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Aims: To gain insight in the uptake and practice variation in the prescription of 2 new medicine groups for common conditions in primary care (direct-acting oral anticoagulants [DOACs] and incretin-based therapies) from introduction, around 2007, to 2019 and the correlation between the adoption of those medicines in primary care. Methods: Prescription data from general practices in the Dutch Nivel Primary Care Database from 2007 to 2019 were used. The percentage of patients with prescriptions for DOACs of all patients with prescriptions for DOACs and vitamin K antagonists was calculated per practice per year, as was the percentage of patients prescribed incretin-based therapies as a proportion of all patients with diabetes medication. Multilevel models were used to estimate practice variation for DOACs and incretin-based therapies, expressed as intraclass correlation coefficients. Linear regression analysis was used to study the association between the prescription of DOACs and incretin-based therapies. Results: Per year, 46–424 general practices and 179 933–1 654 376 patients were included. In 2019, the mean percentage of patients per practice using DOACs or incretin-based therapies was 54.9 and 9.7%, respectively. The intraclass correlation coefficient decreased from 0.75 to 0.024 for DOACs and from 0.33 to 0.074 for incretin-based medicines during the study period. No clear correlation was found between the prescription of DOACs and incretin-based therapies. Conclusion: DOACs and incretin-based therapies have different adoption profiles and practice variation is large, especially in the years before these medicines were introduced in guidelines. Early adopters of both medicine classes differ.

In this multi-professional review, we will provide the in-depth knowledge required to work in the expanding field of obesity treatment. The prevalence of obesity has doubled in adults and quadrupled in children over the last three decades. The most common treatment offered has been lifestyle treatment, which has a modest or little long-term effect. Recently, several new treatment options-leading to improved weight loss-have become available. However, long-term care is not only about weight loss but also aims to improve health and wellbeing overall. In the era of personalized medicine, we have an obligation to tailor the treatment in close dialogue with our patients. The main focus of this review is new pharmacological treatments and modern metabolic surgery, with practical guidance on what to consider when selecting and guiding the patients and what to include in the follow-up care. Furthermore, we discuss common clinical challenges, such as patients with concurrent eating disorder or mental health problems, and treatment in the older adults. We also provide recommendations on how to deal with obesity in a non-stigmatizing way to diminish weight stigma during treatment. Finally, we present six microcases-obesity treatment for persons with neuropsychiatric disorders and/or intellectual disability; obesity treatment in the nonresponsive patient who has "tried everything"; and hypoglycemia, abdominal pain, and weight regain after metabolic surgery-to highlight common problems in weight-loss treatment and provide personalized treatment suggestions.

ObjectivesCancer related pain (CRP) is among the most frequent collateral effects of cancer, with chronic CRP, lasting at least three months, affecting >40% of cancer survivors.Evidence based treatments, including pain-focused Cognitive Behavioral Therapy(CBT) are available, but it appears that cancer patients/survivors are often poorlyinformed about CRP or the potential benefits of CBT for such pain. The present studyexamines current experience of Swedish cancer patients/survivors in relation to CRP.MethodsParticipants (N= 276; 83% female; mean age = 55.5 years, SD=11.9) were recruited to an online survey via cancer websites in Sweden, and provided information about their history of chronic CRP, and whether they received information about or treatment for CRP from a healthcare professional.ResultsParticipants had a history of breast (36%), gynecological (12%), lung (10%), colon(8%) and other forms of cancer (36%). A majority (74%) reported a history of chronicCRP and being prescribed analgesic medications (70%). Less than half (47%)received information from their healthcare provider about the risk of CRP and only 13% with chronic CRP received psychological treatment, and of these only 33% received CBT. Among those receiving psychological treatment for chronic CRP, satisfaction rates were moderate, reported as an average of 6 on a 0-10 scale (SD 2.6).ConclusionsGreater efforts are needed to raise awareness among cancer patients/survivors, andhealthcare providers about the risk of CRP and evidence-based interventions,including CBT, the first-line intervention for chronic pain. These efforts will need to be matched with increases in treatment capacity, particularly pain-focused CBT.

Dysregulation of sleep heightens pain sensitivity and may contribute to pain chronification. Interventions which consolidate and lengthen sleep have the potential to improve pain control. The main objective of this systematic review was to examine the effects of sleep-promoting pharmacotherapy on pain intensity in patients with chronic pain. Multiple electronic databases were searched from inception to January 2022 to identify relevant randomized controlled trials (RCTs). Two independent reviewers screened titles, abstracts, and full-text articles; extracted data; and assessed risk of bias for each included study. The GRADE approach was used to determine the strength of evidence. The search identified 624 articles. After full-text screening, 10 RCTs (n = 574 randomized participants) involving 3 pharmacologic interventions (melatonin, zopiclone, and eszopiclone) and 7 different chronic pain populations were included. Minimum clinically significant pain reduction >/=30% was reported in 4 studies. There is low-quality evidence (downgraded due to inconsistency and imprecision) that 2 to 8 weeks treatment with a sleep-promoting medication alone or in combination with an analgesic (6 trials, n = 397) decreases pain intensity compared with placebo or the same analgesic treatment alone (SMD -0.58 [95% confidence interval -1.00, -0.17], P = 0.006). Analyses of associations between changes in sleep and pain outcomes were only provided in 2 articles, with inconsistent findings. Notably, pain-relieving effects were most consistent in melatonin trials. Only 3 studies implemented polysomnography to obtain objective sleep measures. Low-quality evidence indicates that pharmacologic sleep promotion may decrease pain intensity in chronic pain populations. More research is needed to fully understand the influence of sleep-targeting interventions on pain control., Andersson, Emelie Kander, Thomas Werner, Mads U Cho, Joshua H Kosek, Eva Bjurstrom, Martin F eng Review 2023/01/27 Pain Rep. 2023 Jan 6;8(1):e1061. doi: 10.1097/PR9.0000000000001061. eCollection 2023 Jan.

BACKGROUND // Tobacco is the most consumed drug in the world and each year it causes the death of more than eight million people. The pharmacist is the healthcare professional most accessible to smokers, therefore they are essential in the treatment and prevention of smoking. The study´s aim was to implement a multidisciplinary anti-smoking program in a pharmacy and evaluate the effect of pharmaceutical care on smoking cessation. METHODS // The study was carried out in two army pharmacies located in Spain and Lebanon in which a smoking cessation plan was developed in 2020 and 2021. As the requirements for participants selection, all those patients in the area of influence of pharmacies that agreed to participate in the program were accepted, with a sample size of thirty-eight people. The patients underwent an addiction, motivation and smoking habit test, and a descriptive analysis of the data provided was carried out, using the chi-square test for the comparison of values. Only those with a probability value less than 0.05 are considered statistically significant. RESULTS // The multidisciplinary work allowed treatment with prescription drugs. The study shows that 63% of patients managed to quit smoking. CONCLUSIONS // Pharmacies can implement and lead smoking cessation programs that facilitate cessation and adherence to treatments. The classification of patients according to their history of smoking is key to carrying out an adequate and personalized treatment., FUNDAMENTOS // El tabaco es la droga más consumida en el mundo y cada año provoca la muerte de más de ocho millones de personas. El farmacéutico es el profesional de la salud más accesible a los fumadores, por lo que es fundamental en el tratamiento y prevención del tabaquismo. El objetivo de este estudio fue implantar un programa antitabaco multidisciplinar en una oficina de farmacia y evaluar el efecto de la atención farmacéutica en la cesación del consumo de tabaco. MÉTODOS // El estudio se realizó en dos farmacias del Ejército de Tierra situadas en España y Líbano en las que se desarrolló un plan de deshabituación al consumo de tabaco durante los años 2020 y 2021. Como criterio de selección de participantes se aceptó a todos aquellos pacientes del área de influencia de las farmacias que aceptasen participar en el programa, siendo el tamaño muestral de treinta y ocho personas. Los pacientes se sometieron a test de adicción, motivación y hábito de consumo de tabaco, y se realizó un análisis descriptivo de los datos aportados, usando el test de chi-cuadrado para la comparación de valores, considerándose estadísticamente significativos solo aquellos con un valor de probabilidad inferior a 0,05. RESULTADOS // El trabajo multidisciplinar permitió el tratamiento con medicamentos mediante prescripción médica. El 63% de los pacientes del estudio consiguieron dejar de fumar. CONCLUSIONES // Las oficinas de farmacia pueden implantar y liderar programas de deshabituación al consumo de tabaco que faciliten la cesación y la adhesión a los tratamientos. La clasificación de los pacientes según su historial de tabaquismo resulta clave para realizar un tratamiento adecuado y personalizado.

