WNT5B drives osteosarcoma stemness, chemoresistance and metastasis.

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. RESULTS: In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. CONCLUSIONS: Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. KEY POINTS: WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Characterization of Fine Motor and Visual Motor Skills in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.In a cohort of 74 subjects, the Peabody Developmental Motor Scales-2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales-2 scores within a genotype was assessed by interquartile ranges (IQRs).Peabody Developmental Motor Scales-2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales-2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data. When feasible, prospective studies are often cross-sectional rather than longitudinal and are unlikely to capture pre- or early- symptomatic disease trajectories, limiting their utility in characterizing the full natural history of the disease. Therapeutic development in leukodystrophies is subject to these same obstacles. The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) comprises of a network of research institutions across the United States, supported by a multi-center biorepository protocol, to map the longitudinal clinical course of disease across leukodystrophies. As part of GLIA-CTN, we developed Standard Operating Procedures (SOPs) that delineated all study processes related to staff training, source documentation, and data sharing. Additionally, the SOP detailed the standardized approach to data extraction including diagnosis, clinical presentation, and medical events, such as age at gastrostomy tube placement. The key variables for extraction were selected through face validity, and common electronic case report forms (eCRF) across leukodystrophies were created to collect analyzable data. To enhance the depth of the data, clinical notes are extracted into "original" and "imputed" encounters, with imputed encounter referring to a historic event (e.g., loss of ambulation 3 months prior). Retrospective Functional Assessments were assigned by child neurologists, using a blinded dual-rater approach and score discrepancies were adjudicated by a third rater. Upon completion of extraction, data source verification is performed. Data missingness was evaluated using statistics. The proposed methodology will enable us to leverage existing medical records to address the persistent gap in natural history data within this unique disease group, allow for assessment of clinical trajectory both pre- and post-formal diagnosis, and promote recruitment of larger cohorts.

Systematic analysis of genotype-phenotype variability in siblings with Aicardi Goutières Syndrome (AGS).

OBJECTIVE: Aicardi Goutières Syndrome (AGS) is a genetic interferonopathy associated with multisystemic heterogeneous disease and neurologic dysfunction. AGS includes a broad phenotypic spectrum which is only partially explained by genotype. To better characterize this variability, we will perform a systematic analysis of phenotypic variability in familial cases of AGS. METHODS: Among thirteen families, twenty-six siblings diagnosed with AGS were identified from the Myelin Disorders and Biorepository Project (MDBP) at the Children's Hospital of Philadelphia. Data were collected on the age of onset, genotype, neurologic impairment, and systemic complications. Neurologic impairment was assessed by a disease-specific scale (AGS Severity Scale) at the last available clinical encounter (range: 0-11 representing severe - attenuated phenotypes). The concordance of clinical severity within sibling pairs was categorized based on the difference in AGS Scale (discordant defined as >2-unit difference). The severity classifications were compared between sibling sets and by genotype. RESULTS: Five genotypes were represented: TREX1 (n = 4 subjects), RNASEH2B (n = 8), SAMHD1 (n = 8) ADAR1 (n = 4), and IFIH1 (n = 2). The older sibling was diagnosed later relative to the younger affected sibling (median age 7.32 years [IQR = 14.1] compared to 1.54 years [IQR = 10.3]). Common presenting neurologic symptoms were tone abnormalities (n = 10/26) and gross motor dysfunction (n = 9/26). Common early systemic complications included dysphagia and chilblains. The overall cohort median AGS severity score at the last encounter was 8, while subjects presenting with symptoms before one year had a median score of 5. The TREX1 cohort presented at the youngest age and with the most severe phenotype on average. AGS scores were discordant for 5 of 13 sibling pairs, most commonly in the SAMHD1 pairs. Microcephaly, feeding tube placement, seizures and earlier onset sibling were associated with lower AGS scores (respectively, Wilcoxon rank sum: p = 0.0001, p < 0.0001, p = 0.0426, and Wilcoxon signed rank: p = 0.0239). CONCLUSIONS: In this systematic analysis of phenotypic variability in familial cases, we found discordance between siblings affected by AGS. Our results underscore the heterogeneity of AGS and suggest factors beyond AGS genotype may affect phenotype. Understanding the critical variables associated with disease onset and severity can guide future therapeutic interventions and clinical monitoring. This report reinforces the need for further studies to uncover potential factors to better understand this phenotypic variability, and consequently identify potential targets for interventions in attempt to change the natural history of the disease.

Eravacycline, the first four years: health outcomes and tolerability data for 19 hospitals in 5 U.S. regions from 2018 to 2022.

