DNA content analysis of colorectal cancer defines a distinct ‘microsatellite and chromosome stable’ group but does not predict response to radiotherapy

Colorectal cancers (CRC) are thought to have genetic instability in the form of either microsatellite instability (MSI) or chromosomal instability (CIN). Recently, tumours have been described without either MSI or CIN, that is, microsatellite and chromosome stable (MACS) CRCs. We investigated the (i) frequency of the MACS-CRCs and (ii) whether this genotype predicted responsiveness to neoadjuvant chemoradiotherapy. To examine the frequency of MACS-CRCs, DNA content (ploidy) was examined in 89 sporadic microsatellite-stable CRCs using flow cytometry. The tumours were also screened for mutations in KRAS/BRAF/TP53/PIK3CA by QMCPCR. To examine the value of tumour ploidy in predicting response to chemoradiotherapy, DNA content was tested in a separate group of 62 rectal cancers treated with neoadjuvant chemoradiotherapy. Fifty-one of 89 CRCs (57%) were aneuploid and 38 (43%) were diploid. There was no significant association between mutations in TP53/KRAS/BRAF/PIK3CA and ploidy. Testing of association between mutations revealed only mutual exclusivity of KRAS/BRAF mutation (P < 0.001). Of the 62 rectal cancers treated with neoadjuvant chemoradiotherapy, 22 had responded (Mandard tumour regression grade 1/2) and 40 failed to respond (Grade 3–5). Twenty-five of 62 (40%) tumours were diploid, but there was no association between ploidy and response to therapy. We conclude that MACS-CRCs form a significant proportion of microsatellite-stable CRCs with a mutation profile overlapping that of CRCs with CIN. A diploid genotype does not, however, predict the responsiveness to radiotherapy

VARIABILITY IN COMPETITIVE PERFORMANCE OF ELITE TRACK CYCLISTS

This study calculated the individual variation in performance times for cyclists competing in international track cycling events as Typical Error and attempted to express that variation in terms of power. Performance times were collated from six international events during the 2005/06 UCI Track Season and log transformed. Typical Error was calculated via the back transformation of the RMSE from a two-way ANOVA excluding the interaction term. The average Typical Error over all events was 1.0% (0.8 – 1.3 95% CL). Theoretically when performance is expressed as average power, the variation is approximately 3%. Modelling of power output for typical male and female pursuit cyclists appears to confirm this relationship under typical race conditions. These results can be used to assess the suitability of a field-based aerodynamic test for measuring the smallest worthwhile performance enhancing change in drag, whether a cyclist has shown worthwhile improvements in power during a laboratory performance test or in performance time during a competitive season

The Polar Bear: A Matter for International Concern

Discusses the decline in polar bear population, in part associated with recession of the polar ice cap, but also with excessive hunting. Annual worldwide harvest (ca 1200 reported) is about 5-10% of the population. An international commission is needed to coordinate study of population dynamics and movement patterns of these bears, and to regulate harvesting in the polar seas

The challenge of measuring physical activity

Measuring physical activity accurately and reliably is essential when physical activity is either an intervention or an outcome measure. Measurement of physical activity in population groups has been undertaken in a number of ways, including self-report, observation, heart rate measurement and activity monitors. The strengths and weaknesses of each of these methods will be reviewed. The measurement of physical activity in children is an additional challenge and data from the recently completed pilot study of the Kajian Aktiviti Fizikal dan Sukan Pelajar Sekolah Malaysia 2008 (KAFS08) will be used to illustrate these complexities. Questionnaire and activity monitoring data were collected from 163 children attending four schools in Kuala Lumpur with an age range of 9-18 years. Three models of activity monitors were used (YAMAX SW-700, OMRON HJ113, ACTIGRAPH GT1M) and on completion of data collection, significant differences were found between pedometer steps recorded on each monitor, after allowing for age and gender differences. A subsequent study on the differences between the three monitors was undertaken involving over 15 individuals and over 40 days of measurement where one individual wore each of the three monitors for a full day. In addition, the accuracy of each monitor was determined by comparing the step count registered by the monitor with actual number of steps counted

Evaluation of the Implementation of Best Practice Models in the Treatment of Addiction Problems in Greenland

