Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers.

Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.

Typing myalgic encephalomyelitis by infection at onset: A DecodeME study.

Background: People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) experience core symptoms of post-exertional malaise, unrefreshing sleep, and cognitive impairment. Despite numbering 0.2-0.4% of the population, no laboratory test is available for their diagnosis, no effective therapy exists for their treatment, and no scientific breakthrough regarding pathogenesis has been made. It remains unknown, despite decades of small-scale studies, whether individuals experience different types of ME/CFS separated by onset-type, sex or age. Methods: DecodeME is a large population-based study of ME/CFS that recruited 17,074 participants in the first 3 months following full launch. Detailed questionnaire responses from UK-based participants who all reported being diagnosed with ME/CFS by a health professional provided an unparalleled opportunity to investigate, using logistic regression, whether ME/CFS severity or onset type is significantly associated with sex, age, illness duration, comorbid conditions or symptoms. Results: The well-established sex-bias among ME/CFS patients is evident in the initial DecodeME cohort: 83.5% of participants were females. What was not known previously was that females tend to have more comorbidities than males. Moreover, being female, being older and being over 10 years from ME/CFS onset are significantly associated with greater severity. Five different ME/CFS onset types were examined in the self-reported data: those with ME/CFS onset (i) after glandular fever (infectious mononucleosis); (ii) after COVID-19 infection; (iii) after other infections; (iv) without an infection at onset; and, (v) where the occurrence of an infection at or preceding onset is not known. Among other findings, ME/CFS onset with unknown infection status was significantly associated with active fibromyalgia. Conclusions: DecodeME participants differ in symptoms, comorbid conditions and/or illness severity when stratified by their sex-at-birth and/or infection around the time of ME/CFS onset.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is a chronic disease that affects an estimated 250,000 people in the UK. Its defining symptom is post-exertional malaise, an excessive delayed worsening of symptoms following even minor physical or mental exertion. For those with it, ME/CFS means disability and poor quality of life. DecodeME is a research study which is looking for DNA differences between people with ME/CFS and people without any health problems. People with ME/CFS who take part in DecodeME complete a questionnaire that assesses their symptoms and whether they will then be invited to donate a DNA sample. This paper analyses the answers to this questionnaire; we will publish results of the DNA analysis separately. So far, more than 17 thousand people with ME/CFS have completed the DecodeME questionnaire. Their answers help us to address the question: "Are there different types of ME/CFS linked to different causes and how severe it becomes?" Results show that people with ME/CFS do not form a single group reporting similar symptoms and additional medical conditions. Instead, participants who had an infection at the start of their ME/CFS reported a different pattern of symptoms and conditions compared to those without an infection. It is well known that most people with ME/CFS are females. What was not clear previously was that females tend to have more additional health conditions. Also, being female, being older and being over 10 years from ME/CFS onset all make it more likely that someone is more severely affected by their ME/CFS. These findings could indicate that by studying people with different ME/CFS onset-types separately ­ rather than analysing all people with ME/CFS together ­ it will be easier to understand what is going wrong.

Same-day discharge robot-assisted laparoscopic prostatectomy: feasibility, safety and patient experience.

OBJECTIVES: To report a single centre's experience of the feasibility, safety and patient acceptability of same-day discharge robot-assisted laparoscopic prostatectomy (RALP). SUBJECTS/PATIENTS AND METHODS: Between June 2015 and December 2021, a total of 180 pre-selected consecutive patients underwent RALP with the intention to discharge on the same day as surgery. Cases were performed by two surgeons. An enhanced recovery after surgery (ERAS) programme was used. The feasibility of same-day discharge was analysed, along with the complication rate, oncological outcomes, and postoperative patient experience. RESULTS: Of 180 patients, 169 (93.8%) were successfully discharged on the same day as surgery. The median (range) age was 63 ( 44-74) years. The median (range) console time was 97 (61-256) min and blood loss was 200 (20-800) mL. The resection specimen pathology results were: pT2 69.4%, pT3a 24.4% and pT3b 6.5%. With regard to Gleason Grade Group (GGG), 25.9% had GGG 1, 65.7% had GGG 2-3 and 8.4% had GGG 4-5 disease. Positive surgical margins were present in 25 cases (14.7%), 18 (15.5%) of which occurred in pT2 cases, and seven (13.4%) in pT3 cases. There were no early (<90 days) biochemical relapses (defined as prostate-specific antigen level >0.2 ng/mL). The 30-day readmission rate was 3%. A total of 13 early (0-30 days) complications were observed, five of which were Clavien-Dindo grade ≥3, however, none of these would have been avoided had the patient remained in hospital on the first postoperative night. Of 121 consecutive patients, 107 (88%) returned a satisfaction questionnaire, and 92% of responders stated they preferred recovery at home, with 94% stating they felt ready to go home. CONCLUSION: Robot-assisted laparoscopic prostatectomy combined with an ERAS programme allows patients to be safely discharged home on the same day of their surgery. This is a feasible option, well-liked by patients, with morbidity and oncological outcomes similar to non-day-case or 23 h stay RALP.

Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases.

BACKGROUND: To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy. METHODS: The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence. FINDINGS: PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects. INTERPRETATION: This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects. FUNDING: None.

DecodeME: community recruitment for a large genetics study of myalgic encephalomyelitis / chronic fatigue syndrome.

BACKGROUND: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy. METHODS: Here we describe DecodeME, an ongoing study co-produced by people with lived experience of ME/CFS and scientists. Together we designed the study and obtained funding and are now recruiting up to 25,000 people in the UK with a clinical diagnosis of ME/CFS. Those eligible for the study are at least 16 years old, pass international study criteria, and lack any alternative diagnoses that can result in chronic fatigue. These will include 5,000 people whose ME/CFS diagnosis was a consequence of SARS-CoV-2 infection. Questionnaires are completed online or on paper. Participants' saliva DNA samples are acquired by post, which improves participation by more severely-affected individuals. Digital marketing and social media approaches resulted in 29,000 people with ME/CFS in the UK pre-registering their interest in participating. We will perform a genome-wide association study, comparing participants' genotypes with those from UK Biobank as controls. This should generate hypotheses regarding the genes, mechanisms and cell types contributing to ME/CFS disease aetiology. DISCUSSION: The DecodeME study has been reviewed and given a favourable opinion by the North West - Liverpool Central Research Ethics Committee (21/NW/0169). Relevant documents will be available online ( www.decodeme.org.uk ). Genetic data will be disseminated as associated variants and genomic intervals, and as summary statistics. Results will be reported on the DecodeME website and via open access publications.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

IgG glycan patterns are associated with type 2 diabetes in independent European populations.

BACKGROUND: Type 2 diabetes results from interplay between genetic and acquired factors. Glycans on proteins reflect genetic, metabolic and environmental factors. However, associations of IgG glycans with type 2 diabetes have not been described. We compared IgG N-glycan patterns in type 2 diabetes with healthy subjects. METHODS: In the DiaGene study, a population-based case-control study, (1886 cases and 854 controls) 58 IgG glycan traits were analyzed. Findings were replicated in the population-based CROATIA-Korcula-CROATIA-Vis-ORCADES studies (162 cases and 3162 controls), and meta-analyzed. AUCs of ROC-curves were calculated using 10-fold cross-validation for clinical characteristics, IgG glycans and their combination. RESULTS: After correction for extensive clinical covariates, 5 IgG glycans and 13 derived traits significantly associated with type 2 diabetes in meta-analysis (after Bonferroni correction). Adding IgG glycans to age and sex increased the AUC from 0.542 to 0.734. Adding them to the extensive model did not substantially improve the AUC. The AUC for IgG glycans alone was 0.729. CONCLUSIONS: Several IgG glycans and traits firmly associate with type 2 diabetes, reflecting a pro-inflammatory and biologically-aged state. IgG glycans showed limited improvement of AUCs. However, IgG glycans showed good prediction alone, indicating they may capture information of combined covariates. The associations found may yield insights in type 2 diabetes pathophysiology. GENERAL SIGNIFICANCE: This work shows that IgG glycomic changes have biomarker potential and may yield important insights into pathophysiology of complex public health diseases, illustrated here for the first time in type 2 diabetes.

The Association Between Glycosylation of Immunoglobulin G and Hypertension: A Multiple Ethnic Cross-Sectional Study.

