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Bone health declines in the initial years after Roux-en-Y gastric bypass (RYGB), but long-term skeletal effects are unclear. To document longitudinal changes in bone mineral density (BMD) and microarchitecture 5 years after RYGB. Prospective 5-year observational study of 21 adults with severe obesity receiving RYGB at an academic medical center. Spine and hip areal BMD were measured by dual-energy X-ray absorptiometry, and trabecular volumetric BMD (vBMD) of the spine was assessed by quantitative CT (QCT). We measured vBMD and microarchitecture of the distal radius and tibia by high-resolution peripheral QCT in a subset of subjects. Serum type I collagen C-terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (P1NP) were also measured. Areal BMD declined by -7.8% ± 7.6% at the spine and -15.3% ± 6.3% at the total hip by 5 years after RYGB (P ≤ 0.001), although the rate of bone loss slowed in later years. Trabecular spine vBMD decreased by -12.1% ± 12.3% by 5 years (P ≤ 0.001). At peripheral sites, vBMD continued to decrease steadily throughout 5 years, with parallel declines in cortical and trabecular microarchitecture, leading to decreases in estimated failure load of -20% and -13% at the radius and tibia, respectively (P < 0.001). Five years after RYGB, CTX and P1NP were 150% and 34% above baseline (P < 0.001 and P = 0.017, respectively). Sustained high-turnover bone loss and bone microarchitectural deterioration occur in the 5 years after RYGB. Adults receiving RYGB warrant assessment of bone health.

Abstract Background A significant proportion of patients with ulcerative colitis (UC) have suboptimal responses to medical therapy. Expansion of regulatory T cells (Tregs), but not conventional T cells (Tcons), through the use of low doses (LD) of the T cell growth factor Interleukin-2 (IL-2, Proleukin®), has been a promising approach in other immune-mediated diseases and pre-clinical humanized UC mouse models. We performed a phase 1b/2a clinical trial in patients with moderate-to-severe UC to determine if subcutaneously (SC) administered LD IL-2 is safe and results in a biological response. Methods An open-label single arm phase 1b/2a trial of LD SC IL-2 in moderate-to-severe UC patients involving 2 phases: (1) dose escalation phase, in which three sequentially increasing dose levels were tested: 0.3x106 IU/m2/day (Dose A), 1x106 IU/m2/day (Dose B) or 1.5x106 IU/m2/day (Dose C); (2) treatment at the maximum tolerated dose (MTD) phase, defined as the highest tolerated dose level at which fewer than 2 evaluable subjects experienced a dose limiting toxicity (DLT). Adult patients with UC and a Mayo score of 6–12 were included and received a daily SC injection. The primary objectives were safety and determination of MTD. Clinical and laboratory assessments occurred pre-treatment and at weeks 1, 2, 4, 6, 8 and 12, with sigmoidoscopy at baseline and week 8. Peripheral Treg (pTreg) expansion was defined as >2X increase in % CD4+CD25+ cells. Tcon activation is measured by pSTAT5 in CD4+CD25- cells. Results 26 patients were enrolled. Baseline characteristics were similar among groups. There were no serious adverse events (AEs). Common (occuring in >10% of patients) AEs included injection site reactions and malaise across all doses. In the dose escalation phase, 4 patients received Dose A: pTreg expansion was noted in 2/4; 1 achieved clinical remission. 7 patients received Dose B: 1 developed a rash deemed a DLT; 2 achieved remission and 1 achieved response. pTreg expansion was noted in all patients at this dose. 5 patients received Dose C. No DLT was observed. pTreg expansion was seen in all patients in this group, but unwanted Tcon activation was also observed at this dose level. No patient achieved clinical response at this dose. Therefore, MTD was modified to maximum effective dose (MED) and Dose B was considered MED; 10 additional patients were enrolled: 2 achieved remission, 4 response, 2 had no response and 2 withdrew (headaches and worsening colitis). Overall, 38.4% (10/26) have achieved either response or remission including 53% in Dose B alone (9/17). Although all Dose B subjects had pTreg expansion, Treg expansion in the colonic mucosa was not necessary for clinical response. Conclusion LD SC IL-2 was well tolerated and associated with a biological response and pTreg expansion in patients with moderate-to-severe UC. 1x106 IU/m2 was found to be the MED.

In the current study, ten participants walked for two hours while carrying no load or a 40 kg load. During the second hour, treadmill grade was manipulated between a constant downhill or changing between flat, uphill, and downhill grades. Throughout the prolonged walk, participants performed two cognitive tasks, an auditory go no/go task and a visual target detection task. The main findings were that the number of false alarms increased over time in the loaded condition relative to the unloaded condition on the go no/go auditory task. There were also shifts in response criterion towards responding yes and decreased sensitivity in responding in the loaded condition compared to the unloaded condition. In the visual target detection there were no reliable effects of load carriage in the overall analysis however, there were slower reaction times in the loaded compared to unloaded condition during the second hour.

