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This article examines the impact of the reporting practice and paper technologies like forms on reports that were later used for national morbidity statistics by studying the Swiss reporting system for infectious diseases between 1886 and 1921. Analysing the production processes of notifications shows the difficulties and solutions in the implementation of the statutory reporting process. Two disease outbreaks-a smallpox outbreak in Schaffhausen and a typhoid outbreak in the canton of Lucerne-serve as case studies. It is shown that reports are not only objective representations of diseases, but also symbolize the medico-social interactions that produce them, timed by administrative tools like reporting forms and the act of reporting. This destabilises historical statistics and illustrates the complexity of the historical source material, as these interactions and their impact on reporting must be considered. These findings are further supported by examining the Swiss reporting system during the Spanish flu of 1918 and its failure to record influenza cases., (© 2024. The Author(s).)

The growing prevalence and burden of Alzheimer's disease has catalysed huge investments in research on its causes, diagnosis, treatment and care. After many high-profile failures, recent clinical trials of anti-amyloid drugs have marked a turning point for the field, leading to the approval of the first disease-modifying therapies for Alzheimer's disease by the FDA. It is now up to European regulators to determine whether there is sufficient evidence to approve these drugs for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease. Here, we outline Alzheimer Europe's position on anti-amyloid therapies for Alzheimer's disease, which was adopted by the Board of Alzheimer Europe following consultations with our member associations and with the European Working Group of People with Dementia. Beyond questions of drug efficacy, safety and cost, we highlight important issues that must be addressed by industry, regulators, payers, healthcare systems and governments, to ensure that patients have timely, appropriate and equitable access to innovative treatments, regardless of their socio-economic background, insurance status, or place of residence. We also call for continued investment in research on treatments that might benefit people with more advanced Alzheimer's disease - as well as support and care services that can help people live well with dementia at all stages of the disease., Competing Interests: Angela Bradshaw and Jean Georges are employees of Alzheimer Europe, which has received grants from the European Union’s Health, Horizon Europe and Citizens, Equality, Rights and Values programme (CERV) programmes, the Innovative Health Initiative, the Joint Programme for Neurodegenerative Disease Research (JPND) and the Luxembourg Fonds National de la Recherche, as well as sponsorship and support from AbbVie, Biogen, Eisai, Essity, Fujirebio, GE Healthcare, Grifols, Janssen, Lilly, MSD, Novo Nordisk, Nutricia, Prothena, Roche and TauRx.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence., Competing Interests: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. MS has served on advisory boards/consultancies Acadia, Otsuka, Avanir, Medesis Pharma, Servier, Eisai, Roche, Biogen, Lilly and Ethypharm. PBR has received research grants from the National Institutes of Aging, Alzheimer’s Clinical Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer’s Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Acadia, MedaCorp, ExpertConnect, HMP Global, Synaptogenix, and Neurology Week. CL has received support from Functional Neuromodulation, Ltd, Orion, Servier, Astellas, SVB Leerink, Roche, Avanir, Karuna, Maplight,Axsome, GW Research Limited, Merck, EXCIVA GmbH, Otsuka, and IntraCellular Therapies. DM is a full-time employee of Signant Health. MC has no disclosures. BV is an investigator in clinical trials sponsored by Biogen, Lilly, Roche, Eisai, Pfizer, Pierre Fabre Pharmaceuticals and the Toulouse University Hospital. He has served as SAB member for Biogen, Alzheon, Green Valley, Norvo Nordisk, Longeveron, Rejuvenate Biomed Clinical Pfizer, Eisai France, Advisory Board Meeting - but received no personal compensation. He has served as consultant and/or SAB member for Roche, Lilly, Eisai, TauX, Cerecin with personal compensation. CB has Grants and personal fees from Acadia, Lundbeck, Synexus, Novo Nordisk, and Enterin; and personal fees from Janssen, GW Pharma, TauRx, Biogen, Orion, Roche, Otsuka, Novartis, Eli Lilly, Suven, Sunovion, ADDEX and Exciva. SG has been a member of SAB for Alzheon, AmyriAD, Eisai Canada, EnigmaUSA, Lilly Canada, Medesis, Otsuka Canada, and TauRx, and has given lectures for Biogen Canada, and Lundbeck Korea. ZI has served on advisory boards/consultancies for Acadia, Biogen, Lundbeck, Otsuka, Roche, and the Canadian Agencies for Drugs and Technologies in Health and serves on the Government of Canada Ministerial Advisory Board for Dementia. He has received honoraria from Lundbeck/Otsuka and his institution has received fees from Acadia, Biogen, and Roche in lieu.