OBJECTIVE: To evaluate the effect of common weight loss pharmacotherapies among low-income, racially diverse adult patients at an urban safety-net weight management clinic. METHODS: Our retrospective review from 2015 to 2019 examined patients who took either GLP-1 analog (GL) or phentermine/topiramate (PT) for ≥90 days and patients who exclusively pursued non-pharmacologic treatment for comparison. Changes in weight, blood pressure, and hemoglobin A1c at 1-year follow-up were reported. RESULTS: We analyzed 22 GL and 26 PT patients and included 40 patients who pursued only lifestyle modifications (LM). All three groups achieved significant weight loss at one year: GL -3.69 (interquartile range (IQR): -11.0, -1.77) kg (p=0.0004), PT -7.01 (IQR: -13.4, -1.45) kg (p<0.001), and LM -3.01 (IQR: -6.81, 1.13) kg (p=0.005). There was no significant difference in the median weight loss (p=0.11) between the three groups. We observed no significant changes in systolic blood pressure but saw a significant change of -0.75 in hemoglobin A1c (IQR: -1.35, -0.25) (p=0.01) among patients with diabetes in the GL group. CONCLUSIONS: Our real-world applications of GLP-1 and phentermine/topiramate suggest that both are effective weight loss medication regimens in low-socioeconomic status patients.

BACKGROUND: Tobacco and cannabis co-use is a growing public health problem. The synergistic effects of cannabis and nicotine on neurobiological systems that mediate reward and shared environmental cues reinforcing use may make tobacco smoking cessation more difficult. N-acetylcysteine (NAC), an FDA-approved medication and over-the-counter supplement, has shown promise in animal studies and randomized controlled trials (RCTs) in reducing tobacco and cannabis craving and use. NACs potential efficacy in treating addiction may be attributable to its central nervous system effects in reducing excessive glutamatergic activity, oxidative stress, and inflammation. To date, no RCT has examined NAC for smoking cessation among dual users of tobacco and cannabis. METHOD: In a double-blind, placebo-controlled RCT, we will examine NAC for smoking cessation among dual users of tobacco and cannabis. Sixty adult cigarette-cannabis co-users are randomized to receive NAC 3600 mg per day or placebo over 8 weeks. Participants in both groups receive 8 weekly cognitive behavioral therapy sessions addressing smoking cessation and cannabis reduction. Outcomes are assessed at Weeks 0, 4, 8, and 12. Primary aims are to determine NACs efficacy in decreasing cigarette craving, nicotine dependence, and use; and cannabis craving and use. Exploratory aims include examination of changes in neurocognition with NAC and their potential mediational effects on cigarette and cannabis use outcomes. CONCLUSION: Results will inform smoking cessation treatment among dual users of tobacco and cannabis. CLINICALTRIALS: gov Identifier: NCT04627922.

BACKGROUND: Delirium is common in critically ill patients. Haloperidol has long been used for the treatment of delirium. Dexmedetomidine has recently been used to treat delirium among intubated critically ill patients. However, the efficacy of dexmedetomidine for delirium in non-intubated critically ill patients remains unknown. We hypothesize that dexmedetomidine is superior to haloperidol for sedation of patients with hyperactive delirium, and would reduce the prevalence of delirium among non-intubated patients after administration. We will conduct a randomized controlled trial to compare dexmedetomidine and haloperidol for the treatment of nocturnal hyperactive delirium in non-intubated patients in high dependency units (HDUs). METHODS: This is an open-label, parallel-group, randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for nocturnal hyperactive delirium in non-intubated patients at two HDUs of a tertiary hospital. We will recruit consecutive non-intubated patients who are admitted to the HDU from the emergency room, and allocate them in a 1:1 ratio to the dexmedetomidine or haloperidol group in advance. The allocated investigational drug will be administered only when participants develop hyperactive delirium (Richmond Agitation-Sedation Scale [RASS] score ≥1 and a positive score on the Confusion Assessment Method for the ICU between 19:00 and 6:00 the next day) during the night at an HDU. Dexmedetomidine is administered continuously, while haloperidol is administered intermittently. The primary outcome is the proportion of participants who achieve the targeted sedation level (RASS score of between -3 and 0) 2h after the administration of the investigational drug. Secondary outcomes include the sedation level and prevalence of delirium on the day following the administration of the investigational drugs, and safety. We plan to enroll 100 participants who develop nocturnal hyperactive delirium and receive one of

Dysregulation of sleep heightens pain sensitivity and may contribute to pain chronification. Interventions which consolidate and lengthen sleep have the potential to improve pain control. The main objective of this systematic review was to examine the effects of sleep-promoting pharmacotherapy on pain intensity in patients with chronic pain. Multiple electronic databases were searched from inception to January 2022 to identify relevant randomized controlled trials (RCTs). Two independent reviewers screened titles, abstracts, and full-text articles; extracted data; and assessed risk of bias for each included study. The GRADE approach was used to determine the strength of evidence. The search identified 624 articles. After full-text screening, 10 RCTs (n = 574 randomized participants) involving 3 pharmacologic interventions (melatonin, zopiclone, and eszopiclone) and 7 different chronic pain populations were included. Minimum clinically significant pain reduction >= 30% was reported in 4 studies. There is low-quality evidence (downgraded due to inconsistency and imprecision) that 2 to 8 weeks treatment with a sleep-promoting medication alone or in combination with an analgesic (6 trials, n = 397) decreases pain intensity compared with placebo or the same analgesic treatment alone (SMD -0.58 [95% confidence interval -1.00, -0.17], P = 0.006). Analyses of associations between changes in sleep and pain outcomes were only provided in 2 articles, with inconsistent findings. Notably, pain-relieving effects were most consistent in melatonin trials. Only 3 studies implemented polysomnography to obtain objective sleep measures. Low-quality evidence indicates that pharmacologic sleep promotion may decrease pain intensity in chronic pain populations. More research is needed to fully understand the influence of sleep-targeting interventions on pain control.