IMPORTANCE: The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline's efficacy in addressing the pressing global challenge of MDR bacterial infections.

Residual Infusion Performance Evaluation (RIPE): A Single-Center Evaluation of Residual Volume Post-Intravenous Eravacycline Infusion.

Intravenous (IV) drugs are administered through infusion pumps and IV administration sets for patients who are seen in healthcare settings. There are multiple areas of the medication administration process that can influence the amount of a drug a patient receives. For example, IV administration sets that deliver a drug from an infusion bag to a patient vary in terms of length and bore. In addition, fluid manufacturers report that the total acceptable volume range for a 250 mL bag of normal saline can be anywhere from 265 to 285 mL. At the institution chosen for our study, each 50 mg vial of eravacycline is reconstituted using 5 mL of diluent, and the total dose is administered as a 250 mL admixture. This single-center, retrospective, quasi-experimental study evaluated the residual medication volume after the completion of an IV eravacycline infusion in patients admitted during the pre-intervention study period compared to those in the post-intervention study period. The primary outcome of the study was to compare the residual antibiotic volume remaining in the bags following IV infusions of eravacycline before and after the implementation of interventions. The secondary outcomes included the following: comparing the amount of the drug lost in the pre- and post-intervention periods, determining whether the amount of residual volume was affected by nursing shifts (day versus night), and lastly assessing the cost of facility drug waste. On average, approximately 15% of the total bag volume was not infused during the pre-intervention period, which was reduced to less than 5% in the post-intervention period. Clinically, the average estimated amount of eravacycline discarded decreased from 13.5 mg to 4.7 mg in the pre- and post-intervention periods, respectively. Following the statistically significant results of this study, the interventions were expanded at this facility to include all admixed antimicrobials. Further studies are needed to determine the potential clinical impact when patients do not receive complete antibiotic infusions.

Progress and priorities in reducing the time to cancer diagnosis.

Key developments in early diagnosis research and policy since the publication of the highly cited BJC review "Is increased time to diagnosis and treatment associated with poorer outcomes?" by Neal et al. in 2015 are summarised. Progress achieved since 2015 is described and priorities for further research identified.

Early recognition of patients with leukodystrophies.

Leukodystrophies are defined as differences in normal myelin development and maintenance in the central nervous system. They typically present as white matter imaging abnormalities in young children with delayed developmental milestones. As the scientific community begins to better understand and research the mechanisms underlying leukodystrophies, clinical trials and approved therapies for specific disorders are becoming available. These interventions, ranging from repurposing of existing small molecules to recently approved gene therapies, are highly dependent on early diagnosis. It is essential for pediatricians to identify affected individuals promptly, but they face challenges including lack of awareness of the disorders and nonspecific symptom presentation (e.g., cognitive or motor developmental delay). This review provides five hypothetical clinical presentations and describes the disease mechanisms, typical symptoms, and treatments currently available for common leukodystrophies: Krabbe Disease, Aicardi Goutières Syndrome (AGS), Metachromatic leukodystrophy (MLD), Alexander Disease (AxD), Pelizaeus-Merzbacher Disease (PMD), and X-Linked Adrenoleukodystrophy (X-ALD.) This review educates pediatricians to recognize the presentation of leukodystrophies in affected children. These clinical vignettes can serve as a framework for pediatricians to identify potentially treatable rare disorders among their patients.

Clinical Outcomes of Eravacycline in Patients Treated Predominately for Carbapenem-Resistant Acinetobacter baumannii.

Forty-six patients were treated with eravacycline (ERV) for Acinetobacter baumannii infections, where 69.5% of isolates were carbapenem resistant (CRAB). Infections were primarily pulmonary (58.3%), and most patients received combination therapy (84.4%). The median (IQR) ERV duration was 6.9 days (5.1 to 11.1). Thirty-day mortality was 23.9% in the cohort and 21.9% in CRAB patients. One patient experienced an ERV-possible adverse event. IMPORTANCE Acinetobacter baumannii, particularly when carbapenem resistant (CRAB), is one of the most challenging pathogens in the health care setting. This is complicated by the fact that there is no consensus guideline regarding management of A. baumannii infections. However, the recent Infectious Diseases Society of America guidelines for treatment of resistant Gram-negative infections provided expert recommendations for CRAB management. The panel suggest using minocycline among tetracycline derivatives rather than eravacycline (ERV) until sufficient clinical data are available. Therefore, we present the largest multicenter real-world cohort in patients treated with ERV for A. baumannii, where the majority of isolates were CRAB (69.5%). Our analysis demonstrate that patients treated with ERV-based regimens achieved a 30-day mortality of 23.9% and had a low incidence of ERV-possible adverse events (2.1%). This study is important as it fills the gap in the literature regarding the use of a novel tetracycline (i.e., ERV) in the treatment of this challenging health care infection.

