The malicious URLs have been a constant threat to cybersecurity because hackers are constantly creating phishing, malware, spam, and defacement links that resemble authentic Web layouts and bypass static security measures. Despite very promising results of machine learning (ML) and deep learning (DL) models in URL classification, the effectiveness of these models is usually limited by high dimensional spaces of features that have redundant and irrelevant qualities, which leads to increased computation costs and potentially less generalization ability. To cope with this, this study will present a wrapper-based Bat Algorithm (BA) feature selection model to determine small and discriminative subsets of features in detecting malicious URLs. The bio-inspired metaheuristic BA offers a good tradeoff of exploration and exploitation in high dimensional optimization issues and thus is useful in feature subset selection. The proposed BA model is tested on ensemble ML (XGBoost, AdaBoost, Gradient Boosting, CatBoost and LightGBM) and DL (CNN, RNN, LSTM and CNN-LSTM) architectures with two datasets the multi-class ISCX-URL-2016 dataset and the more recent URL Phishing (2026) dataset. Experiments results indicate that BA has a significant dimensionality reduction: It reduces original feature space on ISCX-URL-2016 by 51.90% in the case of Defacement, by 67.09% in the case of Malware, by 49.37% in the case of Phishing, by 59.49% in the case of Spam, and 45.91% in the case of Phishing on URL Phishing (2026). This reduction notwithstanding, BA shows consistent improvements in the classification of both datasets. BA-enhanced LightGBM had the best overall results of all the tested models, with an accuracy of 99.92% on ISCX-URL-2016 and 98.17% on URL Phishing (2026), and high values of ROC-AUC and good computational efficiency. A statistical analysis also supports the fact that the improvements noticed are significant. Altogether, the proposed BA-based feature selection model is an efficient, scalable, and reliable solution to malicious URL detection intelligent, with good possibilities of being implemented into real-world systems in terms of cybersecurity.
Cannabis-impaired driving is an increasing public health concern. Effective communication strategies are essential for shaping risk perceptions, influencing normative beliefs, and encouraging safer behaviors. UC San Diego Transportation Research and Education for Driving Safety Center evaluated how cannabis consumers perceive and respond to cannabis-impaired driving messages, message sources, and strategies to promote safer driving behaviors. Eligible participants were adults who reported cannabis use within the past three months, perceived it as safe to drive on the same day of use, and resided in one of eight U.S. states selected for diversity in cannabis policy contexts. The study aimed to recruit 800 participants. Using a cross-sectional, mixed-methods design, participants reported cannabis use patterns and driving behaviors before reviewing a series of cannabis-impaired driving messages. Messages were developed through an iterative process informed by literature, expert review, and formative testing, and represented communication styles commonly used in safety campaigns. Participants rated each message on attention, appeal, relevance, believability, influence on behavioral intentions, and source credibility. 846 cannabis users participated. Messages emphasizing concrete effects and impairment (e.g., Feel Different, Drive Different) consistently received the highest ratings across attention, appeal, relevance, and believability. In contrast, more informational or evaluative messages (e.g., Studies Show) performed significantly less favorably. Factual messages yielded the highest proportion of participants reporting they were very likely to increase wait time before driving (59%), while self-reflective messages were most effective in encouraging alternative transportation (55%). All message types produced similar effects on intentions to remain in the same location (56-58%), and substantially fewer participants reported intentions to reduce cannabis use overall (23-29%). Message responsiveness varied by driving risk profile. Ultra-high-risk drivers reported lower likelihood of engaging in safer behaviors compared with medium- and high-risk drivers, although differences were not uniformly statistically significant. Qualitative findings indicated that exaggerated, fear-based, or stigmatizing messages were viewed negatively across groups, whereas messaging that was clear, evidence-based, and nonjudgmental was perceived as credible and effective. Source trust also varied, with healthcare providers and science-based organizations rated most credible and celebrities and social media influencers rated least trustworthy. This study offers new evidence on how cannabis users respond to messaging about cannabis-impaired driving. Messages emphasizing concrete effects and impairment, particularly those that are factual, direct, and evidence-based, were most consistently associated with higher ratings on outcome measures. However, differences in behavioral intentions across message types were modest, with limited impact on intentions to reduce cannabis use. Findings also indicate that individuals reporting higher-risk cannabis use and driving behaviors, particularly ultra-high-risk drivers, may be less responsive to messaging overall and may require more tailored approaches and complementary strategies to mitigate impaired driving. Across groups, messages perceived as exaggerated, stigmatizing, or fear-based were viewed as less credible and potentially counterproductive. These results can inform the development of user-centered, harm-reduction safety campaigns as cannabis legalization expands, while underscoring the need for continued evaluation and refinement of messaging strategies.
