Category: 8. Health

Baseline characteristics

Table 1 displays baseline CVD risk factors stratified by CTI index tertiles. Finally, the final analysis included 5723 participants for CVD and 5847 participants for all-cause mortality. Individuals in the highest CTI tertile exhibit marked differences versus the lowest on various indicators. People in the top CTIs were the elderly and had high levels of BMI, SBP, DBP, fast blood glucose, HbA1c, LDL-C, TG, TC, serum creatinine, TyG, CRP, CTI. In addition, the prevalence of comorbidities such as hypertension, dyslipidemia, and diabetes was notably higher in people with elevated CTI levels. Baseline characteristics were compared between participants with and without CVD and all-cause death in Tables S4 and S5, while the detailed baseline characteristics comparison.

Association of CTI index with CVD and total mortality in CKM syndrome patients

As shown in Table 2, multivariable-adjusted analysis revealed a graded cardiovascular risk profile associated with CTI. Among CKM stage 0–3 individuals, the highest CTIQ quartile (Q3) showed 52% increased CVD risk versus Q1 in the crude model (HR 1.52, 95% CI (1.44, 1.59), P < 0.0001), which remained significant after adjusting for demographic (age, gender, smoking, drinking status, marital status) and clinical confounders (BMI, eGFR, hypertension, diabetes, dyslipidemia, Hypertension treatment, Diabetes treatment, dyslipidemia treatment,), with 18% excess risk in Model 2 (HR 1.18, 95% CI 1.12, 1.24, P < 0.0001; P-trend < 0.001). Meanwhile, the highest quartile (Q3) showed adjusted hazard ratios of 1.35 for TyG (95% CI 1.26–1.44; P < 0.001) and 1.43 for standardized CRP values (CRP-SD) (95% CI 1.34–1.52; P < 0.001). Both were lower than the CTI’s highest quartile HR of 1.52 (95% CI (1.44, 1.59), P < 0.0001) (Table S7). For all-cause mortality, each unit increase in continuous CTI corresponded to 60% higher risk (Model 2: HR 1.60, 1.29–1.99, P < 0.0001). Stratified analysis demonstrated a 111% mortality increase in Q3 versus Q1 (Model 2: HR 2.11, 1.35–3.30, P = 0.001), whereas Q2 showed non-significant association (P = 0.52), indicating a threshold effect of CTI.

RCS and threshold effect analysis

We performed RCS analysis and threshold analysis to verify the association of CTI and CVD prevalence and mortality rates. For CVD incidence, standard Cox regression revealed non-linear association between CTI and CVD incidence (HR 1.075–1.224, P < 0.0001) (Fig. 2). Two-piecewise linear regression revealed a critical inflection point at CTI = 8.602: Below this threshold, each unit increase in CTI significantly elevated CVD risk (Model 2: HR 1.153, 95% CI 1.060–1.254, P < 0.001). Conversely, above the IP, CTI showed no significant association with CVD incidence in the fully adjusted Model 2 (HR 0.997, 95% CI 0.954–1.042, P = 0.89). The log-likelihood ratio test (P < 0.0001) confirmed the superiority in segmented model, highlighting a nonlinear dose–response pattern between CTI and CVD risk (Table S8). For all-cause mortality, standard Cox regression showed a notable linear trend between CTI and overall mortality (HR 1.486–1.674, P < 0.0001) (Fig. 2). While two-piecewise linear regression suggested a potential risk transition at CTI = 8.606 (HR 1.427–1.779, P ≤ 0.021 above the threshold; no significant association below the threshold, HR 1.245–1.443, P ≥ 0.345), the log-likelihood ratio tests (P ≥ 0.829 for all models) indicated no statistically significant improvement in model fit with segmentation. Thus, despite localized risk differences near the inflection point, the overall relationship predominantly aligns with a linear pattern (Table S9).

Kaplan–Meier (K–M) survival curves

The Kaplan–Meier (K–M) survival curves showed an elevated CVD incidence or overall mortality in the high CTI group. The log-rank test’s P values for the Q2 and Q3 groups, all below 0.05, confirm a higher risk compared to the Q1 group (Figure S1).

Subgroup analyses

To delve deeper into the connection between CTI and the likelihood of CVD or all-cause mortality, researchers conducted subgroup and interaction analyses on various variables, which include age, gender, tobacco use, alcohol consumption, marital status, education attainment, diabetes statuse, hypertension, dyslipidemia, glucose levels (including NGR, Pre-DM, and DM), and CKM syndrome (0–3 stages). For CVD incidence, sex stratification revealed markedly higher CVD risk in males (HR 1.627, 95% CI 1.451–1.824; P < 0.0001) compared to females (HR 1.359, 95% CI 1.223–1.510; P < 0.0001), with a pronounced interaction effect (P = 0.02). A dose–response relationship was evident, as higher CTIQ quartiles (Q3 vs. Q1) consistently correlated with elevated CVD risk across all strata (P for trend < 0.0001). Notably, smoking status (P = 0.029) and marital status (P < 0.0001) exhibited significant interactions, where current smokers (HR 1.722, Q2 vs. Q1) and married individuals (HR 1.809, Q3 vs. Q1) showed heightened vulnerability. Conversely, no interaction was observed for age, hypertension, or dyslipidemia (P > 0.05). Education level further modulated risk, with individuals above junior high school education displaying the steepest CTIQ-associated risk gradient (HR 2.935, Q3 vs. Q1; P < 0.0001) (Figure S4, Table S12). For overall mortality, lower education (e.g., “Junior high school and below”: HR 1.656, P < 0.001) and non-drinkers (HR 1.774, P < 0.0001) showed elevated mortality. CTI consistently predicted mortality across most subgroups (e.g., males: HR 1.538; females: HR 1.628, both P < 0.01), despite nonsignificant interactions for sex (P = 0.783) and age (P = 0.658). Notably, pre-diabetic individuals exhibited a non-significant trend toward heightened risk (HR 1.497, P = 0.254), warranting further investigation. The most pronounced interaction emerged in CKM strata (P < 0.001), which revealed CKM = 0 individuals have an exceptionally high risk (HR 8.225, 95% CI 2.558–27.964, P < 0.001). Therefore, the future study assessed the connection between CTIQ and overall death in the 0–3 stage of CKM group: CKM Stage 0 exhibited an extreme hazard ratio (Q3 vs. Q1: HR 19.611, 95% CI 2.251–171.300, P = 0.004), but with wide confidence intervals (Figure S5, Table S13).

AUC and ROC

For CVD risk, CRP and CTI retained comparable performance (AUC = 0.66 and 0.61, respectively), whereas TyG again performed at chance level (AUC = 0.5). Similarly, for all-cause mortality, CRP demonstrated moderate predictive utility (AUC = 0.66, 95% CI 0.61–0.66), just ahead of CTI (AUC = 0.61, 95% CI 0.56–0.61), while TyG showed no discriminative capacity (AUC = 0.5, 95% CI 0.45–0.5). The findings indicate that CTI could outperformed CRP and the TyG index in assessing overall mortality risk stratification (Figure S6).

