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The aim of this review is to raise awareness and knowledge among healthcare professionals and policymakers about late adverse effects in survivors of childhood leukemia. With contemporary treatment, over 90% of children with acute lymphoblastic leukemia (ALL) and over 60% with acute myeloid leukemia (AML) are cured. Large cohort studies demonstrate that 20% of ALL and most AML survivors have at least one chronic health condition by 20-25 years after diagnosis. These are life-changing or threatening in some survivors and contribute to increased premature mortality. We describe the frequency, causes, clinical features, and natural history of the most frequent and severe late adverse effects in childhood leukemia survivors, including subsequent malignant neoplasms, metabolic toxicity, gonadotoxicity and impaired fertility, endocrinopathy and growth disturbances, bone toxicity, central and peripheral neurotoxicity, cardiotoxicity, psychosocial late effects, accelerated ageing and late mortality. The wide range of late effects in survivors of haemopoietic stem cell transplant is highlighted. Recent developments informing the approach to long-term survivorship care are discussed, including electronic personalized patient-specific treatment summaries and care plans such as the Survivor Passport (SurPass), surveillance guidelines and models of care. The importance of ongoing vigilance is stressed given the increasing use of novel targeted drugs with limited experience of long-term outcomes. CONCLUSION: It is vital to raise awareness of the existence and severity of late effects of childhood leukemia therapy among parents, patients, health professionals, and policymakers. Structured long-term surveillance recommendations are necessary to standardize follow-up care., (Copyright © 2024 Roganovic et al. This article is available under a Creative Commons License (Attribution 4.0 International).)

Background: High-dose methotrexate (HD-MTX) is used in the treatment of different childhood cancers, including leukemia, the most common cancer type and is commonly defined as an intravenous dose of at least 1 g/m 2 body surface area per application. A systematic review on late effects on different organs due to HD-MTX is lacking., Method: We conducted a systematic literature search in PubMed, including studies published in English or German between 1985 and 2020. The population of each study had to consist of at least 75% childhood cancer survivors (CCSs) who had completed the cancer treatment at least twelve months before late effects were assessed and who had received HD-MTX. The literature search was not restricted to specific cancer diagnosis or organ systems at risk for late effects. We excluded case reports, case series, commentaries, editorial letters, poster abstracts, narrative reviews and studies only reporting prevalence of late effects. We followed PRISMA guidelines, assessed the quality of the eligible studies according to GRADE criteria and registered the protocol on PROSPERO (ID: CRD42020212262)., Results: We included 15 out of 1731 identified studies. Most studies included CCSs diagnosed with acute lymphoblastic leukemia (n = 12). The included studies investigated late effects of HD-MTX on central nervous system (n = 10), renal (n = 2) and bone health (n = 3). Nine studies showed adverse outcomes in neuropsychological testing in exposed compared to non-exposed CCSs, healthy controls or reference values. No study revealed lower bone density or worse renal function in exposed CCSs. As a limitation, the overall quality of the studies per organ system was low to very low, mainly due to selection bias, missing adjustment for important confounders and low precision., Conclusions: CCSs treated with HD-MTX might benefit from neuropsychological testing, to intervene early in case of abnormal results. Methodological shortcomings and heterogeneity of the tests used made it impossible to determine the most appropriate test. Based on the few studies on renal function and bone health, regular screening for dysfunction seems not to be justified. Only screening for neurocognitive late effects is warranted in CCSs treated with HD-MTX., (© 2022. The Author(s).)

Importance: Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate., Objective: To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women., Data Sources: MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis., Evidence Review: The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing., Results: A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis., Conclusions and Relevance: The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence.

