There is interest in PrEP uptake amongst young people at high risk of HIV. However, there is a significant decline in PrEP starting from three to six months after PrEP initiation, thus affecting PrEP persistence and continuation due to pausing and stopping of PrEP, with a few restarting it. Understanding why AGYW pause PrEP use and what motivates the few to restart is critical for enhancing PrEP adherence and continuation. We explored pausing of PrEP and restarting it amongst AGYW in an HIV prevention program, in Kampala, Uganda, to inform future HIV health education interventions aimed at strengthening PrEP continuation. Between November 2023 and March 2024, a qualitative study using 17 follow up interviews was carried out in Kampala, Uganda at month six of PrEP initiation. Participants were purposively sampled from AGYW aged 14 to 24-years-old who were HIV-negative and at high risk of acquiring HIV. Data were transcribed verbatim, coded in Nvivo 14, analyzed thematically using iterative categorization, and interpreted using the Health Belief Model. PrEP side effects were the major reason for missing and eventually pausing. Mobility of AGYW led to pausing PrEP, as some reported forgetting to travel with their pills or travelling with inadequate pills, and lack of access to PrEP in new locations. Anxiety about using PrEP during pregnancy and having other new health conditions requiring long-term oral medication led to pausing of PrEP. However, when they pause, they mitigate the risk by using other HIV prevention methods such as condoms. The major reasons for PrEP restart were high HIV risk awareness, including having multiple sexual partners of unknown status. Inconsistent condom use, due to men refusing or removing condoms and higher pay for condomless sex during sex work, motivated restarting PrEP. Lastly, future marriage prospects and getting into long-term relationships motivated AGYW to remain HIV-negative through PrEP use. Some AGYW who pause PrEP intend to restart in the future and, during the period of pausing PrEP, they mitigate HIV risk by using other HIV prevention methods. Therefore, tailored comprehensive HIV-prevention messages should be implemented to normalize challenges in the PrEP journey, emphasizing the importance of restarting PrEP and of using other HIV prevention methods during the pause period to enhance HIV prevention persistence and continuation.
Novel regimens aimed at achieving functional cure of chronic hepatitis B (CHB) in virologically suppressed participants require the withdrawal of nucleos(t)ide analogue (NA). However, data from clinical trials are limited. Piranga is a Phase 2 platform trial that evaluated 4 xalnesiran regimens with or without an immunomodulator in virologically suppressed participants with CHB. All participants continued the established NA therapy until NA stopping criteria were met at the end of treatment or during follow-up. Participants who stopped NA were monitored and restarted NA if restarting criteria were met. This post hoc evaluation reports the NA discontinuation events and outcomes. Among 121 participants, 58 (48%) met NA stopping criteria and 40 (33%) discontinued NA. Of these 40, 17 (43%) met NA restarting criteria, 16 (40%) restarted NA, and 24 (60%) remained off NA by the end of the study (EOS). Among participants who remained off NA, 5 achieved and maintained HBsAg loss (HBsAg <0.05 IU/mL) and HBV DNA undetectable (HBV DNA <10 IU/mL); all were in treatment arms with an immunomodulator. Of the 40 participants who discontinued NA, 19 (48%) experienced virological relapse (VR), 3 (8%) of whom further developed clinical relapse (CR). The majority of participants restarted NA following VR. VR and CR events were associated with preserved liver function and resolved without sequelae. NA discontinuation after xalnesiran-based therapy was safely managed with the application of prespecified NA stopping and restarting criteria and close monitoring. Five participants achieved and maintained HBsAg loss and undetectable HBV DNA while off NA until EOS. NCT04225715.
