A potential novel treatment for cirrhosis-related ascites: Empagliflozin is safe and tolerable in advanced chronic liver disease.

AIMS: Advanced chronic liver disease and advanced chronic liver disease-related ascites have a high mortality. The pharmacological treatment of ascites and fluid overload has changed little over time. Empagliflozin, a sodium-glucose cotransporter type 2 inhibitor is an untested potential novel treatment in cirrhosis, as it has survival benefits in heart failure, which has similar pathophysiological fluid overload mechanisms. Before investigating empagliflozin's potential benefit in cirrhosis, its safety must be addressed. METHODS: Ten participants (five each with compensated or decompensated advanced chronic liver disease, based on Child-Pugh class) received empagliflozin 10 mg orally daily for 4 weeks with 2 weeks follow-up. Empagliflozin safety, pharmacokinetics and pharmacodynamics were investigated. RESULTS: In total, eight patients (80%) reported an adverse event, and three patients (30%) experienced a serious adverse event, one of which was attributed to empagliflozin. Overall, the frequency of adverse events was similar to previous phase 3 trials of gliflozins. Higher plasma empagliflozin concentrations did not significantly increase the risk of adverse events. CONCLUSIONS: Four-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data support assessment of long-term treatment on disease-related and mortality outcomes in patients with cirrhosis through randomized control trials.

Ceftazidime Plasma Concentrations and Neurotoxicity: The Importance of Therapeutic Drug Monitoring in Patients Undergoing Different Modalities of Renal Replacement Therapy. A Grand Round.

ABSTRACT: Ceftazidime-avibactam (CTZ-AVM) is a novel cephalosporin/beta-lactamase inhibitor with broad-spectrum activity against multidrug-resistant Pseudomonas aeruginosa . Ceftazidime-induced neurotoxicity is a well-described adverse effect, particularly in patients with renal insufficiency. However, appropriate dosing of ceftazidime-avibactam in patients undergoing renal replacement therapy (RRT) is sparsely investigated, and therapeutic drug monitoring to guide dosing remains lacking. Furthermore, when dose adjustment for impaired renal function is based on CTZ-AVM product information, inferior cure rates have been obtained compared with those with the standard therapy for intra-abdominal infections. Maintaining an effective dose while avoiding toxicity in these patients is challenging. Here, the authors describe the case of a critically ill patient, undergoing 2 modalities of RRT, who developed ceftazidime-induced neurotoxicity as confirmed using ceftazidime therapeutic drug monitoring. This case illustrates a therapeutic drug monitoring-based approach for guiding ceftazidime-avibactam dosing in this context and in diagnosing the cause of neurological symptoms and signs.

The Placental Function Beyond Pregnancy: Insights from Latin America.

Currently, more than 100,000 papers had been published studying the placenta in both physiological and pathological contexts. However, relevant health conditions affecting placental function, mostly found in low-income countries, should be evaluated deeper. This review will raise some - of what we think necessary - points of discussion regarding challenging topics not fully understood, including the paternal versus maternal contribution on placental genes imprinting, placenta-brain communication, and some environmental conditions affecting the placenta. The discussions are parts of an international effort to fulfil some gaps observed in this area, and Latin-American research groups currently evaluate that.

Understanding the Pharmacokinetics of Antibiotics in Pregnancy: Is There a Role for Therapeutic Drug Monitoring? A Narrative Review.

PURPOSE: Antibiotics are commonly used during pregnancy. However, physiological changes during pregnancy can affect the pharmacokinetics of drugs, including antibiotics, used during this period. Pharmacokinetic evaluations have shed light on how antibiotics are affected during pregnancy and have influenced dosing recommendations in this context. METHODS: A narrative review was conducted and included reports providing data reflecting drug distribution and exposure in the context of pregnancy. RESULTS: Pharmacokinetic parameters of antibiotics in pregnancy and transplacental passage of antibiotics are comprehensively presented. CONCLUSIONS: Knowledge about the impact on pharmacokinetics and fetal exposure is especially helpful for complicated or severe infections, including intra-amniotic infection and sepsis in pregnancy, where both mother and fetus are at risk. Further studies are warranted to consolidate the role of therapeutic drug monitoring in complicated or severe infections in pregnant patients.