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This study aimed to examine the symptom burden reported by survivors treated in survivorship clinics by describing the severity of symptoms and symptom interference with life activities, comparing symptom severity by sex, and identifying predictors of the three most prevalent moderate to severe symptoms. This secondary data analysis examined patient-reported symptom burden data using the MD Anderson Symptom Inventory collected for clinical purposes from January to December 2023. Sex differences in symptom burden were compared using t-tests. Multivariate logistic regressions identified predictors of the three most prevalent moderate to severe symptoms. Among 2550 survivors (mean age 61.9 ± 12.1 years; 69.9% female, 36.4% breast cancer), the average time in survivorship care was 4.04 ± 4.00 years. Over 75% of survivors reported experiencing ≥ 1 symptom, and 45% reported ≥ 1 moderate-severe symptom. The three most prevalent moderate to severe symptoms were fatigue (25%), sleep disturbance (24%), and problems remembering (15%). Compared with males, females reported significantly more symptoms (p < 0.05) and more moderate to severe symptoms (p < 0.01). Female survivors and those under the age of 65 were more likely to report moderate to severe fatigue, sleep disturbance, and problems remembering (all p < 0.01). The high prevalence of persistent symptoms among cancer survivors in this sample supports the need for routine symptom assessments in survivorship care. Age and sex are important considerations in tailoring supportive interventions. As the population of cancer survivors grows, understanding symptom burden across diagnoses is critical to inform effective supportive care strategies.
The unique capability of deuterium metabolic imaging (DMI) to detect downstream metabolic products and trace substrates' transport within tissues using conventional magnetic resonance (MR) scanners can, in theory, be employed with routine positron emission tomography (PET)/MR equipment. Our technical proof-of-concept study proposes a protocol for the simultaneous acquisition of DMI and [¹⁸F]FDG-PET data to enable dual assessment of hepatic glucose metabolism. A protocol that integrates high-dose glucose administration, required for DMI, with [¹⁸F]FDG-PET imaging was applied in a spectroscopy-validated rodent model of metabolic dysfunction-associated fatty liver disease (MAFLD). We acquired and quantified high-quality DMI and PET data of the liver that could provide a distinction between healthy and MAFLD cohorts in the future. RELEVANCE STATEMENT: This proof-of-concept study demonstrates the simultaneous DMI-[18F]FDG-PET acquisition for assessing hepatic glucose metabolism. With its proven viability in healthy and MAFLD livers, hybrid DMI-PET imaging shows promise as a prospective non-invasive tool to improve metabolic disease characterization and support future research applications. KEY POINTS: Simultaneous DMI and [¹⁸F]FDG-PET acquisition is technically feasible on a standard PET/MR system. Hybrid DMI-PET imaging enables dual assessment of hepatic glucose transport and metabolism, offering the advantage of reduced assessment duration. High-dose glucose administration for DMI is compatible with PET imaging, thereby reducing the subject's burden and enhancing liver metabolic evaluation.
The first workshop dedicated to Lassa virus–specific correlates of protection (CoP) was held in 2024 and was convened by the Coalition for Epidemic Preparedness Innovations (CEPI). Experts from multiple disciplines reviewed existing knowledge and identified gaps in understanding Lassa virus- and vaccine-induced immune responses. Discussions covered key areas including epidemiology, immunogenicity, preclinical and clinical research, data science, and regulatory considerations, with the goal of pinpointing opportunities to discover CoP.