RATIONALE: Alcohol administration and cue-reactivity paradigms are frequently used to screen for the initial efficacy of medications for alcohol use disorder (AUD). While medication effects on the primary outcomes for these paradigms are assumed to be qualitatively related, there is a critical lack of quantitative evidence to support this hypothesis. OBJECTIVES: The study aims to test the relationship between medication effect sizes on subjective response to alcohol administration and medication effect sizes for cue-induced craving to cue exposure, using meta-analysis. METHODS: Systematic literature searches were conducted to identify randomized trials, wherein AUD medications were tested using the alcohol administration and/or cue-reactivity paradigms. From these studies, descriptive statistics were collected to compute medication effect sizes on the primary outcomes for each respective paradigm. With medication as the unit of analysis, medication effect sizes in alcohol administration studies were compared with medication effect sizes in cue-reactivity studies using the Williamson-York regression which allows for meta-regression across independent samples. RESULTS: Medication effect sizes on alcohol-induced stimulation and alcohol-induced craving were not significantly associated with medication effect sizes on cue-induced alcohol craving (k stimulation = 10 medications, [Formula: see text] and k craving = 11 medications, [Formula: see text] (SE = 0.237), [Formula: see text]), respectively. Medication effect sizes on alcohol-induced sedation were significantly associated with medication effects on cue-induced craving (k = 10 medications, [Formula: see text] (SE = 0.258), [Formula: see text]), such that medications that increased alcohol-induced sedation were more likely to reduce cue-induced alcohol craving. CONCLUSIONS: With the exception of alcohol-induced sedation, there is little quantitative evidence of medication effects on subjective response domains measur

Introduction: It is necessary to have valid and reliable instruments to identify the factors that influence adherence to treatment in people with cardiovascular risk factors. In Colombia, Bonilla y Gutierrez designed an instrument that has face and content validity. However, construct validity has not been demonstrated. Objective: To determine the construct validity and reliability of the instrument, factors that influence adherence to pharmacological and non-pharmacological treatment in people with cardiovascular risk factors. Methodology: Methodological research. A total of 694 people with risk factors for cardiovascular disease residing in three Colombian cities (Neiva, Espinal and Tunja) participated. Exploratory factor analysis (extraction of principal components and Varimax rotation), confirmatory factor analysis (maximum likelihood estimation) and global and dimensional reliability test (Cronbach’s alpha and Test-retest) were performed. Results: The exploratory factor analysis reported a 30-item instrument with a 4-factor structure (total cumulative variance of 42.6%). The fit indices of the proposed model indicated excellent absolute fit and acceptable incremental fit. The overall Cronbach’s alpha was 0.86, indicating high reliability. Discussion: The study provides evidence of a more robust instrument than other versions. Standardized instruments to measure factors that influence adherence can be very useful for research and practice if they meet psychometric tests of reliability and validity. Conclusion: A valid and reliable instrument is made available to researchers and health personnel. Its use is recommended in populations similar to that of this study., Introducción: es necesario contar con instrumentos válidos y confiables para identificar los factores que influyen en la adherencia al tratamiento en personas con factores de riesgo cardiovascular. En Colombia, Bonilla y Gutiérrez diseñaron un instrumento que cuenta con validez facial y de contenido. Sin embargo, no se ha demostrado la validez de constructo. Objetivo: determinar la validez de constructo y confiabilidad del instrumento, factores que influyen en la adherencia al tratamiento farmacológico y no farmacológico en personas con factores de riesgo cardiovascular. Metodología: investigación metodológica. Participaron 694 personas con factores de riesgo de enfermedad cardiovascular residentes en tres ciudades de Colombia (Neiva, Espinal y Tunja). Se realizó un análisis factorial exploratorio (extracción de componentes principales y rotación Varimax), análisis factorial confirmatorio (estimación de máxima verosimilitud) y una prueba de confiabilidad global y por dimensiones (alfa de Cronbach y Test-retest). Resultados: el análisis factorial exploratorio reportó un instrumento de 30 ítems con estructura de 4 factores (varianza total acumulada de 42,6 %). Los índices de ajuste del modelo propuesto indicaron ajuste absoluto excelente y ajuste incremental aceptable. El alfa de Cronbach global fue 0,86, lo que indica alta confiabilidad. Discusión: el estudio proporciona evidencia de un instrumento más robusto que otras versiones. Los instrumentos estandarizados para medir factores que influyen en la adherencia pueden ser muy útiles para la investigación y la práctica si cumplen con pruebas psicométricas de fiabilidad y validez. Conclusión: se pone a disposición de los investigadores y del personal de salud un instrumento válido y confiable. Se recomienda su uso en poblaciones similares a la de este estudio

BACKGROUND: The efficacy of empiric calcium for patients with undifferentiated cardiac arrest has come under increased scrutiny, including a randomized controlled trial that was stopped early due to a trend towards harm with calcium administration. However, small sample sizes and non-significant findings have hindered precise effect estimates. In this analysis we evaluate the association of calcium administration with survival in a large retrospective cohort of patients with cardiac arrest treated in the emergency department (ED). METHODS: We conducted a retrospective review of medical records from two academic hospitals (one quaternary care center, one county trauma center) in San Francisco between 2011 and 2019. Inclusion criteria were patients aged greater than or equal to 18 years old who received treatment for cardiac arrest during their ED course. Our primary exposure was the administration of calcium while in the ED and the main outcome was survival to hospital admission. The association between calcium and survival to admission was estimated using a multivariable log-binomial regression, and also with two propensity score models. RESULTS: We examined 781 patients with cardiac arrest treated in San Francisco EDs between 2011 and 2019 and found that calcium administration was associated with decreased survival to hospital admission (RR 0.74; 95% CI 0.66-0.82). These findings remained significant after adjustment for patient age, sex, whether the cardiac arrest was witnessed, and including an interaction term for shockable cardiac rhythms (RR 0.60; 95% CI 0.50-0.72) and non-shockable cardiac rhythms (RR 0.87; 95% CI 0.76-0.99). Risk ratios for the association between calcium and survival to hospital admission were also similar between two propensity score-based models: nearest neighbor propensity matching model (RR 0.79; 95% CI 0.68-0.89) and inverse propensity weighted regression adjustment model (RR 0.75; 95% CI 0.67-0.84). CONCLUSIONS: Calcium administr

We appraised the relationship between the biological and the chrono- logical age and estimated the rate of biological aging in HIV-infected patients. Two independent biomarkers, the relative telomere length and iron metabolism parame- ters, were analyzed in younger (,35) and older (.50) HIV-infected and uninfected patients (control group). In our control group, telomeres of younger patients were significantly longer than telomeres of older ones. However, in HIV-infected partici- pants, the difference in the length of telomeres was lost. By combining the length of telomeres with serum iron, ferritin, and transferrin iron-binding capacity, a new for- mula for determination of the aging process was developed. The life expectancy of the healthy population was related to their biological age, and HIV-infected patients were biologically older. The effect of antiretroviral HIV drug therapies varied with respect to the biological aging process. IMPORTANCE This article is focused on the dynamics of human aging. Moreover, its interdisciplinary approach is applicable to various systems that are aging.

