A review of chemotherapeutic drugs-induced arrhythmia and potential intervention with traditional Chinese medicines.

Significant advances in chemotherapy drugs have reduced mortality in patients with malignant tumors. However, chemotherapy-related cardiotoxicity increases the morbidity and mortality of patients, and has become the second leading cause of death after tumor recurrence, which has received more and more attention in recent years. Arrhythmia is one of the common types of chemotherapy-induced cardiotoxicity, and has become a new risk related to chemotherapy treatment, which seriously affects the therapeutic outcome in patients. Traditional Chinese medicine has experienced thousands of years of clinical practice in China, and has accumulated a wealth of medical theories and treatment formulas, which has unique advantages in the prevention and treatment of malignant diseases. Traditional Chinese medicine may reduce the arrhythmic toxicity caused by chemotherapy without affecting the anti-cancer effect. This paper mainly discussed the types and pathogenesis of secondary chemotherapeutic drug-induced arrhythmia (CDIA), and summarized the studies on Chinese medicine compounds, Chinese medicine Combination Formula and Chinese medicine injection that may be beneficial in intervention with secondary CDIA including atrial fibrillation, ventricular arrhythmia and sinus bradycardia, in order to provide reference for clinical prevention and treatment of chemotherapy-induced arrhythmias.

Drug-induced osteoporosis and mechanisms of bone tissue regeneration through trace elements.

Osteoporosis is associated with an imbalance in bone formation, with certain drugs used in disease treatment being implicated in its development. Supplementation with trace elements may contribute to bone regeneration, offering an alternative approach by enhancing bone mineral density (BMD) and thereby thwarting the onset of osteoporosis. This review aims to assess the mechanisms through which trace elements such as copper (Cu), iron (Fe), selenium (Se), manganese (Mn), and zinc (Zn) are linked to increased bone mass, thus mitigating the effects of pharmaceuticals. Our findings underscore that the use of drugs such as aromatase inhibitors (AIs), proton pump inhibitors (PPIs), antiretrovirals, glucocorticoids, opioids, or anticonvulsants can result in decreased BMD, a primary contributor to osteoporosis. Research indicates that essential elements like Cu, Fe, Se, Mn, and Zn, through various mechanisms, can bolster BMD and forestall the onset of the disease, owing to their protective effects. Consequently, our study recommends a minimum daily intake of these essential minerals for patients undergoing treatment with the aforementioned drugs, as the diverse mechanisms governing the effects of trace elements Cu, Fe, Mn, Se, and Zn facilitate bone remodeling.

High-dose vitamin D to attenuate bone loss in patients with prostate cancer on androgen deprivation therapy: A phase 2 RCT.

BACKGROUND: Androgen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT-induced bone loss are limited. METHODS: A phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high-dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25-hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual-energy x-ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured. RESULTS: The HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low-dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low-dose group (p = .06). Stratified analyses showed that, for those with baseline 25-hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low-dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N-terminal telopeptide of type 1 collagen (p < 0.01) and C-terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups. CONCLUSIONS: HDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25-hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.

The Use of Herbal Medicines Among Cancer Patients.

