Genetic risk scores: are they important for diabetes management? results from multiple cross-sectional studies.

Several genetic risk scores (GRS) for type 2 diabetes (T2DM) have been published, but not replicated. We aimed to 1) replicate previous findings on the association between GRS on prevalence of T2DM and 2) assess the association between GRS and T2DM management in a sample of community-dwelling people from Switzerland. Four waves from a prospective study conducted in Lausanne. Seven GRS related to T2DM were selected, and compared between participants with and without T2DM, and between controlled and uncontrolled participants treated for T2DM. Data from 5426, 4017, 2873 and 2170 participants from the baseline, first, second and third follow-ups, respectively, was used. In all study periods, participants with T2DM scored higher than participants without T2DM in six out of seven GRS. Data from 367, 437, 285 and 207 participants with T2DM was used. In all study periods, approximately half of participants treated for T2DM did not achieve adequate fasting blood glucose or HbA <sub>1</sub> c levels, and no difference between controlled and uncontrolled participants was found for all seven GRS. Power analyses showed that most GRS needed a sample size above 1000 to consider the difference between controlled and uncontrolled participants as statistically significant at p = 0.05. In this study, we confirmed the association between most published GRS and diabetes. Conversely, no consistent association between GRS and diabetes control was found. Use of GRS to manage patients with T2DM in clinical practice is not justified

Prevalence of functional bowel disorders and faecal incontinence: an Australian primary care survey

Accepted Article online 30 October 2014. The copyright line for this article was changed on 14 February, 2017 after original online publication.Aim: Interest in functional bowel disorders (FBDs) and faecal incontinence (FI) has increased amongst coloproctologists. The study aimed to assess the prevalence of FBDs and FI (including its severity) among Australian primary healthcare seekers using objective criteria. Method: A cross-sectional survey was conducted in a primary care setting in Sydney, Australia. A self-administered questionnaire was used to collect demographic information and diagnose FBDs (irritable bowel syndrome, constipation, functional bloating and functional diarrhoea) based on Rome III criteria. The severity of FI was determined using the Vaizey incontinence score. Associations with medical/surgical history and healthcare utilization were assessed. Results: Of 596 subjects approached, 396 (66.4%) agreed to participate. Overall, 33% had FBD and/or FI. Irritable bowel syndrome was present in 11.1% and these participants were more likely to report anxiety/depression (P 8). Participants with FI were more likely to have irritable bowel syndrome, urinary incontinence and previous anal surgery (P < 0.01). Conclusion: FBDs and FI are prevalent conditions amongst primary healthcare seekers and the needs of those affected appear to be complex given their coexisting symptoms and conditions. Currently, the majority do not reach colorectal services, although increased awareness by primary care providers could lead to sufferers being referred for specialist management.K.-S. Ng, N. Nassar, K. Hamd, A. Nagarajah and M. A. Gladma

Pretransplant characteristics of kidney transplant recipients that predict posttransplant outcome

Better characterization of the potential kidney transplant recipient using novel biomarkers, for example, pretransplant plasma endotrophin, will lead to improved outcome after transplantation. This mini-review will focus on current knowledge about pretransplant recipients’ characteristics, biomarkers, and immunology. Clinical characteristics of recipients including age, obesity, blood pressure, comorbidities, and estimated survival scores have been introduced for prediction of recipient and allograft survival. The pretransplant immunologic risk assessment include histocompatibility leukocyte antigens (HLAs), anti-HLA donor-specific antibodies, HLA-DQ mismatch, and non-HLA antibodies. Recently, there has been the hope that pretransplant determination of markers can further improve the prediction of posttransplant complications, both short-term and long-term outcomes including rejections, allograft loss, and mortality. Higher pretransplant plasma endotrophin levels were independently associated with posttransplant acute allograft injury in three prospective European cohorts. Elevated numbers of non-synonymous single-nucleotide polymorphism mismatch have been associated with increased allograft loss in a multivariable analysis. It is concluded that there is a need for integration of clinical characteristics and novel molecular and immunological markers to improve future transplant medicine to reach better diagnostic decisions tailored to the individual patient

ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer

Alanine, serine, cysteine-preferring transporter 2 (ASCT2; SLC1A5) mediates uptake of glutamine, a conditionally essential amino acid in rapidly proliferating tumour cells. Uptake of glutamine and subsequent glutaminolysis is critical for activation of the mTORC1 nutrient-sensing pathway, which regulates cell growth and protein translation in cancer cells. This is of particular interest in breast cancer, as glutamine dependence is increased in high-risk breast cancer subtypes. Pharmacological inhibitors of ASCT2-mediated transport significantly reduced glutamine uptake in human breast cancer cell lines, leading to the suppression of mTORC1 signalling, cell growth and cell cycle progression. Notably, these effects were subtype-dependent, with ASCT2 transport critical only for triple-negative (TN) basal-like breast cancer cell growth compared with minimal effects in luminal breast cancer cells. Both stable and inducible shRNA-mediated ASCT2 knockdown confirmed that inhibiting ASCT2 function was sufficient to prevent cellular proliferation and induce rapid cell death in TN basal-like breast cancer cells, but not in luminal cells. Using a bioluminescent orthotopic xenograft mouse model, ASCT2 expression was then shown to be necessary for both successful engraftment and growth of HCC1806 TN breast cancer cells in vivo. Lower tumoral expression of ASCT2 conferred a significant survival advantage in xenografted mice. These responses remained intact in primary breast cancers, where gene expression analysis showed high expression of ASCT2 and glutamine metabolism-related genes, including GLUL and GLS, in a cohort of 90 TN breast cancer patients, as well as correlations with the transcriptional regulators, MYC and ATF4. This study provides preclinical evidence for the feasibility of novel therapies exploiting ASCT2 transporter activity in breast cancer, particularly in the high-risk basal-like subgroup of TN breast cancer where there is not only high expression of ASCT2, but also a marked reliance on its activity for sustained cellular proliferation

The progeroid phenotype of Ku80 deficiency Is dominant over DNA-PK CS deficiency

Ku80 and DNA-PKCS are both involved in the repair of double strand DNA breaks via the nonhomologous end joining (NHEJ) pathway. While ku80-/- mice exhibit a severely reduced lifespan and size, this phenotype is less pronounced in dna-pkcs -/- mice. However, these observations are based on independent studies with varying genetic backgrounds. Here, we generated ku80-/-, dna-pkcs -/- and double knock out mice in a C57Bl6/J*FVB F1 hybrid background and compared their lifespan, end of life pathology and mutation frequency in liver a

Pretransplant endotrophin predicts delayed graft function after kidney transplantation

Delayed graft function after kidney transplantation is common and increases morbidity and health care costs. There is evidence that endotrophin, a specific fragment of pro-collagen type VI, promotes the inflammatory response in kidney diseases. We tested the hypothesis that pretransplant endotrophin in kidney transplant recipients may be associated with the risk of delayed graft function. Pretransplant plasma endotrophin was assessed using an enzyme-linked immunosorbent assay in three independent cohorts with 806 kidney transplant recipients. The primary outcome was delayed graft function, i.e., the necessity of at least one dialysis session within one-week posttransplant. In the discovery cohort median pretransplant plasma endotrophin was higher in 32 recipients (12%) who showed delayed graft function when compared to 225 recipients without delayed graft function (58.4 ng/mL [IQR 33.4–69.0]; N = 32; vs. 39.5 ng/mL [IQR 30.6–54.5]; N = 225; P = 0.009). Multivariable logistic regression, fully adjusted for confounders showed, that pretransplant plasma endotrophin as a continuous variable was independently associated with delayed graft function in both validation cohorts, odds ratio 2.09 [95% CI 1.30–3.36] and 2.06 [95% CI 1.43–2.97]. Pretransplant plasma endotrophin, a potentially modifiable factor, was independently associated with increased risk of delayed graft function and may be a new avenue for therapeutic interventions

Preliminary survey of knowledge, attitudes and practices among nurses regarding seasonal influenza and influenza vaccination

Health care workers are  at risk of influenza through occupational exposure. Uptake of influenza vaccine is poor even in countries where it is provided free. We sought to determine the knowledge, attitudes and practices regarding seasonal influenza and barriers for vaccination among nurses in Colombo. A cross sectional survey was carried out from February to March 2020 on 97 randomly selected nurses. Level of knowledge was measured using a scoring system. Only a few (n=7; 7.2%) nurses had been immunized against influenza. Overall knowledge regarding influenza and vaccines was average in most nurses (n=53; 55%). The majority (n=62; 63.9%) believed the vaccine was safe and 79.4% (n=77) were willing to be vaccinated if vaccine is provided free. However, 15 of these 77 (19.5%) were reluctant to be vaccinated annually. Identified barriers for vaccination were the perception that the vaccine was not essential, doubt about its efficacy, fear of vaccines and side effects. Knowledge should be improved, and misconceptions and fears need to be addressed through health education and promotion.</p

Update to a randomized controlled trial of lutetium-177-PSMA in Oligo-metastatic hormone-sensitive prostate cancer:the BULLSEYE trial

Background: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. Changes in methods and materials: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; “Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer” and is now partly supported by Advanced Accelerator Applications, a Novartis Company. Conclusions: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced. Trial registration: ClinicalTrials.gov NCT04443062. First posted: June 23, 2020