Age-related mitochondrial DNA depletion and the impact on pancreatic beta cell function

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes

The prevalences of Salmonella Genomic Island 1 variants in human and animal Salmonella Typhimurium DT104 are distinguishable using a Bayesian approach

Throughout the 1990s, there was an epidemic of multidrug resistant Salmonella Typhimurium DT104 in both animals and humans in Scotland. The use of antimicrobials in agriculture is often cited as a major source of antimicrobial resistance in pathogenic bacteria of humans, suggesting that DT104 in animals and humans should demonstrate similar prevalences of resistance determinants. Until very recently, only the application of molecular methods would allow such a comparison and our understanding has been hindered by the fact that surveillance data are primarily phenotypic in nature. Here, using large scale surveillance datasets and a novel Bayesian approach, we infer and compare the prevalence of Salmonella Genomic Island 1 (SGI1), SGI1 variants, and resistance determinants independent of SGI1 in animal and human DT104 isolates from such phenotypic data. We demonstrate differences in the prevalences of SGI1, SGI1-B, SGI1-C, absence of SGI1, and tetracycline resistance determinants independent of SGI1 between these human and animal populations, a finding that challenges established tenets that DT104 in domestic animals and humans are from the same well-mixed microbial population

Supporting weight management services during the COVID-19 pandemic: Phase I insights

Societal changes required to manage the coronavirus (COVID-19) pandemic may have inadvertently promoted weight gain, due to the adverse impact on socio-economics, psychological health, and the resulting metabolic impact of elevated stress, emotional eating and physical inactivity. Evidence on the impact of COVID-19 has rapidly accumulated, to demonstrate that people living with obesity are at higher risk of severe illness from COVID-19 infection. It is therefore important to understand what is happening in terms of weight management practice to develop local and national thinking. This project will explore the impact of the COVID-19 upon the provision of tier 2 and 3 weight management services (WMS) in England during the lockdown period (phase I; March-June 2020); and determine what needs to happen in the future (phase II; September-November 2020). This report documents findings from phase I

Defining the Incremental Utility of Prostate Multiparametric Magnetic Resonance Imaging at Standard and Specialized Read in Predicting Extracapsular Extension of Prostate Cancer

AbstractMultiparametric magnetic resonance imaging (mpMRI) is increasingly used in staging early prostate cancer (PCa) but remains heavily reader-dependent. We aim to define the incremental utility of mpMRI over clinical parameters in determining the pathologic extracapsular extension (pECE) of PCa interpreted in a standard radiologic setting and when further over-read by a specialized reader. We retrospectively reviewed 120 men with clinically localized PCa undergoing mpMRI and radical prostatectomy. We obtained radiologic prediction of pECE from standard radiologic reports (standard read) and by a specialized reader blinded to clinical and pathologic findings (specialized read). We determined the incremental benefit of standard read and specialized read by sequential addition to a baseline clinical parameters-only logistic regression model predicting pECE. The sensitivity and specificity of standard read were 77% and 44%, respectively, whereas those of specialized read were 86% and 81%. The positive likelihood ratio was 1.7 at baseline, 1.7 adding standard read, and 6.5 adding specialized read. The negative likelihood ratio was 0.6 at baseline, 0.5 adding standard read, and 0.1 adding specialized read. Standard read modestly improved prediction of pECE, whereas specialized read improved it moderately.Patient summaryThe incremental benefit of mpMRI over clinical information is small but increases to moderate with a specialized second opinion. This second opinion may be useful when considering active surveillance, nerve-sparing surgery, or focal therapy

Endothelial Function Is Associated with White Matter Microstructure and Executive Function in Older Adults

Age-related declines in endothelial function can lead to cognitive decline. However, little is known about the relationships between endothelial function and specific neurocognitive functions. This study explored the relationship between measures of endothelial function (reactive hyperemia index; RHI), white matter (WM) health (fractional anisotropy, FA, and WM hyperintensity volume, WMH), and executive function (Trail Making Test (TMT); Trail B - Trail A). Participants were 36 older adults between the ages of 59 and 69 (mean age = 63.89 years, SD = 2.94). WMH volume showed no relationship with RHI or executive function. However, there was a positive relationship between RHI and FA in the genu and body of the corpus callosum. In addition, higher RHI and FA were each associated with better executive task performance. Tractography was used to localize the WM tracts associated with RHI to specific portions of cortex. Results indicated that the RHI-FA relationship observed in the corpus callosum primarily involved tracts interconnecting frontal regions, including the superior frontal gyrus (SFG) and frontopolar cortex, linked with executive function. These findings suggest that superior endothelial function may help to attenuate age-related declines in WM microstructure in portions of the corpus callosum that interconnect prefrontal brain regions involved in executive function