Background and objective The use of herbal medicines has been increasing among cancer patients, as a way to control cancer and treatment-related symptoms; however, many patients are reluctant to disclose this use to their medical practitioners. The fact that oncological treatments have a narrow therapeutic margin, associated with the lack of control and clinical evidence concerning these supplements, makes medication-herbal interactions a reality. These interactions could lead to increased toxicity or a decreased effectiveness of oncological treatment. In light of this, we aimed to assess the prevalence of herbal medicine use in a patient population at a Portuguese central hospital: Centro Hospitalar Lisboa Ocidental. Materials and methods Patients with breast, prostate, or colorectal cancer diagnoses between August 2022 and July 2023 and undergoing oncological treatment were included. Data were collected through a survey during their first appointment, as well as by consulting the patients' clinical files. An interaction evaluation was carried out to assess potential medication-herbal interactions. Finally, a statistical analysis was performed to identify predictive factors for the use of herbal medicines. Results Among the 65 patients included in the study, 52% were females, and the median age of the cohort was 65 years. Breast cancer was the most prevalent diagnosis and the majority of the patients were undergoing palliative treatment. We found that 46% of patients used herbal medicines regularly: to strengthen the immune system, detoxification of the body, and treat insomnia and constipation. A medication-herbal interaction was found in 37% of the cases, the most frequent being doxorubicin-vitamin C, through an antioxidant mechanism. The univariable analysis failed to show any predictive factors associated with the use of herbal medicines. Conclusions This study sheds light on herbal medicine use among cancer patients and the reality of medication-herbal interactions. There is an urgent need for further research and evidence-based medical protocols regarding herbal medicine use, especially in complex cases such as cancer patients, to provide better and safer care.

CAR­T cell therapy: A breakthrough in traditional cancer treatment strategies (Review).

Chimeric antigen receptor (CAR)­T cell therapy is an innovative approach to immune cell therapy that works by modifying the T cells of a patient to express the CAR protein on their surface, and thus induce their recognition and destruction of cancer cells. CAR­T cell therapy has shown some success in treating hematological tumors, but it still faces a number of challenges in the treatment of solid tumors, such as antigen selection, tolerability and safety. In response to these issues, studies continue to improve the design of CAR­T cells in pursuit of improved therapeutic efficacy and safety. In the future, CAR­T cell therapy is expected to become an important cancer treatment, and may provide new ideas and strategies for individualized immunotherapy. The present review provides a comprehensive overview of the principles, clinical applications, therapeutic efficacy and challenges of CAR­T cell therapy.

Efficacy of Yisui granule on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/ß-catenin signaling pathway.

OBJECTIVE: To unmask the underlying mechanisms of Yisui granule (, YSG) for the treatment of Myelodysplastic syndromes (MDS). METHODS: Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety, assess its effect on overall survival (OS), and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5 (sFRP5) gene and suppressing Wnt/ß-catenin pathway. Bisulfite amplicon sequencing was applied to detect the level of methylation of the sFRP5 gene; western blotting, immunofluorescence staining, and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1 (DNMT1), sFRP5, and other Wnt/ß-catenin pathway-related mRNA and protein expression. RESULTS: The results showed that high-dosage YSG exerted an anti-tumor effect similar to that of decitabine, improved OS, and reduced long-term adverse effects in the long term. Mechanically, YSG reduced the expression of DNMT1 methyltransferase, decreased the methylation, and increased the expression of the Wnt/ß-catenin pathway antagonist-sFRP5. Furthermore, components of the Wnt/ß-catenin pathway, including Wnt3a, ß-catenin, c-Myc, and cyclinD1, were down-regulated in response to YSG, suggesting that YSG could treat MDS by demethylating the sFRP5 gene and suppressing the Wnt/ß-catenin pathway. CONCLUSIONS: Our findings demonstrated that YSG could be used alone or in combination with decitabine to improve outcomes in the MDS animal model, providing an alternative solution for treating MDS.

A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

Low-level red-light therapy for myopia control in children: A systematic review and meta-analysis

