Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD

The characteristics, dynamics and risk of death in COVID-19 positive dialysis patients in London, UK

Background: Dialysis patients, with frequent co-morbidities, advanced age and frailty, visiting treatment facilities frequently are perhaps more prone to SARS-Cov-2 infection and related death - the risk-factors and dynamics of which are unknown. The aim of this study was to investigate the hospital outcomes in SARS-CoV-2 infected dialysis patients. Methods: Data on 224 hemodialysis patients between 02/29/2020 and 05/15/2020 with confirmed SARS-CoV-2 were analyzed for outcomes and potential risk factors for death, using competing risk regression model assessed by sub-distribution hazards ratio (SHR). Results: Crude data analyses suggest an overall case fatality ratio of 22.7(95%CI(17.3-28.3)%) overall but that varies across age groups from 11.4(95%CI(0.9-9.2)) in 80 years; with 60% of deaths occurring in the first 15 days and 80% within 21 days indicating a rapid deterioration towards death after admission. Almost 90% of surviving patients were discharged within 28 days. Death was more likely than hospital discharge in more frail (WHO performance status 3-4) [SHR=2.16(1.25-3.74);p=0.006)], ischemic heart disease [SHR=2.28(1.32-3.94),p=0.003], cerebrovascular disease [SHR=2.11(1.20-3.72),p=0.010], smoking history [SHR=2.69(1.33-5.45),p=0.006], and (completely or partially) hospitalized patients [SHR=10.26.(3.10-33.94),p<.001]; and in patients with high CRP [SHR=1.35(1.10-1.67)] and high neutrophil:lymphocyte ratio [SHR=1.03(1.01-1.04),p<0.001]. Our data did not support differences in the risk of death associated with gender, ethnicity, dialysis vintage or other comorbidities. However, comparison with the entire dialysis population attending these hospitals, and 12.9% being affected, revealed that non-Caucasians (62% vs. 52% in all patients, p=0.001) and diabetic patients (54% vs. 22%, p<0.001) were disproportionately affected. Conclusion: This report discusses the outcomes of a large cohort of dialysis patients with SARS-CoV-2, infection affecting more diabetics and non-Caucasians; with a high case fatality ratio, which increased significantly with age, frailty, smoking, increasing CRP and neutrophil:lymphocyte ratio at presentation

Colorectal Cancer Prognosis Following Obesity Surgery in a Population-Based Cohort Study

Background: Obesity surgery involves mechanical and physiological changes of the gastrointestinal tract that might promote colorectal cancer progression. Thus, we hypothesised that obesity surgery is associated with poorer prognosis in patients with colorectal cancer. Methods: This nationwide population-based cohort study included all patients with an obesity diagnosis who subsequently developed colorectal cancer in Sweden from 1980 to 2012. The exposure was obesity surgery, and the main and secondary outcomes were disease-specific mortality and all-cause mortality, respectively. Cox proportional hazard survival models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for sex, age, calendar year and education level. Results: The exposed and unexposed cohort included 131 obesity surgery and 1332 non-obesity surgery patients with colorectal cancer. There was a statistically significant increased rate of colorectal cancer deaths following obesity surgery (disease-specific HR 1.50, 95% CI 1.00–2.19). When analysed separately, the mortality rate was more than threefold increased in rectal cancer patients with prior obesity surgery (disease-specific HR 3.70, 95% CI 2.00–6.90), while no increased mortality rate was found in colon cancer patients (disease-specific HR 1.10, 85% CI 0.67–1.70). Conclusion: This population-based study among obese individuals found a poorer prognosis in colorectal cancer following obesity surgery, which was primarily driven by the higher mortality rate in rectal cancer

Impact of Low-Level-Viremia on HIV-1 Drug-Resistance Evolution among Antiretroviral Treated-Patients

to determine the emergence and evolution of DRAM during LLV in HIV-1-infected patients while receiving antiretroviral therapy (ART).Retrospective analysis of patients presenting a LLV episode defined as pVL between 40 and 500 c/mL on at least 3 occasions during a 6-month period or longer while on the same ART. Resistance genotypic testing was performed at the onset and at the end of LLV period. Emerging DRAM was defined during LLV if never detected on baseline genotype or before.48 patients including 4 naive and 44 pretreated (median 9 years) presented a LLV episode with a median duration of 11 months. Current ART included 2NRTI (94%), ritonavir-boosted PI (94%), NNRTI (23%), and/or raltegravir (19%). Median pVL during LLV was 134 c/mL. Successful resistance testing at both onset and end of the LLV episode were obtained for 37 patients (77%), among who 11 (30%) acquired at least 1 DRAM during the LLV period: for NRTI in 6, for NNRTI in 1, for PI in 4, and for raltegravir in 2. During the LLV period, number of drugs with genotypic resistance increased from a median of 4.5 to 6 drugs. Duration and pVL level of LLV episode, duration of previous ART, current and nadir CD4 count, number of baseline DRAM and GSS were not identified as predictive factors of resistance acquisition during LLV, probably due to limited number of patients.Persistent LLV episodes below 500 c/ml while receiving ART is associated with emerging DRAM for all drug classes and a decreasing in further therapeutic options, suggesting to earlier consider resistance monitoring and ART optimization in this setting

A pilot, prospective evaluation of a novel alternative for maintenance therapy of breast cancer-associated lymphedema [ISRCTN76522412]

