Therapeutic distant organ effects of regional hypothermia during mesenteric ischemia-reperfusion injury

IntroductionMesenteric ischemia-reperfusion injury (IRI) leads to systemic inflammation and multiple organ failure in clinical and laboratory settings. We investigated the lung structural, functional, and genomic response to mesenteric IRI with and without regional intraischemic hypothermia (RIH) in rodents and hypothesized that RIH would protect the lung and preferentially modulate the distant organ transcriptome under these conditions.MethodsSprague-Dawley rats underwent sham laparotomy or superior mesenteric artery occlusion (SMAO) for 60 minutes with or without RIH. Gut temperature was maintained at 15°-20°C during SMAO, and systemic normothermia (37°C) was maintained throughout the study period. At 6 or 24 hours, lung tissue was collected for (1) histology, (2) myeloperoxidase activity, (3) bronchoalveolar lavage (BAL) fluid protein concentrations, (4) lung wet/dry ratios, and (5) total RNA isolation and hybridization to Illumina's Sentrix BeadChips (>22,000 probes) for gene expression profiling. Significantly affected genes (false discovery rate <5% and fold change ≥1.5) were linked to gene ontology (GO) terms using MAPPFinder, and hypothermia-suppressed genes were further analyzed with Pubmatrix.ResultsMesenteric IRI-induced lung injury, as evidenced by leukocyte trafficking, alveolar hemorrhage, and increased BAL protein and wet/dry ratios, and activated a proinflammatory lung transcriptome compared with sham. In contrast, rats treated with RIH exhibited lung histology, BAL protein, and wet/dry ratios similar to sham. At 6 hours, GO analysis identified 232 hypothermia-suppressed genes related to inflammation, innate immune response, and cell adhesion, and 33 hypothermia-activated genes related to lipid and amine metabolism and defense response. Quantitative real-time polymerase chain reaction validated select array changes in top hypothermia-suppressed genes lipocalin-2 (lcn-2) and chemokine ligand 1 (CXCL-1), prominent genes associated with neutrophil activation and trafficking.ConclusionsTherapeutic hypothermia during SMAO provides distant organ protection and preferentially modulates the IRI-activated transcriptome in the rat lung. This study identifies potential novel diagnostic and therapeutic targets of mesenteric IRI and provides a platform for further mechanistic study of hypothermic protection at the cellular and subcellular level.Clinical RelevanceVisceral organ ischemia-reperfusion injury (IRI) is a common clinical problem in the settings of shock, sepsis, vascular surgery, and organ transplantation and is a particularly vexing problem in the repair of complex aortic aneurysms. IRI is associated with considerable patient morbidity and mortality, for which there are virtually no therapeutic options. It systematically causes local organ injury and dysfunction, systemic inflammation, and multiple organ failure. Clinical trials investigating the efficacy of pharmacologic blockade of individual downstream inflammatory mediators in critically ill patients have been largely unsuccessful, and such studies highlight the need for novel top-down approaches, such as gene expression profiling for biologic discovery, as well as application of broader therapeutic interventions, such as targeted hypothermia. In this study, we demonstrate the potential application of visceral cooling for distant organ protection during mesenteric IRI, identify broad changes in lung gene expression under these conditions, and have elucidated potential novel diagnostic and therapeutic targets for disease targeting

Breast cancer screening beliefs by practice location

BACKGROUND: This study examines variations in breast cancer screening among primary care clinicians by geographic location of clinical practice. METHODS: A cross-sectional survey design was used to examine approaches to breast cancer screening among physicians, nurse practitioners, and physician assistants involved in primary care practice. A summary index of beliefs about breast cancer screening was created by summing the total number of responses in agreement with each of four survey items; values for this summary variable ranged between zero and four. Respondents were classified into urban, rural and suburban categories based upon practise location. RESULTS: Among the 428 respondents, agreement with "correct" responses ranged from 50% to 71% for the individual survey items; overall, half agreed with three or more of the four breast cancer screening items. While no significant differences were noted by practice location, variation in responses were evident. Reported use of written breast cancer guidelines was less in both suburban (OR = 0.51) and urban areas (OR = 0.56) when compared to clinicians in rural areas. CONCLUSION: Development of an evidence-based consensus statement regarding breast cancer screening would support a single set of unambiguous guidelines for implementation in all primary care settings, thus decreasing variations in how breast cancer screening is approached across varied clinical settings

