'Low' faecal immunochemical test (FIT) colorectal cancer: a 4-year comparison of the Nottingham '4F' protocol with FIT10 in symptomatic patients.

AIM: The aim of this work was to evaluate colorectal cancer (CRC) outcomes after 'low' (sub-threshold) faecal immunochemical test (FIT) results in symptomatic patients tested in primary care. METHOD: This work comprised a retrospective audit of 35 289 patients with FIT results who had consulted their general practitioner with lower gastrointestinal symptoms and had subsequent CRC diagnoses. The Rapid Colorectal Cancer Diagnosis pathway was introduced in November 2017 to allow incorporation of FIT into clinical practice. The local '4F' protocol combined FIT results with blood tests and digital rectal examination (DRE): FIT, full blood count, ferritin and finger [DRE]. The outcome used was detection rates of CRC, missed CRC and time to diagnosis in local 4F protocols for patients with a subthreshold faecal haemoglobin (fHb) result compared with thresholds of 10 and 20 µg Hb/g faeces. RESULTS: A single threshold of 10 µg Hb/g faeces identifies a population in whom the risk of CRC is 0.2%, but this would have missed 63 (10.5%) of 599 CRCs in this population. The Nottingham 4F protocol would have missed fewer CRCs [42 of 599 (7%)] despite using a threshold of 20 µg Hb/g faeces for patients with normal blood tests. Subthreshold FIT results in patients subsequently diagnosed with a palpable rectal tumour yielded the longest delays in diagnosis. CONCLUSION: A combination of FIT with blood results and DRE (the 4F protocol) reduced the risk of missed or delayed diagnosis. Further studies on the impact of such protocols on the diagnostic accuracy of FIT are expected. The value of adding blood tests to FIT may be restricted to specific parts of the fHb results spectrum.

Dietary monosodium glutamate increases visceral hypersensitivity in a mouse model of visceral pain.

BACKGROUND: Monosodium glutamate (MSG) has been identified as a trigger of abdominal pain in irritable bowel syndrome (IBS), but the mechanism is unknown. This study examined whether MSG causes visceral hypersensitivity using a water-avoidance stress (WAS) mouse model of visceral pain. METHODS: Mice were divided into four groups receiving treatment for 6 days: WAS + MSG gavage, WAS + saline gavage, sham-WAS + MSG gavage, and sham-WAS + saline gavage. The acute effects of intraluminal administration of 10 µM MSG on jejunal extrinsic afferent nerve sensitivity to distension (0-60 mmHg) were examined using ex vivo extracellular recordings. MSG was also applied directly to jejunal afferents from untreated mice. Glutamate concentration was measured in serum, and in the serosal compartment of Ussing chambers following apical administration. KEY RESULTS: Acute intraluminal MSG application increased distension responses of jejunal afferent nerves from mice exposed to WAS + MSG. This effect was mediated by wide dynamic range and high-threshold units at both physiologic and noxious pressures (10-60 mmHg, p < 0.05). No effect of MSG was observed in the other groups, or when applied directly to the jejunal afferent nerves. Serum glutamate was increased in mice exposed to WAS + MSG compared to sham-WAS + saline, and serosal glutamate increased using WAS tissue (p = 0.0433). CONCLUSIONS AND INFERENCES: These findings demonstrate that repeated exposure to MSG in mice leads to sensitization of jejunal afferent nerves to acute ex vivo exposure to MSG. This may contribute to visceral hypersensitivity reported in response to MSG in patients with IBS.

The East Africa Consortium for human papillomavirus and cervical cancer in women living with HIV/AIDS.

The East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer, and to encourage collaborations between researchers in North America and East African countries. To date, studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on the persistence of HPV, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP. It will now be determined how HPV testing fits into cervical cancer screening programs in Kenya and Uganda, how aflatoxin influences immunological control of HIV, how HPV alters certain genes involved in the growth of tumours in HIV-infected women. Although there have been challenges in performing this research, with time, this work should help to reduce the burden of cervical cancer and other cancers related to HIV infection in people living in sub-Saharan Africa, as well as optimized processes to better facilitate research as well as patient autonomy and safety. KEY MESSAGESThe East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer.Collaborations have been established between researchers in North America and East African countries for these studies.Studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on HPV detection, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP.

