Nonsteroidal anti-inflammatory drugs and pain in cancer patients: a systematic review and reappraisal of the evidence.

BACKGROUND: Emerging data highlights the potential role of cyclooxygenase (COX) inhibitors in the primary prevention of malignancy, reducing metastatic spread and improving overall mortality. Despite nonsteroidal anti-inflammatory drugs (NSAIDs) forming a key component of the WHO analgesic ladder, their use in cancer pain management remains relatively low. This review re-appraises the current evidence regarding the efficacy of COX inhibitors as analgesics in cancer pain, providing a succinct resource to aid clinicians' decision making when determining treatment strategies. METHODS: Medline® and Embase® databases were searched for publications up to November 2018. Randomised controlled trials (RCTs) and double-blind controlled studies considering the use of NSAIDs for management of cancer-related pain in adults were included. Animal studies, case reports, and retrospective observational data were excluded. RESULTS: Thirty studies investigating the use of NSAIDs in cancer pain management were identified. There is a lack of high-quality evidence regarding the analgesic efficacy of NSAIDs in cancer pain, with short study durations and heterogeneity in outcome measures limiting the ability to draw meaningful conclusions. CONCLUSIONS: Despite the renewed interest in these cost-effective, well-established medications in cancer treatment outcomes, there is a paucity of data from the past 15 yr regarding their efficacy in cancer pain management. However, when analgesic strategies in the cancer population are being formulated, it is important that the potential benefits of this class of drug are considered. Further work investigating the role of NSAIDs in cancer pain management is undoubtedly warranted.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

The use of high-intensity focused ultrasound as a novel treatment for painful conditions-a description and narrative review of the literature.

High-intensity focused ultrasound (HIFU) is a non-invasive technique that allows a small, well-circumscribed thermal lesion to be generated within a tissue target. Tissue destruction occurs due to direct heating within the lesion and the mechanical effects of acoustic cavitation. HIFU has been used in a broad range of clinical applications, including the treatment of malignancies, uterine fibroids and cardiac arrhythmias. Interest in the use of the technique to treat pain has recently increased. A number of painful conditions have been successfully treated, including musculoskeletal degeneration, bone metastases and neuropathic pain. The exact mechanism by which HIFU results in analgesia remains poorly understood, but it is thought to be due to localised denervation of tissue targets and/or neuromodulatory effects. The majority of studies conducted investigating the use of HIFU in pain are still at an early stage, although initial results are encouraging. Further research is indicated to improve our understanding of the mechanisms underlying this treatment and to fully establish its efficacy; however, it is likely that HIFU will play a role in pain management in the future. This narrative review provides a synthesis of the recent, salient clinical and basic science research related to this topic and gives a general introduction to the mechanisms by which HIFU exerts its effects.

Agreement between amoA gene-specific quantitative PCR and fluorescence in situ hybridization in the measurement of ammonia-oxidizing bacteria in activated sludge.

Microbial abundance is central to most investigations in microbial ecology, and its accurate measurement is a challenging task that has been significantly facilitated by the advent of molecular techniques over the last 20 years. Fluorescence in situ hybridization (FISH) is considered the gold standard of quantification techniques; however, it is expensive and offers low sample throughput, both of which limit its wider application. Quantitative PCR (qPCR) is an alternative that offers significantly higher throughput, and it is used extensively in molecular biology. The accuracy of qPCR can be compromised by biases in the DNA extraction and amplification steps. In this study, we compared the accuracy of these two established quantification techniques to measure the abundance of a key functional group in biological wastewater treatment systems, the ammonia-oxidizing bacteria (AOB), in samples from a time-series experiment monitoring a set of laboratory-scale reactors and a full-scale plant. For the qPCR analysis, we tested two different sets of AOB-specific primers, one targeting the 16SrRNA gene and one targeting the ammonia monooxygenase (amoA) gene. We found that there was a positive linear logarithmic relationship between FISH and the amoA gene-specific qPCR, where the data obtained from both techniques was equivalent at the order of magnitude level. The 16S rRNA gene-specific qPCR assay consistently underestimated AOB numbers.

