Endocervical glandular neoplasia associated with lobular endocervical glandular hyperplasia is HPV-independent and correlates with carbonic anhydrase-IX expression: a Gynaecological Oncology Group Study.

BackgroundLobular endocervical glandular hyperplasia (LEGH) is a rare lesion of the uterine cervix. It has been proposed that LEGH may represent a precursor lesion to a group of mucinous adenocarcinoma with gastric phenotype (GA) that is independent of high-risk human papillomavirus (H-HPV) infection. Carbonic anhydrase-IX (CA-IX) is highly expressed in conventional glandular lesions (CGLs). However, expression of CA-IX in LEGH or GA has not been studied.MethodsIn all, 12 CGLs, 7 LEGHs, 6 LEGHs with coexisting adenocarcinoma in situ (AIS, 3) and GA (3) were identified from Japanese women with a cytological diagnosis of atypical glandular cells of undetermined significance. Immunostaining was used to detect CA-IX and p16(INK)4(a) (hereafter termed p16) protein expression in the tissues and CA-IX protein expression in the Papanicolaou smears (PSs). Polymerase chain reaction was used to detect H-HPV DNA in liquid-based cytology.ResultsOut of 12 (83%) CGLs, 10 were positive with H-HPV and high levels of CA-IX expression were seen in all (100%) cases. P16 protein expression was observed in 11 out of 12 (92%) cases. None of the LEGHs, LEGHs with AIS or GA were positive for H-HPV and only 8 out of 13 (62%) showed focal weak (1+) p16 expression. In contrast, all cases (100%) exhibited strong CA-IX protein expression.ConclusionOur study suggests that there are different molecular mechanisms of carcinogenesis resulting in CGLs vs LEGHs associated with AIS or GA. There is also a possible link between LEGHs and GAs. Furthermore, CA-IX expression may serve as a useful biomarker for the detection of GAs in the absence of H-HPV infection

Heavy resistance training in hypoxia enhances 1RM squat performance

Purpose: To determine if heavy resistance training in hypoxia (IHRT) is more effective at improving strength, power, and increasing lean mass than the same training in normoxia. Methods: A pair-matched, placebo-controlled study design included 20 resistance-trained participants assigned to IHRT (FIO2 0.143) or placebo (FIO2 0.20), (n = 10 per group). Participants were matched for strength and training. Both groups performed 20 sessions over 7 weeks either with IHRT or placebo. All participants were tested for 1RM, 20-m sprint, body composition, and countermovement jump pre-, mid-, and post-training and compared via magnitude-based inferences. Presentation of Results: Groups were not clearly different for any test at baseline. Training improved both absolute (IHRT: 13.1 ± 3.9%, effect size (ES) 0.60, placebo 9.8 ± 4.7%, ES 0.31) and relative 1RM (IHRT: 13.4 ± 5.1%, ES 0.76, placebo 9.7 ± 5.3%, ES 0.48) at mid. Similarly, at post both groups increased absolute (IHRT: 20.7 ± 7.6%, ES 0.74, placebo 14.1 ± 6.0%, ES 0.58) and relative 1RM (IHRT: 21.6 ± 8.5%, ES 1.08, placebo 13.2 ± 6.4%, ES 0.78). Importantly, the change in IHRT was greater than placebo at mid for both absolute [4.4% greater change, 90% Confidence Interval (CI) 1.0:8.0%, ES 0.21, and relative strength (5.6% greater change, 90% CI 1.0:9.4%, ES 0.31 (relative)]. There was also a greater change for IHRT at post for both absolute (7.0% greater change, 90% CI 1.3:13%, ES 0.33), and relative 1RM (9.2% greater change, 90% CI 1.6:14.9%, ES 0.49). Only IHRT increased countermovement jump peak power at Post (4.9%, ES 0.35), however the difference between IHRT and placebo was unclear (2.7, 90% CI –2.0:7.6%, ES 0.20) with no clear differences in speed or body composition throughout. Conclusion: Heavy resistance training in hypoxia is more effective than placebo for improving absolute and relative strength

A Synergistic Approach for Evaluating Climate Model Output for Ecological Applications