Using the Theoretical Domains Framework to Identify Barriers and Enablers to Implementing a Virtual Tertiary-Regional Telemedicine Rounding and Consultation for Kids (TRaC-K) Model: Qualitative Study.

BACKGROUND: Inequities in access to health services are a global concern and a concern for Canadian populations living in rural areas. Rural children hospitalized at tertiary children's hospitals have higher rates of medical complexity and experience more expensive hospitalizations and more frequent readmissions. The 2 tertiary pediatric hospitals in Alberta, Canada, have already been operating above capacity, but the pediatric beds at regional hospitals are underused. Such imbalance could lead to poor patient safety and increased readmission risk at tertiary pediatric hospitals and diminish the clinical exposure of regional pediatric health care providers, erode their confidence, and compel health systems to further reduce the capacity at regional sites. A Telemedicine Rounding and Consultation for Kids (TRaC-K) model was proposed to enable health care providers at Alberta Children's Hospital to partner with their counterparts at Medicine Hat Regional Hospital to provide inpatient clinical care for pediatric patients who would otherwise have to travel or be transferred to the tertiary site. OBJECTIVE: The aim of this study is to identify perceived barriers and enablers to implementing the TRaC-K model. METHODS: This study was guided by the Theoretical Domains Framework (TDF) and used qualitative methods. We collected qualitative data from 42 participants from tertiary and regional hospitals through 31 semistructured interviews and 2 focus groups. These data were thematically analyzed to identify major subthemes within each TDF domain. These subthemes were further aggregated and categorized into barriers or enablers to implementing the TRaC-K model and were tabulated separately. RESULTS: Our study identified 31 subthemes in 14 TDF domains, ranging from administrative issues to specific clinical conditions. We were able to merge these subthemes into larger themes and categorize them into 4 barriers and 4 enablers. Our findings showed that the barriers were lack of awareness of telemedicine, skills to provide virtual clinical care, unclear processes and resources to support TRaC-K, and concerns about clear roles and responsibilities. The enablers were health care providers' motivation to provide care closer to home, supporting system resource stewardship, site and practice compatibility, and motivation to strengthen tertiary-regional relationships. CONCLUSIONS: This systematic inquiry into the perceived barriers and enablers to the implementation of TRaC-K helped us to gain insights from various health care providers' and family members' perspectives. We will use these findings to design interventions to overcome the identified barriers and harness the enablers to encourage successful implementation of TRaC-K. These findings will inform the implementation of telemedicine-based interventions in pediatric settings in other parts of Canada and beyond. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12913-018-3859-2.

Quantitative FIT stratification is superior to NICE referral criteria NG12 in a high-risk colorectal cancer population.

BACKGROUND: Guidelines for urgent investigation of colorectal cancer (CRC) are based on age and symptom-based criteria. This study aims to compare the diagnostic value of clinical features and faecal immunochemical test (FIT) results to identify those at a higher risk of CRC, thereby facilitating effective triage of patients. METHODS: We undertook a review of all patients referred for investigation of CRC at our centre between September 2016 and June 2018. Patients were identified using a prospectively recorded local database. We performed a logistic regression analysis of factors associated with a diagnosis of CRC. RESULTS: One-thousand-and-seven-hundred-eighty-four patients with FIT results were included in the study. Change in bowel habit (CIBH) was the most common referring clinical feature (38.3%). Patients diagnosed with CRC were significantly older than those without malignancy (74.0 years vs 68.9 years, p = 0.0007). Male patients were more likely to be diagnosed with CRC than females (6.5% vs 2.5%, Chi-squared 16.93, p < 0.0001). CRC was diagnosed in 3.5% (24/684) with CIBH compared to 8.1% (6/74) with both CIBH and iron deficiency anaemia. No individual or combination of referring clinical features was associated with an increased diagnosis of CRC (Chi-squared, 8.03, p = 0.155). Three patients with negative FIT results (< 4 µg Hb/g faeces) were diagnosed with CRC (3/1027, 0.3%). The highest proportion of cancers detected was in the ≥ 100 µg Hb/g faeces group (55/181, 30.4%). CONCLUSION: In a multivariate model, FIT outperforms age, sex and all symptoms prompting referral. FIT has greater stratification value than any referral symptoms. FIT does have value in patients with iron deficiency anaemia.

