A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality.

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19.

Assessing safety and efficacy of a novel glucose-free amino acid oral rehydration solution for watery diarrhea management in children: a randomized, controlled, phase III trial.

Background: Diarrhoeal disease poses a significant global health challenge, especially in children under three years old. Despite the effectiveness of oral rehydration therapy (ORT), its adoption remains low. Glucose-based ORS (GORS) is the standard, but novel formulations like glucose-free amino acid-based VS002A have emerged as potential alternatives. This study aimed to compare the safety and efficacy of VS002A against the standard WHO-ORS in treating non-cholera acute watery diarrhoea in children. Methods: A triple-blind, randomized trial enrolled 310 male infants and children aged 6-36 months, who were assigned to receive WHO-ORS or VS002A over a 16-month period, from June 2021 to September 2022. Both groups received standard of care, including zinc supplementation. The Primary study outcome measured was the duration of diarrhoea. Secondary outcomes included stool output, treatment failure and adverse events. Exploratory endpoints included urinary output, body weight changes, blood biochemistry, stool microbiology and gut health biomarkers. Findings: Both VS002A and WHO-ORS were well-tolerated with a low adverse event rate. While not different statistically (p = 0.10), duration of diarrhoea was shorter in children treated with VS002A vs. WHO-ORS (65.4 h vs. 72.6 h). Similarly, stool output was also lower vs. WHO-ORS in children treated with VS002A, though not statistically different (p = 0.40). Serum citrulline levels, an indicator of gut health, were higher in the VS002A group at 24 h suggesting a potential protective effect (p = 0.06). Interpretation: The findings of this study support the non-inferiority of VS002A, a glucose-free amino acid-based ORS compared to the WHO-ORS standard of care. VS002A was shown to be safe and effective in treating non-cholera acute watery diarrhoea in young children. VS002A may offer advantages in pathogen-driven diarrhoea, supported by trends toward a lower duration of diarrhoea and stool output within the per protocol group. Furthermore, individuals with prolonged diarrhoea, severe malnutrition, environmental enteric dysfunction or have issues with obesity or insulin resistance, could benefit from a glucose-free ORS. This research contributes to addressing the persistent challenge of childhood diarrhoea by presenting an alternative glucose-free ORS formulation with potential advantages in select scenarios, offering a promising avenue for improving paediatric diarrhoea management worldwide. Funding: The study was funded by Entrinsic Bioscience, LLC., Norwood, MA, USA.

Advancing peristalsis deciphering in mouse small intestine by multi-parameter tracking.

Assessing gastrointestinal motility lacks simultaneous evaluation of intraluminal pressure (ILP), circular muscle (CM) and longitudinal muscle (LM) contraction, and lumen emptying. In this study, a sophisticated machine was developed that synchronized real-time recordings to quantify the intricate interplay between CM and LM contractions, and their timings for volume changes using high-resolution cameras with machine learning capability, the ILP using pressure transducers and droplet discharge (DD) using droplet counters. Results revealed four distinct phases, BPhase, NPhase, DPhase, and APhase, distinguished by pressure wave amplitudes. Fluid filling impacted LM strength and contraction frequency initially, followed by CM contraction affecting ILP, volume, and the extent of anterograde, retrograde, and segmental contractions during these phases that result in short or long duration DD. This comprehensive analysis sheds light on peristalsis mechanisms, understand their sequence and how one parameter influenced the other, offering insights for managing peristalsis by regulating smooth muscle contractions.

Effectiveness of an amino acid beverage formulation in diarrhea-predominant irritable bowel syndrome: A pragmatic real-world study.

