Ultrasound-detectable grey scale synovitis predicts future fulfilment of the 2010 ACR/EULAR RA classification criteria in patients with new-onset undifferentiated arthritis

Objective: To determine the clinical outcomes for patients with new-onset undifferentiated arthritis (UA), not fulfilling the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) classification criteria, and the clinical and imaging predictors of disease progression in these patients. Methods: A prospective observational study was conducted in treatment-naïve UA patients. Baseline ultrasound involved semiquantitative assessment of grey scale (GS) synovitis and power Doppler activity (PD) at 26 joints. Outcomes were fulfilment of 2010 RA criteria (joint involvement determined clinically) and initiation of methotrexate over 12 months. Cox proportional hazards analysis was used to investigate predictors of outcome. Results: Of 60 patients, 13(22%) progressed to RA and 32(53%) ever received methotrexate. Analyses of predictors of outcome were conducted in the subgroup (n=41) of patients with complete baseline data. The presence of GS was associated with progression to RA and methotrexate use: HRs (95% CI) were 1.25(1.07 to 1.45) and 1.16(1.02 to 1.32), respectively, for the number of joints with GS≥ grade 2 after adjustment for swollen joints. PD was not predictive in the low levels at which it was observed. Progression to RA was also associated with fulfilment of the 2010 criteria using ultrasound synovitis for enumerating joint involvement, higher baseline disability and radiographic erosion. Conclusions: This is the first report of ultrasound findings in early UA (defined by presence of clinical synovitis and non-fulfilment of 2010 RA criteria). A significant proportion of patients with UA progressed to RA and/or required methotrexate. GS synovitis was predictive of disease progression

A randomized, controlled trial comparing ganciclovir to ganciclovir plus foscarnet (each at half dose) for preemptive therapy of cytomegalovirus infection in transplant recipients

Forty-eight patients who provided 2 consecutive blood samples that tested positive for cytomegalovirus DNA by polymerase chain reaction (PCR) were randomized to receive either full-dose ganciclovir ( 5 mg/kg intravenously [iv] twice daily) or half-dose ganciclovir (5 mg/kg iv once daily) plus half-dose foscarnet (90 mg/kg iv once daily) for 14 days. In the ganciclovir arm, 17 (71%) of 24 patients reached the primary end point of being CMV negative by PCR within 14 days of initiation of therapy, compared with 12 (50%) of 24 patients in the ganciclovir-plus-foscarnet arm (P = .12). Toxicity was greater in the combination-therapy arm. In patients who failed to reach the primary end point, baseline virus load was 0.77 log(10) higher, the replication rate before therapy was faster (1.5 vs. 2.7 days), and the viral decay rate was slower (2.9 vs. 1.1 days) after therapy. Bivariable logistic regression models identified baseline virus load, bone-marrow transplantation, and doubling time and half-life of decay as the major factors affecting response to therapy within 14 days. This study did not support a synergistic effect of ganciclovir plus foscarnet in vivo

Symptoms and patient factors associated with diagnostic intervals for pancreatic cancer (SYMPTOM pancreatic study): a prospective cohort study