Despite advances in biological therapies, a subset of patients with Crohn's disease (CD) remains or becomes refractory to all available treatments. Emerging evidence indicates that autologous hematopoietic stem cell transplantation (aHSCT) may offer a viable therapeutic option for carefully selected treatment-refractory CD patients. We retrospectively analyzed the outcomes of all CD patients who underwent aHSCT for treatment-refractory disease at our IBD referral center between 2011 and 2023. All included patients had severe disease, unsuitable for surgery. We included 24 CD patients (15 females, median age at transplantation 31.0 [27.0-34.5] years, median disease duration 13.0 [9.8-17.3] years) who underwent mobilization, of whom 23 patients proceeded to transplantation. All patients had CD with small bowel involvement, while 10 patients (41.7%) had concomitant perianal disease. After a median follow-up of 114.6 [66.0-138.4] months, 8 patients (34.8%) were still in remission without need for advanced therapy. Persistent disease activity after aHSCT, defined as total SES-CD >3, occurred in 15 patients (65.2%) with median time to restarting advanced therapy of 7.0 [5.0-25.0] months. At last follow-up, all patients are still alive. There were a few ICU admissions because of hemodynamic instability due to neutropenic fever following mobilization and transplantation. In the follow-up period, infectious complications occurred in 12 patients (52.2%). Autologous hematopoietic stem cell transplantation is a safe and effective therapy for inducing and maintaining remission in carefully selected therapy-refractory CD patients after extensive multidisciplinary discussion. Although many patients didn't achieve remission, most regained response to previously ineffective therapies.
Landmark analysis establishes a fixed "landmark" time, including only individuals who remain event-free up to that point and classifying survivors according to their treatment status at the landmark. By restarting follow-up from this time, the method aims to create comparable groups presumed free from immortal time bias. Despite its simplicity and widespread use, landmark analysis has notable limitations. Under potential outcomes and piecewise proportional hazards, we derived closed-form results for naive, exclusion, and landmark analyses and evaluated them via simulations. We found that landmark estimates fail to recover the target causal effect because the reference group mixes "never-treated" and "late-treated" subjects. This mixture attenuates the effect size, generally biasing estimates toward the null, with the magnitude of bias depending on the true effect, treatment rate, and event rate, except under the null hypothesis. In addition, landmark analysis suffers a substantial loss of statistical power due to the exclusion of early events and the attenuation of effect estimates. Indeed, the attenuation alone can make landmark analysis perform considerably worse in power than a randomized trial with equal group sizes. Without clinical context, a small treatment effect observed in a landmark analysis may reflect bias rather than a true null effect. Therefore, caution is warranted when using landmark analysis to address immortal time bias, and time-dependent regression models provide a more robust alternative.
Rett syndrome (RTT) is a rare, X-linked neurodevelopmental disorder that primarily affects females. Trofinetide (TROF) was approved for RTT in individuals aged ≥2 years. Although the DAFFODIL trial examined TROF efficacy in children aged 2-4 years, real-world evidence in this age group remains limited. A retrospective cohort study was conducted using linked medical and pharmacy claims from 01/01/2021-09/30/2024 (study period). Individuals aged 2-4 years with RTT who initiated TROF during 04/01/2023-03/31/2024 (identification period) were included (index date=first TROF RX). Outcomes included baseline characteristics, prescriber specialty, TROF persistence (≤90-day allowable gap), dosing patterns based on shipped/dispensed RXs (BID, mg; % target daily dose [%TDD]), time on treatment, and restarts among non-persistent individuals. Variables were summarized descriptively. Kaplan-Meier analyses assessed the time to treatment non-persistence. Among 159 individuals, 65.4% were persistent and 34.6% were non-persistent; 14.5% of non-persistent individuals restarted TROF. Mean±SD age was 3.2±0.8 vs 3.3±0.7 years in persistent vs non-persistent groups. Females comprised 95.2% vs 87.3%, respectively. Child neurology was the most common prescriber specialty (54.8% vs 