Encephalitozoon cuniculi is an obligate intracellular parasite that affects birds and mammals, including humans, and belongs to the phylum Microsporidia. The innate immune system serves as the first line of defense against infection, but it only partially clears the parasite. Microsporidia are known to modulate the effector functions of phagocytes. They can survive and multiply inside macrophages (MOs) to evade destruction after phagocytosis and also modify the functional properties of dendritic cells. However, the role of neutrophils (PMNs) in microsporidiosis remains poorly understood. In a mouse ear skin model, inflammatory cells, including MOs and PMNs, were rapidly recruited to the cutaneous injection site, and intact spores persisted within phagocytes for several days. We hypothesized that Microsporidia also manipulate the antimicrobial mechanisms of PMNs, including phagocytosis and the formation of neutrophil extracellular traps (NETs), to enhance their survival. Using live and static cell imaging in vitro, along with the mouse ear pinna model, we investigated the dynamics of interactions between PMNs and E. cuniculi parasites. Our observations revealed that the parasites rapidly adhere to and are phagocytosed by PMNs. After activation, infected PMNs exhibited modified structural and functional properties, such as the extension of pseudopodia, parasite lysis inside phagolysosomes, modified motility and shape parameters, and NETs formation. Interestingly, a small proportion of the parasites survived intracellularly, with early developmental stages (meronts, sporonts) observed within PMNs at 24 and 48 h post-infection. Importantly, infected PMNs harboring intact and infectious intracellular spores were later phagocytosed by MOs. Using innovative microscopy and imaging approaches, we discovered that E. cuniculi Microsporidia manipulate PMNs, key innate immune cells, by using them as intracellular niches for their development, and as potential vehicles for their silent transfer to other host target cells.
Integrated care for TB and mental health is critical, as mental disorders worsen TB outcomes. WHO guidelines recommend routine screening for mental health conditions and integrated care for TB patients, yet implementation remains uncertain. We conducted a survey with the participation of 34 experts from 26 countries from the WHO European Region within TBnet and the ADVANCE-TB COST Action, followed by a Delphi process to assess the uptake of WHO recommendations and build consensus on strategies for integrated TB-mental health care. The survey showed substantial gaps: only 21% of experts, representing six countries, reported local or national guidelines integrating mental health into TB care, and systematic screening was rare, including for drug-resistant TB. Building on these findings, the Delphi process reached consensus on the need for validated screening tools at key treatment stages, structured referral pathways, and tighter alignment between TB and mental health services. Eighteen consensus recommendations were developed, addressing training, routine data collection, technology-supported care, and sustainable financing. Mental health remains insufficiently integrated into TB care across the WHO European Region. Routine screening coordinated referral systems and implementation of the proposed recommendations are essential to deliver people-centred, equitable, and effective TB care.
Digital twins are an emerging concept in healthcare that envisions integration of molecular, physiological, functional and clinical data to create computational models of biological systems such as cells, organs and individuals. However, the lack of large, multimodal datasets has so far precluded the realization of comprehensive digital twins in medicine. Ex vivo lung perfusion (EVLP) allows the study of human lungs outside the body under physiological conditions and generates multimodal data from imaging, physiologic monitoring and molecular assays. Here we report lung digital twins developed from the largest known clinical EVLP dataset. We show that the digital twin framework accurately models >75 parameters spanning lung physiology, biochemistry, radiography, transcriptomics, metabolomics and proteomics. Furthermore, direct comparison to experimental data on EVLP lungs treated with alteplase demonstrates that digital twins can precisely assess therapeutic efficacy. Together, these results establish human lung digital twins developed using EVLP as a data-rich approach to improve the evaluation of therapeutic effects.