Sensitivity analyses

To check the stability of our findings, we conducted multiple sensitivity analyses. Firstly, in order to tackle the issue of missing data and to limit the possibility of bias, we employed multiple imputations. Subsequent analysis revealed that the correlation among CTI and CVD incidence and overall mortality was in accordance with the basic results (Table S10). Secondly, the application of logistic regression models to investigate the connection between CTI and CVD incidence, as well as all-cause mortality, yields consistent results. (Table S11). Thirdly, the analysis of the piecewise Cox regression model confirmed result stability (Tables S12–S13). Fourthly, we also assessed the correlation among CTI and CVD incidence and overall mortality stratified by sex, age, and glucose level (grouped into NGR, Pre-DM, and DM). (Table S14). Furthermore, we explored additional analyses to analyze the associations of TyG and CRP standardized values (CRP-SD) with both CVD incidence and all-cause mortality, thereby validating the robustness of our primary findings (Table S7). Moreover, analyses stratified by sex and CKM stage (0–3) revealed consistent associations between CTI and adverse outcomes, as evidenced by Kaplan–Meier curves (all log-rank P < 0.05) (Figures S2 and S3). We excluded those individuals who died within 2 years of baseline to reduce potential bias from early terminal events (Table S6). Finally, RCS analyses (4 knots located at Harrell’s recommended percentiles) were also adopted to further assess the nonlinear associations of CTI and the risk of CVD and death (Table Figure S7).

When a JAMA Network Open study reported earlier this year that suicide remains the leading cause of death among medical residents, many experts were saddened but unsurprised.

“It signals that there are underlying problems that we should solve,” said Srijan Sen, MD, PhD, director of the Frances and Kenneth Eisenberg and Family Depression Center and professor of depression and neurosciences at the University of Michigan, Ann Arbor, Michigan.

Aditee Narayan, MD, MPH, pointed to the challenges that exist in today’s healthcare system for all physicians, including residents.

“This system may escalate moral injury among our residents — they want to do more for our patients but are limited to what is available for them,” said Narayan, vice dean for Medical and Health Professions Education at the Duke University School of Medicine in Durham, North Carolina.

According to the JAMA Network Open study, the actual incidence of suicide, while higher from 2000 to 2014 than from 2015 to 2021, was still relatively rare. In fact, the study noted that the suicide rate in the 30- to 34-year-old age group was 70% lower than in the same age group in the general population.

That doesn’t mean that it should be ignored or dismissed, said Christine Moutier, MD, chief medical officer of the American Foundation for Suicide Prevention.

“My hope is that we would not be inured to this tragic public health concern,” she said.

Instead, efforts to address mental health among residents should be intentional and proactive, she said.

Intentional Efforts to Address Mental Health

Stress can push even well-adjusted people to the limit, and plenty of stress exists in the life of most medical residents. However, there are a number of perceived barriers to accessing care, including lack of time, concerns over confidentiality, stigma, uncertainty about where to access care, cost, a preference to receive care outside their own organization, and others, according to research.

As a result, despite the high-pressure environments in which they work and high stress levels, residents report a low use of mental health services, according to a 2024 study in the Journal of Graduate Medical Education.

In response, a growing number of programs are not waiting for their residents to reach a crisis point.

Some programs have experimented with opt-out programs for mental health support for residents to reduce barriers to accessing care and to minimize stigma. For example, Riverside Community Hospital, a clinical rotation site for the University of California, Riverside School of Medicine in Southern California, found that residents were more likely to access free, confidential teletherapy sessions when the initial appointment was already scheduled for them.

At the University of Texas Health Science Center at San Antonio, new residents are asked to voluntarily complete a form that helps assess their risk for factors that could take a toll on their psychological health and well-being: the Transition to Residency Risk Index. Their score shows whether they are low, medium, or high risk, and resources are made available to them.

Jon Alan Courand, MD, who created the index, said the first few months of the postgraduate year 1 are considered the highest risk period, according to the latest research.

“There’s a lot of turmoil that happens in these transitions,” said Courand, professor of pediatrics and the assistant dean for Wellbeing for Graduate Medical Education at the University of Texas Health Science Center at San Antonio.

Making sure that residents know that multiple kinds of support are available is also crucial. The program has recently added an opt-out program for incoming residents called Circle of Care as another possible way to reach them and offer support.

“We might be preventing one very negative outcome, and that might be enough to justify everything else that we’re doing,” said Adriana Dyurich, PhD, LPC, who helped edit and validate the risk index. “We don’t have to look for super high numbers because the meaning of one or two suicides is devastating for institutions, for programs, for everyone that is around.”

Case Study: Columbia

As soon as interns begin their training at Columbia University Irving Medical Center, New York City, they encounter Laurel Mayer, MD. Mayer, a professor of psychiatry, is a faculty member for the CopeColumbia program, and she talks to all the new interns during orientation about stress, burnout, and risk factors for suicide. She shows them statistics.

“If you take care of yourself, and you are working as your best self, you will take better care of your patients,” she tells them.

Then she tells them to call her. In fact, she encourages them to put her phone number into their phones so they don’t have to ask anyone how to contact her if they need help.

“I’ve actually had a number of residents call me,” said Mayer. “Not even just internship year, but later. They say, ‘I had your information in my phone.’”

Mayer can help connect residents with therapists, and she and her team make sure that the providers are educated about the unique issues associated with caring for physicians in training. She’s also working to address cost and confidentiality concerns: Through the organization’s Cope GME program, residents can receive eight therapy sessions per year at no charge. Beyond that, Mayer works to make sure that residents are connected with providers who accept their insurance. While care may be documented in the resident’s own electronic medical record, the information is flagged and protected for privacy.

They’re also piloting a new opt-out program based on a series of one-on-one check-ins, where everyone gets a 30-minute session with someone on her team. It’s not a psychiatric evaluation — just time to talk.

“We have data that 96% of the residents, at the end of that check-in, thought it was helpful and thought it should become part of the residency curriculum,” Mayer said, noting that her team is now evaluating if those check-ins facilitate access to mental health treatment.

Additional Resources and Strategies

The Accreditation Council for Graduate Medical Education (ACGME) offers a Mental Health and Well-Being During Transitions tool kit, among other resources, to help programs start new or bolster existing efforts to address the mental health and well-being of their resident workforce.

Nicholas Yaghmour, MPP, director of the Resident Experience, Well-Being, and Milestones Research at the ACGME, suggested that residency programs also consider providing annual physicals to their residents. Yaghmour was also the leading author of the JAMA Network Open study.

“We may be able to catch more undiagnosed mental health problems like depression and anxiety,” he said. “We also may prevent the other causes of death and disease, such as neoplastic diseases and infectious diseases.”

Individuals in training program leadership roles who commit to setting positive examples can also be a part of suicide prevention efforts, according to Mark Olfson, MD, PhD, professor of epidemiology and professor of psychiatry, medicine, and law at Columbia University Medical School in New York City.

