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Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ∼550,000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52,775 cases and 45,940 controls) using Mendelian randomization (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4,043 incident CRC cases and 332,773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, CI(95%): 0.78-0.99,P=0.04; OR: 0.93, CI(95%): 0.88-0.98,P=0.01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, CI(95%): 0.80-0.97,P=0.01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, CI(95%): 0.76-0.93,P=6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, CI(95%): 0.93-0.99,P=0.02] and following adjustment for the other WBC subtypes [RR: 0.96, CI(95%): 0.93-0.99,P=0.001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.What is already known of this topicWhile previous observational studies have suggested a protective role for eosinophils in colorectal cancer development and implicated neutrophils, whether changes in the levels of circulating white blood cells causes colorectal cancer has not been explored.What this study addsOur study is the first to use Mendelian randomization (MR) to investigate this relationship. In parallel, for comparison, we also conduct the largest cohort study to date on the topic. We found evidence to suggest that elevated eosinophil and lymphocyte count may have a protective effect on CRC risk, adding new insights into the pathogenesis of CRC.How this study might affect research, practice or policyOur findings will encourage further mechanistic exploration to understand the biological mechanisms underpinning our findings, which may lead to new therapeutic approaches or risk reduction strategies.

Funder: Oxford Biomedical Research Centre, Funder: EU-ERDF, Funder: Wellcome Trust; funder-id: http://dx.doi.org/10.13039/100010269, Funder: GlaxoSmithKline; funder-id: http://dx.doi.org/10.13039/100004330, Funder: Sepsis Research, Funder: Intensive Care Society; funder-id: http://dx.doi.org/10.13039/501100000846, BACKGROUND: Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. METHODS AND FINDINGS: We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. CONCLUSIONS: IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N=1,086,394, replication N=3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis and 15 additional loci in the multi-ancestry analysis (6 novel). All 81 variants replicated in a separate European analysis. Eleven variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African). While four variants appeared to be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL signals in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Paper presented at the World Congress of Soil Science on 4th August 2022 as part of the Ecological Continuity Trust's Fringe event

While artificial intelligence (AI) offers promising solutions in healthcare, it also poses a number of threats to human health and well-being via social, political, economic and security-related determinants of health. We describe three such main ways misused narrow AI serves as a threat to human health: through increasing opportunities for control and manipulation of people; enhancing and dehumanising lethal weapon capacity and by rendering human labour increasingly obsolescent. We then examine self-improving ‘artificial general intelligence’ (AGI) and how this could pose an existential threat to humanity itself. Finally, we discuss the critical need for effective regulation, including the prohibition of certain types and applications of AI, and echo calls for a moratorium on the development of self-improving AGI. We ask the medical and public health community to engage in evidence-based advocacy for safe AI, rooted in the precautionary principle.

IntroductionSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.MethodsWe performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis.ResultsIn the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results.ConclusionsIL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Background: Obesity is associated with increased risk of multiple sclerosis (MS); however, the underlying mechanisms remain unclear. Objective: To determine the extent to which decreased vitamin D bioavailability and altered levels of adiponectin and leptin mediate the association between obesity and MS. Methods: We performed Mendelian randomization (MR) analyses to estimate the effects on MS of body mass index (BMI), 25-hydroxyvitamin D (25OHD), adiponectin, and leptin levels in a cohort of 14,802 MS cases and 26,703 controls. We then estimated the proportion of the effect of obesity on MS explained by these potential mediators. Results: Genetic predisposition to higher BMI was associated with increased MS risk (odds ratio (OR) = 1.33 per standard deviation (SD), 95% confidence interval (CI) = 1.09–1.63), while higher 25OHD levels reduced odds of MS (OR = 0.72 per SD, 95% CI = 0.60–0.87). In contrast, we observed no effect of adiponectin or leptin. In MR mediation analysis, 5.2% of the association between BMI and MS was attributed to obesity lowering 25OHD levels (95% CI = 0.3%–31.0%). Conclusions: This study found that a minority of the increased risk of MS conferred by obesity is mediated by lowered vitamin D levels, while leptin and adiponectin had no effect. Consequently, vitamin D supplementation would only modestly reverse the effect of obesity on MS.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%. A genetic link suggests that interventions that halve the risk of malaria episodes could reduce the prevalence of iron deficiency in African children by nearly 50%.