Primary hemiarthroplasty for treatment of proximal humeral fractures

Background: Primary hemiarthroplasty of the shoulder is used to treat complex proximal humeral fractures, although the reported functional results following this method of treatment have varied widely. The aim of this study was to prospectively assess the prosthetic survival and functional outcomes in a large series of patients treated with shoulder hemiarthroplasty for a proximal humeral fracture. By determining the factors that affected the outcome, we also aimed to produce models that could be used clinically to estimate the functional outcome at one year following surgery.Methods: A thirteen-year observational cohort study of 163 consecutive patients treated with hemiarthroplasty for a proximal humeral fracture was performed. Twenty-five patients died or were lost to follow-up in the first year after treatment, leaving 138 patients who had assessment of shoulder function with use of the modified Constant score at one year postinjury.Results: The overall rate of prosthetic survival was 96.9% at one year, 95.3% at five years, and 93.9% at ten years. The overall median modified Constant score was 64 points at one year, with a typically good score for pain relief (median, 15 points) and poorer scores, with a greater scatter of values, for function (median, 12 points), range of motion (median, 24 points), and muscle power (median, 14 points). Of the factors that were assessed immediately after the injury, only patient age, the presence of a neurological deficit, tobacco usage, and alcohol consumption were significantly predictive of the one-year Constant score (p &lt; 0.05). Of the factors that were assessed at six weeks postinjury, those that predicted the one-year Constant score included the age of the patient, the presence of a persistent neurological deficit, the need for an early reoperation, the degree of displacement of the prosthetic head from the central axis of the glenoid seen radiographically, and the degree of displacement of the tuberosities seen radiographically.Conclusions: Primary shoulder hemiarthroplasty performed for the treatment of a proximal humeral fracture in medically fit and cooperative adults is associated with satisfactory prosthetic survival at an average of 6.3 years. Although the shoulder is usually free of pain following this procedure, the overall functional result, in terms of range of motion, function, and power, at one year varies. A good functional outcome can be anticipated for a younger individual who has no preoperative neurological deficit, no postoperative complications, and a satisfactory radiographic appearance of the shoulder at six weeks. The results are poorer in the larger group of elderly patients who undergo this procedure, especially if they have a neurological deficit, a postoperative complication requiring a reoperation, or an eccentrically located prosthesis with retracted tuberosities.<br /

Examining Social Vulnerability and the association With Covid-19 incidence in Harris County, Texas

Studies have investigated the association between social vulnerability and SARS-CoV-2 incidence. However, few studies have examined small geographic units such as census tracts, examined geographic regions with large numbers of Hispanic and Black populations, controlled for testing rates, and incorporated stay-at-home measures into their analyses. Understanding the relationship between social vulnerability and SARS-CoV-2 incidence is critical to understanding the interplay between social determinants and implementing risk mitigation guidelines to curtail the spread of infectious diseases. The objective of this study was to examine the relationship between CDC\u27s Social Vulnerability Index (SVI) and SARS-CoV-2 incidence while controlling for testing rates and the proportion of those who stayed completely at home among 783 Harris County, Texas census tracts. SARS-CoV-2 incidence data were collected between May 15 and October 1, 2020. The SVI and its themes were the primary exposures. Median percent time at home was used as a covariate to measure the effect of staying at home on the association between social vulnerability and SARS-CoV-2 incidence. Data were analyzed using Kruskal Wallis and negative binomial regressions (NBR) controlling for testing rates and staying at home. Results showed that a unit increase in the SVI score and the SVI themes were associated with significant increases in SARS-CoV-2 incidence. The incidence risk ratio (IRR) was 1.090 (95% CI, 1.082, 1.098) for the overall SVI; 1.107 (95% CI, 1.098, 1.115) for minority status/language; 1.090 (95% CI, 1.083, 1.098) for socioeconomic; 1.060 (95% CI, 1.050, 1.071) for household composition/disability, and 1.057 (95% CI, 1.047, 1.066) for housing type/transportation. When controlling for stay-at-home, the association between SVI themes and SARS-CoV-2 incidence remained significant. In the NBR model that included all four SVI themes, only the socioeconomic and minority status/language themes remained significantly associated with SARS-CoV-2 incidence. Community-level infections were not explained by a communities\u27 inability to stay at home. These findings suggest that community-level social vulnerability, such as socioeconomic status, language barriers, use of public transportation, and housing density may play a role in the risk of SARS-CoV-2 infection regardless of the ability of some communities to stay at home because of the need to work or other reasons

Social Constructivism and Case-Writing for an Integrated Curriculum

Case-writing within an integrated, systems-based health professions education curriculum presents many unique challenges. Specifically, case-writing in this context must consider integration of multidisciplinary learning objectives and synthesis of biomedical and clinical sciences. Establishing an effective process for content integration and determining who should be involved in the case-writing process can be a daunting task and this specific context requires a new model for effective casewriting. This paper provides a model for the cycle of case development, implementation, evaluation and modification in an integrated, systems-based health professions curriculum. We highlight how this collaborative case-writing model parallels the social constructivist approach promoted by the problem-based learning process in which our students engage

Increased HIV Incidence in Men Who Have Sex with Men Despite High Levels of ART-Induced Viral Suppression: Analysis of an Extensively Documented Epidemic

Background: There is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ART coverage has increased for reasons which remain unclear. Methods: We analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour. Results: HIV-incidence has increased (estimated mean incidence 0.30/100 person-years 1990–1997, 0.45/100 py 1998–2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006–2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections. Conclusion: A rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections

Francisella tularensis Transmission by Solid Organ Transplantation, 20171.

In July 2017, fever and sepsis developed in 3 recipients of solid organs (1 heart and 2 kidneys) from a common donor in the United States; 1 of the kidney recipients died. Tularemia was suspected only after blood cultures from the surviving kidney recipient grew Francisella species. The organ donor, a middle-aged man from the southwestern United States, had been hospitalized for acute alcohol withdrawal syndrome, pneumonia, and multiorgan failure. F. tularensis subsp. tularensis (clade A2) was cultured from archived spleen tissue from the donor and blood from both kidney recipients. Whole-genome multilocus sequence typing indicated that the isolated strains were indistinguishable. The heart recipient remained seronegative with negative blood cultures but had been receiving antimicrobial drugs for a medical device infection before transplant. Two lagomorph carcasses collected near the donor's residence were positive by PCR for F. tularensis subsp. tularensis (clade A2). This investigation documents F. tularensis transmission by solid organ transplantation