Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

BACKGROUND: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. METHODS: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. RESULTS: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. CONCLUSIONS: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

Laryngeal Dysfunction in Acute Organophosphorus and Carbamate Poisoning.

Background: Organophosphorus (OP) and carbamate pesticides are widely used for crop protection. We describe the spectrum of laryngeal abnormalities in patients admitted to the intensive care unit (ICU) with acute OP and carbamate poisoning as there is limited information on it. Materials and methods: Consecutive patients admitted to the ICU with acute OP and carbamate poisoning over 20 months (December 2014-July 2016) were recruited. Patients were followed up post-discharge if they had undergone tracheostomy or developed hoarseness of voice or stridor following extubation. Asymptomatic individuals who consented underwent laryngoscopy after ICU discharge. The primary outcome was the development of laryngeal dysfunction. Other outcomes included length of stay, need for ventilation, mortality, tracheostomy, and time to decannulation of tracheostomy. Results: Of the 136 patients recruited, 71 (52%) underwent laryngoscopy. The overall mortality rate was 9.6%. Of the 71 patients who underwent laryngoscopy, 18 had abnormal findings, which included unilateral or bilateral vocal cord paresis or palsy (n = 14) and/or aspiration (n = 9), subglottic stenosis (n = 1), tracheal stenosis (n = 1), or arytenoid granuloma (n = 1). Laryngeal dysfunction was associated with the ingestion of a dimethyl OP compound (p = 0.04) and quantum consumed (p <0.001). Patients with laryngeal dysfunction had significantly (p = 0.004) longer hospital stay (19.1 ± 10.7 vs 11.8 ± 8.3 days). Conclusion: Laryngeal dysfunction is not uncommon in OP and carbamate poisoning and is associated with the ingestion of larger quantity of a dimethyl OP compound and longer hospital stay. Otorhinolaryngologists could be involved early to help identify these abnormalities and initiate an appropriate treatment to ensure a functional voice and good airway. How to cite this article: Mani GS, Mathews SS, Victor P, Peter JV, Yadav B, Albert RRA. Laryngeal Dysfunction in Acute Organophosphorus and Carbamate Poisoning. Indian J Crit Care Med 2022;26(2):167-173.

Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. METHODS: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ2) test (p < 0·05 was considered as unstable). RESULTS: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment. CONCLUSION: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited. TRIAL REGISTRATION: The study was registered with Clinical trials.gov Identifier: NCT04534569.

Clinical Profile and Outcome of Critically Ill Patients with Tuberculosis.

AIM AND OBJECTIVE: Although studies have described the clinical profile of patients admitted to the intensive care unit (ICU) with tuberculosis, it is unclear if the type of tuberculosis (pulmonary, extrapulmonary, or disseminated) impacts outcome. MATRIALS AND METHODS: Demographic data, microbiology, treatment, and outcomes over 5 years (2012-16) were obtained from electronic records. Patients were categorized as pulmonary, extrapulmonary, or disseminated tuberculosis. Comparisons were done using t test and Fisher's exact test as appropriate. Predictors of outcome were explored using bivariate and multivariate logistic regression analysis and expressed as odds ratio (OR) with 95% confidence intervals (CI). RESULTS: Of the 428 ICU admissions with suspected tuberculosis, 212 (121 male) patients with mean (standard deviation) age of 41.9 (16.7) years and APACHE-II score of 20.8 (6.6) were diagnosed as pulmonary (n = 55) and extrapulmonary (n = 52) or disseminated tuberculosis (n = 105). In 50.5%, the diagnosis of tuberculosis was established during the current ICU admission when they presented with organ dysfunction. Overall, microbiological confirmation was possible in 75.5%; 14 (10.3%) isolates were Rifampicin resistant. ICU admission was required primarily for ventilation (n = 176; 83%) and hemodynamic instability (n = 67; 32%). Hospital mortality was 50%. Outcomes were similar in the three groups except for longer duration of stay (p value = 0.04) in disseminated tuberculosis. On multivariate logistic regression analysis, pulmonary tuberculosis (OR 2.83; 95% CI 1.15-6.95) and vasoactive treatment (OR 15.8; 95% CI 6.4-39.2) were independently associated with death; need for ventilation predicted mortality perfectly. CONCLUSION: In this cohort of patients admitted to ICU with tuberculosis, 50% were newly diagnosed during ICU admission. Pulmonary site of involvement and need for organ support are independent risk factors for death. HOW TO CITE THIS ARTICLE: Thomas L, Chacko B, Jupudi S, Mathuram A, George T, Gunasekaran K, et al. Clinical Profile and Outcome of Critically Ill Patients with Tuberculosis. Indian J Crit Care Med 2021;25(1):21-28.

