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The aim of our study was to analyse red blood cells from the high-altitude avian species alpine accentor (Prunella collaris). We caught 79 alpine accentors in the High Tatra Mountains (the West Carpathians, Slovakia) from 2001 to 2008. Blood samples were collected from the vena ulnaris cutanea. The cells and nuclei of juveniles tend to be wider and larger while adults, especially males, tend to have elongated (narrow) cells. The largest erythrocytes were found in winter and the smallest in summer, in June. Red blood cells with larger, elongated nuclei but overall smaller in size occurred at the beginning and the end of the breeding season, while larger, rounded cells with smaller nuclei were found in the middle of the breeding season. This kind of reshaping of erythrocytes of alpine accentors in summer is probably a response to hypoxia and elevated summer temperature in high mountains. As regards the length/width ratio, in August and September, erythrocytes were more elongated (both cell and nucleus) than in the other months. This study is probably the first assessment of seasonal effects on size and shape of red blood cells of bird species permanently living and breeding at high altitudes of the Palearctic mountains.

Analges slovakiensis Dabert, Mironov and Janiga, 2018 is a mite species that has co-evolved with the Alpine accentor Prunella collaris (Scopoli, 1786), an alpine songbird. We captured 150 Alpine accentors in the Western Carpathians in Slovakia to study the ecology and morphology of Analges slovakiensis. Seasonal variations in size were found only in females. In spring, female mites were larger with a higher intensity of infestation, however with the lowest prevalence. In contrast, autumn generations of female mites were smaller and the intensity of infestation by mites was lower due to a large dispersal to host birds. The prevalence of mites was high in autumn and in summer. Males of A. slovakiensis did not differ in size or shape among seasons. Morphophysiological plasticity combined with population dynamics allows the mites to survive effectively on hosts living at high altitudes in the mountains. The results also suggest that A. slovakiensis spreads through vertical transmission, as it radiates and increases in size during breeding season.

A four port network adder-subtractor module, for surface plasmon polariton (SPP) waves based on a ring resonator filter is proposed. The functionality of module is achieved by the phase difference manipulation of guided SPPs through different arms connected to the ring resonator. The module is designed using the concepts of a basic two-port device proposed in this paper. It is shown that two port network eliminates odd, and transmits even SPP modes of a single source. Moreover, in the case of four-port adder (with two individual sources), it is elucidated that according to the location of each output port, one can achieve the consequent added or subtracted outputs, correspondingly. Two distinct peaks are observed in the transmission spectrum of adder and subtractor outputs, where increasing the individual source phase difference, leads to a red shift in the adder output, and a blue shift in the subtractor output peaks. The proposed module can be used as the building block for implementing arithmetic operations in plasmonic integrated circuits. The transmission line theory verifies the numerical simulation results, and demonstrates the functionality of the adder/subtractor module.

Reprinted and translated from Journal of the European Academy of Dermatology and Venereology 28 (2014) “2014 European guideline on the management of syphilis” pp. 1581-1593, Copyright 2014 with permission © 2014 European Academy of Dermatology and Venereology. Background. Syphilis remains a major public health problem in Europe (both in Eastern Europe since the 1990’s and in Western Europe since the re-emergence of the disease in the late 1990’s-early 2000’s). Methods. This guideline is an update of the IUSTI: 2008 European guideline on the management of syphilis and is produced by the European Guideline Editorial Board (http://www.iusti.org/regions/Europe/pdf/2013/Editorial_Board.pdf) and EDF Guideline Committee. Results . It provides recommendations concerning the diagnosis and management of syphilis in Europe. Major advances include (1) broader use of PCR, immunohistochemistry, subtyping of the etiological agent Treponema pallidum subspecies pallidum, new treponemal tests, and rapid-point-of-care (POC) tests detecting both treponemal and non-treponemal antibodies, (2) more flexible options for screening (TT-treponemal test – first or NTT – non treponemal test – first or both TT and NTT), and (3) procaine penicillin is no longer the first line therapy option in any phase of the disease, i.e. long acting penicillin G (i.e. benzathine penicillin G-BPG) is the only first line therapy regimen in early syphilis and in late latent syphilis. Conclusions . Syphilis is a disease that is relatively easy to detect by appropriate serological tests, however, all laboratory results should be considered together with clinical data and sexual risk anamnesis. Syphilis is also easy to treat with BPG. A major concern about the supply of BPG in many European countries could threaten the efficacy of the policies of eradication of the disease in Europe.

The study investigates the relations between secondary school teachers' work-role fit, job enrichment, supervisor relationships, co-worker relationships, psychological meaningfulness of work and intention to leave. A cross-sectional survey was used. The participants were 502 secondary school teachers in Namibia. The following measuring instruments were used: Work-role Fit Scale, Job Enrichment Scale, Co-worker and Supervisor Relationships Scales, Psychological Meaningfulness Scale and Turnover Intention Scale. Work-role fit and job enrichment both had direct positive effect on experiences of psychological meaningfulness at work, while poor work-role fit and low psychological meaningfulness both had a direct effect on teachers' intentions to leave. An analysis of the indirect effects showed that poor work-role fit and poor job enrichment affected intention to leave due to the concomitant experience of low psychological meaningfulness. These findings have implications for the retention of teachers in secondary schools.