Observation of turbulent intermittency scaling with magnetic helicity in an MHD plasma wind tunnel.

The intermittency in turbulent magnetic field fluctuations has been observed to scale with the amount of magnetic helicity injected into a laboratory plasma. An unstable spheromak injected into the MHD wind tunnel of the Swarthmore Spheromak Experiment displays turbulent magnetic and plasma fluctuations as it relaxes into a Taylor state. The level of intermittency of this turbulence is determined by finding the flatness of the probability distribution function of increments for magnetic pickup coil fluctuations B˙(t). The intermittency increases with the injected helicity, but spectral indices are unaffected by this variation. While evidence is provided which supports the hypothesis that current sheets and reconnection sites are related to the generation of this intermittent signal, the true nature of the observed intermittency remains unknown.

Observation of a relaxed plasma state in a quasi-infinite cylinder.

A helical relaxed plasma state is observed in a long cylindrical volume. The cylinder is long enough so that the predicted minimum energy state is a close approximation to the infinite cylinder solution. The plasma is injected at v ≥ 50 km/s by a coaxial magnetized plasma gun located at one end of the cylindrical volume. The relaxed state is rapidly attained in 1-2 axial Alfvén times after initiation of the plasma. Magnetic data are favorably compared with an analytical model. Magnetic data exhibit broadband fluctuations of the measured axial modes during the formation period. The broadband activity rapidly decays as the energy condenses into the lowest energy mode, which is in agreement with the minimum energy eigenstate of [Symbol: see text] × B = λB.

Mutations in PROP1 cause familial combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1, which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report, we have identified four CPHD families with homozygosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

City-wide wastewater genomic surveillance through the successive emergence of SARS-CoV-2 Alpha and Delta variants.

Genomic surveillance of SARS-CoV-2 has provided a critical evidence base for public health decisions throughout the pandemic. Sequencing data from clinical cases has helped to understand disease transmission and the spread of novel variants. Genomic wastewater surveillance can offer important, complementary information by providing frequency estimates of all variants circulating in a population without sampling biases. Here we show that genomic SARS-CoV-2 wastewater surveillance can detect fine-scale differences within urban centres, specifically within the city of Liverpool, UK, during the emergence of Alpha and Delta variants between November 2020 and June 2021. Furthermore, wastewater and clinical sequencing match well in the estimated timing of new variant rises and the first detection of a new variant in a given area may occur in either clinical or wastewater samples. The study's main limitation was sample quality when infection prevalence was low in spring 2021, resulting in a lower resolution of the rise of the Delta variant compared to the rise of the Alpha variant in the previous winter. The correspondence between wastewater and clinical variant frequencies demonstrates the reliability of wastewater surveillance. However, discrepancies in the first detection of the Alpha variant between the two approaches highlight that wastewater monitoring can also capture missing information, possibly resulting from asymptomatic cases or communities less engaged with testing programmes, as found by a simultaneous surge testing effort across the city.

Neuroablative surgical treatments for pain due to cancer.

Cancer pain is common and challenging to manage - it is estimated that approximately 30% of cancer patients have pain that is not adequately controlled by analgesia. This paper discusses safe and effective neuroablative treatment options for refractory cancer pain. Current management of cancer pain predominantly focuses on the use of medications, resulting in a relative loss of knowledge of these surgical techniques and the erosion of the skills required to perform them. Here, we review surgical methods of modulating various points of the neural axis with the aim to expand the knowledge base of those managing cancer pain. Integration of neuroablative approaches may lead to higher rates of pain relief, and the opportunity to dose reduce analgesic agents with potential deleterious side effects. With an ever-increasing population of cancer patients, it is essential that neurosurgeons maintain or train in these techniques in tandem with the oncological multi-disciplinary team.

Human myelomeningocele risk and ultra-rare deleterious variants in genes associated with cilium, WNT-signaling, ECM, cytoskeleton and cell migration.