Time to defervescence evaluation for extended- vs. standard-infusion cefepime in patients with acute leukemia and febrile neutropenia.

BACKGROUND/OBJECTIVES: Febrile neutropenia (FN) occurs in up to 80% of patients with hematologic malignancies. Evidence suggests using extended infusions (EI) of beta-lactams can improve outcomes in some populations, but there is limited clinical literature comparing cefepime standard infusion (SI) versus EI for FN. The FDA-approved regimen for FN was used at a large community teaching hospital for patients with FN until a hospital-wide EI beta-lactam protocol was introduced that allowed for EI cefepime in FN at the physicians' discretion. We sought to compare outcomes between patients with FN who received SI and EI cefepime. METHODS: Patients with acute myeloid or lymphocytic leukemia who developed FN between April 2014 and January 2021 were included in this single-center, retrospective study. The primary outcome was to compare mean time to defervescence after the initiation of cefepime SI or EI regimens. SI regimens consisted of IV cefepime 2G q8h/0.5 h, and EI regimens as IV cefepime 1G q8h/4 h. Secondary outcomes included 30-day all-cause mortality, hospital length of stay (LOS), duration of cefepime, and need to escalate therapy. RESULTS: Overall, 193 patients were included. Baseline characteristics were similar between groups. Time to defervescence was significantly shorter with EI compared with the SI group (median 48 h [48-100.5] vs. 70 h [48-113], p = 0.005). Cefepime duration of therapy was significantly shorter in the EI compared with the SI group (median 6.0 days vs. 8.0 days, p = 0.002). There was no difference between other secondary outcomes including LOS, mortality, and antibiotic escalation. CONCLUSION: Despite reduced total daily dose of cefepime, EI cefepime administered as a 1G/0.5 h LD followed 2 h later by 1G q8h/4 h for FN acutely achieves more rapid defervescence than the FDA-approved SI regimen and ultimately attains comparable patient outcomes.

Direct and indirect costs for hospitalized patients with dengue in Southern Sri Lanka.

BACKGROUND: The Southern Province of Sri Lanka is endemic with dengue, with frequent outbreaks and occurrence of severe disease. However, the economic burden of dengue is poorly quantified. Therefore, we conducted a cost analysis to assess the direct and indirect costs associated with hospitalized patients with dengue to households and to the public healthcare system. METHODS: From June 2017-December 2018, we prospectively enrolled children and adults with acute dengue hospitalized at the largest, public tertiary-care (1800 bed) hospital in the Southern Province, Sri Lanka. We administered a structured questionnaire to obtain information regarding direct costs spent by households on medical visits, medications, laboratory testing, and travel for seeking care for the illness. Indirect costs lost by households were estimated by identifying the days of work lost by patients and caregivers and school days lost by children. Direct hospital costs were estimated using gross costing approach and adjusted by multiplying by annual inflation rates in Sri Lankan rupees and converted to US dollars. RESULTS: A total of 1064 patients with laboratory-confirmed dengue were enrolled. The mean age (SD) was 35.9 years (15.6) with male predominance (66.2%). The mean durations of hospitalization for adults and paediatric patients were 3.86 (SD = 1.51) and 4 (SD = 1.32) days, respectively. The per-capita direct cost borne by the healthcare system was 233.76 USD, and was approximately 14 times greater than the per-capita direct cost borne by households (16.29 USD, SD = 14.02). The per-capita average number of loss of working days was 21.51 (SD = 41.71), with mean per-capita loss of income due to loss of work being 303.99 USD (SD = 569.77), accounting for over 70% of average monthly income. On average, 10.88 days (SD = 10.97) of school days were missed due to the dengue episode. School misses were expected to reduce future annual income of affected children by 0.44%. CONCLUSIONS: Dengue requiring hospitalization had a substantial economic burden on the public healthcare system in Sri Lanka and the affected households. These findings emphasize the importance of strengthening dengue control activities and improved use of hospital-based resources for care to reduce the economic impact of dengue in Sri Lanka.

Faecal immunochemical testing (FIT): sources of result variation based on three years of routine testing of symptomatic patients in English primary care.