63.6%). Non-persistent individuals had higher rates of dysphagia (34.5% vs 16.3%), gastrostomy (20.0% vs 3.8%), and breathing irregularities (16.4% vs 1.9%). Mean BID dose and %TDD were similar between groups across shipments. Median (IQR) time on treatment was 13.3 (6.1-17.2) months in the persistent group vs 4.4 (0.8-12.6) months in the non-persistent group. Kaplan-Meier analysis showed >87.5% remained on TROF beyond 3 months and >65.0% remained on TROF through end of available follow-up. In routine US practice, approximately two-thirds of children aged 2-4 years initiating TROF remained persistent during available follow-up, with sustained use beyond 1 year and a subset (14.5% of non-persistent children) restarting after discontinuation. Non-persistent children had significantly higher baseline rates of dysphagia, gastrostomy, and breathing irregularities, suggesting that early disease-related multisystem complications may be associated with reduced treatment continuity. These findings complement DAFFODIL and provide early real-world evidence on TROF persistence, restarts, and dosing patterns in this young RTT population. Why was the study done? Rett syndrome is a rare genetic disorder that impacts brain development, primarily in young girls. In March 2023, the drug trofinetide became the first approved treatment for this condition in the United States. While clinical trials showed the drug is safe and effective for young children aged 2 to 4, doctors and families need real-world evidence to see how well children stick with the treatment in everyday life outside of strict trial settings. What did the researchers do and find? We analyzed health insurance and pharmacy data for 159 children aged 2 to 4 with Rett syndrome who started trofinetide between April 2023 and March 2024. We looked at how long they stayed on the medication, their daily dosages, and whether those who stopped eventually restarted. Our study revealed that: Two-thirds of the children (65.4%) successfully stayed on their trofinetide treatment continuously for over a year.Children who stopped taking the medication usually did so around the 4-month mark. However, about 14.5% of those children eventually restarted the drug after a break.Children who stopped the medication had higher rates of other health issues before starting, such as stomach problems and seizures, compared to those who stayed on it. What do these results mean? Real-world data shows most young children with Rett syndrome stay on trofinetide long-term. Since those with more pre-existing health issues often stop treatment, doctors can use this information to closely support high-risk patients.
This study aimed to evaluate the impact of summer drug holidays on metacognitive and theory of mind (ToM) skills in children with Attention-Deficit/Hyperactivity Disorder (ADHD) treated with methylphenidate (MPH). A naturalistic, prospective study was conducted at a child psychiatry outpatient clinic. Fifty-six treatment-naïve children or those restarting treatment after >6 months (aged 9-17, 76.8% male) with ADHD were enrolled. Participants were assessed at baseline, after two months of MPH treatment, and after a two-month summer drug holiday. Assessments included the Clinical Global Impressions-Severity (CGI-S) scale, the DSM-IV-Based Screening Scale for Disruptive Behavior Disorders (D-S-DBD), the Faux-Pas Test (FPT), the Test of Perception of Affect via Nonverbal Cues (TPANC), and the Metacognition Questionnaire for Children (MCQ-C). Attrition was high; only 12 children (21.4% of original sample) completed the full protocol. Analyses were conducted for both completers and the full sample using the Last Observation Carried Forward (LOCF) method. MPH treatment significantly improved CGI-S, parent-rated hyperactive/impulsive and oppositional symptoms, and performance on FPT and affect perception tasks (all p<0.05). In the completer sample, the gains in ToM and affect perception were not significantly reversed after the two-month drug holiday. However, this finding is preliminary due to substantial attrition and limited statistical power. MCQ-C did not show significant change at any time point. Sensitivity analyses revealed that children lost to follow-up had higher baseline symptom and metacognitive problem scores, indicating potential selection bias. Methylphenidate treatment was associated with significant improvements in ADHD symptoms, ToM, and affect perception. The results highlight the need for larger, multi-center studies to reliably assess the impact of drug holidays on higher-order cognitive and social skills in ADHD.
