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Background: Medications initially intended for diabetes treatment are now being used by other patients for weight loss. In the specialized literature, there are numerous meta-analyses investigating this aspect., Areas of Uncertainty: The authors aimed to explore whether the application of scientometric methods for literature review within meta-analyses could provide clear answers to specific research questions. This approach could help develop a rapid system for selecting articles to read during the information process for clinicians or researchers., Data Sources: We obtained research data from Web of Science Core Collection, using the search phrase "GLP-1 AND Body Weight," reviews from the past 5 years. This approach led to the identification of 31 relevant articles in the field., Results: A total of 31 reviews were identified in the WOS database and investigated using the VOSviewer bibliographic coupling method. Among these, 7 reviews were found to have the highest influence. The authors analyzed these articles and determined that only these 7 reviews directly address the research question. In addition, an analysis of the impact factor of the journals where the articles are published, the influence power of these articles, and the countries of origin of the authors was conducted. A strong correlation was demonstrated between the impact factor and the total link strength for these 7 reviews. The correlation coefficient of 0.116709 between journal impact factor and number of citations suggests a very weak or nonexistent relationship. A strong positive correlation of 0.879736 exists between journal impact factor and total link strength, indicating a significant association. The correlation coefficient of -0.12505 between citations and total link strength shows a very weak or negligible relationship., Conclusions: Scientometric methods such as VOSviewer are useful in the work of both researchers and clinicians, highlighting the fact that articles in a research field can be identified by several criteria: impact factor, number of citations, authors from research teams that addressed this topic. The weak correlation between journal impact factor and number of citations implies that the prestige of the journal does not significantly affect the citation count of articles. Researchers should focus on the quality and relevance of their work rather than solely targeting high-impact journals. However, the strong positive correlation between impact factor and total link strength suggests that articles in prestigious journals are more likely to share content similarities. Researchers should consider this when selecting journals for publication and aim to contribute to impactful and interconnected research areas. This approach allows quick and easy identification of key articles, serving as a fundamental basis for rapid analysis of research in the field, starting from the analysis of authors' competence, degree of trust of the journal, or degree of interest that researchers have for that article., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The nocebo effect is often disregarded in medical practice and is certainly much less known than the placebo effect, although, in reality, both can influence therapeutic decision making and the quality of life of patients. However, the nocebo effect raises a number of issues not only of a practical nature related to clinical activity but also ethical dilemmas related to the observance of the patient's autonomy, nonmaleficence, or informed consent and the information on which it is based., Areas of Uncertainty: The ethical dilemmas raised by the nocebo effect revolve around how informed consent can be achieved, the accuracy and volume of information that is transmitted to the patient, and how to report negative side effects of therapeutic treatment., Data Sources: In September 2023, a narrative analysis of the literature was conducted using a combination of keywords such as nocebo, placebo, ethics, therapeutic relationship from PubMed, Scopus, Google Scholar, and so on, as well as from official documents developed at an international level (World Health Organization), for a period of 10 years (2012-2021)., Results: Analyzing the articles that remarked upon the significant impact of ethics in nocebo research or in the therapeutic relationship, we can state that the existence of several relevant issues of interest have been detected regarding the ethical use of nocebo and its impact in research or in clinics and thus the need for proper knowledge and management of the impact of nocebo effects. The ethical paradox of obtaining informed consent with the 2 goals, first, the need for complete information and second, the preservation of the autonomy of the patient, respectively, that of "primum non-nocere" and of avoiding unnecessary harm by revealing probable adverse effects is a point of interest for numerous studies. The potential for a nocebo effect is present when we inform patients about the risks and benefits of treatment, there being a clear link between the moral and ethical duty to inform patients and the need to avoid situations that increase the nocebo impact on how the disease or the adverse effects of the treatment are perceived. Adapting information about the side effects of medicines should focus on ensuring a balance between transparency and caution, especially in patients with a high potential for nocebo effect., Conclusions: The nocebo effect had for a long time been unknown or denied, although it can interfere with the results of the treatment used. As the nocebo phenomenon becomes increasingly known in medical practice, the clinical and ethical implications are identified by medical staff, and nocebo's adverse responses are no longer ignored., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Artificial intelligence (AI) is considered the fourth industrial revolution that will change the evolution of humanity technically and relationally. Although the term has been around since 1956, it has only recently become apparent that AI can revolutionize technologies and has many applications in the medical field., Areas of Uncertainty: The ethical dilemmas posed by the use of AI in medicine revolve around issues related to informed consent, respect for confidentiality, protection of personal data, and last but not least the accuracy of the information it uses., Data Sources: A literature search was conducted through PubMed, MEDLINE, Plus, Scopus, and Web of Science (2015-2022) using combinations of keywords, including: AI, future in medicine, and machine learning plus ethical dilemma., Ethics and Therapeutic Advances: The ethical analysis of the issues raised by AI used in medicine must mainly address nonmaleficence and beneficence, both in correlation with patient safety risks, ability versus inability to detect correct information from inadequate or even incorrect information. The development of AI tools that can support medical practice can increase people's access to medical information, to obtain a second opinion, for example, but it is also a source of concern among health care professionals and especially bioethicists about how confidentiality is maintained and how to maintain cybersecurity. Another major risk may be related to the dehumanization of the medical act, given that, at least for now, empathy and compassion are accessible only to human beings., Conclusions: AI has not yet managed to overcome certain limits, lacking moral subjectivity, empathy, the level of critical thinking is still insufficient, but