Background Small observational studies have observed poor persistency to sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and glucacon-like-peptide-1-receptor agonists (GLP1-RA), contrary to what has been reported in clinical trials. Therefore, we investigated the risk of discontinuing SGLT2-is and GLP1-RAs in patients with type 2 diabetes (T2D) in a nationwide population. Methods From Danish nationwide registers, all first-time users of SGLT2-is and GLP1-RAs from 2013 to 2021 were identified. Adherence over the first year of therapy, the five-year risk of discontinuing therapy for the first time and the subsequent one-year probability of reinitiating therapy, was assessed. The Aalen-Johansen estimator was used to account for censoring and competing risks and multivariable Cox regression models were used to identify covariates associated with discontinuation. Findings A total of 77,745 first-time users of SGLT2-is (64% male, median age 64 [interquartile range 56–72]) and 56,037 first-time users of GLP1-RAs (56% male, median age 61 [53–70]) were included. The absolute five-year risk of discontinuing therapy was 56% (95% CI: 55–57) and 45% (45–46) for SGLT2-i- and GLP1-RA users, respectively, with a significantly decreased risk over the period studied. The subsequent one-year probability of reinitiating therapy was 24% (95% CI: 24–25) for initial SGLT2-i users and 26% (25–27) for GLP1-RA users. Interpretation Approximately half of the users of SGLT2-is and GLP1-RAs discontinued therapy within five years, respectively. However, a large proportion of these patients reinitiated therapy during the following year. Further insight into the reasons for discontinuation and initiatives to reduce the time to reinitiation in eligible patients are warranted. Funding The work was funded by an unrestricted research grant from ‘Department of Cardiology, Herlev and Gentofte University Hospital’., Background: Small observational studies have observed poor persistency to sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and glucacon-like-peptide-1-receptor agonists (GLP1-RA), contrary to what has been reported in clinical trials. Therefore, we investigated the risk of discontinuing SGLT2-is and GLP1-RAs in patients with type 2 diabetes (T2D) in a nationwide population. Methods: From Danish nationwide registers, all first-time users of SGLT2-is and GLP1-RAs from 2013 to 2021 were identified. Adherence over the first year of therapy, the five-year risk of discontinuing therapy for the first time and the subsequent one-year probability of reinitiating therapy, was assessed. The Aalen-Johansen estimator was used to account for censoring and competing risks and multivariable Cox regression models were used to identify covariates associated with discontinuation. Findings: A total of 77,745 first-time users of SGLT2-is (64% male, median age 64 [interquartile range 56–72]) and 56,037 first-time users of GLP1-RAs (56% male, median age 61 [53–70]) were included. The absolute five-year risk of discontinuing therapy was 56% (95% CI: 55–57) and 45% (45–46) for SGLT2-i- and GLP1-RA users, respectively, with a significantly decreased risk over the period studied. The subsequent one-year probability of reinitiating therapy was 24% (95% CI: 24–25) for initial SGLT2-i users and 26% (25–27) for GLP1-RA users. Interpretation: Approximately half of the users of SGLT2-is and GLP1-RAs discontinued therapy within five years, respectively. However, a large proportion of these patients reinitiated therapy during the following year. Further insight into the reasons for discontinuation and initiatives to reduce the time to reinitiation in eligible patients are warranted. Funding: The work was funded by an unrestricted research grant from ‘ Department of Cardiology, Herlev and Gentofte University Hospital’.

This thesis aimed to understand how childhood trauma (CT), conceptualized as emotional/physical/sexual abuse or emotional/physical neglect before the age of 18 years, shapes mental health, what the potential underlying mechanisms of CT are, and what can be done about it in the context of adult depressive and/or anxiety disorders. The exploration of cross-sectional, longitudinal, and ecological momentary assessment (EMA) data from the Netherlands Study of Depression and Anxiety (NESDA), as well as a meta-analytic combination of results from multiple (inter)national clinical trials on depression treatment was used to examine the impact of CT on psychopathology, explore potential CT mechanisms that may heighten vulnerability for psychopathology, and investigate the impact of CT in the clinical setting. Our findings indicated that CT is associated with increased severity of various symptoms, including total depressive, anxiety, worry, and fear/phobic, suggesting a broad and nonspecific impact on psychopathology. Moreover, symptom severity persisted over the years, indicating increased chronicity. Our results also revealed that individuals with CT show alterations in the brain, mind, and body, including maladaptive personality characteristics and cognitions, accelerated biological aging, somatic health decline, brain structural and functional changes, greater alterations in daily affect intensity, dysregulated biological stress systems (particularly innate immune system capacity), and engagement in unhealthier lifestyle behaviors. The adverse effects were most pronounced in severe CT cases, characterized by multiple types or higher frequencies of trauma, with minimal differences between CT types. In the clinical setting, depressed adults with CT experienced significant symptom improvement following first-line pharmacological and psychotherapeutic treatments, but were more severely depressed before and after treatment. Hence, our results suggest that CT constitut

Introduction: Social anxiety disorder (SAD) is associated with scarce functioning and poor quality of life. Although selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are currently first-line treatments, side effects are common and affect treatment compliance in approximately 50% of patients. This review aimed to summarize data on the efficacy of unlabeled molecules for SAD treatment. Areas covered: Research in the main psychiatric databases was conducted (PubMed, PsychINFO, and EMBASE-Ovid) to select studies investigating the efficacy of marketed molecules not labeled for SAD treatment. Expert opinion: Pregabalin at high doses (450–600 mg/day) appears to be a reliable alternative strategy for SAD treatment. Among the SSRIs not labeled for SAD, citalopram showed the most promising results. Quetiapine, levetiracetam, and other antidepressants/serotonergic agents, such as fluoxetine, duloxetine, monoamine oxidase inhibitors, tricyclics, mirtazapine, atomoxetine, nefazodone, vilazodone, and buspirone, presented negative, limited, or contrasting results. Data on anticonvulsants, olanzapine, tiagabine, and ketamine were positive, but preliminary. The risk/benefit ratio must be considered in the prescription of unlabeled compounds; treatment with pregabalin may be associated with somnolence and dizziness. Future research may contribute to the identification of targeted molecules for the treatment of this disorder.

BACKGROUND: Patients with Brugada syndrome (BrS) are recommended to avoid drugs that may increase their risk of arrhythmic events. We examined treatment with such drugs in patients with BrS after their diagnosis. METHODS AND RESULTS: All Danish patients diagnosed with BrS (2006– 2018) with >12 months of follow-up were identified from nationwide registries. Nonrecommended BrS drugs were grouped into drugs to “avoid” or “preferably avoid” according to http://www.brugadadrugs.org. Cox proportional hazards analyses were performed to identify factors associated with any nonrecommended BrS drug use, and logistic regression analyses were performed to examine associated risk of appropriate implantable cardioverter defibrillator therapy, mortality, and a combined end point indicating an arrhythmic event of delayed implantable cardioverter defibrillator implantation, appropriate implantable cardioverter defibrillator therapy, and mortality. During a median follow-up of 6.8 years, 93/270 (34.4%) patients with BrS (70.4% male, median age at diagnosis 46.1 years [interquartile range, 32.6– 57.4]) were treated with ≥1 nonrecommended BrS drugs. No difference in any nonrecommended BrS drug use was identified comparing time before BrS diagnosis (12.6%) with each of the 5 years following BrS diagnosis (P>0.05). Factors associated with any nonrecommended BrS drug use after diagnosis were female sex (hazard ratio [HR]) 1.83 [95% CI, 1.15– 2.90]), psychiatric disease (HR, 3.63 [1.89– 6.99]), and prior use of any nonrecommended BrS drug (HR, 4.76 [2.45– 9.25]). No significant association between any nonrecommended BrS drug use and implantable cardioverter de-fibrillator therapy (n=20/97, odds ratio [OR], 0.7 [0.2– 2.4]), mortality (n=10/270, OR, 3.4 [0.7–19.6]), or the combined end point (n=38/270, OR, 1.7 [0.8– 3.7]) was identified. CONCLUSIONS: One in 3 patients with BrS were treated with a nonrecommended BrS drug after BrS diagnosis, and a BrS diagnosis did not change prescri

Aims: It remains unknown whether the consistently observed increase in haematocrit with sodium–glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I–III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8–4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59–0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86–1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (pinteraction >0.05). Conclusion: These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin.

Not abstract available

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy.METHODS: In this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose.RESULTS: The study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, -1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, -1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence.CONCLUSIONS: Solriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy.