The aims of this study were to investigate lymphocyte proliferation activity and to identify chemical constituents of active fractions of star fish Acanthaster planci. A. planci was collected from Ternate Island, North Moluccas, extracted with distilled methanol and water, partitioned with gradient chloroform-hexane-methanol-water and fractionated in column chromatography using silica gel and hexane-ethyl acetate-methanol. The active compound had been purified by Thin Layer Chromatography (TLC) and identified by Gas Chromatography-Mass Spectrometry (GC-MS). The lymphocyte proliferation activity was measured based on % Stimulation Index (SI) from sample absorbency and control absorbency. The result showed that the 3 fractions of hexane fraction exhibited lymphocyte proliferation activity. Fraction 1 was able to increase lymphocyte proliferation at 48 hours and 72 hours by 55% (80 µl/ml) and 88% (160 µl/ml) increase, and fraction 2 had 77% (160 µl/ml) and 86% (640 µl/ml) increase. Meanwhile, fraction 3 had 75% (640 µl/ml) and 89% (640 µl/ml) increase. Metabolite analysis of active fraction using GC-MS yielded a number of chemical constituents that was dominated by fatty acid. The study concluded that star fish A. planci from Ternate Island has a potential source of immunostimulator.

The optical interaction mechanism of a nanohole pair milled in an opaque gold film by means of surface plasmon polaritons (SPPs) propagation is investigated. This interaction depends on the polarization direction of the incident light and the separation distance between the nanoholes. It is found that when the nanoholes are illuminated by a plane wave incident light polarized parallel to the axis of the nanohole pair, the SPP waves can propagate between the nanoholes, and therefore, the nanoholes can interact through SPPs. In contrast, it is shown that for the incident plane wave polarized perpendicular to the pair axis, the propagation direction of the SPPs is normal to the pair axis, and thus, a weak interaction through the SPPs can occur between the nanoholes. It is also shown that in order to investigate the interaction of the nanoholes through the SPP waves, each nanohole can be modeled by a magnetic dipole, which propagates SPPs. Thus, the optical properties of the interacting nanoholes can be modeled using a magnetic-coupled dipole approximation method accounting SPPs to confirm the simulation results.

Sodium/proton antiporter activity in the plasma membrane and tonoplast of cucumber seedling roots treated with 200 mM NaCl for 24 h was determined. It was observed that plasma membrane and tonoplast antiporter activity was only present in membranes from salt-treated plants. In addition, the plasma membrane antiporter protein was present in membranes after induction with NaCl, whereas tonoplast antiporter protein was observed in control and at elevated level in NaCl-treated plants. Moreover, based on the affinity of studied antiporter proteins to sodium ions, it could be assumed that excess sodium ions are firstly translocated from the cytosol to the vacuole and then excluded to the apoplast through the plasma membrane.

The authors described the problems which appeared in fractures of the upper parts of the middle thirds and the lower parts of the overhead of the facial skeleton.The patients described in the article were treated at the Department of the Stomatology and Maxillofacial surgery, Jessenius Faculty of Medicine and Martin Faculty Hospital. The article summed up the aetiology, incidence, seasonality, sex distribution, type of the treatment and complications. The authors underlined the importance of interdisciplinary cooperation in the management of the cranio-maxillofacial trauma.

Metabolic studies using the in vitro non-recirculating blood-perfused isolated heart model require large volumes of blood. The present study was designed to determine whether heterologous pig blood collected from a slaughterhouse can be used as perfusate for isolated pig hearts perfused under aerobic and constant reduced flow conditions. Eight isolated working pig hearts perfused for 90 min at a constant flow of 1.5 ml g-1 min-1 with non-recirculated blood diluted with Krebs-Henseleit bicarbonate buffer at a hematocrit of 23% were compared to eight hearts subjected to the same protocol but perfused only with Krebs-Henseleit bicarbonate buffer solution. Hearts were paced at 100 bpm and subjected to aerobic perfusion at 38ºC. Hearts were weighed before perfusion and at the end of the experiment and the results are reported as percent weight gain (mean ± SD). Comparisons between groups were performed by the Student t-test (P

Studie je věnována otázce mnohojazyčnosti jako dílčímu cíli jazykového vzdělávání. Záměrem autora je nabídnout čtenáři vhled do problematiky výuky dalších cizích jazyků ve škole v kontextu podpory mnohojazyčnosti. V první části textu vymezíme koncepci mnohojazyčnosti, kterou chápeme jako zastřešující teoretický rámec pro naše pojetí (tedy pojetí mnohojazyčnosti jako dílčího cíle výuky cizích jazyků). Protože mnohojazyčnost definujeme jako schopnost žáka ovládat alespoň tři jazyky, navrhneme v následující části, jak tyto jazyky označovat a řadit. V další části nahlédneme osvojování dalších (tedy druhých, třetích, čtvrtých…) cizích jazyků a jejich specifika. Ve čtvrté části se zaměříme na didaktické uchopení koncepce mnohojazyčnosti a na možnou implementaci podpory mnohojazyčnosti do výuky dalších cizích jazyků. V poslední části se zaměříme na učitele a na jeho kompetence, kterými by měl disponovat, aby mohl ve výuce cizích jazyků smysluplně podporovat mnohojazyčnost.

Studie se zabývá problematikou interakčního stylu učitelů tělesné výchovy na 2. stupni ZŠ. Teoretickým východiskem je Learyho teorie interpersonálního chování, na jejímž základě byl sestaven Dotazník interakčního stylu učitele (QTI). Tento dotazník byl distribuovaný učitelům tělesné výchovy (n = 19) a jejich žákům (n = 889) ve třech krajích ČR (Jihomoravský, Zlínský, Olomoucký). Výsledky studie se vztahují k odlišnostem ve vnímání učitelů sebou samými a ve vnímání učitelů jejich žáky, k genderovým odlišnostem ve vnímání interakčního stylu učitele, k odlišnostem v závislosti na délce praxe učitele a k odlišnostem daným povahou vyučovacího předmětu, v jehož rámci byla výzkumná studie realizována.