Abstract Introduction Low-Level Red-Light (LLRL) Therapy is a safe and natural way to promote healing and reduce inflammation in the body. When it comes to treating myopia in children, LLRL therapy is recent, and its efficacy and safety still are not clear. Methods A systematic review and meta-analysis of the literature for LLRL was conducted in accordance with the PRISMA guidelines on November 5, 2022. Databases, including PUBMED, Cochrane Library, Web of Science, and Embase were queried. A meta-analysis of random effects was conducted. Inclusion criteria included Randomized Controlled Trials (RCTs) or observational studies where LLRL therapy was used in children (3‒15 years old) with myopia. Exclusion criteria were studies with other ocular abnormalities. Efficacy was evaluated through the mean change in Axial Length (AL) and cycloplegic Spherical Equivalent Error (SER), while safety was evaluated by monitoring adverse effects. Results A total of 5 final studies were included (4 RCTs, and 1 observational), in which 685 total patients were analyzed. The mean age was 9.7 ± 0.66 years, with 48,2% female patients. The number of eyes in the LRLL arm is 714 and, in the control, arm is 656. LLRL showed better results in SER and AL mean change (OR = 0.58; 95% CI 0.33 to 0.83; p < 0.00001, and MD -0.33; 95% CI -0.52 to -0.13; p = 0.001, respectively), in comparison to the control group. There was no significant difference in adverse effects between groups (MD = 5.76; 95% CI 0.66 to 50.14; p = 0.11). Conclusion LLRL therapy is a non-invasive, effective, and safe short-term treatment option; however, long-term evaluation, particularly in comparison to other therapies, requires additional investigation.

The impact of the extent of surgery on late adverse effects following cytoreductive surgery and HIPEC.

AIM: To investigate the impact of the surgical extent on late adverse effects (LAE) following cytoreductive surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). METHOD: A prospective cohort study including patients undergoing CRS + HIPEC due to peritoneal metastases from gastrointestinal tumour origin. From 2006 through 2019, consecutive patients treated with CRS + HIPEC were followed at 3, 6 and 12 months, and LAEs were assessed using the symptom scales and items from the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30). Surgical extent was categorized into three groups (major, intermediate, minor) based on peritonectomy procedures and colorectal resections performed as part of CRS. EORTC data were analysed using a linear mixed effects regression model adjusted for age, gender, origin of tumour and comorbidity. RESULTS: In total, 257 patients who responded to at least one questionnaire during the follow-ups were included. Only diarrhoea symptoms were positively associated with surgical extent (mean differences: major vs. minor: 8.4 (-0.5; 17.2) (p = 0.06) and major vs. intermediate: 10.9 (3.8; 18.0) (p = 0.00)). Additionally, diarrhoea symptoms persisted throughout the study period and did not change over time (mean difference 12-3 months: -3.6 (-9.1; 1.7) (p-value = 0.18)). Overall, the levels of different symptom scales (fatigue, nausea and vomiting, pain, dyspnoea, and appetite loss) significantly decreased from 3 to 12 months. CONCLUSION: Patients undergoing extensive CRS suffer from persistent impaired gastrointestinal function in terms of diarrhoea compared patients undergoing to less extensive surgery. Attention should be directed at detecting such LAE and to guide patients accordingly.

Hepatotoxicity due to dietary supplements: state-of-the-art, gaps and perspectives.

Food supplements are products intended to complement the normal diet and consist of concentrated sources of nutrients or other substances with a nutritional or physiological effect. Although they are generally considered safe if the manufacturer's recommendations are followed, many of them have shown hepatotoxic properties. This can cause many diseases (e.g. steatohepatitis and cirrhosis) characterized by progressive damage and malfunction of the liver that in the long term can lead to death. A review of the literature was carried out to elucidate which dietary supplements have been associated with cases of hepatotoxicity in recent years, with emphasis on those relevant to the consumer and the new trends (e.g. cannabidiol). It has been reported that the supplements described as hepatotoxic are mainly of botanical origin (e.g. green tea or turmeric) and those used in sports (mainly anabolic androgenic steroids). There is a great variability of compounds described as causing liver damage, although sometimes it is not possible to identify them, because they are contaminants or adulterants of the products. In addition, the prevalence of toxic effects after the administration of supplements is difficult to define due to underreporting and the lack of specific studies. Globally regarding hepatotoxicity of dietary supplements, there is a paucity of well-conducted clinical trials on the efficacy of these compounds and the frequency of related liver damage, as the use of these products is largely uncontrolled.

Development of neutropenic sepsis during the eradication phase with co-trimoxazole in patients with melioidosis: two case reports.