BACKGROUND: Amino-acid based medical foods have shown promise in alleviating symptoms of drug induced gastrointestinal side effects; particularly, diarrhea-predominant symptoms. Irritable bowel syndrome (IBS) is a gastrointestinal disorder that affects up to 9% of people globally, with diarrhea predominant IBS (IBS-D) being the most prevalent subtype. Further trials are needed to explore potential added benefits when integrated into standard care for IBS-D. AIM: To assess the effectiveness of an amino acid-based medical food as an adjunct to standard of care for adults with IBS-D. METHODS: This is a pragmatic, real world, open label, single arm study comparing a 2-week baseline assessment to a 2-week intervention period. One hundred adults, aged 18 to 65 years, with IBS-D, according to Rome IV criteria, were enrolled after completing a 2-week baseline assessment period and received a 2-week supply of an amino acid based medical food which was consumed at home twice daily on top of their standard of care. The primary outcome was an assessment of tolerability after 2-weeks of consumption, while secondary outcomes included changes in stool consistency (Bristol Stool Form Scale), severity of abdominal pain & discomfort, symptoms of urgency, Global Improvement Survey (GIS), and the IBS severity scoring system (IBS-SSS). RESULTS: The test product was well-tolerated as each participant successfully completed the full 14-day trial, and there were no instances of dropouts or discontinuation of the study product reported. Forty percent of participants achieved a 50% or more reduction in the number of days with type 6-7 bowel movements (IBS-D stool consistency responders). Fifty-three percent of participants achieved a clinically meaningful reduction of 30% in mean weekly pain scores, and 55% experienced the same for mean weekly discomfort scores (IBS-D pain and discomfort responders). Participants experienced a mean -109.4 (95% confidence interval: -130.1, -88.8) point reduction on the IBS-SSS and 52% experienced a minimally clinically important difference of > 95 points. An IBS-SSS category shift from severe to moderate or mild occurred in 69% of participants. For functional symptoms, 76% of participants reported symptom relief on the GIS. CONCLUSION: The amino acid-based medical food was well-tolerated, when added to the standard of care, and demonstrated improvements in both overall IBS symptom severity and IBS-D symptoms within just 2 wk.

Optimizing Maternal Nutrition: The Importance of a Tailored Approach.

Improving nutritional status during pregnancy is a global interest. Frequently, women either fail to meet or exceed nutrient recommendations. Current strategies to improve maternal nutrition focus on a "one-size-fits-all" approach and fail to consider individual factors that affect the mother's overall nutritional status. The objectives of this review were to determine the importance of key nutrients for optimal maternal and fetal health, to explore to what extent current recommendations consider individual factors, and to explore novel strategies to close the gap between current guidelines and real-world challenges through more personalized approaches. This review intercalated different nutritional guidelines and recent scientific publications and research initiatives related to maternal nutrition. Based on that, an overview of current recommendations, challenges related to present approaches, and perspectives for future directions are described. Current guidelines are not optimally supporting adequate nutrient intake and health of expectant mothers and their offspring. Existing recommendations are not consistent and do not sufficiently take into account how interindividual variation leads to differences in nutrient status. Personalized nutrition offers women the opportunity to improve their health by using strategies that are tailored to their unique nutritional needs. Such strategies can include personalized supplementation, holistic lifestyle interventions, digital and application-based technologies, and dietary assessment through blood biomarker and genetic analysis. However, these approaches warrant further investigation and optimization. More personalized approaches have the potential to optimize mothers' and their offspring's health outcomes more appropriately to their nutritional needs before, during, and after pregnancy. Moving away from a generalized "one-size-fits-all" approach can be achieved through a variety of means. Future aims should be to provide supporting evidence to create customized subpopulation-based or individualized recommendations, improve nutrition education, and develop novel approaches to improve adherence to dietary and lifestyle interventions.

A Novel In Vitro Model for Determining the Optimum pH and Dose Volume of New Liquid Alginate for Infant Reflux Suppression.

BACKGROUND: Gastroesophageal reflux frequently occurs in infants from birth to 2 years and is characterised by reflux and regurgitation often occurring during or immediately after feeds. These reflux events can range in both frequency and severity, and as the reflux events increase, they become increasingly distressing for both the infant and the parent. The study aimed to characterise the properties of a new infant liquid alginate product, determining the optimum gastric pH and dose volume for maximum reflux suppressant activity. METHODS: An in vitro infant stomach model was designed and developed that allowed products to be assessed for their reflux suppression activity. The validation of the model was completed by three independent operators comparing a milk control with infant Gaviscon to evaluate the models' robustness, reproducibility, and ease of use. The model was used to establish reflux suppression activity of a new liquid alginate infant formulation in comparison with a milk control. Suppression activity was assessed at varying doses and pH within a physiological range. RESULTS: The validation study demonstrated no significant difference in refluxate volumes for the milk control within each reflux event when comparing across the three individual operators. Similarly, no statistical differences were seen during the infant Gaviscon experiments, confirming the robustness and reproducibility of the model. Significant reflux suppression was seen across the pH range (except at pH 5.75); the pH most advantageous for reflux suppression was pH 5.25. The optimum dose volume for consistently suppressing reflux was shown to be 5 ml. An infant stomach model was designed for evaluating reflux suppression activity of a formulation of liquid alginate. The optimum gastric pH and dose volume for demonstrating significant reflux suppression and the thickening of formula milk by the infant liquid alginate formulation were established. CONCLUSION: This study confirms the mode of action of the alginate formula, demonstrating a superior reduction in the retrograde movement of in vitro gastric contents and volume of regurgitation. The study also demonstrates that optimal performance occurs in conditions that are in line physiologically with the target patient. Both actions compliment and support the efficacy of the alginate formulation as a reflux therapy agent.