Myxofibrosarcoma is an aggressively malignant soft-tissue neoplasm of the upper or lower extremities that occurs in adults. At the time of diagnosis, upto 73% of cancer patients complain of varying degrees of pain. The ultimate goal of treatment is pain relief and functional recovery. The authors describe the case of a 59-year-old female patient who presented with complaints of excruciating brachialgia of the right upper limb. She had a pain score of 10 based on the Visual Analogue Scale (VAS 0-10). Her pain was initially managed conservatively with systemic analgesics but it failed to offer adequate relief. Often, there is an inadequate response to conservative treatment. These patients may benefit from various interventional modalities. Hence, epidural neurolysis with phenol was done by slowly injecting 2 mL of 6% aqueous phenol into the epidural space under Computed Tomography (CT) and fluoroscopy guidance. Upon follow-up, the patient’s Visual Analog Scale (VAS) was recorded as one, morphine consumption decreased with eventual discontinuation, and paraesthesia had reduced by 50%. This patient was suffering from chronic pain, which significantly reduced her Quality of Life (QoL). The injection of phenol into the appropriate space resulted in satisfactory sustained analgesia. She did not have any sensory or motor loss. Her pain was adequately controlled by paracetamol 500 mg as needed. The patient remained pain-free for five months after the procedure but eventually succumbed to her illness.

