Integrin α2β1 Expression Regulates Matrix Metalloproteinase-1-Dependent Bronchial Epithelial Repair in Pulmonary Tuberculosis.

Pulmonary tuberculosis (TB) is caused by inhalation of Mycobacterium tuberculosis, which damages the bronchial epithelial barrier to establish local infection. Matrix metalloproteinase-1 plays a crucial role in the immunopathology of TB, causing breakdown of type I collagen and cavitation, but this collagenase is also potentially involved in bronchial epithelial repair. We hypothesized that the extracellular matrix (ECM) modulates M. tuberculosis-driven matrix metalloproteinase-1 expression by human bronchial epithelial cells (HBECs), regulating respiratory epithelial cell migration and repair. Medium from monocytes stimulated with M. tuberculosis induced collagenase activity in bronchial epithelial cells, which was reduced by ~87% when cells were cultured on a type I collagen matrix. Matrix metalloproteinase-1 had a focal localization, which is consistent with cell migration, and overall secretion decreased by 32% on type I collagen. There were no associated changes in the specific tissue inhibitors of metalloproteinases. Decreased matrix metalloproteinase-1 secretion was due to ligand-binding to the α2β1 integrin and was dependent on the actin cytoskeleton. In lung biopsies, samples from patients with pulmonary TB, integrin α2β1 is highly expressed on the bronchial epithelium. Areas of lung with disrupted collagen matrix showed an increase in matrix metalloproteinases-1 expression compared with areas where collagen was comparable to control lung. Type I collagen matrix increased respiratory epithelial cell migration in a wound-healing assay, and this too was matrix metalloproteinase-dependent, since it was blocked by the matrix metalloproteinase inhibitor GM6001. In summary, we report a novel mechanism by which α2β1-mediated signals from the ECM modulate matrix metalloproteinase-1 secretion by HBECs, regulating their migration and epithelial repair in TB

Marine bivalve records of Antarctic seasonality and biological responses to environmental change over the Cretaceous-Paleogene mass extinction interval

The Cretaceous-Paleogene mass extinction event occurred 66 million years ago and had a profound effect on the course of evolutionary history, with the extinction of up to 75% of life and larger effects on the broader Earth system. A number of studies posit that the severity of this extinction event may have been amplified by climate variability and destabilisation in the latest Cretaceous – immediately prior to the extinction event. The strong seasonal forcing in the polar high latitudes is likely to have enhanced any such effects during this time period; additionally, the historical mismatch between late Cretaceous proxy data and climate simulations is particularly pronounced at high latitudes and both the effects of a stronger seasonal cycle on proxy temperature conversions, and misrepresentation of seasonality in climate models have been suggested as factors in the mismatch. This makes the Antarctic an extremely valuable location to study with regards to seasonality from a proxy- and model- based perspective. Seymour Island is a rare and valuable Antarctic K-Pg boundary site with a good framework of fossil, stratigraphic and sedimentological study, which makes fossil material ideal for investigation of the effects and impacts of seasonality and environmental change across the mass extinction interval. This thesis presents a detailed study focusing on using fossil bivalve shell material from the Seymour Island section to reconstruct records of Antarctic climate and seasonality across the K-Pg mass extinction event. New data were obtained about the seasonal growth patterns of these bivalves to understand their growth and ontogenetic response to potential climate variability and the effects of the mass extinction. For the first time, sub-annual resolution stable carbon and oxygen isotopic data were produced from Seymour Island’s bivalve shells to show seasonal changes in temperatures and detect changes in biogeochemical cycling and methane influence through the section. These data were integrated with a series of oxygen isotope enabled climate simulations to address potential issues converting from isotopic to temperature data in a highly seasonal environment and provide further information regarding the influence of sea ice. Combining new proxy- and model- based knowledge in a series of sensitivity experiments, it was shown that both sets of data display good agreement under realistic sets of parameters, suggesting that seasonality was important for the development of polar ecosystems. Warm summer temperatures may have been key in permitting the ecological strategy in these bivalves of slow growth to large sizes, which in turn may have contributed to survivorship across the K-Pg boundary

Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study

BACKGROUND AND AIMS: Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. METHODS: A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP ( 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP 2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years. CONCLUSIONS: This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines

Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth

NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer

The influence of 'significant others' on persistent back pain and work participation: a qualitative exploration of illness perceptions