Faecal immunochemical testing and blood tests for prioritization of urgent colorectal cancer referrals in symptomatic patients: a 2-year evaluation.

BACKGROUND: A novel pathway incorporating faecal immunochemical testing (FIT) for rapid colorectal cancer diagnosis (RCCD) was introduced in 2017. This paper reports on the service evaluation after 2 years of pathway implementation. METHODS: The RCCD protocol was based on FIT, blood results and symptoms to stratify adult patients in primary care. Two-week-wait (2WW) investigation was indicated for patients with rectal bleeding, rectal mass and faecal haemoglobin (fHb) level of 10 µg Hb/g faeces or above or 4 µg Hb/g faeces or more in the presence of anaemia, low ferritin or thrombocytosis, in all other symptom groups. Patients with 100 µg Hb/g faeces or above had expedited investigation . A retrospective audit of colorectal cancer detected between 2017 and 2019 was conducted, fHb thresholds were reviewed and critically assessed for cancer diagnoses. RESULTS: In 2 years, 14788 FIT tests were dispatched with 13361 (90.4 per cent) completed returns. Overall, fHb was less than 4 µg Hb/g faeces in 9208 results (68.9 per cent), 4-9.9 µg Hb/g in 1583 (11.8 per cent), 10-99.9 µg Hb/g in 1850 (13.8 per cent) and 100 µg Hb/g faeces or above in 720 (5.4 per cent). During follow-up (median 10.4 months), 227 colorectal cancers were diagnosed. The cancer detection rate was 0.1 per cent in patients with fHb below 4 µg Hb/g faeces, 0.6 per cent in those with fHb 4-9.9 µg Hb/g faeces, 3.3 per cent for fHb 10-99.9 µg Hb/g faeces and 20.7 per cent for fHb 100 µg Hb/g faeces or above. The detection rate in the cohort with 10-19.9 µg Hb/g faeces was 1.4 per cent, below the National Institute for Health and Care Excellence threshold for urgent referral. The colorectal cancer rate in patients with fHb below 20 µg Hb/g faeces was less than 0.3 per cent. CONCLUSION: Use of FIT to "rule out" urgent referral from primary care misses a small number of cases. The threshold for referral may be adjusted with blood results to improve stratification .

GP access to FIT increases the proportion of colorectal cancers detected on urgent pathways in symptomatic patients in Nottingham.

OBJECTIVE: Service evaluation of GP access to Faecal Immunochemical Test (FIT) for colorectal cancer (CRC) detection in Nottinghamshire and use of FIT for "rule out", "rule in" and "first test selection". DESIGN: Retrospective audit of FIT results, CRC outcomes and resource utilisation before and after introduction of FIT in Primary Care in November 2017. Data from the new pathway up to December 2018 was compared with previous experience. RESULTS: Between November 2017 and December 2018, 6747 GP FIT test requests yielded 5733 FIT results, of which 4082 (71.2%) were <4.0 µg Hb/g faeces, 579 (10.1%) were 4.0-9.9 µg Hb/g faeces, 836 (14.6%) were 10.0-149.9 µg Hb/g faeces, and 236 (4.1%) were ≥150.0 µg Hb/g faeces. The proportion of "rule out" results <4.0 µg Hb/g faeces was significantly higher than in the Getting FIT cohort (71.2% vs 60.4%, Chi squared 42.8, p < 0.0001) and the proportion of "rule in" results ≥150.0 µg Hb/g faeces was significantly lower (4.1% vs 8.1%, Chi squared 27.3,P < 0.0001). There was a 33% rise in urgent referrals across Nottingham overall during the evaluation period. 2 CRC diagnoses were made in 4082 patients who had FIT<4.0 µg Hb/g faeces. 58.4% of new CRC diagnoses associated with a positive FIT were early stage cancers (Stage I and II). The proportion of all CRC diagnoses that follow an urgent referral s rose after introduction of FIT. CONCLUSIONS: FIT allows GP's to select a more appropriate cohort for urgent investigation without a large number of missed diagnoses. FIT appears to promise a "stage migration" effect which may ultimately improve CRC outcomes.