Objective: The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis)., Methods: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive., Results: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg., Conclusion: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years., Trial Registration: TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Because of the nature of the Fontan physiology, patients are at an increased risk of thromboembolic complications. As such, warfarin or aspirin is generally prescribed lifelong for thromboprophylaxis. This study aimed to compare long-term rates of cerebrovascular injury, thrombosis, bleeding, bone mineral density, and quality of life in people living with Fontan circulation receiving warfarin compared with aspirin., Methods: This was a multicenter study of a selected cohort from the Australia and New Zealand Fontan population. Participants underwent cerebral magnetic resonance imaging to detect the presence of cerebrovascular injury (n = 84) and dual-energy X-ray absorptiometry to assess bone mineral density (n = 120). Bleeding (n = 100) and quality of life (n = 90) were assessed using validated questionnaires: Warfarin and Aspirin Bleeding assessment tool and Pediatric Quality of Life Inventory, respectively., Results: Stroke was detected in 33 participants (39%), with only 7 (6%) being clinically symptomatic. There was no association between stroke and Fontan type or thromboprophylaxis type. Microhemorrhage and white matter injury were detected in most participants (96% and 86%, respectively), regardless of thromboprophylaxis type. Bleeding rates were high in both groups; however, bleeding was more frequent in the warfarin group. Bone mineral density was reduced in our cohort compared with the general population; however, this was further attenuated in the warfarin group. Quality of life was similar between the warfarin and aspirin groups. Home international normalized ratio monitoring was associated with better quality of life scores in the warfarin group., Conclusions: Cerebrovascular injury is a frequent occurrence in the Australia and New Zealand Fontan population regardless of thromboprophylaxis type. No benefit of long-term warfarin prophylaxis could be demonstrated over aspirin; however, consideration must be given to important clinical features such as cardiac function and lung function. Furthermore, the association of reduced bone health in children receiving warfarin warrants further mechanistic studies., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid use. However, the analgesic efficacy of such a regimen requires further investigation before widespread adoption. We have recently reported that a 4-day pharmacological conditioning procedure, which paired morphine (6 mg/kg) with contextual cues, elicited placebo analgesia in subpopulations of male (35%) and female (25%) rats with sciatic nerve chronic constriction injury (CCI). Here, we investigated how an escalating morphine dosage during conditioning affects the incidence and strength of placebo analgesia. Forty-four male, Sprague-Dawley rats received CCI. Thirty-eight (86%) rats developed strong cold allodynia by day 6 post-surgery, as measured by hind paw withdrawal (HPW) behaviour on a 5°C cold plate (120 s). In this experiment, pharmacological conditioning consisted of an escalating morphine dose over 4 days (8/9/10/12 mg/kg). This dosing regimen produced strong reductions in HPW behaviour and counteracted the effects of morphine tolerance during conditioning. However, none of the rats given the placebo treatment (n = 12) demonstrated reductions in HPW behaviour when morphine was substituted for saline (i.e. placebo analgesia), but instead showed a strong behavioural response (rearing). These results demonstrate that a high, escalating dose of morphine failed to produce conditioned placebo analgesia in rats with CCI. It is possible that admixing placebos with opioids may be similarly ineffective in chronic pain patients when the opioids regimen is high or escalating., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks., Methods: In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks., Results: In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients., Conclusions: In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Abstract: In view of the renewed interest in psychedelics in psychiatry it is timely to analyze psychedelic treatment in historical cohorts. Recently the therapeutic efficacy of psychedelics has been linked to the so-called phenomenon of "connectedness." The aim of the present study was to explore whether long-lasting personality changes were observed in any of the 151 Danish psychiatric patients who were treated with Lysergic acid diethylamide (LSD) from 1960 to 1974.The exploration included a reanalysis of a subgroup as well from a 1964 Danish historical cohort. Medical records and other case materials of the above mentioned 151 patients are kept in the Danish State Archives. The present author was granted access to the LSD case materials in the Danish State Archives, and respected confidentiality per the Archives Law. According to the LSD Damages Law from 1986, they all received financial compensation for LSD-inflicted harm.Analysis did not reveal any personality changes such as "connectedness;" however, other lasting personality changes were observed in 2 to 4 patients and in quite a few patients unwanted effects persisted for weeks or months following acute treatment. In the present analysis of the 1964 cohort, the same percentage of patients improved with LSD treatment as in the historical analysis. In the latter, however, little attention was given to side effects, such as suicide attempts, suicides, and one homicide.Future psychedelic research with psychiatric patients should respect the potential toxicity of LSD and other psychedelics and meticulously monitor possible side effects., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Crossover between direct oral anticoagulants (DOACs) has been underinvestigated, but happens frequently in clinical practice. The purpose of this study was to evaluate causes, rates and outcomes of a DOAC-to-DOAC switch., Methods: Patients receiving their first DOAC prescription at the Anticoagulation Center, Cardiology Dept, Bologna-Bellaria Hospital in 2017-2018 were consecutively included and prospectively followed up. DOAC-to-DOAC switch was the main outcome; causes of switch (cardiovascular events and noncardiovascular drug-related adverse events) had direct biannual assessment before and after the switch., Results: Among 300 patients enrolled (mean age = 79.3 years, mean follow-up = 1.5 years), with no difference in cardiovascular risk factors depending on index DOAC, 13% underwent DOAC-to-DOAC switch, minor bleeding and noncardiovascular adverse events being the most frequent causes. Dabigatran carried a three-fold increase in risk of switch compared with other DOACs, but the mean age of patients who switched was 83. Factors leading to switch resolved in 87% of cases afterwards. Annual rates of cardiovascular/noncardiovascular V events did not differ before and after the switch., Conclusion: DOAC-to-DOAC switch happens in 9% of patients using DOAC each year, and seems not to impact rates of cardiovascular events after switch. Dabigatran, in the elderly, might be associated with a higher risk of DOAC-to-DOAC switch. Further studies are needed to confirm the long-term safety and effectiveness of switching paradigm., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic warrants an imperative necessity for effective and safe vaccination, to restrain Coronavirus disease 2019 (COVID-19) including transmissibility, morbidity, and mortality. In this regard, intensive medical and biological research leading to the development of an arsenal of vaccines, albeit incomplete preconditioned evaluation, due to emergency. The subsequent scientific gap raises some concerns in the medical community and the general public. More specifically, the accelerated vaccine development downgraded the value of necessary pre-clinical studies to elicit medium- and long-term beneficial or harmful consequences. Previous experience and pathophysiological background of coronaviruses' infections and vaccine technologies, combined with the global vaccines' application, underlined the obligation of a cautious and qualitative approach, to illuminate potential vaccination-related adverse events. Moreover, the high SARS-CoV-2 mutation potential and the already aggregated genetical alterations provoke a rational vagueness and uncertainty concerning vaccines' efficacy against dominant strains and the respective clinical immunity. This review critically summarizes existing evidence and queries regarding SARS-CoV-2 vaccines, to motivate scientists' and clinicians' interest for an optimal, individualized, and holistic management of this unprecedented pandemic.

Importance: Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children., Objective: To describe the use of rituximab and to assess whether its use is associated with short- or long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people., Design, Setting, and Participants: This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children's Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020., Exposure: One or more doses of rituximab., Main Outcomes and Measures: Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events., Results: We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19+ or CD20+ cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-for-age B cell counts. Recovery of CD27+ memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM., Conclusions and Relevance: Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued.

Introduction: Psychoactive drug use (PDU) is reported in up to 40% of trauma patients and is associated with a higher rate of in-hospital complications. However, little is known about its long-term impact on trauma patients. We aimed to assess the long-term functional, mental, and psychosocial outcomes of PDU in trauma patients 6 to 12 months after injury., Methods: Trauma patients with moderate to severe injuries (Injury Severity Score, >9) who had a toxicology screen upon admission to one of three level 1 trauma centers were contacted by phone 6 to 12 months postinjury. Psychoactive drug use was defined as the presence of a psychoactive, nonprescribed substance on toxicology screen including amphetamine, barbiturate, benzodiazepine, cannabinoid, methamphetamine, methadone, opioid, oxycodone, methylenedioxymethamphetamine (ecstasy), phencyclidine, tricyclic antidepressant, and cocaine. The interviews systematically evaluated functional limitations, social functioning, chronic pain, and mental health (posttraumatic stress disorder, depression, anxiety). Patients with a score of ≤47 on the Short-Form Health Survey version 2.0 social functioning subdomain were considered to have social dysfunction. Multivariable regression models were built to determine the independent association between PDU and long-term outcomes., Results: Of the 1,699 eligible patients, 571 (34%) were included in the analysis, and 173 (30.3%) screened positive for PDU on admission. Patients with PDU were younger (median age [interquartile range], 43 [28-55] years vs. 66 [46-78] years, p < 0.001), had more penetrating injuries (8.7% vs. 4.3%, p = 0.036), and were less likely to have received a college education (41.3% vs. 54.5%, p = 0.004). After adjusting for patients' characteristics including the presence of a baseline psychiatric comorbidity, patients with PDU on admission were more likely to suffer from daily chronic pain, mental health disorders, and social dysfunction 6 to 12 months after injury. There was no difference in the functional limitations between patients with and without PDU., Conclusion: On the long term, PDU in trauma patients is strongly and independently associated with worse mental health, more chronic pain, and severe impairment in social functioning. A trauma hospitalization presents an opportunity to identify patients at risk and to mitigate the long-term impact of PDU on recovery., Level of Evidence: Prognostic/epidemiologic, level III., (Copyright © 2021 American Association for the Surgery of Trauma.)