Inappropriate polypharmacy is highly prevalent among older adults and presents a significant healthcare concern. Conducting medication reviews and implementing deprescribing strategies in multimorbid older adults with polypharmacy are an inherently complex and challenging task. Recognizing this, the Special Interest Group on Pharmacology of the European Geriatric Medicine Society has compiled evidence on medication review and deprescribing in older adults and has formulated recommendations to enhance appropriate prescribing practices. The current evidence supports the need for a comprehensive and widespread transformation in education, guidelines, research, advocacy, and policy to improve the management of polypharmacy in older individuals. Furthermore, incorporating deprescribing as a routine aspect of care for the ageing population is crucial. We emphasize the importance of involving geriatricians and experts in geriatric pharmacology in driving, and actively participating in this transformative process. By doing so, we can work towards achieving optimal medication use and enhancing the well-being of older adults in the generations to come., (© 2023. The Author(s).)

Background: Visual analogue scales (VASs) are used in a variety of patient-, observer- and clinician-reported outcome measures. While typically included in measures originally developed for pen-and-paper completion, a greater number of clinical trials currently use electronic approaches to their collection. This leads researchers to question whether the measurement properties of the scale have been conserved during the migration to an electronic format, particularly because electronic formats often use a different scale length than the 100 mm paper standard., Methods: We performed a review of published studies investigating the measurement comparability of paper and electronic formats of the VAS., Results: Our literature search yielded 26 studies published between 1997 and 2018 that reported comparison of paper and electronic formats using the VAS. After excluding 2 publications, 23 of the remaining 24 studies included in this review reported electronic formats of the VAS (eVAS) and paper formats (pVAS) to be equivalent. A further study concluded that eVAS and pVAS were both acceptable but should not be interchanged. eVAS length varied from 21 to 200 mm, indicating that 100 mm length is not a requirement., Conclusions: The literature supports the hypothesis that eVAS and pVAS provide comparable results regardless of the VAS length. When implementing a VAS on a screen-based electronic mode, we recommend following industry best practices for faithful migration to minimise the likelihood of non-comparability with pVAS., (© 2022. The Author(s).)

Falls prevention and management in older adults is a critical global challenge. One of the key risk factors for falls is the use of certain medications. Therefore, to prevent medication-related falls, the following is recommended in the recent World Guidelines for Falls Prevention and Management: (1) assess for fall history and the risk of falls before prescribing potential fall-risk-increasing drugs (FRIDs), (2) use a validated, structured screening and assessment tool to identify FRIDs when performing a medication review, (3) include medication review and appropriate deprescribing of FRIDs as a part of the multifactorial falls prevention intervention, and (4) in long-term care residents, if multifactorial intervention cannot be conducted due to limited resources, the falls prevention strategy should still always include deprescribing of FRIDs.In the present statement paper, the working group on medication-related falls of the World Guidelines for Falls Prevention and Management, in collaboration with the European Geriatric Medicine Society (EuGMS) Task and Finish group on FRIDs, outlines its position on how to implement and execute these recommendations in clinical practice.Preferably, the medication review should be conducted as part of a comprehensive geriatric assessment to produce a personalized and patient-centered assessment. Furthermore, the major pitfall of the published intervention studies so far is the suboptimal implementation of medication review and deprescribing. For the future, it is important to focus on gaining which elements determine successful implementation and apply the concepts of implementation science to decrease the gap between research and practice., (© 2023. The Author(s).)

Infections caused by resistant microorganisms are a complex global public health challenge, and the way to combat the increase of resistance is the development of more modern and faster techniques for resistance detection. This study aimed to evaluate the transport of inactivated bacteria impregnated in a filter paper disk to detect carbapenem resistance genes by multiplex real-time PCR (qPCR) using high-resolution melting (HRM). A total of 88 isolates of 10 different species of Enterobacterales harboring well-characterized carbapenem resistance genes were evaluated. A full 10-µL loop of fresh growth of bacteria were impregnated in a filter paper disk, which was left at room temperature for 2 days in order to simulate the time spent in transportation. Bacterial inactivation was performed with 70% ethanol at 15 min. Afterwards, the DNA was extracted from the paper disks for further analysis by qPCR HRM. The time of 15 min in 70% ethanol was enough to inactivate all the isolates tested. It was possible to correctly identify the presence of the carbapenem resistance gene by HRM qPCR in 87 isolates (98.87%) that were transported in the filter paper disks. Our results indicated that it is possible to use filter paper to transport inactivated bacteria and to identify carbapenem resistance genes by qPCR HRM. This alternative tends to facilitate the access to this technology by many laboratories which do not have the qPCR equipment., (© 2021. Sociedade Brasileira de Microbiologia.)

