Risk Of Serious Side Effects Research Articles

Progress and Challenges in the Management of Congenital Cytomegalovirus Infection

Congenital cytomegalovirus (CMV) infection is the most common intrauterine viral infection with a significant impact on the foetus and newborn. Current diagnostic practice includes serological testing for specific antibodies, but there are no global screening protocols. Maternal CMV screening is often performed in conjunction with antenatal ultrasound. While most infections are asymptomatic, severe cases can lead to long-term disability or death. Antiviral therapies, mainly ganciclovir and valganciclovir, are reserved for symptomatic patients, especially those with central nervous system involvement. Although effective, these treatments are associated with significant side effects such as neutropenia and hepatotoxicity. Foscarnet and cidofovir are used as alternatives, but their efficacy and safety require further study in paediatric patient populations. The effectiveness of passive prophylaxis is still uncertain. The lack of universally accepted guidelines for diagnosis, treatment, and prevention and the risk of serious side effects highlight the need for continued research. This review evaluates current therapeutic strategies, discusses their efficacy and associated risks, and highlights the need for innovative approaches to improve outcomes for affected neonates.

Criteria for Re-Irradiation.

The treatment options for patients with progressive malignant tumors despite primary radiotherapy are often limited. In selected cases, re-irradiation can be offered. This article concerns the selection criteria and results of re-irradiation for certain types of cancer. This review is based on pertinent publications retrieved by a selective search in PubMed, with particular attention to glioblastoma, head and neck tumors, and prostatic carcinoma. The published studies of re-irradiation are few in number and often of limited methodological quality. For glioblastoma, a randomized controlled trial (RCT) found that adding re-irradiation to treatment with bevacizumab yielded no significant improvement in either median progression-free survival or median overall survival (hazard ratio [HR] 0.73; p = 0.05 and HR 0.98; p = 0.46, respectively). Re-irradiation is a treatment option for locoregional recurrences of head and neck tumors after primary radiotherapy, but it carries a risk of serious side effects. For unresectable recurrences of nasopharyngeal carcinoma, an RCT has shown that hyperfractionated re-irradiation is more effective than normofractionated re-irradiation (overall survival: HR 0.54, p = 0.014). For locally recurrent prostatic carcinoma after radiotherapy, re-irradiation can yield good oncologic outcomes with an acceptable level of urogenital and gastrointestinal side effects (5-year recurrence-free survival: stereotactic body radiation therapy (SBRT), 58%; high dose rate (HDR) brachytherapy, 77%; versus salvage prostatectomy, 72%). RCTs on this topic are lacking. Re-irradiation is a treatment option for selected cancer patients. As the available scientific evidence is limited, multidisciplinary collaboration and participatory decision-making are particularly important.

Effect of repeated intra-articular administration of collagen as a treatment for knee osteoarthritis: a case report.

Intra-articular injections aimed at correcting underlying pathophysiological processes and providing pain relief are essential for managing knee osteoarthritis (KOA). Collagen, the primary component of articular cartilage, has a long half-life, making it a promising candidate for intra-articular injections with a low risk of serious side effects. The first of the two cases in this report involved a woman in her early 70s with a 6-year history of persistent left knee pain. The second case involved a woman in her mid-50 s with a >7-year history of right knee pain. Both patients received hyaluronic acid injections every 6 months, totaling 10 injections over 5 years. They were diagnosed with Kellgren-Lawrence grade 2 KOA. The patients received two 3-mL intra-articular injections of 6% collagen, administered at baseline and 6 months later. Improvements in clinical outcomes, including visual analog scale scores and Western Ontario and McMaster Universities Osteoarthritis Index scores, were observed and maintained in both patients, with no side effects reported. In summary, when collagen injections were administered to these two patients with KOA, clinical improvements lasted approximately 6 months, and repeated treatments demonstrated efficacy and safety similar to the initial course.

A Simple HPLC-DAD Method for the Therapeutic Monitoring of Clozapine and Related Metabolites in Human Plasma and Urine Samples.