Background and aims:Pharmacovigilance reports, associating hydrochlorothiazide (HCT) with skin cancer, resulted in a significant decrease of HCT prescriptions for hypertension and heart failure. Whether HCT exhibits phototoxic properties thereby causing skin cancer remains unknown. This study aimed to examine the photosensitizing, phototoxic and carcinogenic potential of HCT in a randomized, placebo-controlled, double-blind trial in vivo and also in vitro.Methods:The trial assigned 30 healthy, normotensive adult volunteers in a 2:1 ratio to either HCT 25 mg/day or placebo for 15 days. Photosensitivity of the skin with and without the effect of HCT treatment were assessed. Following whole-body ultraviolet A (UVA) and B (UVB, 311 nm) irradiation, phototoxic and carcinogenic reactions by measuring urinary excretion of pyrimidine dimers were evaluated. For the in-vitro studies, human keratinocytes (HaCaT) were incubated with HCT, irradiated with UVB, and analysed for markers of inflammation, apoptosis and carcinogenesis.Results:Skin photosensitivity following exposure to UVA and UVB remained unchanged from baseline to 15-day follow-up in both groups (UVA change HCT 0.0 J/cm2 vs. placebo 0.0 J/cm2; P = 0.99; UVB change HCT 0.0 J/cm2 vs. placebo -0.2 J/cm2; P = 0.06). Pyrimidine dimers were not detected in either group. In vitro, combination of HCT and UVB irradiation did not induce the expression of oxidative stress marker proteins, inflammatory proteins, apoptotic proteins or activation of oncoproteins.Conclusion:HCT did not increase photosensitivity for UVA or UVB in healthy volunteers compared with placebo, and was not associated with phototoxic or carcinogenic reactions. In vitro, HCT was also not associated with phototoxicity or carcinogenesis (NCT04654312).

Borderline personality disorder (BPD) is a highly studied condition. During the last 3 decades, the understanding of the disorder has substantially changed, based on thorough, accumulating research. At the same time, the interest in BPD is still not decreasing but continues to grow. This article aims to critically discuss research trends in clinical trials of personality disorders in general and BPD in particular, to highlight topics that deserve closer attention, and to give recommendations for the design and conduct of future psychotherapy or pharmacotherapy studies in the field.

Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss (WL) through lifestyle changes results in modest WL long-term possibly due to compensatory biological adaptations (increased appetite and reduced energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted in >= 15% WL and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development of new medications over the last decade for the treatment of obesity with main target the reduction of appetite. The efficacy of semaglutide 2.4 mg/week-the latest glucagon-like peptide-1 (GLP-1) receptor analogue-on WL for people with obesity suggests that we are entering a new era in obesity pharmacotherapy where >= 15% WL is feasible. Moreover, the WL achieved with the dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional WL compared with GLP-1 receptor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between bariatric surgery and the currently available pharmacotherapies.

Producción Científica, Precision medicine utilizing the genetic information of genes involved in the metabolism and disposition of drugs can not only improve drug efficacy but also prevent or minimize adverse events. Polypharmacy is common among multimorbid patients and is associated with increased adverse events. One of the main objectives in health care is safe and efficacious drug therapy, which is directly correlated to the individual response to treatment. Precision medicine can increase drug safety in many scenarios, including polypharmacy. In this report, we share our experience utilizing precision medicine over the past ten years. Based on our experience using pharmacogenetic (PGx)-informed prescribing, we implemented a five-step precision medicine protocol (5SPM) that includes the assessment of the biological–clinical characteristics of the patient, current and past prescription history, and the patient’s PGx test results. To illustrate our approach, we present cases highlighting the clinical relevance of precision medicine with a focus on patients with a complex history and polypharmacy., Instituto de Salud Carlos III y Fondo Europeo de Desarrollo Regional (FEDER) - (grant IMP/00009 y RD16/0006/0019)

Producción Científica, Background and Objectives: One of the most serious clinical outcomes in hospitalized patients with COVID-19 is severe acute respiratory syndrome (SARS). The aim is to analyze pharmacological treatment, survival and the main mortality predictors. Materials and Methods: A real-world data study from COVID-19-hospitalized patients with SARS from 1 March to 31 May 2020 has been carried out. Variables such as hospital length of stay, ventilation type and clinical outcomes have been taken into account. Results: In Castile and Leon, 14.03% of the 7307 in-hospital COVID-19 patients developed SARS, with a mortality rate of 42.53%. SARS prevalence was doubled in males compared to females, and 78.54% had an age of 65 years or more. The most commonly used medicines were antibiotics (89.27%), antimalarials (68.1%) and corticosteroids (55.9%). Survival of patients developing SARS was lower compared to patients without this complication (12 vs. 13 days). The main death predictors were disseminated intravascular coagulation (DIC) (OR: 13.87) and age (>65 years) (OR: 7.35). Conclusions: Patients older than 65 years who develop DIC have a higher probability of hospital death. Tocilizumab and steroids have been linked to a lower incidence of hospital death, being the main treatment for COVID-19 hospitalized patients with SARS., Junta de Castilla y León, Gerencia Regional de Salud - (Grant GRS COVID 10/A/20)

Background: Previous studies have highlighted a robust bidirectional relationship between alcohol and cigarette use. Co-use of these substances impacts treatment outcomes, as there are no FDA approved medications for the co-use of cigarettes and alcohol. The combination of 2 FDA approved medications for smoking cessation (varenicline) and alcohol use disorder (naltrexone) have shown promise as a treatment option for heavy drinking smokers. Methods: The dissertation project examined both etiology and treatment of the unique subgroup of heavy drinking smokers. Chapter 1 (etiology) utilized a behavioral economics framework in a sample of non-treatment seeking heavy drinking smokers to examine demand for each substance using a hypothetical purchase task in which participants indicate how much of a substance they would consume at varying prices. Chapters 2 and 3 (treatment) consisted of a community sample of treatment-seeking heavy drinking smokers who completed a 12-week randomized clinical trial comparing varenicline plus placebo versus varenicline plus naltrexone for smoking cessation and drinking reduction. Chapter 2 examined the impact of sex hormones in response to pharmacotherapy for female heavy drinking smokers. Chapter 3 examined whether drinking outcomes mediated the relationship between pharmacotherapy and smoking outcomes. Results: Results from Chapter 1 (etiology) revealed cross-substance relationships, with use of one substance predicting greater demand of the opposite substance. Notably, we found a stronger effect of nicotine use on demand for alcohol than vice versa. Results from Chapter 2 (treatment) showed no interaction of sex hormones and pharmacotherapy on smoking outcomes. However, greater ratio of progesterone to estradiol was associated with greater percent days abstinent from alcohol for females assigned to the varenicline plus naltrexone condition. Results from Chapter 3 (treatment) indicated that drinking outcomes did not mediate the relations

Background Several cancer therapies have been associated with cardiovascular harm in early-phase clinical trials. However, some cardiovascular harms do not manifest until later-phase trials. To limit interdisease variability, we focused on breast cancer. Thus, we assessed the reporting of cardiovascular safety monitoring and outcomes in phase 2 and 3 contemporary breast cancer clinical trials. Methods and Results We searched Embase and Medline records for phase 2 and 3 breast cancer pharmacotherapy trials. We examined exclusion criterion as a result of cardiovascular conditions, adverse cardiovascular event reporting, and cardiovascular safety assessment through cardiovascular imaging, ECG, troponin, or natriuretic peptides. Fisher's exact test was utilized to compare reporting. Fifty clinical trials were included in our study. Patients were excluded because of cardiovascular conditions in 42 (84%) trials. Heart failure was a frequent exclusion criterion (n=31; 62% trials). Adverse cardiovascular events were reported in 43 (86%) trials. Cardiovascular safety assessments were not reported in 23 (46%) trials, whereas natriuretic peptide and troponin assessments were not reported in any trial. Cardiovascular safety assessments were more frequently reported in industry-funded trials (69.2% versus 0.0%; P<0.001), and in trials administering targeted/immunotherapy agents compared with only hormonal/conventional chemotherapy (78.6% versus 22.7%, P<0.001). Conclusions Our findings demonstrate significant under-representation of patients with cardiovascular conditions or prevalent cardiovascular disease in contemporary later-phase breast cancer trials. Additionally, cardiovascular safety is not routinely monitored in these trials. Therefore, contemporary breast cancer clinical trials may possibly underestimate the cardiovascular risks of cancer pharmacotherapy agents for use in clinical practice.

