Early Diet Liberalization After Anterior Lumbar Interbody Fusion Improves Postoperative Recovery: Study

Tiffany Bridges et al conducted a study to assess the impact of diet liberalization on short-term outcomes in patients undergoing anterior interbody lumbar fusion (ALIF).

The purpose of the study was to evaluate postoperative outcomes and complications, such as post operative ileus (POI), length of stay (LOS), and urinary retention (POUR) based on diet status following anterior lumbar surgery. The findings of this study may serve to contribute to new spine specific Enhanced Recovery After Surgery (ERAS) protocols which can help surgeons and patients plan for optimization of the postoperative recovery period.

A retrospective review was performed for patients undergoing ALIF at three tertiary care institutions. Electronic medical records were reviewed for demographics, surgical characteristics, and 90-day postoperative outcomes.

Key findings of the study were:

• A total of 515 patients who underwent combined anterior (ALIF) and posterior (PLF or PLDF) lumbar surgery were included in the study.

• In total, 413 patients (80.2%) comprised the “Delayed Diet” group while 102 patients (19.8%) were in the “Full Diet” cohort.

• Demographic data (age, sex, race, ethnicity, BMI, diabetes, smoking status, CCI) was similar amongst both groups other than a greater percentage of male patients in the “Full Diet” group (61.8% vs 45.0%, P = .004)

• All other patients had a delay of at least 1 day (average 1.6 days) until a full diet was provided. This group was found to have a higher rate of postoperative ileus (10.2% vs 2.9%) and urinary retention (16.0% vs 3.9%).

• The readmission rate and percent of patients presenting to the emergency department within 90 days postoperatively were similar.

• On multivariate regression analysis, same-day, full-diet patients had decreased odds of developing urinary retention (OR = .17) and a shorter length of hospital stay (Estimate: -.99).

• Immediate full diet had no impact on the development of ileus (OR: .33).

The authors concluded – “An immediate postoperative full diet following an anterior approach to the lumbar spine was not found to be associated with an increased risk of postoperative ileus in patients deemed appropriate for early diet liberalization. Moreover, an early full diet was found to reduce length of hospitalization and risk of postoperative urinary retention. Reconsideration of postoperative diet protocols may help optimize patient outcomes and recovery.”

Study Design: Retrospective Cohort Study.

Further reading:

Early Diet Liberalization after Anterior Lumbar Interbody Fusion Improves Postoperative Recovery

Tiffany Bridges et al

Global Spine Journal

DOI: 10.1177/21925682231223461

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Regulating cholesterol levels key to improving cancer treatment, finds study

A team of researchers from Aarhus University has made a remarkable discovery that could improve cancer treatment and the treatment of a number of other illnesses.

The key lies in regulating cholesterol levels, which can help make existing treatments more effective.

“We’ve identified a new mechanism that can regulate a crucial immune pathway in the fight against cancer, and this gives us a deeper understanding of how we can activate the body’s own defence against the disease,” explains Professor Martin Roelsgaard Jakobsen from the Department of Biomedicine and one of the last three authors of the study.

Special focus on an essential protein

The researchers have focused on the so-called STING protein, an important element of the immune system’s defence against cancer cells.

By manipulating cholesterol levels, the researchers were able to improve the function of the STING protein, thereby opening up new ways of bolstering the body’s natural defences against cancer.

Effective cancer treatment depends on the strength of the patient’s immune system and how well it can be boosted to kill cancer cells.

According to Martin Roelsgaard Jakobsen, cancer treatment requires a combination of treatment strategies that trigger local immune activation in the tumour, attract cytotoxic T cells, and stimulate broader activation of immune cells.

And this is where the new mechanism presents new opportunities.

“The STING protein has already shown promise in cancer treatment, but we haven’t yet discovered how to activate it in a clinical context. Our research provides a new approach to boosting the activity of the STING protein, giving us another way of harnessing the body’s natural defences against cancer,” he explains.

Result of cross-disciplinary collaboration

The study is the result of an interdisciplinary collaboration between researchers at Aarhus University and Aalborg University, including Martin Roelsgaard Jakobsen and Emil Kofod-Olsen, who are specialists in STING signalling and cancer immunology, and Baocun Zhang and Søren Riis Paludan, who have in-depth knowledge of the molecular biology of the STING protein and its role in a number of illnesses.