Clozapine and its metabolites require close therapeutic monitoring (TDM) in patients due to poor correlation between the administrated doses and resulting plasma concentrations, the narrow therapeutic interval, high inter-individual variability, and the risk of serious side effects once toxic levels are exceeded. The aim of the study was to develop a simple (relatively cheap) LC-UV method for the quantification of clozapine and its metabolites in plasma and urine samples. For sample preparation, liquid-liquid extraction (LLE) in n-octanol was more efficient and less limiting in injection volumes compared to the in-situ formation of SUPRAS. When analyzing urine, an alkalinization step before extraction was required. The proposed method produced linear concentration responses with/without internal standard (IS) for the target analytes, with LLOQs within the targeted range of 50 ppb and %RSD within the acceptable 15% range. Furthermore, sample stability studies proved that pre-extracted samples were stable for the short term at room temperature and long-term when frozen.

Public Views on Whether the Use of Pharmaceutical Neuroenhancements Should Be Allowed.

Some individuals are using drugs to try to enhance cognitive and social-affective functioning and asking physicians for off-label prescriptions for neuroenhancement (e.g., stimulants). Several medical societies released guidance on prescribing neuroenhancers, some of which refer to potential societal effects of neuroenhancement (e.g., distributive justice), besides risks and benefits to users. Which institutions (e.g., medical societies, government, universities) should make decisions on allowing neuroenhancement and whether they should consider potential societal effects are unclear. We examined whether and how much support for allowing pharmaceutical neuroenhancers was influenced by the institution and potential individual and societal effects of neuroenhancers. We conducted a discrete-choice experiment using a constructed representative sample of the US adult public. Multinomial logit models were used to analyze the data. Participants (n = 927) demographically resembled the US population. Risks of serious side effects (OR 0.20, CI 0.18-0.22) and a lack of benefits for users (OR 0.31, CI 0.26-0.38) had the largest negative effect on participants' support for allowing neuroenhancers. A risk of mild side effects had a moderate negative effect on participants' support for allowing neuroenhancers (OR 0.67, CI 0.62-0.74) and the prospect of more meaningful, long-lasting benefits for users a moderate positive effect (OR 1.74, CI 1.61-1.87). Positive or negative effects of neuroenhancers on the average well-being of people in society and on equality had moderate effects on participants' support for allowing neuroenhancers. For example, the odds of participants' support for allowing enhancers with a negative effect on societal well-being were around half (OR 0.45, CI 0.40-0.50) and the odds of allowing enhancers that worsen inequality were approximately 40% lower compared with enhancers without such effects (OR 0.62, CI 0.55-0.71). The odds of participants allowing neuroenhancers were slightly (10%) lower if enhancers reduced users' authenticity (OR 0.90, CI 0.84-0.97). The institution regulating neuroenhancers and neuroenhancers providing users with an unfair advantage did not affect participants' decisions. When presented with both individual and societal considerations, the public seems to support medical societies and other institutions making policy decisions about neuroenhancers based on risks and benefits for users, as well as, but to a lesser extent, effects on equality and societal well-being.

Contemporary review of IgA nephropathy.

IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%-50% of patients progress to kidney failure. The pathogenesis is incompletely understood. Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage. Diagnosis requires a biopsy interpreted by the Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, and C4d staining. Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology. Acceptable surrogate endpoints for therapeutic trials include ongoing proteinuria and rate of eGFR decline. The significance of persisting hematuria remains uncertain. The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric). Immunosuppression should be considered for those at high risk after maximal supportive care. Corticosteroids are controversial with the most positive results observed in Chinese. They carry a high risk of serious side effects. Similarly, mycophenolate may be most effective in Chinese. Other immunosuppressants are of uncertain benefit. Tonsillectomy appears efficacious in Japanese. Active areas of investigation include B-cell inhibition with agents targeting the survival factors BAFF and APRIL and complement inhibition with agents targeting the alternate pathway (Factors B and D), the lectin pathway (MASP-2), and the common pathway (C3 and C5). Hopefully soon, the who and the how of immunosuppression will be clarified, and kidney failure can be forestalled.