“We need to set examples, if we’re involved with training physicians, to normalize stress and acknowledge when it occurs and talk about it openly, to help set up a culture that lowers the stigma around behavioral healthcare services among medical trainees,” said Olfson, whose research includes a focus on suicide prevention.

Plus, it may also encourage other physicians to access care when they need it.

“The more we can normalize physicians at all professional stages reaching out for mental health care and for emergency support when they feel they are in crisis, the better we can be as a field in preventing deaths by suicide,” said Yaghmour.

Introduction

Historically, ethnomedicine has made extensive use of the plant’s whole spectrum of parts, including its bark, fruit, leaves, stem, and roots, all of which have therapeutic qualities.People recognise the use of herbal medicine and botanical extracts as a substitute for synthetic or pharmaceutical medications, often due to their reduced side effects. The evidence indicates that the application of herbal medicine techniques aligns with a resurgence in natural remedies that typically have fewer or no side effects.^1,2 For thousands of years, this plant has been utilized not only as a preventative and curative measure for various ailments but also as a vegetable with high nutritional value.³ It is extensively described in the Vedic literature for the treatment of various diseases.⁴ Burn injuries constitute a major public health issue globally, particularly in low- and middle-income nations where resources for advanced burn treatment are scarce. The World Health Organisation (WHO) reports that burns result in over 180,000 deaths each year, predominantly in developing regions.⁵ Infection is a significant complication of burn injuries, potentially delaying healing, causing systemic complications, and increasing mortality rates. The impaired skin barrier in burn victims facilitates colonisation and invasion by opportunistic pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Candida albicans.^6,7 The standard method for managing burn wound infections involves the administration of systemic or topical antibiotics. The emergence of multidrug-resistant (MDR) organisms has markedly reduced treatment efficacy and heightened the strain on healthcare systems.^8,9 The increasing challenge of antimicrobial resistance (AMR) has prompted investigations into alternative therapies, particularly those originating from natural sources like medicinal plants.¹⁰ Jatropha curcas L., belonging to the Euphorbiaceae family, has been used in traditional medicine to treat various conditions, including skin disorders, infections, and inflammation. The latex comprises various secondary metabolites, including flavonoids, tannins, alkaloids, saponins, terpenoids, and glycosides, which are recognised for their antimicrobial, anti-inflammatory, and wound-healing properties.^11,12 Herbal medicine has contributed numerous powerful medications to the extensive drug arsenal of contemporary medical research worldwide, both in crude form and as a pure chemical on which modern medicines are structured.¹³ Recent studies have demonstrated the antimicrobial efficacy of J. curcas latex. Kumar et al formulated a topical herbal cream using J. curcas latex, which demonstrated notable inhibition of prevalent burn pathogens and enhanced wound healing in an in vivo rat model.¹⁴ Ikoyi et al demonstrated that ethanol extracts of J. curcas leaves and latex were effective against clinical isolates of S. aureus, E. coli, and C. albicans obtained from surgical wounds.¹⁵ The results corroborate previous research that emphasised the wound-healing capabilities of J. curcas latex, which are attributed to its proteolytic and angiogenic properties.¹⁶ This study contrasts J. curcas latex with established antibiotics, including ofloxacin, tetracycline, and fluconazole, rather than evaluating herbal extracts in isolation as previous research has done. The results indicate that the latex demonstrates either superior or comparable inhibitory effects against certain pathogens, thereby supporting its potential as a complementary or alternative treatment in response to increasing antimicrobial resistance.^9,15 This study associates the antimicrobial activity of latex with its bioactive constituents, including tannins, flavonoids, saponins, and alkaloids. It quantifies this effect using Minimum Inhibitory Concentration (MIC) values, offering mechanistic insights into its efficacy.^11,12 Considering its favourable antimicrobial properties and historical applications, J. curcas latex merits additional research as a possible alternative or complement to standard antimicrobials in the management of burn wounds. This research evaluates the antimicrobial efficacy of J. curcas latex against clinical sample was isolated for this research from infected burn wounds in Sana’a, Yemen, and compares its effectiveness with that of commonly used antibiotics.

Methodology

Study Design and Setting

This study was carried out in a laboratory setting in Sana’a City, Yemen. We conducted the study at the Microbiology Laboratories of Ibin Sina Hospital and the National Centre of Public Health Laboratories, with a focus on pathogen isolation. Phytochemical screening and antimicrobial analysis were performed in the Microbiology Laboratory at the Faculty of Medicine and Health Sciences, Sanaa University.

Collection and Identification of Plant Material

We cultivated healthy Jatropha curcas specimens in Sana’a to obtain fresh latex. Botanical authentication was conducted at the Botany Unit within the Department of Plant Biology at Sanaa University. We extracted the latex by incising mature stems, collected the exudate in sterile amber bottles, and stored it at 4°C.

Test Microorganisms

Clinical isolates were obtained from infected wound and burn swabs collected from patients at Ibin Sina Hospital. The microorganisms included:

Staphylococcus aureus

Escherichia coli

Klebsiella pneumoniae

Pseudomonas aeruginosa

Candida albicans.

Standard ATCC Reference Strains Were Also Tested for Comparison

S. aureus ATCC 13704

E. coli ATCC 35218

K. pneumoniae ATCC 10273

P. aeruginosa ATCC 27853

C. albicans ATCC 10231

Identification was confirmed using standard microbiological techniques, including culture, Gram staining, and biochemical tests, as shown in Figures 1–6.

Figure 1 Culture morphology of Escherichia coli.

Figure 2 Culture morphology of Klebsiella pneumonia.

Figure 3 Culture morphology of Pseudomonas aeruginosa.

Figure 4 Culture morphology of Staphylococcus aureus.

Figure 5 Culture morphology of Candida albicans.

Figure 6 Culture morphology of Staphylococcus aureus on agar medium.

Preparation of Latex Extract

The crude latex was diluted with 20% dimethyl sulfoxide (DMSO) to create a stock solution at a concentration of 100 mg/mL. Serial dilutions were conducted for the assessment of Minimum Inhibitory Concentration (MIC).

Antimicrobial Susceptibility Testing

The agar diffusion method using wells was employed to assess antimicrobial activity. Mueller-Hinton agar plates, intended for bacterial cultures, and Sabouraud Dextrose agar plates, designed for fungal cultures, were inoculated with 0.1 mL of a standardised microbial suspension at approximately 10⁸ CFU/mL. Wells with a diameter of 6 mm were filled with 100 μL of latex extract at a concentration of 100 mg/mL. Plates were incubated at 37°C for 24 hours for bacterial cultures and at 25°C for 48 hours for fungal cultures. The inhibition zones were quantified in millimetres. DMSO functioned as a negative control. Standard antibiotics, including ofloxacin (5 µg), tetracycline (30 µg), and fluconazole (25 µg), were used as positive controls. The study was conducted by.¹⁷

Antimicrobial Susceptibility Testing

Agar Well Diffusion Method

The antibacterial activity of J. curcas latex was determined using the agar well diffusion method. To test for bacteria and Candida albicans, 0.1 mL of a standard microbial suspension (about 10⁸ CFU/mL) was added to Mueller-Hinton agar and Sabouraud Dextrose agar, respectively. Agar wells with a diameter of 6 mm were filled with 100 µL of latex extract (100 mg/mL). Plates were left at room temperature for 30 minutes to allow for pre-diffusion before being incubated at 37°C for 24 hours (bacteria) or 25°C for 48 hours (fungi). The sizes of the inhibition zones were measured in millimetres.as shown in Figure 7.