no matter who will practice preventive or curative medicine in the next period, they will not be able to ignore AI, which under human control can be an important tool in medical practice., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The promotion of the latest medicines produced by the pharmaceutical industry is an important issue both from an ethical point of view (the level of accessibility, the way research is carried out) and from the point of view of marketing and especially from the lobbying issues raised., Areas of Uncertainty: The ethical dilemmas raised by the promotion of new drugs revolve between the need to discover new molecules important for treating a wide range of diseases and the need to establish a battery of ethical rules, absolutely necessary for regulations in the field to be compliant with all ethical principles., Data Sources: A literature search was conducted through PubMed, MEDLINE, Plus, Scopus, and Web of Science (2015-2023) using combinations of keywords, including drugs, medical publicity, and pharma marketing plus ethical dilemma., Ethics and Therapeutic Advances: The promotion of medicines is governed by advertising laws and regulations in many countries, including at EU level, based on the need for countries to ensure that the promotion and advertising of medicines is truthful, based on information understood by consumers. The ethical analysis of the issues raised is more necessary and complex as the channels used for promotion are more accessible to the population, and the information, easier to obtain, can be the cause of increased self-medication and overeating. Large amounts of money invested in the development of new molecules, but also the risk of scientific fraud through manipulation of data during clinical trials, selective or biased publication of information can have repercussions on the health of the population., Conclusions: The development of new pharmaceutical molecules is necessary to intervene and treat as many conditions as possible, but marketing must not neglect the observance of ethical principles. The promotion of medicines should be the attribute especially of the medical staff, which should also be a mandatory part of the mechanism for approving the marketing methods and means used by the pharmaceutical companies., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This study aims to evaluate the efficacy of transcranial magnetic stimulation (TMS) in patients with depression and whether concurrent psychotropic medication use negatively affects the treatment outcome of TMS. Patients' characteristics, predictors of treatment response, the relationship between demographics, and the selection of TMS as a treatment modality were also analyzed., Study Question: Can psychotropic medication be a factor that can negatively affect the efficacy of TMS in patients with depression?, Study Design: This pilot-controlled study included 40 subjects from Romanian clinical practice who were treated with pharmacological treatment and TMS for major depressive disorder. The severity of depression and anxiety symptoms was measured using validated scales at baseline (day 1) and follow-up (day 30)., Data Sources: All patients' characteristics and information were collected manually from the clinic's medical records, deidentified, and then introduced into an electronic database for analysis., Limitations: Conducting the study in a clinical routine practice, it was not possible to include an active and/or sham control group. In addition, because TMS is not used as a monotherapy in this type of practice, we could not evaluate its safety and efficacy without concomitant pharmacological treatment. The study sample is small; therefore, the results cannot be generalized., Results: Sixty percentage of patients (n = 24) included in this study obtained a clinical response, and 30% of patients (n = 12) obtained remission of depression. The group with pharmacological treatment obtained clinical responses in 80% of patients (n = 16) and remission of depression in 45% of patients (n = 9). The group with pharmacological treatment and TMS obtained clinical responses in 40% of patients (n = 8) and remission of depression in 15% (n = 3) of cases., Conclusions: The study results show a lack of efficacy for TMS as an adjunctive therapy to pharmacological treatment for patients with depression. In addition, a negative impact of psychotropic medication on TMS efficacy is observed in our study sample., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cholera is a potentially lethal diarrheal disease produced by Vibrio cholerae serotypes O1 El Tor and O139. Known since antiquity, the condition causes epidemics in many areas, particularly in Asia, Africa, and South America. Left untreated, the mortality may reach 50%. The crucial therapeutic intervention is intravenous or oral rehydration and correction of acidosis, dyselectrolytemia, and renal impairment. Antibiotic use represents the main pharmacological intervention., Study Question: What are the milestones of the antibiotics use recommended by experts for the pharmacological management of cholera in the past century?, Study Design: To determine the changes in the experts' approach to the management of cholera and particularly the use of antibiotics as presented in a widely used textbook in the United States., Data Sources: The chapters describing the management of cholera in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Sulfonamides were recommended in 1947, followed by the introduction of tetracyclines, chloramphenicol, and furazolidone in 1955. The options were restricted in 2000 to doxycycline. In the past decade, patients infected with strains known to have a degree a resistance to tetracyclines were treated with azithromycin or ciprofloxacin. Antibiotic use decreases the volume of stool and the duration of diarrhea but has not been considered lifesaving. Drugs with antimotility, antiemetic, or antisecretory properties are not useful., Conclusions: The utility of antibiotic use in cholera has been endorsed by experts, but only as an adjunct to rapid and complete fluid and electrolyte replacement., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The history of medicine has flowed in the wake of knowledge and social perceptions about the body and corporeality. There is no idea of health without reference to the notion of body (although "health" can have other meanings, figuratively). Considering the same history, the body was the subject of numerous segregations and categorizations due to which it was and is a "social object" and a "political object." In turn, the spatial and cultural framework was the environment and determinant of the medicine development which is not only a science but also an inter-human interactive practice., Areas of Uncertainty: In this article, we will analyze the current social (re)construction of the notions of body and space by referring to the technological and structural changes that are manifested in medicine and society and their ethical implications., Data Sources: A review of the specialized literature was performed in June-July 2023, using keywords like human enhancement, therapeutic enhancement, transhumanist medicine, ethics from PubMed, Scopus, Web of Science, and Google Scholar, and official documents issued at the international level (World Health Organization, European Commission)., Ethics and Therapeutic Advances: This literature review suggests that few practical solutions to human enhancement, both curative and preventive, whether cognitive or physical, have been approached