Reflections from the OARSI 2022 clinical trials symposium: The pain of OA-Deconstruction of pain and patient-reported outcome measures for the benefit of patients and clinical trial design.

OBJECTIVE: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. METHOD: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. RESULTS: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. CONCLUSIONS: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.

Early Release Science of the exoplanet WASP-39b with JWST NIRSpec PRISM.

Transmission spectroscopy1-3 of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres4,5. However, these previous inferences with the Hubble and Spitzer Space Telescopes were hindered by the observations' relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species-in particular the primary carbon-bearing molecules6,7. Here we report a broad-wavelength 0.5-5.5 µm atmospheric transmission spectrum of WASP-39b8, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec's PRISM mode9 as part of the JWST Transiting Exoplanet Community Early Release Science Team Program10-12. We robustly detect several chemical species at high significance, including Na (19σ), H2O (33σ), CO2 (28σ) and CO (7σ). The non-detection of CH4, combined with a strong CO2 feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO2 (2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST's sensitivity to a rich diversity of exoplanet compositions and chemical processes.

An absolute sodium abundance for a cloud-free 'hot Saturn' exoplanet.

Broad absorption signatures from alkali metals, such as the sodium (Na I) and potassium (K I) resonance doublets, have long been predicted in the optical atmospheric spectra of cloud-free irradiated gas giant exoplanets1-3. However, observations have revealed only the narrow cores of these features rather than the full pressure-broadened profiles4-6. Cloud and haze opacity at the day-night planetary terminator are considered to be responsible for obscuring the absorption-line wings, which hinders constraints on absolute atmospheric abundances7-9. Here we report an optical transmission spectrum for the 'hot Saturn' exoplanet WASP-96b obtained with the Very Large Telescope, which exhibits the complete pressure-broadened profile of the sodium absorption feature. The spectrum is in excellent agreement with cloud-free, solar-abundance models assuming chemical equilibrium. We are able to measure a precise, absolute sodium abundance of logεNa = [Formula: see text], and use it as a proxy for the planet's atmospheric metallicity relative to the solar value (Zp/Zʘ = [Formula: see text]). This result is consistent with the mass-metallicity trend observed for Solar System planets and exoplanets10-12.

Helium in the eroding atmosphere of an exoplanet.

Helium is the second-most abundant element in the Universe after hydrogen and is one of the main constituents of gas-giant planets in our Solar System. Early theoretical models predicted helium to be among the most readily detectable species in the atmospheres of exoplanets, especially in extended and escaping atmospheres 1 . Searches for helium, however, have hitherto been unsuccessful 2 . Here we report observations of helium on an exoplanet, at a confidence level of 4.5 standard deviations. We measured the near-infrared transmission spectrum of the warm gas giant 3 WASP-107b and identified the narrow absorption feature of excited metastable helium at 10,833 angstroms. The amplitude of the feature, in transit depth, is 0.049 ± 0.011 per cent in a bandpass of 98 angstroms, which is more than five times greater than what could be caused by nominal stellar chromospheric activity. This large absorption signal suggests that WASP-107b has an extended atmosphere that is eroding at a total rate of 1010 to 3 × 1011 grams per second (0.1-4 per cent of its total mass per billion years), and may have a comet-like tail of gas shaped by radiation pressure.

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction.

We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na+] and [Cl-] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.

CD4+ Th2 cells are directly regulated by IL-10 during allergic airway inflammation.

Interleukin-10 (IL-10) is an important regulatory cytokine required to control allergy and asthma. IL-10-mediated regulation of T cell-mediated responses was previously thought to occur indirectly via antigen-presenting cells. However, IL-10 can act directly on regulatory T cells and T helper type 17 (Th17) cells. In the context of allergy, it is therefore unclear whether IL-10 can directly regulate T helper type 2 (Th2) cells and whether this is an important regulatory axis during allergic responses. We sought to determine whether IL-10 signaling in CD4+ Th2 cells was an important mechanism of immune regulation during airway allergy. We demonstrate that IL-10 directly limits Th2 cell differentiation and survival in vitro and in vivo. Ablation of IL-10 signaling in Th2 cells led to enhanced Th2 cell survival and exacerbated pulmonary inflammation in a murine model of house dust mite allergy. Mechanistically, IL-10R signaling regulated the expression of several genes in Th2 cells, including granzyme B. Indeed, IL-10 increased granzyme B expression in Th2 cells and led to increased Th2 cell death, identifying an IL-10-regulated granzyme B axis in Th2 cells controlling Th2 cell survival. This study provides clear evidence that IL-10 exerts direct effects on Th2 cells, regulating the survival of Th2 cells and severity of Th2-mediated allergic airway inflammation.