Figure 7 Anti sensitivity test of J. curcas latex on different microorganism (A) Escherichia coli, (B) candida albicans, (C) Pseudomonas aeruginosa, (D) Klebsiella pneumonia, (E) Staphylococcus aureus).

Controls

Negative control: 20% DMSO

Positive controls

• Ofloxacin (5 µg) and Tetracycline (30 µg) for bacterial isolates
• Fluconazole (25 µg) for C. albicans.^17–19

Minimum Inhibitory Concentration (MIC) Determination

As shown in Figures 8 and 9 we assessed the minimum inhibitory concentration (MIC) values using the broth microdilution method on sterile 96-well microplates. Serial two-fold dilutions of latex extract, ranging from 100 to 0.19 mg/mL, were prepared in nutrient broth. Each well was treated with 100 µL of diluted latex and 5 µL of microbial suspension. The plates underwent incubation at 37°C for a duration of 24 hours. The minimum inhibitory concentration (MIC) was defined as the lowest concentration that prevented visible microbial growth. Optical density was assessed at 600 nm using a microplate reader.²⁰

Figure 8 MIC of Jatropha latex against the isolated microorganisms in the band1 in well of ELISA microplate.

Figure 9 MIC of Jatropha latex against the isolated microorganisms in the band2 in well of ELISA. Microplate.

Statistically Analysis

Data were analyzed by using the SPSS program (Social Package of Statistical Science) version 21, were checked for normally distribution, and were expressed as percent, mean ± SD. Differences in variables were tested by using Independent sample T-test and chi- square test. Parametric multiple comparisons between the control and the treatment groups and the significant interrelationships between parameters were, analyzed by using One-way ANOVA. The significant differences were indicated if P-value < 0.05.

Results

Table 1 illustrates that Staphylococcus aureus was the predominant bacterium detected in burn wound infections, succeeded by P. aeruginosa. This research indicates that these two bacteria are significant contributors to wound sepsis in the study population, highlighting the need for effective antimicrobial treatments for both species.

Table 1 Prevalence of the Isolated Pathogens From the Clinical Burn Wounds Samples

Table 2 indicates that latex displayed a stronger inhibitory effect on E. coli than both antibiotics, especially against the standard strain. The evidence demonstrates that the latex possesses significant antibacterial activity against E. coli.

Table 2 Mean of Inhibition Zone (in Mm) of Jatropha Latex and the Studied Antibiotics (Positive Control) Against the Isolated E. Coli From the Clinical Burn Wounds Samples

Table 3 shows that Latex displayed either marginally higher or comparable inhibition relative to Ofloxacin and significantly exceeded Tetracycline, thus confirming its effectiveness against P. aeruginosa, a recognised drug-resistant pathogen.

Table 3 Mean of Inhibition Zone (in Mm) of Jatropha Curcas Latex and the Studied Antibiotics (Positive Control) Against the Isolated Pseudomonas Aeruginosa From the Clinical Burn Wounds Samples

Table 4 illustrates Ofloxacin showed marginally better results; however, the latex displayed significant antimicrobial activity and surpassed tetracycline, which was largely ineffective.

Table 4 Mean of Inhibition Zone (in Mm) of Jatropha Curcas Latex and the Studied Antibiotics (Positive Control) Against the Isolated Klebsiella Pneumonia From the Clinical Burn Wounds Samples

Table 5 indicates that latex exhibited superior antibacterial activity against S. aureus compared to both antibiotics, with inhibition zones exceeding 30 mm.

Table 5 Mean of Inhibition Zone (in Mm) of Jatropha Curcas Latex and the Studied Antibiotics (Positive Control) Against the Isolated Staphylococcus Aureus From the Clinical Burn Wounds Samples

Table 6 demonstrates that Latex exhibits greater antifungal activity than the established treatment, Fluconazole, indicating its considerable antifungal potential.

Table 6 Mean of Inhibition Zone (in Mm) of Jatropha Curcas Latex and the Studied Antibiotics (Positive Control) Against the Isolated Candida Albicans From the Clinical Burn Wounds Samples

Table 7 indicates a statistically significant enhancement (p < 0.05) in the inhibition of S. aureus by latex. K. pneumoniae demonstrated diminished inhibition from latex; however, this effect remained significant, likely due to variability.

Table 7 The Association Between Jatropha Curcas Latex and the Studied Ofloxacin (5mcg) (Positive Control) Against the Isolated Microorganisms From the Clinical Burn Wounds Samples

Table 8 displays in all cases, J. curcas latex demonstrated enhanced efficacy relative to tetracycline, suggesting its potential as a broad-spectrum agent.

Table 8 The Association Between Jatropha Curcas Latex and the Studied Tetracycline (30mcg) (Positive Control) Against the Isolated Microorganisms From the Clinical Burn Wounds Samples

Table 9 indicates that the antifungal efficacy of latex surpassed that of fluconazole (p = 0.002).

Table 9 The Association Between Jatropha Curcas Latex and the Studied Fluconazole (Positive Control) Against the Isolated Candida Albicans From the Clinical Burn Wounds Samples

All strains exhibited sensitivity to latex; however, several strains displayed resistance or an intermediate response to conventional pharmaceuticals, emphasising the advantage of latex in addressing resistant diseases, as demonstrated in Table 10.

Table 10 The Susceptibility of Latex of Jatropha Curcas Against the Isolated Microorganisms From the Clinical Burn Wounds Samples

Tables 11 and 12 exhibit MIC values that validate the effectiveness of latex, especially against E. coli and K. pneumoniae. The increased MICs for S. aureus and P. aeruginosa remain within a therapeutic range.