[Perfectionism, academic stress and social anxiety in female medical students and the risk for eating disorders]. / Perfeccionismo, estrés académico y ansiedad social en mujeres estudiantes de medicina y riesgo de padecer un trastorno alimentario: un modelo multivariado.

BACKGROUND: Both perfectionism and social anxiety have been described in patients with eating disorders (ED) and medical students. Academic stress also can increase the risk of developing ED. AIM: To analyze the dimensions of perfectionism, social anxiety, and academic stress associated with the risk of developing ED in female medical students. MATERIAL AND METHODS: The Multidimensional Perfectionism Scale, the Liebowitz Social Anxiety Scale, the SISCO academic stress inventory and the Eating Attitudes Test-26, were applied to 163 female medical students from all levels of the career. The groups with and without risk of ED were compared according to these variables. RESULTS: Twenty-four percent of respondents were at risk of ED. There were significant differences between scores of perfectionism, social anxiety, and academic stress between respondents with and without risk for ED. In general, there was a significant correlation among the variables. In a multivariate analysis, the predictors of ED risk were the perception of academic stress (Odds ratio (OR) 1.09; 95% confidence intervals (CI) 1.03-1.16) and personal standards in the context of perfectionism (OR 1.16; 95% CI 1.06-1.27). CONCLUSIONS: A substantial proportion of female medical students were at risk for ED. The risk of ED was determined mainly by academic stress and personal standards in the context of perfectionism. In this sample, social anxiety did not play a relevant role.

The FcγRIIIA-158 VV genotype increased the risk of post-transplant lymphoproliferative disorder in T-cell-depleted kidney transplant recipients - a retrospective study.

Post-transplantation lymphoproliferative disorder (PTLD) is a severe complication in organ transplant recipients. The use of T lymphocyte-depleting antibodies (TLDAb), especially rabbit TLDAb, contributes to PTLD, and the V158F polymorphism of Fc gamma receptor IIIA (FcγRIIIA) also named CD16A could affect the concentration-effect relationship of TLDAb. We therefore investigated the association of this polymorphism with PTLD in kidney transplant recipients. We characterized the V158F polymorphism in two case-control cohorts (discovery, n = 196; validation, n = 222). Then, we evaluated the binding of rabbit IgG to human FcγRIIIA-158V and FcγRIIIA-158F. The V158F polymorphism was not linked to PTLD in the overall cohorts, but risk of PTLD was increased in VV homozygous recipients receiving TLDAb compared with F carriers in both cohorts, especially in recipients receiving TLDAb without muromonab (discovery: HR = 2.22 [1.03-4.76], P = 0.043, validation: HR = 1.75 [1.01-3.13], P = 0.049). In vitro, we found that the binding of rabbit IgG to human NK-cell FcγRIIIA was increased when cells expressed the 158-V versus the 158-F allotype. While the 158-V allotype of human FcγRIIIA binds rabbit immunoglobulin-G with higher affinity, the risk of PTLD was increased in homozygous VV kidney transplant recipients receiving polyclonal TLDAb.

[Cluster C personality traits and attention deficit disorder in medical students. An analytical cross-sectional study]. / Rasgos de personalidad del grupo C y trastorno por déficit de atención en estudiantes de medicina: estudio transversal analítico.