entirely from an ethical point of view. The historical evolution of the concept of human enhancement has led to debates between "transhumanists" and "bioconservatives" depending on how they relate to the improvement of the human condition without or with reticence interventions to improve human capabilities being related to various interventions, from pharmacological, surgical ones to those in the field of genetics, nanomedicine, or cybernetics. In addition to the technical aspects, which are often the major concern of researchers and those applying new technologies, there are also ethical and legislative aspects, to better understand the impact that the dynamics and diffusion of these processes have on the evolution of the human species., Conclusions: In interference with these technologies, the body is exposed to possibilities of change and evolution with colossal (expected) social impact that can change norms and values that have been stable for centuries. Social space and place are also proving to be "processes in the making'" for which we need to detect what developments are possible or have already imposed themselves as a trend in the social and medical world., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Complete bed rest has been a component of the management of acute myocardial infarction, which was first diagnosed in the United States in 1912. The prescribed duration of bed rest has been progressively shortened in the past century., Study Question: What are the milestones of the changes in the expert approach to the duration of bed rest for patients with acute myocardial infarction?, Study Design: To determine the changes in the experts' approach to the duration of bed rest after a diagnosis of acute myocardial infarction, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of myocardial infarction in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Complete rest for 2-6 weeks was recommended by the Cecil's experts from 1927 through 1967. The practice was questioned since the early 1950s, but the recommended duration of bed rest was decreased to 3-4 days only in 1971, after most US hospitals opened coronary care units. The required time in bed was further decreased to 1 day in 1992 and to 12 hours in 2004. By 2007, the literature contained data from 15 trials with a total of 1471 patients kept in bed "longer" and 1487 patients who had been prescribed bed rest for "shorter" periods after an acute uncomplicate myocardial infarction and there was no difference between the groups regarding reinfarction, cardiac mortality, or all-cause mortality., Conclusions: The duration of bed rest after acute myocardial infarction recommended by experts in the United States has had a downward trend with an inflection point in the early 1970s. The change reflected experts' opinion, rather than evidence produced by randomized controlled trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cardiovascular diseases are an important public health problem, the main cause of death in both men and women, with a continuous increasing prevalence and consequences upon morbidity in economic, physical, and psychological terms.The new technology have made possible the development of innovative devices, which have increased the possibility of therapeutic interventions today, extending the life of the population with cardiovascular pathology, transforming the patient care, and providing a complex, personalized therapeutic approach., Fields of Uncertainty: The aim of the study was to evaluate from an ethical perspective the need, feasibility, and safety of reusing cardiac pacemakers to revise the legal terms and requirements.In recent years, the problem of accessibility to cardiovascular drugs has been increasingly accompanied by the accessibility to technology, interventional cardiology advancing recently, and becoming an increasingly important standard of care., Data Sources: A review of the specialized literature was performed in March 2023, using keywords such as implantable cardiac devices, reuse, ethics from PubMed, Scopus, Web of Science, and Google Scholar, as well as official documents issued at the international level (World Health Organization)., Ethics and Therapeutic Advances: An ethical analysis assesses the extent to which a medical act (PM reimplantation) is covered by the 4 universally accepted principles: nonmaleficence, beneficence, autonomy (respect for the person), and social justice, the analysis addressing to the risk-benefit ratio based on studies that analyzed the phenomenon over the past 50 years. The ethical analyzed issues start from the fact that although 80% of pacemakers, most of them working perfectly, with a battery life of more than 7 years are buried with their owners, while approximately 3 million patients die annually due to the lack of access to these devices in undeveloped and developing countries.But beyond the ethical issues, legal practice has meant that in many countries, reusing of these devices is prohibited, mostly being single-use devices. Low-income countries continue to accept this practice as the only one economically accessible to them, considering the prohibition of reusing them to be an economic rather than a medical issue., Conclusions: Reusing implantable cardiac devices is of great interest because of the costs, being in certain situations, the only possibility that certain people can have access to a therapeutic method that ensures their health recovery and increases their quality of life. But this is not possible without clear procedures, without clear criteria on how sterilization should be performed, how the technique should be performed, without obtaining a truly informed consent, and especially without a proper patient's follow-up., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The COVID-19 pandemic has brought new ethical challenges to both health care professionals and the general public. Among the ethical problems amplified during this period were the making of medical decisions to quickly introduce some drugs into therapeutic practice with unproven or insufficiently proven effects (such as ivermectin), the validity of drug testing, and the allocation of limited resources., Fields of Uncertainty: The COVID-19 pandemic brought to the attention of the entire scientific world a new problem, which exceeded the guidelines and rules known until then. Out of the desire to quickly solve this medical problem, a series of measures were taken, however not sufficiently validated in scientific terms; the recommendations regarding the use of drugs known for their properties to treat a greater number of conditions, such as ivermectin, was tried., Data Sources: A narrative review of the specialized literature was carried out using keywords such as COVID-19, ivermectin, ethics, and off-label medication from Scopus and Google Scholar but also of official documents developed at the international level (World Health Organization)., Ethics and Therapeutic Advances: The off-label use of ivermectin alone or in combination with other medications during COVID pandemic raised problems related to the demonstration of its effectiveness, but also to ethics, starting from the expectations that both the medical staff and the population had of it. Ivermectin therapy was also evaluated by analyzing the behavior of ivermectin based on ethical principles (nonmaleficence, beneficence, and respect for one's autonomy) or on justice. Even in times of pandemic, exceptionalism must not triumph, and finding an effective treatment must be done through studies that respect ethical