imaging, and microbiological evaluation. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach.

Empirical antifungal therapy for health care-associated intra-abdominal infection: a retrospective, multicentre and comparative study.

BACKGROUND: Current guidelines recommend using antifungals for selected patients with health care-associated intra-abdominal infection (HC-IAI), but this recommendation is based on a weak evidence. This study aimed to assess the association between early empirical use of antifungals and outcomes in intensive care unit (ICU) adult patients requiring re-intervention after abdominal surgery. METHODS: A retrospective, multicentre cohort study with overlap propensity score weighting was conducted in three ICUs located in three medical institutions in France. Patients treated with early empirical antifungals for HC-IAI after abdominal surgery were compared with controls who did not receive such antifungals. The primary endpoint was the death rate at 90 days, and the secondary endpoints were the death rate at 1 year and composite criteria evaluated at 30 days following the HC-IAI diagnosis, including the need for re-intervention, inappropriate antimicrobial therapy and death, whichever occurred first. RESULTS: At 90 days, the death rate was significantly decreased in the patients treated with empirical antifungals compared with the control group (11.4% and 20.7%, respectively, p = 0.02). No differences were reported for the secondary outcomes. CONCLUSION: The use of early empirical antifungal therapy was associated with a decreased death rate at 90 days, with no effect on the death rate at 1 year, the death rate at 30 days, the rate of re-intervention, the need for drainage, and empirical antibiotic and antifungal therapy failure at 30 days.

Effect of preoperative frailty on postoperative infectious complications and prognosis in patients with colorectal cancer: a propensity score matching study.

BACKGROUND: Few studies have explored the impact of preoperative frailty on infectious complications in patients with a diagnosis of colorectal cancer (CRC). Therefore, this study aimed to investigate the effect of preoperative frailty on postoperative infectious complications and prognosis in patients with CRC using propensity score matching (PSM). METHODS: This prospective single-centre observational cohort study included 245 patients who underwent CRC surgery at the Department of Gastrointestinal Surgery, The Affiliated Lianyungang Hospital of Xuzhou Medical University between August 2021 to May 2023. Patients were categorised into two groups: frail and non-frail. They were matched for confounders and 1:1 closest matching was performed using PSM. Rates of infectious complications, intensive care unit (ICU) admission, 30-day mortality, and 90-day mortality, as well as postoperative length of hospital stay, total length of hospital stay, and hospital costs, were compared between the two groups. Binary logistic regression using data following PSM to explore independent factors for relevant outcome measures. RESULTS: After PSM, each confounding factor was evenly distributed between groups, and 75 pairs of patients were successfully matched. The incidence of intra-abdominal infectious complications was significantly higher in the frail group than in the non-frail group (10.7% vs. 1.3%, P < 0.05). There were no significant differences in ICU admission rate, postoperative length of hospital stay, total length of hospital stay, hospital costs, 30-day mortality rate, or 90-day mortality rate between the two groups (P > 0.05). Our logistic regression analysis result showed that preoperative frailty (OR = 12.014; 95% CI: 1.334-108.197; P = 0.027) was an independent factor for intra-abdominal infection. CONCLUSIONS: The presence of preoperative frailty elevated the risk of postoperative intra-abdominal infectious complications in patients undergoing CRC surgery. Therefore, medical staff should assess preoperative frailty in patients with CRC early and provide targeted prehabilitation interventions.

Postoperative morbidity following Hartmann's procedure in comparison to anterior resection and abdominoperineal resection for rectal cancer-a population-based study.