Purpose: The COVID-19 pandemic has been a dramatic trigger that has challenged the intrinsic capacity of older adults and of society. Due to the consequences for the older population worldwide, the Special Interest Group on Comprehensive Geriatric Assessment (CGA) of the European Geriatric Medicine Society (EuGMS) took the initiative of collecting evidence on the usefulness of the CGA-based multidimensional approach to older people during the COVID-19 pandemic., Methods: A narrative review of the most relevant articles published between January 2020 and November 2022 that focused on the multidimensional assessment of older adults during the COVID-19 pandemic., Results: Current evidence supports the critical role of the multidimensional approach to identify older adults hospitalized with COVID-19 at higher risk of longer hospitalization, functional decline, and short-term mortality. This approach appears to also be pivotal for the adequate stratification and management of the post-COVID condition as well as for the adoption of preventive measures (e.g., vaccinations, healthy lifestyle) among non-infected individuals., Conclusion: Collecting information on multiple health domains (e.g., functional, cognitive, nutritional, social status, mobility, comorbidities, and polypharmacy) provides a better understanding of the intrinsic capacities and resilience of older adults affected by SARS-CoV-2 infection. The EuGMS SIG on CGA endorses the adoption of the multidimensional approach to guide the clinical management of older adults during the COVID-19 pandemic., (© 2023. The Author(s).)

Scientific writing is an important skill in both academia and clinical practice. The skills for writing a strong scientific paper are necessary for researchers (comprising academic staff and health-care professionals). The process of a scientific research will be completed by reporting the obtained results in the form of a strong scholarly publication. Therefore, an insufficiency in scientific writing skills may lead to consequential rejections. This feature results in undesirable impact for their academic careers, promotions and credits. Although there are different types of papers, the original article is normally the outcome of experimental/epidemiological research. On the one hand, scientific writing is part of the curricula for many medical programs. On the other hand, not every physician may have adequate knowledge on formulating research results for publication adequately. Hence, the present review aimed to introduce the details of creating a strong original article for publication (especially for novice or early career researchers)., (© 2021. The Author(s).)

Background: The study tests the effects of data collection modes on patient responses associated with the multi-item measures such as Patient-Reported Outcomes Measurement System (PROMIS ® ), and single-item measures such as Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Numerical Rating Scale (NRS) measures., Methods: Adult cancer patients were recruited from five cancer centers and administered measures of anxiety, depression, fatigue, sleep disturbance, pain intensity, pain interference, ability to participate in social roles and activities, global mental and physical health, and physical function. Patients were randomized to complete the measures on paper (595), interactive voice response (IVR, 596) system, or tablet computer (589). We evaluated differential item functioning (DIF) by method of data collection using the R software package, lordif. For constructs that showed no DIF, we concluded equivalence across modes if the equivalence margin, defined as ± 0.20 × pooled SD, completely surrounds 95% confidence intervals (CI's) for difference in mean score. If the 95% CI fell totally outside the equivalence margin, we concluded systematic score difference by modes. If the 95% CI partly overlaps the equivalence margin, we concluded neither equivalence nor difference., Results: For all constructs, no DIF of any kind was found for the three modes. The scores on paper and tablet were more comparable than between IVR and other modes but none of the 95% CI's were completely outside the equivalence margins, in which we established neither equivalence nor difference. Percentages of missing values were comparable for paper and tablet modes. Percentages of missing values were higher for IVR (2.3% to 6.5% depending on measures) compared to paper and tablet modes (0.7% to 3.3% depending on measures and modes), which was attributed to random technical difficulties experienced in some centers., Conclusion: Across all mode comparisons, there were some measures with CI's not completely contained within the margin of small effect. Two visual modes agreed more than visual-auditory pairs. IVR may induce differences in scores unrelated to constructs being measured in comparison with paper and tablet. The users of the surveys should consider using IVR only when paper and computer administration is not feasible., (© 2021. The Author(s).)