Antidotes in Poisoning.

INTRODUCTION: Antidotes are agents that negate the effect of a poison or toxin. Antidotes mediate its effect either by preventing the absorption of the toxin, by binding and neutralizing the poison, antagonizing its end-organ effect, or by inhibition of conversion of the toxin to more toxic metabolites. Antidote administration may not only result in the reduction of free or active toxin level, but also in the mitigation of end-organ effects of the toxin by mechanisms that include competitive inhibition, receptor blockade or direct antagonism of the toxin. MECHANISM OF ACTION OF ANTIDOTES: Reduction in free toxin level can be achieved by specific and non-specific agents that bind to the toxin. The most commonly used non-specific binding agent is activated charcoal. Specific binders include chelating agents, bioscavenger therapy and immunotherapy. In some situations, enhanced elimination can be achieved by urinary alkalization or hemadsorption. Competitive inhibition of enzymes (e.g. ethanol for methanol poisoning), enhancement of enzyme function (e.g. oximes for organophosphorus poisoning) and competitive receptor blockade (e.g. naloxone, flumazenil) are other mechanisms by which antidotes act. Drugs such as N-acetyl cysteine and sodium thiocyanate reduce the formation of toxic metabolites in paracetamol and cyanide poisoning respectively. Drugs such as atropine and magnesium are used to counteract the end-organ effects in organophosphorus poisoning. Vitamins such as vitamin K, folic acid and pyridoxine are used to antagonise the effects of warfarin, methotrexate and INH respectively in the setting of toxicity or overdose. This review provides an overview of the role of antidotes in poisoning. HOW TO CITE THIS ARTICLE: Chacko B, Peter JV. Antidotes in Poisoning. Indian J Crit Care Med 2019;23(Suppl 4):S241-S249.

Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units.