Background: Despite more than 30 years after utilization of sulfur mustard or bis (2-chloroethyl) sulfide (SM) by Iraqi troops against Iranian military members and civilians, there are a lot of reported delayed complications for the exposed people. Nonetheless, the molecular mechanism of action from this chemical warfare agent is not recognized yet., Material and Method: In this study, we employed two dimensional gel electrophoresis (2DE) technique to investigate the serum proteins from chemical exposed people compared to non-exposed individuals to provide an inside into molecular mechanism of this chemical agent. Each group was divided into two subgroups including individuals with, and without respiratory complications. For each group, 10 individuals were included after informed consent., Result: The results showed protein spots, which were exclusively/mainly expressed in chemical exposed patients with complications, including T cell receptor alpha, and hematopoietic cell signal transducer. Also there were protein spots that were expressed only in all exposed groups (with and without complications). On the other hand, we could identify protein spots that were exclusively expressed/altered only in non-exposed group with complications including Pre T-cell antigen receptor, CD40 ligand, and multidrug and toxin extrusion proteins., Conclusion: Our investigation could result in identification of proteins that are associated to chemical exposure, as well as those specific for respiratory complications irrespective of chemical exposure. These candidate proteins can be used as biomarker, as well as a base for understanding the molecular mechanism of this chemical agent., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest in this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aristolochia herbals have a 2500-year history of medicinal use. We focused this article on Portland's Powders, an 18 th -century British gout medicine containing Aristolochia herbs. The powders constitute an 18 th -century iteration of an herbal remedy, which was used, with variations, since at least the fifth century BCE. The use of Portland's Powders in Great Britain may appear to be an unusual choice for investigating a public health problem currently widespread in Asia. Yet it exemplifies long-term medicinal use of Aristolochia herbs, reflecting our argument that aristolochic acid nephropathy (AAN) is a historically persistent iatrogenic disease. Moreover, we provide compelling evidence that individuals taking Portland's Powders for gout would have ingested toxic quantities of aristolochic acid, which causes AAN and cancer. Several factors, including long history of use, latency of toxic effects, and lack of effective regulation, perpetuate usage of Aristolochia herbals to the present day., (Copyright ©2020, Yale Journal of Biology and Medicine.)

Aims: To investigate the healing process and nickel release of the Hyperion occluder (Comed BV, Netherlands), as compared to the Amplatzer septal occluder (ASO) (St. Jude Medical Inc., St. Paul, MN, USA) in a chronic swine model., Background: Some long-term complications occurring after percutaneous atrial septal defect (ASD) closure may be partially associated with an inappropriate healing of the device and increased nickel release. There is no direct comparative study of different occluders for healing and nickel release., Methods: After percutaneous ASD creation, 12 pigs were implanted with 15 mm Hyperion ( n  = 6) and 15 mm ASO ( n  = 6) devices. After 1 month ( n  = 3 for each device) and 3 months ( n  = 3 for each device) of follow-up, device explantation was performed and healing was assessed using histopathological workup. Systemic and tissular nickel release was performed., Results: Implantation was successful in 100% without complications. Device coverage was observed as early as 1 month after implantation and was almost complete after 3 months. A granulation tissue with a predominantly mononuclear inflammatory reaction was observed in contact with nitinol wires while an inflammatory reaction was seen in contact with textile fibers. We found no statistically significant difference between the 2 devices whether for histological grading scores or systemic nickel release, regardless to follow-up duration., Conclusions: In this preclinical study, we demonstrated that Amplatzer septal occluder and Hyperion occluder were not significantly different for device healing and nickel release processes., Competing Interests: Z. J. received speaker honoraria and research grant from Abbott. J. B. T. and X. I. act as proctors for Abbott. The other authors have no conflicts of interest to declare., (Copyright © 2020 Zakaria Jalal et al.)

Hydroxycarbamide is a cytotoxic drug that is used in haematological cancers. On long-term use (2-15 years) of 1500-2000 mg a day, there is a 9% risk of developing ulcers. This patient's ulcer was painful, of punched out aspect, with a necrotic base and swollen wound edges. Upon discontinuation of hydroxycarbamide, the wound healed within 2 months.

Background: Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2 ndG /3 rdG TKIs) in the real-life practice., Methods: We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib., Results: The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control., Conclusion: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Early-life antibiotic exposure may provoke long-lasting microbiota perturbation. Since a healthy gut microbiota confers resistance to enteric pathogens, we hypothesized that early-life antibiotic exposure would worsen the effects of a bacterial infection encountered as an adult. To test this hypothesis, C57BL/6 mice received a 5-day course of tylosin (macrolide), amoxicillin (β-lactam), or neither (control) early in life and were challenged with Citrobacter rodentium up to 80 days thereafter. The early-life antibiotic course led to persistent alterations in the intestinal microbiota and even with pathogen challenge 80 days later worsened the subsequent colitis. Compared to exposure to amoxicillin, exposure to tylosin led to greater disease severity and microbiota perturbation. Transferring the antibiotic-perturbed microbiota to germfree animals led to worsened colitis, indicating that the perturbed microbiota was sufficient for the increased disease susceptibility. These experiments highlight the long-term effects of early-life antibiotic exposure on susceptibility to acquired pathogens. IMPORTANCE The gastrointestinal microbiota protects hosts from enteric infections; while antibiotics, by altering the microbiota, may diminish this protection. We show that after early-life exposure to antibiotics host susceptibility to enhanced Citrobacter rodentium -induced colitis is persistent and that this enhanced disease susceptibility is transferable by the antibiotic-altered microbiota. These results strongly suggest that early-life antibiotics have long-term consequences on the gut microbiota and enteropathogen infection susceptibility., (Copyright © 2019 Roubaud-Baudron et al.)