standard., Conclusions: The failures or rather lack of success in decision making during the pandemic showed that alongside scientific knowledge and the development of health policies, it is necessary to constantly evaluate the measures and decisions from an ethical point of view, and the prevention of slippages and abuses is not only necessary but even mandatory., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Genetic engineering has allowed a major development of research in this field, with specialists attempting to edit the human genome, after the successful editing of the genomes of plants and animals. However, human gene editing technologies are at the center of ethical debates around the world., Areas of Uncertainty: Ethical concerns about genetic editing of the human embryo raise several issues that can be viewed through the prism of optimism and reluctance leading to a number of recommendations regarding the acceptance of what may soon become a reality., Data Sources: A literature search was conducted through PubMed, MEDLINE, Plus, Scopus, and Web of Science (2015-2022) using combinations of keywords, including: human genome or gene editing plus ethics., Ethics and Therapeutic Advances: Gene therapy is seen by researchers as a way to solve congenital diseases, multifactorial diseases in general or specific diseases such as cystic fibrosis, muscular dystrophy, or can increase resistance to HIV infection. Genome editing technologies, germline gene editing, clustered regularly interspaced short palindromic repeats gene editing technology, technologies such as zinc finger nucleases are not only advanced gene therapies that require solving technical problems, but also techniques that require complex and complete analysis of ethical problems. Genetic engineering raises many ethical concerns such as: safety concerns especially the risk of off-target effects; autonomy of the individual-with the limitation of the future generations to consent for an intervention over their genome; social justice-keeping in mind the costs of the procedures and their availability to the general population. Discussions can go further from questions such as "How can we do this?" to questions such as "Should we do this?" or "Is society ready to accept this technology and is it able to manage it rationally?", Conclusions: The ethics of biomedical research should be based on global dialogue, on the involvement of experts and the public, to achieve a broad social consensus. The fundamental review of the ethics of genetics is a desire and an opportunity of the current period., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for pulmonary tuberculosis have had an extraordinary impact on the incidence of tuberculosis in the United States in the past century, which has decreased from 113/100,000 persons in 1920 to 2.2/100,000 in 2020. Modern treatments have contributed to a remarkable decrease in hospitalizations and mortality and have had a significant impact on the duration and severity of illness, quality of life, and work potential of affected persons., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of pulmonary tuberculosis in the past century?, Study Design: To determine the changes in the experts' approach to the management of pulmonary tuberculosis, as presented in a widely used textbook in the United States., Data Sources: The chapters describing the management of pulmonary tuberculosis in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: In the preantibiotic era (1927-1943), the Cecil authors emphasized rest, good food, and fresh air as the treatment pillars for pulmonary tuberculosis. The modern era (1947-1971) recorded the discovery of all the drugs that are still used for the initial treatment, in the following order: streptomycin, para-aminosalicylic acid, isoniazid, pyrazinamide, ethambutol, cycloserine, kanamycin, ethionamide, capreomycin, and rifampin. In the postmodern era (1975-2020), therapeutic advances continued with trials of many drug combinations aimed at ameliorating the duration of treatment, drug resistance adverse effects, and poor the recent addition of fluoroquinolones, bedaquiline, and clofazimine., Conclusions: The pharmacological management of tuberculosis has remained archaic until the middle of the 20th century. Fundamental progress occurred in a very short period (1947-1971) and was because of the recognition of the antituberculous effect of many antibiotics and chemotherapy agents. The challenges created by mycobacterial infections resistant to multiple drugs remain and have prompted the addition of new drugs in the past decade., Competing Interests: The authors have no conflicts of interest to declare. P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining author has no conflict of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for inflammatory bowel disease (IBD) [Crohn disease and ulcerative colitis (UC)] have contributed to a decrease in the severity of these chronic and disabling conditions., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of IBD in the past century?, Study Design: To determine the changes in the experts' approach to the management of regional ileitis and UC, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of IBD in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: No specific interventions existed from 1927 through 1942. The pharmacological management of IBD has had 3 slightly overlapping eras starting in 1943. During the first period (1943-1951), the medical management relied on antibiotics, primarily sulfonamides and chloramphenicol. In the second (1955-75), experts recommended the use of adrenocorticotropic hormone or corticosteroids and 5-aminosalicylate. In the third era, which commenced in 1979 and is continuing to date, the pharmacological interventions have been expanded and refined to include 5 main drug classes, 5-aminosalicylates (sulfasalazine, mesalamine, and olsalazine), corticosteroids (prednisone and budesonide), immunomodulators (azathioprine, 6-mercaptopurine, cyclosporine, and tofacitinib), biologics (infliximab adalimumab certolizumab pegol, and natalizumab), and antibiotics (metronidazole and ciprofloxacin). A consensus exists that the monoclonal antibodies again tumor necrosis factor alpha are cost-effective for induction and maintenance of clinical remission in both UC (golimumab) and Crohn disease (certolizumab pegol). The newer agents ustekinumab (a monoclonal antibody to the interleukin p40 subunit) and vedolizumab (a monoclonal antibody to the homing receptor integrin complex) have also performed well., Conclusions: The pharmacological management of IBD has been the focus of intense research and development in the past 60 years. The pillars of drug treatment have been 5-aminosalicylates and corticosteroids. Recent pharmacological innovations (immunomodulators and biologicals) constitute an encouraging paradigm shift in the treatment of UC and Crohn disease., Competing Interests: P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Innovations in drug therapy for obesity have had a limited impact on the body mass index, prevalence of medical complications, quality of life, and work potential of a substantial majority of affected persons., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of obesity in the past century?, Study Design: To determine the changes in the experts' approach to the management of obesity, as presented in a widely used textbook in the United States., Data Sources: The primary sources were chapters describing the management of obesity in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. Secondary