AIM: There is ongoing controversy regarding the extent to which Hartmann's procedure (HP) should be used in rectal cancer treatment. This study was designed to investigate 30-day postoperative morbidity and mortality following HP, anterior resection (AR) and abdominoperineal resection (APR) for rectal cancer using a national registry. METHODS: All patients operated for rectal cancer, tumour height 5-15 cm, between the years 2010 and 2017, were identified through the Swedish colorectal cancer registry. RESULTS: A total of 8476 patients were included: 1210 (14%) undergoing HP, 5406 (64%) AR and 1860 (22%) APR. HP was associated with an increased risk of intra-abdominal infection (OR 1.7, CI 1.26-2.28, P = 0.0004) compared to AR and APR, while APR was related to an increased risk of overall complications (OR 1.18, CI 1.01-1.40, P = 0.040). No significant difference was observed in the rate of reoperations and readmissions between HP, AR and APR, and type of surgical procedure was not a risk factor for 30-day mortality. Findings from a subgroup analysis of patients with a tumour 5-7 cm from the anal verge revealed that HP was not associated with increased risk for complications or 30-day mortality. CONCLUSIONS: For patients where AR is not appropriate HP is a valid alternative with a favourable outcome. APR was associated with the highest overall 30-day complication rate.

Acute Cholecystitis Due to Lactococcus lactis and Single-Center Experience With Infections Due to Lactococcus spp.

Background: Lactococcus species are used to ferment milk to yogurt, cheese, and other products. The gram-positive coccus causes diseases in amphibia and fish and is a rare human pathogen. Patients and Methods: A 51-year-old male underwent laparoscopic cholecystectomy for acute and chronic calculous cholecystitis. Lactococcus lactis was isolated from pus from his gallbladder empyema. Results: Our institutional database was searched for other cases of Lactococcus spp. infections and four patients (2 males, 2 females; aged 51, 64, 78, and 80 years) were identified during a four-year period. The three other patients had positive blood cultures associated with pneumonia, toxic megacolon, and severe gastroenteritis. All isolates were monocultures with Lactococcus lactis (2), Lactococcus garvieae (1) and Lactococcus raffinolactis (1). Two patients died related to their sepsis. We report the second case of cholecystitis involving Lactococcus. Conclusions: Lactococcus is a very rare pathogen mainly causing blood stream infections but needs to be considered to cause serious surgical infections in humans.

Utility of paired plasma and drainage fluid mNGS in diagnosing acute intra-abdominal infections with sepsis.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) has been increasingly applied in sepsis. We aimed to evaluate the diagnostic and therapeutic utility of mNGS of paired plasma and peritoneal drainage (PD) fluid samples in comparison to culture-based microbiological tests (CMTs) among critically ill patients with suspected acute intra-abdominal infections (IAIs). METHODS: We conducted a prospective study from October 2021 to December 2022 enrolling septic patients with suspected IAIs (n = 111). Pairwise CMTs and mNGS of plasma and PD fluid were sent for pathogen detection. The mNGS group underwent therapeutic regimen adjustment based on mNGS results for better treatment. The microbial community structure, clinical features, antibiotic use and prognoses of the patients were analyzed. RESULTS: Higher positivity rates were observed with mNGS versus CMTs for both PD fluid (90.0% vs. 48.3%, p < 0.005) and plasma (76.7% vs. 1.6%, p < 0.005). 90% of enrolled patients had clues of suspected pathogens combining mNGS and CMT methods. Gram-negative pathogens consist of most intra-abdominal pathogens, including a great variety of anaerobes represented by Bacteroides and Clostridium. Patients with matched plasma- and PD-mNGS results had higher mortality and sepsis severity. Reduced usage of carbapenem (30.0% vs. 49.4%, p < 0.05) and duration of anti-MRSA treatment (5.1 ± 3.3 vs. 7.0 ± 8.4 days, p < 0.05) was shown in the mNGS group in our study. CONCLUSIONS: Pairwise plasma and PD fluid mNGS improves microbiological diagnosis compared to CMTs for acute IAI. Combining plasma and PD mNGS could predict poor prognosis. mNGS may enable optimize empirical antibiotic use.

Meropenem versus piperacillin-tazobactam for the treatment of pancreatic necrosis.