Objective: To evaluate the long-term safety and efficacy of bremelanotide as treatment for hypoactive sexual desire disorder in premenopausal women., Methods: Women who completed the 24-week double-blind core phase of RECONNECT, composed of two parallel phase 3 trials (301 and 302) examining the safety and efficacy of bremelanotide compared with placebo in premenopausal women with hypoactive sexual desire disorder, could enroll in the 52-week open-label extension, provided they had not experienced serious adverse events during the core phase. Efficacy was assessed using the coprimary endpoints from the core phase, and all adverse events were collected during the open-label extension. All statistical analyses were descriptive., Results: The study 301 open-label extension began on July 17, 2015, and concluded on July 13, 2017; the study 302 open-label extension began on October 5, 2015, and concluded on June 29, 2017. Of the 856 eligible patients who completed the core phase, 684 elected to participate in the open-label extension, and 272 completed it. The most common treatment-emergent adverse events considered related to study drug were nausea (40.4%), flushing (20.6%), and headache (12.0%), and the only severe treatment-emergent adverse event experienced by more than one participant in both studies was nausea during the open-label extension. The change in Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 from baseline to end of the open-label extension ranged from 1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during the core phase, and 0.70-0.77 and -0.9, respectively, for patients who received placebo during the core phase., Conclusion: During the 52-week open-label extension of RECONNECT, no new safety signals were observed, and premenopausal women treated with bremelanotide exhibited sustained improvements in hypoactive sexual desire disorder symptoms., Clinical Trial Registration: ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302)., Funding Source: Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Background: Long-term use of benzodiazepines (BZD) and Z-drugs is associated with the risk of developing dependency. Many older patients use these drugs for long durations, which is often associated with low-dose dependency without an increase in dose., Aim: The aim of this study is to investigate the reasons, symptoms, and side effects, as well as the prescription conditions among older patients who were prescribed BZD or Z-drugs within the last 12 months., Methods: A 9-page questionnaire was sent to 4,000 patients of the AOK-NordWest, stratified according to age group (50-56 years;>65 years) and intake behavior (long-term use/ guideline incompatible; short-term use/ guideline compatible). Patients provided demographic data and indicated on a comprehensive list of BZD and Z-drugs, which substances they had used or were currently using. In addition, patients were asked about the reasons and underlying symptoms for taking these medications, possible side effects, and previous attempts to discontinue the medications., Results: A total of 466 patients returned completed questionnaires (11.7%). A further 43 privately insured patients were recruited through pharmacies. 169 patients, mainly from the group with guideline-compatible prescriptions, indicated that they had never taken these medications. The remaining 340 patients were 68.5% female and the average age was 72.1 years. Compared to patients with guideline-compatible prescriptions, a greater proportion of patients with guideline-incompatible prescriptions were taking Z-drugs. The average daily dose (DDD) consumed was significantly higher than in those with guideline-compatible prescriptions, although on average both patient groups took low doses (<1 DDD) of the medication. In both groups, the main reason for taking BZD and Z-drugs was sleeping problems., Conclusions: Considering the recommendation that BZD and Z-drugs are to be taken only short-term for sleeping problems, the extent of insomnia indications is high. The low doses suggest a careful and controlled prescription behavior in both groups, with the majority of long-term consumers likely to have developed low-dose dependency. This is associated with only a limited need for intervention, since only few medication-dependent people underwent addiction treatment., Competing Interests: Uwe Verthein erhielt innerhalb der letzten 3 Jahre Vortrags- und Beratungshonorar sowie Reisekostenerstattungen von Mundipharma GmbH. Jens Reimer erhielt innerhalb der letzten 3 Jahre Vortrags-, Autoren- und Beratungshonorar, Reisekostenerstattungen sowie Forschungsunterstützung von Indivior, Camurus und Mundipharma GmbH. Die anderen Autoren hatten keine Verbindungen i.o.g. Sinne., (© Georg Thieme Verlag KG Stuttgart · New York.)

Little is known about the toxicity of various therapeutics for cancer over time because randomized controlled clinical trials that compare several treatments are limited. In this study, we focused on the toxicities most frequently discussed, which are investigations (lab abnormalities), gastrointestinal disorders, skin and subcutaneous tissue disorders, and cardiac disorders, and compared their longitudinal toxicity data among four types of cancer therapeutics. In total, 28,235 patients who were enrolled into 772 early-phase trials to evaluate the monotherapies of cytotoxic drugs, molecularly targeted agents, immunomodulatory drugs, or cancer vaccines were evaluated. For each toxicity, we compared their grade prevalence, mean grade at each cycle, and time to toxicity occurrence and identified the potential underlying similarities and differences of longitudinal toxicities among the four cancer treatment types. Our results will further help in understanding the profile of cancer therapeutic toxicities and their impact on oncology treatment in practice., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Background: Management of atrial fibrillation (AF) with rate and rhythm therapy can cause bradyarrhythmia., Objectives: To assess overall risk, temporal risk, and subgroup at risk of bradyarrhythmia-related events by rate and/or rhythm therapy drugs., Methods: Using Danish nationwide registries, patients with AF between 2000 and 2014 were included if prescribed with rate-lowering drugs (RLDs) or antiarrhythmic drugs (AADs). An adjusted time-dependent Poisson regression model estimated the association between RLDs and AADs with a composite endpoint of pacemaker, temporary pacing, and bradyarrhythmia hospitalization. Secondary outcomes were each individual event., Results: Among 135,017 AF patients, 9196 (6.8%) patients experienced the composite endpoint with a median follow-up of 3.7 (interquartile range [IQR]: 1.6-7.0) years. Median age was 74 (IQR: 65-82) years and 47.6% were women. With rate-lowering monotherapy as the reference, the incidence rate ratios (IRR) (95% confidence interval) for the composite endpoint were 1.36 (1.29-1.43) for rate-lowering dual therapy, 1.62 (1.43-1.84) for antiarrhythmic monotherapy, and 2.49 (2.29-2.71) for AAD combined with RLDs. Similar trend was found for each secondary outcome. Particularly amiodarone increased the risk. This association was strongest within the first 2 weeks of treatment. In those treated with AAD combined with RLDs, high-risk populations were patients ≥70 years (IRR: 3.35 [2.51-4.45] compared to patients <60 years), and women (IRR: 1.35 [1.15-1.57], compared to men)., Conclusions: In real-world AF patients, rate-lowering dual therapy, antiarrhythmic monotherapy, and AADs combined with RLDs were positively associated with bradyarrhythmia-related events. The risk was highest in those treated with amiodarone, in the initial 2 weeks of treatment, in women, and in the elderly., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to compare 1.25 and 1.75 mmol/L dialysate calcium for their effects on parathyroid hormone (PTH) and mineral metabolism in peritoneal dialysis (PD)., Methods: The PubMed, Cochrane Library, and EmBase databases were searched from inception to October 2016. Methodological quality assessment of the included studies was performed using the risk of bias tool of the Review Manager software. The meta-analysis was carried out with the Stata12.0 software. Subgroup analysis was performed by study design [randomized controlled trial (RCT) and non-RCT]. Odds ratios or standardized mean differences were used to assess the outcome measures, including intact parathyroid hormone (i-PTH) levels, serum total calcium amounts, ionized calcium levels, phosphate concentrations, and peritonitis episodes., Results: Seven studies were enrolled in the synthesized analysis, including 4 RCTs and 3 non-RCTs. All studies compared 1.25 mmol/L and 1.75 mmol/L dialysate calcium for PD. Pooled analysis revealed that 1.75 mmol/L dialysate calcium significantly reduced i-PTH levels compared with the 1.25 mmol/L dose in PD patients. However, 1.25 mmol/L dialysate calcium was superior to the 1.75 mmol/L dose in decreasing the levels of serum total calcium and ionized calcium in PD patients. No significant differences in phosphate amounts and peritonitis episodes were observed between the two groups., Conclusion: These findings indicated that 1.75 mmol/L dialysate calcium is more appropriate for PD patients with secondary hyperparathyroidism. Meanwhile, 1.25 mmol/L dialysate calcium is more favorable to PD patients with secondary hypercalcemia. However, further well-designed and high-quality studies are required to validate these findings.