The combination of different disciplines has been crucial in linking cholesterol levels with immune responses to cancer.

“Our discovery is a direct result of bringing together experts from different fields. The collaboration has created a unique understanding of how we can fight back against cancer more effectively,” says Martin Roelsgaard Jakobsen.

Could pave the way for several drugs

The discovery of how cholesterol affects the STING protein not only opens new doors to cancer treatment. Researchers also expect the mechanism to play a role in the fight against a number of other illnesses.

“Thanks to increased knowledge about both the mechanism of action in the STING protein and how the protein contributes to a number of illnesses, it is now more likely that a number of new drugs against those illnesses can be developed,” says Professor Søren Riis Paludan.

This would include autoimmune diseases and neurodegenerative diseases, in which the immune system also plays a crucial role.

Reference:

Zhang, Bc., Laursen, M.F., Hu, L. et al. Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds. Nat Commun 15, 2760 (2024). https://doi.org/10.1038/s41467-024-47046-5.

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Ethanol Ablation of Ranulas Shows Promise, but Recurrence Risk Analysis Urged: Study

Korea: Ranulas, those pesky mucous cysts that can form beneath the tongue, have long plagued patients and clinicians alike with their tendency to recur after traditional surgical removal. However, a new study sheds light on a promising alternative treatment: ethanol ablation. While this method shows considerable efficacy, researchers caution that understanding risk factors for recurrence is crucial for optimizing patient outcomes.

The study, published in JAMA Otolaryngology-Head & Neck Surgery, suggests that early ethanol ablation is a treatment option for ranula, however, there is a need for more research to establish the exact role in ranula management.

“In the case-series study of 70 ranula patients, the recurrence rate was 33%, with multivariate analysis showing that the time interval between ranula presentation and ethanol ablation may be a risk factor for recurrence,” the researchers reported.

“Most patients experienced their first recurrence within 12 months following ethanol ablation, with a maximum diameter of 5 cm or higher as a possible risk factor; no risk factors were significantly associated with subsequent surgery.”

Ethanol ablation (EA) involves the injection of ethanol directly into the ranula cavity, causing dehydration and subsequent cyst shrinkage. Unlike traditional surgery, this minimally invasive technique boasts shorter recovery times and reduced risk of complications. However, few studies have assessed long-term outcomes and recurrence of ranula after EA.

Against the above background, Pae Sun Suh, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, and colleagues aimed to evaluate the long-term outcomes and the risk factors for recurrence and receipt of subsequent surgery in patients who underwent treatment with EA for ranula.

For this purpose, the researchers conducted a case-series study at a single tertiary hospital and assessed patients treated with EA between 2009 and 2021. Among 70 consecutive patients, it excluded those with follow-up loss or who were followed up for less than 24 months.

The primary outcome was recurrence at the last follow-up after single or multiple EA sessions. Secondary outcomes included recurrence-free survival (RFS) rate and receipt of subsequent surgery after initial EA. Factors possibly associated with outcomes included patient sex and age; the presentation-to-EA interval; ranula site, type, diameter, volume, and echogenicity; and sublingual gland herniation.

The study led to the following findings:

  • Fifty-seven patients (mean age, 26.4 years; 42% females) were included and were followed up for a median of 57 months.
  • The recurrence rate was 33%, and 19% underwent subsequent surgery.
  • Among patients with recurrence, 86% experienced first recurrence within 12 months after initial EA.
  • A presentation-to-EA interval of 12 months or longer was associated with an increased risk of recurrence (adjusted odds ratio [OR], 3.74).
  • No risk factors were significantly associated with subsequent surgery (highest OR in parapharyngeal space extension: adjusted OR, 4.96).
  • Among the initial cohort of 70 patients, 2-year RFS was lower in maximum diameter of ranula of 5 cm or higher than less than 5 cm (24% versus 50%; difference, 26%).

In conclusion, the case-series study found that the ranula’s recurrence rate after EA was 33%. A presentation-to-EA interval of 12 months or longer may be a risk factor for recurrence, indicating that early intervention with EA might minimize recurrence. Most first recurrences occurred within 12 months following EA, with a maximum diameter of ranula of 5 cm or higher being a possible risk factor.