More than half of all known proteins, and almost all membrane and extra-cellular proteins have oligosaccharide structures or glycans attached to them. Defects in glycosylation pathways are directly involved in at least 30 severe human diseases.A multiple center cross-sectional study (China, Croatia, and Scotland) was carried out to investigate the possible association between hypertension and IgG glycosylation. A hydrophilic interaction chromatography of fluorescently labeled glycans was used to analyze N-glycans attached to IgG in plasma samples from a total of 4757 individuals of Chinese Han, Croatian, and Scottish ethnicity.Five glycans (IgG with digalactosylated glycans) significantly differed in participants with prehypertension or hypertension compared to those with normal blood pressure, while additional 17 glycan traits were only significantly differed in participants with hypertension compared to those of normal blood pressure. These glycans were also significant correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP).The present study demonstrated for the 1st time an association between hypertension and IgG glycome composition. These findings suggest that the individual variation in N-glycosylation of IgG contributes to pathogenesis of hypertension, presumably via its effect on pro- and/or anti-inflammatory pathways.

Early Upper Paleolithic chronology in the Levant: new ABOx-SC accelerator mass spectrometry results from the Mughr el-Hamamah Site, Jordan.

Methodological developments and new paleoanthropological data remain jointly central to clarifying the timing and systemic interrelationships between the Middle-Upper Paleolithic (MP-UP) archaeological transition and the broadly contemporaneous anatomically modern human-archaic biological turnover. In the recently discovered cave site of Mughr el-Hamamah, Jordan, in situ flint artifacts comprise a diagnostic early Upper Paleolithic (EUP) assemblage. Unusually well-preserved charcoal from hearths and other anthropogenic features associated with the lithic material were subjected to acid-base-wet oxidation-stepped combustion (ABOx-SC) pretreatment. This article presents the ABOx-SC accelerator mass spectrometry (AMS) radiocarbon dates on nine charcoal specimens from a single palimpsest occupation layer. Date calibration was carried out using the INTCAL13 radiocarbon calibration dataset. With the bulk of the material dating to 45-39 ka cal BP (thousands of years calibrated before present), the Mughr el-Hamamah lithic artifacts reveal important differences from penecontemporaneous sites in the region, documenting greater technological variability than previously known for this time frame in the Levant. The radiocarbon data from this EUP archaeological context highlight remaining challenges for increasing chronological precision in documenting the MP-UP transition.

New method for analysis of facial growth in a pediatric reconstructed mandible.

INTRODUCTION: The aim of this article was to present a new method of analysis for the assessment of facial growth and morphology after surgical resection of the mandible in a growing patient. METHODS: This was a 2-year longitudinal study of facial growth in a child who had undergone segmental resection of the mandible with immediate reconstruction as a treatment for juvenile aggressive fibromatosis. Three-dimensional digital stereo-photogrammteric cameras were used for image acquisition at several follow-up intervals: immediate, 6 months, and 2 years postresection. After processing and superimposition, shell-to-shell deviation maps were used for the analysis of the facial growth pattern and its deviation from normal growth. The changes were seen as mean surface changes and color maps. An average constructed female face from a previous study was used as a reference for a normal growth pattern. RESULTS: The patient showed significant growth during this period. Positive changes took place around the nose, lateral brow area, and lower lip and chin, whereas negative changes were evident at the lower lips and cheeks area. An increase in the vertical dimension of the face at the chin region was also seen prominently. CONCLUSIONS: Three-dimensional digital stereo-photogrammetry can be used as an objective, noninvasive method for quantifying and monitoring facial growth and its abnormalities.

The aging farm population and rural aging research.

This article explores the potential and the promise of convergence between gerontological and occupational health researchers to better understand challenges faced by aging farmers including declining economic viability of family farms, the aging of the population of working farmers, and probability of work-related injury or disability among older farmers. Although the need for research seems obvious, the economic, demographic, and psychosocial dynamics of continued work among aging farmers is under-studied in the occupational health literature and absent in the gerontological literature. Following examination of studies of aging farmers drawn from the occupational health literature, we review studies of rural aging in the gerontological literature. First, we compare varying definitions of rural across federal agencies that impact the ability of researchers using these data to examine variability across rural places. Next, we review studies based upon primary data that include rural residence among their independent variables. We describe different definitions of rural residence across federal agencies with an eye toward their methodological and conceptual impact on the rural aging literature. Then we describe inadequate and incomplete definition and measurement of rural residence across published studies of primary data. Following discussion of the implications of these shortcomings for rural aging research including farmers and others engaged in extractive activities, we discuss the potential for joint work among gerontologists and occupational health researchers to better understand the significance of aging for transition in the agricultural economy and the viability of family farms. We recommend attention to the definition and measurement of rural residence to include variability in rural farm and non-farm populations and refocusing the occupational health literature on aging farmers to include a life course perspective from gerontological theory applied through longitudinal research designs.

