Data-driven drug-induced QT prolongation surveillance using adverse reaction signals derived from 12-lead and continuous electrocardiogram data.

Drug-induced QT prolongation is one of the most common side effects of drug use and can cause fatal outcomes such as sudden cardiac arrest. This study adopts the data-driven approach to assess the QT prolongation risk of all the frequently used drugs in a tertiary teaching hospital using both standard 12-lead ECGs and intensive care unit (ICU) continuous ECGs. We used the standard 12-lead ECG results (n = 1,040,752) measured in the hospital during 1994-2019 and the continuous ECG results (n = 4,835) extracted from the ICU's patient-monitoring devices during 2016-2019. Based on the drug prescription frequency, 167 drugs were analyzed using 12-lead ECG data under the case-control study design and 60 using continuous ECG data under the retrospective cohort study design. Whereas the case-control study yielded the odds ratio, the cohort study generated the hazard ratio for each candidate drug. Further, we observed the possibility of inducing QT prolongation in 38 drugs in the 12-lead ECG analysis and 7 drugs in the continuous ECG analysis. The seven drugs (vasopressin, vecuronium, midazolam, levetiracetam, ipratropium bromide, nifedipine, and chlorpheniramine) that showed a significantly higher risk of QT prolongation in the continuous ECG analysis were also identified in the 12-lead ECG data analysis. The use of two different ECG sources enabled us to confidently assess drug-induced QT prolongation risk in clinical practice. In this study, seven drugs showed QT prolongation risk in both study designs.

Post-COVID-19 vaccination IgA vasculitis in an adult.

Leukocytoclastic vasculitis has been reported in the setting of COVID-19 infection and post-COVID-19 vaccination. We report a case of IgA vasculitis (IgAV) post-COVID-19 vaccination, with immunoglobulin A (IgA) immune deposits in the skin and renal involvement. SARS-CoV spike protein immunohistochemical staining was negative. IgAV with skin and renal involvement is a potential reaction to COVID-19 vaccination.

COVID Arm After Moderna Booster in Healthcare Worker: A Case Report.

SARS CoV-2 virus has infected more than 200 million people worldwide and more than 4.4 million in Indonesia. The vaccination program has become one of the solutions launched by many countries globally, including Indonesia, to reduce the transmission rate of COVID-19. Various vaccination platforms are produced, such as inactivated, viral vector, mRNA, and protein subunit. The vaccination booster program with mRNA platform (Moderna) was launched by the Indonesian government to give better protection for health care workers, particularly from delta variant. In this case report, we discuss one of the typical side effects of Moderna vaccine, which is referred to as the COVID arm.

Chemotherapy-Induced Intestinal Microbiota Dysbiosis Impairs Mucosal Homeostasis by Modulating Toll-like Receptor Signaling Pathways.

Chemotherapy-induced intestinal mucositis, a painful debilitating condition affecting up to 40-100% of patients undergoing chemotherapy, can reduce the patients' quality of life, add health care costs and even postpone cancer treatment. In recent years, the relationships between intestinal microbiota dysbiosis and mucositis have drawn much attention in mucositis research. Chemotherapy can shape intestinal microbiota, which, in turn, can aggravate the mucositis through toll-like receptor (TLR) signaling pathways, leading to an increased expression of inflammatory mediators and elevated epithelial cell apoptosis but decreased epithelial cell differentiation and mucosal regeneration. This review summarizes relevant studies related to the relationships of mucositis with chemotherapy regimens, microbiota, TLRs, inflammatory mediators, and intestinal homeostasis, aiming to explore how gut microbiota affects the pathogenesis of mucositis and provides potential new strategies for mucositis alleviation and treatment and development of new therapies.

Treatment-related adverse events of PD-1 and PD-L1 inhibitor-based combination therapies in clinical trials: a systematic review and meta-analysis.

BACKGROUND: Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies. METHODS: We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I2 statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617). FINDINGS: We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I2=75%) for all-grade adverse events and 68·3% (60·7-75·0; I2=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I2=86%) for all-grade adverse events and 47·3% (37·3-57·5; I2=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I2=94%) for all-grade adverse events and 35·9% (29·5-42·9; I2=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I2=74%) for all-grade adverse events and 12·4% (4·4-30·6; I2=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias. INTERPRETATION: Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care. FUNDING: National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund.

