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Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Analgesia and sedation are commonly administered to critically ill children to treat pain, provide amnesia, and facilitate interaction with mechanical ventilation and other therapeutic interventions. The development of pain and sedation assessment tools validated in critically ill children has optimized analgosedation delivery. While improved critical care has decreased mortality, new morbidities, including those secondary to prolonged analgosedation administration, are being identified. Tolerance is positively associated with synthetic opioids and continuous infusions. Drug dose and duration of exposure to opioids, benzodiazepines, and dexmedetomidine correlate with increased risk for iatrogenic withdrawal syndrome. Management strategies include multimodal analgesia, regional anesthesia, targeted sedation to reduce drug exposure, IWS screening with validated tools, and slow weaning of analgosedative infusions with or without transition to intermittent receptor-specific replacement agents. Large-scale studies need to be performed to identify drug dosing regimens and develop clinical practice guidelines to prevent and manage tolerance and withdrawal.

Critically ill children frequently experience pain either as a consequence of their primary reason for pediatric intensive care unit (PICU) admission, required diagnostic and therapeutic procedures, or even routine care. Administering sedative and analgesic infusions to blunt awareness is no longer a standard of care and may contribute to the development of tolerance and withdrawal, delirium, and post-intensive care syndrome among other agent-related unique adverse effects. Multimodal analgesia incorporating non-opioid analgesics is an important strategy in critically ill children. Ontogeny of pediatric pharmacodynamics requires age-specific consideration regarding drug selection and dosing. Acetaminophen and nonsteroidal anti-inflammatory drug (NSAID) co-administration provides effective management of mild to moderate pain with addition of opioids if escalation is needed to manage moderate to severe pain. If opioids are ineffective and dose escalation is limited by side effects, adjunctive medications, including ketamine, dexmedetomidine, or gabapentin, may optimize pain management. While critically ill children are closely monitored, certain higher-risk populations, such as those with obstructive sleep apnea (OSA), obesity, and cardiopulmonary disease, are at potentially higher risk for opioid-related adverse effects and should be monitored accordingly.

With decreasing mortality in PICUs, a growing number of survivors experience long-lasting physical impairments. Early physical rehabilitation and mobilization during critical illness are safe and feasible, but little is known about the prevalence in PICUs. We aimed to evaluate the prevalence of rehabilitation for critically ill children and associated barriers.National 2-day point prevalence study.Eighty-two PICUs in 65 hospitals across the United States.All patients admitted to a participating PICU for greater than or equal to 72 hours on each point prevalence day.None.The primary outcome was prevalence of physical therapy- or occupational therapy-provided mobility on the study days. PICUs also prospectively collected timing of initial rehabilitation team consultation, clinical and patient mobility data, potential mobility-associated safety events, and barriers to mobility. The point prevalence of physical therapy- or occupational therapy-provided mobility during 1,769 patient-days was 35% and associated with older age (adjusted odds ratio for 13-17 vs3 yr, 2.1; 95% CI, 1.5-3.1) and male gender (adjusted odds ratio for females, 0.76; 95% CI, 0.61-0.95). Patients with higher baseline function (Pediatric Cerebral Performance Category, ≤ 2 vs2) less often had rehabilitation consultation within the first 72 hours (27% vs 38%; p0.001). Patients were completely immobile on 19% of patient-days. A potential safety event occurred in only 4% of 4,700 mobility sessions, most commonly a transient change in vital signs. Out-of-bed mobility was negatively associated with the presence of an endotracheal tube (adjusted odds ratio, 0.13; 95% CI, 0.1-0.2) and urinary catheter (adjusted odds ratio, 0.28; 95% CI, 0.1-0.6). Positive associations included family presence in children less than 3 years old (adjusted odds ratio, 4.55; 95% CI, 3.1-6.6).Younger children, females, and patients with higher baseline function less commonly receive rehabilitation in U.S. PICUs, and early rehabilitation consultation is infrequent. These findings highlight the need for systematic design of rehabilitation interventions for all critically ill children at risk of functional impairments.

Source at https://doi.org/10.1007/s10689-018-0072-8. Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15–20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.

Background Mechanical ventilation (MV) is often used for bronchiolitis in the Pediatric Intensive Care Unit (PICU), and typically requires analgesic and sedative medications to treat pain and agitation and to prevent dislodgement of life-sustaining equipment. Sedative side effects include bradycardia, hypotension, decreased respiratory drive, and withdrawal, but it is unknown if cumulative dosages of these medications within the first 36hrs of MV are associated with unfavorable outcomes. Methods With IRB approval, charts of PICU patients

There are established associations between adverse health outcomes and poverty, but little is known regarding these associations in critically ill children. We hypothesized that living in poorer communities would be associated with unfavorable outcomes in children with critical bronchiolitis. This retrospective study included children with bronchiolitis admitted to a pediatric intensive care unit (PICU) over a 2-year period. Median household income was estimated from patient ZIP codes and 2014 US Census Bureau data. The 2014 Federal Poverty Threshold (FPT) for a family of 4 was $24 008. Patients were classified as living in ZIP codes below or above the 150% FPT (150FPT). Living