Homologous recombination deficiency (HRD) has transformed the therapeutic landscape of breast cancer through the clinical success of poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. Central to this vulnerability is radiation sensitivity 51 (RAD51), the recombinase that executes homologous DNA repair and stabilizes stalled replication forks. In breast cancer susceptibility type 1 (BRCA1)- and breast cancer susceptibility type 2 (BRCA2)-mutant tumors, impaired RAD51 loading produces profound sensitivity to DNA-damaging agents. However, accumulating evidence indicates that restoration of RAD51 function-particularly its role in replication fork protection-is an important mechanism underlying therapeutic resistance. Beyond its canonical role in strand exchange-mediated double-strand break (DSB) repair, RAD51 orchestrates replication fork reversal, stabilization, and restart under conditions of oncogene-driven replication stress. These fork-associated functions can be mechanistically separable from classical homologous recombination and may be sufficient to confer resistance to PARP inhibitors even in tumors with persistent genomic scar signatures. Thus, breast cancer evolution under therapeutic pressure can be conceptualized as a transition from RAD51 deficiency-driven vulnerability to RAD51-dependent adaptive survival. In this review, we integrate structural, mechanistic, and translational insights into RAD51 biology and propose a dynamic framework in which replication fork protection represents a central adaptive axis in resistant breast cancer. We discuss functional biomarkers of RAD51 activity, subtype-specific dependency patterns, and emerging strategies to therapeutically target RAD51 in PARP inhibitor-refractory and replication stress-high disease. Understanding when RAD51 is deficient and when it becomes indispensable will be critical for refining precision oncology approaches in breast cancer. We argue that future precision oncology strategies must move beyond static HRD classification toward dynamic assessment of RAD51-dependent replication stress tolerance.
Out-of-hospital cardiac arrest (OHCA) incidence rate exhibits considerable geographical variations. In Lombardy, the presence of densely populated areas alongside isolated rural municipalities makes analysing health inequalities important. Given their spatial heterogeneity, an explicitly spatial analytical approach is needed. A retrospective ecological study was conducted at the municipal level using data from the Lombardia CARe registry (2021-2024). The incidence of OHCA was calculated for 924 municipalities. Socio-demographic determinants (population density, ageing index and percentage of taxpayers with an annual income below EUR 10,000) were analysed using geographically weighted regression (GWR). Spatial analyses (Moran's I, LISA and Getis-Ord Gi*) were also applied to identify clusters and hotspots. During the study period, 22,201 OHCA events occurred (incidence rate: 126 per 100,000 inhabitants). Marked spatial heterogeneity emerged, with hotspots primarily located in mountainous and hilly areas, and cold-spots predominantly found in urban and lowland zones. GWR identified spatially non-uniform associations: incidence was inversely associated with population density in some areas, whereas it was positively associated with the ageing index and proportion of low-income taxpayers in others. The incidence of OHCA in Lombardy exhibits important spatial disparities. A spatial analytical approach can effectively identify vulnerable areas, guiding public health policies towards equity and spatial justice.
Intrauterine pregnancy occurring with a correctly positioned levonorgestrel-releasing intrauterine system (LNG-IUS) is extremely rare. Most pregnancies associated with LNG-IUS use result from device malposition, unnoticed expulsion, or insertion during an undiagnosed early pregnancy. Pregnancy with an intrauterine device in situ is associated with an increased risk of miscarriage, preterm delivery, and intra-amniotic infection. We report the case of a 39-year-old gravida 4 para 2 abortus 1 woman with a correctly positioned 52-mg LNG-IUS who presented at 12 weeks' gestation with leakage of amniotic fluid. One week earlier, an ultrasound had confirmed a viable intrauterine pregnancy with correct device positioning in the uterine fundus. Because the IUS strings were not visible on examination, no immediate removal was attempted. The patient wished to continue the pregnancy. During hospitalization, intrauterine fetal demise occurred, followed by pharmacological induction of miscarriage and uterine curettage with device removal. This case highlights the clinical challenges of pregnancy with an LNG-IUS in situ and emphasizes that the lack of visible strings should not preclude consideration of removal. Current evidence suggests that hysteroscopic removal in early pregnancy may reduce adverse outcomes and should be considered in patients wishing to continue pregnancy.