Introduction: We aimed to determine the analytical capabilities of a commonly used faecal immunochemical test (FIT) to detect faecal haemoglobin (Hb) in symptomatic people attending primary care in the context of the English NICE DG30 guidance.Materials and Methods: Data obtained from independent verification studies and clinical testing of the HM-JACKarc FIT method in routine primary care practice were analysed to derive performance characteristics.Results: Detection capabilities for the FIT method were 0.5 µg/g (limit of blank), 1.3 µg/g (limit of detection) and 3.0 µg/g (limit of quantitation). Of 33 non-homogenized specimens, 31 (93.9%) analysed in triplicate were consistently categorized relative to 10 µg/g, compared to all 33 (100%) homogenized specimens. Imprecision was higher (median 27.8%, (range 20.5% to 48.6%)) in non-homogenized specimens than in homogenized specimens (10.2%, (7.0 to 13.5%)). Considerable variation was observed in sequential clinical specimens from individual patients but no positive or negative trend in specimen degradation was observed over time (p = 0.26).Discussion: The FIT immunoassay evaluated is capable of detecting faecal Hb at concentrations well below the DG30 threshold of 10 µg/g and is suitable for application in this context. The greatest practical challenge to FIT performance is reproducible sampling, the pre-analytical step associated with most variability. Further research should focus on reducing sampling variability, particularly as post-COVID-19 guidance recommends greater FIT utilization.

Individual inflammatory marker abnormalities or inflammatory marker scores to identify primary care patients with unexpected weight loss for cancer investigation?

BACKGROUND: Combinations of inflammatory markers are used as prognostic scores in cancer patients with cachexia. We investigated whether they could also be used to prioritise patients attending primary care with unexpected weight loss for cancer investigation. METHODS: We used English primary care electronic health records data linked to cancer registry data from 12,024 patients with coded unexpected weight loss. For each individual inflammatory marker and score we estimated the sensitivity, specificity, likelihood ratios, positive predictive value (PPV) and the area under the curve along with 95% confidence intervals for a cancer diagnosis within six months. RESULTS: The risk of cancer associated with two abnormal inflammatory markers combined in a score was higher than the risk associated with individual inflammatory marker abnormalities. However, the risk of cancer in weight loss associated with individual abnormalities, notably a raised C-reactive protein, was sufficient to trigger further investigation for cancer under current NICE guidelines. CONCLUSIONS: If scores including pairs of inflammatory marker abnormalities were to be used, in preference to individual abnormalities, fewer people would be investigated to diagnose one cancer with fewer false positives, but fewer people with cancer would be diagnosed overall.

Determinants and extent of weight recording in UK primary care: an analysis of 5 million adults' electronic health records from 2000 to 2017.

BACKGROUND: Excess weight and unexpected weight loss are associated with multiple disease states and increased morbidity and mortality, but weight measurement is not routine in many primary care settings. The aim of this study was to characterise who has had their weight recorded in UK primary care, how frequently, by whom and in relation to which clinical events, symptoms and diagnoses. METHODS: A longitudinal analysis of UK primary care electronic health records (EHR) data from 2000 to 2017. Descriptive statistics were used to summarise weight recording in terms of patient sociodemographic characteristics, health professional encounters, clinical events, symptoms and diagnoses. Negative binomial regression was used to model the likelihood of having a weight record each year, and Cox regression to the likelihood of repeated weight recording. RESULTS: A total of 14,049,871 weight records were identified in the EHR of 4,918,746 patients during the study period, representing 26,998,591 person-years of observation. Around a third of patients had a weight record each year. Forty-nine percent of weight records were repeated within a year with an average time to a repeat weight record of 1.92 years. Weight records were most often taken by nursing staff (38-42%) and GPs (37-39%) as part of a routine clinical care, such as chronic disease reviews (16%), medication reviews (6-8%) and health checks (6-7%), or were associated with consultations for contraception (5-8%), respiratory disease (5%) and obesity (1%). Patient characteristics independently associated with an increased likelihood of weight recording were as follows: female sex, younger and older adults, non-drinkers, ex-smokers, low or high BMI, being more deprived, diagnosed with a greater number of comorbidities and consulting more frequently. The effect of policy-level incentives to record weight did not appear to be sustained after they were removed. CONCLUSION: Weight recording is not a routine activity in UK primary care. It is recorded for around a third of patients each year and is repeated on average every 2 years for these patients. It is more common in females with higher BMI and in those with comorbidity. Incentive payments and their removal appear to be associated with increases and decreases in weight recording.

Serum carcinoembryonic antigen trends for diagnosing colorectal cancer recurrence in the FACS randomized clinical trial.