sources were publications retrieved from Medline that clarified technical issues related to the development, regulatory approval, and use of the drugs mentioned in the Cecil Textbook of Medicine., Results: Pharmacological interventions aimed at increasing caloric expenditures through thermogenesis were recommended from 1927 through 1943. Thyroid extracts were prescribed even in the absence of demonstrated hypothyroidism or decreased basal metabolic rate throughout this period. Dinitrophenol was mentioned in 1937, but was banned soon thereafter. Appetite suppression with amphetamine was considered useful from 1943 through 1988, after which the drug was replaced with other centrally acting molecules, such as fenfluramine in 1988, sibutramine in 2000, and rimonabant in 2008, which were in turn withdrawn because of major adverse effects. In the past decade, obesity has been treated with the appetite suppressants phentermine-topiramate, bupropion-naltrexone, lorcaserin, and liraglutide, and with orlistat, a drug promoting fat malabsorption. The change in weight produced by these drugs is generally modest and transient., Conclusions: The pharmacological management of obesity has remained frustratingly inefficient. The reasons for the relative lack of success may reside in the ever-growing access to dense, palatable, and relatively inexpensive food, coupled with the decrease in energy expenditure created by a sedentary lifestyle., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Older adults with serious mental illness have a high prevalence of coronary artery disease and of its major risk factors, that is, arterial hypertension, dyslipidemia, and diabetes mellitus. The prevalence and clinical control of these conditions have not been compared in geropsychiatric inpatients with dementia versus those with mood or psychotic disorders., Study Question: What is the prevalence and acuity of coronary artery disease, arterial hypertension, dyslipidemia, and diabetes mellitus among patients with dementia, mood, and psychotic disorders admitted for geropsychiatric care?, Study Design: Patients 65 years of age or older were identified in a cohort of 1000 patients consecutively admitted over a 3-year period to the geropsychiatric unit of a 200-bed mental health hospital in suburban New York. All patients had a structured clinical and laboratory evaluation within 72 hours of admission., Data Sources: Primary psychiatric diagnoses, medical history, the frequency of poorly controlled cardiometabolic comorbidity requiring an immediate change in the management plan, and the Charlson Comorbidity Index (CCI)., Results: The 65 years and older patient sample (N = 689) had a mean age of 74.8 years, and 58.8% of the subjects were women. The 205 patients with dementia were older ( P < 0.001) than the 337 patients with mood disorders and the 147 patients with psychotic syndromes. The numbers of medical conditions and the CCI after exclusion of dementia were similar in patients with dementia versus patients without dementia. A substantial number of patients had poorly controlled arterial hypertension (51.2%), dyslipidemia (25.4%), diabetes (24.2%), and coronary artery disease (15.4%). Patients with dementia had a lower prevalence of poorly controlled dyslipidemia ( P = 0.0006), diabetes ( P = 0.0089), and coronary artery disease ( P = 0.045)., Conclusions: Compared with mood or psychotic disorder, a diagnosis of dementia with behavioral disturbance seemed to be associated with better control of coronary artery disease, dyslipidemia, and diabetes mellitus in geropsychiatric inpatients., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for primary (or essential) arterial hypertension have contributed to a significant decrease in the frequency and severity of strokes, coronary artery disease and heart failure, and chronic renal insufficiency., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of arterial hypertension in the past century?, Study Design: To determine the changes in the experts' approach to the management of arterial hypertension, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of arterial hypertension in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: The pharmacological management of arterial hypertension has had 3 overlapping eras in the timeframe subject to our investigation. In the empiric era (1927-1947), experts were recommending nonspecific interventions for sedation. The premodern era (1955-1963) relied on ganglion blockers, sympathetic blockers, and direct vasodilators. The modern era (1967-2020), which includes drugs used in current clinical practice, saw the introduction of diuretics (1967), beta-blockers (1971), alpha-blockers (1982), calcium channel blockers (1985), angiotensin-converting enzyme inhibitors (1985), angiotensin receptor blockers (2000), and direct renin inhibitors (2008)., Conclusions: The pharmacological management of arterial hypertension has been the focus of intense and successful research and development in the second half of the 20th century., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Opioid use disorder continues to have a significant impact on public health morbidity and mortality throughout the United States and elsewhere. Managing opioid withdrawal is a critical treatment goal in individuals entering treatment with an active opioid use., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of heroin withdrawal syndrome in the past century?, Study Design: To determine the changes in the expert approach to the management of heroin withdrawal syndrome, as presented in a widely used textbook in the United States., Data Sources: The chapters on opioid dependence in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Opioid replacement taper with morphine (1927-1947), codeine (1931-1943), and methadone (1951-present) administered for 3-10 days has remained the main intervention. The anticholinergic drugs, scopolamine and atropine, were recommended from 1927 to 1943, but their use has never been backed by scientific evidence. Newer approaches relied on clonidine, an alpha-2 receptor agonist used since 1982, and buprenorphine, an opioid agonist/antagonist endorsed for the treatment of heroin withdrawal in 2000., Conclusions: The pharmacological management of heroin withdrawal syndrome in the past century has progressed from the introduction of methadone to the utilization of clonidine and buprenorphine. More recent advances in treating opioid use disorder have changed the goals of opioid withdrawal management to achievement of abstinence from all opioids to facilitation of long-term treatment with medications for opioid use disorder., Competing Interests: P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for atrial fibrillation (AF) have had a significant impact on the quality of life of a substantial majority of affected persons, which has contributed to a remarkable decrease in the frequency and severity of thromboembolic complications, hospitalizations, and mortality., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of AF in the past century?, Study Design: To determine the changes in the experts' approach to the management of AF, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of AF in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: AF was consistently described in Cecil Textbook of Medicine as the most common sustained arrhythmia in adults. The authors emphasized its thromboembolic complications and potential for hemodynamic deterioration. Rate control with digitalis and rhythm control with quinidine were the standard in 1927. The