Background: Oxaliplatin, combined with capecitabine (CAPOX) or infused 5-fluorouracil (FOLFOX), is standard of care in the adjuvant treatment of colorectal cancer (CRC). Prospective data on prevalence of oxaliplatin induced acute and long-term neuropathy in a real-life patient population and its effects on quality of life (QOL) and survival is limited, and scarce in CAPOX versus FOLFOX treated, especially in a subarctic climate., Methods: One hundred forty-four adjuvant CRC patients (all 72 CAPOX cases and 72 matched FOLFOX controls) were analyzed regarding oxaliplatin induced sensory neuropathy, which was graded according to NCI-CTCAEv3.0. Ninety-two long-term survivors responded to the QOL (EORTC QLQ-C30) and Chemotherapy-Induced Peripheral Neuropathy (EORTC CIPN20) questionnaires and were interviewed regarding long-term neuropathy., Results: Acute neurotoxicity was present in 94% (136/144) during adjuvant therapy and there was a significant association between acute neurotoxicity and long-term neuropathy (p < .001). Long-term neuropathy was present in 69% (grade 1/2/3/4 in 36/24/8/1%) at median 4.2 years. Neuropathy grades 2-4 did not influence global health status, but it was associated with decreased physical functioning (p = .031), decreased role functioning (p = .040), and more diarrhea (p = .021) in QLQ-C30 items. There were no differences in acute neurotoxicity, long-term neuropathy, or in QOL between CAPOX and FOLFOX treated. Neuropathy showed no pattern of variation according to starting and stopping month or treatment during winter., Conclusions: Neuropathy following oxaliplatin containing adjuvant chemotherapy is present in two-thirds, years after cessation, and impairs some QOL scales. There is no difference in severity of acute or long-term neuropathy between CAPOX and FOLFOX treated and QOL is similar. No seasonal variation in neuropathy was noted.

Background: Millions of people are treated with antidepressants like selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This clinical practice is based on short-term trials that have exaggerated the benefits and underestimated the harms. We also know too little about long-term harms., Aim: To assess harms of SSRIs and SNRIs that persist after end of drug intake., Methods: Systematic review of placebo-controlled randomised trials of any length in patients with a psychiatric diagnosis and a follow-up of at least six months. Our primary outcomes were mortality, functional outcomes, quality of life and core psychiatric events. We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials and checked the references for eligible articles. One researcher extracted data and another checked the data extraction., Results: Our searches returned 9,153 unique records. We included 22 papers for 12 trials on SSRIs. Median intervention and follow-up periods were 15 and 52 weeks, respectively. Median number of randomised participants was 51; only two trials had a drop-out rate below 20%.Outcome reporting was less thorough during follow-up than for the intervention period and only two trials maintained the blind during follow-up. All authors concluded that the drugs were not beneficial in the long term.All trials reported harms outcomes selectively or did not report any. Only two trials reported on any of our primary outcomes (school attendance and number of heavy drinking days)., Conclusion: The randomised trials currently available cannot be used to investigate persistent harms of antidepressants.

Rationale: Testosterone is important for the development of secondary sexual characteristics in female-to-male transsexuals. On the contrary, it can increase the risk of breast cancer., Patient Concerns: We present a rare case of breast cancer in female-to-male transsexual patient after long-term hormonal therapy., Diagnosis: Breast cancer in female-to-male transsexual patient., Interventions: The patient underwent mastectomy and chemotherapy., Outcomes: The patient had local recurrence of the disease and he underwent re-excision, radiotherapy and the tamoxifen treatment. After this treatment, the patient is in the remission from the disease., Lessons: Breast cancer in transsexuals appears to be rare. However, there is a potential risk that testosterone exposure can increase the risk of developing breast cancer by the stimulation of breast tissue. There is limited published literature on the risk of breast cancer in transsexual patients.