OBJECTIVES: No guidelines are available regarding initiation of enteral nutrition in children with bronchiolitis on high-flow nasal cannula (HFNC) support. We hypothesized that the incidence of feeding-related adverse events (AEs) would not be associated with HFNC support. METHODS: This retrospective study included children ≤24 months old with bronchiolitis receiving HFNC in a PICU from September 2013 through April 2014. Data included demographics, respiratory support during feeding, and feeding-related AEs. Feeding-related AEs were extracted from nursing documentation and defined as respiratory distress or emesis. Feed route and maximum HFNC delivery were recorded in 8-hour shifts (6 am–2 pm, 2 pm–10 pm, and 10 pm–6 am). RESULTS: 70 children were included, with a median age of 5 (interquartile range [IQR] 2–10) months. HFNC delivery at feed initiation varied widely, and AEs related to feeding occurred rarely. Children were fed in 501 of 794 (63%) of nursing shifts, with AEs documented in only 29 of 501 (5.8%) of those shifts. The incidence of AEs at varying levels of respiratory support did not differ (P = .092). Children in the “early feeding” (fed within first 2 shifts) group (n = 22) had a shorter PICU length of stay (2.2 days [IQR 1.4–3.9] vs 3.2 [IQR 2.5–5.3], P = .006) and shorter duration of HFNC use (26.0 hours [IQR 15.8–57.0] vs 53.5 [IQR 37.0–84.8], P = .002), compared with children in the “late feeding” group (n = 48). CONCLUSIONS: In this small, single-institution patient cohort, feeding-related AEs were rare and not related to the delivered level of respiratory support.

OBJECTIVES New definitions of pediatric acute respiratory distress syndrome include criteria to identify a subset of children "at risk for pediatric acute respiratory distress syndrome." We hypothesized that, among PICU patients with bronchiolitis not immediately requiring invasive mechanical ventilation, those meeting at risk for pediatric acute respiratory distress syndrome criteria would have worse clinical outcomes, including higher rates of pediatric acute respiratory distress syndrome development. DESIGN Single-center, retrospective chart review. SETTING Mixed medical-surgical PICU within a tertiary academic children's hospital. PATIENTS Children 24 months old or younger admitted to the PICU with a primary diagnosis of bronchiolitis from September 2013 to April 2014. Children intubated before PICU arrival were excluded. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Collected data included demographics, respiratory support, oxygen saturation, and chest radiograph interpretation by staff radiologist. Oxygen flow (calculated as FIO2 × flow rate [L/min]) was calculated when oxygen saturation was 88-97%. The median age of 115 subjects was 5 months (2-11 mo). Median PICU length of stay was 2.8 days (1.5-4.8 d), and median hospital length of stay was 5 days (3-10 d). The criteria for at risk for pediatric acute respiratory distress syndrome was met in 47 of 115 subjects (40.9%). Children who were at risk for pediatric acute respiratory distress syndrome were more likely to develop pediatric acute respiratory distress syndrome (15/47 [31.9%] vs 1/68 [1.5%]; p < 0.001), had longer PICU length of stay (4.6 d [2.8-10.2 d] vs 1.9 d [1.0-3.1 d]; p < 0.001) and hospital length of stay (8 d [5-16 d] vs 4 d [2-6 d]; p < 0.001), and increased need for invasive mechanical ventilation (16/47 [34.0%] vs 2/68 [2.9%]; p < 0.001), compared with those children who did not meet at risk for pediatric acute respiratory distress syndrome criteria. CONCLUSIONS Our data suggest that the recent definition of at risk for pediatric acute respiratory distress syndrome can successfully identify children with critical bronchiolitis who have relatively unfavorable clinical courses.

Background With the advent of novel drugs improved overall survival in patients with multiple myeloma, including patients who received up-front autologous stem cell transplantation (ASCT), has been reported from several centers. Here we report on overall survival in a population-based cohort of patients receiving ASCT as first line treatment and in whom novel agents were an option for second and later lines of treatment. Methods Patients with multiple myeloma ≤ 65 years of age who were considered for ASCT from 01.01.2001–31.06.2005 (period 1) and from 01.07.2005 until 31.12.2009 (period 2) at Oslo University Hospital (OUH) were identified. Relevant data were collected from the patients’ medical records. Results Altogether, 293/355 patients received ASCT. In all, median OS was 82.9 months in patients ≤ 60 years of age and 59.0 months in patients 61–65 years. For patients ≤ 60 years of age median OS increased from 70.6 months to 87.7 months (p = 0. 22) and median survival after start of second line therapy increased from 34.5 months to 46.5 months (p = 0.015) between the two periods. For patients 61–65 years of age median OS increased from 57.3 months to 61.2 months (p = 0. 87) and median survival after start of second line therapy was practically unchanged (32.6 months vs. 33.1 months (p = 0.97) between the periods. In patients ≤ 60 years of age salvage ASCT was used in 34% of the patients while in patients 61–65 years of age salvage ASCT was used in 7.3% of the patients. The use of salvage ASCT and novel drugs, as well as the number of treatment lines, were higher in patients ≤ 60 years of age and increased during the study period. Conclusion In patients ≤ 60 years of age an increased median OS of 17 months between the two periods were noted, but the difference failed to reach statistical significance. However, a statistically significant difference in median survival of 12 months after start of second line therapy was found in this age group, which may be explained by a more active second line treatment. In patients 61–65 years only a slight increase of survival, not statistically significant, was noted between the periods.

