Synthesis of 2,2-dimethyl-chroman-based stereochemically flexible and constrained anti-breast cancer agents.

Receptors are proteinous macromolecules which remain in the apo form under normal/unliganded conditions. As the ligand approaches, there are specific stereo-chemical changes in the apo form of the receptor as per the stereochemistry of a ligand. Accordingly, a series of substituted dimethyl-chroman-based stereochemically flexible and constrained Tamoxifen analogs were synthesized as anti-breast cancer agents. The synthesized compounds 19a-e, 20a-e, 21, and 22a-e, showed significant antiproliferative activity against estrogen receptor-positive (ER+, MCF-7) and negative (ER-, MDA MB-231) cells within IC50 value 8.5-25.0 µM. Amongst all, four potential molecules viz 19b, 19e, 22a, and 22c, were evaluated for their effect on the cell division cycle and apoptosis of ER+ and ER- cancer cells (MCF-7 & MDA MB-231cells), which showed that these compounds possessed antiproliferative activity through triggering apoptosis. In-silico docking experiments elucidated the possible affinity of compounds with estrogen receptors-α and -ß.

Pulse oximetry in patients with pigmented skin: What I should know.

Pulse oximetry is widely used to non-invasively estimate the oxygen saturation of haemoglobin in arterial blood (SpO2). It is used widely throughout healthcare and was used extensively during the Covid-19 pandemic to detect and treat hypoxic patients. Research has suggested that pulse oximetry is less accurate in patients with darker skin. This led the US Food and Drug Administration agency (FDA) to issue a safety statement warning that pulse oximeters may be inaccurate when patients have pigmented skin. Evidence suggests that the oxygen saturation of arterial blood (SaO2) may be being overestimated by measuring SpO2 in those with pigmented skin. The degree of overestimation increases as SaO2 decreases especially when SpO2 reads below 80%. We review how pulse oximetry works and consider the implications for a patient's health when interpreting SpO2 in individuals with pigmented skin.

Subthreshold laser compared to oral spironolactone for the treatment of chronic central serous chorioretinopathy: a retrospective study.

PURPOSE: To compare functional and morphological outcomes of Subthreshold Laser (STL) and Oral Spironolactone (SPR) in treating chronic central serous chorioretinopathy (CSCR). METHODS: This is a retrospective observational study. Treatment-naïve patients with chronic CSCR treated with STL or SPR were included, and data was reviewed at baseline, 1, 3, 6 and 12-month follow-up. Main outcome measures were changes in Central Macular Thickness (CMT) and Subretinal Fluid (SRF) height, and complete resolutions of SRF. Sub-analysis based on retinal pigmented epithelium (RPE) status at baseline was performed. RESULTS: 47 and 47 patients received STL and SPR, respectively. At all timepoints, both treatments significantly improved CMT and SRF (p < 0.05). No significant changes in best corrected visual acuity (BCVA) were recorded and no significant differences between treatment groups were present at each corresponding follow-up. Complete resolution of SRF was achieved in 29% and 36% of patients treated with STL or SPR, respectively, at 12-months follow up. Eyes treated with STL and intact RPE showed significant SRF decrease at 6 months and significantly better BCVA at 1, 3 and 6 months compared to eyes with disrupted RPE layer (p < 0.05). In both treatment groups, intact RPE was associated with a higher rate of complete SRF resolutions, with 43% vs 13% in the STL group and 50% vs 26% in the SPR group. CONCLUSION: STL and SPR are effective treatments for chronic CSCR. Greater resolution of subretinal fluid was observed in eyes with intact RPE, hence both treatments should be initiated in the earlier stages of the disease.

Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA).

BACKGROUND: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. METHODS: COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients' and carers' views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. RESULTS: Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV1) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). CONCLUSIONS: This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.

Synthesis of 6-alkoxy and 6-hydroxy-alkyl amine derivatives of braylin as vasorelaxing agents.

Braylin (10b) is a 8,8-dimethyl chromenocoumarin present in the plants of the family Rutaceae and Meliaceae and possesses vasorelaxing and anti-inflammatory activities. In this study, six 6-alkoxy (10b, 15-19), and twelve 6-hydroxy-alkyl amine (20a-20l) derivatives of braylin (11 and 12) were synthesized to delineate its structural requirement for vasorelaxing activity. The synthesized compounds were evaluated for vasorelaxation response in preconstricted intact rat Main Mesenteric Artery (MMA). The compounds showed l-type VDCC channel blockade depended and endothelium-independent vasorelaxation within the range of Emax < 50.00-96.70 % at 30 µM. Amongst all, 6-alkoxy derivatives were more active than 6-hydroxy-alkyl amine derivatives. The structural refinements about braylin showed that deletion of its methoxy group or homologation beyond ethoxy group presented deleterious effect on vasorelaxation response of braylin. Interestingly, substituting the ethoxy group in 10b presented the best activity and selectivity towards l-type VDCC channel blockade, a specific target cardiovascular function.