First two decades of the twenty-first century are characterised by epidemics of non-communicable diseases such as many hundreds of millions of patients diagnosed with cardiovascular diseases and the type 2 diabetes mellitus, breast, lung, liver and prostate malignancies, neurological, sleep, mood and eye disorders, amongst others. Consequent socio-economic burden is tremendous. Unprecedented decrease in age of maladaptive individuals has been reported. The absolute majority of expanding non-communicable disorders carry a chronic character, over a couple of years progressing from reversible suboptimal health conditions to irreversible severe pathologies and cascading collateral complications. The time-frame between onset of SHS and clinical manifestation of associated disorders is the operational area for an application of reliable risk assessment tools and predictive diagnostics followed by the cost-effective targeted prevention and treatments tailored to the person. This article demonstrates advanced strategies in bio/medical sciences and healthcare focused on suboptimal health conditions in the frame-work of Predictive, Preventive and Personalised Medicine (3PM/PPPM). Potential benefits in healthcare systems and for society at large include but are not restricted to an improved life-quality of major populations and socio-economical groups, advanced professionalism of healthcare-givers and sustainable healthcare economy. Amongst others, following medical areas are proposed to strongly benefit from PPPM strategies applied to the identification and treatment of suboptimal health conditions:Stress overload associated pathologiesMale and female healthPlanned pregnanciesPeriodontal healthEye disordersInflammatory disorders, wound healing and pain management with associated complicationsMetabolic disorders and suboptimal body weightCardiovascular pathologiesCancersStroke, particularly of unknown aetiology and in young individualsSleep medicineSports medicineImproved individual outcomes under pandemic conditions such as COVID-19., Competing Interests: Conflicts of interestThe authors declare no competing interests., (© The Author(s) 2021.)

An increasing interest in a healthy lifestyle raises questions about optimal body weight. Evidently, it should be clearly discriminated between the standardised "normal" body weight and individually optimal weight. To this end, the basic principle of personalised medicine "one size does not fit all" has to be applied. Contextually, "normal" but e.g. borderline body mass index might be optimal for one person but apparently suboptimal for another one strongly depending on the individual genetic predisposition, geographic origin, cultural and nutritional habits and relevant lifestyle parameters-all included into comprehensive individual patient profile. Even if only slightly deviant, both overweight and underweight are acknowledged risk factors for a shifted metabolism which, if being not optimised, may strongly contribute to the development and progression of severe pathologies. Development of innovative screening programmes is essential to promote population health by application of health risks assessment, individualised patient profiling and multi-parametric analysis, further used for cost-effective targeted prevention and treatments tailored to the person. The following healthcare areas are considered to be potentially strongly benefiting from the above proposed measures: suboptimal health conditions, sports medicine, stress overload and associated complications, planned pregnancies, periodontal health and dentistry, sleep medicine, eye health and disorders, inflammatory disorders, healing and pain management, metabolic disorders, cardiovascular disease, cancers, psychiatric and neurologic disorders, stroke of known and unknown aetiology, improved individual and population outcomes under pandemic conditions such as COVID-19. In a long-term way, a significantly improved healthcare economy is one of benefits of the proposed paradigm shift from reactive to Predictive, Preventive and Personalised Medicine (PPPM/3PM). A tight collaboration between all stakeholders including scientific community, healthcare givers, patient organisations, policy-makers and educators is essential for the smooth implementation of 3PM concepts in daily practice., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2021.)

Implementation of decentralized approaches can improve access to clinical trials. The Australian government has focused on a teletrial model, which resources and upskills health care organisations to enable collaboration in trials to extend to rural and remote areas. This commentary describes the Australian teletrial model, its context within the established DCT model, its value, and likely challenges moving forward., (© 2024. The Author(s).)

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11 th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

The FTA card has emerged as a promising alternative for nucleic acid extraction. The FTA card is a filter paper impregnated with chemicals that preserve and stabilize the genetic material present in the sample, allowing for its storage and transport at room temperature. The aim of this study was to test the card for the detection of RNA and DNA nucleic acids. Two RNA viruses (Senecavirus A and classical swine fever virus) and two DNA viruses (African swine fever virus and suid alphaherpesvirus 1) were tested, and in all cases, there was a decrease in sensitivity. The methods exhibited good repeatability and demonstrated a rapid and practical use for sample transport and nucleic acid extraction., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Monitoring dynamics of airborne fungal species and controlling of harmful ones are of vital importance to conservation of cultural relics. However, the evaluation of air quality and the community structure characteristics of microorganisms, especially fungi, in the atmosphere of archives is in a stage of continuous exploration though more than 4,000 archives were constructed in China. Seventy-two air samples were collected in this study under different spatial and weather conditions from the archives of Kunming Medical University, located in the Kunming metropolitan area, Yunnan province, southwestern China. A total of 22 airborne fungal classes, 160 genera and 699 ASVs were identified, the species diversity is on the rise with the strengthening of air circulation with the outside space, and thus the intensive energy metabolism and activity were found in the spaces with window and sunny weather, except for the higher lipid synthesis of indoor samples than that of outdoor ones. Furthermore, there were significant differences in fungal community composition and abundance between sunny and rainy weathers. A considerable number of species have been identified as indicator in various environmental and weather conditions of the archives, and temperature and humidity were thought to have significant correlations with the abundance of these species. Meanwhile, Cladosporium and Alternaria were the dominant genera here, which may pose a threat to the health of archive professionals. Therefore, monitoring and controlling the growth of these fungal species is crucial for both conservation of paper records and health of archive professionals., (© 2024. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Introduction: Qualification of medical product evaluation tools is underway in the United States, Europe, and Japan to reflect the advancements in the basic science of medical products. In Europe and the U.S., Guidance of Guidances (GoG) policies that clarify regulators'processes, tasks, and methods of sponsor involvement are adopted to issue tool guidance. However, in Japan, a non-GoG type policy focusing on supporting the research and development for tools without defining a tool guidance-making process has been adopted., Methods: In this study, an analytical framework for the lifecycle of development tools was constructed, including pre- and post-tool qualification processes, to compare the two above-mentioned approaches. For this study, Japanese cases were selected as experimental cases, whereas Western cases served as controls. The progress of tool qualification and composition of deliverables were analyzed., Results and Conclusions: It was indicated that in the GoG type policy, in which processes are defined, and involvement methods are clarified, tool qualification can progress more smoothly than in a non-GoG type policy. This policy indicates that deliverables may have a consistent composition. Contrastingly, GoG-type policies alone present challenges in connecting upstream tools for R&D support., (© 2024. The Author(s).)