Myelomeningocele (MMC) affects one in 1000 newborns annually worldwide and each surviving child faces tremendous lifetime medical and caregiving burdens. Both genetic and environmental factors contribute to disease risk but the mechanism is unclear. This study examined 506 MMC subjects for ultra-rare deleterious variants (URDVs, absent in gnomAD v2.1.1 controls that have Combined Annotation Dependent Depletion score ≥ 20) in candidate genes either known to cause abnormal neural tube closure in animals or previously associated with human MMC in the current study cohort. Approximately 70% of the study subjects carried one to nine URDVs among 302 candidate genes. Half of the study subjects carried heterozygous URDVs in multiple genes involved in the structure and/or function of cilium, cytoskeleton, extracellular matrix, WNT signaling, and/or cell migration. Another 20% of the study subjects carried heterozygous URDVs in candidate genes associated with gene transcription regulation, folate metabolism, or glucose metabolism. Presence of URDVs in the candidate genes involving these biological function groups may elevate the risk of developing myelomeningocele in the study cohort.

Causal mechanism of injection-induced earthquakes through the Mw 5.5 Pohang earthquake case study.

Causal mechanisms for fluid injection-induced earthquakes remain a challenge to identify. Past studies largely established spatiotemporal correlations. Here, we propose a multi-process causal mechanism for injection-induced earthquakes through a case study of the 2017 Mw 5.5 induced earthquake near Pohang Enhanced Geothermal System, Korea, where detailed hydraulic stimulation and on-site seismicity monitoring data provide an unprecedented opportunity. Pore pressure modeling reveals that pore pressure changes initiate seismicity on critically stressed faults and Coulomb static stress transfer modeling reveals that earthquake interactions promote continued seismicity, leading to larger events. On the basis of these results, we propose the following causal mechanism for induced seismicity: pore pressure increase and earthquake interactions lead to fault weakening and ultimately triggering larger earthquakes later in the process. We suggest that it is prudent that pore pressure change, initial seismicity locations, and Coulomb static stress transfer from seismicity earlier in the sequence are assessed in real-time.

Observation of a helical self-organized state in a compact toroidal plasma.

A nonaxisymmetric stable magnetohydrodynamic (MHD) equilibrium within a prolate cylindrical conducting boundary has been produced experimentally. It has m=1 azimuthal symmetry, helical distortion, and flat lambda profile, all in agreement with the computed magnetically relaxed minimum magnetic energy Taylor state. Despite varied initial conditions determined by two helicity injectors on the device, this same equilibrium consistently emerges as the final state. These results therefore describe a new example of self-organization in an MHD plasma.

Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia.

A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.

Infection by a symbiotic polydnavirus induces wasting and inhibits metamorphosis of the moth Pseudoplusia includens.

Insect pathogens and parasites often affect the growth and development of their hosts, but understanding of these processes is fragmentary. Among the most species-rich and important mortality agents of insects are parasitoid wasps that carry symbiotic polydnaviruses (PDVs). Like many PDV-carrying wasps, Microplitis demolitor inhibits growth and pupation of its lepidopteran host, Pseudoplusia includens, by causing host hemolymph juvenile hormone (JH) titers to remain elevated and preventing ecdysteroid titers from rising. Here we report these alterations only occurred if P. includens was parasitized prior to achieving critical weight, and were fully mimicked by infection with only M. demolitor bracovirus (MdBV). Metabolic assays revealed that MdBV infection of pre-critical weight larvae caused a rapid and persistent state of hyperglycemia and reduced nutrient stores. In vitro ecdysteroid assays further indicated that prothoracic glands from larvae infected prior to achieving critical weight remained in a refractory state of ecdysteroid release, whereas infection of post-critical weight larvae had little or no effect on ecdysteroid release by prothoracic glands. Taken together, our results suggest MdBV causes alterations in metabolic physiology, which prevent the host from achieving critical weight. This in turn inhibits the endocrine events that normally trigger metamorphosis.

A flow cytometry method for bacterial quantification and biomass estimates in activated sludge.