To assess the effect of different types of contemporary hormonal contraceptives on the risk of developing colorectal cancer in women of reproductive age. Nationwide cohort study. Denmark based on national registers. The study included women aged 15-49 years living in Denmark between 1995 and 2021, who had at least five years of residence and no history of cancer, hysterectomy, oophorectomy, or sterilisation. Adjusted incidence rate ratios with 95% confidence intervals (CIs) for a first time diagnosis of colorectal cancer by type and duration of hormonal contraceptive use. Among 1 956 948 women followed for a median of 12.5 years (24.5 million person years in total), 1878 colorectal cancers were detected. Compared to never users, the incidence rate ratio of colorectal cancer among all current and recent users was 0.94 (95% CI 0.83 to 1.06). The incidence rate ratio with less than five years of use was 0.97 (0.85 to 1.11) and 0.86 with more than 10 years of use (0.62 to 1.18). The incidence rate ratio in previous users was similar to never users, however, with some indication for a decreased incidence rate ratio 10 or more years after cessation (0.81, 95% CI 0.66 to 0.99). No consistent differences in risk between newer and older combined oral contraceptives were observed. The most used progestogen-only pills gave an incidence rate ratio of 1.09 (0.74 to 1.61) and the most used progestogen-only non-oral product, the levonorgestrel releasing intrauterine device, gave an incidence rate ratio of 0.96 (0.81 to 1.15). The risk of colorectal cancer was not substantially affected by current or recent use of contemporary hormonal contraception, suggesting that modern products neither protect against nor contribute to the rising incidence in young women. Although some subgroup estimates were imprecise, no support was found for an association between hormonal contraceptive use and colorectal cancer.
Colchicine-resistant familial Mediterranean fever (cr-FMF) represents a therapeutic challenge, and anakinra, a recombinant interleukin-1 receptor antagonist, is widely used in clinical practice. Our aim was to describe real-world practices of pediatric rheumatologists regarding anakinra use in patients with cr-FMF, with a focus on treatment initiation, tapering strategies, and discontinuation approaches. This survey-based study included pediatric rheumatologists with at least one year of clinical experience in managing cr-FMF. The survey assessed physician characteristics, treatment practices including initiation, tapering, and discontinuation strategies. Data were collected via an online survey platform between September and November 2025. A total of 81 pediatric rheumatologists participated, mostly practicing in Türkiye (92.6%). Most respondents preferred once-daily anakinra at 1-2 mg/kg/day and assessed response within the first month. Among tapering strategies, 90.1% favored interval extension, most commonly every 3 days or weekly. 79.0% considered discontinuation after sustained remission (median 6 months). During tapering-related flares, clinicians preferred interval shortening (43.2%) or dose escalation (37.0%), while 19.8% switched to an alternative biologic. After discontinuation-related relapse, 81.5% restarted anakinra at the previous effective dose. While anakinra initiation and relapse management appear relatively consistent, tapering and discontinuation strategies remain highly variable, underscoring the need for evidence-based guidance.
Iatrogenic transmission of amyloid beta can cause cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD), but the relationship between these phenotypes is unclear. We retrospectively analyzed standardized neuropsychological and neuroimaging data from 11 patients with iatrogenic CAA (iCAA). Brain MRI was assessed for medial temporal lobe atrophy (MTA), the posterior atrophy score for parietal atrophy, and global cortical atrophy (GCA). All patients (mean age 42 ± 8.3 years) had childhood neurosurgery; 91% had confirmed cadaveric dura exposure. Six patients (55%) presented with intracerebral hemorrhage, and none showed MTA, parietal atrophy, or GCA at presentation. Over a median 5-year follow-up, 8/11 (73%) developed atrophy on at least one score, moderate to severe in three patients. Cognitive impairment was present in 9/11 (82%) at a median 3-year follow-up. AD was confirmed histopathologically in 2/4 (50%) examined cases. Progressive brain atrophy and cognitive impairment are common in iCAA, suggesting frequent co-existing neurodegeneration and possible AD pathology. Vigilance for cognitive decline may enable earlier identification and management.