This is the final version. Available on open access from Elsevier via the DOI in this recordBackground Pancreatic cancer is the tenth most common cancer in the UK; however, outcomes are poor, in part due to late diagnosis. We aimed to identify symptoms and other clinical and sociodemographic factors associated with pancreatic cancer diagnosis and diagnostic intervals. Methods We did this prospective cohort study at seven hospitals in two regions in England. We recruited participants aged 40 years or older who were referred for suspicion of pancreatic cancer. Data were collected by use of a patient questionnaire and primary care and hospital records. Descriptive and regression analyses were done to examine associations between symptoms and patient factors with the total diagnostic interval (time from onset of the first symptom to the date of diagnosis), comprising patient interval (time from first symptom to first presentation) and health system interval (time from first presentation to diagnosis). Findings We recruited 391 participants between Jan 1, 2011, and Dec 31, 2014 (24% response rate). 119 (30%) participants were diagnosed with pancreatic cancer (41 [34%] had metastatic disease), 47 (12%) with other cancers, and 225 (58%) with no cancer. 212 (54%) patients had multiple first symptoms whereas 161 (41%) patients had a solitary first symptom. In this referred population, no initial symptoms were reported more frequently by patients with cancer than by those with no cancer. Several subsequent symptoms predicted pancreatic cancer: jaundice (51 [49%] of 105 patients with pancreatic cancer vs 25 [12%] of 211 patients with no cancer; p<0·0001), fatigue (48/95 [51%] vs 40/155 [26%]; p=0·0001), change in bowel habit (36/87 [41%] vs 28/175 [16%]; p<0·0001), weight loss (55/100 [55%] vs 41/184 [22%]; p<0·0001), and decreased appetite (41/86 [48%] vs 41/156 [26%]; p=0·0011). There was no difference in any interval between patients with pancreatic cancer and those with no cancer (total diagnostic interval: median 117 days [IQR 57–234] vs 131 days [IQR 66–284]; p=0·32; patient interval 18 days [0–37] vs 15 days [1–62]; p=0·22; health system interval 76 days [28–161] vs 79 days [30–156]; p=0·68). Total diagnostic intervals were shorter when jaundice (hazard ratio [HR] 1·38, 95% CI 1·07–1·78; p=0·013) and decreased appetite (1·42, 1·11–1·82; p=0·0058) were reported as symptoms, and longer in patients presenting with indigestion (0·71, 0·56–0·89; p=0·0033), back pain (0·77, 0·59–0·99; p=0·040), diabetes (0·71, 0·52–0·97; p=0·029), and self-reported anxiety or depression, or both (0·67, 0·49–0·91; p=0·011). Health system intervals were likewise longer with indigestion (0·74, 0·58–0·95; p=0·0018), back pain (0·76, 0·58–0·99; p=0·044), diabetes (0·63, 0·45–0·89; p=0·0082), and self-reported anxiety or depression, or both (0·63, 0·46–0·88; p=0·0064), but were shorter with male sex (1·41, 1·1–1·81; p=0·0072) and decreased appetite (1·56, 1·19–2·06; p=0·0015). Weight loss was associated with longer patient intervals (HR 0·69, 95% CI 0·54–0·89; p=0·0047). Interpretation Although we identified no initial symptoms that differentiated people diagnosed with pancreatic cancer from those without pancreatic cancer, key additional symptoms might signal the disease. Health-care professionals should be vigilant to the possibility of pancreatic cancer in patients with evolving gastrointestinal and systemic symptoms, particularly in those with diabetes or mental health comorbidities. Funding National Institute for Health Research and Pancreatic Cancer Action.National Institute for Health Research (NIHR

Tool-Use Training in a Species of Rodent: The Emergence of an Optimal Motor Strategy and Functional Understanding

Tool use is defined as the manipulation of an inanimate object to change the position or form of a separate object. The expansion of cognitive niches and tool-use capabilities probably stimulated each other in hominid evolution. To understand the causes of cognitive expansion in humans, we need to know the behavioral and neural basis of tool use. Although a wide range of animals exhibit tool use in nature, most studies have focused on primates and birds on behavioral or psychological levels and did not directly address questions of which neural modifications contributed to the emergence of tool use. To investigate such questions, an animal model suitable for cellular and molecular manipulations is needed.) to use a rake-like tool with their forelimbs to retrieve otherwise out-of-reach rewards. Eventually, they mastered effective use of the tool, moving it in an elegant trajectory. After the degus were well trained, probe tests that examined whether they showed functional understanding of the tool were performed. Degus did not hesitate to use tools of different size, colors, and shapes, but were reluctant to use the tool with a raised nonfunctional blade. Thus, degus understood the functional and physical properties of the tool after extensive training.Our findings suggest that tool use is not a specific faculty resulting from higher intelligence, but is a specific combination of more general cognitive faculties. Studying the brains and behaviors of trained rodents can provide insights into how higher cognitive functions might be broken down into more general faculties, and also what cellular and molecular mechanisms are involved in the emergence of such cognitive functions

Bayesian paternity analysis and mating patterns in a parasitic nematode, Trichostrongylus tenuis