Background Post-infectious fatigue syndrome (PIFS), also known as post-viral fatigue syndrome, is a complex condition resulting in physical, cognitive, emotional, neurological, vocational and/or role performance disabilities in varying degrees that changes over time. The needs for health care resources are high, and costly, as is the economic burden on the affected individuals. Many factors may impact the trajectory, and frequently PIFS develops into a chronic condition. Health professionals lack understanding and knowledge, which results in delayed diagnosis, lack of recognition, appropriate treatment, support and practical help. The aim of our study was to explore, from the perspective of persons who had lived with PIFS for four years following an outbreak of Giardia l. induced enteritis, factors that may have impacted their illness trajectory and how these factors had played a role during different phases. Methods In this retrospective exploratory qualitative study a group of 26 affected adults between 26 and 59 years old were selected for in-depth interviews. A maximum variation sample was recruited from a physician-diagnosed cohort of persons with PIFS enrolled at a tertiary outpatient fatigue clinic. The interviews were audio-recorded, transcribed verbatim and subjected to qualitative content analysis. Results Unhelpful and helpful factors were associated with the healthcare system, health professionals and the affected persons were experienced as having an impact on the trajectory. External impacting factors which are related to the health care system, providers and the social security system are misdiagnosis, trivialization of symptoms, unhelpful advice, delayed diagnosis and lack of appropriate help. Internal impacting factors related to the affected individuals were lack of knowledge, overestimating functional capacity, assuming the condition will pass, ignoring body signals and denial. A model of impacting factors in each phase of the trajectory is presented. Conclusion Unmet needs may result in unnecessary disability and high societal and personal costs. Enhanced knowledge of impacting factors in each phase of the trajectory may contribute to more timely and tailored health care services and less use of health services. Increased functional capacity, improved health and ability to work or study may reduce the societal costs and the economic burden for the affected individuals.

Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.

The aim of this study was to evaluate the outcome of risk-reducing mastectomy in BRCA1/2 mutation carriers with and without breast cancer. Uptake, methods of operation and reconstruction, complications, patient satisfaction and histopathological findings were registered at all five departments of genetics in Norway. Data from 267 affected and unaffected BRCA1/2 mutation carriers were analyzed, including a study-specific questionnaire returned by 178 mutation carriers. There was a steady increase in the uptake of risk-reducing mastectomies during the study period. Complications were observed in 106/266 (39.7%) women. Patient satisfaction was high. The majority of women expressed great relief after risk-reducing mastectomy and would have chosen the same option again.

We report the 5- and 10-year survival rate of women diagnosed with breast cancer in the context of an annual MRI-based surveillance program. In 2001, as part of a national initiative, women in Norway with a BRCA1 mutation were offered annual screening with breast MRI in addition to mammography. 802 women with a BRCA1 mutation were screened one or more times and followed for a mean of 4.2 years. As of December 2011, 68 of 802 women in the screening program were diagnosed with DCIS or invasive breast cancer (8.5 %), including eight prevalent, 50 incident screen-detected and eight interval cancers. Two latent cancers were detected at prophylactic mastectomy. Sixty-three of the cancers were invasive and five were in situ. The mean tumour size was 1.4 cm (range 0.2-4.5 cm), and 85 % of the patients were node-negative. Ten of the 68 patients died of cancer in the follow-up period. The 5-year breast cancer-specific survival for women with cancer was 75 % (95 % CI 56-86 %) and the 10-year survival was 69 % (95 % CI: 48-83 %). The 5-year survival for women with Stage 1 breast cancer was 82 % compared to 98 % in the population. The 5- and 10-year survival of women with a BRCA1-associated breast cancer detected in a national MRI-based screening program in BRCA1 mutation carriers Norway was less than anticipated. The benefit of annual MRI surveillance on reducing breast cancer mortality in BRCA1 mutation carriers remains to be proven.

Item does not contain fulltext Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment. 01 juni 2010

A cytochemical method for studying fibrinolytic (proteolytic) activity in specified white cells in blood and bone marrow smears has been developed and the spontaneous fibrinolytic activity at pH 6.0 and 7.65 as well as the activity of a plasminogen-like proenzyme were studied. These fibrinolytic enzymes appeared in the granulocytic and monocytic series; their activity depending upon the maturation stage. The enzymes appear in promyelocytes, reach the highest activity in metamyelocytes and in band cells and then gradually decrease during maturation. No significant differences between mature neutrophils, eosinophils and basophils were observed. Megakaryocytes, erythroblasts, erythrocytes and lymphocytes were devoid of significant fibrinolytic activity. Some implications of these findings are discussed.

A case of haemophilia A (Factor VIII deficiency) in a family of Samojed dogs is described. The Factor VIII activity was about 3 per cent of normal dog level. The dog died from a haematoma in the mediastinum. No other bleeders were recorded in its family.