A Survey to Identify Determinants That Influence Self-Perceived Sensitive Skin in a British Population: Clues to Developing a Reliable Screening Tool for Sensitive Skin.

BACKGROUND: Skin sensitivity characteristics and triggers have been identified in populations in previous studies. However, few have compared these characteristics among self-reported sensitive skin. OBJECTIVE: The aim of the study was to evaluate and compare specific intrinsic and extrinsic triggers of skin sensitivity between individuals with self-reported sensitive skin and non-sensitive skin. METHODS: A systematic literature review was undertaken to identify intrinsic and extrinsic factors associated with sensitive skin. A 167-item survey was developed on the basis of the literature review. The survey was completed online by a sample of adult participants drawn from the general United Kingdom population. Participants also completed sociodemographic and self-reported health questions. RESULTS: A total of 3050 surveys were completed: 1526 participants with self-reported skin sensitivity and 1524 participants not reporting skin sensitivity. There was a decrease in self-reported skin sensitivity with increasing age (p<0.05), and proportionally more women reported sensitive skin. Smoking also led to a higher frequency of sensitive skin. All signs and symptoms of sensitive skin, such as itch, dryness/flakiness, roughness and flushing/blushing were more commonly reported by those with self-reported sensitive skin. These were frequently reported in association with external factors (cold/windy weather, clothes and fabrics), as well as internal factors such as pre-existing skin conditions and atopy. CONCLUSION: The study evaluated self-reported sensitive skin against a non-sensitive skin in order to identify common inherent and external triggers to distinguish between these groups in a large general population study in the United Kingdom. The key symptoms and signs of this syndrome identified in the literature were confirmed to be reported significantly more when compared with those without sensitive skin. However, no correlation or pattern of symptomology could be identified, reinforcing the complexity of this condition. Given the strong differentiation from the non-sensitive group, the results of this research could be utilised for the development of a clinically meaningful screening tool.

The Humanistic and Economic Impact of Vaginal Dryness in Premenopausal, Perimenopausal, and Postmenopausal Women.

Background: Vaginal dryness is a highly prevalent condition. Much of previous research has focused on postmenopausal women. The aim of this study was to evaluate the impact of vaginal dryness on a predominantly premenopausal sample of women. Methods: The study was conducted online. Participants with self-reported vaginal dryness completed the Work Productivity and Activity Impairment (WPAI) scale, and a generic quality-of-life instrument, the assessment of quality of life instrument (AQoL)-4D. Information regarding sociodemographics was also collected. National (United Kingdom) median age-specific weekly wages were used to derive the economic cost of vaginal dryness. Results: A total of 524 women completed the study. The average age was 40.18 years (range 18-70 years) and just under 62% of the sample was premenopausal. Around 40% of women reported severe or very severe vaginal dryness. The average AQoL-4D score was 0.584 (standard deviation [SD]: 0.286) and decreased in line with level of severity (p = 0.014). Quality of life was not related to either age (p = 0.14) or menopausal status (p = 0.055). Of those women in employment (n = 369), 16.5% (SD: 24.3%) of their working hours were lost due to vaginal dryness; work impairment level was 34.4% (SD: 31.8%). The average lost weekly wage was £67.82 (SD: £130.88). The estimated average loss to employers was £82.56 (SD: £109.38) with a total weekly loss of £31,622. Conclusions: This study has shown the significant impact vaginal dryness has on premenopausal and postmenopausal women in terms of quality of life and economic burden, as well as the potential cost of this condition to society.

Clinically Meaningful Difference for the Infant Gastroesophageal Questionnaire Revised version (I-GERQ-R): A Quantitative Synthesis.

BACKGROUND: Gastroesophageal reflux disease (GORD) is a common condition affecting 30% of infants aged 0-23 months. The Infant Gastroesophageal Questionnaire Revised version (I-GERQ-R) is an observer-reported outcome measures (ObsRO) developed to evaluate the impact of GORD on young infants. However, evidence regarding the clinically important difference (CID) for the I-GERQ-R is limited. The aim of this study was to determine a CID for the I-GERQ-R. METHODS: A literature review was undertaken (PsycInfo, Embase, MedLine and EconLit databases) for longitudinal studies involving the I-GERQ-R. Articles were not limited by language or publication date. A random effects model was applied to calculate an overall CID, along with I2 and Q statistics. Publication bias was also assessed. RESULTS: The search identified 42 articles; 11 were selected for full-text review and 7 articles were identified for full data extraction. The studies included a total of 661 infants (range: 30 to 313); 424 infants had been diagnosed with GORD (64%). The age range of the infants across the studies was from birth to 7 months. The overall CID was -6.54 (95% confidence interval: -4.35 to -8.74), Q = 17.96, p=0.08 and I2=22.04. CONCLUSION: This study derived a CID for the I-GERQ-R and indicated a threshold around 6 could signify a clinically important difference for this instrument. The lower limit of the 95% confidence interval suggested a threshold of 3 to 4 could represent a minimally important difference. These results may help inform clinical decisions in evaluating meaningful change in symptom severity in children affected by GORD.