Mating behaviour is a fundamental aspect of the evolutionary ecology of sexually reproducing species, but one that has been under-researched in parasitic nematodes. We analysed mating behaviour in the parasitic nematode Trichostrongylus tenuis by performing a paternity analysis in a population from a single red grouse host. Paternity of the 150 larval offspring of 25 mothers (sampled from one of the two host caeca) was assigned among 294 candidate fathers (sampled from both caeca). Each candidate father's probability of paternity of each offspring was estimated from 10-locus microsatellite genotypes. Seventy-six (51%) offspring were assigned a father with a probability of &gt;0.8, and the estimated number of unsampled males was 136 (95% credible interval (CI) 77-219). The probability of a male from one caecum fathering an offspring in the other caecum was estimated as 0.024 (95% CI 0.003-0.077), indicating that the junction of the caeca is a strong barrier to dispersal. Levels of promiscuity (defined as the probability of two of an adult's offspring sharing only one parent) were high for both sexes. Variance in male reproductive success was moderately high, possibly because of a combination of random mating and high variance in post-copulatory reproductive success. These results provide the first data on individual mating behaviour among parasitic nematodes

Adaptation of gastrointestinal nematode parasites to host genotype: single locus simulation models

Background: Breeding livestock for improved resistance to disease is an increasingly important selection goal. However, the risk of pathogens adapting to livestock bred for improved disease resistance is difficult to quantify. Here, we explore the possibility of gastrointestinal worms adapting to sheep bred for low faecal worm egg count using computer simulation. Our model assumes sheep and worm genotypes interact at a single locus, such that the effect of an A allele in sheep is dependent on worm genotype, and the B allele in worms is favourable for parasitizing the A allele sheep but may increase mortality on pasture. We describe the requirements for adaptation and test if worm adaptation (1) is slowed by non-genetic features of worm infections and (2) can occur with little observable change in faecal worm egg count. Results: Adaptation in worms was found to be primarily influenced by overall worm fitness, viz. the balance between the advantage of the B allele during the parasitic stage in sheep and its disadvantage on pasture. Genetic variation at the interacting locus in worms could be from de novo or segregating mutations, but de novo mutations are rare and segregating mutations are likely constrained to have (near) neutral effects on worm fitness. Most other aspects of the worm infection we modelled did not affect the outcomes. However, the host-controlled mechanism to reduce faecal worm egg count by lowering worm fecundity reduced the selection pressure on worms to adapt compared to other mechanisms, such as increasing worm mortality. Temporal changes in worm egg count were unreliable for detecting adaptation, despite the steady environment assumed in the simulations. Conclusions: Adaptation of worms to sheep selected for low faecal worm egg count requires an allele segregating in worms that is favourable in animals with improved resistance but less favourable in other animals. Obtaining alleles with this specific property seems unlikely. With support from experimental data, we conclude that selection for low faecal worm egg count should be stable over a short time frame (e.g. 20 years). We are further exploring model outcomes with multiple loci and comparing outcomes to other control strategies

The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia.

BACKGROUND: Rural Australians have poorer survival for most common cancers, due partially to later diagnosis. Internationally, several initiatives to improve cancer outcomes have focused on earlier presentation to healthcare and timely diagnosis. We aimed to measure the effect of community-based symptom awareness and general practice-based educational interventions on the time to diagnosis in rural patients presenting with breast, prostate, colorectal or lung cancer in Western Australia. METHODS: 2 × 2 factorial cluster randomised controlled trial. Community Intervention: cancer symptom awareness campaign tailored for rural Australians. GP intervention: resource card with symptom risk assessment charts and local cancer referral pathways implemented through multiple academic detailing visits. Trial Area A received the community symptom awareness and Trial Area B acted as the community campaign control region. Within both Trial Areas general practices were randomised to the GP intervention or control. PRIMARY OUTCOME: total diagnostic interval (TDI). RESULTS: 1358 people with incident breast, prostate, colorectal or lung cancer were recruited. There were no significant differences in the median or ln mean TDI at either intervention level (community intervention vs control: median TDI 107.5 vs 92 days; ln mean difference 0.08 95% CI -0.06-0.23 P=0.27; GP intervention vs control: median TDI 97 vs 96.5 days; ln mean difference 0.004 95% CI -0.18-0.19 P=0.99). There were no significant differences in the TDI when analysed by factorial design, tumour group or sub-intervals of the TDI. CONCLUSIONS: This is the largest trial to test the effect of community campaign or GP interventions on timeliness of cancer diagnosis. We found no effect of either intervention. This may reflect limited dose of the interventions, or the limited duration of follow-up. Alternatively, these interventions do not have a measurable effect on time to cancer diagnosis

Does the surgeon still have a role to play in the diagnosis and management of lymphomas?