Table 11 Absorbance of Jatropha Curcas Latex Concentration of Each Cell in the Brands Against the Isolated Microorganisms

Table 12 Minimum Inhibitory Concentration (MIC) of Jatropha Curcas Latex Against the Isolated Microorganisms

Discussions

Because of tissue necrosis, moisture, and immunosuppression, burned wounds provide an ideal environment for microbial colonisation, which usually results in severe infections that impede healing and increase patient morbidity.^6,21 The most common pathogens found in this study were Staphylococcus aureus (33.3%) and Pseudomonas aeruginosa (25%), which supports previous research that found both species to be common in nosocomial burn wound infections.^22,23

According to our findings, Jatropha curcas latex had broad antibacterial activity against all of the wound pathogens that were investigated, including the fungus Candida albicans, Gram-positive bacteria (S. aureus), and Gram-negative bacteria (E. coli, K. pneumoniae, and P. aeruginosa). These results are consistent with other studies that showed the antibacterial efficacy of J. curcas extracts, including those derived from latex and leaves.^12,14

S. aureus had the greatest sensitivity to latex, displaying the largest zone of inhibition (31.3 mm), significantly exceeding those of ofloxacin and tetracycline (p < 0.05). This discovery is important because of the global rise of methicillin-resistant Staphylococcus aureus (MRSA), which poses a considerable challenge in wound treatment.⁸ The latex exhibited significant antifungal efficacy against C. albicans, exceeding that of fluconazole (p = 0.002), which is noteworthy given the increasing resistance to azole antifungals.¹⁰

The Minimum Inhibitory Concentration (MIC) values confirmed the effectiveness of the latex. The minimum inhibitory concentrations (MICs) were determined to be 6.25 mg/mL for E. coli, K. pneumoniae, and C. albicans, while S. aureus and P. aeruginosa required higher concentrations of 25 mg/mL. The observed values correspond with previous studies highlighting species-specific variations in sensitivity to J. curcas extracts.^15,17

The latex is effective against bacteria that are resistant to common antibiotics, particularly tetracycline. In certain instances, the latex produced inhibitory zones for K. pneumoniae and P. aeruginosa, while tetracycline showed none. According to this research, J. curcas latex may be a useful treatment for burn wound infections that are resistant to many drugs, especially in settings with limited resources when second-line antibiotics are not available.^5,9

Conclusions

According to this study, Jatropha curcas latex exhibits potent and wide-ranging antimicrobial activity against the main bacterial and fungal pathogens linked to burn wound infections, including Candida albicans, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus. The latex showed exceptional effectiveness against clinical isolates, including those resistant to common antibiotics like tetracycline and fluconazole, in addition to inhibiting the growth of common laboratory strains. The antibacterial qualities of the latex are probably due to the presence of active phytochemicals like flavonoids, tannins, saponins, alkaloids, and terpenoids. Crucially, the study found that J. curcas latex had low minimum inhibitory concentrations (MICs) and was just as effective—and occasionally even more effective—than conventional antibiotics, especially against Gram-negative bacteria and fungi. According to these results, J. curcas latex has a lot of promise as a natural, plant-based antibacterial agent for burn wound infections, especially in places where access to pharmaceutical therapies is restricted and antibiotic resistance is a growing problem. Isolating active compounds, assessing safety and toxicity profiles, and confirming these results in in vivo wound healing models should be the main goals of future research.

Data Sharing Statement

All data included in the manuscript are available upon request.

Consent to Participate

Written informed consent was obtained from all.

Institutional Review Board

The Institutional Review Board of the Ethics Committee of the Faculty of Medicine and Health Science, Sanaa University, Yemen, authorized this study, which was carried out in accordance with the Declaration of Helsinki’s criteria (Research code: REC-25-2024).

Acknowledgments

Our gratitude goes out to every one of the study participants.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors of this study declare that no funding for this study.

Disclosure

The authors of this study report no conflicts of interest.

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7. Gomez M, Garcia M, Martinez M, et al. Antimicrobial resistance in burn infections: an update. Infect Drug Resist. 2020;13:4211–4224.

8. Ventola CL. The antibiotic resistance crisis. Pharm Ther. 2021;46(1):50–57.

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11. Akinwale JA, Adeosun OO, Ogunjobi AA, et al. Antibacterial activity of Jatropha curcas latex: a potential treatment for skin infections. J Herbal Pharmacothe. 2022;21(4):275–284.

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Discover how a simple daily dose of red date vinegar helped adults with diabetes cut blood sugar and cholesterol in ten weeks, suggesting effects on key disease pathways.

Study: Clinical and computational exploration of red date fruit vinegar: synergistic effects on cardiovascular and type 2 diabetes pathways. Image credit: New Africa/Shutterstock.com

A randomized controlled trial involving adults with type 2 diabetes and dyslipidemia reported that daily intake of date fruit vinegar for ten weeks significantly improves blood glucose and lipid biomarkers (HbA1c, fasting blood sugar, LDL, total cholesterol, and HDL). These biomarker improvements suggest potential for reducing cardiovascular and metabolic risks. The trial findings are published in Frontiers in Nutrition.

Background

Cardiovascular disease is a leading cause of mortality worldwide, with almost 18 million deaths reported in 2017. This death toll is projected to exceed 23 million by 2030. Type 2 diabetes, characterized by high blood glucose level, is one of the significant risk factors of cardiovascular disease.

It has been hypothesized that both cardiovascular disease and type 2 diabetes share common genetic and environmental risk factors, including obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia.

Plant-based foods containing high amounts of bioactive compounds have shown promise in managing cardiovascular disease and diabetes. Dates are one such nutritious fruit that contains various bioactive compounds, including polyphenols, flavonoids, vitamins, and dietary fiber.

Fermentation of dates into vinegar is an effective strategy to increase the bioavailability of these bioactive compounds. This makes date vinegar a more effective alternative for managing diseases like cancer, heart disease, diabetes, and gastrointestinal disorders.

In this randomized controlled trial, researchers investigated the effects of date vinegar on blood glucose and lipid profiles in adults with type 2 diabetes and dyslipidemia. They also explored molecular mechanisms of its bioactive compounds in managing cardiovascular disease and diabetes.

Trial design

A total of 50 adults aged 30 to 60 were enrolled in the trial. The participants were randomly assigned to the intervention and control groups. The intervention group participants consumed 20 milliliters of date vinegar daily for 10 weeks. The control group participants consumed a placebo drink containing honey, water, and lemon juice matched for acidity but without bioactive compounds for the same duration.  

Computational docking and molecular dynamics simulations assessed the therapeutic mechanisms of date vinegar. These simulations determined the interactions of vinegar-derived bioactive compounds with key proteins related to cardiovascular disease and type 2 diabetes.

Important observations

The trial findings on glycemic control revealed that date vinegar intake causes a significant reduction in fasting blood glucose (from 168.4 to 147.6 mg/dL) and glycated hemoglobin (HbA1c, from 6.85% to 6.08%), both p < 0.05. These findings highlight the beneficial effects of consuming date vinegar in controlling hyperglycemia in the short term, though the study notes that clinical endpoints like complication rates were not assessed. In the control group, these parameters increased over the 10 weeks.

Regarding lipid profile, the trial reported that date vinegar intake is associated with a significant reduction in total cholesterol (225.1 to 213.1 mg/dL) and low-density lipoprotein (LDL) levels (121.1 to 111.1 mg/dL) in the blood. These findings indicate that date vinegar is effective in improving lipid markers linked to cardiovascular risk. In the control group, these parameters showed minimal reduction.

High-density lipoprotein, which plays a vital role in promoting cardiovascular health, showed a significant increase (from 43.2 to 46.5 mg/dL) in the vinegar group compared to that in the control group. This increase may also contribute to the health benefits observed in participants consuming date vinegar. However, triglycerides and very low-density lipoproteins (VLDL) levels showed no significant differences between the vinegar and control groups, suggesting that not all lipid parameters were affected.