PURPOSE: To date, there are three published guidelines discussing management of infected pancreatic necrosis (IPN) with conflicting recommendations. Specifically, The World Society of Emergency Surgery lists piperacillin-tazobactam as a treatment option in addition to meropenem and ciprofloxacin plus metronidazole. Piperacillin-tazobactam may serve as an effective carbapenem-sparing alternative. Although previous studies shed light on antimicrobial penetration data, there is a lack of clinical data comparing piperacillin-tazobactam to meropenem. The purpose of this study is to compare the efficacy of meropenem and piperacillin-tazobactam for the treatment of IPN. METHODS: This was a multicenter, retrospective cohort study conducted across three institutions. Patients with IPN who received either meropenem or piperacillin-tazobactam from January 2015 to December 2020 were included. The primary composite outcome was the incidence of 90-day clinical failure, which encompassed 90-day all-cause mortality and 90-day intra-abdominal infection recurrence. Secondary outcomes included length of hospital stay, antimicrobial duration of therapy, and the need for surgical intervention. RESULTS: We identified 229 patients with IPN that received either meropenem or piperacillin-tazobactam during hospital admission. After screening, 63 patients were included in the study. Incidence of 90-day clinical failure was observed in 33 % of the meropenem group and 50 % in the piperacillin-tazobactam group (OR, 1.98; 95 % CI 0.57 to 7.01, p = 0.259). The meropenem group had a lower incidence of 90-day infection recurrence in the piperacillin-tazobactam group (56 % vs 29 %, p = 0.047). CONCLUSIONS: Piperacillin-tazobactam may be an efficacious carbapenem-sparing treatment alternative for infected pancreatic necrosis.

Perioperative pancreaticoduodenectomy management strategy focusing on postoperative early drain colonization.

PURPOSE: Pancreatoduodenectomy (PD) is a highly invasive procedure. Intra-abdominal infections and pancreatic fistulas are strongly correlated complications. In the present study, we identified the risk factors for postoperative early drain colonization (POEDC) and established a perioperative management strategy. METHODS: A total of 205 patients who underwent pancreatoduodenectomy were included in the study. POEDC was defined as a positive drain fluid culture before postoperative day (POD) 4. We retrospectively investigated the correlation between POEDC, postoperative outcomes, and clinical factors. RESULTS: POEDC was observed in 26 patients (12.6%) with poor postoperative outcomes, including pancreatic fistulas (P < 0.001). A multivariate analysis demonstrated a correlation between these postoperative outcomes and the age (P = 0.002), body mass index (BMI) (P = 0.002), procalcitonin (PCT) level (P < 0.001), and drain amylase level on POD 1 (P = 0.032). Enterococcus was detected most frequently, being found in 15 patients. CONCLUSION: We observed a strong correlation between POEDC and poor postoperative outcomes. The BMI, age, and PCT and drain amylase level on POD 1 should be considered POEDC risk factors, with the need to propose an antibiotic perioperative strategy. POEDC control may represent the key to improving postoperative outcomes after PD.

Postoperative encapsulated hemoperitoneum in a patient with gastric stromal tumor treated by exposed endoscopic full-thickness resection: A case report.