Reference:

Suh PS, Lee JH, Roh YH, et al. Ethanol Ablation of Ranulas and Risk Factor Analysis for Recurrence. JAMA Otolaryngol Head Neck Surg. Published online May 02, 2024. doi:10.1001/jamaoto.2024.0183

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Ginge-Cal promising material for treatment of infected root canal when used as obturation material: Study

Ginge-Cal is a promising material for treating infected root canals when used as obturation material suggests a study published in the International Journal of Dentistry.

The tendency to use dental materials of plant origin is one of the prevailing trends in dentistry to reduce exposure to materials that could have some toxic impact in the long term. A study was done to evaluate the efficacy of calcium hydroxide combined with gingerols (Ginge-Cal) as a novel obturation material for treating infected primary teeth and decreasing the recurrence of infection. The study was conducted on 30 lower primary molars with infected pulp for children aged 4–8 years. The sample was randomly divided into two groups depending on the tested obturation material: Ginge-Cal group and the Metapex group. The evaluation was done by different parameters clinically and radiographically at various intervals up to 12 months. Results. Based on chi-squared and McNamara’s test with a 5% significance level, the clinical results indicated that Ginge-Cal group was more effective than the Metapex group in reducing or eliminating pain () after 1 week, sensitivity to percussion () at 3 months of follow-up, purulent swelling () at 6 and 9 months of follow-up, fistula, and tooth mobility. The radiographic results, based on the periapical and furcation area radiolucency at 12 months of follow-up, favored Ginge-Cal group over the Metapex group (), (), respectively. There were no statistically significant differences in pathological root resorption and periodontal space. The differences within the Ginge-Cal group were directly influenced by the time intervals in a statistically significant manner, ranging from () to (). The success percentage was 87.5% for Ginge-Cal group and 64.3% for Metapex group. Ginge-Cal can be considered a promising material for treating the infected root canal when used as an obturation material for the infected root canal.

Reference:

Fathi A. Qasem, Salwa M. Awad, Rizk A. Elagamy, “Effectiveness of Calcium Hydroxide and Gingerols Mixture as a Novel Obturation Material for Infected Root in Primary Teeth: A Randomized Clinical Trial”, International Journal of Dentistry, vol. 2024, Article ID 5528260, 10 pages, 2024. https://doi.org/10.1155/2024/5528260

Keywords:

​​Ginge-Cal, promising, material, treatment, infected, root canal, obturation material, study, International Journal of Dentistry, Fathi A. Qasem, Salwa M. Awad, Rizk A. Elagamy

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Hydroxyurea dose escalation enhances clinical outcomes in children with sickle cell anemia: Study

The Realizing Effectiveness Across Continents with Hydroxyurea (REACH) trial unveiled promising results in the treatment of sickle cell anemia among children in sub-Saharan Africa. The findings of this study was published in a recent issue of The Lancet Haematology which highlights the effectiveness of the extended hydroxyurea treatment over a period of 8 years.

This research was conducted across 4 clinical sites in Kenya, Uganda, Angola and the Democratic Republic of Congo by enrolling a total of 635 children aged 1 to 10 years with documented sickle cell anemia. Over the course of the study, 606 children received hydroxyurea treatment, with 522 continued treatment for a median duration of 93 months.

The key findings of this study revealed a significant improvement in the treatment outcomes. The children who received hydroxyurea expressed an increased mean hemoglobin concentration and fetal hemoglobin level along with a reduction in the absolute neutrophil count. The dose escalation to the maximum tolerated dose (MTD) with dose optimization led to a marked reduction in vaso-occlusive episodes, acute chest syndrome events, recurrent stroke events, malaria infections, non-malarial infections, serious adverse events and mortality rates when compared to fixed-dose hydroxyurea.

Incidence rate ratios indicated a substantial decrease in various adverse events that included vaso-occlusive episodes, acute chest syndrome events, and malaria infections, among others. The dose-limiting toxicity rates remained similar between the fixed-dose and MTD phases by suggesting the safety and feasibility of the treatment approach. Also, grade 3 and 4 adverse events were infrequent, with serious adverse events uncommon and no treatment-related deaths were reported. This signifies a significant move in enhancing the quality of life and prognosis for the children battling sickle cell anemia in the region.