The molecular docking analysis identified several important bioactive compounds in date vinegar, including pectin, yamogenin acetate, diosgenin, zeaxanthin, and antheraxanthin. These compounds showed strong binding potential to key target proteins, including angiotensin-converting enzyme (ACE), β1 adrenergic receptor (β1AR), angiotensin II receptor (AR), dipeptidyl peptidase-IV (DPP-IV), and sodium-glucose cotransporter 1 (SGLT1). 

The trial also assessed the sugar dynamics of date vinegar using different pressure vacuum drying temperatures. The findings revealed that moderate drying temperatures (65 and 70 °C) retained more sugar (53.7 to 55.1%) but better-preserved bioactive compounds, whereas 75 °C significantly reduced sugar (34.4%, close to fresh dates’ 33.6%) but degraded bioactive compounds.

Significance

The trial findings highlight the therapeutic potential of date vinegar in managing glucose and lipid metabolism and improving cardiovascular health in adults with type 2 diabetes and dyslipidemia.

Based on the findings, researchers proposed hypothesized mechanistic pathways associated with the health benefits of date vinegar. The bioactive compounds present in the vinegar was predicted to interact with key target proteins, including ACE, DPP-IV, and AR, which may contribute to reducing hyperglycemia, hyperlipidemia, and cytokine-mediated inflammation.

These interactions are proposed to promote nitric oxide production, prevent lipotoxicity and cell death, reduce oxidative stress, and improve mitochondrial function, mitigating endothelial dysfunction, atherosclerosis, and cardiovascular risk.

Diabetic patients often avoid consuming fresh dates because they contain a high amount of natural sugar. Fermentation-mediated conversion of dates into vinegar offers a promising alternative that helps reduce sugar content and preserve bioactive compounds.

Overall, the trial, by integrating computational predictions with experimental findings, highlights the potential of date vinegar as a dual-target therapeutic agent in managing cardiovascular disease and type 2 diabetes, but emphasizes that larger and longer clinical studies are needed to confirm long-term benefits and risk reduction.

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The diagnosis came just as Nathan Kirkland and his wife were preparing for the birth of their second child in April 2024.

Tests showed Kirkland, then 35 years, had intrahepatic cholangiocarcinoma, a rare form of cancer that develops in parts of the bile ducts housed within the liver. Kirkland’s only chance for a cure was a liver transplant, but his tumor was too large to meet the criteria for the surgery.

“Cholangiocarcinoma just isn’t a cancer most people come out on the other side of,” Kirkland told Medscape Medical News. “The doctor said to me, ‘Don’t plan on seeing your daughter born in a few short months.’”

Devastated, but determined to fight, Kirkland started a chemotherapy regimen that month to help shrink the tumor. To improve his chances for a liver transplant, his oncology team also recommended a noninvasive procedure, known as a histotripsy, that uses high-intensity sound waves to precisely target and eliminate liver tumors while avoiding the complications of surgery or radiation. The technique, which the FDA authorized in 2023, has shown a 95% success rate for treating liver lesions.

Despite the data and FDA authorization, Kirkland’s insurer, Anthem Blue Cross Blue Shield, denied a prior authorization request for the procedure in May. In July, Anthem approved a subsequent request, and Kirkland had his first histotripsy later that month.

But this approval shift did not indicate better times ahead for Kirkland. The opposite.

Starting in early August, Anthem denied approval for Kirkland’s two subsequent histotripsy procedures, calling the procedure “not medically necessary,” and, in November, reversed its July approval because of a coding issue.

Anthem’s medical policy considers histotripsy an “experimental or investigational treatment for liver cancer,” Janey Kiryluik, staff vice president for corporate communications at Anthem’s parent company Elevance Health, told Medscape Medical News in a statement.

After numerous appeals in the fall of 2024, the insurer upheld its decision not to cover Kirkland’s histotripsy procedures. Without coverage, the three procedures cost about $150,000 out of pocket, according to Kirkland.

Although the exact frequency remains hard to pin down, coverage denials have become increasingly common among major health insurers, like Anthem, and the rise appears to be fueled, in part, by insurers’ use of artificial intelligence (AI) algorithms to review prior authorization requests and then deny claims in batches. In some cases, rates of denials may be 16 times higher when reviewed by AI tools than by humans, according to figures from a recent American Medical Association report.

While most denials are ultimately overturned, that can take days, sometimes weeks or months, and delay life-saving cancer care. In a 2024 survey of radiation oncologists, for instance, 30% reported that the prior authorization process harmed their patients, and 7% said it led or contributed to a patient’s death.

“Every time insurers create a delay or a hurdle, it potentially complicates care,” said Kirkland’s Oncologist, Laura Tenner, MD, MPH, an associate professor in the Division of Oncology and Hematology at the University of Nebraska Medical Center, Omaha, Nebraska. “There have been some significant delays in prior authorizations and coverage by insurance companies that have delayed care to the point where patients missed out on curative intensive therapy for cancers.”

To limit the delays, patients like Kirkland may be left with an impossible choice: Find a way to pay for their care and potentially fall into deep debt or delay their care while fighting the insurance company.

Kirkland couldn’t wait. In October and November 2024, he underwent two more histotripsies. To cover the cost, Kirkland and his wife exhausted their children’s college funds and borrowed money from friends and family.

In January 2025, Kirkland received some encouraging news: The procedures, plus the chemotherapy, had killed off enough of his cancer for his medical team to approve him for a liver transplant.

“I was on cloud nine once I got the good news from being cleared for transplant,” Kirkland said. “I thought ‘This is the best news ever! I’m going to be there for my kids.’” 

Kirkland started the transplant testing process. His brother agreed to be his donor, and a transplant date was tentatively set for February 14.

But those plans halted abruptly. The family received a letter from Anthem denying coverage for the transplant. 

In the letter, dated February 6, 2025, Anthem claimed that the requested transplant was “medically unnecessary.” 

“Medical studies do not show that this surgery will improve your short- or long-term health,” Anthem officials wrote in the letter, which Kirkland shared with Medscape Medical News.

“It was a gut punch,” Kirkland said. “This can’t be real.”

Denial-Fighting AI Enters the Scene

Desperate to get the care he needed, Kirkland and his family turned to social media. By this point, Kirkland’s out-of-pocket costs totaled about $250,000.

Within days of sharing his story, Kirkland’s posts on Facebook and LinkedIn garnered more than 6000 shares. The LinkedIn post even caught the attention of billionaire Mark Cuban who offered to help pay for the transplant.

But it was a new AI startup called Claimable that turned the tables for Kirkland’s insurance fight. The company, which launched in October 2024, is one of a growing crop of AI-based companies using the technology to help patients and providers analyze health insurance claim denials, uncover issues, and ultimately appeal and overturn denials.

Health policy analysts say the new wave of companies is part of a growing “battle of the bots” as health insurers increasingly use AI to deny claims.