Racial bias in recruitment to clinical trials on paediatric asthma.

Asthma is now the commonest chronic disease of childhood, but not all children with asthma receive equivalent standards of medical care which influences their clinical outcomes. In this paper we sought to determine the proportion of participants in registered clinical trials relating to paediatric or adolescent asthma over the last decade that were from white and non-white backgrounds. We searched the ClinicalTrials.gov database for all completed interventional studies between the dates 1st January 2011 and 1st January 2021 that were on the topic of 'asthma', and included participants below 18 years of age. Of the 500 studies returned, 208 had results available on the ClinicalTrials.gov website. In total, of the 112,327 patients studied, almost 69 % (77,333) of the patients were described as White or Caucasian, and fewer than 13 % (14,189) were described as Black, African, or African-American. Overall, approximately 30 % of study participants - some 34,207 children - were from non-white backgrounds. To redress this imbalance, researchers designing clinical trials must ensure that their study populations are as representative of the target population for the intervention as possible.

Synthesis of amide derivatives of 3-aryl-3H-benzopyrans as osteogenic agent concomitant with anticancer activity.

The present study reports a series of 3-aryl-3H-benzopyran-based amide derivatives as osteogenic agents concomitant with anticancer activity. Six target compounds viz 22e, 22f, 23i, and 24b-d showed good osteogenic activity at 1 pM and 100 pM concentrations. One of the potential molecules, 24b, effectively induced ALP activity and mRNA expression of osteogenic marker genes at 1 pM and bone mineralization at 100 pM concentrations. These molecules also presented significant growth inhibition of osteosarcoma (MG63) and estrogen-dependent and -independent (MCF-7 and MDA-MB-231) breast cancer cells. The most active compound, 24b, inhibited the growth of all the cancer cells within the IC50 10.45-12.66 µM. The mechanistic studies about 24b showed that 24b induced apoptosis via activation of the Caspase-3 enzyme and inhibited cancer cell migration. In silico molecular docking performed for 24b revealed its interaction with estrogen receptor-ß (ER-ß) preferentially.

Physical activity and liver disease affect the fat-free mass in adolescents with cystic fibrosis.

Cystic fibrosis (CF) is predominantly a lung disease but is also characterised by impaired skeletal muscularity and a reduction in fat-free mass. We aimed to test the hypothesis that clinical and anthropometric parameters would determine fat-free mass impairment in adolescents with CF. We measured the fat-free mass index (FFMI) using bioelectrical impedance, the lung function using spirometry, the number of shuttles as a measure of exercise tolerance and the reported physical activity in children and young people with CF in a tertiary centre at King's College Hospital, London, UK. CF-related liver disease was diagnosed by abnormal liver enzymes and/or ultrasonography. We studied 28 children and young people (11 male) with a median (interquartile range (IQR)) age of 15 (13-17) years. They had a median (IQR) FFMI of 13.5 (11.6-15.1) kg/m2. The FFMI significantly correlated with age (rho = 0.568, p = 0.002), number of shuttles (rho = 0.691, p < 0.001) and reported hours of activity per day (rho = 0.426, p = 0.024). The median (IQR) FFMI was significantly higher in male [15.1 (13.1-18.6) kg/m2] compared to female participants [12.7 (11.6-14.1) kg/m2, p = 0.008]. The median (IQR) FFMI was significantly lower in the 10 (36%) participants with liver disease [11.9 (11.5-13.4) kg/m2] compared to the FFMI in the remaining 18 participants without liver disease [14.4 (12.5-15.9) kg/m2, p = 0.027]. CONCLUSION: Fat-free mass increases with increasing age and growth in adolescents with CF. Physical activity exerts a beneficial effect on fat-free mass, and CF-related liver disease negatively affects fat-free mass in adolescents with CF. WHAT IS KNOWN: • Health behaviours in adolescence influence lifelong health in cystic fibrosis (CF). • A normal body mass index in CF might fail to reveal a low fat-free mass (FFM), and quality of life in CF is strongly associated with a reduced FFM. WHAT IS NEW: • FFM increases with increasing age and growth in adolescents with CF. • Physical activity exerts a beneficial effect, and liver disease negatively affects FFM in adolescents with CF.