BaggrundÅbningen i 2016 af et nyt nationalt ambulant behandlingstilbud for afhængighedsproblemer i Grønland skabte en unik mulighed for afhængighedssforskning. Det nye behandlingstilbud i Grønland, Allorfik, har åbnet fem nye behandlingssteder – et i hver kommune – og bruger den internationalt tilgængelige evidens og best-practice om afhængighedsbehandling, men med tilpasninger til de lokale forhold. Allorfik introducerede således både øget tilgængelighed til behandling og en ny behandlingsmetodologi. Før Allorfik var afhængighedsbehandling kun tilgængelig i hovedstaden Nuuk, hvorfor kun beboere i Nuuk og få andre udenfor Nuuk havde mulighed for behandling.Der er ikke meget evidens for behandling af afhængighed blandt oprindelige befolkninger som den grønlandske. Den gyldne standard for afhængighedsbehandling er baseret på vestlige befolkninger, hvor afhængighedsmønstre, livsstil og tilgang til sundhedsydelser er meget forskelligt fra den grønlandske. Formålet med denne afhandling er at evaluere implementeringen og funktionen af Allorfik. Afhandlingen vil præsentere resultaterne af de gennemførte undersøgelser, hvilket starter med en beskrivelse af baggrunden for og den politiske proces bag etableringen af Allorfik (studie 1), hvorvidt Allorfik har levet op til intentionerne (studie 2), er lykkedes med at implementere de forventede behandlingstiltag (studie 3), og omkring dødeligheden blandt patienter, der er påbegyndt behandling for afhængighed, i forhold til baggrundsbefolkningen (studie 4).Metode og resultater Studie 1: Wishing for a more sober society: a scoping review on addiction problems and addiction treatment services in Greenland leading to the 2016 national strategy for treatment for addiction in Greenland.Denne undersøgelse havde til formål at undersøge offentligt tilgængelige dokumenter om afhængighedsproblemer og behandlingsbehov i årene før en ny strategi for afhængighedsbehandlingen i Grønland blev besluttet. Undersøgelsen var inspireret af fremgangsmåden for scoping reviews og dokumentanalyser. De indsamlede data var videnskabelige artikler og rapporter, politiske dokumenter og referater fra møder i Landstingets Familie- og Sundhedsudvalg om debatterne om afhængighedssbehandling i årene 2010-2016. Analysen identificerede 54 relevante dokumenter: 26 politiske dokumenter, 13 regeringsdokumenter og 15 videnskabelige dokumenter, der blev inkluderet til analyse. Undersøgelsen identificerede tre dokumenter, der illustrerede de afgørende skridt for oprettelsen af et nyt nationalt afhængighedsbehandlingstilbud.Studie 2: A qualitative study of the implementation and organization of the national Greenlandic addiction treatment service.Denne undersøgelse havde til formål at undersøge implementeringen og organiseringen af det nye behandlingstilbud, Allorfik fra de involveredes perspektiv. Undersøgelsen søgte inspiration i RE-AIM (et evalueringsværktøj fra Implementeringsforskning) i udformningen af interviewguiden og tilrettelæggelse og udførelse af interviews. Undersøgelsen er baseret på semistrukturerede interviews med 23 personer. Interviewepersoner repræsenterer Allorfik-medarbejdere, embedsmænd og personale fra samarbejdspartnere som, fx sundhedsvæsenet, kommunerne og lokale NGO'er. Interviewemnerne var etablering, vanskeligheder og styrker i implementeringsprocessen, samt hvordan behandlingstilbuddet fungerede på tidspunktet for samtalen. Interviewdataene blev kondenseret og analyseret ved hjælp af en generelle induktive tilgang. Den tematiske analyse identificerede tre hovedtemaer i dataene: implementeringen, samarbejder og udfordringer/barrierer. Hvert tema havde flere undertemaer. Undersøgelsen konkluderer, at implementering og organisering af Allorfik ser ud til at være blevet leveret efter hensigten og hvad der blev lovet. Allorfik er også blevet mere end det afhængighedsbehandlingstilbud, det var planlagt til at være – det har udviklet sig til et tilbud med let adgang for borgere med behov for forskellige former for hjælp, som ellers ikke er tilgængelig eller er svært begrænset. Studie 3: A quality assurance study of the development of quality of care in outpatient clinics for treatment of addiction in Greenland.Denne undersøgelse havde til formål at bruge auditeringer af notater fra patientjournaler til at undersøge udviklingen i behandlingens kvalitet fra 2019 til 2021. Fokus for auditerne var kvaliteten af dokumentation og indhold for 10 specifikke områder i hver patientjournal. Hvert område blev scoret på en Likertskala fra 0-4 for begge parametre. Statistiske analyser blev udført med Stata 17, og P-værdier &lt; 0,05 blev betragtet som statistisk signifikante. Analysen var baseret på audit af notater fra patienter fra fem forskellige behandlingssteder. Det gennemsnitlige antal uger i afhængighedsbehandling var 12,7, og gennemsnitsalderen for personerne i de gennemgåede journaler var 39 år. Kvaliteten af dokumentationen blev forbedret med 0,21 point (p-værdi = &lt;0,001) hver måned i perioden 2019-2021, mens kvaliteten af indholdet blev forbedret med 0,27 point (p-værdi = &lt;0,001) hver måned.Studie 4: Excess Mortality Among Individuals Who Have Undergone Addiction Treatment: A Study from Greenland.Denne undersøgelse havde til formål at undersøge dødeligheden hos mennesker, der har været i afhængighedsbehandling i Grønland. Deltagerne i denne undersøgelse er alle personer, der har været i offentlig behandling for afhængighedsproblemer fra 2012 til 2022. 