Ag-Pt@BSA bimetallic nanoparticles for breast cancer radiation treatment dose augmentation

Cancer has traditionally been treated with surgery and chemotherapy. Radiation therapy (RT) is a branch of oncology based on radiation therapy that can be used alone or in combination with surgery and chemotherapy to achieve local control of breast cancer. Radiosensitizers make tumor cells more responsive and sensitive to ionizing radiation, consequently facilitating production of free radicals and hastening DNA damages. Stages I to III of breast cancer is managed with curative intent with multimodality treatment including radiotherapy. The current cancer therapies in particular radiotherapy have a high risk of serious side effects to the healthy tissues and do not guarantee remission. In response to this challenge, the present study developed bovine serum albumin capped platinum and silver nanoparticles (Ag-Pt@BSA NPs), a bimetallic radiosensitizer, which is a remedy to the aforementioned issue. This research makes use of a nanoplatform that contains two high-Z nanoparticles— Pt and Ag. A variety of methods were used to fully characterize the developed Ag-Pt@BSA NPs. Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), dynamic light scattering (DLS), UV–Vis, X-ray diffractometery (XRD) and energy-dispersive X-ray spectroscopy (EDS) techniques were used to investigate the physical and chemical features of designed bimetallic nanoradiosensitizer. The Ag-Pt@BSA naoradiosensitizer was proven to have successfully prepared by FTIR, XRD and EDX. According to the DLS result, the hydrodynamic size of the NPs is 35.42 nm, and the average diameter in the TEM image is around 7.8 ± 2.6 nm. The initial hydrodynamic size Ag-Pt@BSA was around 35 nm and within the storage time its size remained below 40 nm which indicating the unique colloidal stability of fabricated nanoradiosensitizers. The zeta potential of Ag-Pt@BSA radio-enhancement was determined to be approximately −17.9 mV, providing additional support for the nanoparticles’ colloidal stability. The results showed that the utilization of Ag-Pt@BSA NPs in conjunction with X-ray irradiation could substantially enhance the effectiveness of cancer therapy. This is supported by research, examining a series of in vitro tests including reactive oxygen species generation (ROS), cell viability, apoptosis and colony formation assay. Furthermore, the dosage-dependent radiosensitizing ability of the Ag-Pt@BSA NPs was also observed in the apoptosis and MTT assay against 4 T1 cells by increasing the localized radiation dosage. Ag-Pt@BSA NPs could be a potential radio-enhancer agent against breast cancers and, by extension, other cancers, since it multiplies the therapeutic effect of low-dose radiation while reducing the damage to normal tissues compared to high-dose radiation therapy. Increasing the concentration of Ag-Pt@BSA NPs and the dosage of X-ray irradiation boosted the radiosensitizing capacity in a dose-dependent way.

Systemic isotretinoin in modern clinical guidelines on acne management

Objective — to analyze the medical and technological documents developed on the basis of evidence­based medicine (guidelines, recommendations, consensuses) regarding the treatment of patients with acne of various degrees of severity with systemic retinoids (systemic isotretinoin preparations) dating from 2013 to 2023, as also to focus attention on the pharmacokinetic features of the original systemic isotretinoin according to innovative Lidose technology. Materials and methods. An analysis was conducted of clinical European guidelines (French guideline and those of the European Dermatology Forum), guidelines of the American Academy of Dermatology, the National Institute for Health Protection and Improvement of Medical Care (NICE) of Great Britain in conjunction with the British Dermatology Association and the Canadian Dermatology Association, recommendations of the American Academy of Pediatrics and the French Society of Dermatology, the International Consensus of the Global Alliance for the Improvement of Acne Treatment Outcomes, and consensus­based practical and daily guideline for the management of acne patients. The key words for the search were «acne», «clinical guideline», «consensus», «systemic treatment», «isotretinoin», «isotretinoin­ Lidose». Results and discussion. Clinical guidelines (2013, 2015, 2016) for the management of acne recommend isotretinoin at a dose of 0.5—1 mg/kg/day for 16—24 weeks to a total (cumulative) dose of 120—150 mg/kg for severe acne (nodular/conglobate acne). Low-­dose regimens of isotretinoin (< 0.5 mg/kg/day) have been used with varying degrees of success in the treatment of severe papulopustular/moderate nodular acnе. The International Consensus of the Global Alliance to Improve Acne Treatment Outcomes (2017) supports standard isotretinoin dosing for severe acne until the cumulative dose is reached. At the same time, for patients that have severe papulopustular acne, poor tolerance, risk of serious side effects, or rash regression before the cumulative dose is achieved it is recommended to continue taking the drug until the skin is completely cleansed of acne­elements and for additional 1—2 months. Such provisions are set out in the guidelines developed jointly with the British Association of Dermatologists (2021). According to the American Academy of Dermatology (2023) guidelines, standard isotretinoin or isotretinoin ­Lidose® is recommended for patients for whom isotretinoin is indicated, which is supported by high­quality evidence. Due to the Lidose technology, the soluble fraction of isotretinoin increases, while the insoluble fraction responsible for side effects, on the contrary, decreases. The bioavailability of the drug increases, which allows lowering the daily and course doses of the drug. Conclusions. Systemic isotretinoin has a convincing evidence base as highly effective treatment for severe and moderate forms of acne, providing a sustained therapeutic effect at standard or low doses. In current US guidelines, isotretinoin and isotretinoin­ Lidose® are recommended for the treatment of severe acne, as well as acne that causes psychosocial burden or scarring, or acne that does not respond to treatment with oral or topical therapy. The use of isotretinoin ­Lidose® due to extrabioavailability, high solubility, independence from food intake allows to obtain better clinical results, has a favorable safety profile, characterized by a minimal frequency of adverse reactions.