Fifteen-minute consultation: A structured approach to children with parapneumonic effusion and empyema thoracis.

Parapneumonic effusion is defined as the accumulation of pleural fluid associated with lung infection/pneumonia. Parapneumonic effusions can be uncomplicated or complicated. They are caused by the spread of infection and inflammation to the pleural space, and can develop into empyema thoracis-frank pus in the pleural space. Chest radiograph and thoracic ultrasound are the key imaging modalities for the diagnosis of parapneumonic effusion. Management aims are reducing inflammation and bacteria in the pleural cavity, and enabling full lung expansion. Broad-spectrum intravenous antibiotics, with the addition of chest tube drainage and fibrinolytic therapy for larger collections, are the mainstays of management. This article provides a clear, evidence-based and structured approach to the assessment and management of parapneumonic effusion/empyema thoracis in children and young people.

Effect of health promotion interventions on small portion size consumption behavior among college students.

Background: Large food portion size is contributing toward overweight and obesity rates and has been found directly proportional to increase in portion size. Objectives: The study was done to see the effect of health promotion intervention on small portion size consumption behavior using multitheory model (MTM). Materials and Methods: A quasi-experimental study was conducted among students of age groups 18 - 21 years in two different colleges from North India between 2019 to 2020. About 150 participants in the intervention group as well as control group were selected and health promotion intervention in the form of motivational group counseling, one-to-one counseling, Power Point presentations, lectures, and messages were given to participants in intervention group. Difference in difference of proportions for meal consumption behavior and the difference in the difference of means for body mass index, waist-hip ratio and for constructs of MTM for portion size consumption behavior were calculated. Paired t-test was used to test the significance between the continuous variables. Results: There was a significant reduction (46% vs. 11%, P < 0.001) in proportion of participants consuming large portion-sized meals in the intervention group as compared to the control group. The mean change in constructs (participatory dialogues,behavioral confidence, change in physical environment, emotional transformation and practice for change) for portion size consumption behavior of participants in the intervention and control groups at base line and end line was found statistically significant. Conclusion: MTM is a useful tool for health promotion and health education to predict the initiation and sustenance of health behavior change.

Blood eosinophils in managing preschool wheeze: Lessons learnt from a proof-of-concept trial.

BACKGROUND: Management of preschool wheeze is based predominantly on symptom patterns. OBJECTIVE: To determine whether personalizing therapy using blood eosinophils or airway bacterial infection results in fewer attacks compared with standard care. METHODS: A proof-of-concept, randomized trial to investigate whether the prescription of inhaled corticosteroids (ICS) guided by blood eosinophils, or targeted antibiotics for airway bacterial infection, results in fewer unscheduled healthcare visits (UHCVs) compared with standard care. Children aged 1-5 years with ≥2 wheeze attacks in the previous year were categorized as episodic viral wheeze (EVW) or multiple trigger wheeze (MTW). The intervention group was prescribed ICS if blood eosinophils ≥3%, or targeted antibiotics if there is positive culture on induced sputum/cough swab. The control group received standard care. The primary outcome was UHCV at 4 months. RESULTS: 60 children, with a median age of 36.5 (range 14-61) months, were randomized. Median blood eosinophils were 5.2 (range 0-21)%, 27 of 60 (45%) children were atopic, and 8 of 60 (13%) had airway bacterial infection. There was no relationship between EVW, MTW and either blood eosinophils, atopic status or infection. 67% in each group were prescribed ICS. 15 of 30 control subjects and 16 of 30 patients in the intervention group had UHCV over 4 months (p = .8). The time to first UHCV was similar. 50% returned adherence monitors; in those, median ICS adherence was 67%. There were no differences in any parameter between those who did and did not have an UHCV. CONCLUSION: Clinical phenotype was unrelated to allergen sensitization or blood eosinophils. ICS treatment determined by blood eosinophils did not impact UHCV, but ICS adherence was poor.

Promoting smoking cessation in the paediatric respiratory clinic.

Exposure to tobacco smoke is harmful to children and young people (CYP). There is, to our knowledge, no published evidence quantifying the success of smoking cessation interventions targeted at both CYP and their parents or guardians in paediatric respiratory clinics. We offered 102 participants smoking cessation advice, using motivational interviewing and exhaled carbon monoxide measurements to help them quit smoking. In total, 16 of 102 participants quit smoking, with 4 lost to follow-up. A further 40 participants cut down on how much they smoked. CONCLUSION: Formal screening questions on smoking and the provision of smoking cessation advice should form a regular part of all respiratory clinics where CYP and their parents are seen. Simple smoking cessation interventions can lead to reduced smoking in this population. WHAT IS KNOWN: • Tobacco smoking is strongly associated with significant morbidity and mortality. • Adolescents with chronic respiratory diseases may themselves smoke, or may have parents who do so. WHAT IS NEW: • Smoking cessation interventions are well received in paediatric respiratory clinic by patients and their families. • Simple smoking cessation interventions can help young people and their parents to stop smoking or cut down on smoking.