4.786 behandlingsforløb blev via CPR nummer forbundet med dødelighedsdata fra Grønlands Statistik. På grund af et højt antal patienter med flere behandlingsforløb og fejl i personnummer blev 3.286 patienter inkluderet til analyse af dødelighed. Størstedelen af patienterne var kvinder (53,9 %), og medianalderen ved sidst observerede behandling var 37 år. 33,8 % af patienterne havde været i afhængighedssbehandling mere end én gang. Størstedelen af patienterne (60,1%) var i behandling i 2019 eller senere, og halvdelen af patienterne afsluttede planmæssigt deres behandlingsforløb. 94 personer var døde før første kvartal af 2023. Blandt de afdøde døde 50 personer af naturlige årsager, 8 døde som følge af ulykker, 31 personer døde af selvmord og 5 døde af overfald. Kohorten blev fulgt op i 2,89 år (median) og i alt 12,098 personår, og den standardiserede dødelighed (SMR) var 1,42 uden signifikant forskel i SMR mellem mænd og kvinder (p-værdi = 0,207). Der var en signifikant forskel i SMR, afhængig af alder på tidspunktet for behandlingssøgning, hvor de unge aldersgrupper havde en højere SMR end de ældre aldersgrupper (p-værdi = 0,021).KonklusionNærværende afhandling har, gennem fire delstudier, evalueret processen og resultatet af implementeringen af Allorfik, et nationalt ambulant afhængighedsbehandlingstilbud, der blev etableret i 2016. Processen med implementering af Allorfik har været udfordrende, og der er foretaget tilpasninger af den oprindelige plan, men overordnet set endte implementeringen succesfuldt. Kvaliteten af plejen i Allorfik er blevet markant forbedret over tid og var på et fremragende niveau på alle behandlingssteder ved sidste audit. Dødeligheden for personer, der har været i afhængighedsbehandling i Grønland, viste sig at være lidt højere end den forventede i baggrundsbefolkningen, og dødeligheden for de yngre grupper af personer i behandling var signifikant højere end blandt de ældre. Fidelity Framework blev brugt til at diskutere resultaterne af de fire undersøgelser samlet og vurdere troskaben over for implementeringen og planer af Allorfik, og vurderingen var, at der var opnået en høj grad af troskab til intentionerne.BackgroundThe opening in 2016 of a new national outpatient treatment service for addiction problems in Greenlandcreated a unique opportunity for addiction research. The new treatment service in Greenland, Allorfik,opened five new treatment centers—one in each municipality—and uses the internationally availableevidence on addiction treatment but with adaptations to local conditions. Allorfik thus introduced bothincreased availability of treatment and a new treatment methodology. Before Allorfik, addiction treatment was only available in the capital city Nuuk, therefore giving only residents of Nuuk and few othersfrom outside of Nuuk the possibility of treatment.There is not a lot of evidence on addiction treatment services when offered to populations like that ofthe Greenlandic population. The so-called gold standard of addiction treatment is based on Western populations, who have very different addiction patterns as well as way of living and beliefs about health andhealing.This dissertation aims to evaluate the implementation and function of Allorfik. It will present the resultsof the studies conducted, starting with a description of the background and political process behind theestablishment of Allorfik (study 1), whether Allorfik met the expectations (study 2), succeeded in implementing the expected treatment measures (study 3), and the mortality among patients who have initiatedaddiction treatment relative to the background population (study 4).Methods &amp; ResultsStudy 1: Wishing for a more sober society: a scoping review on addiction problems and treatment services in Greenland leading to the 2016 national strategy for treatment for addiction in Greenland.This study aimed to explore the publicly available documents (i.e., government and academia) on addiction problems (alcohol, cannabis, and gambling) or described the needs of and wishes to change howtreatment is offered prior to deciding the current national strategy for treatment of addiction in Greenland. The study followed the scoping review framework for how to progress and scope across differenttypes of literature and sources. The data collected were scientific papers and reports, political documents, and minutes from meetings in the parliamentary Family and Health Committee on the debates ofaddiction treatment in the years 2010-2016. We performed a document analysis of publicly availableliterature detailing the addiction treatment service in Greenland for the historical context. The searchidentified 54 relevant documents: 26 political documents, 11 government documents, and 15 scientific