A study of platelet adhesiveness using platelet-rich plasma with ADP has been performed in different groups of men. Despite large day-to-day variations the method registered individual characteristics in platelet function. A seasonal variation and an increase in adhesiveness with age were found, but the method failed to show any difference between a prospective and a post-infarction group of the same age. Thus this variant for assessing platelet adhesiveness is not useful for detecting the coronary-prone patient.

Among 2014 apparently healthy men aged 40-59 years platelet function was studied with Hellem's retention method in 488 men. In 55 of these 488 men coronary heart disease (CHD) was strongly suspected and coronary angiography confirmed the diagnosis in 34 of 51 angiographied men. Platelet responsiveness was significantly lower among those who had angina pectoris than among their CHD-suspect counterparts without angina, regardless of coronary angiographic findings. Since angiopositive men without angina and 408 "normals" had similar retention values, it seems as if presenting symptoms, but not the development of CHD are linked to platelet function. During a near maximal bicycle exercise test significantly higher peak exercise blood pressure was found among men with very low retention values than among men with retention values in the middle and upper range. This could not be explained by differences in maximal heart rate or work performance. This indicates that blood pressure regulation during exercise may in part be linked to platelet function related mechanisms.

Endometrial cancer is frequent in MMR-mutation carriers. Estimates of annual incidence rates have, however, been based on retrospective studies. The purpose of our study was to prospectively assess the incidence rates of endometrial cancer in women either having a mutation in one of the four MMR genes MLH1, MSH2, MSH6 or PMS2 (Mut+) or belonging to families meeting the revised Amsterdam criteria in which no MMR mutation was detected (Ams+). Eight out of 80 Mut+ (10%) contracted invasive endometrial cancer compared to 1/171 (0.6%) of the Ams+ (P = 0.0006). The annual incidence rate after first control was 2.5% in Mut+ and 0.2% in Ams+. Two of the 8 Mut+ women (25%) had synchronous gynaecological tumours. The numbers included did not allow for firm conclusions, but the results are in keeping with the notion that the inherited colon-endometrial cancer syndrome may be restricted to carriers of MMR mutations.

In recent years persons at risk for colorectal cancers (CRC) have been subjected to follow-up with colonoscopy in many centres. There is, however, limited knowledge about the effect of such interventions. The objective of this study was to report the results of our observations during the past 15 years.Healthy persons were included in the study according to their family history of CRCs, and prospectively followed with colonoscopies.Altogether, 1133 individuals were included and observed for a total of 3474 follow-up years from the first to the last colonoscopy initiated by our activity. Mismatch repair (MMR) mutations were detected in 6.5% of cases. A total of 1383 polyps were removed, 72% were less than 5 mm in diameter. Findings were scored as hyperplastic polyps (n=887), adenomas with mild to moderate dysplasia (n=460), adenomas with high-grade dysplasia (n=30) and cancers (n=6). Two cancers were observed after the first colonoscopy, compared with 2.6 expected by chance and more than 20 expected under the hypothesis of predominant inherited diseases in the families. Observed annual incidence rates for adenomas were similar in all groups, while in the mutation carriers there was a higher frequency of progression to severe dysplasia or infiltrating cancer.A simple explanation for the combined findings may be that all selected families had a similar tendency to produce adenomas, while mutation carriers more frequently demonstrated dysplasia/cancer in the adenomas. The low annual incidence rates for CRC indicated that the removal of adenomas may have prevented cancers.

Background Fatigue is a major problem among individuals with post-infectious fatigue syndrome (PIFS), also known as chronic fatigue syndrome or myalgic encephalomyelitis. It is a complex phenomenon that varies across illnesses. From a nursing perspective, knowledge and understanding of fatigue in this illness is limited. Nurses lack confidence in caring for these patients and devalue their professional role. The aim of this study was to explore in-depth the experiences of fatigue among individuals with PIFS. A detailed description of the phenomenon of fatigue is presented. Increased knowledge would likely contribute to more confident nurses and improved nursing care. Methods A qualitative study with open interviews was employed. In-depth interviews with patients were fully transcribed and underwent a qualitative content analysis. A maximum variation sample of 26 affected adults between 26–59 years old was recruited from a population diagnosed at a fatigue outpatient clinic. Results The fatigue was a post-exertional, multidimensional, fluctuating phenomenon with varying degrees of severity and several distinct characteristics and was accompanied by concomitant symptoms. Fatigue was perceived to be an all-pervasive complex experience that substantially reduced the ability to function personally or professionally. A range of trigger mechanisms evoked or worsened the fatigue, but the affected were not always aware of what triggered it. There was an excessive increase in fatigue in response to even minor activities. An increase in fatigue resulted in the exacerbation of other concomitant symptoms. The term fatigue does not capture the participants’ experiences, which are accompanied by a considerable symptom burden that contributes to the illness experience and the severe disability. Conclusions Although some aspects of the fatigue experience have been reported previously, more were added in our study, such as the dimension of awakening fatigue and the characteristic beyond time, when time passes unnoticed. We also identified trigger mechanisms such as emotional, neurological, social, financial, and pressure on oneself or from others. This in-depth exploration of fatigue in PIFS provides an overview of the dimensions, characteristics, and trigger mechanisms of fatigue, thus making better clinical observations, early recognition, improved communication with patients and more appropriate nursing interventions possible.