BACKGROUND: Attentional deficit hyperactivity disorder (ADHD) in adults is associated with borderline personality characteristics or cluster B (emotional instability), but in certain populations, such as medical students, it might be associated with cluster C traits (perfectionism, dependency, anxiety). This may be compensatory to ADHD. AIM: To analyze the association between ADHD and cluster C personality traits in medical students. MATERIAL AND METHODS: Biodemographic characteristics, the presence of ADHD and personality traits according to clusters A, B and C were evaluated in medical students. These characteristics were compared between students with unlikely diagnosis of ADHD (Group 1) and likely or very likely diagnosis of ADHD (Group 2). RESULTS: We included 336 participants (44% women). A likely or very likely diagnosis of ADHD was present in 64% (Group 2). Concerning personality traits, 45% exhibited traits of cluster A, 57% of cluster B, and 67% of cluster C. Compared to their counterparts of Group 1, participants in Group 2 were more likely to have a history of psychiatric/psychological care, previous diagnosis of ADHD and traits of cluster B (37 and 68% respectively) and C (55 and 74% respectively). The odds ratio of having A, B or C traits when a likely or very likely ADHD was present, were 1.29 95% confidence interval (CI) [0.8-2.07], 3.79 95% CI [2.3-6.22] and 2.4 95% CI [1.46-3.96], respectively. CONCLUSIONS: Cluster C personality traits were frequent among medical students and were significantly associated with ADHD.

Default Mode Network, Meditation, and Age-Associated Brain Changes: What Can We Learn from the Impact of Mental Training on Well-Being as a Psychotherapeutic Approach?

Aging is a physiological process accompanied by cognitive decline, principally in memory and executive functions. Alterations in the connectivity of the default mode network (DMN) have been found to participate in cognitive decline, as well as in several neurocognitive disorders. The DMN has antisynchronic activity with attentional networks (task-positive networks (TPN)), which are critical to executive function and memory. Findings pointing to the regulation of the DMN via activation of TPN suggest that it can be used as a strategy for neuroprotection. Meditation is a noninvasive and nonpharmacological technique proven to increase meta-awareness, a cognitive ability which involves the control of both networks. In this review, we discuss the possibility of facilitating healthy aging through the regulation of networks through meditation. We propose that by practicing specific types of meditation, cognitive decline could be slowed, promoting a healthy lifestyle, which may enhance the quality of life for the elderly.

Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses.

We tested the influence of four polymorphisms and gene duplication in CYP2D6 on in vivo enzyme activity in a Chilean mestizo population in order to identify the most relevant genetic profiles that account for observed phenotypes in this ethnic group. CYP2D6*2 (2850C>T), *3 (2549A>del), *4 (1846G>A), *17 (1023C>T) and gene duplication were determined by PCR-RFLP or PCRL in a group of 321 healthy volunteers. Individuals with different variant alleles were phenotyped by determining debrisoquine 4-hydroxylase activity as a metabolic ratio (MR) using a validated HPLC assay. Minor allele frequencies were 0.41, 0.01, 0.12 and 0.00 for CYP2D6*2, *3, *4 and *17 variants, respectively, and the duplication frequency was 0.003. Genotype analysis correlated with phenotypes in 18 of 23 subjects (78.3%). 11 subjects were extensive metabolizers (EM), 8 were intermediate metabolizers (IM), 2 were poor metabolizers (PM) and 2 were ultra-rapid metabolizers (UM) which is fairly coincident with expected phenotypes metabolic ratios ranged from 0.11 to 126.41. The influence of CYP2D6*3 was particularly notable, although only heterozygote carriers were present in our population. Individuals homozygous for *4 were always PM. As expected, the only subject with gene duplication was UM. In conclusion, there was a clear effect of genotype on observed CYP2D6 activity. Classification of EM, PM and UM through genotyping was useful to characterize CYP2D6 phenotype in the Chilean mestizo population.

It cuts both ways: A single-center retrospective review describing a three-way interaction between flucloxacillin, voriconazole and tacrolimus.