pharmacological advances have focused on atrioventricular nodal blocking for rate control, conversion to and maintenance of sinus rhythm, and preventive anticoagulation. The first new class of drugs for rate control was beta-adrenergic receptor blockers, starting with propranolol which was introduced in 1979, followed by the calcium channel blocker verapamil in 1988. Rhythm control with amiodarone, a potassium channel blocker, has been recommended since 2004, and the sodium channel blockers propafenone and flecainide became part of standard therapy in 2008. Anticoagulation with warfarin was recommended starting in 2000, followed by the introduction of direct thrombin inhibitor in 2012 and factor Xa inhibitors in 2016., Conclusions: The pharmacological management of AF was unchanged for more than 50 years (1927-1979), a period during which the devastating effects of thromboembolic complications were not addressed. The major therapeutic advance is represented by preventive anticoagulation with the newer, safer, and more user-friendly direct thrombin and factor Xa inhibitors., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for myasthenia gravis have had a significant impact on the quality of life and work potential of a substantial majority of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of myasthenia in the past century?, Study Design: To determine the changes in the experts' approach to the management of myasthenia gravis, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of myasthenia gravis in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020., Results: Adequate feeding, absolute rest in bed, and "tonics" were the only interventions recommended for the care of patients with myasthenia gravis in 1927. Ephedrine and glycine were used in the early 1930s. Treatment with the anticholinesterases physostigmine and neostigmine was recommended in 1937, 3 years after Mary Walker discovered it in the United Kingdom. Immunosuppressant pharmacological interventions with prednisone and azathioprine have been considered the standard since 1975, and intravenous immune globulin was added to usual care in 1996. The newer immunosuppressant drugs mycophenolate, cyclosporine, and tacrolimus have expanded the arsenal since 2008, and the monoclonal antibodies rituximab and eculizumab have been mentioned in the textbooks published in 2012-2020. The first randomized clinical trial of drug therapy for myasthenia gravis was published in 1987., Conclusions: The pharmacological management of myasthenia gravis was revolutionized by the epiphany of an astute clinician in the 1930s. Immunosuppressant treatment was a logical step once the autoimmune nature of the condition was established. The major therapeutic advances highlight the values of empiricism and persistent attention to detail in treating relatively rare chronic disorders., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Advances in drug therapy for peptic ulcer have had a significant impact on quality of life and work potential of many millions of affected persons and have contributed to a remarkable decrease in the prevalence of the disease, frequency and severity of complications, hospitalizations, and mortality., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of peptic ulcer in the past century?, Study Design: To determine the changes in the experts' approach to the management of peptic ulcer, as presented in a widely used textbook in the United States., Data Sources: The chapters presenting the management of peptic ulcer in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: Acid neutralization with alkalies was the only pharmacological intervention recommended in the textbooks published from 1927 to 1975. Atropine and other antimuscarinic agents were mainly used to relieve pain and acid secretion according to the paradigm "no acid no ulcer." The shift to the acid suppression paradigm started with the introduction of the histamine-2 receptor antagonist cimetidine in 1979, the proton-pump inhibitor omeprazole in 1988, and the prostaglandin agonist misoprostol in 1992. Finally, the eradication of Helicobacter pylori was codified in 1996., Conclusions: The pharmacological management of peptic ulcer has remained archaic well into the 20th century. Fundamental progress occurred in a very short period (1979-1996) and was due to paradigm shifts from acid neutralization to acid suppression and later the recognition of the role of H. pylori infection., Competing Interests: P. Manu has contributed a chapter to each of the last 4 editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The current pandemic has raised several ethical dilemmas, related to conducting real-time trials for new treatments or vaccines or with decisions such as accessibility to vaccines., Study Question: Should there be a prioritization of access to the vaccine based on ethical and objective criteria or should the access be done at random?, Study Design: To determine the ethics and reality of rationing the accessibility to anti-COVID vaccine according to the official strategies., Data Sources: The study is based on the consultation of (1) scientific articles from international databases (Google Scholar, PubMed, ProQuest, and Clarivate), (2) public health documents, and (3) official information of various governments., Results: The analyzed documents revealed that a few similarities can be observed in European countries when it comes to the first categories of people who have received the vaccine: people living in care facilities and medical staff; it can also be seen that the vaccination plan was adopted by each country for the needs and characteristics of its population, the prioritization being done in 2-14 stages; some of them divided, in their turn, into subsequent substages. Most of the states subject to the analysis assigned the medical staff in the first stage, followed by those in the sectors ensuring the maintenance of essential services, afterward by the elderly or people with comorbidities, only later to expand to other social categories., Conclusions: Prioritization of vaccine administration is not only necessary, unavoidable, but also problematic both ethically and logistically, which should involve leaders in the field of public health, but also medical staff, regardless of their specialization. Prioritization of vaccination can not only have an impact on individual health (physical and emotional) but also on society from public health, economic, and sociocultural point of view., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Drug therapy for diabetes mellitus (DM) has had a significant impact on quality of life and work potential of affected persons and has contributed to a remarkable decrease in the frequency and severity of complications, hospitalizations, and mortality. The current approach is the result of incremental progress in using technological advances to increase the safety and effectiveness of insulin therapy and the introduction of new molecules as oral and injectable antidiabetic drugs., Study Question: What are the milestones of the changes in the expert approach to the pharmacological management of DM in the past century?, Study Design: To determine the changes in the experts' approach to the management of DM, as presented in a widely used textbook in the United States., Data Sources: The chapters on describing the management of DM in the 26 editions of Cecil Textbook of Medicine published from 1927 to 2020., Results: In 1927, DM was treated with insulin extracted from the pancreas of large animals (cattle, hogs, and sheep) and purified