Potential impact of European Medicines Agency measures to minimise risk of serious side effects on JAKi prescribing and utilisation in the UK.

Janus kinase inhibitors (JAKi) or targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) effectively treat rheumatoid arthritis (RA). However, due to safety concerns, the European Medicines Agency (EMA) published risk minimisation measures limiting JAKi prescription to certain at-risk patients unless no suitable alternative is available. This analysis included patients who had started their first-ever JAKi before EMA measures were published in a large national cohort study to investigate the potential impact of these measures on JAKi prescribing and utilisation in UK. RA patients starting first-ever JAK inhibitor therapy in BSRBR-RA between 13-February-2017 and 31-May-2022 were included. Percentages of patients meeting EMA risk criteria were presented. For at-risk patients, previous number of distinct biological (b) DMARD classes were described. A total of 1341 patients were included, and 80% (N = 1075) met ≥1 EMA risk criterion. Of those who met ≥1 risk criterion, 529 patients (49%) had received JAKi as their first or second b/tsDMARD class, whereas 299 (28%) had received ≥3 prior bDMARD classes. Four-in-five RA patients commencing JAKi before the EMA advisory were considered 'at-risk' with prescribing only advised if there was no suitable alternative. Almost a third of those patients had already received ≥3 bDMARDs classes, and alternative therapies would be very limited for them; meanwhile, suitable alternatives might have existed for the remaining proportion, especially for those who received JAKi as their first or second b/tsDMARD, and re-evaluation of the suitability of their treatment may be needed.

OA05 Potential impact of European Medicines Agency measures to minimise risk of serious side effects on those using JAK inhibitors in the UK

Abstract Background/Aims Janus kinase inhibitors (JAKi) are effective therapies for rheumatoid arthritis (RA). However, concerns about their safety in certain 'at-risk' populations have resulted in risk minimisation measures introduced by European Medicines Agency (EMA) in January 2023, which limits JAKi prescription to certain patient subgroups unless no suitable alternative is available. The potential impact on current and future JAKi use in the UK is unknown. Using a national cohort study of patients who have already started their first JAKi, this analysis aimed to describe the proportion meeting ≥1 of these criteria and therefore may be impacted by these changes. Methods RA patients starting their first-ever JAK inhibitor (tofacitinib, baricitinib, upadacitinib, or filgotinib) therapy in the British Society for Rheumatology RA Biologics Register (BSRBR-RA) before 31st May 2022 (pre-EMA warning) were included. Patients with missing data in any EMA criteria related variables were excluded. Descriptive statistics were used to present patients' characteristics at the start of JAKi. This analysis defined four at-risk criteria assessed at the treatment start: 1) aged ≥65; 2) increased risk of major cardiovascular issues (history of hypertension, hyperlipidaemia, diabetes, ischaemic heart disease, or stroke); 3) current or past smokers; 4) increased risk of cancer (defined as prior cancer). The previous number of distinct biological disease-modifying antirheumatic drugs (bDMARDs) classes was described among those who met the criteria. Results A total of 1,362 patients starting their first JAKi were included, most commonly baricitinib (76%), followed by tofacitinib (16%; see Table). The cohort was 78% female, with an average age of 60. Among them, 28% of patients had received ≥3 prior bDMARDs classes. 80% percent of patients (1,090) met ≥1 EMA risk criterion, with the most common individual criterion current/past smoker (54%). Of those who met ≥1 risk criteria, 645 (59%) met ≥1 EMA risk criterion and 29% had already received ≥3 prior bDMARDs classes. Conclusion A very high proportion of patients, four-in-five, initiating JAKi in UK before the EMA advisory would have fallen into the ‘high-risk' category for whom prescribing would only be advised if no suitable alternatives were available. Whilst almost a third of them had previously received ≥3 different bDMARDs classes, it’s likely that many of them would have suitable alternatives. These data highlight the enormous impact of the recent licensing updates for JAKi class. Disclosure Z. Tian: None. L. Kearsley-fleet: None. J. Galloway: Honoraria; Abbvie, Galapagos, Janssen, Lilly, Novartis, Pfizer, UCB, Vifor. Grants/research support; Abbvie, Galapagos, GSK, Janssen, Pfizer. K. Watson: None. M. Lunt: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; Pfizer, BMS.