Purpose: To investigate the changes in pain, physical and activities of daily living (ADL) functioning in vulnerable older adults with chronic pain after proactive primary care intervention., Methods: This study was embedded in a prospective, pragmatic, matched-control multicenter trial at 19 primary care practices in Sweden, with proactive medical and social care (Intervention Group, IG, n = 134) in comparison with usual care (Control Group, CG, n = 121). Patients with chronic pain, defined as pain experienced longer than 3 months, were included in this subgroup analysis. Data on pain aspects, physical and ADL functioning were collected in the questionnaires at baseline, one- and two-year follow-up (FU-1 and FU-2). Data on prescribed pain medications was collected by local health authorities., Results: Mean age was 83.0 ± 4.7 years with almost equal representation of both genders. From baseline until FU-2, there were no significant within-group or between-group changes in pain intensity. Small adjustments of pain medication prescriptions were made in both groups. Compared to FU-1, the functional changes were more measurable at FU-2 as fewer participants had impaired physical functioning in IG (48.4%) in comparison to CG (62.6%, p = 0.027, Effect Size φ = 0.14). Higher scores of ADL-staircase (more dependent) were found in both groups (p < 0.01, Effect Size r = 0.24 in CG and r = 0.16 in IG)., Conclusion: Vulnerable older adults with chronic pain seemed to remain physical and ADL functioning after proactive primary care intervention, but they may need tailored strategies of pain management to improve therapeutic effects., Trial Registration: ClinicalTrials.gov 170608, ID: NCT03180606., (© 2024. The Author(s).)