Increasing concern about the impacts of climate change on ecosystems is prompting ecologists and ecosystem managers to seek reliable projections of physical drivers of change. The use of global climate models in ecology is growing, although drawing ecologically meaningful conclusions can be problematic. The expertise required to access and interpret output from climate and earth system models is hampering progress in utilizing them most effectively to determine the wider implications of climate change. To address this issue, we present a joint approach between climate scientists and ecologists that explores key challenges and opportunities for progress. As an exemplar, our focus is the Southern Ocean, notable for significant change with global implications, and on sea ice, given its crucial role in this dynamic ecosystem. We combined perspectives to evaluate the representation of sea ice in global climate models. With an emphasis on ecologically-relevant criteria (sea ice extent and seasonality) we selected a subset of eight models that reliably reproduce extant sea ice distributions. While the model subset shows a similar mean change to the full ensemble in sea ice extent (approximately 50% decline in winter and 30% decline in summer), there is a marked reduction in the range. This improved the precision of projected future sea ice distributions by approximately one third, and means they are more amenable to ecological interpretation. We conclude that careful multidisciplinary evaluation of climate models, in conjunction with ongoing modeling advances, should form an integral part of utilizing model output

The DNA damage checkpoint pathway promotes extensive resection and nucleotide synthesis to facilitate homologous recombination repair and genome stability in fission yeast.

DNA double-strand breaks (DSBs) can cause chromosomal rearrangements and extensive loss of heterozygosity (LOH), hallmarks of cancer cells. Yet, how such events are normally suppressed is unclear. Here we identify roles for the DNA damage checkpoint pathway in facilitating homologous recombination (HR) repair and suppressing extensive LOH and chromosomal rearrangements in response to a DSB. Accordingly, deletion of Rad3(ATR), Rad26ATRIP, Crb2(53BP1) or Cdc25 overexpression leads to reduced HR and increased break-induced chromosome loss and rearrangements. We find the DNA damage checkpoint pathway facilitates HR, in part, by promoting break-induced Cdt2-dependent nucleotide synthesis. We also identify additional roles for Rad17, the 9-1-1 complex and Chk1 activation in facilitating break-induced extensive resection and chromosome loss, thereby suppressing extensive LOH. Loss of Rad17 or the 9-1-1 complex results in a striking increase in break-induced isochromosome formation and very low levels of chromosome loss, suggesting the 9-1-1 complex acts as a nuclease processivity factor to facilitate extensive resection. Further, our data suggest redundant roles for Rad3ATR and Exo1 in facilitating extensive resection. We propose that the DNA damage checkpoint pathway coordinates resection and nucleotide synthesis, thereby promoting efficient HR repair and genome stability

Where do we go from here? An assessment of navigation performance using a compass versus a GPS unit

The Global Positioning System (GPS) looks set to replace the traditional map and compass for navigation tasks in military and civil domains. However, we may ask whether GPS has a real performance advantage over traditional methods. We present an exploratory study using a waypoint plotting task to compare the standard magnetic compass against a military GPS unit, for both expert and non-expert navigators. Whilst performance times were generally longer in setting up the GPS unit, once navigation was underway the GPS was more efficient than the compass. For mediumto long-term missions, this means that GPS could offer significant performance benefits, although the compass remains superior for shorter missions. Notwithstanding the performance times, significantly more errors, and more serious errors, occurred when using the compass. Overall, then, the GPS offers some clear advantages, especially for non-expert users. Nonetheless, concerns over the development of cognitive maps remain when using GPS technologies

Identifying prognostic indicators for cognitive stimulation therapy for dementia: protocol for a systematic review and individual participant data meta-analysis

BACKGROUND: Cognitive stimulation therapy (CST) is the only non-pharmacological, treatment for dementia recommended by the UK National Institute for Health and Care Excellence, following multiple international trials demonstrating beneficial cognitive outcomes in people with mild-to-moderate dementia. However, there is limited understanding of whether treatment prognosis is influenced by sociodemographic and clinical variables (such as dementia subtype and gender), information which could inform clinical decision-making. AIM: We describe the protocol for a systematic review and individual patient data meta-analysis assessing the prognostic factors related to CST. In publishing this protocol, we hope to increase the transparency of our work, and keep healthcare professionals aware of the latest evidence for effective CST. METHOD: A systematic review will be conducted with searches of the bibliographic databases Medline, EMBASE and PsycINFO, from inception to 7 February 2023. Studies will be included if they are clinical trials of CST, use the Alzheimer's Disease Assessment Scale - Cognitive Subscale (gold-standard measure of cognition in dementia in clinical trials) and include participants with mild-to-moderate dementia. Following harmonisation of the data-set, mixed-effect models will be constructed to explore the relationship between the prognostic indicators and change scores post-treatment. CONCLUSIONS: This is the first individual patient data meta-analyses on CST, and has the potential to significantly optimise patient care. Previous analyses suggest people with advanced dementia could benefit more from CST treatment. Given that CST is currently used post-diagnosis in people with mild-to-moderate dementia, the implications of confirming this finding, among identifying other prognostic indicators, are profound