Machine learning has increasingly been applied to predict opioid-related harms due to its ability to handle complex interactions and generating actionable predictions. This review evaluated the types and quality of ML methods in opioid safety research, identifying 44 studies using supervised ML through searches of Ovid MEDLINE, PubMed and SCOPUS databases. Commonly predicted outcomes included postoperative opioid use (n = 15, 34%) opioid overdose (n = 8, 18%), opioid use disorder (n = 8, 18%) and persistent opioid use (n = 5, 11%) with varying definitions. Most studies (96%) originated from North America, with only 7% reporting external validation. Model performance was moderate to strong, but calibration was often missing (41%). Transparent reporting of model development was often incomplete, with key aspects such as calibration, imbalance correction, and handling of missing data absent. Infrequent external validation limited the generalizability of current models. Addressing these aspects is critical for transparency, interpretability, and future implementation of the results., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: Our study aimed to assess the heart failure/cardiomyopathy-related population-level mortality trends among patients with obesity in the United States and disparities across demographics., Methods: We queried the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research database among adults aged ≥25 from 1999 to 2019. Heart failure/cardiomyopathy were listed as the main causes of death, with obesity as a contributing cause. We calculated age-adjusted mortality rates (AAMR) per 100,000 individuals and estimated the average annual percent change (AAPC). We also evaluated the social vulnerability of United States counties (2014-2018)., Results: There were 29,334 deaths related to heart failure/cardiomyopathy among patients with comorbid obesity. The overall AAMR increased from 0.41 in 1999 to 0.94 in 2019, with an AAPC of 3.78 (95 % CI, 3.41-4.14). The crude mortality rate increase for heart failure/cardiomyopathy was greater in individuals with comorbid obesity than in those without. Males had a higher AAMR than females (0.78 vs 0.55). African Americans also had higher AAMR than Whites (1.35 vs 0.62). The AAMR was higher in rural areas than in urban regions (0.76 vs 0.66). The overall AAMR was higher in counties with social vulnerability index-Quartile 4 (SVI-Q4) (most vulnerable) (1.08) compared to SVI-Q1 (least vulnerable) (0.63) with a risk ratio of 1.71 (95 % CI: 1.61-1.83)., Conclusion: Heart failure/cardiomyopathy mortality in individuals with comorbid obesity was rising. Males, African Americans, and individuals from rural regions had higher AAMR than their counterparts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This case series underscores the crucial role of genetic testing and a multidisciplinary approach to the management of genetic dilated cardiomyopathy. It also highlights the importance of distinguishing dilated cardiomyopathies from other cardiomyopathies to personalize patient care., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Recent fMRI resting-state findings show aberrant functional connectivity within somatomotor network (SMN) in schizophrenia. Moreover, functional connectivity aberrations of the motor system are often reported to be related to the severity of psychotic symptoms. Thus, it is important to validate those findings and confirm their relationship with psychopathology. Therefore, we decided to take an entirely data-driven approach in our fMRI resting-state study of 30 chronic schizophrenia outpatients and 30 matched control subjects. We used independent component analysis (ICA), dual regression, and seed-based connectivity analysis. We found reduced functional connectivity within SMN in schizophrenia patients compared to controls and SMN hypoconnectivity with the cerebellum in schizophrenia patients. The latter was strongly correlated with the severity of alogia, one of the main psychotic symptoms, i.e. poverty of speech and reduction in spontaneous speech,. Our results are consistent with the recent knowledge about the role of the cerebellum in cognitive functioning and its abnormalities in psychiatric disorders, e.g. schizophrenia. In conclusion, the presented results, for the first time clearly showed the involvement of the cerebellum hypoconnectivity with SMN in the persistence and severity of alogia symptoms in schizophrenia., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Plant glucanases, including potato glucanase, are pivotal in biological processes such as cell growth, development, and defense against pathogens. These enzymes hold substantial promises in biotechnological applications, especially genetic engineering for enhancing crop disease resistance and stress tolerance. In this study, from Solanum tuberosum, glycosyl hydrolases family 17 (GH-17) β-1,3-glucanase (Stglu) was cloned, expressed, characterized and its antifungal activity was evaluated. The gene was isolated from infected potato plants and cloned into the pDrive and subsequently into the pET32a (+) protein expression vector. Sequence analysis revealed a 1044 bp open reading frame encoding a 347 amino acid protein with an anticipated molecular weight of 38 kDa and a signature motif (-IEIIVSESGWPSEG-) of the GH-17 family. The recombinant β-1,3-glucanase (Stglu) protein was expressed in E. coli Rosetta-gami 2 (DE3) cells. After recovery from inclusion bodies using urea buffer solubilization and refolding by dialysis, expression of Stglu protein was confirmed by Western blot analysis using an anti-His antibody. Enzymatic assays were performed to characterize β-1,3-glucanase activity which showed its maximum activity at pH 7.0 and 37 °C. Plate assays for substrate specificity showed that the enzyme hydrolyzed azo-barley β-glucan and laminarin. The metal ions strongly affected the enzyme's activity; Ca 2+ acted as a weak activator. Plate assays further indicated the antifungal activity of Stglu against the plant pathogen Fusarium solani, showing a biotechnological potential tool in controlling fungal pathogenicity in crop plants., Competing Interests: Declaration of competing interests The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pain is a common symptom in people with inflammatory arthritis (IA), which has far-reaching impacts on their lives. Recent electronic health record studies demonstrate that UK-based pain care in people with IA commonly involves the prescribing of long-term opioids and gabapentinoids, despite an absence of trial evidence for their efficacy. Patient surveys suggest that non-pharmacological pain management is underused. A UK-specific guideline on pain management for people with IA is required to resolve this. This scoping document outlines the context and prioritized clinical questions for the first British Society for Rheumatology (BSR) guideline on pain management for people with IA. The guideline aims to provide evidence-based recommendations on how pain can be best managed in people with IA (including its assessment, and pharmacological and non-pharmacological treatments), ensuring that people with IA in the UK are offered evidence-based pain management strategies. The guideline is for healthcare professionals involved in the care of people with IA of all ages and genders, people with IA and their families and carers, NHS managers and healthcare commissioners, and other relevant stakeholders such as patient organizations. It will be developed using the methods outlined in the BSR's 'Creating Clinical Guidelines' protocol., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Abstract: Although opioids continue to be used internationally for noncancer pain, evidence to date on the comparative safety of different opioids is sparse and conflicting. The aim of this study was to examine the comparative risk of all-cause mortality in patients newly initiated on opioids for noncancer pain, across 3 jurisdictions in the United Kingdom (UK), United States, and Canada. A multicentre retrospective, population-based cohort study was conducted. Data sources included UK national primary care electronic health records (Clinical Practice Research Datalink), The Partners HealthCare Research Patient Data in Boston (US), and The Montreal Population Health Record data (Canada). New users of opioids aged ≥18 years without cancer were included. Patients with a diagnosis of a pain condition and with known back pain were analysed separately. Fully adjusted hazard ratios (HRs) were calculated using Cox-proportional models and adjusted for confounders. In total, 1,066,216 patients were included (UK: n = 993,294; Boston, US: n = 43,243; Montreal, Canada: n = 26,116). Compared with codeine, patients using morphine had a significantly higher adjusted risk in the UK {HR: 12.58 [95% confidence interval (CI), 11.87-13.32]}, US (HR: 8.62 [95% CI, 3.34-22.27]), and Canadian cohorts (HR: 6.69; [95% CI, 1.35-32.22]). In addition, other factors associated with higher mortality were being on combination opioids, fentanyl, buprenorphine, and oxycodone. Compared with those on <50 morphine milligram equivalents/day, patients on higher-doses experience an incremental increase in risk. In new users of opioids, compared with codeine, strong opioids, including morphine, fentanyl, buprenorphine, oxycodone, and combination opioids, and those on ≥50 morphine milligram equivalent/day were associated with a higher subsequent risk of all-cause mortality., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Clinical Question: In adult patients with inflammatory bowel disease, inflammatory arthritis (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis), or psoriasis taking biologic drugs, does proactive therapeutic drug monitoring (TDM) improve outcomes as compared with standard care?, Context and Current Practice: Standard care for immune mediated inflammatory diseases includes prescribing biologic drugs at pre-determined doses. Dosing may be adjusted reactively, for example with increased disease activity. In proactive TDM, serum drug levels and anti-drug antibodies are measured irrespective of disease activity, and the drug dosing is adjusted to achieve target serum drug levels, usually within pre-specified therapeutic ranges. The role of proactive TDM in clinical practice remains unclear, with conflicting guideline recommendations and emerging evidence from randomised controlled trials., The Evidence: Linked systematic review and pairwise meta-analysis which identified 10 trials including 2383 participants. Inflammatory bowel disease, inflammatory arthritis, and psoriasis were grouped together as best current research evidence on proactive TDM did not suggest heterogeneity of effects on outcomes of interest. Proactive TDM of intravenous infliximab during maintenance treatment may increase the proportion of patients who experience sustained disease control or sustained remission without considerable additional harm. For adalimumab, it remains unclear if proactive TDM during maintenance treatment has an effect on sustained disease control or sustained remission. At induction (start) of treatment, proactive TDM of intravenous infliximab may have little or no effect on achieving remission. No eligible trial evidence was available for proactive TDM of adalimumab at induction (start) of treatment. No eligible trial evidence was available for proactive TDM of other biologic drugs in maintenance or at induction (start) of treatment., Recommendations: The guideline panel issued the following recommendations for patients with inflammatory bowel