Enhancing research in a family medicine program: one institution's story.

BACKGROUND AND OBJECTIVES: To enhance research productivity among East Tennessee State University's faculty, the Department of Family Medicine developed and implemented a multi-component initiative to expand multidisciplinary primary care research. METHODS: The research support infrastructure expanded to include a family physician research director, three PhD faculty researchers, two research assistants, a statistician, and a grant/science writer. A monthly seminar series, quarterly workshops, and a formal mentoring program paired more-experienced with less-experienced faculty researchers. Through a competitive mechanism in which junior faculty submitted proposals, a multidisciplinary committee selected two family physician researchers to receive protected time to develop their research. RESULTS: From 2001-2006, more than 25 experienced researchers served as mentors, lecturers, consultants, or reviewers. Fifteen mentor-mentee pairs were formed. Of 30 family medicine faculty, the number actively engaged in research, including project design, data collection, oral presentation of results, or journal article submissions, increased from seven (23%) to 19 (63%). From 2001-2006 the number of presentations at professional meetings increased, and articles in peer-reviewed journals increased nearly fivefold. Grant submissions increased, with 19 faculty members participating in grant-writing teams. Based on the success of this initiative, the program has expanded to include faculty members in general internal medicine and general pediatrics. CONCLUSIONS: Our multi-component initiative successfully builds and sustains a primary care research program.

Child overweight interventions in rural primary care practice: a survey of primary care providers in southern Appalachia.

Child overweight has reached an epidemic level throughout the United States. A total of 65 primary care providers in southern Appalachia were surveyed to understand current issues in addressing child overweight in rural primary care practice. The study shows that while providers realized the importance of child overweight intervention, many were not ready and did little to address child overweight in their practices. The providers' skill levels in addressing child overweight were generally less than sufficient. Common barriers to child overweight treatment included lack of parental motivation and involvement, lack of supportive services, and lack of clinician time. In conclusion, rural primary care is facing many challenges in addressing child overweight. However, with more training in behavioral intervention skills and through establishing a family-based intervention and a group visit approach, primary care providers could play a more active role in the fight against the epidemic of child overweight.

Subclinical thyroid disorders and cognitive performance among adolescents in the United States.

BACKGROUND: Thyroid hormone plays a crucial role in the growth and function of the central nervous system. The purpose of the study was to examine the relationships between the status of subclinical thyroid conditions and cognition among adolescents in the United States. METHODS: Study sample included 1,327 adolescents 13 to 16 years old who participated in the Third National Health and Nutrition Examination Survey (NHANES III). Serum thyroxine (T4) and thyroid stimulating hormone (TSH) were measured and subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid groups were defined. Cognitive performance was assessed using the subscales of the Wide Range Achievement Test-Revised (WRAT-R) and the Wechsler Intelligence Scale for Children-Revised (WISC-R). The age-corrected scaled scores for arithmetic, reading, block design, and digit span were derived from the cognitive assessments. RESULTS: Subclinical hypothyroidism was found in 1.7% and subclinical hyperthyroidism was found in 2.3% of the adolescents. Cognitive assessment scores on average tended to be lower in adolescents with subclinical hyperthyroidism and higher in those with subclinical hypothyroidism than the score for the euthyroid group. Adolescents with subclinical hypothyroidism had significantly better scores in block design and reading than the euthyroid subjects even after adjustment for a number of variables including sex, age, and family income level. CONCLUSION: Subclinical hypothyroidism was associated with better performance in some areas of cognitive functions while subclinical hyperthyroidism could be a potential risk factor.

Practice locations of graduates of family physician residency and nurse practitioner programs: considerations within the context of institutional culture and curricular innovation through Titles VII and VIII.

BACKGROUND: Studies have described the aggregate results of federal funding for health professions education at the national level, but analysis of the long-term impact of institutional participation in these programs has been limited. PURPOSE: To describe and assess federally supported curricular innovations at East Tennessee State University designed to promote family medicine and nurse practitioner graduate interest in rural and underserved populations. METHODS: Descriptive analysis of a survey to determine practice locations of nurse practitioner graduates (1992-2002) and graduates of 3 family medicine residencies (1978-2002). Graduates' (N = 656) practice locations were documented using specific federal designations relating to health professions shortages and rurality. RESULTS: Overall, 83% of family medicine residency and 80% of nurse practitioner graduates selected practice locations in areas with medically underserved or health professions shortage designations; 48% of family physicians and 38% of nurse practitioners were in rural areas. CONCLUSIONS: Graduates who study in an educational setting with a mission-driven commitment to rural and community health and who participate in curricular activities designed to increase their experience with rural and underserved populations choose, in high numbers, to care for these populations in their professional practice.