Current European guidelines for the management of hypertension and on cardiovascular disease prevention place the threshold for pharmacological treatment at a SBP level of 140 mmHg or above, with the exception of patients at very high risk (mainly because of coronary heart disease). This is in agreement with the current definition of hypertension, that is, the level of blood pressure at which the benefits of treatment outweigh the risks of treatment, as documented by clinical trials. This rationale and definition was recently challenged by meta-analyses using individual participant-level data from 48 randomized trials by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC). The authors calculated for a fixed 5 mmHg pharmacological reduction of SBP an overall 10% risk reduction for major cardiovascular events. It was concluded that there was no reliable evidence of heterogeneity of treatment effects by baseline SBP categories; that the effect was independent from the presence of cardiovascular disease; applied also to old and very old individuals up to 84 years or beyond; and that BP-lowering was also beneficial in individuals with normal or high-normal SBP down to a baseline SBP less than 120 mmHg. In this report, we identify and discuss a number of shortcomings of the BPLTTC meta-analyses. In our view, the conclusions by the BPLTTC must be -together with accompanying suggestions to abandon the definition of hypertension - strongly rejected as they are not justified and may be harmful for cardiovascular health in individuals without hypertension.

Diabetes care is challenging, and the increasing number of available therapeutic options has made it even more complex. Moreover, with an increasing prevalence across the world, it needs to be managed right from the primary care level to a quaternary care hospital. This calls for an easy-to-use algorithm that can be used by a general practitioner, who is often the first contact of a patient to manage diabetes in many countries. There are multiple models to assist in choice of pharmacotherapy, and these have evolved over time. We propose a user-friendly collaborative choice, as an aid to clinical decision-making. This alliterative framework supplements and strengthens existing guidance, by creating a comprehensive, yet simple, thought process for the diabetes care professional.

Drugs are widely prescribed for anorexia nervosa in the nutritional, somatic, and psychiatric fields. There is no systematic overview in the literature, which simultaneously covers all these types of medication. The main aims of this paper are (1) to offer clinicians an overview of the evidence-based data in the literature concerning the medication (psychotropic drugs and medication for somatic and nutritional complications) in the field of anorexia nervosa since the 1960s, (2) to draw practical conclusions for everyday practise and future research. Searches were performed on three online databases, namely MEDLINE, Epistemonikos and Web of Science. Papers published between September 2011 and January 2019 were considered. Evidence-based data were identified from meta-analyses, if there were none, from systematic reviews, and otherwise from trials (randomized or if not open-label studies). Evidence-based results are scarce. No psychotropic medication has proved efficacious in terms of weight gain, and there is only weak data suggesting it can alleviate certain psychiatric symptoms. Concerning nutritional and somatic conditions, while there is no specific, approved medication, it seems essential not to neglect the interest of innovative therapeutic strategies to treat multi-organic comorbidities. In the final section we discuss how to use these medications in the overall approach to the treatment of anorexia nervosa.

Those with Down syndrome (DS)-trisomy for chromosome 21-are routinely impacted by cognitive dysfunction and behavioral challenges in children and adults and Alzheimer's disease in older adults. No proven treatments specifically address these cognitive or behavioral changes. However, advances in the establishment of rodent models and human cell models promise to support development of such treatments. A research agenda that emphasizes the identification of overexpressed genes that contribute demonstrably to abnormalities in cognition and behavior in model systems constitutes a rational next step. Normalizing expression of such genes may usher in an era of successful treatments applicable across the life span for those with DS.

IntroductionIn COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB2 ≫ PGE2 > PGD2 in the lungs, and 11-dehydro-TxB2, a TxA2 metabolite, in the systemic circulation. While TxA2 stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB2 is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD2. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA2/TP and PGD2/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization.Areas coveredEvidence supporting the role of TxA2/TP receptors and PGD2/DP2 receptors in causing rapidly progressive lung injury associated with hypoxemia, a maladaptive immune response and thromboinflammation is discussed. An innovative perspective on the dual antagonism of TxA2/TP and PGD2/DP2 receptor signaling as a therapeutic approach in COVID-19 is presented. This paper examines ramatroban an anti-platelet, immunomodulator, and antifibrotic agent for acute and long-haul COVID-19.Expert opinionRamatroban, a dual blocker of TP and DP2 receptors, has demonstrated efficacy in animal models of respiratory dysfunction, atherosclerosis, thrombosis, and sepsis, as well as preliminary evidence for rapid relief from dyspnea and hypoxemia in COVID-19 pneumonia. Ramatroban merits investigation as a promising antithrombotic and immunomodulatory agent for chemoprophylaxis and treatment.

IMPORTANCE: Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications. OBJECTIVE: To evaluate the safety and efficacy of smoking cessation pharmacotherapy among smokers with MDD. DESIGN: Secondary analysis of a randomized, double-blind, active- (nicotine patch) and placebo-controlled trial of 12 weeks of either varenicline or bupropion with a 12-week follow-up. PARTICIPANTS: Community volunteers 18-75 years of age; smoke 10+ cigarettes/day; with clinically stable MDD (N = 2635) or no psychiatric disorder (N = 4028), from 140 sites in 16 countries. INTERVENTION: Twelve weeks of pharmacotherapy (placebo [PLA], nicotine replacement therapy [NRT], bupropion [BUP], varenicline [VAR]) plus brief cessation counseling. MEASURE(S): Primary safety outcome: the occurrence of ≥1 treatment-emergent, moderate to severe neuropsychiatric adverse event (NPSAE). Primary efficacy outcome: biochemically confirmed continuous abstinence (CA) during the final 4 weeks of treatment (Weeks 9-12). RESULTS: A total of 6653 participants (56% female; 39% MDD) ~47 years old. Risk of NPSAEs did not differ by medication for MDD. MDD had higher risk (p < .0001) for NPSAEs than the NPC. Efficacy (6653; intent-to-treat): CA rates for MDD versus NPC respectively were 31.2% versus 38.0% VAR; 23.0% versus 26.1% BUP; 22.6% versus 26.4% NRT; and 13.4% versus 13.7% PLA but no differential treatment effect was noted within the cohorts. All active treatments differed from PLA but VAR showed the largest effect. CONCLUSIONS: Results suggest that for MDD smokers, inclusive of those with recurrent episode, varenicline plus counseling may be the best pharmacological option for the treatment of smoking given its greater efficacy effect size and similar risk of NPSAEs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01456936. https://clinicaltrials.gov/ct2/show/NCT01456936.

BACKGROUND: Despite the promising implications for novel immune therapeutics, few clinical trials have tested these therapies to date. An understanding of how immune pharmacotherapies influence complex alcohol use disorder (AUD) profiles, including subjective response to alcohol, is very limited. Initial findings show that ibudilast, a neuroimmune modulator, reduces rates of heavy drinking and measures of alcohol craving. METHODS: This study is a secondary analysis of a 2-week clinical trial of ibudilast that enrolled a nontreatment-seeking sample with AUD. Eligible participants (N = 52) were randomized to receive ibudilast or matched placebo and completed daily diary assessments (DDAs) during the 2-week period. Each morning, participants reported on their mood and craving levels both before and during the previous days drinking episode, as well as stimulation and sedation levels during the previous days drinking episode. Multilevel models were used to compare the effects of ibudilast and placebo on subjective alcohol response. Exploratory analyses tested whether ibudilast moderated the relationship between daily stimulation/sedation and alcohol intake and whether withdrawal-related dysphoria moderated ibudilasts effects on subjective response. RESULTS: Ibudilast did not significantly alter mean levels of stimulation or sedation (ps > 0.05). It did, however, moderate the effect of daily stimulation on drinking (p = 0.045). Ibudilast attenuated alcohol-induced increases in craving compared with placebo (p = 0.047), but not other subjective response measures. Ibudilast significantly tempered daily alcohol-induced changes in urge to drink and positive mood only among individuals without withdrawal-related dysphoria. CONCLUSIONS: Ibudilasts effects on subjective alcohol responses appear to be nuanced and perhaps most salient for individuals drinking for positive reinforcement as distinguished from those who drink to feel normal

ObjectiveThe authors sought to determine the efficacy of targeted naltrexone in sexual and gender minority men (SGM) who binge drink and have mild to moderate alcohol use disorder.MethodsIn a double-blind placebo-controlled trial, a total of 120 SGM who binge drink and have mild to moderate alcohol use disorder were randomized in a 1:1 ratio to receive targeted oral naltrexone (50 mg) or placebo with weekly counseling for 12 weeks. The study's primary endpoints were binge-drinking intensity, defined as 1) number of drinks in the past 30 days; 2) any binge drinking in the past week; 3) number of binge-drinking days in the past week; and 4) number of drinking days in the past week. The study also measured changes in alcohol use with two alcohol biomarker measures: ethyl glucuronide in urine samples and phosphatidylethanol (PEth) in dried blood spot samples.ResultsNinety-three percent completed the trial, with 85% of weekly follow-up visits completed. In intention-to-treat analyses, naltrexone was associated with a significantly reduced reported number of binge-drinking days (incidence rate ratio [IRR]=0.74, 95% CI=0.56, 0.98; number needed to treat [NNT]=2), weeks with any binge drinking (IRR=0.83, 95% CI=0.72, 0.96; NNT=7.4), number of drinks per month (IRR=0.69, 95% CI=0.52, 0.91; NNT=5.7 for 10 drinks), and alcohol craving scores (coefficient=-9.25, 95% CI=-17.20, -1.31). In as-treated analyses among those who took their medication on average at least 2.5 days per week (the median frequency in the study), naltrexone reduced any binge drinking (IRR=0.84, 95% CI=0.71, 0.99), number of binge-drinking days (IRR=0.67, 95% CI=0.47, 0.96), and PEth concentrations (coefficient=-55.47, 95% CI=-110.75, -0.20). At 6 months posttreatment, naltrexone had sustained effects in number of drinks per month (IRR=0.69, 95% CI=0.50, 0.97), number of binge-drinking days (IRR=0.67, 95% CI=0.47, 0.95), and any binge drinking in the past week (IRR=0.79, 95% CI=0.63, 0.99).ConclusionsTarget

Introduction: Complex Regional Pain Syndrome encompasses a symptomatology that can be self-limiting or terribly limiting. Despite the enormous interest it arouses in the scientific community, it is not clear what determines its evolution. Currently, it seems clear that treatment must be adjusted based on the predominant pathophysiological mechanisms in each patient according to its evolutionary stage. Physiopathology: It is caused by a complex combination of different factors that start at the time of the trauma and consist of sensitization of the nervous system, dysfunction of the autonomic system and inflammatory changes. There is also an undoubted immunological component, with the presence of autoimmunization, genetic involvement and the finding that certain psychological states seem to influence the progression of the disease. Prevention: The administration of vitamin C is recommended after trauma or surgery on limbs, especially when there are risk factors (distal radius fractures). Also, early mobilization should be encouraged and high levels of anxiety should be treated to prevent its development. Treatment: Treatment should be early, multimodal and coordinated, with the fundamental objective not only of relieving pain, but also of functionally recovering the affected limb. The cornerstone of treatment is rehabilitation. It should be accompanied by pharmacotherapy and psychological treatment. Within the pharmacotherapy, corticoids (in the most acute phases), bisphosphonates and free-radical scavengers are of special relevance. In advanced stages of the disease, intravenous ketamine is considered as a therapeutic option. Interventional treatments should be considered when the evolution of the syndrome is not optimal, especially sympathetic blocks, in case of predominant sympathetic dysfunction, or neuromodulation, which is the treatment modality with the most scientific evidence. Conclusions: In the approach to this complex pathology in which multiple, RESUMEN Introducción: El síndrome de dolor regional complejo abarca una sintomatología que puede ser autolimitada o terriblemente limitante. Pese al enorme interés que despierta en la comunidad científica, no tenemos claro qué determina su evolución. Actualmente, parece claro que hay que ajustar el tratamiento en base a los mecanismos fisiopatológicos predominantes en cada paciente en función de su estadio evolutivo. Fisiopatología: Se produce a causa de una compleja combinación de diferentes factores que se inician en el momento del traumatismo y que consisten en sensibilización del sistema nervioso, disfunción del sistema autónomo y cambios inflamatorios. Hay, además, un indudable componente inmunológico, con presencia de autoinmunización, una implicación genética y la constatación de que determinados estados psicológicos parecen influir en la progresión de la enfermedad. Prevención: Se recomienda la administración de la vitamina C tras traumatismos o cirugías sobre miembros, sobre todo cuando existen factores de riesgo (fracturas distales de radio). Asimismo, hay que incentivar la movilización precoz y tratar los altos niveles de ansiedad para prevenir su desarrollo. Tratamiento: El tratamiento debe ser precoz, multimodal y coordinado, con el objetivo fundamental no solo de aliviar el dolor, sino de recuperar funcionalmente el miembro afecto. La pieza angular del tratamiento es la rehabilitación. Se debe acompañar de farmacoterapia y de tratamiento psicológico. Dentro de la farmacoterapia, tienen especial relevancia los corticoides (en las fases más agudas), los bifosfonatos y los "free-radical scavengers". En fases avanzadas de la enfermedad, la ketamina intravenosa se plantea como una opción terapéutica. Los tratamientos intervencionistas deben considerarse cuando la evolución del síndrome no es óptima, sobre todo los bloqueos simpáticos, en caso de predominio de disfunción simpática, o la neuromodulación, que es la modalidad de tratamiento que mayor evidencia

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients’ self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient’s needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician’s preferences, experience, and local regulatory requirements.

Introduction: Tourette syndrome (TS) is a chronic tic disorder characterized by both motor and vocal tics. The vast majority of patients present with co-morbid behavioral problems, especially tic-related obsessive-compulsive behaviors and attention-deficit and hyperactivity disorder. Evidence-based guidelines on the pharmacotherapy of TS have become available in recent years. Areas covered: The main purpose of this paper is to provide an overview of the current and emerging pharmacotherapeutic strategies for TS. A comprehensive search for the literature on the pharmacotherapy of tics was conducted using multiple databases (MEDLINE, Scopus, Web of Science, and Google Scholar), without date limits. Expert opinion: In consideration of the heterogeneity of the TS phenotypes, pharmacotherapy should be tailored to the individual patient. The choice of the pharmacological agent should take into account both the efficacy-to-tolerability ratio and the presence of co-morbid conditions. Evidence-based pharmacotherapy should aim at improving health-related quality life within a dynamic framework that typically requires active monitoring of the clinical presentation and reevaluation of the treatment intervention over time.

Aims: Despite landmark heart failure (HF) with reduced ejection fraction (HFrEF) trials showing effect of mineralocorticoid receptor antagonists (MRA) on the risk of death and HF hospitalization, it has been suggested that MRAs are underutilized or frequently withdrawn. This study sought to identify temporal trends in the initiation of MRAs and the subsequent risk of withdrawal and adherence of MRAs in HF patients treated with a renin–angiotensin system inhibitor and a beta-blocker in Denmark from 2003–2017. Methods and results: From nationwide registries, we identified patients receiving a diagnosis of HF. Use of MRA was identified by at least one prescription within 6 months after the diagnosis. The absolute risk of withdrawal with treatment was assessed with cumulative incidence, accounting for the competing risk of death. To estimate adherence, we calculated the proportion of days covered. We included 51 512 patients with incident HF. During the study period, 20 779 (40.3%) patients initiated MRA therapy. The incidence of withdrawal of MRA was 49.2% throughout the study period; 48.0% of the HF patients were adherent to the treatment. Among patients withdrawing treatment with MRA, the cumulative incidence of reinitiating was 36.6%. Conclusions: In a nationwide cohort of patients with HF, approximately half of the patients received MRA as third-line therapy within the first 6 months after diagnosis and approximately half of these withdrew MRA within 5 years. These findings warrant an increasing focus on retention to MRA treatment in a real-life setting.