[18F]FDG functional PET (fPET) enables investigation of dynamics in glucose metabolism occurring within seconds. However, the physiological mechanisms supporting rapid metabolic changes necessitate further attention to allow accurate interpretation. This work highlights candidate mechanisms driving [18F]FDG signal changes at high temporal resolution, offering complementary insights to existing interpretations. At rest, metabolic demands are closely matched by glucose supply across the blood-brain barrier (BBB), regulated by glucose transporter 1 (GLUT1). During neuronal activation, glucose transport and phosphorylation by hexokinase are elevated to meet increased energy requirements. Simulations indicate that rapid [18F]FDG signal increases are primarily driven by BBB transport, with subsequent increases in hexokinase activity. Mechanisms supporting increased BBB transport include elevated glucose concentration gradient towards the brain and changes in GLUT1 intrinsic properties, but only minor effects of blood flow. Conversely, moment-to-moment fluctuations in [18F]FDG used for metabolic connectivity, reflect temporally synchronized supply, mediated jointly by blood flow and BBB transport. We emphasize that the coupling between BBB transport and metabolism underpin the [18F]FDG fPET signal. Considering alterations of GLUT1 and subsequent metabolism in numerous brain disorders, stimulation-induced energy demands and metabolic connectivity represent a promising opportunity to investigate the underlying pathophysiological processes.
Although fungi and bacteria commonly co-exist within polymicrobial communities, the molecular mechanisms underlying their interactions are still not well understood. Here, we show that the fungus Candida albicans forms biofilms with the bacterium Staphylococcus aureus along a nutritional axis of mutualism and propose that 'a copper economy' shapes fungal-bacterial biofilm interactions.Using in vitro biofilms formed on plastic, we found that dual-species biofilms are consistently larger than single-species counterparts, indicating a cooperative interaction. Dual-species proteomic analysis revealed non-reciprocal copper handling: C. albicans increased copper uptake via transporter Ctr1, while S. aureus enhanced copper export via regulator CsoR and export chaperone CopZ. Dual-species biofilms exhibited specific sensitivity to both copper depletion and supplementation, with corresponding reductions in biomass. We identified fungal copper import as the crucial element in mutualistic interactions between C. albicans and staphylococcal species. Moreover, fungal hyphae served as a critical scaffold for biofilm architecture, a role that was compromised under copper-replete conditions. Notably, copper nanoparticles disrupted these dual-species biofilms, highlighting a potential therapeutic avenue. Furthermore, we extend the role of C. albicans copper import to mutualistic interactions with additional bacterial species. Our findings establish copper as a central mediator of C. albicans and S. aureus cooperation and suggest that a 'copper economy' underpins mutualistic interactions in biofilms.
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To determine the association between molecular classification and response in patients with endometrial intra-epithelial neoplasia or endometrial cancer treated with a levonorgestrel intra-uterine device. Eligible patients were treated with a levonorgestrel intra-uterine device for endometrial intra-epithelial neoplasia or endometrial cancer for at least 6 months. Immunohistochemistry for MLH1, MSH2, MSH6, PMS2, and p53 was performed. Specimens were categorized using a modified Proactive Molecular Risk Classifier for Endometrial Cancer algorithm as deficient mismatch repair, p53 abnormal, or p53 wild-type. A subset underwent single-gene POLE sequencing. Best response was recorded as pathologic complete response, partial response, stable disease, or progressive disease. Kruskal-Wallis tests and Fisher exact tests were used for statistical analysis. There were 143 patients, including 83 with endometrial intra-epithelial neoplasia and 60 with endometrial cancer. Fertility preservation was desired in 35.7%, 53.8% had significant medical co-morbidities precluding hysterectomy, and 10.5% had levonorgestrel intra-uterine device placement for other indications, including patient preference, placement during the coronavirus disease 2019 pandemic, and logistical considerations for other cancer diagnoses. Molecular characterization showed 90.9% p53 wild-type, 7.0% deficient mismatch repair, and 2.1% p53 abnormal. Only 4.4% of specimens with sequencing had a POLE mutation (2 of 45). The overall response rate was 86.7% (endometrial cancer: complete response 38.3%, partial response 36.7%; endometrial intra-epithelial neoplasia: complete response 67.5%, partial response 27.7%). In patients with endometrial cancer, the response rate was 75% (45 of 60), varying by molecular sub-group: 50% in the p53 abnormal group (1 of 2) and 50% in the deficient mismatch repair group (5 of 10). Only 1 patient with endometrial intra-epithelial neoplasia had p53 abnormal expression; the remaining patients had intact MMR expression and p53 wild-type. The complete response to levonorgestrel intra-uterine device therapy was lower than expected for endometrial intra-epithelial neoplasia. Response rates varied by molecular classification, with worse outcomes observed in deficient mismatch repair and p53 abnormal sub-types. Although limited by sample size, these findings suggest that levonorgestrel intra-uterine device therapy may not be sufficient for all molecular sub-groups.
