Attempted replication of pharmacogenetic association of variants in PPP1R14C and CCDC148 with aromatase inhibitor-induced musculoskeletal symptoms.

Third-generation aromatase inhibitors (AI) are the standard treatment for patients with hormone receptor positive (HR+) breast cancer. While effective, AI can lead to severe adverse events, including AI-induced musculoskeletal syndrome (AIMSS). Genetic predictors of AIMSS have the potential to personalize AI treatment and improve outcomes. We attempted to replicate results from a previous genome-wide association study that found a lower risk of AIMSS in patients carrying PPP1R14C rs912571 and a higher risk in patients carrying CCDC148 rs79048288. AIMSS data were collected prospectively from patients with HR+ breast cancer prior to starting and after 3 and 6 months of adjuvant AI via the Patient-Reported Outcome Measurement Information System and Functional Assessment of Cancer Therapy-Endocrine Symptom. Germline genotypes for PPP1R14C rs912571 and CCDC148 rs79048288 were tested for a similar association with AIMSS as previously reported via $2 tests. Of the 143 patients with AIMSS and genetics data were included in the analysis. There was no association identified between PPP1R14C rs912571 and AIMSS risk ( P  > 0.05). Patients carrying CCDC148 rs79048288 variant alleles had lower AIMSS incidence in a secondary analysis ( P  = 0.04); however, this was in the opposite direction of the previous finding. The study did not replicate previously reported associations with AIMSS risk for genetic variants in PPP1R14C and CCDC148 and AIMSS risk. Further research is needed to discover and validate genetic predictors of AIMSS that can be used to personalize treatment in patients with HR+ breast cancer.

Risk of adverse reactions associated with inhaled corticosteroids for chronic obstructive pulmonary disease: A meta-analysis.

BACKGROUND: In the majority of current therapeutic regimens for chronic obstructive pulmonary disease (COPD), bronchodilators are coupled with inhaled corticosteroids (ICS) to lower the inflammatory response and improve symptoms. This study aims to evaluate the safety of ICS in the treatment of COPD. METHODS: Randomized controlled trials related to ICS for COPD that were eligible up to 1 June 2023 were searched in PubMed, EMBASE, and Cochrane. We searched and screened eligible studies for the occurrence of total adverse events, cardiovascular events, upper respiratory tract infections (URTI), pneumonia, oral Candida infections, and musculoskeletal disorders, and finally analyzed them by Review Manager 5.4.1. RESULTS: The results showed that ICS increased the incidence of adverse reactions in COPD patients (RR = 1.06, 95% CI: 1.03-1.10, P = .0004); ICS treatment did not increase the risk of cardiovascular events in COPD patients (RR = 0.95, 95% CI: 0.88-1.02, P = .14); ICS increased the incidence of URTI in COPD patients (RR = 1.29, 95% CI: 1.02-1.62, P = .03); ICS increased the incidence of pneumonia in patients with COPD (RR = 2.09, 95% CI: 1.63-2.69, P < .00001); ICS treatment significantly increased the incidence of oral Candida in patients with COPD (RR = 2.96, 95% CI: 1.99-4.41, P < .00001); ICS increased the incidence of musculoskeletal disorders in patients with COPD (RR = 2.87, 95% CI: 1.51-5.45, P = .001). CONCLUSION: ICS does not increase the risk of cardiovascular events in patients with COPD, but it does increase the risk of URTI, pneumonia, oral Candida infections, and musculoskeletal disorders in patients with COPD.

Opioid Prescribing for Chronic Musculoskeletal Conditions: Trends over Time and Implementation of Safe Opioid-Prescribing Practices.

OBJECTIVES: This study aimed (1) to determine the impact of a clinical decision support (CDS) tool on rate of opioid prescribing and opioid dose for patients with chronic musculoskeletal conditions and (2) to identify prescriber and facility characteristics associated with adherence to the Centers for Disease Control and Prevention guideline for prescribing opioids for chronic pain in this population.We conducted an interrupted time series analysis to assess trends in percentage of patients from 2016 to 2020, receiving an opioid and the average opioid dose, as well as the change associated with implementation of the CDS toolkit. We conducted a retrospective cohort study to assess the association between prescriber and facility characteristics and safe opioid-prescribing practices. METHODS: We assessed the impact of the CDS intervention on percent of patients receiving an opioid and average opioid dose (morphine milligram equivalents). We operationalized safe opioid prescribing as a composite score of several behaviors (i.e., prescribing naloxone, initiating a pain agreement, prescribing <90 MME, avoiding extended-release prescriptions for opioid-naïve patients, and avoiding coprescribing opioids and benzodiazepines) and used a hierarchical linear regression model to assess associations between prescriber and facility characteristics and safe opioid prescribing. RESULTS: This CDS intervention had a modest but statistically significant 1.6% reduction on the percent of patients (n = 1,290,746) receiving an opioid (mean: 15% preintervention; 10% postintervention). The average dose of opioid prescriptions did not significantly change. Advanced practice providers and prescribers with higher percentages of patients aged 18 to 64 exhibited safer opioid prescribing, while prescribers with higher percentages of white patients and larger numbers of patients on opioids exhibited less safe opioid prescribing. CONCLUSION: A CDS intervention was associated with a small improvement in percent of patients receiving an opioid, but not on average dose. Clinicians are not prescribing opioids for chronic musculoskeletal conditions frequently, when they do, they are generally adhering to guidelines.

Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry.

OBJECTIVES: To describe the safety of vaccines against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal disease (I-RMD). METHODS: Physician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5 February 2021 to 27 July 2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively. RESULTS: The study included 5121 participants from 30 countries, 90% with I-RMDs (n=4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n=517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying antirheumatic drugs (DMARDs), 42% biological DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD). CONCLUSION: The safety profiles of SARS-CoV-2 vaccines in patients with I-RMD was reassuring and comparable with patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients.

Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management.

Aromatase inhibitors (AIs) are a key component in the chemoprevention and treatment of hormone receptor-positive (HR+) breast cancer. While the addition of AI therapy has improved cancer-related outcomes in the management of HR+ breast cancer, AIs are associated with musculoskeletal adverse effects known as the aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) that limit its tolerability and use. AIMSS is mainly comprised of AI-associated bone loss and arthralgias that affect up to half of women on AI therapy and detrimentally impact patient quality of life and treatment adherence. The pathophysiology of AIMSS is not fully understood though has been proposed to be related to estrogen deprivation within the musculoskeletal and nervous systems. This review aims to characterize the prevalence, risk factors, and clinical features of AIMSS, and explore the syndrome's underlying mechanisms and management strategies.

Evidence-based approaches for the management of side-effects of adjuvant endocrine therapy in patients with breast cancer.

The growing availability of more effective therapies has contributed to an increased survival of patients with breast cancer. In hormone receptor-positive early disease, increased survival is strongly correlated with the use of adjuvant endocrine therapy, but this therapy can cause side-effects that have major consequences in terms of treatment adherence and patients' quality of life. In premenopausal breast cancer survivors, these side-effects might be even more prominent due to the abrupt suppression of oestrogen associated with the most intense endocrine therapies. An important ambition of cancer care in the 21st century is to recover pre-cancer quality of life and emotional and social functions, which is only possible through the mitigation of the side-effects of anticancer treatments. This Review presents a comprehensive summary of the efficacy and safety data of the available interventions (hormonal and non-hormonal pharmacological strategies, non-pharmacological approaches, and complementary and alternative medicine) to control selected side-effects associated with adjuvant endocrine therapy (hot flashes, sexual dysfunction, weight gain, musculoskeletal symptoms, and fatigue), providing updated, evidence-based approaches for their management.

Long-term safety and efficacy of imatinib in pediatric patients with chronic myeloid leukemia: single-center experience from China.

Chronic myeloid leukemia (CML) is a rare disease among children. A retrospective study was conducted from November 2002 to March 2019 at a single institution in China. A total of 36 pediatric CML patients (25 male and 11 female) were enrolled. Median follow-up time was 51 months (range 8-144), and 5-year overall survival and event-free survival were 95.5 ± 4.4% and 88.9 ± 6.0%, respectively. Among the 25 patients whose response to imatinib mesylate (IM) was regularly monitored, 92.0% achieved complete hematologic response at 3 months, 80.0% achieved complete cytogenetic response at 12 months, and 64.0% achieved major molecular response at 18 months after IM therapy. A higher WBC count at diagnosis was associated with failure to achieve early molecular response (EMR). Height standard deviation score after long-term treatment was significantly and positively correlated with age at diagnosis and at the start of IM therapy. Overall, IM therapy was effective in treating pediatric CML, and WBC count at diagnosis might be an ideal predictor of EMR. Moreover, retardation of height and weight growth due to IM tended to affect patients younger than 9 years old at diagnosis, and longitudinal growth might normalize further into treatment.

Aromatase Inhibitor Symptom Management Practices: A Retrospective Study.