As sickle cell anemia poses a significant health burden in sub-Saharan Africa where resources for comprehensive care are often limited, the outcomes of this study were profound. The REACH trial offers hope for the population affected by this hereditary blood disorder by demonstrating the effectiveness and safety of extended hydroxyurea treatment. Overall, this comprehensive trial illuminates the importance of tailored treatment strategies for sickle cell anemia in resource-limited settings.

Source:

Aygun, B., Lane, A., Smart, L. R., Santos, B., Tshilolo, L., Williams, T. N., Olupot-Olupot, P., Stuber, S. E., Tomlinson, G., Latham, T., & Ware, R. E. (2024). Hydroxyurea dose optimisation for children with sickle cell anaemia in sub-Saharan Africa (REACH): extended follow-up of a multicentre, open-label, phase 1/2 trial. In The Lancet Haematology. Elsevier BV. https://doi.org/10.1016/s2352-3026(24)00078-4

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Deutetrabenazine and Valbenazine Safe and Effective Treatments for Tardive Dyskinesia, reveals study

Researchers have found that deutetrabenazine and valbenazine are both safe and effective treatment options for managing tardive dyskinesia (TD), a condition characterized by involuntary, repetitive movements. Published in Tremor and Other Hyperkinetic Movements, the research assessed the results of patients treated with these relatively new therapies. The study was conducted by Golsorkhi and colleagues.

Tardive dyskinesia is a challenging side effect of certain medications used to treat psychiatric conditions and other disorders. First-line treatments include tetrabenazine, approved by the US Food and Drug Administration (FDA) in 2008, as well as deutetrabenazine and valbenazine, approved in 2023 and 2017, respectively. Researchers aimed to compare the newer VMAT2 inhibitors deutetrabenazine and valbenazine against the previously approved tetrabenazine.

The researchers conducted a review of 4 double-blind clinical trials, which included a total of 230 patients. The studies examined the efficacy and safety of deutetrabenazine and valbenazine compared with placebo in adult patients with TD. The review focused on clinical trials involving adult human participants that provided data on Abnormal Involuntary Movement Scale (AIMS) scores, a key measure for TD symptoms.

The key findings of the study were:

  • Both deutetrabenazine and valbenazine were associated with significant reductions in AIMS scores compared to placebo.

  • The majority of patients tolerated deutetrabenazine and valbenazine well, with serious adverse events occurring in only 5% of patients. Approximately 10% of patients required dose reduction or cessation.

  • Both deutetrabenazine and valbenazine have longer half-lives compared to tetrabenazine, allowing for less frequent dosing and increased convenience for patients.

Advantages Over Tetrabenazine

The review found deutetrabenazine and valbenazine to be superior to tetrabenazine in several ways:

  • Both new medications demonstrated fewer side effects compared to tetrabenazine.

  • Neither deutetrabenazine nor valbenazine were associated with increased risk of suicidality.

  • The longer half-lives of deutetrabenazine and valbenazine allow for less frequent dosing, making them more convenient for patients.

While the findings support the use of deutetrabenazine and valbenazine as effective treatment options for TD, the researchers emphasized the need for larger studies, especially in diverse populations, to understand long-term outcomes and assess efficacy across different patient groups.

Deutetrabenazine and valbenazine have shown promise as safe, effective treatments for managing TD, offering fewer side effects and more convenient dosing regimens compared to tetrabenazine. Further research is required to explore their long-term efficacy and safety in broader patient populations.

Reference:

Golsorkhi, M., Koch, J., Pedouim, F., Frei, K., Bondariyan, N., & Dashtipour, K. (2024). Comparative analysis of deutetrabenazine and valbenazine as VMAT2 inhibitors for tardive dyskinesia: A systematic review. Tremor and Other Hyperkinetic Movements (New York, N.Y.), 14(1). https://doi.org/10.5334/tohm.842

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Fixation group as effective as non-fixation groups in terrible triad injuries of elbow, reveals study

No significant differences in outcomes between fixation and non-fixation groups in terrible triad injuries of elbow reveals a study published in the BMC Surgery.