disease, inflammatory arthritis, or psoriasis:1. A weak recommendation in favour of proactive TDM for intravenous infliximab during maintenance treatment2. A weak recommendation against proactive TDM for adalimumab and other biologic drugs during maintenance treatment3. A weak recommendation against proactive TDM for intravenous infliximab, adalimumab, and other biologic drugs during induction (start) of treatment., Understanding the Recommendations: When considering proactive TDM, clinicians and patients should engage in shared decision making to ensure patients make choices that reflect their values and preferences. The availability of laboratory assays to implement proactive TDM should also be considered. Further research is warranted and may alter recommendations in the future., How This Guideline Was Created: An international panel including patient partners, clinicians, and methodologists produced these recommendations based on a linked systematic review and pairwise meta-analysis which identified 10 trials including 2383 participants. The panel followed standards for trustworthy guidelines and used the GRADE approach, explicitly considering the balance of benefits and harms and burdens of treatment from an individual patient perspective., Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations interest of disclosure form. MAGIC and The BMJ judged that no panel member or co-chair had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. MAGIC and TheBMJ assessed declared interests from other coauthors of this publication and found no relevant conflicts of interests., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Abstract: Prescription opioids for noncancer pain in the United Kingdom have increased over the past 2 decades, alongside associated harms. Policies addressing opioid prescribing must be tailored to individual patient needs with specific disease systems. The aim of this study was to evaluate clinical conditions associated with new opioid initiation in noncancer pain using nationally representative UK data. Primary care electronic health records from January 1, 2006, to September 31, 2021, were used from the Clinical Research Practice Datalink to identify incident opioid prescriptions. Patient histories were reviewed using code lists for opioid-related conditions with a 5-year look-back for chronic conditions and a 1-year look-back for surgical indications before opioid initiation. In total, 3,030,077 new opioid use episodes in 2,027,402 patients were identified, with 61% being women, 77% aged 45 years and older, and 48% from the highest deprivation quintile. Ten systems associated with opioid initiation were identified, which were not mutually exclusive, as patients could have opioids prescribed for multiple indications. The most common were musculoskeletal (80.8%), respiratory (57.6%), infections (30.4%), trauma/injury (20.4%), neurology (19.9%), and postsurgical indications (5.5%). Osteoarthritis (60.7%) and low back pain (41.0%) were the most frequent musculoskeletal conditions. Orthopedic surgeries accounted for 41.2% of all postsurgical indications. This is the first study in the United Kingdom evaluating large-scale national data to assess indications associated with opioid initiation. Nearly 3 quarters of new opioid prescriptions for noncancer pain were in patients with musculoskeletal conditions, often for conditions with limited evidence for opioid efficacy. These findings could inform targeted interventions and future policies to support nonpharmacological interventions in the most common conditions where opioid harms outweigh benefits., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Objectives: Pain, fatigue and sleep disturbances are common symptoms in patients with rheumatic and musculoskeletal diseases (RMDs) that may prompt the use of over-the-counter (OTC) supplements, sleep aids and analgesics as self-management strategies. This study evaluated the prevalence of OTC supplements, sleep aids and pain relievers and the financial burden associated with their use in rheumatology., Methods: A web-based survey developed with patients was administered in rheumatology clinics in an English hospital. Participants shared demographic information and detailed their use of OTC supplements, sleep aids and pain relief in the past week. The data were analysed using descriptive statistics and logistic regression models to identify influencing factors., Results: A total of 876 people consented to participate in the survey. More than half of patients (54.5%) reported daily supplement intake, typically spending £10/month (interquartile range 5-20), ranging up to £200/month. The most commonly administered supplements were vitamin D, multivitamins, vitamin C, vitamin B/B complex and omega-3/-6 supplements, with multiple overlaps. Prescription, OTC or non-prescription pain relief use was reported by 82% of respondents, with sleep aids being used by 13%. Of the 327 patients who took NSAIDs, 165 (50.4%) also reported taking OTC supplements, while among the 131 patients using opioids (20.5%), 66 (50.3%) reported supplement use, some of which have documented interactions., Conclusion: The use of OTC supplements, pain relief and sleep aids is common in patients with RMDs. Healthcare professionals should be encouraged to proactively ask about these during consultations, especially from a drug safety perspective, but also to provide timely, reliable advice about such strategies that may be sought by patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Up to one in five patients with axial spondyloarthritis (AxSpA) or psoriatic arthritis (PsA) newly initiated on opioids transition to long-term use within the first year. This study aimed to investigate individual factors associated with long-term opioid use among opioid new users with AxSpA/PsA., Methods: Adult patients with AxSpA/PsA and without prior cancer who initiated opioids between 2006-2021 were included from Clinical Practice Research Datalink Gold, a national UK primary care database. Long-term opioid use was defined as having ≥3 opioid prescriptions issued within 90 days, or ≥ 90 days of opioid supply, in the first year of follow-up. Individual factors assessed included sociodemographic, lifestyle factors, medication use and comorbidities. A mixed-effects logistic regression model with patient-level random intercept was used to examine the association of individual characteristics with the odds of long-term opioid use., Results: In total 10 300 opioid initiations were identified from 8,212 patients (3037 AxSpA; 5175 PsA). The following factors were associated with long-term opioid use: being a current smoker (OR : 1.62; 95%CI : 1.38,1.90), substance use disorder (OR : 2.34, 95%CI : 1.05,5.21), history of suicide/self-harm (OR : 1.84; 95%CI : 1.13,2.99), co-existing fibromyalgia (OR : 1.62; 95%CI : 1.11,2.37), higher Charlson Comorbidity Index (OR : 3.61; 95%CI : 1.69,7.71 for high scores), high MME/day at initiation (OR : 1.03; 95%CI : 1.02,1.03) and gabapentinoid (OR : 2.35; 95%CI : 1.75,3.16) and antidepressant use (OR : 1.69; 95%CI : 1.45,1.98)., Conclusions: In AxSpA/PsA patients requiring pain relief, awareness of lifestyle, sociodemographic and prescribing characteristics associated with higher risk of long-term opioid use can prompt timely interventions such as structured medication reviews and smoking cessation to promote safer prescribing and better patient outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/β-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-β) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fatigue is a common symptom of rheumatic diseases and frequently persists even when patients are in a near-remission state. In seeking options to manage troublesome symptoms such as fatigue, complementary and alternative medicines (CAM) are often used by patients despite a lack of evidence base behind such treatment strategies. CAM use is further promoted by social media and 'influencer' marketing without rigorous process to ensure scientific accuracy. One mechanism of recent interest in the CAM market is enhancing cellular pathways of nicotinamide adenine dinucleotide (NAD+), purported to restore mitochondrial function. However, clinical trials of NAD+ pathway supplements lack rigorous trial design, many declare conflicts of interest, and safety data is limited. Ultimately, CAM use by our patients is unavoidable. To adequately inform patients about CAM, we need to keep updated on both the latest scientific literature and social media trends. In so doing, we can then propose to patients how standard-of-care therapies, evidence-based lifestyle modifications and CAM might safely and effectively integrate to form a treatment plan., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Introduction: At the beginning of the COVID-19 pandemic, the UK's Scientific Committee issued extreme social distancing measures, termed 'shielding', aimed at a subpopulation deemed extremely clinically vulnerable to infection. National guidance for risk stratification was based on patients' age, comorbidities and immunosuppressive therapies, including biologics that are not captured in primary care records. This process required considerable clinician time to manually review outpatient letters. Our aim was to develop and evaluate an automated shielding algorithm by text-mining outpatient letter diagnoses and medications, reducing the need for future manual review., Methods: Rheumatology outpatient letters from a large UK foundation trust were retrieved. Free-text diagnoses were processed using Intelligent Medical Objects software (Concept Tagger), which used interface terminology for each condition mapped to Systematized Medical Nomenclature for Medicine-Clinical Terminology (SNOMED-CT) codes. We developed the Medication Concept Recognition tool (Named Entity Recognition) to retrieve medications' type, dose, duration and status (active/past) at the time of the letter. Age, diagnosis and medication variables were then combined to calculate a shielding score based on the most recent letter. The algorithm's performance was evaluated using clinical review as the gold standard. The time taken to deploy the developed algorithm on a larger patient subset was measured., Results: In total, 5942 free-text diagnoses were extracted and mapped to SNOMED-CT, with 13 665 free-text medications (n=803 patients). The automated algorithm demonstrated a sensitivity of 80% (95% CI: 75%, 85%) and specificity of 92% (95% CI: 90%, 94%). Positive likelihood ratio was 10 (95% CI: 8, 14), negative likelihood ratio was 0.21 (95% CI: 0.16, 0.28) and F1 score was 0.81. Evaluation of mismatches revealed that the algorithm performed correctly against the gold standard in most cases. The developed algorithm was then deployed on records from an additional 15 865 patients, which took 18 hours for data extraction and 1 hour to deploy., Discussion: An automated algorithm for risk stratification has several advantages including reducing clinician time for manual review to allow more time for direct care, improving efficiency and increasing transparency in individual patient communication. It has the potential to be adapted for future public health initiatives that require prompt automated review of hospital outpatient letters., Competing Interests: Competing interests: ASK is the former Chief Medical Officer of Intelligent Medical Objects (IMO) and owns a stock in IMO. WGD has received consultancy fees from Google unrelated to the project. Other authors have no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ on behalf of EULAR.)