In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients' self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient's needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician's preferences, experience, and local regulatory requirements.

Introduction: The purpose of this article is to provide an overview, based on a review of the scientific literature, of the pharmacotherapy currently used for autism spectrum disorders (ASD) in the pediatric population. It will also be an opportunity to discuss some of the questions raised by research in the field of pharmacotherapy for ASDs and to situate their place in global care. Material and Method: A search of the scientific literature on medical treatments used in autism spectrum disorders was conducted in Pubmed. International guidelines were also used as references for this article. Results: To date, there are no drug treatments available that target key symptoms. Current evidence-based treatments target the comorbid disorders frequently associated with ASD: sleep disorders (melatonine), agitation or irritability (aripiprazole, risperidone, haloperidol), attention deficit disorder with or without hyperactivity (ADHD) (methylphenidate, atomoxétine, guanfacine). The medical treatment of other co-occuring conditions approach does not differ from the recommendations for the general population in the absence of studies including patients with ASD. There is currently not enough scientific evidence to support the use of metabolic agents or alternative methods such as nutritional methods. Conclusions: Treatment research targeting key symptoms has methodological limitations and has not been successful to date. Pharmacotherapy is reserved for ASD-associated comorbidities, presents clinical challenges and requires additional precautions. The indication of psychoactive medication for the treatment of comorbidities associated with ASD requires a thorough assessment of the individual clinical situation, of the patient and his environment, must exclude a somatic cause, and must be articulated with other non-pharmacological treatments in a multidisciplinary, evolving and coordinated care plan., SCOPUS: ar.j, info:eu-repo/semantics/published

The L-Type Amino Acid transporter, LAT1 (SLC7A5), has a crucial role in mediating amino acid uptake into the cells, thus modulating cell growth and proliferation as well as other intracellular functions. Different studies have reported a central role of LAT1 in glioblastoma development and progression, suggesting that the modulation of its activity could be a novel therapeutic strategy. LAT1 also has an important role in the peripheral immune system, by regulating the activation status of several immune cells through modulation of the mechanistic target of rapamycin kinase. In glioblastoma (GBM), the blood–brain barrier is disrupted, which allows the recruitment of peripheral immune cells to the tumour site. These cells, together with resident microglia, contribute to cancer growth and progression. Currently, little is known about the function of LAT1 in the reprogramming of the immune component of the tumour microenvironment in the context of GBM. In this article, we review the available data on the role of LAT1 in the regulation of GBM biology, including its potential role in the tumour microenvironment, particularly in infiltrating-peripheral immune cells and resident microglial cells. In addition, we review the available data on the main pharmacological inhibitors of LAT1, aiming to evaluate their possible role as novel therapeutics for GBM.

Several drugs gained market authorization based on the demonstration of improved progression-free survival (PFS), adopted as a primary endpoint in Phase 3 clinical trials. In addition, an increasing number of drugs have been granted accelerated approval, and sometimes regular approval, by the main regulatory agencies based on the evaluation of the overall response rate in Phase 1 and 2 clinical trials. However, while the overall survival is an unbiased measure of drug efficacy, these outcomes rely on the assessment of radiological images and patients' categorization using standardized response criteria. The evaluation of these outcomes may be influenced by subjective factors, particularly when the analysis is performed locally. In fact, blinding of treatment is not always possible in modern oncology trials. Therefore, a blinded independent central review is often adopted to overcome the problem of expectation bias associated with local investigator assessments. In this regard, we have recently observed that local investigators tend to overestimate the overall response rate in comparison to central reviewers in Phase 2 clinical trials, whereas we did not find any significant evaluation bias between local investigators and central reviews when considering progression-free survival in both Phase 2 and 3 trials. In the present article, we have tried to understand the reasons behind this discrepancy by reviewing the available evidence in the literature. In addition, a further analysis of Phase 2 and 3 clinical trials that included the evaluation of both endpoints showed that local investigators significantly overestimate overall response rates compared to blinded independent central reviews in uncontrolled oncology trials.

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources, and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on pharmacogenomics implementation. Clinical workforce upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes.

Background: Persistent low grade depression symptoms are common and impairing in major depressive disorder (MDD) yet rarely reported in treatment follow-up studies (Judd et al., 1998a; Kennedy et al., 2004), suggesting that extant sustained remission rates may not reflect this important clinical feature. Furthermore, no long-term MDD treatment follow-up study has reported on quality of life ratings across functioning levels and years throughout the follow-up period, thus the severity, breadth, and persistence of functional impairment remain unclear. Accordingly, the current study evaluated the course of MDD with consideration of low grade depressive symptomatology and holistic features (e.g., quality of life). Methods: We report long-term (9–14 years) follow-up data from individuals with MDD (N = 37) who underwent either Cognitive Therapy (CBT) or a course of selective serotonin reuptake inhibitor (SSRI) treatment. Patients provided retrospective reports of depression symptoms and quality of life in the years following treatment. Results: Chronic depression symptoms (most often mild in severity) and decreased quality of life in multiple domains are frequent and suggest poorer sustained remission rates than previously observed in the literature. Limitations: Study limitations include small sample size recruited via convenience sampling methods. Conclusions: Findings support a conceptualization of depression recovery that entails persistent symptoms and vulnerabilities. Clinical recommendations are provided for discussing these features of depression recovery with patients.

Objetivos: Identificar los fármacos relacionados con la aparición de labio leporino/paladar fisurado con la ingesta de fármacos durante el embarazo y realizar una extensa revisión bibliográfica de las investigaciones más actuales de la etiología de la fisura palatina y labio leporino. Material y Método: Bases de datos PUBMED, SCOPUS y Google académico, además de numerosas revistas y libros, seleccionándose 9 publicaciones una vez aplicados los criterios de inclusión y exclusión. Resultados y Conclusiones: Las hendiduras orofaciales presentan una etiología multifactorial y se ha demostrado la relación con algunos medicamentos. El factor etiológico más predominante en la aparición de labio leporino es genético. El Dizepam, Fluoconazole, los broncodilatadores y corticoides no son fármacos cuyo uso esté asociado a un aumento de casos de paladar fisurado. El Ondansetrón actualmente está contraindicado durante el embarazo y debe evitarse su uso, especialmente durante el primer trimestre, por posibilidad de ocasionar malformaciones (labio leporino/paladar fisurado)., Objectives: To identify the drugs related to the appearance of cleft lip/palate with the ingestion of drugs during pregnancy and to carry out an extensive bibliographic review of the most current research into the aetiology of cleft palate and cleft lip. Material and Method: PUBMED, SCOPUS and Google academic databases, as well as numerous journals and books, 9 publications were selected after applying the inclusion and exclusion criteria. Results and Conclusions: Orofacial clefts present a multifactorial aetiology and a relationship with some medications has been demonstrated. The most predominant aetiological factor in the appearance of cleft lip is genetic. Dizepam, Fluoconazole, bronchodilators and corticosteroids are not drugs whose use is associated with an increase in cleft palate cases. Ondansetron is currently contraindicated during pregnancy and its use should be avoided, especially during the first trimester, due to the possibility of causing malformations (cleft lip/cracked palate).