The ideal treatment of terrble triad injuries and whether fixation of coronoid process fractures is needed or not are still debated. Therefore, we aimed to investigate if terrible triad injuries necessitate coronoid fracture fixation and evaluate if non-fixation treatments have similar efficacies and outcomes as fixation treatments in cases of terrible triad injuries. From August 2011 to July 2020, 23 patients with acute terrible triad injuries without involvement of the anteromedial facet of the coronoid process were included to evaluate the postoperative clinical and radiological outcomes (minimum follow-up of 20 months). According to the preoperative height loss evaluation of the coronoid process and an intraoperative elbow stability test, seven patients underwent coronoid fracture fixation, and the other eight patients were treated conservatively. The elbow range of motion (ROM), Mayo Elbow Performance Score (MEPS), and modified Broberg-Morrey score were evaluated at the last follow-up. In addition, plain radiographs were reviewed to evaluate joint congruency, fracture union, heterotopic ossification, and the development of arthritic changes. Results: At the last follow-up, the mean arcs of flexion-extension and supination-pronation values were 118.2° and 146.8° in the fixation group and 122.5° and 151.3° in the non-fixation group, respectively. The mean MEPSs were 96.4 in the fixation group (excellent, nine cases; good, tow cases) and 96.7 in the non-fixation group (excellent, ten cases; good, two cases). The mean modified Broberg-Morrey scores were 94.0 in the fixation group (excellent, sevev cases; good, four cases) and 94.0 in the non-fixation group (excellent, ten cases; good, tow cases). No statistically significant differences in clinical scores and ROM were identified between the two groups. However, the non-fixation group showed a significantly lower height loss of the coronoid process than the fixation group (36.3% versus 54.5%). There were no significant differences in clinical outcomes between the fixation and non-fixation groups in terrible triad injuries.

Reference:

Ahn, YS., Woo, SH., Kim, S. et al. Does the coronoid fracture in terrible triad injury always need to be fixed?. BMC Surg 24, 125 (2024). https://doi.org/10.1186/s12893-024-02394-3

Keywords:

No, significant, differences, outcomes, between, fixation, non-fixation, group, terrible, triad, injuries, elbow, study, Coronoid fracture, Height loss ratio, Intraoperative elbow stability test, Outcomes, Ahn, YS., Woo, SH., Kim, S, BMC Surgery

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Cancer Pain Guidelines evaluation stresses on safe opioid practice and patient feedback systems, claims study

Cancer pain is the most distressing symptom in a patient’s life, with fear of unrelieved pain sometimes exceeding the patient’s fear of death.

Recently published research paper evaluates the quality of cancer pain guidelines and examines the inclusion of safe opioid practice. It highlights the distressing nature of cancer pain and emphasizes the concept of ‘total pain management’ that incorporates various modalities and safe opioid practices to improve the quality of life for cancer patients. The paper discusses the global challenge of limited access to opioids for cancer pain management and the looming opioid crisis due to misuse and abuse. It emphasizes the need for individualized protocols for different types of cancer pain and the importance of addressing end-of-life care pain management. The methodology involves evaluating the guidelines using the AGREE II and ADAPTE tools, and the primary outcome is to assess the quality of cancer pain guidelines. The review included 14 guidelines, and quality assessment was based on various domains such as rigour of development, applicability, and editorial independence. The study demonstrates good inter-rater reliability and identifies eight high-quality guidelines, with four specific guidelines deemed to be of the highest quality. The comprehensive assessment of the guidelines indicates that safe opioid practices and patient feedback are incorporated into the guidelines, contributing to their quality attributes. Overall, the paper provides a detailed evaluation of cancer pain guidelines and emphasizes the importance of safe opioid practices in cancer pain management.

Researchers  concluded that combined AGREE II and ADAPTE identified eight quality guidelines for quality evaluation, of which four cancer pain guidelines (MOHM, NCCN, NCEC-NCG, and WHO) were evaluated to be of the highest quality. All the evaluated guidelines inherently incorporated safe opioid practice and patient feedback systems, which are quality attributes.

Reference –

Thota, Raghu S.; Ramkiran, Seshadri1; Singh, Sarita2; Damani, Anuja3; Wajekar, Anjana S.4; Koyyalagunta, Lakshmi5. A systematic review and quality analysis of cancer pain guidelines. Indian Journal of Anaesthesia 67(12):p 1051-1060, December 2023. | DOI: 10.4103/ija.ija_325_23

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Home-monitoring tests lack satisfactory diagnostic accuracy to identify neovascular age-related macular degeneration:JAMA

A recent study found home-monitoring tests as a potential solution to reduce the burden of neovascular age-related macular degeneration (nAMD) on patients and healthcare systems. The study published in the Journal of American Medical Association evaluated three such tests and found that they may not be as effective as hoped.