HO-1 is a key enzyme in the management of heme in humans. A GT(n) repeat length in the gene HMOX1, has previously been widely associated with a variety of phenotypes, including susceptibility and outcomes in diabetes, cancer, infections, and neonatal jaundice. However, studies are generally small and results inconsistent. In this study, we imputed the GT(n) repeat length in two European cohorts (UK Biobank, n = 463,005; and Avon Longitudinal Study of Parents and Children (ALSPAC n = 937), with the reliability of imputation tested in other cohorts (1000 Genomes, HGDP, and UK-PGP). Subsequently, we measured the relationship between repeat length and previously identified associations (diabetes, COPD, pneumonia and infection related mortality in UK Biobank; neonatal jaundice in ALSPAC) and performed a phenome-wide association study (PheWAS) in UK Biobank. Despite high quality imputation (correlation between true repeat length and imputed repeat length >0.9 in test cohorts), no clinical associations were identified in either the PheWAS or specific association studies. These findings were robust to definitions of repeat length and sensitivity analyses. Despite multiple smaller studies identifying associations across a variety of clinical settings; we could not replicate or identify any relevant phenotypic associations with the HMOX1 GT(n) repeat.

OBJECTIVE Holmes tremor (HT) is a rare and debilitating movement disorder comprising both rest and action tremor, and it is known for its resistance to treatment. Its most common causes include ischemic or hemorrhagic insults and trauma. Mechanistically, the combined rest and action tremor is thought to require a double lesion of both the dopaminergic nigrostriatal system and the dentatorubrothalamic pathways, often near the midbrain where both pathways converge. The aim of this study was to characterize HT as a presenting sign in cases of hydrocephalus and to discuss potential pathomechanisms, clinical presentations, and treatment options. METHODS MEDLINE and Web of Science were searched for cases of HT with hydrocephalus from database inception to August 2021, and these were compiled along with the authors’ own unique case of treatment-responsive HT in a child with low-pressure obstructive hydrocephalus secondary to a tectal tumor. Patient characteristics, presenting signs/symptoms, potential precipitating factors, interventions, and patient outcomes were recorded. RESULTS Nine patients were identified including the authors’ video case report. All patients had a triventriculomegaly pattern with at least a component of obstructive hydrocephalus, and 4 patients were identified as having low-pressure hydrocephalus. Parinaud’s syndrome and bradykinesia were the most commonly associated signs. Levodopa and CSF diversion were the most commonly used and effective treatments for HT in this population. This review was not registered and did not receive any funding. CONCLUSIONS HT is a poorly understood and probably underrecognized presentation of hydrocephalus that is difficult to treat, limiting the strength of the evidence in this review. Treatment options include CSF diversion, antiparkinsonian agents, antiepileptic agents, deep brain stimulation, and MR-guided focused ultrasound, and aim toward the nigrostriatal and dentatorubrothalamic pathways hypothesized to be involved in its pathophysiology.

Background Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. Methods We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2. Findings In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 × 10−16) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P = 9.04 × 10−12). Further analyzes using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protection from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P = 2.32 × 10−08, proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence severe SARS-CoV-2 was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P = 0.002), a signal transductor for interleukin-6 type cytokines which are involved in inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples. Interpretation Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease. Funding The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation.

Research on the epidermal growth factor (EGF) family and the family of receptors (EGFR) has progressed rapidly in recent times. New crystal structures of the ectodomains with different ligands, the activation of the kinase domain through oligomerisation and the use of fluorescence techniques have revealed profound conformational changes on ligand binding. The control of cell signaling from the EGFR-family is complex, with heterodimerisation, ligand affinity and signaling cross-talk influencing cellular outcomes. Analysis of tissue homeostasis indicates that the control of pro-ligand processing is likely to be as important as receptor activation events. Several members of the EGFR-family are overexpressed and/or mutated in cancer cells. The perturbation of EGFR-family signaling drives the malignant phenotype of many cancers and both inhibitors and antagonists of signaling from these receptors have already produced therapeutic benefits for patients. The design of affibodies, antibodies, small molecule inhibitors and even immunotherapeutic drugs targeting the EGFR-family has yielded promising new approaches to improving outcomes for cancer patients. In this review, we describe recent discoveries which have increased our understanding of the structure and dynamics of signaling from the EGFR-family, the roles of ligand processing and receptor cross-talk. We discuss the relevance of these studies to the development of strategies for designing more effective targeted treatments for cancer patients.

Introductory paragraphThe inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.We found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.