Introduction: Burkholderia pseudomallei is the bacterium that causes melioidosis. It is mostly a tropical disease, and particularly common in Southeast Asia and northern Australia. The intensive intravenous phase and the oral prolonged eradication phase are the two phases of melioidosis treatment. The current recommended treatment for melioidosis eradication is oral co-trimoxazole (TMP/SMX). Case report: Two patients were diagnosed with B. pseudomallei bacteremia without a focus and were treated with oral TMP/SMX with folic acid during the eradication phase. Both presented with neutropenic sepsis with pneumonia and pyelonephritis at days 48 and 45 following TMP/SMX 320/1600 mg q12h (4 tablets) and in both of them, the folic acid compliance was poor. One patient died and the other survived following intensive treatment for neutropenia. At the presentation following neutropenic sepsis among both patients, the red blood cells and platelets were within normal limits. Both patients were on a high dose of TMP/SMX, as both were within 40-60 kg of body weight the ideal TMP/SMX dose would be 240/1200 mg q12h (3 tablets). Pancytopenia caused by TMP/SMX can frequently develop gradually over time. Alternately, it can develop rapidly and swiftly escalate to fulminant sepsis, disseminated intravascular coagulation, and fast hemolysis. However, the development of isolated neutropenia is rarely described in the literature. Conclusions: Prolonged use of TMP/SMX is important to eradicate B. pseudomallei and always the possibility of rare adverse effects has to be considered. Always weight-based TMP-SMX dosing has to be encouraged with need to ensure the compliance of folic acid. During the eradication phase, continuous monitoring of blood cell lines with weekly full blood count would be essential to identify neutropenia in advance.

Case Report: Limbic encephalitis following treatment with durvalumab for small-cell lung cancer.

Background: Durvalumab is an immune checkpoint Inhibitor (ICIs) that is used in the treatment of malignant tumors, such as lung cancer and melanoma. ICIs are associated with immune-related adverse events including autoimmune encephalitis, although both paraneoplastic phenomena and ICI treatment may lead to autoimmunity. Case presentation: We describe a 72-year old male patient with small-cell lung cancer, who during adjuvant treatment with Durvalumab developed GABABR1 and GAD65 antibodies and both diabetes and autoimmune limbic encephalitis. Because he was followed prospectively as part of a treatment study, we had access to repeated serum samples and cognitive assessments over time prior to developing encephalitis and diabetes, in addition to later assessments. A high titer of GABABR1 antibodies appeared early, while GAD65 antibodies appeared later with a lower titer in parallel with the development of diabetes. As he subsequently developed clinical signs of encephalitis, verified by EEG and brain MRI, he also had CSF GABABR1 antibodies. Durvalumab was discontinued and steroid treatment with subsequent plasmapheresis were started, resulting in reduction of both CSF and serum antibody levels. Clinical signs of encephalitis gradually improved. Conclusion: This case illustrates the importance of being aware of possible serious autoimmune adverse reactions, including neurological syndromes such as encephalitis, when treating patients with high risk of para-neoplasia with ICIs. In addition, the case shows the development of autoantibodies over time.

Lung Cancer Screening: Low-Dose Thoracic Computed Tomography Performed in a High-Risk Portuguese Population.

INTRODUCTION: The Urgeiriça mines were once the main uranium producer in Portugal. The aim of this study was to estimate the benefit of low-dose chest computed tomography (LDCT) for lung cancer screening in former miners that were considered as being at high-risk. METHODS: A subgroup of former miners of the Uranium National Company exposed to uranium and with a smoking load greater than 20 pack-years, agreed to perform a LDCT. The Fleischner Society Guidelines were used to classify the nodules and establish follow-up. RESULTS: Initially, 265 former employees of the Uranium National Company were included. The mean time of employment was 15 (0 - 45) years. The non-smokers represented 50.9% and 30.2% were ever smokers; the remaining chose not to respond. One diagnosis of lung cancer was initially made. In the second phase, a subgroup of 66 former miner underwent a LDCT, 37 of whom presented pulmonary nodules. Most computed tomography (CT) scans revealed one single nodule (n = 13) and the mean size was 5 (1 - 16) mm. A suspicious 16 mm spiculated nodule was evaluated with PET/CT, and percutaneous and surgical biopsies, ultimately revealing a benign lesion. CONCLUSION: The data highlights the importance of lung cancer screening in high-risk populations. This was, to the best of our knowledge, the first study performed in Portugal and can act as a bridge towards a wider implementation in the country.