Mitochondrial sequence data is often used to reconstruct the demographic history of Pleistocene populations in an effort to understand how species have responded to past climate change events. However, departures from neutral equilibrium conditions can confound evolutionary inference in species with structured populations or those that have experienced periods of population expansion or decline. Selection can affect patterns of mitochondrial DNA variation and variable mutation rates among mitochondrial genes can compromise inferences drawn from single markers. We investigated the contribution of these factors to patterns of mitochondrial variation and estimates of time to most recent common ancestor (TMRCA) for two clades in a co-operatively breeding avian species, the white-browed babbler Pomatostomus superciliosus. Both the protein-coding ND3 gene and hypervariable domain I control region sequences showed departures from neutral expectations within the superciliosus clade, and a two-fold difference in TMRCA estimates. Bayesian phylogenetic analysis provided evidence of departure from a strict clock model of molecular evolution in domain I, leading to an over-estimation of TMRCA for the superciliosus clade at this marker. Our results suggest mitochondrial studies that attempt to reconstruct Pleistocene demographic histories should rigorously evaluate data for departures from neutral equilibrium expectations, including variation in evolutionary rates across multiple markers. Failure to do so can lead to serious errors in the estimation of evolutionary parameters and subsequent demographic inferences concerning the role of climate as a driver of evolutionary change. These effects may be especially pronounced in species with complex social structures occupying heterogeneous environments. We propose that environmentally driven differences in social structure may explain observed differences in evolutionary rate of domain I sequences, resulting from longer than expected retention times for matriarchal lineages in the superciliosus clade.

Introduction Women vaccinated through the initial catch-up HPV vaccination programme (2011/12 to 2013/14) first became eligible for cervical screening in 2019 at age 25. This study aims to examine the changes in detection of HG cytology outcomes in 25-year-olds screened from 2010 to 2022 compared to population data on HPV vaccination in this group. Methods This was an ecological-type study. Cytology results from the CervicalCheck database from 2010 to 2022 (High Grade, Low Grade, and No Abnormality Detected) were plotted against data from the National Immunisation Office on the uptake of HPV vaccinations in females from 2010 to 2022. Results Vaccination rates in the catch-up programme were lower (44–70%) than for routine HPV immunisation at age 12/13 in 2010/11 (81%). The rate of high-grade cytology in 25-year-olds in 2015–2018 was 3.7% of all cytology tests taken in this age group. For the corresponding period from 2019 to 2022 (when vaccinated women were attending screening), the average percentage of HG cytology in 25-year-olds was 1.5%, representing a significant reduction in HG cytology proportions ( p  < 0.001). Conclusion This study provides early evidence of the potential impact of HPV vaccination on cervical disease in the Republic of Ireland. Despite lower vaccination uptake in the initial catch-up group, we are seeing early signs of the positive protective effect of HPV vaccination in women at the time of their first cervical screening test. Plans to incorporate individual-level HPV vaccination status for women on the cervical screening register will allow more detailed assessment of the impact of HPV vaccination.

Mitochondrial sequence data is often used to reconstruct the demographic history of Pleistocene populations in an effort to understand how species have responded to past climate change events. However, departures from neutral equilibrium conditions can confound evolutionary inference in species with structured populations or those that have experienced periods of population expansion or decline. Selection can affect patterns of mitochondrial DNA variation and variable mutation rates among mitochondrial genes can compromise inferences drawn from single markers. We investigated the contribution of these factors to patterns of mitochondrial variation and estimates of time to most recent common ancestor (TMRCA) for two clades in a co-operatively breeding avian species, the white-browed babbler Pomatostomus superciliosus. Both the protein-coding ND3 gene and hypervariable domain I control region sequences showed departures from neutral expectations within the superciliosus clade, and a two-fold difference in TMRCA estimates. Bayesian phylogenetic analysis provided evidence of departure from a strict clock model of molecular evolution in domain I, leading to an over-estimation of TMRCA for the superciliosus clade at this marker. Our results suggest mitochondrial studies that attempt to reconstruct Pleistocene demographic histories should rigorously evaluate data for departures from neutral equilibrium expectations, including variation in evolutionary rates across multiple markers. Failure to do so can lead to serious errors in the estimation of evolutionary parameters and subsequent demographic inferences concerning the role of climate as a driver of evolutionary change. These effects may be especially pronounced in species with complex social structures occupying heterogeneous environments. We propose that environmentally driven differences in social structure may explain observed differences in evolutionary rate of domain I sequences, resulting from longer than expected retention times for matriarchal lineages in the superciliosus clade.

Regionalization and devolution bring various things, but from an archaeological point of view, they generally encourage greater investment in heritage matters and cultural research, and an increased local awareness of, and pride in, the depth of the region's history. Scientific methods and studies, wide-ranging historical surveys, philosophical and theoretical preoccupations, panEuropean comparisons of sites, technologies and societies, have stimulated a progressive archaeological tradition that places Ireland in the forefront of research and understanding. The enactment of stronger protective legislation in the Republic of Ireland, and the launch of the Discovery Programme, together with growing public interest and centres of archaeological scholarship throughout Ireland, are shown to be major stimulants in the country's archaeological development. The site is one of only two World Heritage sites in the Republic of Ireland, and it has been subject to a major programme of repair and study.