with alcohol to prevent the tissues' proteolytic action on the hormone. The therapeutic milestones in DM marked 2 avenues for innovation. The first created advances in insulin therapy, starting with processes that led to the production of crystalline insulin and protamine zinc insulin (1937), synthetic human insulin (1996), and prandial (2000) and basal (2004) insulin analogues. The second was an effort to develop and introduce in clinical practice in the United States oral antidiabetic drugs, starting with tolbutamide, a sulfonylurea (1955), followed by metformin, a biguanide (1996), thiazolidinediones, alpha-glucosidase inhibitors, and benzoic acid derivatives (2000), dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists (2008), and sodium glucose cotransporter 2 inhibitors (2020). A latent period of 40 years between significant advances was likely because of searches for new technologies (eg, recombinant DNA for the production of synthetic insulin and analogues) and, at least in part, to the impact of the controversial University Group Diabetes Project on the development and acceptance of oral antidiabetic drugs., Conclusions: The pharmacological management of DM has progressed unevenly, with a long latency period in the second half of the last century followed by highly encouraging advances in the first 2 decades of the 21st century. In chronological order, the major advances were synthetic insulins obtained through DNA recombinant technology, adoption of metformin as first line therapy, and introduction of antidiabetic medication classes that also promote weight reduction and cardiovascular health., Competing Interests: P. Manu has contributed a chapter to each of the last four editions of Cecil Medicine (2008, 2012, 2016 and 2020).The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Drug therapy for heart failure influences quality of life and work potential of affected persons and has contributed to decrease in hospitalizations and cardiovascular mortality. The current approach is the result of incremental progress in understanding the pathophysiology of the syndrome, introduction of new molecules, and repurposing existing drugs., Study Question: What are the milestones of the changes in the expert clinicians' approach to the pharmacological management in the past century?, Study Design: To determine the changes in the experts' approach to the management of heart failure, as presented in a widely used textbook in the United States., Data Sources: The chapters on the management of heart failure in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020., Results: In 1927, heart failure was treated with powdered leaf or tincture of digitalis, mercury chloride, and theophylline. Patients with acute pulmonary edema received injections of atropine, adrenaline, and ouabain. The therapeutic milestones in heart failure were the introduction of loop diuretics and aldosterone antagonists (1971), vasodilator treatment with hydralazine and nitroglycerine (1979-1985), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and selective beta-adrenergic blockers (1992-2000), and sacubitril-valsartan (2016). For acute pulmonary edema, the durable milestone was the treatment with morphine and furosemide (1971)., Conclusions: The pharmacological management of heart failure in the past century has progressed in fits and starts, with latent periods between significant advances lasting 8-40 years. In chronological order, the major advances were efficient diuresis, afterload reduction, and blunting the neurohormonal response to hemodynamic stress and cardiac remodeling., Competing Interests: P. Manu has contributed a chapter to each of the last four editions of Cecil Medicine (2008, 2012, 2016, and 2020). The remaining authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Pain and depression have a high impact on caring for the people who need palliative care, but both of these are neglected compared with the approach for other symptoms encountered by these patients., Areas of Uncertainty: There are few studies in humans that support the existence of common neural circuits between depression and pain that also explore the use of drugs with effects in both conditions. More knowledge is needed about the relationship of these clinical entities that will lead to the optimization of the treatment and improvement of quality of life., Data Sources: We conducted a search in PubMed to identify relevant articles and reviews that have been published in the last 5 years, concerning the topic of common pathways between depression and pain (2014-April 2019)., Therapeutic Advances: The connections between the 2 clinical entities start at the level of the cortical regions. The hippocampus is the main site of neural changes, modification of the immune system, neuromodulators, neurotransmitters, and signaling pathways implicated in both conditions. Increased levels of peripheral proinflammatory cytokines and neuroinflammatory changes are related to the physiopathology of these entities. Inflammation links depression and pain by altering neural circuits and changes in their common cortical regions. Antidepressants are used to treat depression and chronic, pain but more experimental studies are needed to determine which antidepressant drugs are the most effective in treating the 2 entities., Conclusions: Pharmacological and nonpharmacological interventions targeting cortical changes in pain and depression are promising, but more clinical studies are needed to validate their usefulness.

Background: In patients with coronary artery disease, cardiovascular mortality and other acute events showed a clear correlation with risk factors and biomarkers including platelet activation., Study Question of This Research: Which was the incidence of low response to clopidogrel and its correlation with risk factors and biomarkers in coronary artery disease?, Study Design: Four hundred patients (pts) with coronary artery disease-stable angina (SA) and acute coronary syndrome-were divided into 8 groups of study, consistent with low response to clopidogrel and the type of coronary artery disease. Low response to clopidogrel-defined as adenosine diphosphate test-ADP-test of >46 U by multiple electrode platelet aggregometry was evaluated in correlation with cardiovascular risk factors and biomarkers of oxidative stress, endothelial dysfunction, hypercoagulability, high platelet reactivity., Results: In coronary artery disease, low response to clopidogrel significantly correlated with older than 65 years, smoking, hypertension, diabetes mellitus, body mass index of >25, previous aspirin treatment (P < 0.05), high value of total and low-density lipoprotein cholesterol, low value of high-density lipoprotein cholesterol, low response to aspirin, high mean platelets volume and von Willebrand factor activity, low flow-mediated vasodilatation, total antioxidant status (P < 0.01) and only in patients with SA of male gender (P < 0.01). The incidence of other hypercoagulability biomarkers, such as reduced values of S protein, C protein, antithrombin III, and V Factor Leiden resistance to activated protein C, was very low and not correlated with low response to clopidogrel., Conclusions: In coronary artery disease, low response to clopidogrel significantly correlated with the most of old cardiovascular risk factors, with previous aspirin treatment, low response to aspirin, higher mean platelets volume, higher von Willebrand factor activity, lower flow-mediated vasodilatation, and lower total antioxidant status values and only in patients with SA of male gender.

