Search Results (28)

Hereditary cancer syndromes (HCSs), including BRCA 1/2-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS), confer substantial lifetime cancer risks, yet adherence to recommended risk-management strategies remains variable. This population-based retrospective cohort study examined cancer prevention practices, outcomes, and predictors of cancer occurrence among 476 BRCA and LS carriers identified through the Provincial Medical Genetics Program in Newfoundland and Labrador, Canada (2001–2022). Linked genetic, surgical, screening, and cancer registry data were evaluated, with adherence assessed during two intervals (2018–2020 and 2020–2022) based on NCCN guidelines. Participants were predominantly female (69%), with a mean age of 48.5 years at genetic testing; nearly 70% of primary cancers were already diagnosed at the time of testing. BRCA carriers demonstrated higher uptake of breast MRI (58–61%) and risk-reducing salpingo-oophorectomy (63–66%) compared with LS carriers’ colonoscopy uptake (42–44%). In univariate analyses, non-adherence during 2018–2020 was associated with increased odds of cancer after testing (OR ≈ 4.43, p < 0.001); this remained significant in the multivariate model (OR = 8.70; p = 0.0004). Individuals who did not follow recommended risk-management guidelines had nearly nine times greater odds of developing cancer after genetic testing than those who fully adhered to guidelines. Older age at referral (OR = 1.07/year, p < 0.001) also increased the odds of developing cancer. Study findings indicate that late referral and pre-existing cancers diminish the preventive impact of guideline-based risk management. System-level initiatives to promote earlier genetic testing, enhance cascade outreach, and strengthen surveillance pathways are needed to optimize cancer prevention and earlier cancer detection in high-risk populations. Full article

The Democratic Republic of the Congo faces a high tuberculosis (TB) burden. In 2022, 61% of an estimated 402,000 TB cases were reported (World Health Organization Global tuberculosis report). To enhance case detection, the national TB program (NTP) introduced a program quality and efficiency approach (PQE), integrating systematic TB screening into outpatient departments (OPDs). Observational data of the PQE on the TB care cascade (from screening to treatment) across 70 sites in Kinshasa that initiated PQE during the first quarter of 2023 are presented. Data were collected monthly and validated during supervision visits, and disaggregated by sex, healthcare facility type (public, private, or faith-based), facility level (primary or secondary), and OPD within each facility. In 2024, 639,464 individuals were consulted in various OPDs in the participating facilities, 57% of which were female. The median number needed to screen (NNS) was 22.1, with an interquartile range of [9.5–104.3]. There was a significantly lower NNS observed in general practice and human immunodeficiency virus departments. Throughout the TB care cascade, women were less likely than men to be screened, tested, or treated. These findings, to be interpreted within the context of Kinshasa pilot facilities, provide insights to the NTP for developing PQE implementation research aimed at understanding the reasons for these discrepancies and informing NTP scale-up at the national level. Full article

Context: Code recommendation plays an important role in improving programming efficiency and software quality. Existing approaches mainly focus on method- or API-level recommendations, which limits their effectiveness to local code contexts. From a multi-stage recommendation perspective, class-level code recommendation aims to efficiently narrow a large candidate code space while preserving essential structural information. Objective: This paper proposes RioCC, a class-level code recommendation framework that leverages deep forest-based code clone detection to progressively reduce the candidate space and improve recommendation efficiency in large-scale code spaces. Method: RioCC models the recommendation process as a coarse-to-fine candidate reduction procedure. In the coarse-grained stage, a quick search-based filtering module performs rapid candidate screening and initial similarity estimation, effectively pruning irrelevant candidates and narrowing the search space. In the fine-grained stage, a deep forest-based analysis with cascade learning and multi-grained scanning captures context- and structure-aware representations of class-level code fragments, enabling accurate similarity assessment and recommendation. This two-stage design explicitly separates coarse candidate filtering from detailed semantic matching to balance efficiency and accuracy. Results: Experiments on a large-scale dataset containing 192,000 clone pairs from BigCloneBench and a collected code pool show that RioCC consistently outperforms state-of-the-art methods, including CCLearner, Oreo, and RSharer, across four types of code clones, while significantly accelerating the recommendation process with comparable detection accuracy. Conclusions: By explicitly formulating class-level code recommendation as a staged retrieval and refinement problem, RioCC provides an efficient and scalable solution for large-scale code recommendation and demonstrates the practical value of integrating lightweight filtering with deep forest-based learning. Full article