Inconsistent and variably interpreted definitions of spasticity, alongside evolving mechanistic understanding, highlight the need for a clear, clinically relevant consensus definition. An international expert panel used a modified Delphi process to develop a concise, clinically applicable definition that reflects current understanding and supports consistent assessment and management. Participants reviewed existing definitions, completed a pre‑meeting survey, and engaged in structured discussions, with draft definitions iteratively refined through successive rounds of voting to achieve consensus. Key components identified included disordered sensorimotor control, central nervous system involvement, and velocity‑ and length‑dependent resistance to passive stretch, while existing definitions were considered either overly narrow or insufficiently relevant to clinical practice. The consensus definition characterizes spasticity as "A disorder of sensorimotor control resulting from upper motor neuron disease. It is characterized by velocity- and length-dependent involuntary muscle overactivity, which is intermittent or sustained, during passive stretch." This definition integrates contemporary mechanistic concepts with clinical applicability and is intended to improve conceptual clarity, facilitate communication, and promote consistency in diagnosis, measurement, and treatment.
Device expulsion is a common complication of the levonorgestrel-releasing intrauterine system (LNG-IUS), with a higher incidence among high-risk patients presenting with enlarged uterine cavities, cervical laxity or menorrhagia. At present, no commercially available frameless LNG-IUS is marketed in mainland China, leaving these high-risk patients without effective clinical interventions. This study describes the assembly procedures and clinical application of a modified frameless LNG-IUS based on the GyneFix anchoring system (GyneFix-LNG-IUS), and the intrauterine retention performance is preliminarily assessed alongside its capacity to reduce expulsion risk. This was a retrospective, self-controlled, observational prognostic study. A total of 15 consecutive cases were included. All included cases had a documented history of conventional LNG-IUS expulsion and multiple high-risk factors for expulsion, including enlarged uterine cavities, menorrhagia and cervical laxity. The modified device was assembled using the GyneFix anchoring component and a standard LNG-IUS, and inserted under hysteroscopic guidance. The 12-month device retention rate and its corresponding 95% confidence interval were calculated. All insertions of GyneFix-LNG-IUS were completed successfully in a single attempt, and no intra-operative or post-operative complications were recorded. Gynaecological ultrasound data acquired at 12 months or longer after placement were collected for all cases. Ultrasonographic examinations confirmed that all devices were positioned within the uterine fundus, with no signs of downward displacement or expulsion observed. The 12-month retention rate was 100% (95% CI: 78.2%-100%). Based on the limited data from this small cohort, the modified GyneFix-LNG-IUS features simple assembly and smooth intrauterine insertion. Preliminary findings indicate that this device may reduce expulsion risk among patients prone to conventional LNG-IUS loss. It may serve as a viable clinical alternative in settings without access to commercial frameless LNG-IUS.
Endometrial hyperplasia (EH) is an estrogen-driven proliferative disorder with a measurable risk of progression to endometrial carcinoma. Although many guidelines have been issued over the years, clinical practice remains heterogeneous. In this paper, we aim to compare and summarize key recommendations and disagreements among major international guidelines for managing endometrial hyperplasia, focusing especially on conservative and fertility-sparing strategies. All guidelines align with some key principles: they all adopt the 2020 WHO classification, strongly prefer hysteroscopy-directed sampling, and recommend progestin therapy as the first-line treatment for non-atypical EH, favoring the levonorgestrel-releasing intrauterine system (LNG-IUS) over oral regimens. They designate total hysterectomy as definitive management for atypical hyperplasia/intraepithelial endometrial neoplasia (AEH/EIN) due to the substantial prevalence of concurrent carcinoma. Nevertheless, several key discrepancies appear, mainly concerning how long to continue progestin therapy and when to escalate treatment; and how intensively and for how long to conduct post-treatment surveillance. Variations in diagnostic and therapeutic protocols reflect evidence gaps and differences across healthcare settings. Future research should focus on harmonized outcomes, comparative studies of conservative strategies, and the integration of new pathology tools for personalized management.