Purpose Hereditary nonpolyposis colorectal cancer (HNPCC) may be caused by mutations in mismatch repair (MMR) genes. The aim of this study was to validate immunohistochemistry and family history as prescreening tools to predict germline mutations in MLH1, MSH2, and MSH6. Patients and Methods Pedigrees from 250 families were extended, cancer diagnoses were verified, and families were classified according to the Amsterdam and the Bethesda criteria. Tumor specimens were examined with immunohistochemistry for the presence of MLH1, MSH2, and MSH6 proteins. Mutation analyses were performed in blood samples from the same patients. Results Blood samples from affected index persons in 181 families and tumor specimens from 127 of the affected index persons were obtained. Thirty tumors lacked one or more gene products. Sensitivity of immunohistochemistry to detect mutation carriers was 100%, specificity was 82%, and positive predictive value was 85%. Sensitivities, specificities, and positive predictive values for the Amsterdam criteria were 82%, 8%, and 45%, respectively, and for the Bethesda criteria were 100%, 0%, and 48%, respectively. Distribution of mutations was MLH1 = 4, MSH2 = 11, and MSH6 = 4. Conclusion Wide clinical criteria to select HNPCC kindreds, followed by immunohistochemistry of tumor material from one affected person in each family, had high sensitivity and specificity to predict MMR mutations.

Contains fulltext : 185698.pdf (Publisher’s version ) (Open Access) PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations. PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives. RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant. CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.

Aims Since atherosclerosis is a chronic inflammation and the erythrocyte sedimentation rate is an appropriate test for monitoring chronic inflammatory responses, we wanted to investigate whether the erythrocyte sedimentation rate might carry prognostic information on the risk of sustaining coronary heart disease events. Method The erythrocyte sedimentation rate was determined in 2014 apparently healthy men aged 40-60 years during an extensive cardiovascular survey in 1972-75, and the test was repeated in an identical follow-up examination 7 years later. Cause-specific mortality and rates of non-fatal myocardial infarction were followed for 23 years. Results The erythrocyte sedimentation rate was strongly correlated with age, haemoglobin level, smoking status, total cholesterol level and systolic blood pressure. After adjusting for all these associations in multivariate Cox regression analyses, the erythrocyte sedimentation rate emerged as a strong short- and long-term predictor of coronary heart disease mortality, particularly in men who had developed angina pectoris and/or had a positive exercise ECG test at the second survey. Increases in non-coronary heart disease deaths and in non-fatal myocardial infarctions were only seen in the upper erythrocyte sedimentation rate range. Conclusions The erythrocyte sedimentation rate is a strong predictor of coronary heart disease mortality, and appears to be a marker of aggressive forms of coronary heart disease. The erythrocyte sedimentation rate probably gives substantial information in addition to that given by fibrinogen on the risk of coronary heart disease death.

Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes.

Two-thirds of osteogenesis imperfecta (OI) patients claimed that they bruised easily. We have studied haemostasis in 58 subjects with OI, tarda type. The most frequent abnormalities were increased capillary fragility (35%), decreased platelet retention (33%) and reduced factor VIII R:Ag (23%). Reduced ristocetin cofactor, deficient platelet aggregation induced by collagen and prolonged bleeding time were less common findings. The combination of vascular, platelet related and plasmatic defects may reflect that OI is a heterogeneous group of disorders with common clinical expression. The tourniquet test is the most valuable screening test of the haemostatic defects observed in OI.

This is a case of a 3-week-old male who presented to the emergency department with intermittent apnea and cyanosis. While in the emergency department, he had respiratory compromise with stress and required intubation. Further evaluation confirmed the diagnosis of a thyroglossal duct cyst. Congenital lesions causing extrinsic airway compression should be considered in all neonates with apnea, cyanosis, and respiratory compromise. Knowledge of pediatric airway anatomy and physiology is important in all cases where obstructive apnea is suspected.

No standardized educational curriculum exists for pediatric sedation practitioners. We sought to describe the curriculum and implementation of a pediatric sedation provider course and assess learner satisfaction with the course curriculum.The course content was determined by formulating a needs assessment using published sedation guidelines, reports of sedation related adverse events, and a survey of sedation practitioners. Students provided feedback regarding satisfaction with the course immediately following the course and 6 months later.The course consisted of 5 didactic lectures, 1 small-group session, 6 simulation scenarios, a course syllabus, and a written examination. The course was conducted over 1 day at 3 different locations. Sixty-nine students completed the course and were uniformly satisfied with the course curriculum.A standardized pediatric sedation provider course was developed for sedation practitioners and consisted of a series of lectures and simulation scenarios. Overall satisfaction with the course was positive.