Background: Despite the implementation of numerous evidence-based interventions, the 2024 Point-in-Time count in the United States (U.S.) reported that 259,473 people in families with children under 18 years old were experiencing homelessness, a record high since the count began in 2007. Recent findings suggest that co-developed interventions may increase engagement with vulnerable populations and, in turn, the effectiveness of health-based programs among them. Objective: In this review, we sought to systematically search and assess the current evidence on co-developed community-based interventions with and for children under age 18 and families experiencing homelessness (CFEH) in high-income countries and their impact on health and well-being outcomes. Methods: Seven databases (e.g., Medline, CINAHL, Embase) and four additional scholarly sources (e.g., Health CASCADE) were searched (publication dates between January 2000 and February 2025). In our analysis, methodological “quality” was assessed through two primary criteria: internal validity and the extent of CFEH involvement. Results: A total of 1617 studies were screened for eligibility, and nine studies were found to have co-developed interventions with CFEH in the U.S. (n = 6) and the United Kingdom (n = 3). These were categorized thematically by socio-structural, behavioral, and combined intervention types. Five studies reported positive engagement among families and staff, whereas three reported improved mental health outcomes. Conclusions: This review highlights the potential impact of co-developed interventions on CFEH’s mental and physical well-being as well as process-based outcomes. Limitations include different definitions of “co-” terminology and homelessness across studies, as well as a lack of transparency about the extent of CFEH’s involvement in these studies. The dearth of evidence indicates that future research should employ community-based participatory research while striking a balance of working with CFEH and other partners and ensuring the data are reliable and reproducible. Full article

Background/Objectives: Postoperative cognitive dysfunction (POCD) represents a significant and potentially preventable complication in elderly patients undergoing colorectal cancer surgery, with reported incidence ranging from 2.8% to 62.2% depending on perioperative management strategies and assessment methods. This narrative review synthesizes current evidence on the epidemiology, pathophysiology, risk factors, and prevention strategies for POCD in this vulnerable population. Methods: A comprehensive narrative review was conducted to examine the current literature on POCD in elderly colorectal cancer patients. Evidence was synthesized from published studies addressing epidemiology, assessment tools, risk factors, pathophysiological mechanisms, and prevention strategies, with a particular focus on Enhanced Recovery After Surgery (ERAS) protocols and multicomponent interventions. Results: Advanced age, pre-existing cognitive impairment, frailty, and surgical complexity emerge as key risk factors for POCD. ERAS protocols demonstrate substantial protective effects, reducing POCD incidence from 35% under conventional care to as low as 2.8% in optimized pathways. The pathophysiology involves multifactorial mechanisms, including neuroinflammation, blood–brain barrier disruption, neurotransmitter dysregulation, and oxidative stress, with surgical trauma triggering systemic inflammatory cascades that activate microglial responses within the central nervous system. Evidence-based prevention strategies include preoperative cognitive and frailty screening, minimally invasive surgical techniques, multimodal opioid-sparing analgesia, regional anesthesia, depth-of-anesthesia monitoring, and structured postoperative care bundles adapted from the Hospital Elder Life Program. Conclusions: The integration of comprehensive perioperative cognitive care protocols represents a critical priority as surgical volumes in elderly populations continue to expand globally. Emerging directions include biomarker development for early detection and risk stratification, precision medicine approaches targeting individual vulnerability profiles, and novel therapeutic interventions addressing neuroinflammatory pathways. Standardized assessment tools, multidisciplinary collaboration, and implementation of evidence-based preventive interventions offer substantial promise for preserving cognitive function and improving long-term quality of life in elderly colorectal cancer patients. Full article

Substance use during pregnancy is an increasingly important yet under-recognized threat to maternal and child health. This narrative review synthesizes the current evidence available on the epidemiology, pathophysiology, clinical management, and policy landscape of prenatal exposure to alcohol, tobacco, opioids, benzodiazepines, cocaine, cannabis, methamphetamines, and other synthetic drugs. All major psychoactive substances readily cross the placenta and can remain detectable in breast milk, leading to a shared cascade of obstetric complications (hypertensive disorders, placental abruption, pre-term labor), fetal consequences (growth restriction, structural malformations), and neonatal morbidities such as neonatal abstinence syndrome and sudden infant death. Mechanistically, trans-placental diffusion, oxidative stress, inflammatory signaling, and placental vascular dysfunction converge to disrupt critical neuro- and cardiovascular developmental windows. Early identification hinges on the combined use of validated screening questionnaires (4 P’s Plus, CRAFFT, T-ACE, AUDIT-C, TWEAK) and matrix-specific biomarkers (PEth, EtG, FAEE, CDT), while effective treatment requires integrated obstetric, addiction, and mental health services. Medication for opioid use disorders, particularly buprenorphine, alone or with naloxone, confers superior neonatal outcomes compared to methadone and underscores the value of harm-reducing non-punitive care models. Public-health strategies, such as Mexico’s “first 1 000 days” framework, wrap-around clinics, and home-visiting programs, demonstrate the potential of multisectoral interventions, but are hampered by structural inequities and punitive legislation that deter care-seeking. Research gaps persist in polysubstance exposure, culturally tailored therapies, and long-term neurodevelopmental trajectories. Multigenerational, omics-enabled cohorts, and digital longitudinal-care platforms represent promising avenues for closing these gaps and informing truly preventive perinatal health policies. Full article

Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the “new use” of the “old drug” menadione in CRC treatment. Full article

Background: Cervical cancer is a major global health concern, causing approximately 350,000 deaths annually. It is also preventable through effective prevention and early detection. To facilitate elimination, the World Health Organization (WHO) set targets for HPV vaccination, screening, and treatment. Achieving these goals requires frameworks to monitor screening program performance. As many regions transition to HPV primary screening, a standardized Cervical Cancer Screening Cascade can track performance, identify gaps in follow-up, and optimize resource allocation. Methods: This paper introduces a structured cascade developed to monitor uptake, retention, and outcomes in HPV-based screening programs. The Cascade was created through collaboration between public health experts, clinicians, and researchers at the University of British Columbia (UBC), the Women’s Health Research Institute, and BC Cancer. Results: The Cascade outlines four phases: screening, triage, detection, and treatment. Each phase includes two substages: “uptake” and “results,” with an additional substage in screening (“invitation”). “Screening” assesses invitation effectiveness and participation. “Triage” tracks follow-up after a positive screen. “Detection” evaluates attendance at diagnostic appointments, and “Treatment” measures the treatment rate for those with precancerous lesions. Conclusions: The Cascade can guide emerging and existing HPV screening programs within Canada and other similarly resourced settings and serve as a benchmark tool for programs to assess their progress towards cervical cancer elimination. Full article

Background: Ischemic stroke (IS) is a severe condition with limited therapeutic options. Pyroptosis, a type of programmed cell death linked to inflammation, is closely associated with IS-related damage. Studies suggest inflammation aligns with the traditional Chinese medicine (TCM) concept of “fire-heat syndrome”. Huanglian Jiedu Decoction (HLJD), a TCM formula known for clearing heat and purging fire, has shown therapeutic effects on IS, potentially by regulating pyroptosis. Study design: Eight-week-old male mice were divided into six groups: sham operation, model, positive drug, and low-, medium-, and high-dose HLJD groups. After a week of adaptive feeding, mice received respective treatments for five days, followed by modeling on the sixth day, with samples collected 23 h post-perfusion. Analyses included multi-omics, physiology, histopathology, virtual drug screening, target affinity assessment, and molecular biology techniques to measure relevant indicators. Results: HLJD effectively mitigated IS-related damage, maintaining neurological function, reducing ischemic levels, protecting cellular morphology, inhibiting neuronal apoptosis, and preserving blood–brain barrier integrity. Bioinformatics of high-throughput omics data revealed significant activation of pyroptosis and related inflammatory pathways in IS. ScRNA-seq identified neutrophils, macrophages, and microglia as key pyroptotic cell types, suggesting potential therapeutic targets. Network pharmacology and molecular docking identified NLRP3 as a critical target, with 6819 ligand–receptor docking results. SPR molecular fishing, LC-MS, molecular dynamics, and affinity measurements identified small molecules with high affinity for NLRP3. Molecular biology techniques confirmed that HLJD regulates pyroptosis via the classical inflammasome signaling pathway and modulates the inflammatory microenvironment. Conclusions: Following IS, pyroptosis in myeloid cells triggers an inflammatory cascade, leading to neural damage. HLJD may inhibit NLRP3 activity, reducing pyroptosis and associated inflammation, and ultimately mitigating damage. Full article