BACKGROUND: Upper gastrointestinal (GI) bleeding due to stress ulcers contributes to increased morbidity and mortality in people admitted to intensive care units (ICUs). Stress ulceration refers to GI mucosal injury related to the stress of being critically ill. ICU patients with major bleeding as a result of stress ulceration might have mortality rates approaching 48.5% to 65%. However, the incidence of stress-induced GI bleeding in ICUs has decreased, and not all critically ill patients need prophylaxis. Stress ulcer prophylaxis can result in adverse events such as ventilator-associated pneumonia; therefore, it is necessary to evaluate strategies that safely decrease the incidence of GI bleeding. OBJECTIVES: To assess the effect and risk-benefit profile of interventions for preventing upper GI bleeding in people admitted to ICUs. SEARCH METHODS: We searched the following databases up to 23 August 2017, using relevant search terms: MEDLINE; Embase; the Cochrane Central Register of Controlled Trials; Latin American Caribbean Health Sciences Literature; and the Cochrane Upper Gastrointestinal and Pancreatic Disease Group Specialised Register, as published in the Cochrane Library (2017, Issue 8). We searched the reference lists of all included studies and those from relevant systematic reviews and meta-analyses to identify additional studies. We also searched the World Health Organization International Clinical Trials Registry Platform search portal and contacted individual researchers working in this field, as well as organisations and pharmaceutical companies, to identify unpublished and ongoing studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs with participants of any age and gender admitted to ICUs for longer than 48 hours. We excluded studies in which participants were admitted to ICUs primarily for the management of GI bleeding and studies that compared different doses, routes, and regimens of one drug in the same class because we were not interested in intraclass effects of drugs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. MAIN RESULTS: We identified 2292 unique records.We included 129 records reporting on 121 studies, including 12 ongoing studies and two studies awaiting classification.We judged the overall risk of bias of two studies as low. Selection bias was the most relevant risk of bias domain across the included studies, with 78 studies not clearly reporting the method used for random sequence generation. Reporting bias was the domain with least risk of bias, with 12 studies not reporting all outcomes that researchers intended to investigate.Any intervention versus placebo or no prophylaxisIn comparison with placebo, any intervention seems to have a beneficial effect on the occurrence of upper GI bleeding (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.57; moderate certainty of evidence). The use of any intervention reduced the risk of upper GI bleeding by 10% (95% CI -12.0% to -7%). The effect estimate of any intervention versus placebo or no prophylaxis with respect to the occurrence of nosocomial pneumonia, all-cause mortality in the ICU, duration of ICU stay, duration of intubation (all with low certainty of evidence), the number of participants requiring blood transfusions (moderate certainty of evidence), and the units of blood transfused was consistent with benefits and harms. None of the included studies explicitly reported on serious adverse events.Individual interventions versus placebo or no prophylaxisIn comparison with placebo or no prophylaxis, antacids, H2 receptor antagonists, and sucralfate were effective in preventing upper GI bleeding in ICU patients. Researchers found that with H2 receptor antagonists compared with placebo or no prophylaxis, 11% less developed upper GI bleeding (95% CI -0.16 to -0.06; RR 0.50, 95% CI 0.36 to 0.70; 24 studies; 2149 participants; moderate certainty of evidence). Of ICU patients taking antacids versus placebo or no prophylaxis, 9% less developed upper GI bleeding (95% CI -0.17 to -0.00; RR 0.49, 95% CI 0.25 to 0.99; eight studies; 774 participants; low certainty of evidence). Among ICU patients taking sucralfate versus placebo or no prophylaxis, 5% less had upper GI bleeding (95% CI -0.10 to -0.01; RR 0.53, 95% CI 0.32 to 0.88; seven studies; 598 participants; moderate certainty of evidence). The remaining interventions including proton pump inhibitors did not show a significant effect in preventing upper GI bleeding in ICU patients when compared with placebo or no prophylaxis.Regarding the occurrence of nosocomial pneumonia, the effects of H2 receptor antagonists (RR 1.12, 95% CI 0.85 to 1.48; eight studies; 945 participants; low certainty of evidence) and of sucralfate (RR 1.33, 95% CI 0.86 to 2.04; four studies; 450 participants; low certainty of evidence) were consistent with benefits and harms when compared with placebo or no prophylaxis. None of the studies comparing antacids versus placebo or no prophylaxis provided data regarding nosocomial pneumonia.H2 receptor antagonists versus proton pump inhibitorsH2 receptor antagonists and proton pump inhibitors are most commonly used in practice to prevent upper GI bleeding in ICU patients. Proton pump inhibitors significantly more often prevented upper GI bleeding in ICU patients compared with H2 receptor antagonists (RR 2.90, 95% CI 1.83 to 4.58; 18 studies; 1636 participants; low certainty of evidence). When taking H2 receptor antagonists, 4.8% more patients might experience upper GI bleeding (95% CI 2.1% to 9%). Nosocomial pneumonia occurred in similar proportions of participants taking H2 receptor antagonists and participants taking proton pump inhibitors (RR 1.02, 95% CI 0.77 to 1.35; 10 studies; 1256 participants; low certainty of evidence). AUTHORS' CONCLUSIONS: This review shows that antacids, sucralfate, and H2 receptor antagonists might be more effective in preventing upper GI bleeding in ICU patients compared with placebo or no prophylaxis. The effect estimates of any treatment versus no prophylaxis on nosocomial pneumonia were consistent with benefits and harms. Evidence of low certainty suggests that proton pump inhibitors might be more effective than H2 receptor antagonists. Therefore, patient-relevant benefits and especially harms of H2 receptor antagonists compared with proton pump inhibitors need to be assessed by larger, high-quality RCTs to confirm the results of previously conducted, smaller, and older studies.

Pressure-controlled versus volume-controlled ventilation for acute respiratory failure due to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS).

BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) account for one-quarter of cases of acute respiratory failure in intensive care units (ICUs). A third to half of patients will die in the ICU, in hospital or during follow-up. Mechanical ventilation of people with ALI/ARDS allows time for the lungs to heal, but ventilation is invasive and can result in lung injury. It is uncertain whether ventilator-related injury would be reduced if pressure delivered by the ventilator with each breath is controlled, or whether the volume of air delivered by each breath is limited. OBJECTIVES: To compare pressure-controlled ventilation (PCV) versus volume-controlled ventilation (VCV) in adults with ALI/ARDS to determine whether PCV reduces in-hospital mortality and morbidity in intubated and ventilated adults. SEARCH METHODS: In October 2014, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Isssue 9), MEDLINE (1950 to 1 October 2014), EMBASE (1980 to 1 October 2014), the Latin American Caribbean Health Sciences Literature (LILACS) (1994 to 1 October 2014) and Science Citation Index-Expanded (SCI-EXPANDED) at the Institute for Scientific Information (ISI) Web of Science (1990 to 1 October 2014), as well as regional databases, clinical trials registries, conference proceedings and reference lists. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs (irrespective of language or publication status) of adults with a diagnosis of acute respiratory failure or acute on chronic respiratory failure and fulfilling the criteria for ALI/ARDS as defined by the American-European Consensus Conference who were admitted to an ICU for invasive mechanical ventilation, comparing pressure-controlled or pressure-controlled inverse-ratio ventilation, or an equivalent pressure-controlled mode (PCV), versus volume-controlled ventilation, or an equivalent volume-controlled mode (VCV). DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected trials, assessed risk of bias and extracted data. We sought clarification from trial authors when needed. We pooled risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with their 95% confidence intervals (CIs) using a random-effects model. We assessed overall evidence quality using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. MAIN RESULTS: We included three RCTs that randomly assigned a total of 1089 participants recruited from 43 ICUs in Australia, Canada, Saudi Arabia, Spain and the USA. Risk of bias of the included studies was low. Only data for mortality and barotrauma could be combined in the meta-analysis. We downgraded the quality of evidence for the three mortality outcomes on the basis of serious imprecision around the effect estimates. For mortality in hospital, the RR with PCV compared with VCV was 0.83 (95% CI 0.67 to 1.02; three trials, 1089 participants; moderate-quality evidence), and for mortality in the ICU, the RR with PCV compared with VCV was 0.84 (95% CI 0.71 to 0.99; two trials, 1062 participants; moderate-quality evidence). One study provided no evidence of clear benefit with the ventilatory mode for mortality at 28 days (RR 0.88, 95% CI 0.73 to 1.06; 983 participants; moderate-quality evidence). The difference in effect on barotrauma between PCV and VCV was uncertain as the result of imprecision and different co-interventions used in the studies (RR 1.24, 95% CI 0.87 to 1.77; two trials, 1062 participants; low-quality evidence). Data from one trial with 983 participants for the mean duration of ventilation, and from another trial with 78 participants for the mean number of extrapulmonary organ failures that developed with PCV or VCV, were skewed. None of the trials reported on infection during ventilation or quality of life after discharge. AUTHORS' CONCLUSIONS: Currently available data from RCTs are insufficient to confirm or refute whether pressure-controlled or volume-controlled ventilation offers any advantage for people with acute respiratory failure due to acute lung injury or acute respiratory distress syndrome. More studies including a larger number of people given PCV and VCV may provide reliable evidence on which more firm conclusions can be based.

Clinical and Genomic Evolution of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections over Two Time Periods at a Tertiary Care Hospital in South India: A Prospective Cohort Study.

INTRODUCTION: The objective of this study was to examine the evolution of carbapenem-resistant Klebsiella pneumoniae (CRKp) infections and their impact at a tertiary care hospital in South India. METHODS: A comparative analysis of clinical data from two prospective cohorts of patients with CRKp bacteremia (C1, 2014-2015; C2, 2021-2022) was carried out. Antimicrobial susceptibilities and whole genome sequencing (WGS) data of selected isolates were also analyzed. RESULTS: A total of 181 patients were enrolled in the study, 56 from C1 and 125 from C2. CRKp bacteremia shifted from critically ill patients with neutropenia to others (ICU stay: C1, 73%; C2, 54%; p = 0.02). The overall mortality rate was 50% and the introduction of ceftazidime-avibactam did not change mortality significantly (54% versus 48%; p = 0.49). Oxacillinases (OXA) 232 and 181 were the most common mechanisms of resistance. WGS showed the introduction of New Delhi metallo-ß-lactamase-5 (NDM-5), higher genetic diversity, accessory genome content, and plasmid burden, as well as increased convergence of hypervirulence and carbapenem resistance in C2. CONCLUSIONS: CRKp continues to pose a significant clinical threat, despite the introduction of new antibiotics. The study highlights the evolution of resistance and virulence in this pathogen and the impact on patient outcomes in South India, providing valuable information for clinicians and researchers.