Elite athletes undergo intense physical training and experience substantial physiological stress, which could affect the composition and function of their gut microbiome. This study compared the gut microbiomes of 148 German junior and senior elite athletes with those of 108 healthy adults to identify taxonomic and functional features associated with elite athletic status. Group comparisons were conducted between healthy adults, senior athletes, and junior athletes, and a matched-subgroup analysis was performed in adults only, controlling for age, sex, body mass index, and dietary pattern. Significant differences in taxonomic composition were observed between athletes and healthy adults. Healthy adults exhibited greater microbial evenness and diversity than junior athletes, whereas senior athletes displayed higher microbial richness. Principal coordinate analysis revealed distinct clustering by athletic status. Linear discriminant analysis effect size identified taxa such as Escherichia-Shigella as being enriched in athletes. Predictive metagenomic profiling (PICRUSt2) indicated differences in microbial functional potential between adult athletes and matched controls, including pathways related to amino acid metabolism, glycolysis, fatty acid β-oxidation, and quinone biosynthesis. Together, these findings demonstrate distinct taxonomic and predicted functional microbiome signatures associated with elite athletic status.IMPORTANCEElite athletic training and lifestyle are associated with the gut microbiome. Our research has revealed distinct microbial structures in elite athletes, characterized by reduced evenness in junior athletes and increased richness in senior athletes, compared to healthy adults. Matched-subgroup analyses confirmed these group-specific differences. The gut microbiomes of athletes were enriched in pathways related to amino acid biosynthesis, glycolysis, fatty acid β-oxidation, and quinone synthesis. These microbiome features may be relevant for metabolic efficiency and resilience to oxidative stress. Combining taxonomic and functional prediction data from a uniquely characterized cohort of junior and senior elite athletes provides novel insight into microbiome signatures associated with sustained physical and psychological stress, with potential implications for performance, recovery, and health.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03582020.
Full birth histories that enable analysis of mothers' ages at birth and birth intervals by parity are rare in historical data. Partial birth histories can be obtained from retrospective fertility surveys and census data that record the numbers of children ever born, children deceased, and ages of surviving co-resident children. In a 1988 article published in Population Studies, Luther and Cho proposed a method for reconstructing full birth histories by probabilistically imputing the ages of deceased and non-co-resident children, and in a 2020 article in Historical Methods, Hacker extended this method to historical census data from the United States. In this paper I further adapt the reconstruction method using a sample from the 1911 Census of England and Wales and census records linked from 1881 onwards; this reduces the number of missing observations in the partial birth histories. Birth histories based on linked data particularly improve estimates of duration-specific marital fertility for women who married and had children more than 15 years before the survey date.
