Late effects of high-dose methotrexate treatment in childhood cancer survivors-a systematic review.

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/m2 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.

Association of Hormonal Contraceptive Use With Adverse Health Outcomes: An Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies.

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.

Escalating morphine dosage fails to elicit conditioned analgesia in a preclinical chronic neuropathic pain model.

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.

Early LSD treatment in Denmark from 1960 to 1974: An analysis of possible and long-lasting changes in the adult personality following psychedelic treatment. A historical retrospective cohort study.

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.

Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors.

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.

Does COVID-19 Vaccination Warrant the Classical Principle "ofelein i mi vlaptin"?

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.

Long-term outcomes of warfarin versus aspirin after Fontan surgery.

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.

Association of Rituximab Use With Adverse Events in Children, Adolescents, and Young Adults.

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.

Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study.

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.

Long-term outcomes of psychoactive drug use in trauma patients: A multicenter patient-reported outcomes study.

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.

Switching across direct oral anticoagulants: a real-life-setting pilot prospective study.

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.

Two dimensional proteomic analysis of serum shows immunological proteins exclusively expressed in sulfur mustard exposed patients with long term pulmonary complications.

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.

Comparison of Two Percutaneous Atrial Septal Defect Occluders for Device Healing and Nickel Release in a Chronic Porcine Model.

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.

Aristolochia Herbs and Iatrogenic Disease: The Case of Portland's Powders.

Aristolochia herbals have a 2500-year history of medicinal use. We focused this article on Portland's Powders, an 18th-century British gout medicine containing Aristolochia herbs. The powders constitute an 18th-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.

[An 84-year-old man with an ulcer on his ankle]. / Een 84-jarige man met een ulcus op zijn enkel.

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.

Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leukaemia patients treated with second- and third-generation tyrosine kinase inhibitors.

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 (2ndG/3rdG 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 ±â€¯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.

Long-Term Effects of Early-Life Antibiotic Exposure on Resistance to Subsequent Bacterial Infection.

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 (ß-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.

Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder.

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.