Acute management of COVID-19 in the emergency department: An evidence-based review.

Coronavirus disease (COVID-19) has been relentlessly battering the world wave after wave in different countries at different rates and times. Emergency departments (EDs) around the globe have had to constantly adapt to this ever-changing influx of information and recommendations by various national and international health agencies. This review compiles the available evidence on the guidelines for triaging, evaluation, and management of critically ill patients with COVID-19 presenting to the ED and in need of emergency resuscitation. The quintessential components of resuscitation focus on airway, breathing, and circulation with good supportive care as the cornerstone of acute management of critically ill COVID-19 patients. Irrational investigations and therapeutics must be avoided during these times of medical uncertainty and antibiotic stewardship should be diligently followed.

Infection control in the intensive care unit: expert consensus statements for SARS-CoV-2 using a Delphi method.

During the current COVID-19 pandemic, health-care workers and uninfected patients in intensive care units (ICUs) are at risk of being infected with SARS-CoV-2 as a result of transmission from infected patients and health-care workers. In the absence of high-quality evidence on the transmission of SARS-CoV-2, clinical practice of infection control and prevention in ICUs varies widely. Using a Delphi process, international experts in intensive care, infectious diseases, and infection control developed consensus statements on infection control for SARS-CoV-2 in an ICU. Consensus was achieved for 31 (94%) of 33 statements, from which 25 clinical practice statements were issued. These statements include guidance on ICU design and engineering, health-care worker safety, visiting policy, personal protective equipment, patients and procedures, disinfection, and sterilisation. Consensus was not reached on optimal return to work criteria for health-care workers who were infected with SARS-CoV-2 or the acceptable disinfection strategy for heat-sensitive instruments used for airway management of patients with SARS-CoV-2 infection. Well designed studies are needed to assess the effects of these practice statements and address the remaining uncertainties.

Sugars and Sweet Taste: Addictive or Rewarding?

The notion of food "addiction" often focuses on the overconsumption of sweet tasting foods or so-called sugar "addiction". In the extreme, some have suggested that sugar and sweet tastes elicit neural and behavioral responses analogous to those observed with drugs of abuse. These concepts are complicated by the decades long uncertainty surrounding the validity and reproducibility of functional magnetic resonance imaging (fMRI) methodologies used to characterize neurobiological pathways related to sugar and sweet taste stimuli. There are also questions of whether sweet taste or post-ingestion metabolic consequences of sugar intake would lead to addiction or excessive caloric intake. Here, we present a focused narrative review of literature related to the reward value of sweet taste which suggests that reward value can be confounded with the construct of "addictive potential". Our review seeks to clarify some key distinctions between these constructs and questions the applicability of the addiction construct to human over-eating behaviors. To adequately frame this broad discussion requires the flexibility offered by the narrative review paradigm. We present selected literature on: techniques used to link sugar and sweet tastes to addiction neurobiology and behaviors; sugar and sweet taste "addiction"; the relationship of low calorie sweetener (LCS) intake to addictive behaviors and total calorie intake. Finally, we examined the reward value of sweet tastes and contrasted that with the literature describing addiction. The lack of reproducibility of fMRI data remains problematic for attributing a common neurobiological pathway activation of drugs and foods as conclusive evidence for sugar or sweet taste "addiction". Moreover, the complicated hedonics of sweet taste and reward value are suggested by validated population-level data which demonstrate that the consumption of sweet taste in the absence of calories does not increase total caloric intake. We believe the neurobiologies of reward value and addiction to be distinct and disagree with application of the addiction model to sweet food overconsumption. Most hypotheses of sugar "addiction" attribute the hedonics of sweet foods as the equivalent of "addiction". Further, when addictive behaviors and biology are critically examined in totality, they contrast dramatically from those associated with the desire for sweet taste. Finally, the evidence is strong that responses to the palatability of sweets rather than their metabolic consequences are the salient features for reward value. Thus, given the complexity of the controls of food intake in humans, we question the usefulness of the "addiction" model in dissecting the causes and effects of sweet food over-consumption.

Daily Eating Frequency in US Adults: Associations with Low-Calorie Sweeteners, Body Mass Index, and Nutrient Intake (NHANES 2007-2016).

Studies of relationships between eating frequency and/or timing and energy intake have not examined associations with low-calorie sweeteners (LCS). We assessed the frequency of eating behavior related to LCS consumption emphasizing timing, calorie intake, and body mass index (BMI) among United States (US) adults aged ≥19 years. Using the National Health and Nutrition Examination Survey (NHANES) 2007-2016, we defined eating episodes as food and/or beverage intake within 15 min of one another over the first 24-h dietary recall. We coded items ingested during episodes (n = 136,938) and assessed LCS presence using US Department of Agriculture (USDA) food files. Episode analysis found intakes of foods only (27.4%), beverages only (29.5%), and foods with beverages (43.0%). LCS items were consumed without concurrent calories from other sources in fewer than 2.7% of all episodes. Within participants having normal weight (29.4%), overweight (33.6%) and obese (37.1%) BMIs, LCS consumers (35.2% overall) evidenced: more episodes/day; and fewer: calories, carbohydrates, fats, and protein per episode. Per person, those consuming LCS had lower total calories and higher fiber intake per day. LCS consumption was associated with higher BMI. Number of eating episodes/day and longer hours when eating episodes occurred were also consistently associated with higher BMI. Consuming LCS did not modify these relationships. These results did not show that LCS consumption was associated with increased caloric intake from other dietary sources.

Reported Consumption of Low-Calorie Sweetener in Foods, Beverages, and Food and Beverage Additions by US Adults: NHANES 2007-2012.

BACKGROUND: Low-calorie sweeteners (LCSs), artificial sweeteners, or high-intensity sweeteners are incorporated into foods, beverages, and food and beverage additions (FBAs). Many prior studies have focused on LCS beverage consumption, but not included LCS consumption from foods or FBAs. OBJECTIVES: We aimed to describe the prevalence of LCS consumption by US adults, and to examine the relation between intake of products containing LCSs and macronutrients. METHODS: Two nonconsecutive 24-h dietary recalls from NHANES 2007-2012 and the National Cancer Institute usual intake method were used to estimate prevalence of LCS intake from foods, beverages, and FBAs, and macronutrients among US adults aged ≥19 y (n = 14,098, weighted n = 218,391,752) in a cross-sectional study. The prevalence of LCS consumption from reported foods, beverages, and FBAs among US adults was examined by sociodemographic characteristics and body mass index (BMI). Logistic regression estimated ORs and 95% CIs for associations between sociodemographic characteristics and LCS use (overall and in foods, beverages, and FBAs). RESULTS: Among adults, 47.8% reported intake of ≥1 food, beverage, or FBA containing LCSs over 2 d. Intake was higher among: women non-Hispanic whites, college graduates or higher, and those with higher income and obese BMIs (P < 0.001). Intake of beverages containing LCSs was higher for ages 51-70 y than 19-30 y and those with overweight and obese BMIs (P < 0.001) than for normal-weight individuals. Calories, carbohydrate, and sugar intake were lower and fiber was higher in LCS-consumers than in nonconsumers. Specifically, calories from beverages were lower in those who reported LCS intake. CONCLUSIONS: Individuals reporting LCS consumption demonstrated lower total energy intake than did individuals without LCS intake. Although the main source of LCSs in the US adult diet was beverages (31.9%), we found that FBAs also present a significant contribution (25.2%), surpassing food (9.3%). This enables targeted understanding of national consumption of these products as well as dietary education and intervention opportunities.

Low-Calorie Sweeteners: Exploring Underutilized Database Resources to Understand Dietary Patterns and Obesity.

The use and impact of low-calorie sweeteners (LCS) in relation to the national challenges of overweight and obesity are complex and controversial. Most research on LCS have focused on the prevalence of consumption of LCS in beverages. The 2015 Dietary Guidelines Advisory Committee emphasized dietary patterns and health rather than a focus on specific nutrients or foods. The committee took this approach to shift the national emphasis onto the context of total rather than individual nutrient consumption. A broader research paradigm is needed to elucidate the actual exposure to LCS and how they are consumed within dietary patterns in the US population. National-level databases exist that can be used to broaden scientific understanding of the effects of LCS and health outcomes. These databases are underutilized, and they provide potential tools for grasping a fuller picture of LCS in the US diet.

Low-Calorie Sweeteners in Foods, Beverages, and Food and Beverage Additions: NHANES 2007-2012.

BACKGROUND: Most publications about low-calorie sweeteners (LCSs) focus on person-level intake prevalence. OBJECTIVE: We assessed LCS distribution in foods, beverages, and food and beverage additions (FBAs), e.g., mayonnaise, in the US adult diet as reported in the NHANES (2007-2012). METHODS: Dietary items reported in the first 24-h recall were coded for LCS and/or nutritive sweeteners (NSs) with the use of USDA What We Eat in America food files. We calculated the number of times items were reported and LCS/NS content. RESULTS: Of reported items, 56.1% were foods, 29.1% were beverages, and 14.8% were FBAs. LCS was contained in 0.7% of foods, 8.1% of beverages, and 10.4% of FBAs. This food-level analysis identified FBAs as a significant source of LCSs in the US diet. CONCLUSION: Identifying the diversity of LCS and NS sources will enhance exposure classification for examining diet and health relations, including body weight management.

Effect of conjugated equine estrogens on oxidative metabolism in middle-aged and elderly postmenopausal women.

The effects of conjugated equine estrogens (CEE) 0.625 mg daily on cytochrome P450 (CYP) were quantified in 12 middle-aged and 13 elderly postmenopausal women at baseline and 6 months later. CYP phenotype was characterized by caffeine (CYP1A2), chlorzoxazone (CYP2E1), dapsone (CYP, N-acetyltransferase 2), dextromethorphan (CYP2D6), and mephenytoin (CYP2C19) metabolism. CEE significantly decreased CYP1A2 (caffeine metabolic ratio: 0.57 +/- 0.20 before, 0.40 +/- 0.20 after, P = .001) and significantly increased CYP2D6 (dextromethorphan/dextrorphan ratio: 0.0116 +/- 0.0143 before, 0.0084 +/- 0.0135 after, P = .022) metabolism. CEE had no overall effect on CYP2C19, CYP2E1, CYP-mediated dapsone metabolism, and N-acetyltransferase 2. The dextromethorphan metabolic ratio decreased only in the seniors. The dapsone recovery ratio decreased in the middle-aged group and increased in the seniors. CEE significantly influenced CYP1A2, CYP2D6, and CYP-mediated dapsone oxidative metabolism but not CYP2C19, CYP2E1, or N-acetyltransferase 2 metabolism in postmenopausal women. Age influenced CYP2D6 metabolism and dapsone hydroxylation.

Patterns of Adverse Drug Reaction in the Medical Wards of a Teaching Hospital: A Prospective Observational Cohort Study.

INTRODUCTION: According to the World Health Organization (WHO) definition, an Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis, and treatment of disease. The risk factors of ADR are multi-factorial and include poly-pharmacy, age, gender, race, genetics and inter-current disease. PATIENTS AND METHODS: This was a hospital based, prospective, observational cohort study undertaken in a tertiary care hospital in south India to assess the different patterns of adverse drug reaction in medical wards over 6 months. The severity of ADR was assessed using Hartwig Siegel scale and causality by Naranjo and WHO UMC Scale. Preventability was assessed using Schumock and Thornton scale and other parameters such as incidence, onset, duration, management and outcome were also assessed. Risk factors were assessed by bi-variate logistic regression analysis and length of hospital stay by T test. RESULTS: The incidence of ADR was 10.42% in medicine wards. The causality of ADR done by Naranjo scale showed that most of the ADRs were probable (7.38%). Anti-tubercular agents were the leading cause of ADR. Duration of hospitalization was significantly longer (7.18 ± 2.64 vs. 5.06 ± 2.13 days) in patients with ADR (Odds ratio 1.38, 95% Confidence interval 1.26 to 1.51). 7.28% of ADRs were moderately severe. Seriousness criteria assessment showed that 0.33% were serious reactions. Most of the ADRs were definitely preventable. Most of the ADRs were managed by discontinuing the suspected drug. The present study showed female gender predominance over males for ADRs and no relationship with age. CONCLUSION: Adverse drug reactions impose significant burden on hospitals through prolonging patient stay and by increasing admission rates. The occurrence of ADR in this study was higher when compared to that reported in previous studies. This study highlights the importance of ADR reporting among ADR reporting among health care professionals in hospital.