Belimumab in a Patient with Systemic Lupus Erythematosus with Juvenile Onset and Steroid-induced Diabetes: Clinical Case

Background. The management of children with systemic lupus erythematosus (SLE) is usually associated with lifelong systemic glucocorticoids administration and, thereby, high risk of serious side effects, including steroid-induced diabetes. The belimumab (B-lymphocyte stimulator inhibitor) administration significantly reduces the glucocorticoids dose, the risk and severity of steroid therapy complications. Clinical case description. The patient was diagnosed with SLE at the age of 16 years. Therapy with hydroxychloroquine and oral glucocorticoid at a high dose (methylprednisolone 56 mg per day) was initiated. Steroid-induced diabetes was diagnosed 1 month after the therapy start; avascular necrosis sites were revealed in 2 months. Mycophenolate mofetil made it possible to achieve the disease activity control. However, the belimumab was prescribed 5 months after diagnosis verification due to continuous insulin requirement and avascular necrosis progression. Conclusion. Belimumab is the only genetically engineered biologic drug approved for the treatment of children with SLE. As a result of its use, it was possible to stabilize the patient's condition quickly (within 3 months), to reduce significantly the dose of oral glucocorticoid, methylprednisolone (from 24 to 8 mg/day), to achieve remission of steroidinduced diabetes with further insulin withdrawal, and also to relieve avascular necrosis clinical symptoms.

Treatment Preferences Among Patients with Renal Cell Carcinoma: Results from a Discrete Choice Experiment.

The treatment landscape for advanced/metastatic renal cell carcinoma (aRCC) has evolved quickly with the introduction of immunotherapies as a first-line treatment option. This study examined the preferences of patients with aRCC to better understand the characteristics of preferred treatments and the tradeoffs patients are willing to make when choosing treatment. An online, cross-sectional survey was conducted in the US from May to August 2022 with adult patients with aRCC. A discrete-choice experiment assessed treatment preferences for aRCC. Attributes were identified through literature review and qualitative interviews and included progression-free survival, survival time, objective response rate, duration of response, risk of serious side effects, quality of life (QoL), and treatment regimen. Survey results from 299 patients with aRCC were analyzed. Patients had a mean age of 55.7 years, were primarily White (50.5%) and were evenly representative of males (49.8%) and females (48.8%). Improvements in all attributes influenced treatment choice. On average, increasing survival time from 10% to 55% was most important, followed by improvements in QoL (ie, from worsens a lot to improves) and improvements to treatment regimen convenience (ie, less frequent infusions). Risk of serious adverse events and increased progression-free time, objective response rate (ORR), and duration of response (DOR) were of lesser importance. In this study, patients highlighted that improving survival time was the most important and that QoL is also an important consideration. Discussions during treatment decision-making may benefit from broader conversations around treatment characteristics, including impacts on QoL and convenience of the regimen.

Exploring the effects of taurolidine on tumor weight and microvessel density in a murine model of osteosarcoma.