This study assessed the diagnostic accuracy of three vision home-monitoring tests when compared to traditional hospital follow-up for detecting active nAMD. The tests evaluated were the KeepSight Journal (KSJ), the MyVisionTrack (mVT) app and the MultiBit (MBT) app. This research was conducted across six UK hospital eye clinics and included a total of 297 patients who were over 50 years, with at least one eye treated for active nAMD. The participants were asked to perform the home-monitoring tests weekly, with mVT and MBT scores automatically transmitted, while KSJ scores were returned to the research office every 6 months.

Despite the potential promise of these home-monitoring tools, the results were not very promising. The study highlighted that the estimated area under the receiver operating characteristic curve (AUROC) for all three tests was less than 0.6. None of the tests demonstrated satisfactory diagnostic accuracy for identifying active nAMD when compared to in-hospital ophthalmologist examination.

Of the 3 tests evaluated, only the KSJ summary score showed association with lesion activity. But, even this association was not strong enough to provide reliable detection of active nAMD. These findings have significant implications for the management of nAMD. While home-monitoring tests may offer convenience and reduce the burden on patients and caregivers, their limited accuracy points that they may not be suitable as standalone diagnostic tools.

The study illuminates the importance of continued research and innovation in the field of nAMD monitoring. While home-monitoring tests may not be ready for widespread clinical use, the ongoing advancements in technology and healthcare delivery may eventually lead to more effective solutions. The patients and clinicians must remain cautious and rely on the established methods for monitoring and managing nAMD. While the promise of home-monitoring tests remains, further research and extensive studies are needed to ensure their reliability and effectiveness in clinical practice.

Reference:

Hogg, R. E., Sivaprasad, S., Wickens, R., O’Connor, S., Gidman, E., Ward, E., Treanor, C., Peto, T., Burton, B. J. L., Knox, P., Lotery, A. J., Donnelly, M., Rogers, C. A., & Reeves, B. C. (2024). Home-Monitoring Vision Tests to Detect Active Neovascular Age-Related Macular Degeneration. In JAMA Ophthalmology. American Medical Association (AMA). https://doi.org/10.1001/jamaophthalmol.2024.0918

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In Preterm babies, Lung ultrasound scores useful to predict Bronchopulmonary dysplasia: Study

In a recent study published in the Pediatric Pulmonology unveiled the potential of lung ultrasound (LUS) as a rapid and effective method for evaluating preterm infants facing respiratory distress.

The study was conducted at an academic tertiary Neonatal Intensive Care Unit focused on infants younger than 32 weeks by bringing out LUS as a promising predictor for bronchopulmonary dysplasia (BPD) in preterm neonates.

This retrospective observational study encompassed 218 patients from the years 2018 to 2023, to understand the relationship between LUS scores within the first three days of life and critical respiratory outcomes. The lungs were divided into six regions with each assigned a score ranging from 0 to 3 points. The total score was obtained by summing these regional scores which proved to be an important indicator.

The key findings of study were;

Infants with the highest and lowest LUS scores within the initial three days expressed a significant association with the development of moderate-to-severe BPD (p < .001) with the area under the receiver operating characteristic (ROC) curve values from 0.684 to 0.913 and 0.647 to 0.902, respectively. High LUS scores were also linked to the requirement for mechanical ventilation (p < .001) despite no significant correlation found with the duration of mechanical ventilation.

The highest LUS scores within the first three days of life being sepsis and the presence of hemodynamically significant patent ductus arteriosus (hsPDA) emerged as significant risk factors.

This study establishes LUS scores as predictors of BPD and the need for invasive ventilation. These findings open possibilities for early intervention and personalized care strategies for the vulnerable preterm population by potentially reshaping the management of respiratory distress in neonatal intensive care units.

Reference:

Aliyev, F., Kayki, G., Annakkaya Kocyigit, T., İyigun, İ., & Yigit, S. (2023). Lung ultrasound scores within the first 3 days of life to predict respiratory outcomes. In Pediatric Pulmonology. Wiley. https://doi.org/10.1002/ppul.26804

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