AIM: Tacrolimus is a CYP3A4 substrate with a narrow therapeutic index that requires dose adjustment when used with voriconazole, a recognized CYP3A4 inhibitor. Interactions involving flucloxacillin and tacrolimus or voriconazole individually have been shown to result in decreased concentrations of the latter two drugs. Tacrolimus concentrations have been reported to be unaffected by flucloxacillin when voriconazole is administered; however, this has not been extensively investigated. METHODS: Retrospective review of voriconazole and tacrolimus concentrations and subsequent dose adjustment following flucloxacillin administration. RESULTS: Eight transplant recipients (five lung, two re-do lung, one heart) received concurrent flucloxacillin, voriconazole and tacrolimus. Voriconazole trough concentrations were measured before flucloxacillin initiation in three of eight patients and all trough concentrations were therapeutic. Following flucloxacillin initiation, all eight patients exhibited subtherapeutic concentrations of voriconazole (median concentration 0.15 mg/L [interquartile range (IQR) 0.10-0.28]). In five patients, voriconazole concentrations remained subtherapeutic despite dose increases, and treatment for two patients was changed to alternative antifungal agents. All eight patients required tacrolimus dose increases to maintain therapeutic concentrations after flucloxacillin initiation. Median total daily dose prior to flucloxacillin treatment was 3.5 mg [IQR 2.0-4.3] and this increased to 13.5 mg [IQR 9.5-20] (P=0.0026) during flucloxacillin treatment. When flucloxacillin was ceased, the median tacrolimus total daily dose reduced to 2.2 mg [IQR 1.9-4.7]. Supra-therapeutic tacrolimus concentrations were observed in seven patients after flucloxacillin discontinuation (median concentration 19.7 µg/L [IQR 17.9-28.0]). CONCLUSION: A significant three-way interaction was shown between flucloxacillin, voriconazole and tacrolimus, resulting in subtherapeutic voriconazole concentrations, and requiring substantial tacrolimus dose increases. Administration of flucloxacillin to patients receiving voriconazole should be avoided. Tacrolimus concentrations should be closely monitored, and dosing adjusted during and after flucloxacillin administration.

Estrogen rapid effects: a window of opportunity for the aging brain?

Estrogen produces several beneficial effects in healthy neurological tissues and exhibits cardioprotective effects. Hormone therapy has been widely used to treat menopausal estrogen deficiency for more than 80 years. Despite high initial expectations of cardioprotective effects, there has been substantial distrust following important randomized clinical trials, such as the Women's Health Initiative. Subsequently, the timing of treatment in relation to the onset of menopause came under consideration and led to the proposal of the timing hypothesis, that early initial treatment is important, and benefits are lost as the timing since menopause becomes prolonged. Subsequent analyses of the Women's Health Initiative data, together with more recent data from randomized and observational trials, consistently show reductions in coronary heart disease and mortality in younger menopausal women. Regarding cognitive function, the timing hypothesis is consistent with observations from basic and animal studies. There is some clinical evidence to support the benefits of hormonal therapy in this context, though skepticism remains due to the paucity of clinical trials of substantial length in younger menopausal women. It is likely that the effects of estrogens on cognitive performance are due to rapid mechanisms, including mechanisms that influence Ca2+ homeostasis dynamics, provide protection in a hostile environment and reduce inflammatory signals from neural tissues. In the future, inflammatory profiles accounting for early signs of pathological inflammation might help identify the 'window of opportunity' to use estrogen therapy for successful cognitive protection.

[Immunosenescence, viral infections and nutrition: A narrative review of scientific available evidence]. / Inmunosenescencia, infecciones virales y nutrición: revisión narrativa de la evidencia científica disponible.

Aging of the immune system, or immunosenescence, alters the viral immune response in the elderly, especially when frailty exists. Research findings have demonstrated an imbalance in pro- and anti-inflammatory mechanisms, reduced production and diversification of T lymphocytes, and an alteration in immunovigilance and antibody synthesis. In this context, nutrition has a role in combating sarcopenia and frailty. Some food components that contribute to immune-competence are protein, vitamin D, n-3 fatty acids, antioxidant vitamins (vitamins C and E), zinc, selenium and iron. In times of a pandemic, nutritional recommendations for immune-competence in the elderly should be based on clinical studies. In this article, immunosenescence and its relationship to nutrition are addressed, including interventions studied in the context of the COVID-19 pandemic.

Therapeutic drug monitoring in oncology - What's out there: A bibliometric evaluation on the topic.