Introduction: Potentially harmful excipients (PHEs) for children have been reported and the need for information collection has been advocated. However, studies on the actual occurrence of adverse events are limited. This study investigated the quantitative exposure of PHEs via injection and their association with adverse events in children under 2 years of age., Materials and Methods: As a single-center observational study, children aged 0-23 months received injectable drugs from April 1, 2018, to March 31, 2023 were included. Information on PHE exposure and adverse events after administration were extracted from medical records. Sodium benzoate, benzyl alcohol, ethanol, glycerol, lactose, polyethylene glycol paraben, polysorbate, propylene glycol, sorbitol, sucrose, sulfite, and thimerosal were selected as PHEs., Results and Discussion: 6265 cases, 333,694 prescriptions, and 368 drugs (264 ingredients) were analyzed. The median age was 0.63 years (interquartile range [IQR] 0.1-1.1). 72,133 prescriptions, 132 drugs and 99 ingredients contained PHE; 2,961 cases exposed to PHE and 1825 cases exceeding permitted daily exposure. The drug with the highest number of exposure cases was hydroxyzine, and the highest number of prescriptions was heparin (both drugs contain benzyl alcohol). In association between adverse events and PHE exposure, higher doses in cases of adverse event occurrence were found in benzyl alcohol, glycerol, polyethylene glycol, and polysorbate exposed cases. Among thimerosal-exposed cases, "developmental delay" was more frequent in exposed cases, but the causal relationship was unknown. Further investigation is needed to clarify the relationship between adverse events and PHE exposure. Additionally, more precise information on PDE for pediatrics including neonates is necessary., (© 2023. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Enzymatic compounds can be found abundantly and provide numerous advantages in microbial organisms. Xylanases are used in various pharmaceutical, food, livestock, poultry, and paper industries. This study aimed to investigate xylanase-producing yeasts, xylose concentration curve and their enzymatic activity under various factors including carbon and nitrogen sources, temperature, and pH. Enzyme activity was evaluated under different conditions before, during, and after purification. The yeast strains were obtained from the wood product workshop and were subsequently cultivated on YPD (yeast extract peptone dextrose) medium. Additionally, the growth curve of the yeast and its molecular identification were conducted. The optimization and design process of xylan isolated from corn wood involved the use of Taguchi software to test different parameters like carbon and nitrogen sources, temperature, and pH, with the goal of determining the most optimal conditions for enzyme production. In addition, the Taguchi method was utilized to conduct a multifactorial optimization of xylanase enzyme activity. The isolated species were partially purified using ammonium sulfate precipitation and dialysis bag techniques. The results indicated that 3 species (8S, 18S, and 16W) after molecular identification based on 18S rRNA gene sequencing were identified as Candida tropicalis SBN-IAUF-1, Candida tropicalis SBN-IAUF-3, and Pichia kudriavzevii SBN-IAUF-2, respectively. The optimal parameters for wheat carbon source and peptone nitrogen source were found at 50 °C and pH 9.0 through single-factor optimization. By using the Taguchi approach, the best combination for highest activity was rice-derived carbon source and peptone nitrogen source at 50 °C and pH 6.0. The best conditions for xylanase enzyme production in single-factor optimization of wheat bran were 2135.6 U/mL, peptone 4475.25 U/mL, temperature 50 °C 1868 U/mL, and pH 9.0 2002.4 U/mL. Among the tested yeast, Candida tropicalis strain SBN-IAUF-1 to the access number MZ816946.1 in NCBI was found to be the best xylanase product. The highest ratio of enzyme production at the end of the delayed phase and the beginning of the logarithmic phase was concluded by comparing the growth ratio of 8S, 16W, and 18S yeasts with the level of enzymatic activity. This is the first report on the production of xylan polymer with a relative purity of 80% in Iran. The extracellular xylanases purified from the yeast species of C. tropicalis were introduced as a desirable biocatalyst due to their high enzymatic activity for the degradation of xylan polymers., (© 2023. The Author(s) under exclusive licence to Sociedade Brasileira de Microbiologia.)

Sensitive images represent a new challenge in enterprise imaging. These images, often containing nudity or gruesome content, have the potential to cause emotional harm to patients and people who view the images. Unfortunately, the interoperability standards used in imaging informatics have not yet addressed this issue. Because of this, the software solutions used in healthcare information technology are not able to offer patients and other viewers of image protections. In this Health Information Management Systems Society (HIMSS)/Society for Imaging Informatics in Medicine (SIIM) Enterprise Imaging Community Whitepaper, we define sensitive images, identify unique challenges related to their management, and provide recommendations for future solutions to protect our patients., (© 2024. The Author(s).)

In 1891 Cambridge biologist William Bateson (1861-1926) announced his idea that the symmetrical segmentation in living organisms resulted from energy peaks of some vibratory force acting on tissues during morphogenesis. He also demonstrated topographically how folding a radially symmetric organism could produce another with bilateral symmetry. Bateson attended many lectures at the Cambridge Philosophical Society and viewed mechanical models prepared by eminent physicists that illustrated how vibrations affected materials. In his subsequent research, Bateson utilized analogies and metaphors based upon his observations of nature to build a thought model on the effects of vibrations on living tissue, because he realized that the chemistry and biology of his day lacked technologies to perform actual experiments on the subject. He concluded the production of organic segmentation was both a chemical and mechanical phenomenon. By the time of his death Bateson had incorporated new ideas about embryonic organizer regions to suggest a center from which a rhythmic force emanated and then produced the observed repetitive segmentation as a common feature in living organisms., (© 2024. Springer Nature Switzerland AG.)