documents that were included for analysis. The study identified three documents that revealed the keysteps in determining the path to a new national addiction treatment service.Study 2: A qualitative study of the implementation and organization of the national Greenlandic addiction treatment service.This study aimed to investigate the implementation and organization of the new treatment service, Allorfik, as seen through the eyes of those involved. The study was inspired by the methodological framework RE-AIM - especially for the design of the interview guide and deciding who to include in the interviews. This study is based on semi-structured interviews with 23 individuals. The interviewees represent internal Allorfik staff, government officials, and personnel from collaborating partner organizations, e.g., the health care system, the municipalities, and local NGOs. The interview topics were the establishment, difficulties, and strengths in the implementation process, and how the treatment serviceworked at the time of the interview. The interview data were condensed and analyzed using the generalinductive approach. A thematic analysis identified three major themes in the data: the implementation,collaborations, and challenges/barriers. Each theme had several sub-themes. The study concludes thatthe implementation and organization of Allorfik seems to have been delivered as intended and promised.Allorfik has also become more than the addiction treatment service it was planned to be – it has developed into a service with easy access for citizens needing of different kinds of help that is otherwise unavailable or difficult to access.Study 3: A quality assurance study of the development of quality of care in outpatient clinics for treatment of addiction in GreenlandUsing the auditor’s case notes, this study aimed to investigate the development of quality of treatmentfrom 2019 to 2021. The focus of the audits was the quality of documentation and content for ten specificareas in each patient record. Each area was scored on a Likert scale of 0-4 for both outcomes. Statisticalanalyses were done using Stata 17, and P-values &lt; 0.05 were considered statistically significant. Theanalysis was based on audits of the case notes of 454 patients from five different treatment centers. Themean number of weeks in addiction treatment was 12.7, and the mean age for the people in the auditedcase notes was 39 years. The quality of documentation improved by 0.21 points (p-value = &lt;0.001) eachmonth during the 2019-2021 period, while the quality of content improved by 0.27 points (p-value =&lt;0.001) each month.Study 4: Excess Mortality Among Individuals Who Have Undergone Addiction Treatment: A Studyfrom GreenlandThis study aimed to examine the mortality of people attending addiction treatment in Greenland. Participants of this study are all persons who have attended public treatment for addiction problems from 2012to 2022. 4,786 treatment entries were linked with mortality data using personal identification numbers. Due to a high number of patients with multiple treatment courses and a few errors in the personal identification number, 3286 patients were included for analysis of mortality. The majority of patients werefemale (53.9%) and the median age at last observed treatment was 37 years. 33.8% of the patients hadattended addiction treatment more than once. The majority of patients (60.1%) had attended treatment in2019 or later and half of the patients completed their treatment course. 94 persons had deceased beforethe first quarter of 2023. Among those who died, 50 persons died of natural causes, eight died becauseof accidents, 31 persons died by suicide and five died by assault. The cohort was followed up for a median of 2.89 years and a total of 12.068 person-years and the standardized mortality (SMR) rate was1.42 death with no significant difference in SMR between males and females (p-value = 0.207). Therewas a significant difference in SMR, depending on age at the time of treatment seeking, where theyoung ages groups had a higher SMR than the older age groups (p-value = 0.021). ConclusionThe present dissertation has evaluated the process and outcome of implementing Allorfik, a nationaloutpatient addiction treatment service established in 2016, through four sub-studies.The implementation process of Allorfik has been challenging, and adaptations of the original plan havebeen made, but overall, the implementation ended successfully. The quality of care in Allorfik has significantly improved over time and was at an excellent level in all treatment centers at the last audit. Themortality rate of people who have attended addiction treatment in Greenland was found to be higherthan the background population, and the mortality rate of the younger groups of people attending treatment was significantly higher than among the older groups. The Fidelity Framework was used to discussthe results of the four studies collectively and evaluate the fidelity to the implementation and plans ofAllorfik. The assessment proved a high level of fidelity was achieved. <br/