PURPOSE: Aromatase inhibitor (AI)-associated symptoms contribute to early therapy discontinuation. Although guidelines exist for management of these symptoms, little is known about the degree to which physicians address symptoms and adhere to the guidelines for treatment. PATIENTS AND METHODS: In this retrospective chart review, women with hormone receptor-positive breast cancer who were prescribed an AI between October 15, 2012, and September 14, 2017, were randomly selected from the institution's cancer registry. Patient medical records were reviewed to identify the prevalence of symptom documentation and management. Documented symptoms were categorized into musculoskeletal, vasomotor, and urogenital. Symptom treatment guidelines were compiled from the National Comprehensive Cancer Network (NCCN) and the American Cancer Society/American Society of Clinical Oncology (ACS/ASCO). Treatments were categorized as either meeting or not meeting the guidelines. Among patients with symptoms recorded, chi-square tests and time-to-event models were used to examine factors associated with treatment and factors associated with guideline-based treatment. RESULTS: Among 179 women prescribed an AI, 82% had at least one symptom and 46% had multiple symptoms. Of the 147 women with any documented symptom, 97 (66%) received some form of symptom-palliating treatment. Seventy-seven patients (52%) received guideline-based treatments or guideline-based treatments in combination with non-guideline-based treatments. There were no differences in receipt of treatment overall (ie, guideline based or non-guideline based) for either vasomotor or musculoskeletal symptoms by age, race, or stage. CONCLUSION: Although 82% of patients had symptoms documented in their medical records, just over half of those patients received guideline-based treatment.

Aromatase Inhibitors-Induced Musculoskeletal Disorders: Current Knowledge on Clinical and Molecular Aspects.

Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren't side effect-free; frequent adverse events involve the musculoskeletal system, in the form of bone loss, AI-associated arthralgia (AIA) syndrome and autoimmune rheumatic diseases. In this narrative review, we reported the main clinical features of these three detrimental conditions, their influence on therapy adherence, the possible underlying molecular mechanisms and the available pharmacological and non-pharmacological treatments. The best-known form is the AIs-induced osteoporosis, whose molecular pathway and therapeutic possibilities were extensively investigated in the last decade. AIA syndrome is a high prevalent joint pain disorder which often determines a premature discontinuation of the therapy. Several points still need to be clarified, as a universally accepted diagnostic definition, the pathogenetic mechanisms and satisfactory management strategies. The association of AIs therapy with autoimmune diseases is of the utmost interest. The related literature has been recently expanded, but many issues remain to be explored, the first being the molecular mechanisms.

Health status among greenhouse workers exposed to different levels of pesticides: A genetic matching analysis.

(1) Objective: Greenhouse workers are considered a special occupational group who are exposed to more toxic and harmful substances than ordinary farmers. The health problem of this group is a public health problem that warrants attention. Taking greenhouse workers in Ningxia, China, as the research sample, this study analyzed the health risk to practitioners posed by the greenhouse working environment. (2) Method: To analyze the relationship between pesticide exposure and the health of greenhouse workers, the genetic matching method was used to exclude the influence of covariates on the results. (3) Results: The results showed a statistical significance regarding the prevalence of cardiovascular diseases (CVD), skeletal muscle system diseases (SMSD) and digestive diseases between the different exposure groups. Researching the disease symptoms found that different levels of exposure to pesticides in greenhouses could cause multisystem and multisymptom discomfort. In addition to some irritant symptoms such as eye itching, itching, and sneezing, there were also differences in terms of the frequency of discomfort such as back pain, a decline in sleep quality, memory loss, joint pain, swelling and weakness, upper abdominal pain and flatulence, in the different exposure groups. (4) Conclusion: Different levels of exposure to pesticides in greenhouses may be one of the risk factors for practitioners to suffer from various systemic diseases, affecting their health and work efficiency. This hazard is manifested not only in some acute irritant symptoms but also in chronic diseases due to long-term exposure.

An MRI study of immune checkpoint inhibitor-induced musculoskeletal manifestations myofasciitis is the prominent imaging finding.