Background Individual illness perceptions have been highlighted as important influences on clinical outcomes for back pain. However, the illness perceptions of 'significant others' (spouse/partner/close family member) are rarely explored, particularly in relation to persistent back pain and work participation. The aim of this study was to initiate qualitative research in this area in order to further understand these wider influences on outcome. Methods Semi-structured interviews based on the chronic pain version of the Illness Perceptions Questionnaire-Revised were conducted with a convenience sample of UK disability benefit claimants, along with their significant others (n=5 dyads). Data were analysed using template analysis. Results Significant others shared, and perhaps further reinforced, claimants' unhelpful illness beliefs including fear of pain/re-injury associated with certain types of work and activity, and pessimism about the likelihood of return to work. In some cases, significant others appeared more resigned to the permanence and negative inevitable consequences of the claimant's back pain condition on work participation, and were more sceptical about the availability of suitable work and sympathy from employers. In their pursuit of authenticity, claimants were keen to stress their desire to work whilst emphasising how the severity and physical limitations of their condition prevented them from doing so. In this vein, and seemingly based on their perceptions of what makes a 'good' significant other, significant others acted as a 'witness to pain', supporting claimants' self-limiting behaviour and statements of incapacity, often responding with empathy and assistance. The beliefs and responses of significant others may also have been influenced by their own experience of chronic illness, thus participants lives were often intertwined and defined by illness. Conclusions The findings from this exploratory study reveal how others and wider social circumstances might contribute both to the propensity of persistent back pain and to its consequences. This is an area that has received little attention to date, and wider support of these findings may usefully inform the design of future intervention programmes aimed at restoring work participation

Photographed Rapid HIV Test Results Pilot Novel Quality Assessment and Training Schemes

HIV rapid diagnostic tests (RDTs) are now used widely in non-laboratory settings by non-laboratory-trained operators. Quality assurance programmes are essential in ensuring the quality of HIV RDT outcomes. However, there is no cost-effective means of supplying the many operators of RDTs with suitable quality assurance schemes. Therefore, it was examined whether photograph-based RDT results could be used and correctly interpreted in the non-laboratory setting. Further it was investigated if a single training session improved the interpretation skills of RDT operators. The photographs were interpreted, a 10-minute tutorial given and then a second interpretation session was held. It was established that the results could be read with accuracy. The participants (n = 75) with a range of skills interpreted results (>80% concordance with reference results) from a panel of 10 samples (three negative and seven positive) using four RDTs. Differences in accuracy of interpretation before and after the tutorial were marked in some cases. Training was more effective for improving the accurate interpretation of more complex results, e.g. results with faint test lines or for multiple test lines, and especially for improving interpretation skills of inexperienced participants. It was demonstrated that interpretation of RDTs was improved using photographed results allied to a 10-minute training session. It is anticipated that this method could be used for training but also for quality assessment of RDT operators without access to conventional quality assurance or training schemes requiring wet samples

The Loss of Species: Mangrove Extinction Risk and Geographic Areas of Global Concern

Mangrove species are uniquely adapted to tropical and subtropical coasts, and although relatively low in number of species, mangrove forests provide at least US $1.6 billion each year in ecosystem services and support coastal livelihoods worldwide. Globally, mangrove areas are declining rapidly as they are cleared for coastal development and aquaculture and logged for timber and fuel production. Little is known about the effects of mangrove area loss on individual mangrove species and local or regional populations. To address this gap, species-specific information on global distribution, population status, life history traits, and major threats were compiled for each of the 70 known species of mangroves. Each species' probability of extinction was assessed under the Categories and Criteria of the IUCN Red List of Threatened Species. Eleven of the 70 mangrove species (16%) are at elevated threat of extinction. Particular areas of geographical concern include the Atlantic and Pacific coasts of Central America, where as many as 40% of mangroves species present are threatened with extinction. Across the globe, mangrove species found primarily in the high intertidal and upstream estuarine zones, which often have specific freshwater requirements and patchy distributions, are the most threatened because they are often the first cleared for development of aquaculture and agriculture. The loss of mangrove species will have devastating economic and environmental consequences for coastal communities, especially in those areas with low mangrove diversity and high mangrove area or species loss. Several species at high risk of extinction may disappear well before the next decade if existing protective measures are not enforced