Absolute bacterial quantification receives little serious attention in the literature compared to sequencing, conceivably because it is considered unimportant and facile, or because existing methods are tedious, laborious and/or biased in nature. This is particularly true in engineered systems, including activated sludge, where such information underpins their design and operation. To overcome these limitations we built upon existing work and optimised and comprehensively validated, through comparison with epifluorescence microscopy (EFM), a rapid and precise flow cytometric protocol to enumerate total bacterial numbers in activated sludge. Insights into potential biases were evaluated using appropriate statistical analyses on this comparison, which spanned four orders of magnitude, as well as comparing volatile suspended solid (VSS) concentrations. The results suggest flow cytometry (FCM) is a rapid, reproducible and economical technique for quantifying total bacterial numbers and biomass concentrations in activated sludge, despite within order of magnitude discrepancies with EFM counts, which had inherent and evidently greater errors and biases than FCM. The use of FCM for routine monitoring over both EFM and VSS should help further understanding of the microbial ecology in, and the operation of, engineered systems.

Coupled virus - bacteria interactions and ecosystem function in an engineered microbial system.

Viruses are thought to control bacterial abundance, affect community composition and influence ecosystem function in natural environments. Yet their dynamics have seldom been studied in engineered systems, or indeed in any system, for long periods of time. We measured virus abundance in a full-scale activated sludge plant every week for two years. Total bacteria and ammonia oxidising bacteria (AOB) abundances, bacterial community profiles, and a suite of environmental and operational parameters were also monitored. Mixed liquor virus abundance fluctuated over an order of magnitude (3.18 × 108-3.41 × 109 virus's mL-1) and that variation was statistically significantly associated with total bacterial and AOB abundance, community composition, and effluent concentrations of COD and NH4+- N and thus system function. This suggests viruses play a far more important role in the dynamics of activated sludge systems than previously realised and could be one of the key factors controlling bacterial abundance, community structure and functional stability and may cause reactors to fail. These findings are based on statistical associations, not mechanistic models. Nevertheless, viral associations with abiotic factors, such as pH, make physical sense, giving credence to these findings and highlighting the role that physical factors play in virus ecology. Further work is needed to identify and quantify specific bacteriophage and their hosts to enable us to develop mechanistic models of the ecology of viruses in wastewater treatment systems. However, since we have shown that viruses can be related to effluent quality and virus quantification is simple and cheap, practitioners would probably benefit from quantifying viruses now.

Measuring the equations of state in a relaxed magnetohydrodynamic plasma.

We report measurements of the equations of state of a fully relaxed magnetohydrodynamic (MHD) laboratory plasma. Parcels of magnetized plasma, called Taylor states, are formed in a coaxial magnetized plasma gun, and are allowed to relax and drift into a closed flux conserving volume. Density, ion temperature, and magnetic field are measured as a function of time as the Taylor states compress and heat. The theoretically predicted MHD and double adiabatic equations of state are compared to experimental measurements. We find that the MHD equation of state is inconsistent with our data.

Evaluation of Quality of Life Outcomes Following Palliative Treatment of Bone Metastases with Magnetic Resonance-guided High Intensity Focused Ultrasound: An International Multicentre Study.

AIMS: To determine quality of life (QoL) outcomes after palliation of pain from bone metastases using magnetic resonance-guided high intensity focused ultrasound (MR-guided HIFU), measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL and the QLQ-BM22 questionnaires. MATERIALS AND METHODS: Twenty patients undergoing MR-guided HIFU in an international multicentre trial self-completed the QLQ-C15-PAL and QLQ-BM22 questionnaires before and on days 7, 14, 30, 60 and 90 post-treatment. Descriptive statistics were used to represent changes in symptom and functional scales over time and to determine their clinical significance. QoL changes were compared in pain responders and non-responders (who were classified according to change in worst pain score and analgesic intake, between baseline and day 30). RESULTS: Eighteen patients had analysable QoL data. Clinically significant improvements were seen in the QoL scales of physical functioning, fatigue, appetite loss, nausea and vomiting, constipation and pain in the 53% of patients who were classified as responders at day 30. No significant changes were seen in the 47% of patients who were non-responders at this time point. CONCLUSION: Local treatment of pain from bone metastases with MR-guided HIFU, even in the presence of disseminated malignancy, has a substantial positive effect on physical functioning, and improves other symptomatic QoL measures. This indicated a greater response to treatment over and above pain control alone. MR-guided HIFU is non-invasive and should be considered for patients with localised metastatic bone pain and poor QoL.