“It’s not surprising that new AI companies have sprung up,” said Michelle M. Mello, JD, a health law scholar at Stanford Law School who researches the effects of law and regulation on healthcare delivery. “On the provider side, there are more denials than people to process them, and one of the things AI tools can do is help figure out which denials are most likely to be overturned if appealed. Often, the reason something is denied is just that information is missing. So having AI systems in place that can figure out, can learn, and can put in that additional information, that seems really valuable.”

Claimable does not specialize in cancer cases, but when the company caught wind of Kirkland’s story through social media, Warris Bokhari, MD, a former National Health Service physician behind the company, wanted to help.

“We probably spent a couple of hours on the phone with Nathan and then spent the rest of the day working with his brother and his sister to piece together the story,” said Bokhari, who previously led healthcare strategy and innovation across corporate America, including Anthem. “We went through every test, every imaging result. We went through all of the evidence. And over the course of the day, we basically put together an appeal that was then elevated to visibility at the insurance company.”

Bokhari discovered that Anthem had Kirkland’s diagnosis wrong on the liver transplant denial. And it wasn’t the first time.

Anthem had initially misidentified Kirkland’s cancer as neuroendocrine cancer, not intrahepatic cholangiocarcinoma, in a previous histotripsy denial. Although the original denial letters and initial appeal letter referred to liver cancer, Kiryluik told Medscape Medical News that the “‘neuroendocrine cancer’ term was inadvertently inserted by a medical director reviewer from a drop-down screen in place of ‘liver cancer’ which appears immediately above on the drop-down screen.” But “this error did not impact the decision,” Kiryluik wrote.

The second time occurred in the transplant denial letter from February 6, which listed Kirkland’s cancer as hilar primary sclerosing cholangiocarcinoma — also a form of bile duct cancer, but one that develops outside the liver.

The crux of Kirkland’s appeal, however, was that Anthem was using data from 2004 to support its denial, Bokhari said.

This is not unusual. Bokhari has found that many insurance companies rely on poor or out-of-date evidence or inconsistent enforcement of policies to make claim decisions.

To unearth such issues, Claimable’s AI platform analyzes patients’ medical cases alongside clinical evidence, policy details, and appeal precedents in similar cases. The company charges patients about $50 fee for the service.

In Kirkland’s case, Claimable pointed to studies starting in 2018 that showed outcomes for patients with cholangiocarcinoma drastically improved following neoadjuvant chemotherapy and a liver transplant. The 5-year survival rate was close to 60%, according to a recent study.

“That was significant,” he said. “And ultimately, our involvement was really to show that this should be a clinical decision between the transplant surgeon and Nathan.”

Bokhari said it’s unclear if Anthem used AI in Kirkland’s claim denials — he becomes suspicious when denials include errors and incorrect terms — but the denials could have also been based on “incompetent review,” he added.

Anthem denies using AI in its coverage decisions. “AI is not used in denial decisions,” Kiryluik told Medscape Medical News. “Denial decisions are made by an appropriate medical director through our peer clinician review process.”

‘Battle of the Bots’

Claimable sits alongside a small but growing number of companies using AI to help physicians and patients fight health coverage denials.

In June 2024, Flight Health Insurance launched a platform to help patients appeal denials and, in April 2025, expanded its reach to providers with a platform called Fight Paperwork. In November 2024, Cofactor AI introduced an AI-powered platform called Cofactor Denial Suite that supports claim appeals for providers. In January 2025, payment software company Waystar announced the launch of Waystar AltitudeAI™ to help providers appeal denied medical claims. And in April 2025, Red Sky Health unveiled its new AI-solution, Daniel, which helps providers identify and correct claims errors.

Holden Karau, a software development engineer who created Flight Health Insurance, has been thinking about insurance coverage issues since being hit by a car in 2019. While the insurer paid for her “bones to be fixed,” Karau said nearly every other aspect of the process ended in a payment dispute.

Only recently has the technology gotten to a point where it made sense to work on a platform to help fight denials, Karau said. Like Claimable, Karau’s company keeps the process simple and the costs low for patients and providers.

“The hope is to keep the prices low because we think that there’s just so many denials out there that aren’t being appealed,” Karau said.

A Hard-Won Transplant That Didn’t Come to Pass

Six days after the February 6 transplant denial, Kirkland learned that Anthem had reversed its decision based on “new information.”

According to Bokhari, Claimable is currently beating about 85% of health coverage denials.

Kiryluik told Medscape Medical News via email that the initial coverage request was “denied due to lack of medical necessity based on the provided information.”

“After Mr Kirkland contacted us on February 9, we initiated an appeal process, which included further discussions between our oncology medical director and his transplant surgeon,” Kiryluik said in a statement.

“It was during this review that new details were provided, including an updated diagnosis and data on the transplant center’s success rates for patients with similar diagnosis,” Kiryluik explained.

Claimable’s letter, for instance, corrected Kirkland’s cancer diagnosis and cited data from Kirkland’s transplant team showing that all 10 patients with intrahepatic cholangiocarcinoma who had received a liver transplant at their institution had survived. “With this new information, Anthem approved coverage for Mr Kirkland’s liver transplant and informed him of the decision,” Kiryluik said.

But time was not on Kirkland’s side.

After Anthem reversed its denial, Kirkland’s medical team immediately rescheduled his transplant. Physicians knew it was urgent he received his transplant before his cancer metastasized.

Kirkland was prepped and headed into surgery on February 14, which he called “fitting” because the date happened to be National Organ Donor Day.

Surgeons opened him up. Before the transplant, his team first wanted to biopsy a retroperitoneal lymph node. The biopsy came back positive for cancer, indicating the tumor had metastasized.

Because the lymph node was outside the surgical resection field, Kirkland’s cancer would not have been fully removed, even with a liver transplant, explained Tenner.

The transplant procedure was cancelled. Kirkland and his family were crushed.

A curative liver transplant is now off the table for Kirkland and the goal is to explore palliative therapies to extend his life and give him the best quality possible, Tenner said. His oncology team is also looking into clinical trials for him, she said.

But there’s a lingering question: Did Kirkland miss the slim window he may have had for curative intent therapy because Anthem’s prior authorization process and coverage denials delayed his care?

“There is a chance that had things been approved quicker and a biopsy obtained, the cancer would not have spread at that time, but I can’t give you a definitive ‘yes’ or ‘no’ on that,” Tenner said.

Ultimately, Anthem also reversed its denials of Kirkland’s histotripsy procedures after Claimable got involved. Kirkland also believes the social media attention surrounding his case contributed to Anthem’s shift.

But the insurer told Medscape Medical News that “Anthem approved coverage of the histotripsy following an external review by an independent peer review organization. Consideration was given to several factors, including the member’s unique clinical circumstances and documentation by the treating facility that the member had exhausted all evidence-based therapies, and other alternative medical services were not available outside of a clinical trial.”

In late May, Kirkland finally received his first reimbursement check for $97,000 of the $250,000 he had paid.

Even the reimbursement process was “slow and messy,” he said. He is still waiting for the remaining amount, and his surgeon is still waiting to be paid by Anthem, he said.