The loss of species: mangrove extinction risk and failure of critical exosystem services

Mangrove species are uniquely adapted to tropical and subtropical coasts, and although relatively low in number of species, mangrove forests provide at least US $1.6 billion each year in ecosystem services and support coastal livelihoods worldwide. Globally, mangrove areas are declining rapidly as they are cleared for coastal development and aquaculture and logged for timber and fuel production. Little is known about the effects of mangrove area loss on individual mangrove species and local or regional populations. To address this gap, species-specific information on global distribution, population status, life history traits, and major threats were compiled for each of the 70 known species of mangroves. Each species\u27 probability of extinction was assessed under the Categories and Criteria of the IUCN Red List of Threatened Species. Eleven of the 70 mangrove species (16%) are at elevated threat of extinction. Particular areas of geographical concern include the Atlantic and Pacific coasts of Central America, where as many as 40% of mangroves species present are threatened with extinction. Across the globe, mangrove species found primarily in the high intertidal and upstream estuarine zones, which often have specific freshwater requirements and patchy distributions, are the most threatened because they are often the first cleared for development of aquaculture and agriculture. The loss of mangrove species will have devastating economic and environmental consequences for coastal communities, especially in those areas with low mangrove diversity and high mangrove area or species loss. Several species at high risk of extinction may disappear well before the next decade if existing protective measures are not enforced

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Scleroderma and related disorders: 223. Long Term Outcome in a Contemporary Systemic Sclerosis Cohort

Background: We have previously compared outcome in two groups of systemic sclerosis (SSc) patients with disease onset a decade apart and we reported data on 5 year survival and cumulative incidence of organ disease in a contemporary SSc cohort. The present study examines longer term outcome in an additional cohort of SSc followed for 10 years. Methods: We have examined patients with disease onset between years 1995 and 1999 allowing for at least 10 years of follow-up in a group that has characteristics representative for the patients we see in contemporary clinical practice. Results: Of the 398 patients included in the study, 252 (63.3%) had limited cutaneous (lc) SSc and 146 (36.7%) had diffuse cutaneous (dc) SSc. The proportion of male patients was higher among the dcSSc group (17.1% v 9.9%, p = 0.037) while the mean age of onset was significantly higher among lcSSc patients (50 ± 13 v 46 ± 13 years ± SD, p = 0.003). During a 10 year follow-up from disease onset, 45% of the dcSSc and 21% of the lcSSc subjects developed clinically significant pulmonary fibrosis, p < 0.001. Among them approximately half reached the endpoint within the first 3 years (23% of dcSSc and 10% of lcSSc) and over three quarters within the first 5 years (34% and 16% respectively). There was a similar incidence of pulmonary hypertension (PH) in the two subsets with a steady rate of increase over time. At 10 years 13% of dcSSc and 15% of lcSSc subjects had developed PH (p=0.558), with the earliest cases observed within the first 2 years of disease. Comparison between subjects who developed PH in the first and second 5 years from disease onset demonstrated no difference in demographic or clinical characteristics, but 5-year survival from PH onset was better among those who developed this complication later in their disease (49% v 24%), with a strong trend towards statistical significance (p = 0.058). Incidence of SSc renal crisis (SRC) was significantly higher among the dcSSc patients (12% v 4% in lcSSc, p = 0.002). As previously observed, the rate of development of SRC was highest in the first 3 years of disease- 10% in dcSSc and 3% in lcSSc. All incidences of clinically important cardiac disease developed in the first 5 years from disease onset (7% in dcSSc v 1% in lcSSc, p < 0.001) and remained unchanged at 10 years. As expected, 10-year survival among lcSSc subjects was significantly higher (81%) compared to that of dcSSc patients (70%, p = 0.006). Interestingly, although over the first 5 years the death rate was much higher in the dcSSc cohort (16% v 6% in lcSSc), over the following years it became very similar for both subsets (14% and 13% between years 5 and 10, and 18% and 17% between years 10 and 15 for dcSSc and lcSSc respectively). Conclusions: Even though dcSSc patients have higher incidence for most organ complications compared to lcSSc subjects, the worse survival among them is mainly due to higher early mortality rate. Mortality rate after first 5 years of disease becomes comparable in the two disease subsets. Disclosure statement: The authors have declared no conflicts of interes