Iatrogenic male infertility: medical and surgical treatments that impair male fertility.

Many medical and surgical treatments result in impaired male fertility. Sometimes impairments are permanent, while other times they may be reversible. Clinicians who treat urologic and nonurologic problems, as well as those of us who treat male and female infertility should understand what treatments affect which aspects of reproduction and what options for management are available. Conditions for which treatment may impair fertility range from benign prostatic hyperplasia to cancer to behavioral health issues. This month's Views and Reviews summarizes these conditions, the mechanisms of fertility impairment as well as preemptive and posttreatment approaches for management.

Prevalence of adverse drug reactions in the primary care setting: A systematic review and meta-analysis.

BACKGROUND: Adverse drug reactions (ADRs) represent a major cause of iatrogenic morbidity and mortality in patient care. While a substantial body of work has been undertaken to characterise ADRs in the hospital setting, the overall burden of ADRs in the primary care remains unclear. OBJECTIVES: To investigate the prevalence of ADRs in the primary care setting and factors affecting the heterogeneity of the estimates. METHODS: Studies were identified through searching of Medline, Embase, CINAHL and IPA databases. We included observational studies that reported information on the prevalence of ADRs in patients receiving primary care. Disease and treatment specific studies were excluded. Quality of the included studies were assessed using Smyth ADRs adapted scale. A random-effects model was used to calculate the pooled estimate. Potential source of heterogeneity, including age groups, ADRs definitions, ADRs detection methods, study setting, quality of the studies, and sample size, were investigated using sub-group analysis and meta-regression. RESULTS: Thirty-three studies with a total study population of 1,568,164 individuals were included. The pooled prevalence of ADRs in the primary care setting was 8.32% (95% CI, 7.82, 8.83). The percentage of preventable ADRs ranged from 12.35-37.96%, with the pooled estimate of 22.96% (95% CI, 7.82, 38.09). Cardiovascular system drugs were the most commonly implicated medication class. Methods of ADRs detection, age group, setting, and sample size contributed significantly to the heterogeneity of the estimates. CONCLUSION: ADRs constitute a significant health problem in the primary care setting. Further research should focus on examining whether ADRs affect subsequent clinical outcomes, particularly in high-risk therapeutic areas. This information may better inform strategies to reduce the burden of ADRs in the primary care setting.

Heart Rate Variability as a Non-invasive Objective Parameter for Predicting the Occurrence of Chemotherapy-induced Peripheral Neuropathy in Patients With Gastrointestinal Cancer.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common chemotoxicities. However, no effective clinical CIPN screening methods have been reported. This study aimed to investigate whether changes in heart rate variability (HRV) could predict the development of CIPN for early symptom control in chemotherapy-prescribed patients with gastrointestinal (GI) cancer. PATIENTS AND METHODS: Fifty-five GI cancer outpatients undergoing palliative chemotherapy including taxanes and/or platinum compounds were enrolled. CIPN was diagnosed using National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI-CTCAE). HRV measures were derived from electrocardiogram signals. RESULTS: Twelve weeks after starting chemotherapy, 39 (70.9%) patients who complained of NCI-CTCAE grade 1-3 sensory changes were diagnosed with CIPN. Standard deviation of normal-to-normal R-R intervals (SDNN), high frequency (HF), low frequency (LF), and LF/HF ratio changed significantly during 3 assessment periods. Percentage changes in SDNN and HF were related to the occurrence of CIPN symptoms. A decision tree model indicated that patients with a rapid percentage change decrease in SDNN and HF were CIPN-positive. CONCLUSION: Using SDNN and HF, our decision tree predicted CIPN occurrence. The changes in HRV may occur earlier than sensory CIPN symptoms.

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

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

N-Acetylcysteine treatment of neonatal acetaminophen toxicity caused by transplacental transfer - a case report.

We describe a case of maternal acetaminophen toxicity leading to Caesarean section delivery of a pre-term neonate with acetaminophen-induced hepatic injury and encephalopathy at 33 weeks gestational age. Delayed treatment with N-acetylcysteine (NAC) was initiated in the baby 11 h after delivery, with eventual discharge of a healthy baby at 12 days of age. The baby was treated with a standard but extended duration NAC protocol. Post-operatively, liver biopsy of the mother demonstrated acetaminophen-induced hepatic injury overlying mild hepatic steatosis. This was also managed with NAC therapy leading to complete clinical resolution of acetaminophen induced hepatic injury and discharge on post-operative day 10. This case of delayed NAC therapy for the treatment of pre-term neonatal acetaminophen toxicity is one of very few reported in the literature and can be used as a guide in the management of subsequent cases.