Is acupuncture safe in the ICU? A systematic review and meta-analysis.

Background and purpose: The safety of interventions for critically ill patients is a crucial issue. In recent years, several studies have treated critically ill patients with acupuncture. However, the safety of acupuncture in this setting remains to be systematically measured. Methods: In May 2022, the electronic databases of PubMed and the Cochrane Library were searched for studies comparing acupuncture interventions to control interventions in critically ill patients. Study outcomes examined the incidence of severe adverse events (AEs), minor AEs, adverse reactions, ICU stays, and 28-day mortality. Results: A total of 31 articles were analyzed, and no serious AEs related to acupuncture treatment were identified. No significant differences were found between the groups in the meta-analysis of minor AEs (risk ratio [RR] 5.69 [0.34, 96.60], P = 0.23, I2 = 76%). A reduced risk in the incidence of adverse reactions following acupuncture intervention was evidenced (RR 0.33 [0.22, 0.50], P = 0.00001, I2 = 44%). The patients in the acupuncture arm spent significantly less time in the intensive care unit (ICU) (Mean difference -1.45 [-11.94, -10.97], P = 0.00001, I2 = 56%) and also exhibited lower 28-day mortality rates (odds ratio 0.61 [0.48, 0.78], P = 0.0001, I2 = 0%). Conclusion: There is no evidence to indicate a higher risk of severe or minor AEs in patients who receive acupuncture. Acupuncture demonstrated favorable results in both ICU stay and 28-day mortality measurements, in addition to presenting with fewer adverse reactions compared to routine ICU care. However, the low certainty of the evidence resulting from a high risk of bias in the included studies merits substantial consideration, and further research is still warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=142131, identifier: CRD42020142131.

Conjugated linoleic acid (CLA) as a functional food: Is it beneficial or not?

Conjugated linoleic acid (CLA) has attracted great attention in recent years as a popular class of functional food that is broadly used. It refers to a group of geometric and positional isomers of linoleic acid (LA) with a conjugated double bond. The main natural sources of CLA are dairy products, beef and lamb, whereas only trace amounts occur naturally in plant lipids. CLA has been shown to improve various health issues, having effects on obesity, inflammatory, anti-carcinogenicity, atherogenicity, immunomodulation, and osteosynthesis. Also, compared to studies on humans, many animal researches reveal more positive benefits on health. CLA represents a nutritional avenue to improve lifestyle diseases and metabolic syndrome. Most of these effects are attributed to the two major CLA isomers [conjugated linoleic acid cis-9,trans-11 isomer (c9,t11), and conjugated linoleic acid trans-10,cis-12 isomer (t10,c12)], and their mixture (CLA mix). In contrast, adverse effects of CLA have been also reported, such as glucose homeostasis, insulin resistance, hepatic steatosis and induction of colon carcinogenesis in humans, as well as milk fat inhibition in ruminants, lowering chicken productivity, influencing egg quality and altering growth performance in fish. This review article aims to discuss the health benefits of CLA as a nutraceutical supplement and highlight the possible mechanisms of action that may contribute to its outcome. It also outlines the feasible adverse effects of CLA besides summarizing the recent peer-reviewed publications on CLA to ensure its efficacy and safety for proper application in humans.

Efficacy and safety of Tripterygium wilfordii multiglucoside for idiopathic membranous nephropathy: a systematic review with bayesian meta-analysis.