BACKGROUND: Vaccine-induced immunity against pneumococcal infection relies on the generation of high concentrations of antibody and B-cell memory. Both the 10- and the 13-valent pneumococcal conjugate vaccines (PCV-10 and PCV-13) effectively reduce disease caused by vaccine serotypes. It is unknown whether the generation of B-cell memory requires several doses of the same vaccine or whether different PCVs are interchangeable. METHODS: Children in the UK (n=178) who had previously received PCV-13 at 2 and 4 months were randomized 1:1 to receive a PCV-13 or PCV-10 booster at age 12 months. Peripheral blood memory B cells (BMEM) were quantified before and at 1 and 12 months following vaccination using a cultured ELISpot assay for pneumococcal serotypes 1, 3, 4, 9V, 14, 19A and diphtheria and tetanus toxoid. Correlations between BMEM frequencies and simultaneously measured antibody (IgG and OPA) was also assessed. RESULTS: A significant rise in post-booster BMEM frequency was seen for 5 out of six serotypes in the PCV-13 group and none in the PCV-10 group. In the PCV-13 group, there was a particularly large increase in serotype 3-specific BMEM associated with only a small increase in antibody. Post-booster BMEM responses correlated positively with antibody, but correlations between pre-booster BMEM and subsequent BMEM and antibody responses were inconsistent. CONCLUSIONS: Following priming with PCV-13 in early infancy, a booster dose of PCV-10 does not induce detectable peripheral blood BMEM responses but a PCV-13 booster does induce robust responses. Booster responses to pneumococcal conjugate vaccines may be dependent on homologous carrier protein priming.

Effective literature searching for research. Sarah Gash Only connect: shaping networks and knowledge for the new millennium. Trevor Haywood Information sources for the press and broadcast media. Sarah Adair (ed.). Exploring the contexts of information behaviour. Thornas D. WiIson and David K. Allen. Researching markets by industry sectors: a guide to sources and services. David Mort (ed.). Change management for information services. Sharon Penfold. LISU Reports - NHS libraries: statistics 1997-98. Public library materials fund and budget survey 1998-2000.Perspectives of public library use 2: a compendium of survey information.

The introduction of vaccines containing the capsular polysaccharides of N. meningitidis, S. pneumonia, and H. influenzae type b has driven a significant reduction in cases of disease caused by these bacteria. The polysaccharide-specific antibody responses following vaccination are well characterized, however less is known about the B cells underlying this response. Here, we summarize the plasma cell (PC) and memory B cell (BMEM) responses following plain polysaccharide and protein-polysaccharide conjugate vaccination, drawing together studies covering a range of vaccines and age groups. These studies show that infant primary PC and BMEM responses to polysaccharide-conjugate vaccines are low in relation to older age groups but are significantly higher following booster doses. PC kinetics have generally been found to follow a similar pattern irrespective of vaccine type or age group, whereas divergent BMEM responses have been reported following plain polysaccharide and conjugate vaccination. A degree of correlation between early BMEM responses and maintenance of protective antibody levels has been identified in some studies, but the relationship between the 2 remains unclear. Identification of the B cell subsets involved and the mechanisms by which they are induced may provide a better understanding of the role of B cells in maintaining protective immunity through vaccination.

Evaluation of health impacts arising from inhalation of pollutant particles

Inhalation of particulate pollutants below 10 μm in size (PM10) is associated with adverse health effects. Here we use magnetic remanence measurements of roadside tree leaves to examine levels of vehicle-derived PM around Lancaster, UK. Leaf saturation remanence (SIRM) values exhibit strong correlation with both the SIRM and particulate mass of co-located, pumped-air samples, indicating that these leaf magnetic values are an effective proxy for ambient PM10 concentrations. Biomagnetic monitoring using tree leaves can thus provide high spatial resolution data sets for assessment of particulate pollution levels at pedestrian-relevant heights. Leaf SIRM values not only increase with proximity to roads with higher traffic volumes, but are also ~ 100 % higher at 0.3 m than at ~ 1.5 – 2 m height. Magnetic and SEM data indicate that the particle populations are dominated by spherical, iron-rich particles ~ 0.1 – 1 μm in diameter, with fewer larger, more angular, silica-rich particles. Comparison of the roadside leaf-calculated PM10 concentrations with PM10 concentrations predicted by a widely-used atmospheric dispersion model (ADMS-urban, CERC Ltd. Cambridge, UK; CERC, 2009), indicates some agreement between them. However, the model under-predicts PM10 concentrations at ‘urban hotspots’ such as major-minor road junctions and traffic lights. Conversely, the model over-predicts PM10 concentrations with distance from the road wherever one tree is screened by another, indicating the filtering/protective effect of roadside trees in leaf.