BACKGROUND: Most guidelines recommend that patients who have undergone curative resection for primary colorectal cancer are followed up for 5 years with regular blood carcinoembryonic antigen (CEA) tests to trigger further investigation for recurrence. However, CEA may miss recurrences, or patients may have false alarms and undergo unnecessary investigation. METHODS: The diagnostic accuracy of trends in CEA measurements for recurrent colorectal cancer, taken as part of the FACS (Follow-up After Colorectal Surgery) trial (2003-2014), were analysed. Investigation to detect recurrence was triggered by clinical symptoms, scheduled CT or colonoscopy, or a CEA level of at least 7 µg/l above baseline. Time-dependent receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic accuracy of CEA trends with single measurements. CEA trends were estimated using linear regression. RESULTS: The area under the ROC curve (AUC) for CEA trend was at least 0·820 across all 5 years of follow-up. In comparison, the AUCs for single measurements ranged from 0·623 to 0·749. Improvement was most marked at the end of the first year of follow-up, with the AUC increasing from 0·623 (95 per cent c.i. 0·509 to 0·736) to 0·880 (0·814 to 0·947). However, no individual trend threshold achieved a sensitivity above 70 per cent (30 per cent missed recurrences). CONCLUSION: Interpreting trends in CEA measurements instead of single CEA test results improves diagnostic accuracy for recurrence, but not sufficiently to warrant it being used as a single surveillance strategy to trigger further investigation. In the absence of a more accurate biomarker, monitoring trends in CEA should be combined with clinical, endoscopic and imaging surveillance for improved accuracy.

Low performance on mathematical tasks in preschoolers: the importance of domain-general and domain-specific abilities.

BACKGROUND: Different domain-specific and domain-general cognitive precursors play a key role in the development of mathematical abilities. The contribution of these domains to mathematical ability changes during development. Primary school-aged children who show mathematical difficulties form a heterogeneous group, but it is not clear whether this also holds for preschool low achievers (LAs) and how domain-specific and domain-general abilities contribute to mathematical difficulties at a young age. The aim of this study was to explore the cognitive characteristics of a sample of preschool LAs and identify sub-types of LAs. METHODS: 81 children were identified as LAs from 283 preschoolers aged 3 to 5 years old and were assessed on a number of domain-general and domain-specific tasks. RESULTS: Cluster analysis revealed four subgroups of LAs in mathematics: (1) a weak processing sub-type; (2) a general mathematical LAs sub-type; (3) a mixed abilities sub-type; and (4) a visuo-spatial deficit sub-type. Whilst two of the groups showed specific domain-general difficulties, none showed only domain-specific difficulties. CONCLUSIONS: Current findings suggest that preschool LAs constitute a heterogeneous group and stress the importance of domain-general factors for the development of mathematical abilities during the preschool years.

Weight loss as a predictor of cancer and serious disease in primary care: an ISAC-approved CPRD protocol for a retrospective cohort study using routinely collected primary care data from the UK.

BACKGROUND: Unexpected weight loss is a symptom of serious disease in primary care, for example between 1 in 200 and 1 in 30 patients with unexpected weight loss go on to develop cancer. However, it remains unclear how and when general practitioners (GPs) should investigate unexpected weight loss. Without clarification, GPs may wait too long before referring (choosing to watch and wait and potentially missing a diagnosis) or not long enough (overburdening hospital services and exposing patients to the risks of investigation). The overall aim of this study is to provide the evidence necessary to allow GPs to more effectively manage patients with unexpected weight loss. METHODS: A retrospective cohort analysis of UK Clinical Practice Research Datalink (CPRD) data to: (1) describe how often in UK primary care the symptom of reported weight loss is coded, when weight is measured, and how GPs respond to a patient attending with unexpected weight loss; (2) identify the predictive value of recorded weight loss for cancer and serious disease in primary care, using cumulative incidence plots to compare outcomes between subgroups and Cox regression to explore and adjust for covariates. Preliminary work in CPRD estimates that weight loss as a symptom is recorded for approximately 148,000 eligible patients > 18 years and is distributed evenly across decades of age, providing adequate statistical power and precision in relation to cancer overall and common cancers individually. Further stratification by cancer stage will be attempted but may not be possible as not all practices within CPRD are eligible for cancer registry linkage, and staging information is often incomplete. The feasibility of using multiple imputation to address missing covariate values will be explored. DISCUSSION: This will be the largest reported retrospective cohort of primary care patients with weight measurements and unexpected weight loss codes used to understand the association between weight measurement, unexpected weight loss, and serious disease including cancer. Our findings will directly inform international guidelines for the management of unexpected weight loss in primary care populations.

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge.

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1 and interferon (IFN) gamma-induced protein (IP)-10 as early as 12-29 h post-inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll-like receptor (TLR)-signalling, innate anti-viral immunity and fever production are all over-represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being expressed actively in circulating cells, while others (IL-6, IL-8, IFN-α and IFN-γ) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down-regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts.