Rhabdomyolysis Associated With Mirtazapine and Quetiapine Therapy: A Case Report and Review of the Literature.

Rhabdomyolysis has been reported as a rare adverse effect of psychotropic use. This paper presents a case of rhabdomyolysis in a 39-year-old man with depression and substance use disorder. He had been started on quetiapine two months before and mirtazapine two weeks before developing symptoms of pain and weakness. His creatine kinase (CK) was elevated to 5870 U/L, with no other contributing factors elicited. He improved with symptomatic treatment along with cessation of psychotropics. A literature review on rhabdomyolysis associated with quetiapine and/or mirtazapine therapy found 12 cases with quetiapine, one case with mirtazapine, and three cases with quetiapine and mirtazapine combination treatment. The majority were men, aged 19 to 70 years old. There was no clear correlation between dose and maximum CK levels, and the time to onset of symptoms varied from two days to eight months. The proposed mechanism is a serotoninergic or dopaminergic blockade. Rhabdomyolysis associated with quetiapine or mirtazapine can occur even at therapeutic doses and clinicians should be aware of this potentially life-threatening adverse effect.

Serotonin antidepressants and atrial fibrillation burden from cardiac implantable electronic devices.

Objective: Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF. However, no studies have examined the relationship between antidepressant use and AF burden (time in AF). This retrospective cohort study examined cardiac implantable device-detected AF episodes and their relationship with antidepressant use, among other treatment factors. Methods: Consecutive patients from the Western Health Cardiology Department attending pacemaker checks between 2015 and 2021 were included. Patients with permanent AF were excluded, yielding 285 patients with no or paroxysmal AF, with a total of 772 patient encounters. Generalized estimating equations were used to model two processes: binary AF (present/absent) and the number of days in AF for patients with AF. Results: Each yearly increase with age was associated with an increase in the odds of developing AF (OR 1.03 [1.00-1.05], p = .027). Male gender conferred a reduction in AF incidence (OR 0.30 [0.13-0.68], p = .004). Digoxin use was associated with incident AF (OR 4.43 [1.07-18.4], p = .04). Sotalol and heart-failure beta blocker use were associated with a decrease in AF burden (IRR 0.30 [0.12-0.78], p = .013 and 0.33 [0.14-0.81], p = .015). Selective serotonin reuptake inhibitor antidepressant use was associated with reduced AF burden (IRR 0.27 [0.09-0.81], p = .019), as was selective serotonin/noradrenaline reuptake inhibitor use (IRR 0.07 [0.03-0.15], p < .001). Conclusions: Older age, female gender and digoxin are associated with a higher odds of developing incident AF. Sotalol, heart failure beta blockers and serotonin-based antidepressants are associated with reduced AF burden. Further prospective study into the effects of antidepressants on atrial arrhythmias is warranted.

Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications.

Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Supportive care and symptom management in patients with advanced hematological malignancies: a literature review.

BACKGROUND AND OBJECTIVE: Recent advances have led to cure or long-term disease control for patients with hematological malignancy (HM). Unfortunately, some of them still have poor prognoses and are often associated with significant symptom burden and poor quality of life for patients and families. These patients usually require supportive care including red blood cell and platelet transfusion, due to disease itself and the oncological treatment, apart from their symptom management. However, there is currently lack of the literatures review in these aspects. The objective of this review is to summarize practical supportive care recommendations for physicians or nurses practicing in palliative care (PC)/hematology-oncology unit, starting with core approaches in use of blood products for anemia and thrombocytopenia, management of tumor lysis syndrome, PC and oncology nursing care. METHODS: Evidence for this review was obtained from a search of the Cochrane database, PubMed, guidelines of European Society of Medical Oncology, British society of Hematology, American Society of Clinical Oncology, National Comprehensive Cancer Network and peer-reviewed journal articles. KEY CONTENT AND FINDINGS: For asymptomatic cancer patients who are anaemic, a threshold of haemoglobin level of 7 g/dL is considered to be safe and generally favored for blood transfusion. 'Single-unit' red cell transfusion is safer and at least as effective as 'double-unit' transfusion. Prophylactic platelet transfusion should be given to stable patients without bleeding and with platelet count less than 10×109/L. In febrile patients, the threshold is lifted to 20×109/L. There are also recommendations for the use of blood products during COVID-19 pandemic. In general, HM patients were more prone to painful infections when compared with solid cancer patients. Thus, antibiotics to treat underlying infections should be applied whenever possible and as required to control pain. CONCLUSIONS: This narrative review showed the recent literatures in the supportive care and symptom management of advanced HM patients. However, it is limited by some of the 'evidence-based' recommendations for interventions (including symptom management) based on early phase of HM populations rather than those receiving end-of-life care.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Depression, Stress, and Perceived Medical Errors in Singapore Psychiatry Residents.

OBJECTIVE: Doctors in training, especially psychiatrists, are at high risk of depression and burnout, which have been linked to increased medical errors. This study looks at prevalence and risk factors of depression and perceived stress among psychiatry residents in Singapore. METHODS: An anonymous online questionnaire was completed by 65.3% (47/72) of residents, which included the Patient Health Questionnaire-9 (PHQ-9), Perceived Stress Scale (PSS), and 2 burnout screening questions. They were asked if they were concerned about making a medical error. RESULTS: Majority of residents (70.2%) slept 6-8 h/night, while 55.3% worked < 60 h/week. Based on PHQ-9 score ≥ 10, 38.3% had depression. Depression was associated with sleeping < 6 h/night (OR 13.62, 2.96-62.6; p = 0.0008) and working ≥ 60 h/week (OR 3.8, 1.096-13.18; p = 0.035). Six residents (12.8%) endorsed suicidal ideation. The mean score on the PSS scale was 23.89 ± 1.95. Higher PSS scores were associated with sleeping < 6 h/night (OR 4.92, 1.51-8.33; p = 0.007). One third of residents (34%) reported feeling burnt out fairly or very often. Residents who slept < 6 h/night were more likely to report feeling burnt out (OR 6.69, 1.69-26.45; p = 0.0068). PHQ scores correlated highly with PSS scores and burnout measures. Self-perceived medical errors were associated with depressive symptoms, suicidal thoughts, and < 6 h/night of sleep. CONCLUSIONS: Less sleep and longer working hours were associated with higher risk of depression, suicidality, stress, and perceived medical errors in Singapore psychiatry residents. It is important to address depression and stress as it can affect physician well-being and patient care.

Clinical and socio-demographic features in childhood vs adolescent-onset anorexia nervosa in an Asian population.

PURPOSE: Childhood-onset anorexia nervosa (AN) may be under-recognised and under-treated due to atypical presentations. The aims of this study are: (1) describe features of AN in patients ≤ 18 years in an Asian population; and (2) compare childhood-onset and adolescent-onset AN. METHODS: This study involved a retrospective chart review of patients ≤ 18 years in a Asian population who were treated for anorexia nervosa at the Eating Disorders Service at Singapore General Hospital between Jan 2003 and Dec 2014 (n = 435). Childhood-onset AN was defined as onset < 13 years, while adolescent-onset AN was defined as onset between 13 and 18 years. RESULTS: Patients were predominantly female (95.4%) and Chinese (83%). The childhood-onset group (8.3%) had mean age of onset 11.5 ± 1.0 years, compared to 15.2 ± 1.6 years for the adolescent-onset group. The childhood and adolescent-onset groups were similar in socio-demographic variables, as well as gender distribution, AN subtype, number of psychiatric comorbidities, family history of psychiatric illness, body image issues and excessive exercise. The childhood-onset group had significantly longer duration of illness prior to presentation (4.75 vs 2.62 years), greater frequency of comorbid obsessive-compulsive disorder (19.4% vs 5.3%) and were more likely to report teasing as a trigger for AN (58.3% vs 31.6%). The childhood-onset group had significantly longer duration of inpatient stay (5.97 vs 3.22 weeks), as well as a greater number of total admissions (2.78 vs 1.37). CONCLUSION: Our results suggest that cultural factors may impact the development or identification of AN in an Asian context. Possible delay in diagnosis of childhood-onset AN may lead to a more unfavorable clinical course. LEVEL OF EVIDENCE: Level V, descriptive study.

FDG-PET in suspected dementia with Lewy bodies: a case report.

BACKGROUND: Dementia with Lewy bodies (DLB) is still underdiagnosed or mistaken for other types of neurodegenerative diseases. Biomarkers such as 18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) can be helpful. CASE PRESENTATION: A 72-year-old gentleman presented with postural hypotension, hallucination, Parkinsonism and recurrent falls. He also had rapidly progressing cognitive impairment. CT and MRI brain showed atrophy of the frontal lobes with preservation of the hippocampi. FDG-PET was suggestive of DLB. He was subsequently treated with Rivastigmine, with significant improvement of his symptoms. CONCLUSION: This case highlights the challenges in diagnosis of an elderly patient with DLB, the use of neuro-imaging as a diagnostic biomarker, the avoidance of the use of antipsychotic and the response to pharmacological treatment with Rivastigmine after a probable diagnosis of DLB.

Mania following antidepressant discontinuation in depression: two case reports.

OBJECTIVE: Antidepressant-induced mania and an antidepressant discontinuation syndrome are well documented, whereas mania occurring after antidepressant cessation has been infrequently reported. METHOD: We describe antidepressant discontinuation-related mania in two Chinese patients, as well as a review of the literature on this phenomenon in unipolar depression. RESULTS: A 72-year-old man and a 65-year-old woman had late-onset depression with vascular risk factors, but no personal or family history of mood disorders. Manic symptoms started after stopping escitalopram and venlafaxine during depressive relapse, and resolved with the initiation of olanzapine and valproate. In the literature, 29 episodes of antidepressant discontinuation-related mania were reported. Tricyclic antidepressants were most frequently implicated, followed by selective serotonin reuptake inhibitors. There was spontaneous resolution of manic symptoms in half of the cases. CONCLUSION: This is the first report of antidepressant discontinuation-related mania in an Asian population, in the setting of late-onset depression. This phenomenon is rare and is amenable to standard treatment.

Necroptosis Is Involved in CD4+ T Cell-Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection.

BACKGROUND: Despite advances in immunosuppressive therapies, the rate of chronic transplant loss remains substantial. Organ injury involves various forms of cell death including apoptosis and necrosis. We now recognize that early injury of cardiac transplants involves a newly described form of programmed necrotic cell death, termed necroptosis. Because this involves receptor-interacting protein (RIP) kinase 1/3, this study aimed to establish the role of RIP3 in chronic cardiac allograft rejection. METHODS: We used major histocompatibility complex class II mismatched C57BL/6N (H-2; B6) or B6.RIP3 (H-2; RIP3) mice to B6.C-H-2 (H2-Ab1; bm12) mouse cardiac transplantation. Microvascular endothelial cells (MVEC) were developed from B6 and RIP3 cardiac grafts. RESULT: CD4 T cell-mediated cardiac graft rejection is inhibited using RIP3 deficient donor grafts, with reduced cellular infiltration and vasculopathy compared with wild type cardiac grafts. Alloreactive CD4 T cell-mediated MVEC death involves TNFα, Fas ligand (FasL) and granzyme B. Although necroptosis and release of danger molecule high-mobility group box 1 are eliminated by the absence of RIP3, CD4 T cells had attenuated MVEC death through granzyme B and FasL. CONCLUSIONS: CD4 T cell-mediated MVEC death involves in TNFα, FasL and granzyme B. Necroptotic cell death and release of the danger molecule may promote inflammatory responses and transplant rejection. Although loss of RIP3 does not eliminate alloimmune responses, chronic graft injury is reduced. RIP3 is an important therapeutic target but additional granzyme and caspases inhibition is required for sufficiently improving long-term graft survival.

An Overview of Acquired Brain Injury Rehabilitation Randomized Controlled Trials.