Osteosarcoma is the most common malignant primary bone tumor. The prognosis for patients with disseminated disease remains very poor despite recent advancements in chemotherapy. Moreover, current treatment regimens bear a significant risk of serious side effects. Thus, there is an unmet clinical need for effective therapies with improved safety profiles. Taurolidine is an antibacterial agent that has been shown to induce cell death in different types of cancer cell lines. In this study, we examined both the antineoplastic and antiangiogenic effects of taurolidine in animal models of osteosarcoma. K7M2 murine osteosarcoma cells were injected, both intramuscular and intraperitoneal, into 60 BALB/c mice on day zero. Animals were then randomized to receive treatment with taurolidine 2% (800 mg/kg), taurolidine 1% (400 mg/kg), or NaCl 0.9% control for seven days by intravenous or intraperitoneal administration. After 35 days, mice were euthanized, and the tumors were harvested for analysis. Eighteen mice were excluded from the analysis due to complications. Body weight was significantly lower in the 2% taurolidine intraperitoneal treatment group from day 9 to 21, consistent with elevated mortality in this group. Intraperitoneal tumor weight was significantly lower in the 1% (p = 0.003) and 2% (p = 0.006) intraperitoneal taurolidine treatment groups compared to the control. No antineoplastic effects were observed on intramuscular tumors or for intravenous administration of taurolidine. There were no significant differences in microvessel density or mitotic rate between treatment groups. Reduced body weight and elevated mortality in the 2% taurolidine intraperitoneal group suggest that the lower 1% dose is preferable. In conclusion, there is no evidence of antiangiogenic activity, and the antitumor effects of taurolidine on osteosarcoma observed in this study are limited. Moreover, its toxic profile grants further evaluation. Given these observations, further research is necessary to refine the use of taurolidine in osteosarcoma treatment.

Transforming Growth Factor-β-Activated Kinase 1 (TAK1) Alleviates Inflammatory Joint Pain in Osteoarthritis and Gouty Arthritis Preclinical Models.

Joint pain is one of the most commonly reported pain types in the United States. In the case of patients suffering from inflammatory diseases such as osteoarthritis (OA) and gout, persistent inflammation due to long-term overexpression of several key cytokines has been linked to neuronal hypersensitivity and damage within the joints. Ultimately, a subset of patients develop chronic pain. Pharmacologic treatment of joint pain involves the use of analgesics such as acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, as well as intra-articular injections of corticosteroids and hyaluronic acid. However, NSAIDs are short-acting and fail to alleviate severe pain, opioids are generally ineffective at managing chronic pain, and all therapeutic options involve increased risks of serious side effects. We explored the therapeutic and analgesic effects of transforming growth factor-β-activated kinase 1 (TAK1) inhibition in both the monoiodoacetate (MIA) and monosodium urate (MSU) models of joint pain as an innovative strategy for alleviating chronic inflammatory pain. Mechanical allodynia (Von Frey), weight-bearing and histological changes were measured in separate groups of rats receiving either the selective TAK1 inhibitor, HS-276, gabapentin or vehicle. Our data support that TAK1 inhibition effectively prevented the development of mechanical allodynia and differential weight-bearing in the MIA model. In the MSU model of gouty arthritis, treatment with HS-276 significantly reduced mechanical allodynia and knee edema in female rats, but not male rats. Histological evaluation of effected joints in both models showed that HS-276 treatment significantly reduced disease-induced degradation of the joint. Our results support that TAK1 is a critical signaling node in inflammatory joint diseases such as OA and gouty arthritis. Selective pharmacological inhibition significantly attenuated several aspects of the disease, including joint degeneration and mechanical pain. Thus, TAK1 is a novel therapeutic target for the treatment of painful inflammatory joint diseases. This article reports on the therapeutic potential of TAK1 in the treatment of chronic inflammatory joint diseases such as OA and gout. Using the selective TAK1 inhibitor, HS-276, we show the therapeutic and analgesic effects of TAK1 inhibition in two preclinical murine models of inflammatory joint pain.

Update on the efficiency and safety of orally administered nasal decongestants

Nasal congestion leading to obstruction is one of the main symptoms in acute rhinosinusitis (common cold), other upper respiratory infections and allergic rhinitis. The EPOS 2020 guidelines place oral decongestants as an efficient therapy for the relief of nasal obstruction. In Romania, there are more than 50 available nasal decongestants, so it is very important for practitioners from all medical domains to be aware of recent data regarding their effectiveness and safety profile. Recent concerns raised by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regarding the efficacy and safety of pseudoephedrine (PSE) and phenylephrine (PHE) emphasize the need for informed decision-making in prescribing. Notably, there were concerns raised about the association between PSE, reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES). EMA’s safety committee, Pharmacovigilance Risk Assessment Committee (PRAC), recently recommended measures to minimize risks of serious side effects when using medicines containing PSE. PRAC recommends that medicines containing PSE should not be used in patients with severe or uncontrolled hypertension and severe acute or chronic kidney disease or failure. Additionally, PRAC recommends healthcare professionals to counsel patients to discontinue the use of such medicines promptly and seek medical assistance if they experience symptoms suggesting PRES or RCVS, such as sudden onset of severe headache, confusion, vomiting, visual disturbances or seizures. While effectiveness of oral PSE is confirmed by clinical studies, expert consensus is unfavorable to PHE. Both in vitro and in vivo clinical pharmacology data indicate that neither the recommended doses nor higher doses of oral PHE demonstrate efficacy in alleviating symptoms of nasal congestion.