Nephrologists looking for quick answers to diagnostic clinical questions in MEDLINE can use a range of published search strategies or Clinical Query limits to improve the precision of their searches. We aimed to evaluate existing search strategies for finding diagnostic test accuracy studies in nephrology journals.We assessed the accuracy of 14 search strategies for retrieving diagnostic test accuracy studies from three nephrology journals indexed in MEDLINE. Two investigators hand searched the same journals to create a reference set of diagnostic test accuracy studies to compare search strategy results against.We identified 103 diagnostic test accuracy studies, accounting for 2.1% of all studies published. The most specific search strategy was the Narrow Clinical Queries limit (sensitivity: 0.20, 95% CI 0.13-0.29; specificity: 0.99, 95% CI 0.99-0.99). Using the Narrow Clinical Queries limit, a searcher would need to screen three (95% CI 2-6) articles to find one diagnostic study. The most sensitive search strategy was van der Weijden 1999 Extended (sensitivity: 0.95; 95% CI 0.89-0.98; specificity 0.55, 95% CI 0.53-0.56) but required a searcher to screen 24 (95% CI 23-26) articles to find one diagnostic study. Bachmann 2002 was the best balanced search strategy, which was sensitive (0.88, 95% CI 0.81-0.94), but also specific (0.74, 95% CI 0.73-0.75), with a number needed to screen of 15 (95% CI 14-17).Diagnostic studies are infrequently published in nephrology journals. The addition of a strategy for diagnostic studies to a subject search strategy in MEDLINE may reduce the records needed to screen while preserving adequate search sensitivity for routine clinical use.

The purpose of the article is to trace the development of family nursing in Scotland and to describe the work of the Family Nursing Network Scotland (FNNS) since its inception in 1997. Although the origins of the early work are in child health nursing, the Network aims to support family nursing research, education, and practice across all areas of the discipline. Original research provided the impetus for an examination of family nursing in Scotland. Recent research has focused on the preparation of nursing students in Scotland for family nursing practice. Initiatives by the FNNS have raised awareness and encouraged the practice of family nursing. Future goals for the development of family nursing in Scotland are discussed.

The ELISpot assay is used in vaccine studies for the quantification of antigen-specific memory B cells (B(MEM)), and can be performed using cryopreserved samples. The effects of cryopreservation on B(MEM) detection and the consistency of cultured ELISpot assays when performed by different operators or laboratories are unknown. In this study, blood was taken from healthy volunteers, and a cultured ELISpot assay was used to count B(MEM) specific for 2 routine vaccine antigens (diphtheria and tetanus toxoid). Results were assessed for intra- and inter-operator variation, and the effects of cryopreservation. Cryopreserved samples were shipped to a second laboratory in order to assess inter-laboratory variation. B(MEM) frequencies were very strongly correlated when comparing fresh and frozen samples processed by the same operator, and were also very strongly correlated when comparing 2 operators in the same laboratory. Results were slightly less consistent when samples were processed in different laboratories but correlation between the 2 measurements was still very strong. Although cell viability was reduced in some cryopreserved samples due to higher temperatures during transportation, B(MEM) could still be quantified. These results demonstrate the reproducibility of the ELISpot assay across operators and laboratories, and support the use of cryopreserved samples in future B(MEM) studies.

This article describes the foundation in 1997 of a Family Nursing Network (FNN) in Edinburgh involving nurses from local trusts and Scottish universities. The purpose of the FNN is to support the use of family nursing in practice, research and education. Family nursing proposes that health care should focus on the needs of the family as a unit rather than as the context of care for a family member with health needs. Family nursing is not common practice in the UK but some nurses have found it highly relevant to their care. The World Health Organization (WHO) promotes the family health nurse as an important component of health care in the community for the future and family nursing could well provide the foundation for such practice. Definitions of the family and family nursing are offered, the conceptual background is analysed and the work achieved by the FNN is reviewed. The authors write on behalf of the FNN.

Contents: Preface. N. Khattri, D. Sweet, Assessment Reform: Promises and Challenges. D.P. Resnick, L.B. Resnick, Performance Assessment and the Multiple Functions of Educational Measurement. M. Wilson, R.J. Adams, Evaluating Progress with Alternative Assessments: A Model for Title 1. D.E. Wiley, E.H. Haertel, Extended Assessment Tasks: Purposes, Definitions, Scoring, and Accuracy. R.L. Linn, Linking Assessments. R. Hardy, Performance Assessment: Examining the Costs. D.H. Monk, Conceptualizing the Costs of Large-scale Pupil Performance Assessment. S.M. Stiegelbauer, Change has Changed: Implications for Implentation of Assessments from the Organizational Change Literature. L.B. Easton, P.H. Koehler, Arizona's Educational Reform: Creating and Capitalizing on the Conditions for Policy Development and Implementation. E.L. Baker, H.F. O'Neil, Jr., Performance Assessment and Equity.

The Visiting Nurse Service of New York's Community Nursing Organization was developed to test the effectiveness of community-focused nursing case management services with elderly enrollees in a capitated reimbursement system. After 3 years of operation, it is evident that the long-term relationship between the nurse and the enrollee was the key to financial and clinical success.