Background & Aims-Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch Syndromes I & II, and sporadic colorectal cancers (CRCs). Msh2 null mice predominantly develop lymphoma and do not accurately recapitulate the CRC phenotype.

Fatigue is a burdensome, multidimensional, and multifactorial symptom that is associated with a wide array of chronic illnesses, specifically occurring in nearly 50% of patients with inflammatory bowel disease (IBD). Although common, given its subjective nature, physicians often under-recognize and undertreat this debilitating symptom. There are multiple etiologies that can contribute to fatigue in patients with IBD, including disease activity, anemia, medications, psychosomatic symptoms, and alterations to the gut-brain axis. The management of fatigue in IBD can be challenging, as it is often times multifaceted. In this review, we summarize the available tools for the diagnosis and measurement of fatigue, discuss etiologies, and make recommendations for their management. We identify knowledge gaps for the workup and treatment of fatigue and propose an algorithm to aid physicians in the evaluation and management of fatigue in this unique population. However, future research is needed to address several areas of knowledge deficits and improve the management of fatigue in IBD.

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye's vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3–4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3–4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments.

Background The Australian Pharmaceutical Advisory Council guidelines for the continuum of quality use of medicines between hospital and community aim to establish a coordinated approach that encourages continuity in all areas of health care and the community. However, the implementation of these guidelines has been problematic. Aim To identify the number and nature of barriers encountered when organising a home medicines review (HMR) for patients at high risk of medication misadventure, after discharge from hospital. Method A liaison pharmacist organised an appointment for eligible patients (around 2 days post‐discharge) for the general practitioner to make an HMR referral. The pharmacist contacted the patient's community pharmacist to engage an accredited pharmacist to undertake the HMR and arranged for the HMR report to be sent to the outpatient clinic, the general practitioner and community pharmacist. Results 38/50 patients consented to have their general practitioner contacted by the liaison pharmacist. General practitioners agreed to order an HMR for 34 patients. Barriers to HMR uptake included: low patient awareness of HMRs, a low level of general practitioner awareness of the HMR process, reluctance of some community pharmacists to participate in HMR delivery and the time taken for HMRs to be performed. Conclusion Once aware of the HMR service, the majority of patients were willing to participate and general practitioners were prepared to refer their patients for such a service. However, time constraints impacted on both general practitioners and community pharmacists, hence, consideration should be given to extending the support from HMR facilitators to include pharmacies as well as general practitioners.

We have crossed mice carrying the conditional Rb tm2Brn allele with a constitutive Villin-Cre transgenic mouse. The Villin promoter in these animals is highly expressed in adult intestine and kidney proximal tubules and is expressed in the gut and nephros anlagen during embryogenesis. We report here that these mice develop tumors between 12 and 17 months old outside the gastrointestinal (GI) tract. A high penetrance of pituitary tumors and medullar carcinoma of the thyroid is observed with a lower incidence of hyperplasia of pulmonary neuroendocrine cells and aggressive liver, bile duct, stomach, oral cavity tumors, and lipomas. Rb rearrangement due to ectopic Villin promoter activity in neural crest or neural crest stem cells during embryogenesis is most likely responsible for the medullar carcinoma of the thyroid phenotype. The aggressive nature of the medullar carcinoma of the thyroid and its ability to metastasize to unusual sites make the model suitable for the study of tumor progression and mechanism of metastasis. Observed sites of metastasis include the stomach, small intestine, liver, lung, kidney, pancreas, spleen, bone marrow, salivary gland, fat, lymph nodes, and dorsal root ganglion. Because the Villin promoter is highly active throughout the GI and in the nephros anlagen during development, we find that Rb inactivation is not sufficient to initiate tumorigenesis in the GI or kidneys in mice. (Cancer Res 2006; 66(7): 3576-83)

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.

Background: The risk of medication misadventure for patients is greatest during times of change, particularly on discharge from hospital. Patients at high risk of medication misadventure postdischarge should be identified and provided with interventions to ensure the quality use of medicines and positive health outcomes. Home medicines reviews (HMRs) can be used to improve patient health outcomes and reduce the risk of medication misadventure. Aim: To describe the impact of issues raised in post-discharge HMRs, organised via a hospital medication liaison service. Method: HMR reports of participants were evaluated. Issues identified by the accredited pharmacist in each HMR report were classified as either a 'pharmacist intervention' delivered during the HMR or 'information given' that was previously unknown to the medical team. A potential clinical impact of these issues was assigned and the overall clinical significance of all the issues identified in each HMR report was ranked. Results: In 21 HMR reports, 98 issues were identified, with the mean per HMR report of 4.7 ±2.2. Of the 98 issues, 25 were classified as 'pharmacist intervention' and 73 were classified as 'information given'. On 2 occasions, a potential clinical impact of 4 (potentially life-saving) was allocated to an issue identified in the HMR report. 90% of issues identified in the HMR reports were ranked as clinically significant. Conclusion: This pilot demonstrated that a liaison pharmacist was able to implement a hospital medication liaison model for patients at risk of medication misadventure. Evidence suggests that an HMR conducted post-discharge can identify clinically significant medication-related issues.

Flap endonuclease 1 (Fen1) and exonuclease 1 (Exo1) have sequence homology and similar nuclease capabilities. Both function in multiple pathways of DNA metabolism, but appear to have distinct in vivo nucleic acid substrates, and therefore distinct metabolic roles. When combined with Apc 1638N