Sociodemographic factors and attitudes associated with Australian parental acceptance of paediatric COVID-19 vaccination

IntroductionThe COVID-19 vaccine coverage among children in countries where COVID-19 vaccines are recommended has been suboptimal. Conflicting information in the media leads to parental anxiety and confusion around COVID-19 vaccination in children. The scepticism expressed by certain experts regarding the importance of COVID-19 vaccines in children has also had a negative impact on parental attitudes towards COVID-19 vaccination. This study aimed to understand parental concerns and preferences for paediatric COVID-19 vaccination, and identify potential vaccination promotion (“nudge”) interventions to optimise paediatric COVID-19 vaccine uptake. MethodsMixed methods including Focus Group Discussions and a Discrete Choice Experiment survey were used. The Discrete Choice Experiment survey design was based on a literature review and the findings of Focus Group Discussions. The study was conducted on a nationally representative sample of parents in Australia. ResultsIn total, 1039 parents participated in the study. Parents showed strong preferences for a COVID-19 vaccine with lower risk of serious side effects and longer protection duration, followed by higher vaccine effectiveness and delivery via oral tablets. Promotion strategies were similarly preferred by parents. Latent class logit analysis identified three groups, interpretable as COVID-19 vaccine “accepters (35.3%)”, “deliberators (31.7%)”, and “rejecters (33.1%)”. The “deliberators” composed of more parents, residing in metropolitan areas, having concerns about vaccine effectiveness, and believing that disease risks outweigh vaccine benefits than the “accepters”. The “rejecters” were more likely to not be vaccinated themselves, and generally have less trust in vaccines than the “accepters”. The “deliberators” and “rejecters” were less likely to be parents aged ≥25 years and complete final year of high school than the “accepters”. ConclusionsParents’ sociodemographic factors and vaccine perceptions were associated with different levels of acceptance toward paediatric COVID-19 vaccination, which may help to better understand how to “nudge” vaccine hesitancy.

Alveolar macrophages in tissue homeostasis, inflammation, and infection: evolving concepts of therapeutic targeting.

Alveolar macrophages (AMs) are the sentinel cells of the alveolar space, maintaining homeostasis, fending off pathogens, and controlling lung inflammation. During acute lung injury, AMs orchestrate the initiation and resolution of inflammation in order to ultimately restore homeostasis. This central role in acute lung inflammation makes AMs attractive targets for therapeutic interventions. Single-cell RNA-Seq and spatial omics approaches, together with methodological advances such as the generation of human macrophages from pluripotent stem cells, have increased understanding of the ontogeny, function, and plasticity of AMs during infectious and sterile lung inflammation, which could move the field closer to clinical application. However, proresolution phenotypes might conflict with proinflammatory and antibacterial responses. Therefore, therapeutic targeting of AMs at vulnerable time points over the course of infectious lung injury might harbor the risk of serious side effects, such as loss of antibacterial host defense capacity. Thus, the identification of key signaling hubs that determine functional fate decisions in AMs is of the utmost importance to harness their therapeutic potential.