Pulmonary Arterial Hypertension Secondary to Drugs and Toxins.

Pulmonary arterial hypertension secondary to drugs and toxins is an important subgroup of group 1 pulmonary hypertension associated with significant morbidity and mortality. Many drugs and toxins have emerged as risk factors for pulmonary arterial hypertension, which include anorexigens, illicit agents, and several US Food and Drug Administration-approved therapeutic medications. Drugs and toxins are classified as possible or definite risk factors for pulmonary arterial hypertension. This article reviews agents that have been implicated in the development of pulmonary arterial hypertension, their pathologic mechanisms, and methods to prevent the next deadly outbreak of drug- and toxin-induced pulmonary arterial hypertension.

Patogénesis del dolor en la mucositis oral. Revisión de la literatura / Pathogenesis of pain in oral mucositis. Review of the literature

INTRODUCCIÓN: La mucositis oral es una lesión dolorosa que tiene lugar en la mucosa de la cavidad oral, normalmente su etiología se encuentra asociada a tratamientos farmacológicos en pacientes oncológicos. Se presenta como úlceras bien delimitadas cuya sintomatología dolorosa supone en ocasiones la suspensión del tratamiento oncológico o la alimentación por vía parenteral, siendo por tanto un efecto adverso importante, marcando el devenir en este tipo de terapias contra el cáncer. OBJETIVO: El objetivo del presente artículo es poner en relieve cómo se produce el dolor en esta patología que acontece en la mucosa de la cavidad oral. DISCUSIÓN: La mucositis oral se va a presentar tras una cascada de eventos biológicos que implican diferentes procesos moleculares tras el tratamiento con quimioterapia o radioterapia. El dolor en la mucositis oral puede poseer un componente inflamatorio y también un componente neuropático. En su fisiopatología, el dolor va a estar mediado por diferentes familias de receptores y factores. CONCLUSIÓN: La mucositis oral presenta un gran componente doloroso asociado, en el que cobran especial protagonismo en su aparición, las familias de los receptores y factores TRP, ET-1, TNF y ROS, entre otros. El conocimiento de la patogénesis del dolor en esta patología permitirá desarrollar terapéuticas contra el dolor en estudios futuros

INTRODUCTION: Oral mucositis is a painful lesion that occurs in the mucosa of the oral cavity. Its aetiology is usually associated with drug treatments in cancer patients. It presents as well-defined ulcers whose painful symptoms sometimes lead to the suspension of cancer treatment or parenteral nutrition. They therefore represent a significant adverse effect that marks the future in this type of cancer therapy. OBJECTIVE: The objective of this article is to highlight how pain occurs in this pathology that takes place in the mucosa of the oral cavity. DISCUSSION: Oral mucositis will occur following a cascade of biological events involving different molecular processes following treatment with chemotherapy or radiotherapy. Pain in oral mucositis may have an inflammatory component as well as a neuropathic component. In its pathophysiology, pain will be mediated by different families of receptors and factors. CONCLUSION: Oral mucositis has a large associated painful component, in which the families of TRP, ET-1, TNF and ROS receptors and factors, among others, play a major role in its appearance. Knowledge of the pathogenesis of the pain in this pathology will allow pain therapies to be developed in future studies

The predictive value of body mass index on prognosis and adverse events of cancers treated with immunotherapy: a systematic review and meta-analysis.

OBJECTIVE: High body mass index (BMI) greater than 25 kg/m2 has a complex relationship with cancers. The aim of this systematic review and meta-analysis is to explore controversy over whether BMI is correlated with outcomes including survival and immunotherapy-related adverse events (irAEs) in cancer patients treated with immunotherapy. METHODS: We searched PubMed, Embase, Web of Science, and The Cochrane Library for relevant studies published up to June 2020. Title/abstract screening, full-text review, data extraction, and quality assessment were performed independently. Subgroup analysis was based on sex, treatment lines, the status of programmed death-ligand 1 (PD-L1), and tumor types. Sensitivity analysis was performed by synthesizing studies that adjusted for certain covariates or studies with good quality. Statistical heterogeneity was evaluated by the I2 value. Meta-analysis was performed with hazard ratio (HR) / odds ratio (OR) and 95% confidence intervals (CIs) as the effect measures. RESULTS: Twenty studies were included for survival and irAEs analyses. Patients with high BMI who underwent immunotherapy had longer overall survival (OS) (pooled hazard ratio, pHR = 0.71 [95% CI: 0.59-0.85]) and progression-free survival (PFS) (pHR = 0.76 [95% CI: 0.65-0.88]) than those with low BMI; at the same time, high-BMI patients had increased irAEs (OR = 2.54 [95% CI: 1.12-5.79]). CONCLUSION: In general, high BMI was correlated with improved OS and PFS in patients treated with immunotherapy along with a high risk of irAEs. However, discrepant findings from subgroup analyses urgently call for further analysis.

Toxicant effects on mammalian oocyte mitochondria†.

Oocyte mitochondria are unique organelles that establish a founder population in primordial germ cells (PGCs). As the oocyte matures in the postnatal mammalian ovary during folliculogenesis it increases exponentially in volume, and the oocyte mitochondria population proliferates to about 100 000 mitochondria per healthy, mature murine oocyte. The health of the mature oocyte and subsequent embryo is highly dependent on the oocyte mitochondria. Mitochondria are especially sensitive to toxic insults, as they are a major source of reactive oxygen species (ROS), they contain their own DNA (mtDNA) that is unprotected by histone proteins, they contain the electron transport chain that uses electron donors, including oxygen, to generate ATP, and they are important sensors for overall cellular stress. Here we review the effects that toxic insults including chemotherapeutics, toxic metals, plasticizers, pesticides, polycyclic aromatic hydrocarbons (PAHs), and ionizing radiation can have on oocyte mitochondria. This is very clearly a burgeoning field, as our understanding of oocyte mitochondria and metabolism is still relatively new, and we contend much more research is needed to understand the detrimental impacts of exposure to toxicants on oocyte mitochondria. Developing this field further can benefit our understanding of assisted reproductive technologies and the developmental origins of health and disease (DOHaD).

Computational models of cardiac hypertrophy.

Cardiac hypertrophy, defined as an increase in mass of the heart, is a complex process driven by simultaneous changes in hemodynamics, mechanical stimuli, and hormonal inputs. It occurs not only during pre- and post-natal development but also in adults in response to exercise, pregnancy, and a range of cardiovascular diseases. One of the most exciting recent developments in the field of cardiac biomechanics is the advent of computational models that are able to accurately predict patterns of heart growth in many of these settings, particularly in cases where changes in mechanical loading of the heart play an import role. These emerging models may soon be capable of making patient-specific growth predictions that can be used to guide clinical interventions. Here, we review the history and current state of cardiac growth models and highlight three main limitations of current approaches with regard to future clinical application: their inability to predict the regression of heart growth after removal of a mechanical overload, inability to account for evolving hemodynamics, and inability to incorporate known growth effects of drugs and hormones on heart growth. Next, we outline growth mechanics approaches used in other fields of biomechanics and highlight some potential lessons for cardiac growth modeling. Finally, we propose a multiscale modeling approach for future studies that blends tissue-level growth models with cell-level signaling models to incorporate the effects of hormones in the context of pregnancy-induced heart growth.

Alterations of gut microbiota composition in post-finasteride patients: a pilot study.

PURPOSE: Post-finasteride syndrome (PFS) has been reported in a subset of patients treated with finasteride (an inhibitor of the enzyme 5alpha-reductase) for androgenetic alopecia. These patients showed, despite the suspension of the treatment, a variety of persistent symptoms, like sexual dysfunction and cognitive and psychological disorders, including depression. A growing body of literature highlights the relevance of the gut microbiota-brain axis in human health and disease. For instance, alterations in gut microbiota composition have been reported in patients with major depressive disorder. Therefore, we have here analyzed the gut microbiota composition in PFS patients in comparison with a healthy cohort. METHODS: Fecal microbiota of 23 PFS patients was analyzed by 16S rRNA gene sequencing and compared with that reported in ten healthy male subjects. RESULTS: Sexual dysfunction, psychological and cognitive complaints, muscular problems, and physical alterations symptoms were reported in more than half of the PFS patients at the moment of sample collection. The quality sequence check revealed a low library depth for two fecal samples. Therefore, the gut microbiota analyses were conducted on 21 patients. The α-diversity was significantly lower in PFS group, showing a reduction of richness and diversity of gut microbiota structure. Moreover, when visualizing ß-diversity, a clustering effect was found in the gut microbiota of a subset of PFS subjects, which was also characterized by a reduction in Faecalibacterium spp. and Ruminococcaceae UCG-005, while Alloprevotella and Odoribacter spp were increased compared to healthy control. CONCLUSION: Gut microbiota population is altered in PFS patients, suggesting that it might represent a diagnostic marker and a possible therapeutic target for this syndrome.

Efficacy of Aloe-Vera Use for Prevention of Chemotherapy-Induced Oral Mucositis in Children with Acute Lymphoblastic Leukemia: A Randomized Controlled Clinical Trial.

Oral mucositis can be caused by chemotherapy and can affect a patient's quality of life. Nowadays, to prevent chemotherapy-induced oral mucositis (CIOM) is a crucial point in palliative care centers. This trial aimed to assess the effectiveness of aloe-vera in that concept. The trial was accomplished at Hematology Department of Hospital of Children of Damascus University, Syria. Acute lymphoblastic leukemia (ALL) children were the population from which 26 children were enrolled in the study. They were aged between 3 and 6 years old and were randomly referred according to the intervention into two groups, Aloe-vera (AV) and sodium bicarbonate 5% (13 each). Spongeous sticks were used to help in applying the material on tongue, labial and buccal mucosa, lips, floor of the mouth, and hard palate. Two blinded external examiners evaluated oral mucosa weekly for up to 2 months using the World Health Organization grading scale. Mann-Whitney U test was used to analyze data. According to the observed findings, CIOM degrees were less severe in the aloe-vera group than in the sodium bicarbonate group. Statistically significant difference of occurrence of different CIOM degrees between groups was recorded in the 2nd, 3rd, 4th, and 7th weeks of follow-up period. Moreover, Mann-Whitney U test indicated that patients in the sodium bicarbonate group began CIOM sooner than those in the aloe-vera group with a statistically significant difference (p = .001). These findings show that topical application of aloe-vera solution is effective in the prevention of CIOM in ALL children.

Taste Function in Adults Undergoing Cancer Radiotherapy or Chemotherapy, and Implications for Nutrition Management: A Systematic Review.

BACKGROUND: Taste changes are commonly reported by people with cancer undergoing radio- or chemotherapy. Taste changes may compromise dietary intake and nutritional status. OBJECTIVE: To understand whether or not taste change is associated with cancer diagnosis or treatment modality in adults. METHODS: A systematic literature search up to December 31, 2019, was conducted using PubMed, Embase, and PsycInfo (International Prospective Register of Systematic Reviews protocol no. CRD42019134005). Studies in adults with cancer objectively assessing the effect of a cancer diagnosis or chemotherapy and/or radiotherapy treatment on taste function compared with healthy controls or within participant changes were included. Additional outcomes were food liking, appetite, dietary intake, nutritional status, and body composition. Reference lists of relevant articles were searched to identify additional articles. Quality was assessed using the Academy of Nutrition and Dietetics quality criteria checklist. RESULTS: A total of 24 articles were included, one of which consisted of two studies that reported the effects of radiotherapy and chemotherapy separately. From the total 25 studies reported in 24 published articles, 14 studies examined effects of radiotherapy, and remaining 11 studies examined chemotherapy. There is limited evidence of a cancer diagnosis per se contributing to taste dysfunction. Impaired taste function was reported in almost all radiotherapy studies, occurring as early as Week 3 of treatment and lasting for 3 to 24 months posttreatment. During chemotherapy, impairment of taste function was less consistently reported, occurring as early as the first few days of chemotherapy, and persisting up to 6 months posttreatment. Taxane-based chemotherapy was reported to affect taste function more than other treatments. Several studies reported reduced liking for food, appetite, and dietary intake. Only one study reported nutritional status of participants, finding no association between taste function and nutritional status. No studies examined associations between taste changes and body composition. CONCLUSIONS: This review highlights the importance of considering treatment modality in practice. Research is required to identify factors contributing to taste alteration and to inform evidence-based interventions.