Meningioma is a known adverse reaction of high-dose progestogens, but evidence regarding the risk associated with progestogens used as contraception is limited. To examine whether different progestogens used as hormonal contraception are associated with increased risk of meningiomas. This nested case-control study conducted over a 25-year study period from January 1, 2000, to December 31, 2024, is a Danish nationwide population-based register study, which included 3 million females aged 15 to 59 years with residence in Denmark. Meningioma cases were dentified, and for each case, 10 controls were matched on age, birthplace, and marital status and randomly selected from the cohort if considered eligible on the day of the case's meningioma diagnosis. Data were analyzed from July 10, 2025, to May 12, 2026. Use of progestogens was identified in the registers by date of dispensing or procedural records and grouped by route of administration and active substance. Exposure time was determined by redeemed daily doses or product duration. If a female switched to a different product or became pregnant, her exposure time was changed to the new exposure. The females included were allocated to their most recent use, defined as the exposure closest to the matching date. The main outcome was incident meningioma and was identified in the Danish National Cancer Register using validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses and International Classification of Diseases for Oncology, Third Edition codes. A total of 1473 cases and 14 717 controls with a median age of 48 years (IQR, 42-53 years) were included in the nested cohort. For combined oral contraceptives, the estimated odds ratios (ORs) for the association between use of progestogens and meningioma were 1.61 (95% CI, 1.00-2.59) with cyproterone, 1.66 (95% CI, 1.31-2.10) with desogestrel, 1.58 (95% CI, 1.05-2.37) with drospirenone, 1.44 (95% CI, 1.17-1.77) with gestodene, 1.40 (95% CI, 1.12-1.76) with levonorgestrel, 1.38 (95% CI, 0.77-2.47) with norethisterone, and 1.04 (95% CI, 0.70-1.54) with norgestimate. For oral progestogen-only contraceptives, the ORs were 1.73 (95% CI, 1.17-2.56) with desogestrel and 0.95 (95% CI, 0.57-1.57) with norethisterone. For injectable medroxyprogesterone, the OR was 4.55 (95% CI, 2.19-9.45). For intrauterine devices (IUDs) with high-dose levonorgestrel, the OR was 1.58 (95% CI, 1.28-1.94), and for IUDs with low-dose levonorgestrel, the OR was 1.14 (95% CI, 0.59-2.22). Exposure within the past year was associated with the highest risk. In this case-control study conducted using data from the entire Danish population, recent use of the contraceptive progestogens cyproterone, desogestrel, drospirenone, gestodene, levonorgestrel, injectable medroxyprogesterone, and high-dose IUD was associated with increased risk of meningioma. These findings are considered relevant information for the treated women and the prescribing physicians.
Immunotherapy with checkpoint inhibitor (ICI) has revolutionized the treatment of cancer including squamous cell carcinoma. Nevertheless, there is an unmet need to gain a better understanding of the effect of these therapies on pregnancy and fertility. Treatment with anti-PD-1 therapy decreases fetal-maternal tolerance and increases the risk of pregnancy loss in animal studies. However, few data are currently available in humans. We report the case of conception and pregnancy, with successful maternal and fetal outcomes, in a young woman with metastatic squamous cell carcinoma originated from the palatin tonsil. She was 17-year-old at the diagnosis. After surgical removal of the primary tumor, she received adjuvant radiotherapy. Four years later she underwent surgery for a lung relapse and adjuvant chemotherapy. Three years later the patient experienced a pulmonary and mediastinal relapse. Immunotherapy with nivolumab was promptly started with a slow reduction of the disease until a near radiological complete response with a unique residual lung subpleural nodulation. Surgical romoval confirmed the residual disease of squamous cell carcinoma. Patient re-started immunotherapy with nivolumab but after 2 months, she was found to be 4 weeks pregnant. Treatment was stopped and, since the patient expressed her desire to carry her pregnancy to term, she was referred to gynecological and psychological support. She had an uneventful pregnancy, followed by spontaneous vaginal delivery. The baby was healthy and exhibited normal development. Furthermore, the patient breastfed until the sixth month without any adverse effects on the child growth. In November 2025, after 32 months of disease-free survival, the patient developed a new lung recurrence, presenting as a single 4-cm diameter lesion in the right lower lobe. In January 2026, she underwent surgical resection of the lesion and histology was consistent with the diagnosis of metastatic disease. Currently, in the absence of detectable disease, the patient continues active follow-up. Our case provides evidence that pregnancy and normal fetal development may occur after early exposure to nivolumab, Nevertheless, the impact of treatment interruption and pregnancy on disease recurrence remains an unresolved question.