BACKGROUND: Prospective investigations of complete decongestive lymphatic physiotherapy (CDPT), including manual lymphatic drainage (MLD), have validated the efficacy of these interventions for the initial reduction of edema and long-term maintenance of limb volume in lymphedema. However, CDPT demands substantial time and effort from patients to maintain these benefits; the treatments are not always well-accepted, and patients may suffer from a deterioration in quality-of-life or a time-dependent loss of initial treatment benefits. A new device designed for home use by the patient, the Flexitouch™, has been developed to mechanically simulate MLD. We have undertaken a prospective, randomized, crossover study of the efficacy of the Flexitouch™, when compared to massage, in the self-administered maintenance therapy of lymphedema. METHODS: A prospective, randomized, crossover study of maintenance therapy was performed in 10 patients with unilateral breast cancer-associated lymphedema of the arm. Each observation phase included self-administered treatment with the Flexitouch™ or massage, 1 hour daily for 14 days, respectively, followed by crossover to the alternate treatment phase. Each treatment phase was preceded by a 1 week treatment washout, with use of garment only. The sequence of treatment was randomly assigned. The potential impact of treatment modality on quality of life was assessed with serial administration of the SF-36. RESULTS: Statistical analysis disclosed that the order of treatment had no outcome influence, permitting 10 comparisons within each treatment group. Post-treatment arm volume reduced significantly after the Flexitouch™, but not after self-administered massage. The patients' mean weight decreased significantly with Flexitouch™ use, but not with massage. The Flexitouch™ device was apparently well-tolerated and accepted by patients. Serial SF-36 administration showed no deterioration in physical or psychosocial scores compared to baseline measurements; there were no statistical differences in scores when the two treatment modalities were compared. CONCLUSION: This short-term prospective evaluation of the Flexitouch™ suggests that the device may provide better maintenance edema control than self-adiminstered massage in breast cancer-associated lymphedema. The apparent ease of use and reliability of response to the device suggest that further broad-scale testing is warranted

Towards integration of general practitioner posts and accident and emergency departments: a case study of two integrated emergency posts in the Netherlands

<p>Abstract</p> <p>Background</p> <p>Accident and emergency (A&E) departments and general practitioner (GP) posts are often used inappropriately, leading to overcrowding. In the Netherlands, increasingly more integrated emergency posts (IEPs) are being created, integrating the care provided by GP posts and A&E departments, in order to improve the provision of the emergency care.</p> <p>Methods</p> <p>This explorative study compares the efficiency and patient and employee satisfaction in IEPs with those in two GP posts and two A&E departments. To this end, information was retrieved from hospital and GP patient records for the first quarter of the year before and of the year after the creation of IEPs. Patients and employees were sent a questionnaire to measure their satisfaction. Lastly, groups of hospital doctors, GPs, GP assistants, and nurses were interviewed.</p> <p>Results</p> <p>After the creation of IEPs, there was a shift of more than fifteen percent from secondary care to primary care for emergency consultations and waiting/consultation times were shortened by more than ten percent. Compared with the control settings, patients were more satisfied about telephone contact with an IEP, but professionals working at the IEP were less satisfied with several aspects of their work.</p> <p>Conclusion</p> <p>IEPs could be a promising innovation to organize emergency care more efficiently; however, it might take time to convince professionals of the possible advantages. Studies involving more IEPs and longer follow-up times are needed to determine whether such integration should be stimulated.</p

Abnormal function of the vasopressin-cyclic-AMP-aquaporin2 axis during urine concentrating and diluting in patients with reduced renal function. A case control study

<p>Abstract</p> <p>Background</p> <p>The kidneys ability to concentrate and dilute urine is deteriorated during progressive renal insufficiency. We wanted to test the hypothesis that these phenomena could be attributed to an abnormal function of the principal cells in the distal part of the nephron.</p> <p>Methods</p> <p>Healthy control subjects and patients with chronic kidney diseases were studied. Group 1 comprised healthy subjects, n = 10. Groups 2-4 comprised patients with chronic kidney disease (Group 2, n = 14, e-GFR ? 90 m1/min; Group 3, n = 11, 60 m1/min ? e-GFR < 90 ml/min; and Group 4, n = 16, 15 ml/min ? e-GFR < 60 ml/min). The subjects collected urine during 24 hours. A urine concentrating test was done by thirsting during the following 12 hours. Thereafter, a urine diluting test was performed with a water load of 20 ml/kg body weight. The effect variables were urinary excretions of aquaporin2 (u-AQP2), cyclic-AMP (u-c-AMP), urine volume (UV), free water clearance (C_H2O), urine osmolarity (u-Osm), and plasma arginine vasopressin (p-AVP).</p> <p>Results</p> <p>After fluid deprivation, u-Osm increased. In all groups, UV and C_H2Odecreased and u-AQP2 and u-c-AMP increased in Groups 1 and 2, but were unchanged in Group 3 and 4. P-AVP was significantly higher in Group 4 than in the other groups. During urine diluting, UV and C_H2Oreached significantly higher levels in Groups 1-3 than Group 4. Both before and after water loading, u-AQP2 and p-AVP were significantly higher and u-c-AMP was significantly lower in Group 4 than the other groups. Estimated-GFR was correlated negatively to p-AVP and positively to u-c-AMP.</p> <p>Conclusions</p> <p>Patients with moderately severe chronic kidney disease have a reduced renal concentrating and diluting capacity compared to both patients with milder chronic kidney disease and healthy control subjects. These phenomena can be attributed, at least partly, to an abnormally decreased response in the AVP-c-AMP-AQP2 axis.</p> <p>ClinicalTrials.Gov Identifier: NCT00313430</p

Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease:Systematic review and meta-analysis

Complete search strategy. The complete search strategy for the systematic review for both Medline and Embase. (DOCX 22 kb