BACKGROUND: Gastric stromal tumors, originating from mesenchymal tissues, are one of the most common tumors of the digestive tract. For stromal tumors originating from the muscularis propria, compared with conventional endoscopic submucosal dissection (ESD), endoscopic full-thickness resection (EFTR) can remove deep lesions and digestive tract wall tumors completely. However, this technique has major limitations such as perforation, postoperative bleeding, and post-polypectomy syndrome. Herein, we report a case of postoperative serous surface bleeding which formed an encapsulated hemoperitoneum in a patient with gastric stromal tumor that was treated with exposed EFTR. Feasible treatment options to address this complication are described. CASE SUMMARY: A 47-year-old male patient had a hemispherical protrusion found during gastric endoscopic ultrasonography, located at the upper gastric curvature adjacent to the stomach fundus, with a smooth surface mucosa and poor mobility. The lesion was 19.3 mm × 16.1 mm in size and originated from the fourth ultrasound layer. Computed tomography (CT) revealed no significant evidence of lymph node enlargement or distant metastasis. Using conventional ESD technology for mucosal pre-resection, exposed EFTR was performed to resect the intact tumor in order to achieve a definitive histopathological diagnosis. Based on its morphology and immunohistochemical expression of CD117 and DOG-1, the lesion was proven to be consistent with a gastric stromal tumor. Six days after exposed EFTR, CT showed a large amount of encapsulated fluid and gas accumulation around the stomach. In addition, gastroscopy suggested intracavitary bleeding and abdominal puncture drainage indicated serosal bleeding. Based on these findings, the patient was diagnosed with serosal bleeding resulting in encapsulated abdominal hemorrhage after exposed EFTR for a gastric stromal tumor. The patient received combined treatments, such as hemostasis under gastroscopy, gastrointestinal decompression, and abdominal drainage. All examinations were normal within six months of follow-up. CONCLUSION: This patient developed serous surface bleeding in the gastric cavity following exposed EFTR. Serosal bleeding resulting in an encapsulated hemoperitoneum is rare in clinical practice. The combined treatment may replace certain surgical techniques.

Preoperative blood markers and intra-abdominal infection after colorectal cancer resection.

BACKGROUND: Colorectal cancer (CRC) has one of the highest morbidity and mortality rates among digestive tract tumors. Intra-abdominal infection (IAI) is a common postoperative complication that affects the clinical outcomes of patients with CRC and hinders their rehabilitation process. However, the factors influencing abdominal infection after CRC surgery remain unclear; further, prediction models are rarely used to analyze preoperative laboratory indicators and postoperative complications. AIM: To explore the predictive value of preoperative blood markers for IAI after radical resection of CRC. METHODS: The data of 80 patients who underwent radical resection of CRC in the Anorectal Surgery Department of Suzhou Hospital affiliated with Anhui Medical University were analyzed. These patients were categorized into IAI (n = 15) and non-IAI groups (n = 65) based on whether IAI occurred. Influencing factors were compared; general data and laboratory indices of both groups were identified. The relationship between the indicators was assessed. Further, a nomogram prediction model was developed and evaluated; its utility and clinical applicability were assessed. RESULTS: The risk factors for IAI after radical resection of CRC were neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and carcinoembryonic antigen (CEA) levels. NLR was correlated with PLR and SII (r = 0.604, 0.925, and 0.305, respectively), while PLR was correlated with SII (r = 0.787). The nomogram prediction model demonstrated an area under the curve of 0.968 [95% confidence interval (CI): 0.948-0.988] in the training set (n = 60) and 0.926 (95%CI: 0.906-0.980) in the validation set (n = 20). The average absolute errors of the calibration curves for the training and validation sets were 0.032 and 0.048, respectively, indicating a good model fit. The decision curve analysis curves demonstrated high net income above the 5% threshold, indicating the clinical practicality of the model. CONCLUSION: The nomogram model constructed using NLR, PLR, SII, and CEA levels had good accuracy and reliability in predicting IAI after radical resection of CRC, potentially aiding clinical treatment decision-making.

Injectable Phage-Loaded Microparticles Effectively Release Phages to Kill Methicillin-Resistant Staphylococcus aureus.