Pharmacological therapy is the mainstay of treatment for cancer patients. Despite wide interpatient variability in systemic drug concentrations for numerous antineoplastics, dosing based on body size remains the predominant approach. Therapeutic drug monitoring (TDM) is used for few antineoplastics in specific scenarios. We conducted a rapid bibliometric evaluation of TDM in oncology to capture a snapshot of research in this area over time and explore topics that reflect development in the field. Reports with the composite, indexed term 'therapeutic drug monitoring' in the title and abstract were extracted from MEDLINE (inception to August 2021). Reports related to applications in cancer were selected for inclusion and were tagged by study design, antineoplastic drugs and concepts related to TDM. We present a timeline from 1980 to the present indicating the year of first report of antineoplastic agents and key terms. The reports in our sample primarily reflected development and validation of analytical methods with few relating to clinical outcomes to support implementation. Our work emphasises evidence gaps that may contribute to poor uptake of TDM in oncology.

The evidence synthesis and meta-analysis in R conference (ESMARConf): levelling the playing field of conference accessibility and equitability.

Rigorous evidence is vital in all disciplines to ensure efficient, appropriate, and fit-for-purpose decision-making with minimised risk of unintended harm. To date, however, disciplines have been slow to share evidence synthesis frameworks, best practices, and tools amongst one another. Recent progress in collaborative digital and programmatic frameworks, such as the free and Open Source software R, have significantly expanded the opportunities for development of free-to-use, incrementally improvable, community driven tools to support evidence synthesis (e.g. EviAtlas, robvis, PRISMA2020 flow diagrams and metadat). Despite this, evidence synthesis (and meta-analysis) practitioners and methodologists who make use of R remain relatively disconnected from one another. Here, we report on a new virtual conference for evidence synthesis and meta-analysis in the R programming environment (ESMARConf) that aims to connect these communities. By designing an entirely free and online conference from scratch, we have been able to focus efforts on maximising accessibility and equity-making these core missions for our new community of practice. As a community of practice, ESMARConf builds on the success and groundwork of the broader R community and systematic review coordinating bodies (e.g. Cochrane), but fills an important niche. ESMARConf aims to maximise accessibility and equity of participants across regions, contexts, and social backgrounds, forging a level playing field in a digital, connected, and online future of evidence synthesis. We believe that everyone should have the same access to participation and involvement, and we believe ESMARConf provides a vital opportunity to push for equitability across disciplines, regions, and personal situations.

Therapeutic drug monitoring practices of anti-infectives: An Asia-wide cross-sectional survey.

Objectives: The current practice of therapeutic drug monitoring (TDM) in Asia is poorly documented. Our aim was to capture and describe TDM services delivered in hospitals across Asia, including aspects such as assay availability, interpretation of results and clinical decision-making. Methods: An online survey about anti-infective TDM practices, available in English and involving 50 questions, was promoted to people involved in TDM in Asia. The survey was open for responses from September to November 2021. Results: Of 207 responses from participants working in 14 Asian countries, 150 responses from 10 countries could be included. TDM services are available for many anti-infectives, providing assays based on chromatographic assays (100.0%) or immunoassays (39.3%). Clinicians (82.6%) and pharmacists (86.8%) were responsible for ordering and interpreting TDM. Most services provided reference targets and dose recommendations. Interpretative support was available to a varying degree. Assay results were available and clinical decision-making could be completed within 24 h in most hospitals (87.9% and 88.9% respectively). As the turnaround time of assay results decreased, the proportion of clinical decision-making completed within 8 h increased. Barriers to implementation of TDM included lack of funding or equipment (71.1%), lack of clinician interest or cooperation (47.0%), and lack of expertise (42.3%). Lack of expertise was the primary barrier for using precision dosing software (50.5%). Conclusion: There are significant differences and challenges in the development and practice of anti-infective TDM in Asian countries.

Post-transplant lymphoproliferative disease (PTLD): Pharmacological, virological and other determinants.

Post-transplant lymphoproliferative disorders (PTLDs) represent a serious complication in solid organ transplantation and are the first cause of cancer related mortality in this population. Pre-transplant Epstein Barr Virus seronegativity and receipt of T cell depleting agents for induction or severe/refractory rejection are known risk factors, but they primarily impact early occurring disease. On the other hand, late occurring disease, which has typically not correlated with the above or other specific risk factors, has recently been shown to be associated with older recipient age and prolonged receipt of calcineurin inhibitors. Furthermore, recent data has contributed to and, in some instances shed light on, previous debate concerning the role of viruses other than EBV and the level of HLA mismatches as risk factors for PTLD. Gene association studies focusing on key cytokines and their receptors have identified several polymorphisms that may prove useful to identify patients at risk, with distinction for early and late occurring disease. Determining the influence of individual maintenance immunosuppressive agents on lymphomagenesis has been limited by the complexity of the multi-drug regimens used and absence of measures of drug exposure and time-dependent covariates in multivariable analyses. Biomarkers that measure the extent of immunosupression may have a role in avoiding PTLD, and other post-transplant complications.

Efficacy of methadone for the management of postoperative pain in laparoscopic cholecystectomy: A randomized clinical trial. / Eficacia de la metadona para el tratamiento del dolor postoperatorio en colecistectomía laparoscópica: ensayo clínico aleatorizado.

BACKGROUND: Postoperative pain management contributes to reducing postoperative morbidity and unscheduled readmission. Compared to other opioids that manage postoperative pain like morphine, few randomized trials have tested the efficacy of intraoperatively administered methadone to provide evidence for its regular use or be included in clinical guidelines. METHODS: We conducted a randomized clinical trial comparing the use of intraoperative methadone to assess its impact on postoperative pain. Eighty-six patients undergoing elective laparoscopic cholecystectomy were allocated to receive either methadone (0.08 mg/kg) or morphine (0.08 mg/kg). RESULTS: Individuals who received methadone required less rescue morphine in the Post Anesthesia Care Unit for postoperative pain than those who received morphine (p = 0.0078). The patients from the methadone group reported less pain at 5 and 15 minutes and 12 and 24 hours following Post Anesthesia Care Unit discharge, exhibiting fewer episodes of nausea. Time to eye-opening was equivalent between the two groups. CONCLUSION: Intraoperative use of methadone resulted in better management of postoperative pain, supporting its use as part of a multimodal pain management strategy for laparoscopic cholecystectomy under remifentanil-based anesthesia.

INTRODUCCIÓN: El manejo del dolor postoperatorio contribuye a reducir la morbilidad postoperatoria y los reingresos no programados. Pocos ensayos clínicos aleatorizados han evaluado la eficacia de la administración intraoperatoria de metadona en comparación con otros opioides como morfina, para el tratamiento del dolor postoperatorio, como para proporcionar evidencia de su uso regular o incluirse en guías clínicas. MÉTODOS: Realizamos un ensayo clínico aleatorizado comparando el uso de metadona intraoperatoria para evaluar su impacto sobre el dolor postoperatorio. Ochenta y seis pacientes sometidos a colecistectomía laparoscópica electiva fueron asignados para recibir metadona (0,08 mg/kg) o morfina (0,08 mg/kg). RESULTADOS: El grupo de pacientes que recibió metadona requirió menos morfina de rescate en la unidad de cuidados post-anestésicos para el manejo del dolor posoperatorio, en comparación con el grupo morfina (p = 0,0078). Los pacientes del grupo metadona reportaron menos dolor a los 5 y 15 minutos, y a las 12 y 24 horas postoperatorias, además de presentar menos episodios de náuseas. El tiempo de despertar entre ambos grupos fue equivalente. CONCLUSIÓN: El uso intraoperatorio de metadona es superior a morfina en el manejo del dolor postoperatorio, apoyando su uso como parte de la estrategia de manejo multimodal del dolor para colecistectomía laparoscópica bajo anestesia total endovenosa con remifentanilo.