Lynch syndrome (LS) is characterised by the\ud development of colorectal cancer, endometrial cancer\ud and various other cancers, and is caused by a mutation\ud in one of the mismatch repair genes: MLH1, MSH2,\ud MSH6 or PMS2. In 2007, a group of European experts\ud (the Mallorca group) published guidelines for the clinical\ud management of LS. Since then substantial new\ud information has become available necessitating an\ud update of the guidelines. In 2011 and 2012 workshops\ud were organised in Palma de Mallorca. A total of 35\ud specialists from 13 countries participated in the\ud meetings. The first step was to formulate important\ud clinical questions. Then a systematic literature search\ud was performed using the Pubmed database and manual\ud searches of relevant articles. During the workshops the\ud outcome of the literature search was discussed in detail.\ud The guidelines described in this paper may be helpful for\ud the appropriate management of families with LS.\ud Prospective controlled studies should be undertaken to\ud improve further the care of these families.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- CIMBA et al., BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., The study was supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defense Ovarian Cancer Idea award (W81XWH-10-1-0341), grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure; Cancer Research UK grants C12292/A11174 and C1287/A10118; the European Commission's Seventh Framework Programme grant agreement 223175 (HEALTH-F2-2009-223175). Breast Cancer Family Registry Studies (BCFR): supported by the National Cancer Institute, National Institutes of Health under RFA # CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), and University of Melbourne (U01 CA69638). The Australian BCFR was also supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the Victorian Breast Cancer Research Consortium. Melissa C. Southey is a NHMRC Senior Research Fellow and a Victorian Breast Cancer Research Consortium Group Leader. Carriers at FCCC were also identified with support from National Institutes of Health grants P01 CA16094 and R01 CA22435. The New York BCFR was also supported by National Institutes of Health grants P30 CA13696 and P30 ES009089. The Utah BCFR was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH grant UL1 RR025764, and by Award Number P30 CA042014 from the National Cancer Institute. Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): BFBOCC is partly supported by Lithuania (BFBOCC-LT), Research Council of Lithuania grant LIG-19/2010, and Hereditary Cancer Association (Paveldimo vėžio asociacija)., Latvia (BFBOCC-LV) is partly supported by LSC grant 10.0010.08 and in part by a grant from the ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/​016.BRCA-gene mutations and breast cancer in South African women (BMBSA): BMBSA was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van Rensburg. Beckman Research Institute of the City of Hope (BRICOH): Susan L. Neuhausen was partially supported by the Morris and Horowitz Families Endowed Professorship. BRICOH was supported by NIH R01CA74415 and NIH P30 CA033752. Copenhagen Breast Cancer Study (CBCS): The CBCS study was supported by the NEYE Foundation. Spanish National Cancer Centre (CNIO): This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. City of Hope Cancer Center (COH): The City of Hope Clinical Cancer Genetics Community Research Network is supported by Award Number RC4A153828 (PI: Jeffrey N. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): CONSIT TEAM was funded by grants from Fondazione Italiana per la Ricerca sul Cancro (Special Project “Hereditary tumors”), Italian Association for Cancer Research (AIRC, IG 8713), Italian Minitry of Health (Extraordinary National Cancer Program 2006, “Alleanza contro il Cancro” and “Progetto Tumori Femminili), Italian Ministry of Education, University and Research (Prin 2008) Centro di Ascolto Donne Operate al Seno (CAOS) association and by funds from Italian citizens who allocated the 5×1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5×1000’). German Cancer Research Center (DKFZ): The DKFZ study was supported by the DKFZ. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the NWO grant 91109024, the Pink Ribbon grant 110005, and the BBMRI grant CP46/NWO., Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Rosalind A. Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Canter (FCCC): The authors acknowledge support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. Andrew K. Godwin was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): The GEMO study was supported by the Ligue National Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award and the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program. Gynecologic Oncology Group (GOG): This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA 27469), Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committtee (CA 101165). Drs. Mark H. Greene and Phuong L. Mai were supported by funding from the Intramural Research Program, NCI, NIH. Hospital Clinico San Carlos (HCSC): HCSC was supported by RETICC 06/0020/0021, FIS research grant 09/00859, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitivity, and the European Regional Development Fund (ERDF)., Helsinki Breast Cancer Study (HEBCS): The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union, and the Sigrid Juselius Foundation. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong Kong. Molecular Genetic Studies of Breast and Ovarian Cancer in Hungary (HUNBOCS): HUNBOCS was supported by Hungarian Research Grant KTIA-OTKA CK-80745 and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/ÖP-9. Institut Català d'Oncologia (ICO): The ICO study was supported by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Ramón Areces Foundation, Carlos III Health Institute, Catalan Health Institute, and Autonomous Government of Catalonia and contract grant numbers: ISCIIIRETIC RD06/0020/1051, PI09/02483, PI10/01422, PI10/00748, 2009SGR290, and 2009SGR283. International Hereditary Cancer Centre (IHCC): Supported by the Polish Foundation of Science. Katarzyna Jaworska is a fellow of International PhD program, Postgraduate School of Molecular Medicine, Warsaw Medical University. Iceland Landspitali–University Hospital (ILUH): The ILUH group was supported by the Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): INHERIT work was supported by the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program, the Canadian Breast Cancer Research Alliance grant 019511 and the Ministry of Economic Development, Innovation and Export Trade grant PSR-SIIRI-701. Jacques Simard is Chairholder of the Canada Research Chair in Oncogenetics., Istituto Oncologico Veneto (IOVHBOCS): The IOVHBOCS study was supported by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero della Salute (“Progetto Tumori Femminili” and RFPS 2006-5-341353,ACC2/R6.9”). Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): kConFab is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Amanda B. Spurdle is an NHMRC Senior Research Fellow. The Clinical Follow Up Study was funded from 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333. Mayo Clinic (MAYO): MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and grants from the Breast Cancer Research Foundation and the Komen Foundation for the Cure. McGill University (MCGILL): The McGill Study was supported by Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation, and Export Trade. Memorial Sloan-Kettering Cancer Center (MSKCC): The MSKCC study was supported by Breast Cancer Research Foundation, Niehaus Clinical Cancer Genetics Initiative, Andrew Sabin Family Foundation, and Lymphoma Foundation. Modifier Study of Quantitative Effects on Disease (MODSQUAD): MODSQUAD was supported by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101). Women's College Research Institute, Toronto (NAROD): NAROD was supported by NIH grant: 1R01 CA149429-01. National Cancer Institute (NCI): Drs. Mark H. Greene and Phuong L. Mai were supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Rockville, MD. National Israeli Cancer Control Center (NICCC): NICCC is supported by Clalit Health Services in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N. N. Petrov Institute of Oncology (NNPIO): The NNPIO study has been supported by the Russian Foundation for Basic Research (grants 11-04-00227, 12-04-00928, and 12-04-01490), the Federal Agency for Science and Innovations, Russia (contract 02.740.11.0780), and through a Royal Society International Joint grant (JP090615). The Ohio State University Comprehensive Cancer Center (OSU-CCG): OSUCCG is supported by the Ohio State University Comprehensive Cancer Center., South East Asian Breast Cancer Association Study (SEABASS): SEABASS is supported by the Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): The SMC study was partially funded through a grant by the Israel Cancer Association and the funding for the Israeli Inherited Breast Cancer Consortium. Swedish Breast Cancer Study (SWE-BRCA): SWE-BRCA collaborators are supported by the Swedish Cancer Society. The University of Chicago Center for Clinical Cancer Genetics and Global Health (UCHICAGO): UCHICAGO is supported by grants from the US National Cancer Institute (NIH/NCI) and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance, and the Breast Cancer Research Foundation. University of California Los Angeles (UCLA): The UCLA study was supported by the Jonsson Comprehensive Cancer Center Foundation and the Breast Cancer Research Foundation. University of California San Francisco (UCSF): The UCSF study was supported by the UCSF Cancer Risk Program and the Helen Diller Family Comprehensive Cancer Center. United Kingdom Familial Ovarian Cancer Registries (UKFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. University of Pennsylvania (UPENN): The UPENN study was supported by the National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855), Breast Cancer Research Foundation, Rooney Family Foundation, Susan G. Komen Foundation for the Cure, and the Macdonald Family Foundation. Victorian Familial Cancer Trials Group (VFCTG): The VFCTG study was supported by the Victorian Cancer Agency, Cancer Australia, and National Breast Cancer Foundation. Women's Cancer Research Initiative (WCRI): The WCRI at the Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).

