Studies on marginal farm ecosystems in upper Teesdale

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Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

A TRPV Channel Modulates C. elegans Neurosecretion, Larval Starvation Survival, and Adult Lifespan

For most organisms, food is only intermittently available; therefore, molecular mechanisms that couple sensation of nutrient availability to growth and development are critical for survival. These mechanisms, however, remain poorly defined. In the absence of nutrients, newly hatched first larval (L1) stage Caenorhabditis elegans halt development and survive in this state for several weeks. We isolated mutations in unc-31, encoding a calcium-activated regulator of neural dense-core vesicle release, which conferred enhanced starvation survival. This extended survival was reminiscent of that seen in daf-2 insulin-signaling deficient mutants and was ultimately dependent on daf-16, which encodes a FOXO transcription factor whose activity is inhibited by insulin signaling. While insulin signaling modulates metabolism, adult lifespan, and dauer formation, insulin-independent mechanisms that also regulate these processes did not promote starvation survival, indicating that regulation of starvation survival is a distinct program. Cell-specific rescue experiments identified a small subset of primary sensory neurons where unc-31 reconstitution modulated starvation survival, suggesting that these neurons mediate perception of food availability. We found that OCR-2, a transient receptor potential vanilloid (TRPV) channel that localizes to the cilia of this subset of neurons, regulates peptide-hormone secretion and L1 starvation survival. Moreover, inactivation of ocr-2 caused a significant extension in adult lifespan. These findings indicate that TRPV channels, which mediate sensation of diverse noxious, thermal, osmotic, and mechanical stimuli, couple nutrient availability to larval starvation survival and adult lifespan through modulation of neural dense-core vesicle secretion

Women, Schooling, and Marriage in Rural Philippines

Using data from the Bicol region of the Phillipines, we examine why women are more educated than men in a rural, agricultural economy in which women are significantly less likely than men to participate in the labor market. We hypothesize that educational homogamy in the marriage market and cross-productivity effects in the household allow Filipino women to reap substantial benefits from schooling regardless of whether they enter the labor market. Our estimates reveal that the return to schooling for women is approximately 20 percent in both labor and marriage markets. In comparison, men experience a 12 percent return to schooling in the labor market. By using birth order, sibship size, percent of male siblings, and parental education as instruments, we correct for a significant downward bias that is caused by the endogeneity of schooling attainment

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Direct evidence of fluid mixing in the formation of stratabound Pb–Zn–Ba–F mineralisation in the Alston Block, North Pennine Orefield (England)

The North Pennine Orefield Alston Block has produced approximately 4 Mt Pb, 0.3 Mt Zn, 2.1 Mt fluorite, 1.5 Mt barite, 1 Mt witherite, plus a substantial amount of iron ore and copper ore from predominantly vein-hosted mineralisation in Carboniferous limestones. However, a significant proportion of this production (ca. 20%) came from stratabound deposits. Though much is known about the vein mineralisation, the relationship between the veins and the stratabound mineralisation is not well-understood. New petrographic, isotopic and fluid inclusion data derived from samples of stratabound mineralisation allow us to present a unified model that addresses the genesis of both the vein and stratabound styles of mineralisation. The mineralisation can be considered in terms of three episodes: 1. Dolomitisation and ankeritisation Limestones in the vicinity of the stratabound mineralisation were pervasively dolomitised/ankeritised, and developed vuggy porosity in the presence of a high-salinity brine consistent with fluids derived from adjacent mud and shale-filled basins. 2. Main stage fluorite–quartz–sulphide mineralisation Metasomatism of limestone was accompanied by brecciation, dissolution and hydrothermal karstification with modification of the existing pore system. The open space was filled with fluorite, galena, sphalerite, quartz and barite, formed in response to mixing of lowsalinity sodic groundwater with high-salinity calcic brine with elevated metal contents (particularly Fe up to 7,000 ppm) relative to “normal” high total dissolved solids sedimentary brines. 3. Late-stage barite mineralisation paragenetically appears to represent either the waning stages or the distal portions of the main hydrothermal circulation system under cooler conditions