Polar Bear Studies During 1966

Polar bear migratory habits and population dynamics are relatively unknown and to learn more about these aspects, the Arctic Institute of North America (AINA) is supporting a long-range, research project. With funds from the Office of Naval Research the Institute sent Dr. Martin W. Schein to the Arctic Research Laboratory at Point Barrow during April 1965 and he returned to ARL with Dr. Vagn Flyger in March 1966. With the help of the able pilots at the Arctic Research Laboratory and their small ski equipped airplanes, they developed the following technique for capturing bears. When weather permitted they flew out over the ice in the general area north of Point Barrow with Cessna 180 airplanes. While one airplane flew at an elevation of about 100 feet and searched for polar bear tracks, the other airplane, containing Flyger and Schein, flew slightly behind and at an altitude of about 500 feet. Upon finding polar bear tracks, the planes followed them until they came upon the bear. The plane containing the biologists went on ahead about two or three miles in the direction the bear was travelling and deposited Flyger and Schein on the ice where they hid behind a pressure ridge. The plane then took off and the two planes drove the bear to the waiting biologists. When the bear got to within approximately 50 yards, it was shot with an automatic projectile syringe from a rifle. Syringes contained the drug succinylcholine chloride which paralyzed the bear within a few minutes. While the bears were immobile, they were examined, measured, and marked with ear tags and dye so that they could be recognized later if seen. Five bears were captured but of these four died because of a combination of overdoses of the drug and circumstances connected with chasing the bear with aircraft. Much, however, was learned from these animals which made it possible to be more successful in capturing and marking bears in Svalbard during August 1966. The Norsk Polarinstitutt invited Dr. Flyger, supported by AINA, and Dr. Albert W. Erickson, supported by the New York Zoological Society, to accompany them on a polar bear capturing expedition to Svalbard during the summer of 1966. This expedition under the direction of Mr. Thor Larsen from the University of Oslo, operating in the pack ice near Kong Karls Land in a seal hunting vessel was able to capture four bears, mark them, and release them alive. This time a different drug was used: M-99, a synthetic opiate. Working from a ship was much easier than with aircraft because it was possible to observe the bear closely before shooting it with a projectile syringe, thus lessening the chance of an overdose. Plans are now under way for a large scale program to mark polar bears over the entire Arctic. ... The feasibility of studying bear movements with radio transmitter-receivers is being explored with the National Aeronautics and Space Agency (NASA). Telemetric methods which have been used on other animals including brown and black bears are not applicable to arctic conditions. Recently developments in satellite technology have raised the possibility that perhaps polar bears can be studied by employing a Nimbus B satellite. Such a satellite would pick up messages (giving location, heartbeat, respiration rate, internal temperature, and external temperature) from a transmitter-receiver on a collar around the neck of the bear and relay them to a tracking station on earth. The practicability of this is being studied at present with NASA

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors