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Background: PC has become a significant global health challenge, with incidence and mortality rates rising over the past three decades. While traditionally associated with aging, recent data indicate an increasing burden among younger populations. This study aims to analyze global trends in PC incidence and mortality and to identify key contributing factors, particularly modifiable risk factors such as obesity, diabetes, and smoking. Methods: Using data from the Global Burden of Disease Study (GBD) 2021, population-based cancer registries globally and nationally, systematic reviews and analysis trends in PC incidence, mortality and survival were analyzed. To assess epidemiological shifts, we utilized previously published annual percentage change (AAPC) values stratified by region, age group, and sex, as reported in the cited literature. Additionally, the influence of modifiable risk factors was evaluated to determine their contribution to rising incidence rates. Results: Between 1990 and 2021, the global incidence of PC increased by 8.9%, from 5.47 to 5.96 per 100,000, with the highest rates observed in high-Sociodemographic-Index (SDI) regions (10.00 per 100,000) and the lowest in low-SDI regions (1.59 per 100,000). Significant increases in incidence were noted in several countries, particularly among men in Iceland (AAPC 8.85) and women in Malta (AAPC 6.04). Early-onset PC is becoming more prevalent, especially among younger women. Modifiable risk factors, including obesity, diabetes, and smoking, play a critical role, with excess body weight contributing to 17.9% of PC cases and smoking to 13.9% in the United States (U.S.). Conclusions: The rising burden of PC, particularly among younger populations, highlights the need for targeted prevention strategies, early detection efforts, and further research into the underlying mechanisms driving these trends. Addressing modifiable risk factors could be key to mitigating the increasing incidence of this highly lethal cancer.

Background Despite advances in neoadjuvant therapies and surgical techniques, abdominoperineal excision of the rectum (APER) is still necessary in a considerable number of cases, often requiring the creation of a permanent colostomy, which can significantly impact a patient’s quality of life (QOL). Total anorectal reconstruction (TAR) with dynamic graciloplasty has emerged as a reconstructive option for patients undergoing APER, aiming to restore continence by avoiding a permanent abdominal colostomy and improving quality of life. However, this approach presents several challenges, including technical complexity and variable long-term outcomes. Case report We present the case of a 34-year-old female patient who underwent APER with extended resection (rectum and vaginal wall) due to low rectal adenocarcinoma infiltrating the posterior vaginal wall. Following a prolonged postoperative course and the decision against living with an abdominal colostomy, the patient underwent secondary TAR with reconstruction of the posterior vaginal wall and dynamic graciloplasty in 2001. The procedure included creating a neorectum using a myocutaneous flap for vaginal reconstruction and a gracilis muscle wrap with neurostimulation as a neosphincter. Despite early postoperative complications, the patient achieved satisfactory continence with regular transanal irrigation and lived with the reconstruction for over 20 years. In 2024, the patient returned for management due to the obsolescence of her neurostimulator, which was subsequently removed without deterioration in her continence function. Conclusion This case highlights the complex and prolonged management challenges associated with TAR and dynamic graciloplasty for patients with severe anorectal dysfunction following APER. While dynamic graciloplasty has been shown to offer some level of continence in patients with faecal incontinence, the need for additional interventions, such as regular irrigation, is often required to maintain quality of life after TAR following APER. The durability of this reconstructive approach and the patient’s long-term satisfaction underline its potential as a viable, though technically demanding, alternative to conventional colostomy in selected patients. However, the role of electrically induced muscle fiber transformation (“dynamic graciloplasty”) needs to be discussed.

Gastroesophageal reflux disease (GERD) affects millions globally, with traditional treatments like proton pump inhibitors (PPIs) and surgical fundoplication presenting challenges such as long-term medication dependency and disturbing long term side effects following surgery. This review explores emerging, alternative therapies that offer less invasive, personalized alternatives for GERD management. Endoscopic approaches, including Stretta therapy, transoral incisionless fundoplication (TIF), and endoscopic full-thickness plication (EFTP), demonstrate promising but also controversial outcomes in symptom relief and reduced acid exposure. Laparoscopic electrical stimulation therapy (EndoStim®) and the LINX® magnetic sphincter augmentation system address LES dysfunction, while endoscopic anti-reflux mucosectomy and/or ablation techniques aim to construct a sufficient acid barrier. The RefluxStop™ device offers structural solutions to GERD pathophysiology with intriguing results in initial studies. Despite promising results, further research is required to establish long-term efficacy, safety, and optimal patient selection criteria for these novel interventions. This review underscores the importance of integrating emerging therapies into a tailored, multidisciplinary approach to GERD treatment.

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a regulator of transcription and mRNA stability that docks onto Pol II CTD through its SPOC domain. We characterize SPOC as a CTD reader domain that preferentially binds two phosphorylated Serine-2 marks in adjacent CTD repeats. PHF3 drives liquid-liquid phase separation of phosphorylated Pol II, colocalizes with Pol II clusters and tracks with Pol II across the length of genes. PHF3 knock-out or SPOC deletion in human cells results in increased Pol II stalling, reduced elongation rate and an increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 acts as a prominent effector of neuronal gene regulation by bridging transcription with mRNA decay. Here the authors identify PHF3 SPOC domain as a reader of the phosphorylated RNA polymerase II (Pol II) C-terminal domain. They show that PHF3 clusters with Pol II complexes in cells, drives phase separation of Pol II in vitro, and regulates neuronal gene expression and neuronal differentiation.

Drug shortages have been identified as a public health problem in an increasing number of countries. This can negatively impact on the quality and efficiency of patient care, as well as contribute to increases in the cost of treatment and the workload of health care providers. Shortages also raise ethical and political issues. The scientific evidence on drug shortages is still scarce, but many lessons can be drawn from cross-country analyses. The objective of this study was to characterize, compare, and evaluate the current systemic measures and legislative and organizational frameworks aimed at preventing or mitigating drug shortages within health care systems across a range of European and Western Asian countries. The study design was retrospective, cross-sectional, descriptive, and observational. Information was gathered through a survey distributed among senior personnel from ministries of health, state medicines agencies, local health authorities, other health or pharmaceutical pricing and reimbursement authorities, health insurance companies and academic institutions, with knowledge of the pharmaceutical markets in the 28 countries studied. Our study found that formal definitions of drug shortages currently exist in only a few countries. The characteristics of drug shortages, including their assortment, duration, frequency, and dynamics, were found to be variable and sometimes difficult to assess. Numerous information hubs were identified. Providing public access to information on drug shortages to the maximum possible extent is a prerequisite for performing more advanced studies on the problem and identifying solutions. Imposing public service obligations, providing the formal possibility to prescribe unlicensed medicines, and temporary bans on parallel exports are widespread measures. A positive finding of our study was the identification of numerous bottom-up initiatives and organizational frameworks aimed at preventing or mitigating drug shortages. The experiences and lessons drawn from these initiatives should be carefully evaluated, monitored, and presented to a wider international audience for careful appraisal. To be able to find solutions to the problem of drug shortages, there is an urgent need to develop a set of agreed definitions for drug shortages, as well as methodologies for their evaluation and monitoring. This is being progressed.

Familial juvenile hyperuricaemic nephropathy (FJHN) is an autosomal dominant renal disease characterised by juvenile onset of hyperuricaemia, gouty arthritis, and progressive renal failure at an early age. Recent studies in four kindreds showed linkage of a gene for FJHN to the same genomic interval on chromosome 16p11.2, where the gene for the phenotypically similar medullary cystic disease type 2 (MCKD2) has been localised. In this study we performed linkage analysis in additional 15 FJHN families. Linkage of FJHN to 16p11.2 was confirmed in six families, which suggests that, in a large proportion of FJHN kindreds, the disease is likely to be caused by a gene or genes located outside of 16p11.2. Haplotype analysis of the new and previously analysed families provided two non-overlapping critical regions on 16p11.2–FJHN1, delimited by markers D16S499-D16S3036 and FJHN2, delimited by markers D16S412-D16S3116. Considering MCKD2 to be a distinct molecular entity, the analysis suggests that as many as three kidney disease genes may be located in close proximity on 16p11.2. From genomic databases we compiled integrated physical and transcription maps of whole critical genomic region in which 45 known genes and 129 predicted loci have been localised. We selected, analysed and found no pathogenic mutations in seven candidate genes. The linkage and haplotype analysis reported here demonstrates the genetic heterogeneity of FJHN. The report of integrated physical and mostly in-silico predicted transcription maps of the FJHN critical region provides a basis for precise experimental annotation of the current transcript map, which is essential for final identification of the FJHN gene(s).