Background: High educational attainment may protect individuals, particularly middle-aged and older adults, against a wide range of health risks, including memory decline with age; however, this protection is less clear in patients with Alzheimer's disease (AD). In addition, this effect may differ across racial groups. According to the Marginalized-Related Diminished Return (MDR) theory, for example, the protective effect of high educational attainment on mental and physical health shows a weaker protective effect for racial minority groups, particularly Black people compared to White individuals., Objectives: This longitudinal study used data of middle-aged and older adults with AD with two aims: first, to test the association between educational attainment and memory, and second, to explore racial differences in this association in the USA., Methods: Data came from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The total sample was 1673 American middle-aged and older adults. The independent variable was educational attainment measured as years of education. The main outcome was memory operationalized as Rey Auditory Verbal Learning Test (RAVLT) Verbal Forgetting percentage (VF%). Age, gender, and follow-up duration were covariates. Race was the effect modifier. Linear regression model was utilized to analyze the data., Results: Of all participants, 68 (4.1%) were Black, and the remaining were White, with a mean age of 75 years old. In the pooled sample, educational attainment did not show a significant association with memory, independent of confounders. Educational attainment showed a significant interaction with race on memory, with higher educational attainment having a different effect on memory in White patients compared to Black patients., Conclusion: The effect of higher educational attainment on memory differs for Black patients with AD compared to White patients. To prevent cognitive disparities by race, we need to go beyond racial inequality in access to resources (e.g., education) and minimize diminished returns of educational attainment for racial minorities. To tackle health inequalities, social policies should not be limited to equalizing socioeconomic status but also help minority groups leverage their available resources, such as educational attainment, and secure tangible outcomes., (© 2022. W. Montague Cobb-NMA Health Institute.)

Background: Despite advances in perinatal care in the USA, maternal mortality is on the rise, and maternal death is higher than in any other high-income country. Maternal mortality in the USA is a persistent public health concern. This issue disproportionately affects Black/African American women, with their likelihood of pregnancy-related death being three times more likely compared to White women. This study aimed to explore the resources needed for Black/African American women to address the relatively higher maternal mortality rates recorded for them., Methods: An anonymous link with demographic and open-ended questions was sent to US women 18 years and older to participate in the study. A total of 140 participants responded to the survey. We retained a final sample of 118 responses after eliminating responses with missing data. Descriptive statistics are reported for closed-ended items. Open-ended responses were analyzed using content analysis procedures, where we coded and categorized the data into themes., Results: Six themes were identified from the study data: (1) Diversity, Equity, and Inclusion (DEI) training for health providers focused on racial bias and discrimination, (2) Advocacy, (3) Provider selection, (4) Researching doctors and delivery hospitals to inform women's birthing decision-making, (5) Women's care-seeking behaviors, and (6) Addressing the Social Determinants of Health., Conclusion: Based on the study's findings, we recommend DEI training for healthcare professionals providing direct care to pregnant and postpartum women, advocacy and resource-awareness training for pregnant Black/African American women and their spouses/partners, or a family member, to assist them in their pregnancy and birthing journeys., (© 2023. W. Montague Cobb-NMA Health Institute.)

Background: Rearrangements in the anaplastic lymphoma kinase (ALK) gene define a molecular subgroup of non-small-cell lung carcinoma (NSCLC) that should be treated with ALK-targeting tyrosine kinase inhibitors (TKIs)., Objective: This study aimed to portray the Portuguese reality about the diagnosis and treatment of stage IV ALK-positive NSCLC., Methods: Institutions that treat lung cancer in Portugal were invited to participate in an anonymous electronic questionnaire. A total of 22/35 geographically dispersed institutions responded. A descriptive statistical analysis of the results was performed., Results: Reflex molecular testing was done in 54.6% of the institutions. Next-generation sequencing (NGS) was the preferred diagnostic method (90.9%). Typically, physicians obtained molecular study results within 14-21 days. Alectinib was the most commonly used first-line treatment. For patients with brain metastases, 86.4% of the physicians preferred alectinib and 13.6% preferred first-line brigatinib. In the case of asymptomatic oligoprogression in the central nervous system, 85.7% of physicians performed local treatment and kept the patient on a TKI; if symptomatic, 66.7% gave local treatment and stayed with the TKI, while 28.6% gave local treatment and altered the TKI. For patients with symptomatic systemic progression, 47.6% and 38.1% of physicians prescribed lorlatinib after initial treatment with alectinib or brigatinib, respectively. After progression on lorlatinib, 42.9% of respondents chose chemotherapy and 57.1% requested detection of resistance mutations., Conclusions: NGS is widely used for the molecular characterization of ALK-positive NSCLC in Portugal. The country has access to up-to-date therapy. Overall, national clinical practice follows international recommendations for the diagnosis and treatment of ALK-positive NSCLC., (© 2023. The Author(s).)