Objectives: Increasing evidence points to the harmful effects of long-term benzodiazepine treatment. Our objective was to study the incidence of, and predictors for, long-term use of benzodiazepines and Z-drugs in bipolar disorder., Methods: We conducted a population-based cohort study, using data from Swedish national registers. Swedish residents aged 18-75 years with a recorded diagnosis of bipolar disorder or mania between July 2006 and December 2012, and no history of benzodiazepine/Z-drug use in the past year, were included. Patients were followed for 1 year with regard to prescription fills of benzodiazepines/Z-drugs. Initiators were followed for another year during which continuous use for >6 months was defined as "long-term". Patient and prescription characteristics were investigated as potential predictors for long-term use in multivariate logistic regression models., Results: Out of the 21 883 patients included, 29% started benzodiazepine/Z-drug treatment, of whom one in five became long-term users. Patients who were prescribed clonazepam or alprazolam had high odds for subsequent long-term use (adjusted odds ratios [aORs] 3.78 [95% confidence interval (CI) 2.24-6.38] and 2.03 [95% CI 1.30-3.18], respectively), compared to those prescribed diazepam. Polytherapy with benzodiazepines/Z-drugs also predicted long-term use (aOR 2.46, 95% CI 1.79-3.38), as did age ≥60 years (aOR 1.93, 95% CI 1.46-2.53, compared to age <30 years), and concomitant treatment with psychostimulants (aOR 1.78, 95% CI 1.33-2.39)., Conclusions: The incidence of subsequent long-term use among bipolar benzodiazepine initiators is high. Patients on clonazepam, alprazolam or benzodiazepine/Z-drug polytherapy have the highest risk of becoming long-term users, suggesting that these treatments should be used restrictively., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Due to concerns about long-term PPI use in patients with acid reflux, we aimed at minimizing PPI use, either by avoiding initiating therapy, downscaling to other therapies, or introducing endoscopic or surgical options., Aims: To examine the role of esophageal ambulatory pHmetry in minimizing PPI use in patients with heartburn and acid regurgitation., Methods: Retrospective cohort analysis of patients with reflux symptoms, who underwent endoscopy, manometry, and ambulatory pHmetry to define the need for PPI. Patients were classified as: (1) never users; (2) partial responders to PPI; (3) users with complete response to PPI. Patients were then managed as: (1) PPI non-users; (2) PPI-initiated, and (3) PPI-continued., Results: Of 286 patients with heartburn and regurgitation, 103 (36%) were found to have normal and 183 (64%) abnormal esophageal acid exposure (AET). In the normal AET group, 44/103 had not been treated and were not initiated on PPI. Of the 59 who had previously received PPI, 52 stopped and 7 continued PPI. Hence, PPI were avoided in 96/103 patients (93%). In the abnormal AET group, 61/183 had not been treated and 38 were initiated on PPI and 23 on other therapies. In the 122 patients previously treated with PPI, 24 were not treated with PPI, but with H2RAs, prokinetics, endoscopic, or surgical therapy. Hence, PPI therapy was avoided in 47/183 patients (26%)., Conclusions: In patients with GER symptoms, esophageal pHmetry may avert PPI use in 50%. In the era of caution regarding PPIs, early testing may provide assurance and justification.

Aim: The urgency of the study is determined by the lack of data necessary in order to assess the safety of prolonged use of proton pump inhibitors (PPI) in patients with IHD combined with anti-aggregant therapy. The aim of the study was to study the relationship between the use of PPI and the risk of thrombotic complications in patients undergoing planned procedures of percutaneous coronary interventions (PCI) and receiving dual antiplatelet therapy., Materials and Methods: The study is a prospective register of patients who successfully underwent planned percutaneous coronary intervention (PCI). The effect of PPI (omeprazole and pantoprazole) on the frequency of the combined end point cardiovascular death, ACS, AI, TIA, peripheral arterial thrombosis and PE was assessed using the Log-Rank criterion, as well as in a multivariate analysis (Cox proportional risk regression model)., Results: A total of 391 patients were included in the study (23.1% women, mean age 61.2 years ± 10.4 years). The median duration of follow-up was 18 months. During this period of time, 34 adverse events were recorded. Log-Rank analysis showed that the proportion of patients without adverse events in the omeprazole group was significantly lower in comparison with patients who did not receive PPI (0.56 vs. 0.84, Log-Rank p=0.003), and for pantoprazole no such pattern was found (0.89 against 0.84, Log-Rank p=0.21). The average level of residual platelet reactivity (ORT), as well as the number of patients with high ORT (> 208 PRU), did not differ significantly between the groups of omeprazole, pantoprazole and the group of patients not receiving PPI. According to multivariate analysis, omeprazole was an independent predictor of thrombotic complications after a planned PCI (OR 3.75, 95% confidence interval 1.72-8.17, p=----0.0009)., Conclusion: Long-term use of omeprazole (at least 30 days) is an independent predictor of thrombotic complications in patients who underwent planned PCI.

Background: The optimal long-term antithrombotic treatment of patients with stable coronary artery disease (CAD) and atrial fibrillation (AF) is a challenge in daily practice. We sought to determine the prevalence of hemorrhagic complications and ischaemic events depending on antithrombotic strategy in patients with stable CAD and AF., Methods: The primary outcome was major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of cardiovascular mortality, myocardial infarction and ischaemic stroke. The subsequent risks of MACCE and clinically significant bleedings requiring hospitalisation (major safety outcome) were analyzed in a propensity score-matched analysis by adjusted Cox regression models., Results: Six hundred and six patients with high thrombotic and bleeding risks (mean age 73.4 ± 9.8 years, 25.2% female, CHA2DS2-VASc score:4.7 ± 1.5, and HAS-BLED score:3.1 ± 1.0) were included, and 127 propensity-matched pairs were analyzed. At inclusion, 172 patients (28.4%) were on oral anticoagulation (OAC) alone (75.6% on VKA and 24.4% on DOAC) and 434 patients (71.6%) on OAC + single antiplatelet therapy (SAPT) (71.9% on VKA and 28.1% on DOAC). At 5-year follow-up, MACCE rate did not significantly differ in both groups (30.9% in OAC + SAPT vs. 26.8% in OAC alone; adjusted HR 1.1 [0.8-1.5], p = 0.58), but clinically significant bleedings (28.3% vs. 18.5%; adjusted HR 1.8 [1.2-2.8], p = 0.005) and total deaths (29.5% vs. 20.8%; adjusted HR 1.4 [95% CI 1.0-2.2], p = 0.049) were higher in patients with OAC + SAPT than in patients with OAC alone., Conclusions: In patients with stable CAD and AF, the addition of antiplatelet therapy to VKA or DOAC therapy was independently associated with a higher risk of bleeding and overall mortality, without significant reduction in cardiac and cerebral ischaemic events., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A 60-year-old man was diagnosed with melanoma. After receiving 13 infusions of nivolumab, he had fulminant myocarditis. The myocardial biopsy specimen revealed extensive lymphocytic infiltration, interstitial edema, and myocardial necrosis, with predominant CD4+, CD8+, CD20-, and programmed death-1- markers. Programmed death-1 ligand 1 (PD-L1) was predominantly expressed on the surface of the damaged myocardium. Although it is reported that myocarditis induced by the human anti-programmed death-1 inhibitor nivolumab therapy rarely occurred at > 2 months use in clinical trials, this case showed that even if at a late phase, long-term use of immune checkpoint inhibitors might to lead immune-related adverse events including myocarditis., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose In this multicenter study, we evaluated the cumulative burden of morbidity (CBM) among > 1,200 testicular cancer survivors and applied factor analysis to determine the co-occurrence of adverse health outcomes (AHOs). Patients and Methods Participants were ≤ 55 years of age at diagnosis, finished first-line chemotherapy ≥ 1 year previously, completed a comprehensive questionnaire, and underwent physical examination. Treatment data were abstracted from medical records. A CBM score encompassed the number and severity of AHOs, with ordinal logistic regression used to assess associations with exposures. Nonlinear factor analysis and the nonparametric dimensionality evaluation to enumerate contributing traits procedure determined which AHOs co-occurred. Results Among 1,214 participants, approximately 20% had a high (15%) or very high/severe (4.1%) CBM score, whereas approximately 80% scored medium (30%) or low/very low (47%). Increased risks of higher scores were associated with four cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR], 1.96; 95% CI, 1.04 to 3.71) or bleomycin, etoposide, and cisplatin (OR, 1.44; 95% CI, 1.04 to 1.98), older attained age (OR, 1.18; 95% CI, 1.10 to 1.26), current disability leave (OR, 3.53; 95% CI, 1.57 to 7.95), less than a college education (OR, 1.44; 95% CI, 1.11 to 1.87), and current or former smoking (OR, 1.28; 95% CI, 1.02 to 1.63). CBM score did not differ after either chemotherapy regimen ( P = .36). Asian race (OR, 0.41; 95% CI, 0.23 to 0.72) and vigorous exercise (OR, 0.68; 95% CI, 0.52 to 0.89) were protective. Variable clustering analyses identified six significant AHO clusters (χ 2 P < .001): hearing loss/damage, tinnitus (OR, 16.3); hyperlipidemia, hypertension, diabetes (OR, 9.8); neuropathy, pain, Raynaud phenomenon (OR, 5.5); cardiovascular and related conditions (OR, 5.0); thyroid disease, erectile dysfunction (OR, 4.2); and depression/anxiety, hypogonadism (OR, 2.8). Conclusion Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified AHO clusters could guide the development of survivorship care strategies.