Spider webs that serve as snares are one of the most fascinating and abundant type of animal architectures. In many cases they include an adhesive coating of silk lines-so-called viscid silk-for prey capture. The evolutionary switch from silk secretions forming solid fibres to soft aqueous adhesives remains an open question in the understanding of spider silk evolution. Here we functionally and chemically characterized the secretions of two types of silk glands and their behavioural use in the cellar spider, Pholcus phalangioides. Both being derived from the same ancestral gland type that produces fibres with a solidifying glue coat, the two types produce respectively a quickly solidifying glue applied in thread anchorages and prey wraps, or a permanently tacky glue deployed in snares. We found that the latter is characterized by a high concentration of organic salts and reduced spidroin content, showing up a possible pathway for the evolution of viscid properties by hygroscopic-salt-mediated hydration of solidifying adhesives. Understanding the underlying molecular basis for such radical switches in material properties not only helps to better understand the evolutionary origins and versatility of ecologically impactful spider web architectures, but also informs the bioengineering of spider silk-based products with tailored properties.

Background: Opioids administered in hospital during the immediate postoperative period are likely to influence post-surgical outcomes, but inpatient prescribing during the admission is challenging to access. Modified-release(MR) preparations have been especially associated with harm, whilst certain populations such as the elderly or those with renal impairment may be vulnerable to complications. This study aimed to assess postoperative opioid utilisation patterns during hospital stay for people admitted for major/orthopaedic surgery., Methods: Patients admitted to a teaching hospital in the North-West of England between 2010-2021 for major/orthopaedic surgery with an admission for ≥1 day were included. We examined opioid administrations in the first seven days post-surgery in hospital, and "first 48 hours" were defined as the initial period. Proportions of MR opioids, initial immediate-release(IR) oxycodone and initial morphine milligram equivalents (MME)/day were calculated and summarised by calendar year. We also assessed the proportion of patients prescribed an opioid at discharge., Results: Among patients admitted for major/orthopaedic surgery, 71.1% of patients administered opioids during their hospitalisation. In total 50,496 patients with 60,167 hospital admissions were evaluated. Between 2010-2017 MR opioids increased from 8.7% to 16.1% and dropped to 11.6% in 2021. Initial use of oxycodone IR among younger patients (≤70 years) rose from 8.3% to 25.5% (2010-2017) and dropped to 17.2% in 2021. The proportion of patients on ≥50MME/day ranged from 13% (2021) to 22.9% (2010). Of the patients administered an opioid in hospital, 26,920 (53.3%) patients were discharged on an opioid., Conclusions: In patients hospitalised with major/orthopaedic surgery, 4 in 6 patients were administered an opioid. We observed a high frequency of administered MR opioids in adult patients and initial oxycodone IR in the ≤70 age group. Patients prescribed with ≥50MME/day ranged between 13-22.9%. This is the first published study evaluating UK inpatient opioid use, which highlights opportunities for improving safer prescribing in line with latest recommendations., Competing Interests: WGD has received consultancy fees from Google unrelated to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mobilization of clusters of genes called genomic islands (GIs) across bacterial lineages facilitates dissemination of traits, such as, resistance against antibiotics, virulence or hypervirulence, and versatile metabolic capabilities. Robust delineation of GIs is critical to understanding bacterial evolution that has a vast impact on different life forms. Methods for identification of GIs exploit different evolutionary features or signals encoded within the genomes of bacteria, however, the current state-of-the-art in GI detection still leaves much to be desired. Here, we have taken a combinatorial approach that accounted for GI specific features such as compositional bias, aberrant phyletic pattern, and marker gene enrichment within an integrative framework to delineate GIs in bacterial genomes. Our GI prediction tool, DICEP, was assessed on simulated genomes and well-characterized bacterial genomes. DICEP compared favorably with current GI detection tools on real and synthetic datasets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: Radiofrequency ablation (RFA) is a minimally invasive procedure for facet joint pain. The targets for the procedure are the medial branches of the dorsal spinal nerves which innervate the facet joints. Before RFA, patients undergo diagnostic meal branch blocks to ensure appropriate pain relief and confirm the utility of proceeding to RFA. The success of RFA relies heavily on procedural technique and accurate placement near the medial branch., Recent Findings: Motor testing is utilized in the lumbar region to assess the response of the multifidus and ensure proper placement of the RFA probe to prevent inadvertent damage to surrounding spinal anatomy. However, relying on motor responses in this area presents challenges given the frequency of lack of muscle twitching. Factors contributing to limited muscle twitch responses include muscle atrophy, excessive lordosis, facet arthropathy, local anesthetic use before ablation, and previous surgical neurotomy. These complexities highlight the challenges in ensuring precise motor stimulation during RFA. Despite these obstacles, accurate anatomical placement remains crucial. For RFA cases that prove challenging, relying on anatomical placement can be adequate to proceed with the procedure. Bridging knowledge gaps is vital for standardized practices and safer procedures. Further research is necessary to refine techniques, understand patient-specific factors, and enhance the efficacy of RFA in managing chronic lumbar facet joint pain., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Fibromyalgia is frequently treated with opioids due to limited therapeutic options. Long-term opioid use is associated with several adverse outcomes. Identifying factors associated with long-term opioid use is the first step in developing targeted interventions. The aim of this study was to evaluate risk factors in fibromyalgia patients newly initiated on opioids using machine learning., Methods: A retrospective cohort study was conducted using a nationally representative primary care dataset from the UK, from the Clinical Research Practice Datalink. Fibromyalgia patients without prior cancer who were new opioid users were included. Logistic regression, a random forest model and Boruta feature selection were used to identify risk factors related to long-term opioid use. Adjusted ORs (aORs) and feature importance scores were calculated to gauge the strength of these associations., Results: In this study, 28 552 fibromyalgia patients initiating opioids were identified of which 7369 patients (26%) had long-term opioid use. High initial opioid dose (aOR: 31.96, mean decrease accuracy (MDA) 135), history of self-harm (aOR: 2.01, MDA 44), obesity (aOR: 2.43, MDA 36), high deprivation (aOR: 2.00, MDA 31) and substance use disorder (aOR: 2.08, MDA 25) were the factors most strongly associated with long-term use., Conclusions: High dose of initial opioid prescription, a history of self-harm, obesity, high deprivation, substance use disorder and age were associated with long-term opioid use. This study underscores the importance of recognising these individual risk factors in fibromyalgia patients to better navigate the complexities of opioid use and facilitate patient-centred care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate opioid prescribing trends and assess the impact of the COVID-19 pandemic on opioid prescribing in rheumatic and musculoskeletal diseases (RMDs)., Methods: Adult patients with RA, PsA, axial spondyloarthritis (AxSpA), SLE, OA and FM with opioid prescriptions between 1 January 2006 and 31 August 2021 without cancer in UK primary care were included. Age- and gender-standardized yearly rates of new and prevalent opioid users were calculated between 2006 and 2021. For prevalent users, monthly measures of mean morphine milligram equivalents (MME)/day were calculated between 2006 and 2021. To assess the impact of the pandemic, we fitted regression models to the monthly number of prevalent opioid users between January 2015 and August 2021. The time coefficient reflects the trend pre-pandemic and the interaction term coefficient represents the change in the trend during the pandemic., Results: The study included 1 313 519 RMD patients. New opioid users for RA, PsA and FM increased from 2.6, 1.0 and 3.4/10 000 persons in 2006 to 4.5, 1.8 and 8.7, respectively, in 2018 or 2019. This was followed by a fall to 2.4, 1.2 and 5.9, respectively, in 2021. Prevalent opioid users for all RMDs increased from 2006 but plateaued or dropped beyond 2018, with a 4.5-fold increase in FM between 2006 and 2021. In this period, MME/day increased for all RMDs, with the highest for FM (≥35). During COVID-19 lockdowns, RA, PsA and FM showed significant changes in the trend of prevalent opioid users. The trend for FM increased pre-pandemic and started decreasing during the pandemic., Conclusion: The plateauing or decreasing trend of opioid users for RMDs after 2018 may reflect the efforts to tackle rising opioid prescribing in the UK. The pandemic led to fewer people on opioids for most RMDs, providing reassurance that there was no sudden increase in opioid prescribing during the pandemic., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data., Methods: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023., Results: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p < .05) and also had more academic/educational problems., Conclusions: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality., Methods: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data., Results: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs., Conclusions: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The Toronto Adolescent and Youth (TAY) Cohort Study will characterize the neurobiological trajectories of psychosis spectrum symptoms, functioning, and suicidality (i.e., suicidal thoughts and behaviors) in youth seeking mental health care. Here, we present the neuroimaging and biosample component of the protocol. We also present feasibility and quality control metrics for the baseline sample collected thus far., Methods: The current study includes youths (ages 11-24 years) who were referred to child and youth mental health services within a large tertiary care center in Toronto, Ontario, Canada, with target recruitment of 1500 participants. Participants were offered the opportunity to provide any or all of the following: 1) 1-hour magnetic resonance imaging (MRI) scan (electroencephalography if ineligible for or declined MRI), 2) blood sample for genomic and proteomic data (or saliva if blood collection was declined or not feasible) and urine sample, and 3) heart rate recording to assess respiratory sinus arrhythmia., Results: Of the first 417 participants who consented to participate between May 4, 2021, and February 2, 2023, 412 agreed to participate in the imaging and biosample protocol. Of these, 334 completed imaging, 341 provided a biosample, 338 completed respiratory sinus arrhythmia, and 316 completed all 3. Following quality control, data usability was high (MRI: T1-weighted 99%, diffusion-weighted imaging 99%, arterial spin labeling 90%, resting-state functional MRI 95%, task functional MRI 90%; electroencephalography: 83%; respiratory sinus arrhythmia: 99%)., Conclusions: The high consent rates, good completion rates, and high data usability reported here demonstrate the feasibility of collecting and using brain imaging and biosamples in a large clinical cohort of youths seeking mental health care., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