OBJECTIVE: To summarize randomized controlled trials published in the acquired brain injury rehabilitation literature. SETTING: N/A. PARTICIPANTS: N/A. DESIGN: Systematic literature review. MAIN MEASURES: A total of 143 published randomized controlled trials in acquired brain injury rehabilitation literature from January 1980 to October 2012. Measures were area of research, number of studies, sample size, methodological quality, and country of origin. RESULTS: There were no significant differences in median sample sizes (P = .212; 95% confidence interval [CI], 0.199-0.215) or PEDro scores (P = .492; 95% CI, .491-.510) between 4 research areas in acquired brain injury: sensory-motor, cognitive-communication, medical complications, and psychosocial. Between 1980 and 2012, there was no significant difference in median sample sizes (P = .202; 95% CI, 0.198-0.214). Median PEDro scores did not significantly improve between 1983-1987 (median = 4, interquartile range = 4.5) and 2008-2012 (median = 6, interquartile range = 2; P = .100; 95% CI, 0.093-0.105). CONCLUSIONS: This study demonstrates the need for more randomized controlled trials, increased sample sizes, and improved methodological quality to better guide clinical practice for acquired brain injury rehabilitation.

Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study.

PURPOSE: To improve treatment outcome for childhood acute lymphoblastic leukemia (ALL), we designed the Malaysia-Singapore ALL 2003 study with treatment stratification based on presenting clinical and genetic features and minimal residual disease (MRD) levels measured by polymerase chain reaction targeting a single antigen-receptor gene rearrangement. PATIENTS AND METHODS: Five hundred fifty-six patients received risk-adapted therapy with a modified Berlin-Frankfurt-Münster-ALL treatment. High-risk ALL was defined by MRD ≥ 1 × 10(-3) at week 12 and/or poor prednisolone response, BCR-ABL1, MLL gene rearrangements, hypodiploid less than 45 chromosomes, or induction failure; standard-risk ALL was defined by MRD ≤ 1 × 10(-4) at weeks 5 and 12 and no extramedullary involvement or high-risk features. Intermediate-risk ALL included all remaining patients. RESULTS: Patients who lacked high-risk presenting features (85.7%) received remission induction therapy with dexamethasone, vincristine, and asparaginase, without anthracyclines. Six-year event-free survival (EFS) was 80.6% ± 3.5%; overall survival was 88.4% ± 3.1%. Standard-risk patients (n = 172; 31%) received significantly deintensified subsequent therapy without compromising EFS (93.2% ± 4.1%). High-risk patients (n = 101; 18%) had the worst EFS (51.8% ± 10%); EFS was 83.6% ± 4.9% in intermediate-risk patients (n = 283; 51%). CONCLUSION: Our results demonstrate significant progress over previous trials in the region. Three-drug remission-induction therapy combined with MRD-based risk stratification to identify poor responders is an effective strategy for childhood ALL.

Mitochondrial D-loop polymorphisms and mitochondrial DNA content in childhood acute lymphoblastic leukemia.

The mitochondrial displacement loop (D-loop) controls mitochondrial expression, with mutations and mitochondrial DNA (mtDNA) content linked to oncogenesis. We investigated D-loop polymorphisms and mtDNA content in childhood acute lymphoblastic leukemia (ALL). The D-loop was sequenced in 251 children: precursor B ALL (n=114), with 76 paired remission/relapse samples; T-ALL (n=24); cord blood controls (n=113). The mtDNA copy number was analyzed using real-time quantitative polymerase chain reaction for 92 controls and 54 ALL patients at diagnosis and remission. Polymorphisms around H-strand replication origin (nucleotides 150 to 199) and conserved sequence block II (nucleotides 299 to 317) were associated with leukemia biology and treatment response. T-ALL patients were more likely to have longer nt303 poly-C tract. T199C polymorphism was associated with increased risk of ALL in Malays; T152C was more frequent in good responders. There was no difference in mtDNA content between diagnostic ALL samples and controls; however, there was significant decrease in mtDNA content after treatment, especially in samples with OH polymorphisms. Somatic mutations were found in 13% (9 of 76) of patients, suggesting a link to leukemogenesis. Our results suggest that polymorphisms impacting transcriptional control could affect mtDNA replication. Decrease in mtDNA content after treatment may confer susceptibility to chemotherapy and be a clue to the good prognosis of childhood ALL.