The increasing prevalence of bacterial multidrug antibiotic resistance has led to a serious threat to public health, emphasizing the urgent need for alternative antibacterial therapeutics. Lytic phages, a class of viruses that selectively infect and kill bacteria, offer promising potential as alternatives to antibiotics. However, injectable carriers with a desired release profile remain to be developed to deliver them to infection sites. To address this challenge, phage-loaded microparticles (Phage-MPs) have been developed to deliver phages to the infection site and release phages for an optimal therapeutic effect. The Phage-MPs are synthesized by allowing phages to be electrostatically attached onto the porous polyethylenimine-modified silk fibroin microparticles (SF-MPs). The high specific surface area of SF-MPs allows them to efficiently load phages, reaching about 1.25 × 1010 pfu per mg of microparticles. The Phage-MPs could release phages in a controlled manner to achieve potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Unlike the diffuse biodistribution of free phages post-intraperitoneal injection, Phage-MPs could continuously release phages to effectively boost the local phage concentration at the bacterial infection site after they are intraperitoneally injected into an abdominal MRSA-infected mouse model. In a mouse abdominal MRSA infection model, Phage-MPs significantly reduce the bacterial load in major organs, achieving an efficient therapeutic effect. Furthermore, Phage-MPs demonstrate outstanding biocompatibility both in vitro and in vivo. Overall, our research lays the foundation for a new generation of phage-based therapies to combat antibiotic-resistant bacterial infections.

Antibiotics for Patients With a Planned Re-Laparotomy for Intra-Abdominal Infection.

Background: Appropriate antimicrobial therapy for the management of intra-abdominal infection (IAI) continues to evolve based on available literature. The Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial provided evidence to support four days of antibiotic agents in IAI post-source control but excluded patients with a planned re-laparotomy. This study aimed to determine the short- and long-term recurrent infection risk in this population. Patients and Methods: This is a single-center, retrospective, observational study of adult patients admitted to a quaternary medical center between January 1, 2016, and August 1, 2022, with IAI requiring planned laparotomy. Patients were designated as receiving five or less days of antibiotic agents (short course) or more than five days (long course) after source control. The primary outcome was IAI recurrence within 30 days. Results: Of the 104 patients who met inclusion criteria, 78 were included in analysis. Average age was 57 ± 13.3 years, 56% were male, 94% Caucasian, with a mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of 17 ± 7.09. All other baseline characteristics and clinical severity markers were similar between the two groups. Regarding the primary outcome of IAI recurrence, there was no difference when comparing those who received short course versus those who received long course therapy (41.2% vs. 44.4%; p = 0.781). No differences were found between groups with respect to secondary outcomes. Conclusions: In patients admitted with IAI managed with planned re-laparotomy those who received short course antimicrobial therapy were not found to have an increase in IAI recurrence compared to those with longer courses of therapy.

Epidemiology, treatment and outcomes of infected pancreatic necrosis in France: a bicenter study.

INTRODUCTION: Acute necrotizing pancreatitis (ANP) mortality increases when pancreatic necrosis is infected (IPN). Current treatment of IPN relies on prolonged antibiotic therapies associated with a step-up strategy of drainage. The objective of this study was to analyze IPN treatment outcomes in two referral centers in France. METHODS: Data of consecutive patients with documented IPN hospitalized in two expert centers in France between 2014 and 2019 were retrospectively reviewed. The composite primary outcome was the proportion of unsuccessful management outcome, defined as new emergency drainage to treat sepsis with organ failure, an unplanned new antibiotic course, an unplanned prolongation of antibiotic course and/or death by septic shock, within three months following the diagnosis of ANP. RESULTS: All in all, 187 patients (138 males; 74.0%), with documented IPN were included. The most frequently identified microorganism was Escherichia coli (26.2%). Ninety-eight patients (52.4%) were admitted to an intensive care unit or resuscitation ward within the first two days of ANP care. Overall, 126 patients (67.4%) endured an unsuccessful outcome: new emergency drainage to treat acute sepsis (62.0%), unplanned new antibiotic course (47.1%), unplanned prolongation of antibiotic course (44.9%) and/or death by septic shock complicating IPN (8.0%). CONCLUSION: The unfavorable evolution in two thirds of patients shows that determination of optimal drainage timing and choice of antibiotic therapy remain major challenges in 2024.