Determining patient preferences for the medical management of osteoporosis using conjoint analysis

SummaryWe used conjoint analysis—a method that assesses complex decision making—to quantify patients’ choices when selecting an osteoporosis therapy. While 60% of people prioritized medication efficacy when deciding among treatments, the remaining 40% highly valued factors other than efficacy, suggesting the need for personalized shared decision-making tools.IntroductionIn this study, we aimed to examine patient decision-making surrounding osteoporosis medications using conjoint analysis.MethodsWe enrolled osteoporosis patients at an academic medical center to complete an online conjoint exercise which calculated each patient’s relative importance score of 6 osteoporosis medication attributes (higher = greater relative importance in decision-making). We used latent class analysis to identify distinct segments of patients with similar choice patterns and then used logistic regression to determine if demographics and osteoporosis disease features were associated with latent class assignment.ResultsOverall, 304 participants completed the survey. The rank order of medication attributes by importance score was the following: efficacy at preventing hip fractures (accounted for 31.0% of decision making), mode of administration (17.5%); risk of serious side effects (16.6%); dose frequency (13.9%); efficacy at preventing spine fractures (12.5%); risk of non-serious side effects (8.4%). We found that 60.9% of the cohort prioritized medication efficacy as their top factor when selecting among the therapies. Being a college graduate, having stronger beliefs on the necessity of using medications for osteoporosis, and never having used osteoporosis medicines were the only factors associated with prioritizing medication efficacy for fracture prevention over the other factors in the decision-making process.ConclusionsWhile about 60% of patients prioritized efficacy when selecting an osteoporosis therapy, the remaining 40% valued other factors more highly. Furthermore, individual patient characteristics and clinical factors did not reliably predict patient decision making, suggesting that development and implementation of shared decision-making tools is warranted.

Recommendations for assessing the risk of cardiovascular disease and venous thromboembolism before the initiation of targeted therapies for chronic inflammatory rheumatic diseases.

Patients with rheumatoid arthritis (RA) and other chronic inflammatory rheumatic disorders have increased risk of cardiovascular disease (CVD) and venous thromboembolism (VTE) compared with the general population. Moreover, recent data have raised concerns around a possible increased risk of major CV events (MACE) and VTE in patients treated with JAK inhibitors (JAKi). In October 2022, the PRAC has recommended measures to minimize the risk of serious side effects, including CV conditions and VTE, associated with all approved in chronic inflammatory diseases. To provide an adequate and feasible strategy to evaluate, at the individual level, the risk of CVD and VTE in patients with chronic inflammatory rheumatic diseases. A multidisciplinary steering committee comprised 11 members including rheumatologists, a cardiologist, a hematologist expert in thrombophilia and fellows. Systematic literature searches were performed and evidence was categorized according to standard guidelines. The evidence was discussed and summarized by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk of MACE and VTE in patients with chronic inflammatory rheumatic diseases compared with the general population. Second, the rheumatologist has a central role in the evaluation of the risk of CVD and VTE in patient with chronic inflammatory rheumatic diseases. Third, the risk of MACE and VTE should be regularly assessed in patients with chronic inflammatory rheumatic diseases, particularly before initiating targeted therapies. Eleven recommendations were defined to prevent potentially life-threatening complications of CVD and VTE in patients with chronic inflammatory rheumatic diseases, providing practical assessment of CVD and VTE before considering the prescription of targeted therapies, and especially JAKi. These practical recommendations based on expert opinion and scientific evidence provide consensus for the prevention and the assessment of CVD and VTE.

Fractional microneedle radiofrequency - mechanism of action and assessment of safety, effectiveness in the treatment, and possible side effects based on a review of scientific literature

Introduction and purpose: 
 For all skin types, micro-needle radiofrequency (FMR) can be a safe and effective aesthetic medicine procedure for the treatment of various dermatological and aesthetic conditions. The aim of the study is to present the mechanism of action and assess safety, treatment efficacy, and possible side effects on the basis of a review of the scientific literature. 
 Description of the state of knowledge: 
 FMR uses micro-needles to penetrate the skin to a depth of up to 4.5 mm and deliver radiofrequency current in a fractional manner, producing the controlled fractions of micro-injuries in the dermis, inducing neocollagenesis, neoelastinogenesis, and angiogenesis. FMR has a wide range of positive effects such as skin rejuvenation, skin tightening, facial and body scar remodeling, and hair growth through transdermal collagen induction. 
 Summary: 
 Increasingly, patients are looking for minimally invasive methods of skin tightening and fat remodeling. In response, Aesthetic Medicine has proposed a combination of two techniques, micro-needling and radiofrequency. As more and more studies are showing the effectiveness and efficiency of this procedure, also emphasizing its safety, minimal risk of serious side effects, and ease of use, micro-needle radiofrequency is being proposed as an attractive answer to people's desires for a less invasive method of skin rejuvenation. However, further research in this area is needed to optimize the parameters of the treatment to achieve the best results.