Metagenomic Hi-C provides in situ proximity signals that can improve genome binning and enable virus-host-association analysis. However, viral genome recovery remains difficult because virus-virus Hi-C contact matrices are extremely sparse. Viral genomes are small, often low-abundance, and frequently assemble into short contigs, leaving many true within-genome links unobserved and causing viral bins to fragment. We present VirBinn, a graph-diffusion framework for viral binning from metagenomic Hi-C. VirBinn enhances virus-virus connectivity through two complementary mechanisms: random-walk-with-restart enhancement on the sparse virus-virus contact graph and host-guided diffusion that propagates viral seeds through the host network to infer indirect virus-virus associations. The enhanced views are integrated and clustered using Leiden community detection to produce viral metagenome-assembled genomes (vMAGs). On dataset-specific simulation benchmarks with ground truth, VirBinn consistently recovers more high-quality vMAGs than Hi-C-based and shotgun-based baselines and substantially increases the number of near-complete genomes. On four real metagenomic Hi-C datasets spanning human gut, pig gut, sheep gut (long-read assembly), and wastewater, VirBinn yields more high-completeness vMAGs under CheckV and produces bins with strong within-cluster contact support. Finally, host linkage analysis using reconstructed host MAGs reveals habitat-specific host-association patterns and plausible host taxonomic profiles. VirBinn is available at https://github.com/dyxstat/VirBinn. The scripts to reproduce the results and figures in this article are available at https://github.com/dyxstat/Reproduce_VirBinn.
Recurrent cancers are not captured in a standardized way by US tumor registries, making it difficult to conduct research on risk factors for cancer recurrence. We developed rule-based algorithms to be used with electronic health data to identify recurrent cases of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Incident DLBCL and FL cases (2000-2018) were identified in tumor registry data at two health plan study sites. We captured pharmacy and procedure codes to indicate first-line treatment initiation. Recurrent cases were defined as those who completed first-line treatment followed by ≥6 months with no treatment-related codes, but who later restarted treatment. The baseline algorithm was built using a claims-based database from Fallon Health (FH; Massachusetts) and tested using electronic health records and claims data at Henry Ford Health (Michigan). Results were validated by chart review at Henry Ford, and measures of validity calculated overall and by subtype. The algorithm was subsequently revised to reduce the false-positive rate. FH identified 137 DLBCL and 88 FL eligible cases; 42 patients met the baseline algorithm-defined criteria for recurrent disease. Henry Ford identified 246 DLBCL and 146 FL cases. The baseline algorithm identified 115 recurrent cases with a 54% false-positive rate; the revised algorithm (R2D-non-Hodgkin lymphoma [NHL]) identified 60 recurrent cases, with a 10% false-positive rate. Following chart review, the R2D-NHL algorithm had a sensitivity of 74%, specificity of 90%, negative predictive value of 83%, and positive predictive value of 83%. Measures varied slightly between subtypes. We developed a rule-based algorithm that can be applied to electronic health data for population-based research requiring the identification of recurrence for two common but dissimilar NHL subtypes.