Immune reactivity after adenoviral-mediated aquaporin-1 cDNA transfer to human parotid glands.

OBJECTIVES: The purpose of this study was to examine the humoral and cellular immune reactivity to adenoviral vector (AdhAQP1) administration in the human parotid gland over the first 42 days of a clinical gene therapy trial. METHODS: Of eleven treated subjects, five were considered as positive responders (Baum et al, 2012). Herein, we measured serum neutralizing antibody titers, circulating cytotoxic lymphocytes, and lymphocyte proliferation in peripheral blood mononuclear cells. Additionally, after adenoviral vector stimulation of lymphocyte proliferation, we quantified secreted cytokine levels. RESULTS: Responders showed little to modest immune reactivity during the first 42 days following gene transfer. Additionally, baseline serum neutralizing antibody titers to serotype 5-adenovirus generally were not predictive of a subject's response to parotid gland administration of AdhAQP1. Cytokine profiling from activated peripheral blood mononuclear cells could not distinguish responders and non-responders. CONCLUSIONS: The data are the first to describe immune responses after adenoviral vector administration in a human parotid gland. Importantly, we found that modest (2-3 fold) changes in systemic cell-mediated immune reactivity did not preclude positive subject responses to gene transfer. However, changes beyond that level likely impeded the efficacy of gene transfer.

[Preplacentation pregnancy loss in cases of angiotensin-converting enzyme insertion/deletion polymorphism].

The balance between coagulation and fibrinolysis processes is critical for establishment and development of early pregnancy. Angiotensin-converting enzyme (ACE) is related with plasminogen activator inhibitor-1 activity which is a key regulator in embryo implantation. Therefor polymorphisms in ACE gene and variation in ACE activity could be associated with an early pregnancy wastage risk. This study investigated carrier status for insertion/deletion (I/D) polymorphism in introne 16 of ACE gene in 71 women with two or more pregnancy loss in preplacentation period (between 10 and 14 weeks of gestation) and 75 women without pregnancy complications. DD genotype for I/D polymorphism was found respectively in 31% and 24% in patients and controls. Heterozygosity of D allele was found correspondingly in 47.9% and 54.7%. The dominant genetic model was used for allele prevalence comparison. D allele in DD genotype was not significantly prevalent in women with early pregnancy wastage compared with the control subjects, OR = 1.42, 95% CI (0.64-3.15). The study found a weak association between I/D polymorphism and preplacentation pregnancy loss. The additive effect over the pregnancy loss risk of I/D polymorphism could be supposed in a presence of other inherited or acquired factors connected with endometrial receptivity and implantation process.

Self-consistent tilted-axis-cranking study of triaxial strongly deformed bands in 158Er at ultrahigh spin.

Stimulated by recent experimental discoveries, triaxial strongly deformed (TSD) states in (158)Er at ultrahigh spins have been studied by means of the Skyrme-Hartree-Fock model and the tilted-axis-cranking method. Restricting the rotational axis to one of the principal axes--as done in previous cranking calculations--two well-defined TSD minima in the total Routhian surface are found for a given configuration: one with positive and another with negative triaxial deformation γ. By allowing the rotational axis to change direction, the higher-energy minimum is shown to be a saddle point. This resolves the long-standing question of the physical interpretation of the two triaxial minima at a very similar quadrupole shape obtained in the principal-axis-cranking approach. Several TSD configurations have been predicted, including a highly deformed band, which is a candidate for the structure observed in experiment.

Development of IgA nephropathy-like glomerulonephritis associated with Wiskott-Aldrich syndrome protein deficiency.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder caused by mutations in the WAS gene. Glomerulonephritis is a frequent complication, however, histopathological data from affected patients is scarce because the thrombocytopenia that affects most patients is a contraindication to renal biopsies. We found that WASp-deficient mice develop proliferative glomerulonephritis reminiscent of human IgA nephropathy (IgAN). We examined whether increased aberrant IgA production is associated with the development of glomerulonephritis in WASp-deficient mice. Serum IgA and IgA production by splenic B cells was increased in WASp-deficient mice compared to wild-type (WT) mice. A lectin-binding study revealed a reduced ratio of sialylated and galactosylated IgA in the sera from old WASp-deficient mice. Circulating IgA-containing immune complexes showed significantly higher titers in WASp-deficient mice compared to WT mice. These results indicate that the increased IgA production and aberrant glycosylation of IgA may be critically involved in the pathogenesis of glomerulonephritis in WAS.

QSAR models for anti-androgenic effect--a preliminary study.