Background: Traceback testing—identifying and offering testing to people with previous cancer diagnoses who have not received current standard genetic testing—could benefit patients and their at-risk relatives. Methods: We conducted a multisite, nonrandomized pilot implementation study of a Traceback program at three integrated United States health systems. We assessed the reach, fidelity, effectiveness, and acceptability of the program using quantitative and qualitative methods. Results: We identified 597 eligible individuals using administrative data and manual chart review. We attempted to reach everyone identified (100% fidelity). We successfully contacted 354 people, for a reach of 59% of confirmed eligible individuals. In total, 133 people completed Traceback genetic testing. Ten of these (8%) received pathogenic or likely pathogenic results;. Nine of these ten people received positive results for which cascade testing of at-risk relatives would be indicated. None of their relatives underwent cascade testing during the study period. Thirty-six received variants of uncertain significance (VUS). Traceback programs were acceptable to participants and implementers and thought to be applicable to other genetic screening conditions. The time and resources required to accurately identify Traceback-eligible individuals are likely determinants of future sustainability. Conclusions: Education about free cascade testing, reminder calls to probands, and offers to directly contact at-risk relatives did not result in cascade testing in this pilot study. However, participant and implementer discussions suggest that the potential benefits of Traceback programs and high participant acceptability are worthy of further study. Full article

Background: Sickle cell disease (SCD) is consequently associated with increased rates of infant and childhood morbidity and mortality. Therefore, early detection is a crucial aspect of managing SCD to mitigate complications and improve health outcomes for SCD children. Neonatal screening is the primary method for identifying newborns with SCD, enabling early diagnosis, family screening, and comprehensive medical care. The protocol presented in this paper describes a study aimed at screening newborns for SCD in high-prevalence SCD states of India to understand the magnitude of the problem and the benefits of early comprehensive care along with the genotypic and phenotypic correlation. Methods: A prospective cohort study will be conducted across seven sites in six states of India (Rajasthan, Odisha, Tamil Nadu, Maharashtra, Madhya Pradesh, and Gujarat), having a high prevalence of SCD. The cord blood or heel prick samples of all the live-born babies delivered within the facilities of selected regions will be collected for screening SCD by HPLC (High-Performance Liquid Chromatography). All the sickle cell homozygous (SS) babies will be confirmed at 6 weeks for Sickle genotype along with cascade screening. Further, SS babies will be followed up from six weeks up to five years of life with initiation of folic acid, antibiotic prophylaxis, and hydroxyurea treatment at appropriate times. Results: The protocol aims to lay the groundwork for the smooth implementation of newborn screening programs and effective follow-up strategies. Conclusions: It will pave the way for developing a strategic framework for implementing newborn screening programs for haemoglobinopathies in India. Full article

X-linked adrenoleukodystrophy (ALD) is a rare metabolic disorder. Symptoms range from cerebral demyelination (cALD) to adrenal insufficiency and slowly progressive myeloneuropathy. cALD is fatal if not treated with hematopoietic cell transplantation in the early stages of the disease course. This can be achieved through cascade testing or newborn screening (NBS). Due to the lack of predictive measures of disease trajectory, patients are monitored with frequent MRI scans and hormone testing to ensure timely intervention. With this study, we wanted to explore how the diagnosis of ALD, before the development of cALD, and the follow-up program affected patients and their parents. Using semi-structured interviews, we interviewed seven parents of children with ALD aged 3–11 and four patients with ALD aged 18–25. Because NBS for ALD has not been implemented in Denmark, the patients were identified through either cascade testing or after having presented with adrenal insufficiency. We generated five themes: (I) ALD patients maintained mental resilience despite diagnosis and surveillance; (II) patients’ concerns matured with age and centered around situations that confronted them with their patient status; (III) parents of children with ALD had both short-term and long-term worries for their children’s health; (IV) parents took on a huge psychological burden; and (V) due to its rarity, the diagnosis of ALD evoked a sense of isolation and disease-related loneliness. Overall, we found a large discrepancy in the experiences reported by parents and patients. Despite the small sample size, we identified patterns that suggest that while the early diagnosis took a significant psychological toll on the parents, patients lived relatively carefree lives despite their ALD diagnosis. Full article

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies. Full article

As an environmentally friendly technology, enzymatic degradation of waste polyethylene terephthalate (PET) has great application potential. Mono (hydroxyethyl) terephthalate (MHET), an intermediate product of PET degradation, accumulates during the degradation process. MHET reduces the activity of PETase and influences further enzymatic degradation. The combined catalysis of MHETase and PETase is an effective strategy to solve this problem. However, the difference in thermostability between MHETase and PETase limits their combination. In our previous study, a PETase of muEst1 exhibited acceptable PET-degradation ability, but the abundant MHET accumulation in its degradation products limited its further application. In this study, MHETases with good thermostability were screened for combination with muEst1 for the cascade reaction of PET degradation, and a two-stage variable-temperature program was developed. The results of this investigation show that this approach results in a PET-degradation rate of 92.71% with a terephthalic acid content above 85.9%. This investigation provides an alternative method for scaled-up enzymatic PET degradation. Full article

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples’ reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit–harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems. Full article