Cerebroventricular calcitonin gene-related peptide inhibits rat duodenal bicarbonate secretion by release of norepinephrine and vasopressin.

Proximal duodenal bicarbonate secretion is an important factor in humans and animals protecting the mucosa against acid-peptic damage. This study examined the mechanisms responsible for the central nervous system regulation of duodenal bicarbonate secretion by calcitonin gene-related peptide (CGRP) in unrestrained rats. Cerebroventricular administration of rat CGRP significantly inhibited basal duodenal bicarbonate secretion as well as the stimulatory effects of vasoactive intestinal peptide, neurotensin, a luminal PGE1 analogue, misoprostol, and hydrochloric acid. The inhibitory effects of cerebroventricular CGRP were abolished by ganglionic blockade with chlorisondamine, significantly attenuated by noradrenergic blockade with bretylium, and enhanced by vagotomy. Inhibition of duodenal bicarbonate secretion induced by CGRP coincided with significant increases in plasma norepinephrine (NE) and vasopressin concentrations. The alpha adrenergic receptor antagonist, phentolamine, and the vasopressin V1 receptor antagonist, (1-deaminopenicillamine, 2-[O-methyl]Tyr, 8-Arg)-vasopressin, given intravenously reversed the central inhibitory effect of CGRP by approximately 50% each. Pretreatment of the animals with both phentolamine and the vasopressin antagonist completely abolished the central inhibitory effect of CGRP. Peripheral vasopressin and NE significantly decreased duodenal bicarbonate secretion, and their inhibitory effects were additive and prevented by phentolamine and the vasopressin antagonist, respectively. We conclude that cerebroventricular CGRP inhibits rat duodenal bicarbonate secretion by activation of sympathetic efferents and subsequent release of NE and vasopressin that act on alpha adrenergic and vasopressin receptors, respectively.

Corticotropin-releasing factor. Mechanisms to inhibit gastric acid secretion in conscious dogs.

Immunoreactivity similar to that of corticotropin-releasing factor (CRF) is found in regions of the central nervous system that modulate autonomic responses, including gastrointestinal functions. We examined the central nervous system effects of ovine CRF on gastric acid secretion in conscious dogs. Male beagle dogs (11-13 kg) were fitted with chronic intracerebroventricular cannulae and gastric fistulae. Gastric acid secretion in response to intravenously administered gastric secretory stimuli was measured by in vitro titration of gastric juice to pH 7.0 and in response to an intragastric meal by in vivo intragastric titration at pH 5.0. Plasma gastrin was determined by radioimmunoassay. CRF microinjected into the third cerebral ventricle decreased pentagastrin-stimulated gastric acid secretion for 3 h (P less than 0.01) dose-dependently (0.2-6.0 nmol X kg-1). CRF did not inhibit histamine-stimulated gastric secretion but significantly (P less than 0.01) decreased the secretory response after 2-deoxy-D-glucose for 3 h. The gastric inhibitory action of intracerebroventricularly administered CRF on pentagastrin-stimulated gastric acid secretion was completely abolished by ganglionic blockade with chlorisondamine. The opioid antagonist, naloxone, and the vasopressin antagonist, [1-deaminopenicillamine,2-(O-methyl) tyrosine,8-arginine]-vasopressin, significantly suppressed the inhibitory effect of CRF on gastric acid secretion stimulated by pentagastrin. In contrast, truncal vagotomy did not prevent the inhibition of gastric acid secretion induced by CRF. CRF (0.2-2.0 nmol X kg-1) administered intracerebroventricularly decreased gastric acid secretion stimulated by 200-ml liquid meals containing 8% peptone. CRF did not affect plasma gastrin concentrations. These results indicate that CRF microinjected into the third cerebral ventricle inhibits gastric acid secretion in conscious dogs. CRF-induced inhibition of gastric acid secretion appears to be mediated by the sympathetic nervous system and, in part, by opiate and vasopressin-dependent mechanisms.