Gonadotropin-Releasing Hormone Receptor Antagonist Mono- and Combination Therapy With Estradiol/Norethindrone Acetate Add-Back: Pharmacodynamics and Safety of OBE2109.

Context: OBE2109 is a potent, oral gonadotropin-releasing hormone receptor antagonist being developed for the treatment of sex-hormone-dependent diseases in women. Objective: We assessed the pharmacodynamics and safety of OBE2109 alone and combined with estradiol (E2)/norethindrone acetate (NETA) add-back therapy on E2 levels and vaginal bleeding. Design, Setting, and Participants: This was a single-center, open-label, randomized, parallel-group study in 76 healthy premenopausal women. Interventions: Women were randomly assigned to take the following doses (in milligrams) once daily for 6 weeks: OBE2109, 100 or 200; or OBE2109/E2/NETA, 100/0.5/0.1, or 100/1.0/0.5, or 200/1.0/0.5. Main Outcome Measures: E2 concentrations, bleeding pattern, exploratory bone metabolism biomarkers, and adverse events. Results: OBE2109 100 mg and 200 mg alone reduced E2 levels to reach median levels of 19.5 and 3.2 pg/mL, respectively, at week 4. Median E2 levels after combined OBE2109/add-back therapy ranged between 25 and 40 pg/mL. OBE2109 100 mg or 200 mg alone induced amenorrhea. By day 15, >85% of women had no vaginal bleeding during the last 4 weeks of treatment. Add-back therapy partially impaired bleeding control: The highest amenorrhea rate (53%) was observed with OBE2109 100 mg/1.0 mg/0.5 mg. The addition of E2/NETA, particularly at 1 mg/0.5 mg, mitigated the increase of two bone markers induced by OBE2109 200 mg. Conclusion: OBE2109 promptly lowered E2 levels. Add-back therapy may be required to prevent adverse effects on bone in women treated with the 200-mg dose (at 100 mg in some women). These results provide a basis for OBE2109 regimen selection to treat sex-hormone-dependent diseases.

Impact of the GP contract on inequalities associated with influenza immunisation: a retrospective population-database analysis.

BACKGROUND: Influenza immunisation is recommended for all people aged ≥65 years and younger people with particular chronic diseases. The Quality and Outcomes Framework (QOF) has provided new financial incentives for influenza immunisation since 2004. AIM: To determine the impact of the 2004 UK General Medical Services contract on the overall uptake of, and socioeconomic inequalities associated with, influenza immunisation. DESIGN AND SETTING: Retrospective general-practice population database analysis in 15 general practices in Scotland, UK. METHOD: Changes in influenza-immunisation uptake for those in at-risk groups between 2003-2004 and 2006-2007 were measured, and variation in uptake examined using multilevel modelling. RESULTS: Uptake rose from 67.9% in 2003-2004 to 71.4% in 2006-2007. The largest increases were seen in those aged <65 years with chronic disease, with uptake rising from 49.6% to 58.4%, but rates remained considerably lower than in those aged ≥65 years. Differences between practices narrowed (median odds ratio [OR] for two patients randomly selected from different practices: 2.13 (95% confidence interval [CI] = 2.00 to 2.26) in 2003-2004 versus 1.44 (95% CI = 1.40 to 1.49) in 2006-2007. However, inequalities in uptake by patient socioeconomic status did not change: adjusted OR for most deprived versus most affluent was 0.75 (95% CI = 0.70 to 0.80) in 2003-2004 versus 0.72 (95% CI = 0.68 to 0.76) in 2006-2007. CONCLUSION: Overall uptake rose significantly and differences between practices narrowed considerably. However, socioeconomic and age inequalities in influenza immunisation persisted in the first 3 years of the QOF. This contrasts with other ecological analyses, which have concluded that the QOF has reduced inequalities. The impact of financial incentives on inequalities is likely to vary, and some kinds of care may require more targeted improvement activity and support.