OBJECTIVE: To assess: (i) the prevalence, and clinical and imaging characteristics of immune checkpoint inhibitor (ICI)-induced musculoskeletal immune-related adverse events (ir-AEs) in a prospective manner and (ii) whether serum levels of cytokines associated with the Th1/Th2/Th17 response are differentially expressed in patients with and without musculoskeletal Ir-AEs. METHODS: All patients treated with ICI who developed musculoskeletal manifestations were referred to the Rheumatology Department, and an MRI of the involved area(s) was performed. RESULTS: During the study period, a total of 130 patients were treated with ICIs. Of these, 10 (7.7%) developed ICI-induced Ir-AEs. The median time from ICI treatment since development of symptoms was 2.5 months. Three different patterns of musculoskeletal manifestations were found: (i) prominent joint involvement (n = 3); (ii) prominent 'periarticular' involvement (n = 4). These patients had diffuse swelling of the hands, feet or knees. MRI depicted mild synovitis with more prominent myositis and/or fasciitis in the surrounding tissues in all cases; (iii) myofasciitis (n = 3). Clinically, these patients presented with pain in the knee(s)/thigh(s), whereas MRI depicted myofasciitis of the surrounding muscles. Patients with musculoskeletal ir-AEs had significantly higher oncologic response rates compared with patients not exhibiting musculoskeletal ir-AEs (50% vs 12.5%, respectively, P = 0.0016). Cytokine levels associated with a Th1/Th2/Th17 response were similar between patients with and without musculoskeletal ir-AEs. Overall, symptoms were mild/moderate and responded well to treatment, with no need for ICI discontinuation. CONCLUSION: In our cohort, ICI-induced musculoskeletal manifestations developed in 7.7% of patients. Imaging evidence of myofasciitis was found in most patients, indicating that the muscle/fascia is more frequently involved than the synovium.

'Have we missed reporting adverse drug reactions under Revised National TB Control Programme?' - A mixed method study in Bengaluru, India.

OBJECTIVE: Prompt identification, reporting and management of ADRs during anti tuberculosis treatment can ensure better compliance and treatment outcomes. The study was conducted to identify the gaps and associated factors in reporting of ADRs under RNTCP; assess knowledge, attitude and practice of RNTCP staff regarding pharmacovigilance programme and explore the barriers in reporting of ADRs from provider's perspective. METHODS: Mixed method research with sequential explanatory design was carried out in Tuberculosis Units of RNTCP administrative district of Bangalore city during July to December 2017. Quantitative study was carried out among 222 patients on intensive phase of Category I and Category II DOTS to study the incidence, severity and causality of ADRs; and records of these patients were analysed for gaps in reporting. Knowledge, attitude and practice (KAP) regarding recording and reporting aspect of pharmacovigilance programme was assessed among RNTCP staff. As part of the qualitative study, focus group discussion was carried out among RNTCP staff to study barriers for reporting ADRs from the provider's perspective. RESULTS: Record analysis at the time of recruitment showed documentation of ADRs in only five patients. Subsequent analysis of patient records during the middle and end of the intensive phase (IP) did not show documentation of any ADRs. Simultaneously interviews with patients revealed 116 (52.2%), 72 (32.4%) and 53 (23.8%) patients reported one or more symptoms of ADRs. The commonest ADR symptom reported were fatigability and gastrointestinal symptoms followed by musculoskeletal symptoms. KAP among 25 RNTCP staff showed that 96% of them felt reporting of ADRs was necessary and 92% reported the ADRs to their seniors, however 12% were scared to report. The main reason expressed for non-reporting was 'managing ADRs is more important than reporting' (52%). Also, 32% felt the need for retraining of staff on reporting and documentation. Barriers to reporting of ADRs were both health-system related like insufficient training and inadequate guidelines provided to RNTCP staff and patient-related factors like lack of awareness and reluctance to report ADRs. CONCLUSION: Successful implementation of RNTCP and achievement of TB elimination requires provision of adequate information regarding ADRs to patients and intense follow-up and probing at each contact by programme staff to effectively manage ADRs.

The effect of exercise on aromatase inhibitor-induced musculoskeletal symptoms in breast cancer survivors :a systematic review and meta-analysis.

BACKGROUND: Evidence is mixed regarding the effect of exercise programs on improving musculoskeletal symptoms and quality of life. Previous meta-analyses have not focused specifically on the musculoskeletal symptoms. Therefore, this meta-analysis aimed to evaluate the effect of exercise on these outcomes in breast cancer survivors taking aromatase inhibitors. METHODS: PubMed, CINAHL, EMBASE, Web of Science, Wan Fang, CNKI, VIP, and CBM were searched for randomized control trials or quasi-experimental studies from the establishment of the database to May 2019. Studies comparing exercise programs with usual care among breast cancer survivors taking aromatase inhibitors were included. The primary outcome was the degree of musculoskeletal symptoms, as assessed by scores of pain, stiffness, and grip strength. The secondary outcome was the total quality of life score. RESULTS: A total of 9 studies involving 743 participants were included. Exercise programs were more effective than usual care in improving musculoskeletal symptoms among breast cancer patients taking AIs. The subgroup scores of pain (SMD = -0.46, 95% CI -0.79 to -0.13, P = 0.006), stiffness (SMD = -0.40, 95% CI -0.71 to -0.08, P = 0.01), and grip strength (SMD = 0.43, 95% CI 0.16 to 0.71, P = 0.002) benefited from exercise interventions. Similar effects were found for the quality of life scores (SMD = 2.24, 95% CI 0.28 to 4.21, P = 0.03). CONCLUSIONS: Results indicate that exercise relieves musculoskeletal symptoms and improves quality of life, which can be used to motivate patients to exercise actively under professional guidance. Due to a small sample size, further research is required to ensure the effectiveness of exercise on musculoskeletal symptoms and quality of life.

Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab.

We investigated risk factors for immune-related adverse events (irAEs) in patients treated with anti-programmed cell death protein1 antibody pembrolizumab. A retrospective medical record review was performed to identify all patients who received at least one dose of pembrolizumab at Samsung Medical Center, Seoul, Korea between June 2015 and December 2017. Three hundred and ninety-one patients were included in the study. Data were collected on baseline characteristics, treatment details, and adverse events. Univariate and multivariate logistic regression models were used to identify risk factors for irAEs. Sixty-seven (17.1%) patients experienced clinically significant irAEs; most commonly dermatologic disorders, followed by pneumonitis, musculoskeletal disorders, and endocrine disorders. Fourteen patients (3.6%) experienced serious irAEs (grade ≥ 3). Most common serious irAEs were pneumonitis (2.3%). Four deaths were associated with irAEs, all of which were due to pneumonitis. In multivariate regression analysis, a higher body mass index (BMI) and multiple cycles of pembrolizumab were associated with higher risk of irAEs (BMI: odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01-1.16; pembrolizumab cycle: OR 1.15, 95% CI 1.08-1.22). A derived neutrophil-lymphocyte ratio (dNLR) greater than 3 at baseline was correlated with low risk of irAEs (OR 0.37, 95% CI 0.17-0.81). Our study demonstrated that an elevated BMI and higher number of cycles of pembrolizumab were associated with an increased risk of irAEs in patients treated with pembrolizumab. Additionally, increased dNLR at baseline was negatively correlated with the risk of developing irAEs.

Toxicity of cadmium in musculoskeletal diseases.

Epidemiological studies have reported that exposure to toxic metals like cadmium (Cd) may promote the development of musculoskeletal diseases, such as osteoporosis, rheumatoid arthritis (RA), and osteoarthritis (OA), among others. The objective of this review is to summarize the molecular mechanisms of inflammation and oxidative stress activated by Cd at the bone level, particularly in osteoporosis, RA, and OA. Cadmium can increase bone resorption, affect the activity of osteoclasts and calcium (Ca) absorption, and impair kidney function, which favors the development of osteoporosis. In the case of RA, Cd interferes with the activity of antioxidant proteins, like superoxide dismutase (SOD) and catalase (CAT). It also promotes an inflammatory state, inducing the process of citrullination, which affects the proteins of immune response. On the other hand, accumulation of Cd in the tissues and blood of smokers has been related to the development of some musculoskeletal diseases. Therefore, knowing the negative impact of Cd toxicity at the articular level can help understand the damage mechanisms it produces, leading to the development of such diseases.

Assessment of Occupational Safety and Hygiene Perception among Afro-Caribbean Hair Salon Operators in Manchester, United Kingdom.

Because of exposure to a number of potential health hazards within the work environment, hairstylists experience occupational diseases that include occupational asthma, skin conditions and musculoskeletal diseases. The paucity of studies assessing occupational safety and hygiene management among Afro-Caribbean hair salon operators in the UK promoted the study. QualtricsTM was used to assess the participants' perception of exposure to hair products and their personal safety and hygiene knowledge, attitudes, awareness, and risk perceptions at work. In five salons, indoor air quality was monitored over one working week for selected environmental pollutants: temperature, humidity, CO, CO2 and Total Volatile Organic Compounds (TVOCs) using a GrayWolf Direct Sense Indoor Air Quality-IAQ (IQ-610). The use of unflued gas heating to raise the indoor temperature was common among the salons' operators which explains the high carbon monoxide readings recorded. Itchy eyes and nose (44.4%) shoulder, neck and back pain (39.2%) were frequently reported. Age-stratified analysis of reported occupational ailments showed participants within an age bracket of 31-35 reported allergies (24%) and itchy eyes and nose (19.1%) as the most common of occupational ailments. Respiratory, skin and musculoskeletal symptoms ranked as major occupational ill-health experiences among the study population. The study outcome demonstrated that the type of activity and the hair products used play an important role in the level of pollutants in the working environment. The substitution of the more harmful hair products with safer alternatives is needed, as is the encouragement of health surveillance.