A mutation in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Patients with ALS or FTD often develop autoimmunity and inflammation that precedes or coincides with the onset of neurological symptoms, but the underlying mechanisms are poorly understood. Here, we knocked out murine C9orf72 in seven hematopoietic progenitor compartments by conditional mutagenesis and found that myeloid lineage C9orf72 prevents splenomegaly, loss of tolerance, and premature mortality. Furthermore, we demonstrated that C9orf72 plays a role in lymphoid cells to prevent interleukin-17A (IL-17A) production and neutrophilia. Mass cytometry identified early and sustained elevation of the costimulatory molecule CD80 expressed on C9orf72 -deficient mouse macrophages, monocytes, and microglia. Enrichment of CD80 was similarly observed in human spinal cord microglia from patients with C9ORF72 -mediated ALS compared with non-ALS controls. Single-cell RNA sequencing of murine spinal cord, brain cortex, and spleen demonstrated coordinated induction of gene modules related to antigen processing and presentation and antiviral immunity in C9orf72 -deficient endothelial cells, microglia, and macrophages. Mechanistically, C9ORF72 repressed the trafficking of CD80 to the cell surface in response to Toll-like receptor agonists, interferon-γ, and IL-17A. Deletion of Il17a in C9orf72 -deficient mice prevented CD80 enrichment in the spinal cord, reduced neutrophilia, and reduced gut T helper type 17 cells. Last, systemic delivery of an IL-17A neutralizing antibody augmented motor performance and suppressed neuroinflammation in C9orf72 -deficient mice. Altogether, we show that C9orf72 orchestrates myeloid costimulatory potency and provide support for IL-17A as a therapeutic target for neuroinflammation associated with ALS or FTD.