Ethnic differences in the frequency of subtypes of childhood acute lymphoblastic leukemia: results of the Malaysia-Singapore Leukemia Study Group.

Childhood acute lymphoblastic leukemia (ALL) is clinically heterogeneous with prognostically and biologically distinct subtypes. Although racial differences in frequency of different types of childhood ALL have been reported, many are confounded by selected or limited population samples. The Malaysia-Singapore (MA-SPORE) Leukemia Study Group provided a unique platform for the study of the frequency of major subgroups of childhood ALL in a large cohort of unselected multiethnic Asian children. Screening for the prognostically important chromosome abnormalities (TEL-AML1, BCR-ABL, E2A-PBX1, and MLL) using multiplex reverse-transcription polymerase chain reaction was performed on 299 consecutive patients with ALL at 3 study centers (236 de novo, 63 at relapse), with the ethnic composition predominantly Chinese (51.8%) and Malay (34.8%). Reverse-transcription polymerase chain reaction was successful in 278 (93%) of cases screened. The commonest fusion transcript was TEL-AML1 (19.1%) followed by BCR-ABL (7.8%), MLL rearrangements (4.2%), and E2A-PBX1 (3.1%). Chinese have a significantly lower frequency of TEL-AML1 (13.3% in de novo patients) compared with Malays (22.2%) and Indians (21.7%) (P=0.04). Malays have a lower frequency of T-ALL (6.2%) compared with the Chinese and Indians (9.8%). Both Malays (7.4%) and Chinese (5.0%) have significantly higher frequency of BCR-ABL compared with the Indian population (P<0.05) despite a similar median age at presentation. Our study suggests that there are indeed significant and important racial differences in the frequency of subtypes of childhood ALL. Comprehensive subgrouping of childhood ALL may reveal interesting population frequency differences of the various subtypes, their risk factors and hopefully, its etiology.

Minimal residual disease (MRD) measurement as a tool to compare the efficacy of chemotherapeutic drug regimens using Escherichia Coli-asparaginase or Erwinia-asparaginase in childhood acute lymphoblastic leukemia (ALL).

BACKGROUND: L-asparaginase is a crucial drug in childhood acute lymphoblastic leukemia (ALL) induction therapy, but much debate remains regarding the optimal formulation and dosage. As minimal residual disease (MRD) can accurately measure extremely low levels of lymphoblasts, it is a sensitive reflection of leukemia cell kill. We utilized MRD to compare the efficacy of Erwinia-asparaginase (Erwinia-asp) and E. coli-asparaginase (E. coli-asp) during induction therapy for childhood ALL. PROCEDURE: Of 116 precursor-B ALL patients, 22 were treated with Erwinia-asp, 90 with E. coli-asp, and 4 were switched from E. coli-asp to Erwinia-asp. MRD levels at the end of induction were analyzed for 90 patients (Erwinia-asp = 16; E. coli-asp = 74). Patients were stratified into MRD > or =10(-2), between 10(-2)-10(-4) and < or =10(-4). Toxicity information during induction was available for 110 patients. RESULTS: MRD was the only significant prognosticator compared to conventional criteria. Patients treated with Erwinia-asp were 6.7 times more likely to have MRD levels > or =10(-2) (P = 0.031), reflecting slower lymphoblast clearance. While non-asparaginase related toxicities were similar in both groups, more E. coli-asp patients experienced severe asparaginase-related toxicity. CONCLUSION: E. coli-asp is superior to Erwinia-asp in childhood ALL induction. Although E. coli-asp is more toxic, this is balanced by better response to therapy. Early response to treatment as measured by MRD is a direct reflection of leukemic cell kill and is a significant prognosticator of eventual outcome, making it a good surrogate marker to evaluate the efficacy of induction drugs in childhood ALL.