Purpose: Inflammatory factors play a critical role in contrast-induced acute kidney injury (CI-AKI). Prealbumin, a nutritional and inflammatory indicator, is a well-established predictor of short- and long-term outcomes in numerous clinical conditions. The current study investigated the association of pre-procedural prealbumin levels with CI-AKI and long-term outcomes in geriatric patients after elective percutaneous coronary intervention (PCI)., Patients and Methods: A total of 558 patients aged≥75 years, who underwent elective PCI between January 2012 and December 2015, were selected for the current study. Pre-procedural prealbumin levels were measured before PCI. Multivariable logistic regression and Cox proportional hazard regression analyses were performed to identify the independent risk factors for CI-AKI and long-term mortality., Results: Out of 558 patients, 54 developed CI-AKI. The optimal cutoff value of prealbumin for detecting CI-AKI was 185.5 mg/L with 62.7% sensitivity and 70.4% specificity based on the receiver operating characteristic analysis (C-statistic=0.710; 95% confidence interval [CI] 0.673-0.751). Multivariable analysis demonstrated that prealbumin≤185.5 mg/L was significantly associated with CI-AKI (odds ratio [OR] 0.397; 95% CI 0.195-0.808; P =0.011). Cox regression analysis demonstrated that prealbumin≤185.5 mg/L was associated with long-term mortality (adjusted hazard ratio [HR] 0.525; 95% CI 0.289-0.952; P =0.034) during the follow-up., Conclusion: Pre-procedural levels of prealbumin were independently associated with an increased risk of CI-AKI and long-term mortality in elderly patients undergoing elective PCI., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Tardive dyskinesia (TD) is an involuntary movement disorder associated with antipsychotic treatment. Because of the serious and potentially irreversible nature of TD, accurate diagnosis is crucial. However, diagnosing TD can be challenging, since the subtle and often fluctuating symptoms can be easily mistaken for symptoms of mental illness or other side effects. Although the risk of developing TD in relation to treatment with second-generation antipsychotics is lower than that associated with first-generation antipsychotics, the risk still exists and may be greater than once believed. Clinicians prescribe antipsychotics for a variety of illnesses and may underestimate the possibility of a patient developing TD, thus missing early signs of the disorder. In this ACADEMIC HIGHLIGHTS, experts review the prevalence, phenomenology, risk factors, and impact of TD, illustrated by case examples, and provide valuable clinical information to guide early recognition and accurate diagnosis., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Background: Benzodiazepines and Z-drugs are commonly used in patients with cancer for the management of symptoms such as anxiety, agitation and dyspnoea. Clinical staff, patients and relatives have concerns about the impact of these drugs on survival. This potentially decreases prescribing leading to suboptimal symptom control. The aim of this systematic review was to find and assimilate the evidence assessing the association of benzodiazepines and Z-drugs with survival in patients with cancer, to assist in clinical decision-making regarding the use of these drugs in cancer patients., Methods: Systematic review with narrative synthesis designed and conducted according to the recommendations set out in Preferred Reporting Items for Systematic Reviews and MetaAnalyses-Protocol (PRISMA-P) and PRISMA statements. The review protocol was registered on the PROSPERO prior to commencing the searches. The electronic databases MEDLINE, EMBASE, PsychINFO, Cochrane Library, AMED were searched and hand-searches were performed. Screening, extraction and quality assessment were performed in duplicate., Results: A total of 2257 unique records were identified, 116 full-text articles assessed for eligibility, 18 met the inclusion criteria. These contained data on 4117 patients with cancer. All studies were low or very-low quality. Most studies were conducted in patients in the last days/weeks of life. No study found an association between benzodiazepines and survival in patients with cancer., Conclusions: There is no evidence demonstrating an association between benzodiazepines and survival in patients with cancer. These results should be interpreted with caution as all studies were low/very low quality, most did not report or account for other medications and did not have survival as a primary outcome. No study assessed the effect of long-term benzodiazepines on survival. Therefore, definitive conclusions regarding survival impact of benzodiazepine in patients with cancer can be made. Further investigation using high-quality long-term randomised control trials with survival as a primary endpoint are needed.