Recommended Musculoskeletal and Sports Ultrasound Terminology: A Delphi-Based Consensus Statement.

OBJECTIVES: The current lack of agreement regarding standardized terminology in musculoskeletal and sports ultrasound presents challenges in education, clinical practice, and research. This consensus was developed to provide a reference to improve clarity and consistency in communication. METHODS: A multidisciplinary expert panel was convened consisting of 18 members representing multiple specialty societies identified as key stakeholders in musculoskeletal and sports ultrasound. A Delphi process was used to reach consensus which was defined as group level agreement >80%. RESULTS: Content was organized into seven general topics including: 1) General Definitions, 2) Equipment and Transducer Manipulation, 3) Anatomic and Descriptive Terminology, 4) Pathology, 5) Procedural Terminology, 6) Image Labeling, and 7) Documentation. Terms and definitions which reached consensus agreement are presented herein. CONCLUSIONS: The historic use of multiple similar terms in the absence of precise definitions has led to confusion when conveying information between colleagues, patients, and third-party payers. This multidisciplinary expert consensus addresses multiple areas of variability in diagnostic ultrasound imaging and ultrasound-guided procedures related to musculoskeletal and sports medicine.

Recommended musculoskeletal and sports ultrasound terminology: a Delphi-based consensus statement.

The current lack of agreement regarding standardised terminology in musculoskeletal and sports ultrasound presents challenges in education, clinical practice and research. This consensus was developed to provide a reference to improve clarity and consistency in communication. A multidisciplinary expert panel was convened consisting of 18 members representing multiple specialty societies identified as key stakeholders in musculoskeletal and sports ultrasound. A Delphi process was used to reach consensus, which was defined as group level agreement of >80%. Content was organised into seven general topics including: (1) general definitions, (2) equipment and transducer manipulation, (3) anatomical and descriptive terminology, (4) pathology, (5) procedural terminology, (6) image labelling and (7) documentation. Terms and definitions which reached consensus agreement are presented herein. The historic use of multiple similar terms in the absence of precise definitions has led to confusion when conveying information between colleagues, patients and third-party payers. This multidisciplinary expert consensus addresses multiple areas of variability in diagnostic ultrasound imaging and ultrasound-guided procedures related to musculoskeletal and sports medicine.

Evaluation Challenges for the Application of Extended Reality Devices in Medicine.

Augmented and virtual reality devices are being actively investigated and implemented for a wide range of medical uses. However, significant gaps in the evaluation of these medical devices and applications hinder their regulatory evaluation. Addressing these gaps is critical to demonstrating the devices' safety and effectiveness. We outline the key technical and clinical evaluation challenges discussed during the US Food and Drug Administration's public workshop, "Medical Extended Reality: Toward Best Evaluation Practices for Virtual and Augmented Reality in Medicine" and future directions for evaluation method development. Evaluation challenges were categorized into several key technical and clinical areas. Finally, we highlight current efforts in the standards communities and illustrate connections between the evaluation challenges and the intended uses of the medical extended reality (MXR) devices. Participants concluded that additional research is needed to assess the safety and effectiveness of MXR devices across the use cases.

Fifteen-minute consultation: A structured approach to a child with primary spontaneous pneumothorax.

Primary spontaneous pneumothorax (PSP) is an uncommon presentation in children but may occur at any age and occurs in patients with no pre-existing lung disease. Management aims are to re-expand the collapsed lung, relieve pressure in the intrapleural space and avoid a tension pneumothorax. Correct management of PSP will avoid unnecessary intervention, reduce length of hospital stay and also reduce the risk of recurrence. There are no established guidelines for treating PSP in children and there is significant variation in management among centres and clinicians. This article provides a clear, evidence-based and structured approach to assessment and management of PSP in children and young people.

Paediatric and adolescent asthma: A narrative review of telemedicine and emerging technologies for the post-COVID-19 era.