Fibroblast activation plays a key role in plaque instability and coronary artery disease (CAD) progression. In-stent restenosis (ISR) remains a major complication after percutaneous coronary intervention (PCI), increasing the risk of major adverse cardiovascular events (MACEs). This study primarily aimed to investigate whether coronary [¹⁸F]AlF-NOTA-FAPI-04 uptake is associated with major adverse cardiovascular events (MACEs) in symptomatic post-PCI patients, and secondarily to explore its ability to differentiate ISR from in-stent non-restenosis (ISnR) and to evaluate longitudinal changes under lipid-lowering therapy. In this prospective single-centre observational cohort study, we enrolled symptomatic CAD patients with a history of PCI A total of 76 symptomatic CAD patients (30 with acute coronary syndrome [ACS] and 46 with stable coronary syndrome [SCS]) underwent FAPI PET/CT imaging. Twenty-two non-CVD individuals served as controls. Coronary SUVmax and TBR were measured. The primary endpoint was the occurrence of MACEs, while the secondary endpoint was changes in FAPI uptake on follow-up PET/CT. The effects of Lipid-lowering therapy(LLT) on coronary FAPI uptake were also evaluated. FAPI uptake was significantly higher in ACS (SUVmax: 4.06 ± 1.81, TBR: 4.51 ± 2.20) than in SCS (SUVmax: 2.47 ± 1.82, TBR: 2.89 ± 2.23, P < 0.05). ISR plaques exhibited markedly elevated FAPI uptake (SUVmax: 4.06 ± 1.91, TBR: 4.69 ± 2.25) compared to ISnR plaques (SUVmax: 1.69 ± 0.72, TBR: 1.88 ± 0.91, P < 0.0001). Exploratory analyses suggested a trend toward higher MACE risk with elevated uptake, but survival differences were not significant. FAPI PET/CT enables non-invasive assessment of fibroblast-driven plaque activity, particularly in ISR, and identifies high-risk coronary plaques linked to MACEs. While LLT did not significantly modify fibroblast activity in the short term, further studies are needed to explore its long-term effects on plaque stability. (FAPI-PLAQUE Study, NCT06280287).
Increasing evidence from preclinical models has linked the actions of brown adipose tissue (BAT) with protection against atherosclerosis and cardiovascular disease, in part due to its salutary effects on systemic lipid composition. However, human data on the role of BAT in atherosclerosis are scarce. In this cross-sectional study, we examined 65 individuals with obesity and analyzed cold-induced BAT activity and vascular inflammation in the aorta using 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography in combination with systemic lipidomics and proteomics analyses. We identified 21 subjects with cold-induced BAT (BAT positive), whereas 44 individuals had no significant BAT activity (BAT negative) after cold exposure. Both groups had similar age, sex distribution, body mass index, and classical cardiovascular risk profile. However, BAT-positive individuals had significantly less arterial inflammation as evidenced by lower 18F-fluorodeoxyglucose uptake in the ascending aorta and the aortic arch. Notably, BAT volume, SUVmean (mean standardized uptake value), and cold-induced thermogenesis correlated negatively with aortic inflammation, suggesting an atheroprotective role of BAT. Using unbiased lipidomics and proteomics analyses in plasma, we found that anti-inflammatory and potentially antiatherogenic circulating factors, such as cytochrome P450 oxylipin products and the serpin family member SERPINB12 (serpin family B member 12), were increased in BAT positive, whereas proatherogenic and prothrombotic factors, including acute phase protein ORM2 (orosomucoid 2), APOD (apolipoprotein D), FGA (fibrinogen A), and FGB (fibrinogen B), were significantly lower in individuals with active BAT. Likewise, the circulating concentrations of inflammatory markers, such as IL-6 (interleukin-6), were reduced in BAT positive versus BAT negative. Together, these data link human BAT function with protection against arterial inflammation and a potentially antiatherogenic and anti-inflammatory circulating profile. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02381483 and NCT03168009.
Diet is a source of environmental toxicants; however, chemical exposures are not considered in the United States Dietary Guidelines for Americans (DGA). We tested whether higher DGA adherence was associated with gestational chemical exposures. Pregnant participants in the Environmental influences on Child Health Outcomes Cohort completed a food frequency questionnaire or 24-h recall at a median of 21 wk of gestation, which we used to calculate the Healthy Eating Index (HEI)-2015 total and individual component scores to assess DGA adherence. In spot urine samples collected at a median of 22 wk of gestation, we measured 113 analytes representing 10 chemical classes, including insecticides, fungicides/herbicides, organophosphate esters (OPEs), halogenated phenols, benzophenones, bisphenols, parabens, antimicrobials, phthalates/alternatives, and polycyclic aromatic hydrocarbons (PAHs). Using Bayesian generalized linear mixed-effects regression, we estimated covariate-adjusted percentage differences (β; biomarkers with ≥70% detection) or detection risk ratios (biomarkers with 30%-69% detection) and 95% credible intervals (CrIs) in urinary chemical biomarker concentrations for each 10-point increase in HEI-2015 total score. We used quantile-based g-computation to identify the top HEI-2015 component contributors to associations. Most participants (n = 1492) self-identified as non-Hispanic White (40%) or Black (36%), and 50% had incomes ≥$50,000. The median (25th, 75th percentile) HEI-2015 score was 61.9 points (53.6, 70.2; of 100). We detected 53 analytes, representing 45 chemical biomarkers, in >30% of participants. Higher HEI-2015 scores were associated with lower OPE, halogenated phenol, bisphenol, phthalate, and PAH biomarker concentrations, most notably monobenzyl phthalate (β: -13.5%; 95% CrI: -21.0%, -5.8%). However, higher HEI-2015 scores were also associated with higher insecticide, paraben, and benzophenone biomarker concentrations, most notably benzophenone-3 (β: 16.2%; 95% CrI: 5.9%, 26.8%). Lower added sugar and higher protein, vegetable, fruit, and whole-grain intake were consistent predictors of lower or higher chemical biomarker concentrations. Greater DGA adherence may minimize exposure to some, but not all, toxicants.