We describe a new method for quantification of fibrin in thrombi formed in native human blood at venous and arterial shear conditions in a parallel-plate perfusion chamber device. Thrombi consisting of various proportions of fibrin and platelets were digested by plasmin. Fibrin deposition (micrograms/cm2) was calculated from the measured D-dimer levels. Fibrin deposition in thrombi formed on a tissue factor (TF)-rich surface increased with increasing shear rate from 37 micrograms/cm2 at 100/s to 77 micrograms/cm2 at 2600/s (significant at 95%, ANOVA). The plasma levels of thrombin-antithrombin III complexes (TAT) increased in concert. In contrast, fibrin deposition in thrombi formed on collagen fibrils and the corresponding TAT plasma levels were independent of the shear rate and much lower than those elicited by the TF-rich surface (significant at 95%, ANOVA). The intra-individual variation in fibrin deposition was on average 10%, whereas the inter-individual differences were > 500%. Such a large inter-individual difference has not been detected by morphometry which usually is employed in similar studies. The present method is more accurate and less time-consuming than the morphometric approach. The novel method measures fibrin on the surface and in and around the thrombi, thus total deposited fibrin. In contrast, the morphometry approach quantifies surface coverage with fibrin only, thus being semiquantitative at best.

Background: The aims of the present study were to investigate whether ionic and nonionic contrast media (CM) affect: 1) the procoagulant and fibrinolytic activities of cultured human vessel endothelium; and 2) early events of tissue-factor-induced arterial thrombus formation under conditions which may follow a percutaneous transluminal coronary angioplasty (PTCA) procedure. The following 3 CM were studied: iohexol (nonionic monomer, Omnipaque); iodixanol (nonionic dimer, Visipaque); and ioxaglate (ionic dimer, Hexabrix). Saline (0.9%) and glucose (40 vol%) were used as control. Methods and Results: Exposing endothelium to 40 vol% CM for 10 min did not affect the selected parameters of cellular procoagulant (tissue factor), anticoagulant (thrombomodulin), fibrinolytic (tissue plasminogen activator) or antifibrinolytic (plasminogen activator inhibitor-1) activity or antigen. However, ioxaglate had a profound impact on the cell morphology, which was noted already after one minute of exposure. The cells contracted and rounded, exposing large areas of extracellular matrix. Iohexol showed this phenomenon to a considerably lesser extent, whereas iodixanol induced a slight swelling of the cells without detectable exposure of extracellular matrix. The effect of the respective CM on tissue-factor-driven thrombus formation at an arterial shear rate of 2600 s−1 was studied in an ex vivo parallel-plate perfusion chamber device. In this model, human native blood was passed over a tissue factor/phospholipid-rich surface following 30 s exposure to 100% CM. The CM was washed out by nonanticoagulated blood drawn directly from an antecubital vein by a pump positioned distal to the perfusion chamber. Such a pre-exposure of the procoagulant surface to iodixanol reduced the fibrin deposition around the platelet thrombi by 50% (pConclusion: Iodixanol appears to be most biocompatible with endothelium, and has a moderate inhibitory effect on fibrin deposition in flowing blood. This differs from iohexol, and in particular from ioxaglate, which induce endothelial changes in morphology with no effect on fibrin deposition. Since none of the CM affected the platelet aggregate formation, and since ioxaglate has been reported to have stronger anticoagulant and antithrombotic properties than iodixanol or iohexol in in vitro assays, it is apparent that these properties were not reflected in thrombus formation under the experimental conditions of high arterial shear.

SummaryThe Stormorken syndrome is a multifacetted syndrome including a bleeding tendency. No deviations were found in the coagulation- or fibrinolytic systems. Platelet number was low normal, and size abnormal, whereas EM findings were unremarkable. Survival time was half normal. Clot retraction was initially rapid, but clearly decreased, whereas prothrombin consumption was also initially rapid, but complete. Membrane GP’s were normal, so was AA metabolism, PI-cycle, granule storage and secretion, and c-AMP function, whereas 5-HT uptake and storage was decreased. Optical platelet aggregation was low normal with all physiological agonists. The only clearly abnormal finding was that coagulant activity was present on non stimulated platelets at the same level as kaolin-stimulated normal platelets. This indicated a platelet abnormality which should lead to a thrombogenic, not to a haemorrhagic trait. This paradox may have its origin in rheology, because when challenged with in vivo shear rates in an ex vivo perfusion chamber, platelet cohesion was abnormally low. Further studies to better delineate the membrane abnormality are underway.

OBJECTIVES: No guidelines are available regarding initiation of enteral nutrition in children with bronchiolitis on high-flow nasal cannula (HFNC) support. We hypothesized that the incidence of feeding-related adverse events (AEs) would not be associated with HFNC support. METHODS: This retrospective study included children ≤24 months old with bronchiolitis receiving HFNC in a PICU from September 2013 through April 2014. Data included demographics, respiratory support during feeding, and feeding-related AEs. Feeding-related AEs were extracted from nursing documentation and defined as respiratory distress or emesis. Feed route and maximum HFNC delivery were recorded in 8-hour shifts (6 am–2 pm, 2 pm–10 pm, and 10 pm–6 am). RESULTS: 70 children were included, with a median age of 5 (interquartile range [IQR] 2–10) months. HFNC delivery at feed initiation varied widely, and AEs related to feeding occurred rarely. Children were fed in 501 of 794 (63%) of nursing shifts, with AEs documented in only 29 of 501 (5.8%) of those shifts. The incidence of AEs at varying levels of respiratory support did not differ ( P = .092). Children in the “early feeding” (fed within first 2 shifts) group ( n = 22) had a shorter PICU length of stay (2.2 days [IQR 1.4–3.9] vs 3.2 [IQR 2.5–5.3], P = .006) and shorter duration of HFNC use (26.0 hours [IQR 15.8–57.0] vs 53.5 [IQR 37.0–84.8], P = .002), compared with children in the “late feeding” group ( n = 48). CONCLUSIONS: In this small, single-institution patient cohort, feeding-related AEs were rare and not related to the delivered level of respiratory support.

Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII- deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P < .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P < .002 and P < .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P < .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.

Background Duodenal adenomas develop in patients with familial adenomatous polyposis, incurring a risk of carcinoma. When this risk is high, surgery is indicated. The choice of surgical treatment can be difficult as evidence-based data are lacking. Methods This is a systematic review of the literature on the non-medical management of duodenal lesions arising in the setting of familial adenomatous polyposis. Studies were identified through searching MEDLINE. Studies published between January 1965 and October 2009 were included. Data regarding number of subjects, complications, length of follow-up, recurrence rate and outcome were extracted. Results Transduodenal resection does not differ from an endoscopic approach in terms of recurrence. Ampullectomy has limited application as only papillary lesions are amenable to treatment in this manner. Duodenectomy with pancreas preservation is preferable to pancreaticoduodenectomy unless malignancy is present, or cannot be excluded. Conclusion Surgery should be reserved for advanced or malignant polyps.