Background: Behavioral and psychological symptoms in dementia significantly contribute to caregiver burden and impose patient hospitalization. The goal of treatment of admitted patients is the rapid remission of symptoms to allow their return to home as soon as possible. Intervention requires an intrusive approach with parenteral treatment and physical restraints, with a negative emotional impact on patients and their families. Despite the large utilization of antipsychotics for behavioral and psychological symptoms, there is no antipsychotic approved by the Food and Drug Administration for agitation in dementia., Study Question: To evaluate efficacy and tolerability of clozapine in patients with treatment-resistant agitation associated with dementia., Study Design: Cohort study with 337 patients, admitted between January 1, 2012 and December 31, 2016, with dementia according to The Diagnostic and Statistical Manual of Mental Disorders 4th ed. criteria. Clozapine was given in standard titration, starting with 6.25 or 12.5 mg., Measures and Outcomes: Efficacy was measured by the need for physical restraints and time to discharge and tolerability by recording all side effects. Data collected included demographics, psychotropics used, physical restraints, length of stay, destination after discharge, and comorbidities., Results: Of 337 cases, 315 (93.5%) patients received antipsychotics. There were 27 cases treated with clozapine. Before clozapine initiation, haloperidol was given in 16 cases (55.17%, mean = 7.43 mg/d, SD = ±4.01), and the treatment was stopped mainly because of extrapyramidal side effects. Other antipsychotics used were quetiapine (mean dose = 260 mg/d, SD = ±54.77), risperidone (mean dose = 3.3 mg/d, SD = ±0.57), and olanzapine (mean dose = 8.33 mg/d, SD = ±2.88). Mean dose of clozapine was 59.16 mg/d, (SD = ±40.48), ranging from 12.5 to 200 mg/d. There were a lower number of physical restraints after clozapine initiation than before (12 vs. 34, P < 0.05)., Conclusions: Clozapine therapy seemed beneficial in treatment-resistant agitation in patients with dementia. The risk-benefit balance must be well weighed when clozapine is chosen. More studies are needed.

Background: The management strategy for patients with atrial fibrillation (AF) is often very complex, electrical cardioversion (EC) being often used to restore sinus rhythm in those patients. The increased risk of thromboembolic complications was lowered using anticoagulation therapy. Usually, the anticoagulation was achieved using vitamin K antagonists (VKAs), but over the last years we witnessed a wide implementation of the novel oral anticoagulants (NOACs)., Study Question: Study question was to compare the efficacy of NOACs versus VKAs in patients undergoing elective EC for persistent AF, by assessing the presence of left atrial spontaneous contrast and left atrial thrombi (LACS), as well as the occurrence of the thromboembolic events in the first month after the procedure., Study Design: A prospective study, including patients with persistent AF enrolled between January 1, 2015 and December 31, 2016, was conducted in 2 tertiary cardiology clinics. In all these patients, a management strategy based on EC was considered for the treatment of the disease. All patients received anticoagulant therapy for at least 3 weeks before cardioversion. The data of 103 patients were analyzed., Results: The patients were divided into 2 groups: group A-VKAs treated-included 45 patients (43.68%), mean age 65.3 ± 12.47, 36% women; group B-NOACs treated-included 58 patients (56.31%), mean age 66.4 ± 9.79, 46% women. There was a trend toward higher incidence of left atrial thrombi in group B (16.28%) versus group A (7.69%), but the difference was not statistically significant (P = 0.5). The incidence of LACS was 40% in group A and 29% in group B, (P = 0.54)., Conclusion: There are no statistically significant differences between the transesophageal echocardiography characteristics of left atrium and left atrial appendage examinations in the patients who received anticoagulation with VKAs as compared to patients who received anticoagulation with NOACs.

Clinical Features: The term multiple drug intolerance (MDI) is attributed to patients who experience adverse drug reactions to more than 3 different classes of medication without a known immunological mechanism. A special attention should be given to multiple drug-intolerant hypertension (MDI-HTN) that is a cause of drop out from treatment and consequent poor blood pressure control. Patients with MDIs account for 2%-5% of all population. The patient we present is a 63-year-old man with third-degree hypertension identified with intolerance to drugs from 4 major classes of antihypertensive medication., Therapeutic Challenge: Patients with MDIs are difficult to treat. They frequently also have numerous comorbidities and high cardiovascular risk. It is recognized that guidelines for the management of hypertension do not include an algorithm of action in situations of MDIs to medication., Solution: We chose to use a recently proposed four-step algorithm for the management of MDI-HTN. A 1-month follow-up program was established. Weekly visits were scheduled to elicit about side effects and measure blood pressure . Ambulatory blood pressure monitoring was performed after a month. The strategy was first to reuse medication from classes the patient was intolerant to, but in smaller doses and in combinations. Among same class members, we have chosen those with less adverse effects. Not all steps within the algorithm were followed since our patient did not need alternative formulation as liquid or transdermal ones. Anxiety medication was prescribed as nonlicensed antihypertensive medication. At the end of the follow-up month, blood pressure control was satisfactory, 24-hour ambulatory blood pressure monitoring was 135.5/83.0 mm Hg, and the patient did not claim any adverse drug reactions.