Children and young people with asthma need regular monitoring to maintain good asthma control, prevent asthma attacks and manage comorbidities. The COVID-19 pandemic has resulted in healthcare professionals making fundamental changes to the way healthcare is delivered and for patients and families adapting to these changes. Comprehensive remotely delivered, technology-based healthcare, closer to the patients home (reducing hospital footfall and possibly reducing carbon footprint) is likely to be one of the important collateral effects of the pandemic. Telemedicine is anticipated to impact everyone involved in healthcare - providers and patients alike. It is going to bring changes to organization, work areas and work culture in healthcare. Healthcare providers, policymakers and those accessing healthcare services will experience the impact of technology-based healthcare delivery. Telemedicine can play an exciting role in the management of childhood asthma by delivering high-quality care closer to the child's home. However, unlike adults, children still need to be accompanied by their carers for virtual care. Policymakers will need to take into account potential additional costs as well as the legal, ethical and cultural implications of large scale use of telemedicine. In this narrative review, we review evidence regarding the role of telemedicine and related emerging technologies in paediatric and adolescent asthma. Although there are gaps in the current knowledge, there is evidence demonstrating the important role of telemedicine in management of childhood and adolescent asthma. However, there is an urgent need for healthcare researchers and policymakers to focus on improving the technologies and address the disparities in accessing novel technology-based management strategies to improve asthma care.

Synthesis and biological evaluation of substituted amide derivatives of C4-ageratochromene dimer analog.

Substituted amide derivatives of C4-ageratochromene dimer analog (19) were synthesized through structural modification of precocene-I (4a), isolated from the essential oil of Ageratum conyzoides L. The target compounds (18-20, 23I-VI, 24I-VI, and 25I-VI) were evaluated for their bone-forming effect using osteoblast differentiation assay. Seven compounds (23I, 23II, 23IV, 23VI, 24III, 24VI, and 25VI) presented good activity within 1 pM-1 nM concentration. At 1 pM concentration, the most active compound i.e. 23II showed effective mineralization of osteoblast cells along with expression of osteogenic marker genes viz RUNX 2, BMP-2, and type 1 collagen (Type-1 col) without any toxicity towards osteoblast cells. Single crystal X-ray analysis of 18 and 20 revealed that the core nucleus of these molecules bear phenyl rings in a Trans-stilbenoid system and had a good structural correlation with 17ß-estradiol (1) and diethylstilbestrol (DES, 3). In-silico study about 23II showed its structural complementarities with the LBD of estrogen receptor (ER) which indicated possible ER-mediated activity of compounds.

Tiotropium in the management of paediatric and adolescent asthma: Systematic review.

Tiotropium bromide is a long-acting muscarinic antagonist (LAMA) and is the only LAMA licensed for management for patients' ≥6 years old with severe asthma who have experienced one or more severe asthma exacerbations in the preceding year. Recent clinical trials have demonstrated that once-daily tiotropium is safe and efficacious in 6-17 year-olds with symptomatic asthma despite treatment with inhaled corticosteroids (ICSs), with or without additional controllers. In this paper, we review the evidence of the safety and efficacy of tiotropium add-on maintenance treatment in children and adolescents with symptomatic moderate and severe asthma.

Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a new phenomenon reported worldwide with temporal association with Covid-19. The objective of this paper is to evaluate reported cases in children and adolescents. From 1726 papers, 35 documented papers related to MIS-C cases identified 783 individual cases of MIS-C between March-June 2020; with 55% being male (n = 435) and a median age of 8.6 years (IQR, 7-10 years; range 3 months-20 years). Patients with MIS-C were noted to have a high frequency of gastrointestinal symptoms (71%) including abdominal pain (34%) and diarrhea (27%). Cough and respiratory distress were reported in 4.5% and 9.6% cases respectively. Blood parameters showed neutrophilia in 345/418 (83%) of cases and a high CRP in 587/626 (94%). 362/619 (59%) cases were SARS-CoV-2 infection positive (serology or PCR) however only 41% demonstrated pulmonary changes on chest imaging. Severity of illness was high with 68% cases requiring intensive care admission; 63% requiring inotropic support; 244/783 (28%) cases needing some form of respiratory support (138 mechanically ventilated), and 31 required extra-corporeal membrane oxygenation. Treatment strategies included intravenous immunoglobulin (63%) and intravenous steroids (44%). 29 cases received Infliximab, 47 received IL1 (interleukin) receptor antagonist, and 47 received IL6-receptor antagonist. 12/783 (1.5%) children died. In summary, a higher incidence of gastrointestinal symptoms were noted in MIS-C. In contrast to acute Covid-19 infection in children, MIS-C appears to be a condition of higher severity with 68% of cases having required critical care support.