Objective: The aim of this study was to assess the relationship between self-reported non-adherence, non-trough drug levels, immunogenicity and conventional synthetic DMARD (csDMARD) co-therapy in TNF inhibitor (TNF-i) drug response in PsA., Methods: Serum samples and adherence questionnaires were collected at baseline, 3, 6 and 12 months for PsA patients prescribed TNF-i. Non-trough adalimumab (ADL) and etanercept (ETN) drug levels were measured at 3 and 6 months using commercially available ELISAs. Clinical response was assessed using PsA response criteria (PsARC) and change in 28-joint DAS (ΔDAS28) between baseline and 3, 6 and 12 months., Results: In 244 PsA patients (52.5% ADL and 47.5% ETN), self-reported non-adherence was associated with PsARC non-response over 12 months using generalized estimating equation (GEE) modelling ( P  = 0.037). However, there was no significant difference between non-trough ADL or ETN drug levels based on self-reported non-adherence. Higher ETN levels at 3 months were associated with PsARC response at 3 ( P  = 0.015), 6 ( P  = 0.037) and 12 months ( P  = 0.015) and over 12 months using GEE modelling ( P  = 0.026). Increased ADL drug levels at 3 months were associated with greater ΔDAS28 at 3 months ( P  = 0.019). ADL anti-drug antibody-positive status was significantly associated with lower 3- and 6-month ADL levels ( P  < 0.001) and ΔDAS28 and PsARC response at 3, 6 and 12 months. Meanwhile, MTX co-therapy was associated with a reduction in immunogenicity at 3 and 6 months ( P  = 0.008 and P  = 0.024)., Conclusion: Although both were associated with reduced response, the objectively measured non-trough drug levels showed more significant associations with drug response than self-reported non-adherence measures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)