To determine histopathologic outcomes one year after LEEP for CIN2/CIN3 in women living with HIV on ART in Botswana and assess whether a 12-month follow-up interval is appropriate. This was a prospective cohort study of women living with HIV who previously underwent LEEP for confirmed CIN2/CIN3. Participants underwent follow-up approximately 12 months later, either through Ministry of Health or a standardized sub-study protocol, with colposcopy or VIA and tissue sampling performed per clinical algorithm. The primary outcome was histopathologically confirmed CIN2+ at follow-up. Associations between clinical factors, demographics, and CIN2+ were evaluated; chi-square and two-sample T-test were used to compare data and risk ratios (RR) were calculated. Of 127 eligible participants, 90 attended follow-up at a median of 16 months (IQR 13 - 20). Almost all were on ART with a mean CD4 count of 728 (SD ± 310) cells/mm3. Of 66 participants with histopathology results, 29% had CIN2+ and one participant had invasive cancer. Positive endocervical margins at baseline were associated with increased risk of CIN2+, while age, time on ART, and CD4 count were not. Follow-up interval of ≥24 months was associated with more than double the risk of CIN2+ at follow-up (crude RR 2.3, 95% CI 1.1-4.7). In a cohort of women living with HIV on ART, 29% had persistent/recurrent CIN2+ at follow-up. Follow-up interval and endocervical margin status were the strongest predictors. These data support the WHO recommendation for a 12-month follow-up interval in women living with HIV who are well-controlled on ART.
Langerhans cell histiocytosis (LCH) is a rare clonal histiocytic neoplasm that is uncommon in adults and may be diagnostically challenging because of its heterogeneous clinical presentation. We report a case of a 55-year-old male who presented with persistent right ankle pain and multifocal lytic lesions involving the distal tibia, fibula, talus, calcaneus, and cuboid. His medical history was notable for a pituitary lesion with central diabetes insipidus diagnosed two years earlier. Open biopsy of the tibia demonstrated a mixed infiltrate containing characteristic Langerhans cells with grooved nuclei and numerous eosinophils. Immunohistochemistry showed strong positivity for CD1a, S100, and langerin (CD207), confirming LCH. Staging studies revealed pituitary involvement and mild radiologic splenomegaly, without evidence of hematopoietic or hepatic risk-organ dysfunction. Retrospective molecular testing on stored tissue was negative for BRAF V600E. The patient was treated with vinblastine and prednisolone, along with desmopressin and somatotropin replacement. Zoledronic acid was added for osseous disease. Over 70 months of follow-up, the patient achieved durable clinical and radiologic disease control, with pain improving from 7/10 to 1/10 and no evidence of relapse at last contact. Treatment-related toxicity was limited to mild peripheral neuropathy. This case highlights an unusual presentation of adult LCH with distal lower-extremity and tarsal bone involvement, as well as hypothalamic-pituitary disease preceding osseous diagnosis by two years. It underscores the importance of considering LCH in adults with unexplained multifocal lytic bone lesions and endocrine dysfunction, and it demonstrates that durable disease control can be achieved with systemic therapy.