Three modelling systems (MultiCase®, LeadScope® and MDL® QSAR) were used for construction of androgenic receptor antagonist models. There were 923-942 chemicals in the training sets. The models were cross-validated (leave-groups-out) with concordances of 77-81%, specificity of 78-91% and sensitivity of 51-76%. The specificity was highest in the MultiCase® model and the sensitivity was highest in the MDL® QSAR model. A complementary use of the models may be a valuable tool when optimizing the prediction of chemicals for androgenic receptor antagonism. When evaluating the fitness of the model for a particular application, balance of training sets, domain definition, and cut-offs for prediction interpretation should also be taken into account. Different descriptors in the modelling systems are illustrated with hydroxyflutamide and dexamethasone as examples (a non-steroid and a steroid anti-androgen, respectively). More research concerning the mechanism of anti-androgens would increase the possibility for further optimization of the QSAR models. Further expansion of the basis for the models is in progress, including the addition of more drugs.

Epizooic metazoan meiobenthos associated with tubeworm and mussel aggregations from cold seeps of the northern Gulf of Mexico.

The abundance and higher taxonomic composition of epizooic metazoan meiobenthic communities associated with mussel and tubeworm aggregations of hydrocarbon seeps at Green Canyon, Atwater Valley, and Alaminos Canyon in depths between 1400 and 2800 m were studied and compared to the infaunal community of non-seep sediments nearby. Epizooic meiofaunal abundances of associated meiobenthos living in tubeworm bushes and mussel beds at seeps were extremely low (usually <100 ind. 10 cm(-2)), similar to epizooic meiofauna at deep-sea hydrothermal vents, and the communities were composed primarily of nematodes, copepods, ostracods, and halacarids. In contrast, epizooic meiobenthic abundance is lower than previous studies have reported for infauna from seep sediments. Interestingly, non-seep sediments contained higher abundances and higher taxonomic diversity than epizooic seep communities, although in situ primary production is restricted to seeps.

QSAR models for P450 (2D6) substrate activity.

Human Cytochrome P450 (CYP) is a large group of enzymes that possess an essential function in metabolising different exogenous and endogenous compounds. Humans have more than 50 different genes encoding CYP enzymes, among these a gene encoding for the CYP isoenzyme 2D6, a CYP able to metabolise drugs and other chemicals. A training set of 747 chemicals primarily based on in vivo human data for the CYP isoenzyme 2D6 was collected from the literature. QSAR models focusing on substrate/non-substrate activity were constructed by the use of MultiCASE, Leadscope and MDL quantitative structure-activity relationship (QSAR) modelling systems. They cross validated (leave-groups-out) with concordances of 71%, 81% and 82%, respectively. Discrete organic European Inventory of Existing Commercial Chemical Substances (EINECS) chemicals were screened to predict an approximate percentage of CYP 2D6 substrates. These chemicals are potentially present in the environment. The biological importance of the CYP 2D6 and the use of the software mentioned above were discussed.

QSAR models for reproductive toxicity and endocrine disruption in regulatory use--a preliminary investigation.

A special challenge in the new European Union chemicals legislation, Registration, Evaluation and Authorisation of Chemicals, will be the toxicological evaluation of chemicals for reproductive toxicity. Use of valid quantitative structure-activity relationships (QSARs) is a possibility under the new legislation. This article focuses on a screening exercise by use of our own and commercial QSAR models for identification of possible reproductive toxicants. Three QSAR models were used for reproductive toxicity for the endpoints teratogenic risk to humans (based on animal tests, clinical data and epidemiological human studies), dominant lethal effect in rodents (in vivo) and Drosophila melanogaster sex-linked recessive lethal effect. A structure set of 57,014 European Inventory of Existing Chemical Substances (EINECS) chemicals was screened. A total of 5240 EINECS chemicals, corresponding to 9.2%, were predicted as reproductive toxicants by one or more of the models. The chemicals predicted positive for reproductive toxicity will be submitted to the Danish Environmental Protection Agency as scientific input for a future updated advisory classification list with advisory classifications for concern for humans owing to possible developmental toxic effects: Xn (Harmful) and R63 (Possible risk of harm to the unborn child). The chemicals were also screened in three models for endocrine disruption.

[Stromal tumor of the prostate of uncertain malignant potential. A diagnostic rarity]. / Der Stromatumor der Prostata von ungewissem malignem Potential. Eine diagnostische Rarität.

Stromal tumor of the prostate of uncertain malignant potential (STUMP) is an extremely rare entity. The clinical symptoms are nonspecific for this tumor. An abnormal digital rectal examination or an elevated prostate-specific antigen level is possible but not obligatory. The tumor has a high recurrence rate and could develop a sarcomatous dedifferentiation. Therapy varies from a wait-and-see approach to a radical prostatectomy. We report the case of a 74-year-old patient with a STUMP. Based on the case, the clinical, diagnostic, and therapeutic aspects of this rare tumor are discussed.