Genetic variability and phylogeography of the invasive zebra mussel, Dreissena polymorpha (Pallas).

The zebra mussel, Dreissena polymorpha (Pallas), a bivalve species originally native to the Black and Caspian seas, has invaded Ireland in the last decade. Five microsatellite loci were used to investigate genetic diversity and population structure in 10 populations across Europe (Ireland, UK, the Netherlands and Romania) and the Great Lakes (Lake Ontario and Lake St Clair). Levels of allelic diversity and mean expected heterozygosity were high for all populations (mean number of alleles/locus and H(E) were 10-15.2 and 0.79-0.89, respectively). High levels of polymorphism observed in Irish populations suggest that the Irish founder population(s) were large and/or several introductions took place after foundation. Significant deficits of heterozygotes were recorded for all populations, and null alleles were the most probable factor contributing to these deficits. Pairwise comparisons using Fisher exact tests and F(ST) values revealed little genetic differentiation between Irish populations. The UK sample was not significantly differentiated from the Irish samples, most probably reflecting an English origin for Irish zebra mussels. No significant differentiation was detected between the two Great Lakes populations. Our data support a northwest rather than a central or east European source for North American zebra mussels.

A student-run outreach clinic for rural communities in Appalachia.

East Tennessee State University's Department of Family Medicine (DFM) implements a student-run outreach clinic series that addresses health care needs of communities in the southern Appalachians. Offered during the third-year family medicine clerkship, the clinics link academic family physicians and students with community health care providers. Services vary with each community's needs, but include history taking, physical examinations, patient education, and testing. The planning and implementation that begin with an annual meeting of faculty and community representatives include visits by DFM personnel to the rural communities and orientations of medical students conducted by faculty and community representatives. Students rate this experience highly because it provides them with useful hands-on experience, reasonable autonomy, collaboration with community providers, and understanding the needs of the underserved. Community hosts rate students highly in their respect for patients, sensitivity to confidentiality, and professionalism. Identified weaknesses are attributed to the fact that the outreach clinics were established in response to community needs and did not follow a careful curricular development. There was little attempt to standardize the procedures performed by each student or the amount of direct observation and feedback they received from their preceptors. Changes are underway that will strengthen the educational value of the outreach clinics. Participating students are provided a daylong orientation during which they practice full and focused physical examinations and review common medical problems such as diabetes, hypertension, and depression. Students also now document the patients encountered, their medical problems, and the clinical skills practiced.

The endocrine disrupting effect of municipal effluent on the zebra mussel (Dreissena polymorpha).

Municipal effluents have been shown to contain a cocktail of endocrine disrupting chemicals (EDCs). The estrogenic effect of these effluents has been demonstrated on both vertebrate and invertebrate species by the feminisation of the exposed males. This effect was investigated on the freshwater zebra mussel (Dreissena polymorpha) after exposure to tertiary treated effluent from a municipal sewage treatment works (STW). Mussels were exposed to the effluent in situ for 112 days during gametogenesis (December to mid-March). Levels of vitellin (Vn)-like proteins (the major protein found in oocytes) were measured indirectly using the alkali-labile phosphate (ALP) technique and confirmed by gel electrophoresis. Significant increases (P < 0.05) in Vn-like proteins were found in both male and female mussels after exposure to the effluent, indicating that endocrine disruption (ED) had occurred. Using High-performance thin layer chromatography (HPTLC) levels of the mussels main steroid, cholesterol were found to more than double after effluent exposure. General physiological (survival, condition, etc.) and histological effects were also investigated. Histological effects observed included a large increase in interstitial tissue between the seminiferous tubules of the gonad in male mussels exposed to effluent. Effluent samples were tested for estrogenic compounds using the toxicity identification and evaluation method (TIE). A complex mixture of compounds with estrogenic activity was found with 17beta-estradiol, 17alpha-ethynlestradiol and bisphenol A accounting for the majority of the effluents estrogenic activity. Results indicate that the zebra mussel is a suitable bioindicator of endocrine disruption in freshwater environments.