Thrombocytosis helps to stratify risk of colorectal cancer in patients referred on a 2-week-wait pathway.

PURPOSE: Primary care studies suggest that thrombocytosis (platelet counts > 400 × 109/L) is associated with an increased risk of colorectal cancer (CRC). We aimed to establish whether this marker has significant stratification value in patients seen in secondary care. METHODS: A retrospective review of 2991 patients referred to our colorectal 2-week-wait (2WW) pathway between August 2014 and August 2017. Patient demographics were recorded prospectively, and local electronic records systems were used to retrieve full blood counts (FBC) and cancer diagnoses. Patients with no recent platelet count at the time of referral or incomplete records were excluded. RESULTS: 2236 patients were included in this evaluation. There was no significant difference in the age distribution of those with thrombocytosis and those without. There were significantly more females in the thrombocytosis group (72.1% vs 53.9%, chi-squared 24.63, p < 0.0001). 130 CRCs were detected (5.8%) and patients with thrombocytosis were more likely to have CRC (OR 2.62, 95% CI 1.60-4.30). The CRC diagnosis rate was significantly higher in females with thrombocytosis (10.3% vs 2.9%, chi-squared 19.41, p < 0.0001) and males with thrombocytosis (16.1% vs 7.9%, chi-squared 4.62, p = 0.032). CONCLUSION: Thrombocytosis appears to have stratification value in the 2WW population. Further evaluation of its value alone or in combination with other stratification tests is required.

Barriers and enablers to implementing a virtual tertiary-regional Telemedicine Rounding and Consultation (TRAC) model of inpatient pediatric care using the Theoretical Domains Framework (TDF) approach: a study protocol.

BACKGROUND: Over-occupancy at the two tertiary pediatric care hospitals in Alberta, Canada is steadily increasing with simultaneous decline in occupancy of pediatric beds at regional hospitals. Over-occupancy negatively impacts timeliness and potentially, the safety of patient care provided at these two tertiary hospitals. In contrast, underutilization of pediatric beds at regional hospitals poses the risk of losing beds provincially, dilution of regional pediatric expertise and potential erosion of confidence by regional providers. One approach to the current situation in provincial pediatric care capacity is development of telemedicine based innovative models of care that increase the population of patients cared for in regional pediatric beds. A Telemedicine Rounding and Consultation (TRAC) model involves discussing patient care or aspects of their care using telemedicine by employing visual displays, audio and information sharing between tertiary and regional hospitals. To facilitate implementation of a TRAC model, it is essential to understand the perceived barriers among its potential users in local context. The current study utilizes qualitative methodologies to assess these perceived clinician barriers to inform a future pilot and evaluation of this innovative virtual pediatric tertiary-regional collaborative care model in Alberta. METHODS: We will use a qualitative descriptive design guided by the Theoretical Domain Framework (TDF) to systematically identify the tertiary and regional clinical stakeholder's perceived barriers and enablers to the implementation of proposed TRAC model of inpatient pediatric care. Semi-structured interviews and focus groups with pediatricians, nurses and allied health professionals, administrators, and family members will be conducted to identify key barriers and enablers to implementation of the TRAC model using TDF. Appropriate behaviour change techniques will be identified to develop potential intervention strategies to overcome identified barriers. These intervention strategies will facilitate implementation of the TRAC model during the pilot phase. DISCUSSION: The proposed TRAC model has the potential to address the imbalance between utilization of regional and tertiary inpatient pediatric facilities in Alberta. Knowledge generated regarding barriers and enablers to the TRAC model and the process outlined in this study could be used by health services researchers to develop similar telemedicine-based interventions in Canada and other parts of the world.

Inpatient magnetic resonance cholangiopancreatography: does it increase the efficiency in emergency hepatopancreaticobiliary surgery services?