Western Gull Foraging Behavior as an Ecosystem State Indicator in Coastal California

With accelerating climate variability and change, novel approaches are needed to warn managers of changing ecosystem state and to identify appropriate management actions. One strategy is using indicator species—like seabirds as ecosystem sentinels—to monitor changes in marine environments. Here, we explore the utility of western gulls (Larus occidentalis) breeding on Southeast Farallon Island as a proxy of ecosystem state in coastal California by investigating the interannual variability in gull foraging behavior from 2013 to 2019 in relation to upwelling conditions, prey abundances, and overlap with humpback whales (Megaptera novaeangliae) as gulls frequently feed in association with whales. Western gulls have a flexible diet and forage on land and at-sea. We combined gull GPS tracking data during the incubation phase, ecosystem survey data on multiple predator and prey species, and derived oceanographic upwelling products. When foraging at sea, gulls overlapped with cool upwelled waters. During 2015–2017, 25% more gull foraging trips visited land than in other years, where land trips were on average ∼8 h longer and 40% further than sea trips, which coincided with high compression of coastally upwelled waters (habitat compression) in 2015–2016. Gull foraging behavior was related to local prey abundances, where more foraging occurred near shore or on land when prey abundances were low. However, visual surveys indicated that ∼70% of humpback whale observations co-occurred with gulls, and the year with the most foraging on land (2017) corresponded to regionally low relative whale abundances, suggesting gull movement patterns could be an indicator of whale presence. Further, both whales and gulls forage near-shore under high upwelling habitat compression and low krill abundance. Hence, the deployment of year-round tags on gulls with the capability of near real-time data accessibility could provide important fine-scale metrics for conservation and management of the threatened yet recovering eastern Pacific humpback whale population between infrequent and coarse surveys. Entanglement in fishing gear and ship strikes are major inhibitors to whale recovery and have increased concomitantly with human use of ocean resources. Moreover, as climate variability and change increase, novel indicators should be explored and implemented to inform marine spatial planning and protect species across multiple scales from new risks

Odanacatib for the treatment of postmenopausal osteoporosis: Development history and design and participant characteristics of LoFT, the Long-term odanacatib Fracture Trial

Summary: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Introduction: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. Methods: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Results: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. Conclusions: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants

Mammography screening: views from women and primary care physicians in Crete

Background: Breast cancer is the most commonly diagnosed cancer among women and a leading cause of death from cancer in women in Europe. Although breast cancer incidence is on the rise worldwide, breast cancer mortality over the past 25 years has been stable or decreasing in some countries and a fall in breast cancer mortality rates in most European countries in the 1990s was reported by several studies, in contrast, in Greece have not reported these favourable trends. In Greece, the age-standardised incidence and mortality rate for breast cancer per 100.000 in 2006 was 81,8 and 21,7 and although it is lower than most other countries in Europe, the fall in breast cancer mortality that observed has not been as great as in other European countries. There is no national strategy for screening in this country. This study reports on the use of mammography among middleaged women in rural Crete and investigates barriers to mammography screening encountered by women and their primary care physicians. Methods: Design: Semi-structured individual interviews. Setting and participants: Thirty women between 45–65 years of age, with a mean age of 54,6 years, and standard deviation 6,8 from rural areas of Crete and 28 qualified primary care physicians, with a mean age of 44,7 years and standard deviation 7,0 serving this rural population. Main outcome measure: Qualitative thematic analysis. Results: Most women identified several reasons for not using mammography. These included poor knowledge of the benefits and indications for mammography screening, fear of pain during the procedure, fear of a serious diagnosis, embarrassment, stress while anticipating the results, cost and lack of physician recommendation. Physicians identified difficulties in scheduling an appointment as one reason women did not use mammography and both women and physicians identified distance from the screening site, transportation problems and the absence of symptoms as reasons for non-use. Conclusion: Women are inhibited from participating in mammography screening in rural Crete. The provision of more accessible screening services may improve this. However physician recommendation is important in overcoming women's inhibitions. Primary care physicians serving rural areas need to be aware of barriers preventing women from attending mammography screening and provide women with information and advice in a sensitive way so women can make informed decisions regarding breast caner screening