Background: Currently, the optimal therapy plan for idiopathic membranous nephropathy (IMN) remains controversial as there has been no comprehensive and systematic comparison of therapy plans for IMN. Therefore, in this study, a Bayesian meta-analysis was used to systematically evaluate the clinical efficacy and safety of various intervention plans involving traditional Chinese medicine TWM in the treatment of IMN. Methods: An electronic search in 7 databases was conducted from their inception to August 2022 for all published randomized controlled trials (RCTs) of various intervention plans for IMN. Network meta-analysis (NMA) was performed by using software R, and the surface under the cumulative ranking area (SUCRA) probability curve was plotted for each outcome indicator to rank the efficacy and safety of different intervention plans. Results: A total of 30 RCTs were included, involving 13 interventions. The results showed that (1) in terms of total remission (TR), ① GC + CNI + TWM was the best effective among all plans, and the addition and subtraction plan of CNI + TWM was the best effective for IMN; ② All plans involving TWM were more effective than GG; ③ Among monotherapy plans for IMN, TWM was more effective distinctly than GC, while TWM and CNI were similarly effective; ④ Among multidrug therapy plans for IMN, the addition of TWM to previously established therapy plans made the original plans more effective; ⑤The efficacy of combining TWM with other plans was superior to that of TWM alone. (2) In terms of lowering 24 h-UTP, GC + TWM was the best effective and more effective than TWM. (3) In terms of safety, there was no statistically significant difference between all groups. However, CNI + TWM was the safest. No serious adverse events (AEs) occurred in all the included studies. Conclusion: The addition of TWM may be beneficial to patients with IMN. It may enhance the efficacy of previously established treatment protocols without leading to additional safety risks. In particular, GC + CNI + TWM, GC + TWM, and CNI + TWM with better efficacy and higher safety can be preferred in clinical decision-making as the therapy plans for IMN.

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD-a non-inferiority Randomised Controlled Trial (RCT).

BACKGROUND: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64-82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. METHODS/DESIGN: Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. DISCUSSION: If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8-4.6 million (€2.05-5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects. TRIAL REGISTRATION: EudraCT number: 2020-001006-39.

Adverse events in cognitive behavioral therapy and relaxation training for children and adolescents with obsessive-compulsive disorder: A mixed methods study and analysis plan for the TECTO trial.

Background: Knowledge on adverse events in psychotherapy for youth with OCD is sparse. No official guidelines exist for defining or monitoring adverse events in psychotherapy. Recent recommendations call for more qualitative and quantitative assessment of adverse events in psychotherapy trials. This mixed methods study aims to expand knowledge on adverse events in psychotherapy for youth with OCD. Methods: This is an analysis plan for a convergent mixed methods study within a randomized clinical trial (the TECTO trial). We include at least 128 youth aged 8-17 years with obsessive-compulsive disorder (OCD). Participants are randomized to either family-based cognitive behavioral therapy (FCBT) or family-based psychoeducation and relaxation training (FPRT). Adverse events are monitored quantitatively with the Negative Effects Questionnaire. Furthermore, we assess psychiatric symptoms, global functioning, quality of life, and family factors to investigate predictors for adverse events. We conduct semi-structured qualitative interviews with all youths and their parents on their experience of adverse events in FCBT or FPRT. For the mixed methods analysis, we will merge 1) a qualitative content analysis with descriptive statistics comparing the types, frequencies, and severity of adverse events; 2) a qualitative content analysis of the perceived causes for adverse events with prediction models for adverse events; and 3) a thematic analysis of the participants' treatment evaluation with a correlational analysis of adverse events and OCD severity. Discussion: The in-depth mixed methods analysis can inform 1) safer and more effective psychotherapy for OCD; 2) instruments and guidelines for monitoring adverse events; and 3) patient information on potential adverse events. The main limitation is risk of missing data. Trial registration: ClinicalTrials.gov identifier: NCT03595098. Registered on July 23, 2018.