Insulin therapy and dietary adjustments to normalize glycaemia and prevent nocturnal hypoglycaemia after evening exercise in type 1 diabetes: a randomized controlled trial

Introduction Evening-time exercise is a frequent cause of severe hypoglycemia in type 1 diabetes, fear of which deters participation in regular exercise. Recommendations for normalizing glycemia around exercise consist of prandial adjustments to bolus insulin therapy and food composition, but this carries only short-lasting protection from hypoglycemia. Therefore, this study aimed to examine the impact of a combined basal-bolus insulin dose reduction and carbohydrate feeding strategy on glycemia and metabolic parameters following evening exercise in type 1 diabetes. Methods Ten male participants (glycated hemoglobin: 52.4±2.2 mmol/mol), treated with multiple daily injections, completed two randomized study-days, whereby administration of total daily basal insulin dose was unchanged (100%), or reduced by 20% (80%). Participants attended the laboratory at ∼08:00 h for a fasted blood sample, before returning in the evening. On arrival (∼17:00 h), participants consumed a carbohydrate meal and administered a 75% reduced rapid-acting insulin dose and 60 min later performed 45 min of treadmill running. At 60 min postexercise, participants consumed a low glycemic index (LGI) meal and administered a 50% reduced rapid-acting insulin dose, before returning home. At ∼23:00 h, participants consumed a LGI bedtime snack and returned to the laboratory the following morning (∼08:00 h) for a fasted blood sample. Venous blood samples were analyzed for glucose, glucoregulatory hormones, non-esterified fatty acids, β-hydroxybutyrate, interleukin 6, and tumor necrosis factor α. Interstitial glucose was monitored for 24 h pre-exercise and postexercise. Results Glycemia was similar until 6 h postexercise, with no hypoglycemic episodes. Beyond 6 h glucose levels fell during 100%, and nine participants experienced nocturnal hypoglycemia. Conversely, all participants during 80% were protected from nocturnal hypoglycemia, and remained protected for 24 h postexercise. All metabolic parameters were similar. Conclusions Reducing basal insulin dose with reduced prandial bolus insulin and LGI carbohydrate feeding provides protection from hypoglycemia during and for 24 h following evening exercise. This strategy is not associated with hyperglycemia, or adverse metabolic disturbances

Pre-Meal Whey Protein Alters Postprandial Insulinemia by Enhancing β-Cell Function and Reducing Insulin Clearance in T2D

CONTEXT: Treatments that reduce postprandial glycemia (PPG) independent of stimulating insulin secretion are appealing for the management of type 2 diabetes (T2D). Consuming pre-meal whey protein (WP) reduces PPG by delaying gastric emptying and increasing plasma insulin concentrations. However, its effects on β-cell function and insulin kinetics remains unclear. OBJECTIVE: To examine the PPG-regulatory effects of pre-meal WP by modeling insulin secretion rates (ISR), insulin clearance, and β-cell function. METHODS: This was a single-blind, randomized, placebo-controlled, crossover design study in 18 adults with T2D (HbA1c, 56.7 ± 8.8 mmol/mol) who underwent 2 240-minute mixed-meal tolerance tests. Participants consumed WP (15 g protein) or placebo (0 g protein) 10 minutes before a mixed-macronutrient breakfast meal. PPG, pancreatic islet, and incretin hormones were measured throughout. ISR was calculated by C-peptide deconvolution. Estimates of insulin clearance and β-cell function were modeled from glucose, insulin, and ISR. Changes in PPG incremental area under the curve (iAUC; prespecified) and insulin clearance (post hoc) were measured. RESULTS: β-cell function was 40% greater after WP (P = .001) and was accompanied with a -22% reduction in postprandial insulin clearance vs placebo (P < .0001). Both the peak change and PPG iAUC were reduced by WP (-1.5 mmol/L and -16%, respectively; both P < .05). Pre-meal WP augmented a 5.9-fold increase in glucagon and glucagon-like peptide 1 iAUC (both P < .0001), and a 1.5-fold increase in insulin iAUC (P < .001). Although the plasma insulin response was greater following WP, ISR was unaffected (P = .133). CONCLUSION: In adults with T2D, pre-meal WP reduced PPG by coordinating an enhancement in β-cell function with a reduction in insulin clearance. This enabled an efficient postprandial insulinemic profile to be achieved without requiring further β-cell stimulation.Trial registry ISRCTN ID: ISRCTN17563146 Website link: www.isrctn.com/ISRCTN17563146