Background: A summary measure that reflects the global toxicity burden of a treatment is essential for comparing therapies. Current toxicity summaries are ad hoc and do not distinguish among the severities and types of toxicities. Here a clinically feasible method for estimating the toxicity burden, based on a prospective evaluation of the toxicity profile of a randomized clinical trial of 746 prostate cancer patients conducted by SWOG, is proposed., Methods: For 308 patients who experienced severe toxicities, 2 physicians randomly selected from 14 physicians evaluated each toxicity profile and assigned a visual analogue scale score (0-10) based on their impression of the global burden of toxicities. With mixed-effects models, severity scores and a 10-point toxicity burden score (TBS) were derived from 27 predictors accounting for severe (grade 3) and life-threatening (grade 4) toxicities for each organ class of the Common Terminology Criteria for Adverse Events., Results: For most organ classes, grade 3 toxicities had a TBS of 4.14 (95% confidence interval [CI], 3.65-4.63), but infections, cardiovascular events, and pulmonary events had a higher TBS with differences of 0.87 (95% CI, 0.53-1.21), 0.88 (95% CI, 0.51-1.25), and 0.73 (95% CI, 0.22-1.24), respectively. Moreover, most grade 4 events had a higher TBS than grade 3 events, except for hemorrhaging, pain, metabolic events, and musculoskeletal events. The intrarater and interrater correlations were 0.91 and 0.59, respectively., Conclusions: The burden of toxicity grades differs with toxicity types. A TBS provides a toxicity burden summary that incorporates physicians' perspectives and differentiates between severe and life-threatening toxicities and organ classes. Cancer 2018;124:858-64. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

First introduced in 1989, proton pump inhibitors (PPIs) are among the most widely utilized medications worldwide, both in the ambulatory and inpatient clinical settings. The PPIs are currently approved by the US Food and Drug Administration for the management of a variety of gastrointestinal disorders including symptomatic peptic ulcer disease, gastroesophageal reflux disease, and nonulcer dyspepsia as well as for prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy. PPIs inhibit gastric acid secretion, and the most commonly associated adverse effects include abdominal pain, diarrhea, and headache. Although PPIs have had an encouraging safety profile, recent studies regarding the long-term use of PPI medications have noted potential adverse effects, including risk of fractures, pneumonia, Clostridium difficile diarrhea, hypomagnesemia, vitamin B 12 deficiency, chronic kidney disease, and dementia. These emerging data have led to subsequent investigations to assess these potential risks in patients receiving long-term PPI therapy. However, most of the published evidence is inadequate to establish a definite association between PPI use and the risk for development of serious adverse effects. Hence, when clinically indicated, PPIs can be prescribed at the lowest effective dose for symptom control., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids are the mainstay of treatment for GCA. Patients often require long-term treatment that may be associated with numerous adverse effects, depending on the dose and the duration of treatment. Trends in recent decades for glucocorticoid use in GCA suggest increasing cumulative doses and longer exposures. Common adverse events (AEs) reported in glucocorticoid-treated GCA patients include osteoporosis, hypercholesterolaemia, hypertension, posterior subcapsular cataract, infections, diabetes mellitus, Cushingoid appearance, adrenal insufficiency and aseptic necrosis of bone. AEs considered most worrisome by patients and rheumatologists include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections. The challenge is to maximize the benefit-risk ratio by giving the maximum glucocorticoid treatment necessary to control GCA initially and then to prevent relapse but to give the minimum treatment possible to avoid glucocorticoid-related AEs. We discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity.

This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depresssion. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Metal ions released from spinal instruments can cause localized debris and distribute systemically to settle on distant organs. Children with early-onset deformities live with metallic implants for a substantial amount of time. No research focused on metal distribution in growth-friendly instrumentations. The aim of this study was to compare age-matched growing rod (GR) and magnetically controlled growing rod (MCGR) groups to noninstrumented controls., Methods: The study was designed as a multicenter, prospective, cross-sectional case series. GR and MCGR applications of three institutions were included. A total of 52 children were enrolled. Blood samples were collected between December 2014 and February 2015. Biochemical serum analyses were performed to trace and quantify titanium, vanadium, aluminum, and boron. The GR group included 15 children. Mean age was 10.7 (range 6-15). MCGR group included 22 children. Mean age was 8.5 (range 2-13). Fifteen age-matched nonoperated children formed the control group. The mean age was 10.4 (range 5-15). One-way analysis of variance, Kruskal-Wallis, and Mann-Whitney U tests were used for comparisons., Results: The mean serum titanium level in control, GR, and MCGR groups were 2.8 ± 1.4, 7.3 ± 4.3, and 10.2 ± 6.8 μg/L, respectively. GR and MCGR group titanium levels were higher than controls' (p = .008 and p < .001). The mean serum vanadium level in control, GR, and MCGR groups were 0.2 ± 0.0, 0.2 ± 0.0, and 0.5 ± 0.5 μg/L, respectively. MCGR group vanadium level was higher than control (p < .001) and GR groups (p = .004). Mean serum levels in control, GR, and MCGR groups were, respectively, 5.4 ± 4.1, 8.1 ± 7.4, and 7.8 ± 5.1 μg/L for aluminum and 86.7 ± 2.7, 86.9 ± 2.5, and 85.0 ± 6.6 μg/L for boron. The distribution of aluminum and boron were similar across groups (p = .675 and p = .396)., Conclusions: Both GR and MCGR applications significantly release titanium and possibly aluminum. MCGR further releases vanadium. MCGR possibly releases more titanium than traditional GR. Time-dependent alterations of serum ion levels, structural properties of the MCGR device, and exposure caused by magnetic distraction processes warrant investigation., (Copyright © 2017 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

The meta-analyses of observational studies (OBS) showed the risk of any fracture and hip fracture slightly increased with proton pump inhibitor (PPI) treatment depending on the dose and regardless of time. This was not observed with histamine-2 receptor antagonists (H2RA). The risk of bacterial overgrowth and spontaneous bacterial peritonitis were increased with PPI therapy, but not with H2RA. In meta-analyses of OBS, a slight increase was observed in the risk of community-acquired pneumonia (CAP) in the early stages (<1 month) of PPI use and particularly at high doses. In a five-year LOTUS study, no difference was found in vitamin B12, folic acid, vitamin D, and calcium values in terms of the initial and end of follow-up levels. No increase in the risk of premalignant gastric lesions was observed in the meta-analysis of RCTs in which PPI treatment (≥6 months) was given to Helicobacter pylori negative patients. The risk of hypomagnesemia with PPI use was increased in patients having GFR<60, using diuretics, and over 65 years of age. Quasi-experimental studies showed a reduced zinc absorption with PPI use. In the meta-analysis of OBS, long-term (>1 year) PPI use increased the risk of fundic polyps, but no risk was found in shorter use. The meta-analyses of RCTS showed no difference between PPI and surgery or placebo arms and between the arms of H2RA and placebo in terms of all side effects. No difference was found between the PPI and H2RA arms both in all and serious adverse effects.