Despite his outcome, Kirkland said he’s “not done fighting.” He hopes his story will draw attention to unfair insurance denials and lead to changes in company policies.

In February, he filed an ERISA appeal to Anthem, urging the insurer to make changes in its policies for patients who need liver transplants and FDA-backed histotripsy procedures.

“At this stage, it’s more about making sure other people get the opportunity and the care they need to have a better outcome,” he said. “It shouldn’t be such a burden to get treatment.”

Small cell carcinoma of the ovary used to be classified as a tumor of the ovary and subclassified into SCCOHT and SCCOPT in the prior WHO classification [1], but is now subclassified into SCCOHT and OSCNEC [2]. OSCNEC is classified in the new chapter of neuroendocrine neoplasia, which consolidates neuroendocrine neoplasia in gynecological sites such as ovary, uterine corpus and cervix, whereas SCCOHT remains classified as a tumor of the ovary. Therefore, SCCOPT is thought to correspond to OSCNEC pathologically despite this change in pathological classification. OSCNEC are pathologically similar in morphology to neuroendocrine carcinomas of the lung, gastrointestinal tract, pancreas, uterine cervix, and uterine body. OSCNEC and SCCOHT are clinically and histopathologically distinct entities. SCCOHT, which is more common and occurs in adolescents and young women with hypercalcemia, is strongly associated with somatic mutations of SMARCA4 [15]. In contrast, SCCOPT of the ovary, which is not related to this gene mutation, is rarer, occurs more often in peri- or postmenopausal women, and is not associated with hypercalcemia.

SCNEC can occur in the gynecological tract and accounts for less than 1% of gynecological malignancies [2]. SCNEC other than cervical SCNEC typically presents after menopause, consistent with this case. Due to the rarity of OSCNEC, few reports have described possibly characteristic clinical data like preoperative serum NSE levels and detailed MR imaging findings. Most notably, FDG-PET findings associated with preoperative diagnosis have never been reported.

On MRI, this case of OSCNEC appeared as a multicystic mass including hemorrhage and solid component. Septa inside the tumor were irregular, and the solid component showed high SI on DWI and contrast enhancement. In reports describing imaging findings of OSCNEC and SCCOPT on CT and MRI (as shown in Table 1), the morphology of OSCNEC is described as a lobulated mass consisting of not only solid but also cystic components, as in this case. Cystic components sometimes contain hemorrhage, necrosis and/or rupture [4] [7]. These findings are also observed in primary ovarian neoplasms other than OSCNEC and are not specific. Thus, it may be difficult to differentiate OSCNEC from malignant ovarian epithelial tumors such as metastatic ovarian tumors and mucinous carcinoma.

In the present case, high FDG uptake (SUVmax: 13.0) was detected in the solid component, para-aortic lymph node, spinal, iliac, and liver metastases, and peritoneal dissemination on ¹⁸F-FDG PET/CT. To our knowledge, this is the first case report to describe ¹⁸F-FDG PET/CT findings. In previous reports, average SUV max was 7.8 in 66 primary malignant ovarian neoplasms except for OSCNEC [16], compared with 11.3 (range: 2.5–57.6) in primary small cell lung cancer (SCLC) of all stages [17]. Despite this significant overlap in range, SUV max was significantly higher in SCLC. Consequently, OSCNEC may be similar to SCLC not only in pathological morphology but also in high FDG uptake.

Generally, lymphatic metastasis and peritoneal dissemination are the most common metastatic routes in ovarian epithelial cancer, while hematogenic spread is rare [18] [19]. In contrast, NECs of the ovary show significantly higher tendencies for bone, brain, and liver organotrophic metastasis than epithelial ovarian cancer such as endometrioid carcinoma, mucinous carcinoma, serous carcinoma, and adenocarcinoma [20]. In the present case, hematogenic spread as bone and liver metastases were detected by ¹⁸F-FDG PET/CT. Bone metastasis was a particularly notable finding in reports of OSCNEC of the ovary or SCCOPT that mentioned the metastatic sites: three of the six cases with distant metastases had bone metastases, as shown in Table 2. Detection of bone metastases affects the pretreatment staging directly, but is sometimes difficult on CT, especially when bone metastases are intertrabecular vertebral metastases (IVM). SCLC, hepatocellular carcinoma and hematologic malignancies, which have a poor tumor stroma, tend to form IVM. As IVM do not alter the trabecular bone structure [21], they often go undetected on regular imaging modalities that detect osteolytic or osteoplastic structural deformation, such as CT and bone scintigraphy [21]. However, ¹⁸F-FDG PET/CT could detect bone metastases which were not identified by CT [22], corresponding to the clinical determination of IVM in this case (Fig. 2). Ovarian cancer staging is ultimately determined through surgical findings. However, distant metastases, including hepatic, pulmonary, and osseous involvement, cannot be accurately assessed intraoperatively and rely solely on imaging evaluation. Therefore, PET/CT may contribute to precise preoperative staging, ensuring a more comprehensive assessment of disease burden and treatment planning.

In this case, serum levels of NSE were elevated preoperatively. Suzuki [4] reported elevated preoperative serum levels of NSE at 177 ng/ml, and NSE elevation was always accompanied by evidence of recurrence on imaging after surgery for SCCOPT. Yin et al. [7] also reported elevated serum NSE even 10 days after palliative surgery for right ovarian SCCOPT with uterine endometrial cancer metastasizing to the left ovary. NSE, known as enolase-γ, is a neuro- and neuroendocrine-specific isoenzyme of enolase, which is a key enzyme in aerobic glycolysis [23]. Elevated NSE can be observed in several neuroendocrine or neuronal tumors such as SCLC and neuroblastoma [24] [25]. Serum levels of NSE are frequently elevated in SCLC at the time of diagnosis, decrease after remission, and rebound after recurrence [26] [27] [28]. Because OSCNEC is similarly a high-grade carcinoma composed of small to medium-sized cells with scant neuroendocrine differentiation, elevated serum NSE level may also imply OSCNEC in the diagnosis of ovarian tumors, although it is difficult to distinguish OSCNEC from metastatic small cell carcinoma of the lung. Therefore, FDG-PET, which can detect even IVM and rule out primary SCLC in patients with primary ovarian tumors, may be helpful to suggest primary ovarian OSCNEC as a differential diagnosis. Furthermore, since NSE is not routinely measured preoperatively, the identification of hematogenous dissemination, particularly manifesting as bone and liver metastases—as observed in this case—may serve as a clinical prompt to assess NSE levels. This could not only facilitate the early suspicion of OSCNEC but also enhance the detection of postoperative recurrence, thereby contributing to more effective disease monitoring and management.

Preoperative diagnosis of OSCNEC by CT or MRI alone is considered difficult due to the lack of specific findings. However, OSCNEC could be considered when elevated serum NSE at diagnosis and hematogenic spread such as bone or liver metastases are found in a patient with a primary malignant ovarian tumor who does not have a lung tumor on imaging.

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Mark Norman BBC

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