Identifying seasonal distribution patterns of fin whales across the Scotia Sea and the Antarctic Peninsula region using a novel approach combining habitat suitability models and ensemble learning methods

Following their near extirpation by industrial whaling of the 20th century, the population status of Southern Hemisphere fin whales (SHFW) remains unknown. Systematic surveys estimating fin whale abundance in the Southern Ocean are not yet available. Records of fin whale sightings have been collected by a variety of organisations over the past few decades, incorporating both opportunistic data and dedicated survey data. Together, these isolated data sets represent a potentially valuable source of information on the seasonality, distribution and abundance of SHFW. We compiled records across 40 years from the Antarctic Peninsula and Scotia Sea from multiple sources and used a novel approach combining ensemble learning and a maximum entropy model to estimate abundance and distribution of SHFW in this region. Our results show a seasonal distribution pattern with pronounced centres of distribution from January-March along the West Antarctic Peninsula. Our new approach allowed us to estimate abundance of SHFW for discrete areas from a mixed data set of mainly opportunistic presence only data.publishedVersio

Identifying seasonal distribution patterns of fin whales across the Scotia Sea and the Antarctic Peninsula region using a novel approach combining habitat suitability models and ensemble learning methods

Following their near extirpation by industrial whaling of the 20th century, the population status of Southern Hemisphere fin whales (SHFW) remains unknown. Systematic surveys estimating fin whale abundance in the Southern Ocean are not yet available. Records of fin whale sightings have been collected by a variety of organisations over the past few decades, incorporating both opportunistic data and dedicated survey data. Together, these isolated data sets represent a potentially valuable source of information on the seasonality, distribution and abundance of SHFW. We compiled records across 40 years from the Antarctic Peninsula and Scotia Sea from multiple sources and used a novel approach combining ensemble learning and a maximum entropy model to estimate abundance and distribution of SHFW in this region. Our results show a seasonal distribution pattern with pronounced centres of distribution from January-March along the West Antarctic Peninsula. Our new approach allowed us to estimate abundance of SHFW for discrete areas from a mixed data set of mainly opportunistic presence only data

Identifying seasonal distribution patterns of fin whales across the Scotia Sea and the Antarctic Peninsula region using a novel approach combining habitat suitability models and ensemble learning methods

Following their near extirpation by industrial whaling of the 20th century, the population status of Southern Hemisphere fin whales (SHFW) remains unknown. Systematic surveys estimating fin whale abundance in the Southern Ocean are not yet available. Records of fin whale sightings have been collected by a variety of organisations over the past few decades, incorporating both opportunistic data and dedicated survey data. Together, these isolated data sets represent a potentially valuable source of information on the seasonality, distribution and abundance of SHFW. We compiled records across 40 years from the Antarctic Peninsula and Scotia Sea from multiple sources and used a novel approach combining ensemble learning and a maximum entropy model to estimate abundance and distribution of SHFW in this region. Our results show a seasonal distribution pattern with pronounced centres of distribution from January-March along the West Antarctic Peninsula. Our new approach allowed us to estimate abundance of SHFW for discrete areas from a mixed data set of mainly opportunistic presence only data