<p>Abstract</p> <p>Background</p> <p>Over the course of the past 40 years, there have been a significant number of changes in the way in which lymphomatous disease is diagnosed and managed. With the advent of computed tomography, there is little role for staging laparotomy and the surgeon's role may now more diagnostic than therapeutic.</p> <p>Aims</p> <p>To review all cases of lymphoma diagnosed at a single institution in order determine the current role of the surgeon in the diagnosis and management of lymphoma.</p> <p>Patients and methods</p> <p>Computerized pathology records were reviewed for a five-year period 1996 to 2000 to determine all cases of lymph node biopsy (incisional or excisional) in which tissue was obtained as part of a planned procedure. Cases of incidental lymphadenopathy were thus excluded.</p> <p>Results</p> <p>A total of 297 biopsies were performed of which 62 (21%) yielded lymphomas. There were 22 females and 40 males with a median age of 58 years (range: 19–84 years). The lymphomas were classified as 80% non-Hodgkin's lymphoma, 18% Hodgkin's lymphoma and 2% post-transplant lymphoproliferative disorder. Diagnosis was established by general surgeons (n = 48), ENT surgeons (n = 9), radiologists (n = 4) and ophthalmic surgeons (n = 1). The distribution of excised lymph nodes was: cervical (n = 23), inguinal (n = 15), axillary (n = 11), intra-abdominal (n = 6), submandibular (n = 2), supraclavicular (n = 2), periorbital (n = 1), parotid (n = 1) and mediastinal (n = 1). Fine needle aspiration cytology had been performed prior to biopsy in only 32 (52%) cases and had suggested: lymphoma (n = 10), reactive changes (n = 13), normal (n = 5), inadequate (n = 4). The majority (78%) of cervical lymph nodes were subjected to FNAC prior to biopsy whilst this was performed in only 36% of non-cervical lymphadenopathy.</p> <p>Conclusion</p> <p>The study has shown that lymphoma is a relatively common cause of surgical lymphadenopathy. Given the limitations of FNAC, all suspicious lymph nodes should be biopsied following FNAC even if the FNAC is reported normal or demonstrating reactive changes only. With the more widespread application of molecular techniques, and the development of improved minimally-invasive procedures, percutaneous and endoscopic techniques may come to dominate, however, at present; the surgeon still has an important role to play in the diagnosis if not treatment of lymphomas.</p

PDFR and CRY Signaling Converge in a Subset of Clock Neurons to Modulate the Amplitude and Phase of Circadian Behavior in Drosophila

Background: To synchronize their molecular rhythms, circadian pacemaker neurons must input both external and internal timing cues and, therefore, signal integration between sensory information and internal clock status is fundamental to normal circadian physiology. Methodology/Principal Findings: We demonstrate the specific convergence of clock-derived neuropeptide signaling with that of a deep brain photoreceptor. We report that the neuropeptide PDF receptor and the circadian photoreceptor CRYPTOCROME (CRY) are precisely co-expressed in a subset of pacemakers, and that these pathways together provide a requisite drive for circadian control of daily locomotor rhythms. These convergent signaling pathways influence the phase of rhythm generation, but also its amplitude. In the absence of both pathways, PER rhythms were greatly reduced in only those specific pacemakers that receive convergent inputs and PER levels remained high in the nucleus throughout the day. This suggested a large-scale dis-regulation of the pacemaking machinery. Behavioral rhythms were likewise disrupted: in light:dark conditions they were aberrant, and under constant dark conditions, they were lost. Conclusions/Significance: We speculate that the convergence of environmental and clock-derived signals may produce