INTRODUCTION Magnetic resonance cholangiopancreatography (MRCP) is commonly used to evaluate the biliary tree, although indications for patients who require inpatient imaging are not fully defined. The aim of this study was to evaluate inpatient MRCP performed on surgical patients and to devise a treatment pathway for these patients. MATERIAL AND METHODS All adult inpatient MRCP examinations between January 2012 and December 2013 were reviewed. Demographic, clinical and radiological data were collated. RESULTS During the study period, 271 inpatient MRCP were requested, of which 234 examinations were included. The majority of patients were female (n=140) and the median age was 63 years (range 16-93 years). Surgical admissions accounted for 171 (73%) of cases. Indications for inpatient MRCP include gallstone-related complications (n=173; 74%), malignant process (n=17; 7%) and other indications (n=44; 19%). Overall, inpatient MRCP led to further inpatient interventions in 22% (gallstone group, n=32, 18%; patients with malignancy, n=8, 47%; other indications, n=12, 27%). The median duration of inpatient MRCP from request to examination was 2 days (range 0-15 days) and median reporting after examination was 1 day (range 0-14 days). DISCUSSION AND CONCLUSION Improved access and timely reporting of iMRCP may reduce length of hospital stay. Inpatient MRCP also led to further inpatient interventions, in particular, in patients with malignancy.

Functional conservation of MBD proteins: MeCP2 and Drosophila MBD proteins alter sleep.

Proteins containing a methyl-CpG-binding domain (MBD) bind 5mC and convert the methylation pattern information into appropriate functional cellular states. The correct readout of epigenetic marks is of particular importance in the nervous system where abnormal expression or compromised MBD protein function, can lead to disease and developmental disorders. Recent evidence indicates that the genome of Drosophila melanogaster is methylated and two MBD proteins, dMBD2/3 and dMBD-R2, are present. Are Drosophila MBD proteins required for neuronal function, and as MBD-containing proteins have diverged and evolved, does the MBD domain retain the molecular properties required for conserved cellular function across species? To address these questions, we expressed the human MBD-containing protein, hMeCP2, in distinct amine neurons and quantified functional changes in sleep circuitry output using a high throughput assay in Drosophila. hMeCP2 expression resulted in phase-specific sleep loss and sleep fragmentation with the hMeCP2-mediated sleep deficits requiring an intact MBD domain. Reducing endogenous dMBD2/3 and dMBD-R2 levels also generated sleep fragmentation, with an increase in sleep occurring upon dMBD-R2 reduction. To examine if hMeCP2 and dMBD-R2 are targeting common neuronal functions, we reduced dMBD-R2 levels in combination with hMeCP2 expression and observed a complete rescue of sleep deficits. Furthermore, chromosomal binding experiments indicate MBD-R2 and MeCP2 associate on shared genomic loci. Our results provide the first demonstration that Drosophila MBD-containing family members are required for neuronal function and suggest that the MBD domain retains considerable functional conservation at the whole organism level across species.

Regional cerebellar volumes are related to early musical training and finger tapping performance.

The cerebellum has been associated with timing on the millisecond scale and with musical rhythm and beat processing. Early musical training (before age 7) is associated with enhanced rhythm synchronization performance and differences in cortical motor areas and the corpus callosum. In the present study, we examined the relationships between regional cerebellar volumes, early musical training, and timing performance. We tested adult musicians and non-musicians on a standard finger tapping task, and extracted cerebellar gray and white matter volumes using a novel multi-atlas automatic segmentation pipeline. We found that early-trained musicians had reduced volume in bilateral cerebellar white matter and right lobules IV, V and VI, compared to late-trained musicians. Strikingly, better timing performance, greater musical experience and an earlier age of start of musical training were associated with smaller cerebellar volumes. Better timing performance was specifically associated with smaller volumes of right lobule VI. Collectively, these findings support the sensitivity of the cerebellum to the age of initiation of musical training and suggest that lobule VI plays a role in timing. The smaller cerebellar volumes associated with musical training and timing performance may be a reflection of more efficiently implemented low-level timing and sensorimotor processes.

General and substance-specific predictors of young adult nicotine dependence, alcohol use disorder, and problem behavior: replication in two samples.

BACKGROUND: This paper presents two replications of a heuristic model for measuring environment in studies of gene-environment interplay in the etiology of young adult problem behaviors. METHODS: Data were drawn from two longitudinal, U.S. studies of the etiology of substance use and related behaviors: the Raising Healthy Children study (RHC; N=1040, 47% female) and the Minnesota Twin Family Study (MTFS; N=1512, 50% female). RHC included a Pacific Northwest, school-based, community sample. MTFS included twins identified from state birth records in Minnesota. Both studies included commensurate measures of general family environment and family substance-specific environments in adolescence (RHC ages 10-18; MTFS age 18), as well as young adult nicotine dependence, alcohol and illicit drug use disorders, HIV sexual risk behavior, and antisocial behavior (RHC ages 24, 25; MTFS age 25). RESULTS: Results from the two samples were highly consistent and largely supported the heuristic model proposed by Bailey et al. (2011). Adolescent general family environment, family smoking environment, and family drinking environment predicted shared variance in problem behaviors in young adulthood. Family smoking environment predicted unique variance in young adult nicotine dependence. Family drinking environment did not appear to predict unique variance in young adult alcohol use disorder. CONCLUSIONS: Organizing environmental predictors and outcomes into general and substance-specific measures provides a useful way forward in modeling complex environments and phenotypes. Results suggest that programs aimed at preventing young adult problem behaviors should target general family environment and family smoking and drinking environments in adolescence.

Human copy number polymorphic genes.

Recent large-scale genomic studies within human populations have identified numerous genomic regions as copy number variant (CNV). As these CNV regions often overlap coding regions of the genome, large lists of potentially copy number polymorphic genes have been produced that are candidates for disease association. Most of the current data regarding normal genic variation, however, has been generated using BAC or SNP microarrays, which lack precision especially with respect to exons. To address this, we assessed 2,790 candidate CNV genes defined from available studies in nine well-characterized HapMap individuals by designing a customized oligonucleotide microarray targeted specifically to exons. Using exon array comparative genomic hybridization (aCGH), we detected 255 (9%) of the candidates as true CNVs including 134 with evidence of variation over the entire gene. Individuals differed in copy number from the control by an average of 100 gene loci. Both partial- and whole-gene CNVs were strongly associated with segmental duplications (55 and 71%, respectively) as well as regions of positive selection. We confirmed 37% of the whole-gene CNVs using the fosmid end sequence pair (ESP) structural variation map for these same individuals. If we modify the end sequence pair mapping strategy to include low-sequence identity ESPs (98-99.5%) and ESPs with an everted orientation, we can capture 82% of the missed genes leading to more complete ascertainment of structural variation within duplicated genes. Our results indicate that segmental duplications are the source of the majority of full-length copy number polymorphic genes, most of the variant genes are organized as tandem duplications, and a significant fraction of these genes will represent paralogs with levels of sequence diversity beyond thresholds of allelic variation. In addition, these data provide a targeted set of CNV genes enriched for regions likely to be associated with human phenotypic differences due to copy number changes and present a source of copy number responsive oligonucleotide probes for future association studies.

Using a pericentromeric interspersed repeat to recapitulate the phylogeny and expansion of human centromeric segmental duplications.

Despite considerable advances in sequencing of the human genome over the past few years, the organization and evolution of human pericentromeric regions have been difficult to resolve. This is due, in part, to the presence of large, complex blocks of duplicated genomic sequence at the boundary between centromeric satellite and unique euchromatic DNA. Here, we report the identification and characterization of an approximately 49-kb repeat sequence that exists in more than 40 copies within the human genome. This repeat is specific to highly duplicated pericentromeric regions with multiple copies distributed in an interspersed fashion among a subset of human chromosomes. Using this interspersed repeat (termed PIR4) as a marker of pericentromeric DNA, we recovered and sequence-tagged 3 Mb of pericentromeric DNA from a variety of human chromosomes as well as nonhuman primate genomes. A global evolutionary reconstruction of the dispersal of PIR4 sequence and analysis of flanking sequence supports a model in which pericentromeric duplications initiated before the separation of the great ape species (>12 MYA). Further, analyses of this duplication and associated flanking duplications narrow the major burst of pericentromeric duplication activity to a time just before the divergence of the African great ape and human species (5 to 7 MYA). These recent duplication exchange events substantially restructured the pericentromeric regions of hominoid chromosomes and created an architecture where large blocks of sequence are shared among nonhomologous chromosomes. This report provides the first global view of the series of historical events that have reshaped human pericentromeric regions over recent evolutionary time.

Bovine spongiform encephalopathy.

Early epidemiological studies identified bovine spongiform encephalopathy as a feed-borne infection associated with infected meat-and-bone meal in animal feed. The infection may have derived from scrapie in sheep, a spontaneous genetic mutation in cattle, or a transmissible spongiform encephalopathy in another mammalian species. Experimental work on the risk of transmission has necessarily tried to identify risk materials and their infectivity levels, the nature and size of species barriers, the infectious dose, the route of infection, the strain of the agent and the genotype of the animals at risk. The identification of levels of infection in cattle tissues has aided the removal of risk materials from the human and animal food chains. Maternally associated transmission is unlikely to maintain an outbreak, but the offspring of clinical cases appear to be at greater risk when the rate of food-borne exposure is high. Studies of embryo transfer have not shown infection to be transmitted by this means. While the control measures appeared to be straightforward, compliance has at times proved difficult to enforce and quantify. This has necessitated more extensive prohibitions, aggressive enforcement and thorough auditing of compliance levels.

Circular polarisation in star-forming regions: possible implications for homochirality.

Our discovery of high degrees of circular polarisation in some star-forming regions provides an attractive mechanism for the origin of homochirality. The largest degrees of circular polarisation, so far observed at near-infrared wavelengths, are thought to arise from the scattering of stellar radiation from aligned dust grains and are calculated to extend down to UV wavelengths. The extent of the region where circularly polarised light (CPL) of a single handedness originates is very large, and it is likely that the whole of a planetary system would see a single handedness of CPL also. We present the observational data, models of the scattering that leads to the production of CPL, and a model for the origin of homochirality. We also discuss briefly future laboratory and space-based experiments.

Positive selection of a gene family during the emergence of humans and African apes.

Gene duplication followed by adaptive evolution is one of the primary forces for the emergence of new gene function. Here we describe the recent proliferation, transposition and selection of a 20-kilobase (kb) duplicated segment throughout 15 Mb of the short arm of human chromosome 16. The dispersal of this segment was accompanied by considerable variation in chromosomal-map location and copy number among hominoid species. In humans, we identified a gene family (morpheus) within the duplicated segment. Comparison of putative protein-encoding exons revealed the most extreme case of positive selection among hominoids. The major episode of enhanced amino-acid replacement occurred after the separation of human and great-ape lineages from the orangutan. Positive selection continued to alter amino-acid composition after the divergence of human and chimpanzee lineages. The rapidity and bias for amino-acid-altering nucleotide changes suggest adaptive evolution of the morpheus gene family during the emergence of humans and African apes. Moreover, some genes emerge and evolve very rapidly, generating copies that bear little similarity to their ancestral precursors. Consequently, a small fraction of human genes may not possess discernible orthologues within the genomes of model organisms.

Lessons from the human genome: transitions between euchromatin and heterochromatin.

The publication of the human genome draft sequence provides, for the first time, a global view of the structural properties of the human genome. Initial sequence analysis, in combination with previous published reports, reveals that more than half of the transition regions between euchromatin and centromeric heterochromatin contain duplicated segments. The individual duplications originate from diverse euchromatic regions of the human genome, often containing intron-exon structure of known genes. Multiple duplicons are concatenated together to form larger blocks of wall-to-wall duplications. For a single chromosome, these paralogous segments can span >1 Mb of sequence and define a buffer zone between unique sequence and tandemly repeated satellite sequences. Unusual pericentromeric interspersed repeat elements have been identified at the junctions of many of these duplications. Phylogenetic and comparative studies of pericentromeric sequences suggest that this peculiar genome organization has emerged within the last 30 million years of human evolution and is a source of considerable genomic variation between closely related primate species. Interestingly, not all human pericentromeric regions show this proclivity to duplicate and transpose genomic sequence, suggesting at least two different models for the organization of these regions.