A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone.

OBJECTIVE: To characterize potential differences in glycemic control, plasma lipid level, and weight in a cohort of patients previously treated with troglitazone (TROG) who were switched to either pioglitazone or rosiglitazone. RESEARCH DESIGN AND METHODS: After a 2-week washout from TROG, 186 patients were randomly assigned to receive either pioglitazone (PIO) or rosiglitazone (ROSI). Weight, HbA(1c), and fasting lipid profile were documented before discontinuing TROG and at 4 months after starting either pioglitazone or rosiglitazone. Secondarily, the effect of concurrent medications on study outcomes was assessed. RESULTS: A total of 127 patients completed follow-up: 67 individuals in the PIO group (32 women, 35 men) and 60 individuals in the ROSI group (33 women, 27 men). There were no significant differences in gender mix, age, weight, fasting lipid profile, or HbA(1c) between the ROSI and PIO groups. After 4 months of randomized treatment, no change in HbA(1c) from baseline between or within groups was noted. Both groups experienced an equal and significant increase in weight from baseline of approximately 2.0 kg. Thiazolidinedione and HMG-CoA reductase inhibitor therapy had significant and independent effects on lipid profile (P < 0.005). Significant improvements in lipid profile were noted in the PIO group (P < 0.01), whereas none were detected with conversion to ROSI. Specifically, the PIO group experienced an average decrease in total cholesterol of approximately 20 mg/dl. CONCLUSIONS: Differing effects on lipid profile were apparent after random conversion from TROG to either PIO or ROSI, despite similar weight increase and glycemic control. The clinical significance of these differences remains to be determined, and further comparative research is warranted.

The Effects of Lansoprazole on the Disposition of Antipyrine and Indocyanine Green in Normal Human Subjects.

This study was designed to evaluate the potential effects of acute and chronic daily oral doses of lansoprazole (60 mg) on the disposition of antipyrine, an almost completely metabolized low hepatic extraction compound, and indocyanine green, a hepatically secreted compound with high extraction ratio. The study utilized a randomized, placebo-controlled, double-blind, two-period crossover design. Sixteen of 18 subjects completed all phases of the study. Both antipyrine (10 mg kg(minus sign1)) and indocyanine green (0.5 mg kg(minus sign1)) were administered as single intravenous bolus doses on Days 1 and 7 of lansoprazole or placebo dosing. Acute exposure to lansoprazole had no statistically significant effects on the plasma pharmacokinetics of indocyanine green or antipyrine. After the seventh dose, there was a small but statistically significant reductions in indocyanine green total body clearance (CL), and elimination rate constant of 10.6% and 8%, respectively. Additionally, a small statistically significant reduction (8.6%) in antipyrine volume of distribution was detected. No other plasma antipyrine pharmacokinetic parameters were changed with concomitant lansoprazole administration. About a 12% increase in the recovery of one of the major antipyrine urine metabolites (NORA) was detected. Overall, this study demonstrates little or no effect of lansoprazole on the pharmacokinetics of antipyrine and indocyanine green.

Disposition of Misoprostol and Its Active Metabolite in Impaired Hepatic Function.

The pharmacokinetics of misoprostol and its active metabolite, misoprostol acid, was assessed in 17 healthy subjects and 17 subjects with various degrees of hepatic impairment. Before misoprostol administration, subjects underwent antipyrine and indocyanine green clearance studies to assess hepatic functional capacity. Subjects were administered 400 mcg of oral misoprostol in an open-label design. There was a lower antipyrine clearance in the group with hepatic disease as compared to normal volunteers (0.56 versus 0.80 ml min(minus sign1) kg(minus sign1), respectively, p = 0.022). There was no difference in indocyanine green clearance values between groups. The C(max), t(1/2)&bgr, and [Formula: see text] tended to be larger in the hepatic group; however, there was no statistical difference. Adverse events, mostly gastrointestinal in nature, occurred more often in the subjects with hepatic disease. These data suggest the pharmacokinetics of misoprostol may be altered in the presence of hepatic disease. However, because of significant interpatient variability, definitive dosing recommendations cannot be made. Further study in this area is needed.