Variant form of STAT4 is associated with primary Sjögren's syndrome.

Single nucleotide polymorphisms in the STAT4 gene have recently been shown to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Primary Sjögren's syndrome (pSS) is a related autoimmune disease thought to have a pathogenesis similar to these diseases. To test the hypothesis that the variant haplotype of STAT4 seen in RA and SLE is also associated with pSS, we genotyped rs7574865, the most strongly disease-associated SNP in the variant STAT4 haplotype, in 124 Caucasian pSS subjects and compared them to 1143 Caucasian controls. The disease-associated T allele was more common in chromosomes of the pSS patients (29.6%) than in controls (22.3%), leading to a P-value for association of 0.01. These results implicate polymorphisms in the STAT4 gene in the pathogenesis of pSS.

Biologic treatments for systemic rheumatic diseases.

Many rheumatologic disorders, most notably Sjögren's syndrome, are associated with dental complications and in some cases oral diseases may trigger or drive connective tissue disease. During the past three decades the treatment in rheumatology was revolutionized by the introduction of disease-modifying anti-rheumatic drugs. Advances in our understanding of the pathogenesis of rheumatic diseases have led to the discovery of critical mechanisms of inflammation and autoimmunity and the invention of new target-specific biologic agents. In this review, we will summarize the current state of biologic therapies in rheumatology and discuss the implications of these on oral health and disease.

Comparison of different stomatal conductance algorithms for ozone flux modelling.

A multiplicative and a semi-mechanistic, BWB-type [Ball, J.T., Woodrow, I.E., Berry, J.A., 1987. A model predicting stomatal conductance and its contribution to the control of photosynthesis under different environmental conditions. In: Biggens, J. (Ed.), Progress in Photosynthesis Research, vol. IV. Martinus Nijhoff, Dordrecht, pp. 221-224.] algorithm for calculating stomatal conductance (g(s)) at the leaf level have been parameterised for two crop and two tree species to test their use in regional scale ozone deposition modelling. The algorithms were tested against measured, site-specific data for durum wheat, grapevine, beech and birch of different European provenances. A direct comparison of both algorithms showed a similar performance in predicting hourly means and daily time-courses of g(s), whereas the multiplicative algorithm outperformed the BWB-type algorithm in modelling seasonal time-courses due to the inclusion of a phenology function. The re-parameterisation of the algorithms for local conditions in order to validate ozone deposition modelling on a European scale reveals the higher input requirements of the BWB-type algorithm as compared to the multiplicative algorithm because of the need of the former to model net photosynthesis (A(n)).

Multivariate statistical assessment of the pollution sources along the stream of Kamchia River, Bulgaria.

Sixteen sampling sites along the stream of Kamchia River were considered as environmental objects in the multivariate statistical study aimed to identify and apportion patterns of sampling sites, latent factors responsible for the data structure and their relation to the emitter industrial and anthropogenic sources in the vicinity of the sampling sites. As variables 11 surface water parameters monitored for a long time period (up to 11 years) were used. Four main site patterns were revealed by cluster analysis (urban, rural, near-to dam and estuary) and for each site latent factors were identified and apportioned (among them "metallurgical", "food production", "winery", domestic wastes", "natural"). The relative contribution of each identified pollution source to the formation of the total concentration of each chemical species or physicochemical parameter was determined and compared to the real emitters in the region of interest.

Methotrexate use in rheumatoid arthritis is associated with few clinically significant liver function test abnormalities.

OBJECTIVE: To determine the frequency of liver function tests (LFT) abnormalities associated with methotrexate (MTX) use in the treatment of rheumatoid arthritis (RA). METHODS: A retrospective chart review for demographic information, RA-specific history, medication history, complications of therapy, results of all available blood tests (specifically aspartate aminotransferase (AST), alanine aminotransferase (ALT), complete blood count (CBC), albumin, creatinine), and liver biopsy reports was conducted for RA patients, who were currently using or have used MTX in the past. RESULTS: A total of 2791 LFTs were performed among 182 RA patients with 94 abnormal results. 152 patients (83.5%) with 2007 LFT evaluations demonstrated no abnormal results, compared with 30 patients (16.5%) who had at least one abnormal LFT in 784 tests. Twenty-two of the 30 patients with at least one LFT abnormality (73.3%) continued treatment despite the elevation without further evaluation or change in therapy, and subsequent LFT assessments were within normal limits. 128 patients (70.3%) remained on MTX at the time of our study. The most common reason for discontinuation was inadequate response. CONCLUSIONS: MTX appears to be associated with very few clinically significant hepatic side effects. In view of these data, consideration as to revision of the current MTX monitoring guidelines in the direction of less frequent monitoring, especially in patients with no risk factors for liver disease, may be considered.