Purpose: We evaluated oral frailty (OFr) and its association with health-related quality of life (HRQoL), energy and protein intake, and survival among older long-term care residents., Methods: This cross-sectional study with a 3-year follow-up for survival assessed 349 residents in long-term care facilities (73% female, mean age 82 years). We defined OFr with six signs (dry mouth, food residue on oral surfaces, unclear speech, inability to keep mouth open or pain expression during the clinical oral examination, diet pureed/soft) and OFr severity was categorized as Group 1, (mild) = 0-1 signs, Group 2 (moderate) = 2-4 signs, and Group 3 (severe) = 5-6 signs. We measured HRQoL with 15D instrument, and energy and protein intake by a 1- to 2-day food record. Mortality was retrieved from central registers on March 2021., Results: Of the residents, 15% had 0-1, 67% 2-4 and 18% 5-6 OFr signs. HRQoL decreased linearly from Group 1 to Group 3. OFr correlated with such dimensions of HRQoL as mobility, eating, speech, excretion, usual activities, mental function, and vitality. We found no association between OFr categories and energy and protein intake. Survival decreased linearly from Group 1 to Group 3., Conclusions: OFr was common among older long-term care residents and OFr severity predicts poorer outcomes. The six oral signs denoting OFr may be used at the bedside to screen residents at risk for OFr., (© 2023. The Author(s).)

Purpose: To investigate whether the involvement of both registered dietitians and dental hygienists results in greater improvement in swallowing function and activities of daily living (ADL) in patients with dysphagia undergoing rehabilitation., Methods: Of 467 patients enrolled in the Japanese Sarcopenic Dysphagia database, 433 met the study eligibility criteria in a retrospective cohort study. Patients were divided into two groups based on whether or not they received intervention by both registered dietitians and dental hygienists. Outcomes were changes in the Food Intake Level Scale (FILS) and the Barthel Index (BI) at initial and follow-up assessments. Multiple regression analyses adjusted for age, sex, sarcopenia, dwelling, Charlson comorbidity index, malnutrition diagnosed by the Global Leadership Initiative on Malnutrition, and initial FILS or BI were conducted to examine the relationship between the involvement of both registered dietitians and dental hygienists., Results: The mean age was 80.5 and ± 10.7 years, and 222 were female. Both registered dietitians and dental hygienists were involved in 242 (57%) patients. Median and interquartile range changes in FILS and BI were 1 (0, 2) and 15 (0, 32.5), respectively. In multiple regression analyses, the change in the FILS was significantly higher in the involvement of both registered dietitians and dental hygienists (standardized coefficient = 0.075, P = 0.033), however, the change in the BI was not significantly different between the groups., Conclusion: The involvement of both registered dietitians and dental hygienists improved swallowing function, but not ADL. Triad of rehabilitation, nutrition, and oral management may be useful for patients with dysphagia., (© 2023. The Author(s), under exclusive licence to European Geriatric Medicine Society.)

In addition to the threat of serious illness, COVID-19 and subsequent restrictions had devastating economic consequences for many US citizens. This study examines the evolution of food security over the first months of the COVID-19 pandemic testing whether the initial economic stimulus payment improved the nutritional well-being of vulnerable populations. We use data from phase 1 of the Census Bureau's Household Pulse Survey among a nationally representative sample of adults and the 2017-2018 Current Population Survey Food Security Supplement. Using an ordered logistic regression, we assess differences in the incidence and severity of food security across demographic, income, geographic, and employment status cohorts and assess the effects of the first economic stimulus payment. Our results show that marginalized groups faced greater food insecurity and had food-related outcomes worsen over time. Blacks, Hispanics, and individuals living in rural areas became less food secure as the pandemic progressed. However, receipt of a stimulus payment appears to have improved conditions. Rising food prices and persistent high unemployment have the potential to exacerbate food insecurity among marginalized and at-risk groups., (© 2022. W. Montague Cobb-NMA Health Institute.)

Combating undernutrition among children under 5 years is presently an enormous challenge for India. The study aims to determine the prevalence of undernutrition by the Composite Index of Anthropometric Failure (CIAF) and the time-dependent significant determinants of undernutrition among children under 5 years from four recognized social groups, i.e., Scheduled Tribe (ST), Scheduled Caste (SC), Other Backward Class (OBC), and Others, or General group, between 2005-2006 and 2019-2021 in India. It also explains the transition in the probability of CIAF among ST, SC, OBC, and General children belonging to different socio-demographic, economic backgrounds, and geographic regions from 2005-2006 to 2015-2016, 2015-2016 to 2019-2021, and 2005-2006 to 2019-2021 in India. Time-dependent and time-independent logistic regression models are employed to identify the major determinants and predicted probabilities of CIAF, respectively, among four social groups. The predicted probabilities of CIAF among ST, SC, OBC, and General children belonging to various socio-demographic, economic backgrounds, and geographic regions are extracted from logistic regression models and represented graphically. The study outlines a higher prevalence of CIAF among ST children, followed by SC, OBC, and General children throughout the last 15 years. Since 2005-2006, the magnitude of CIAF risk elimination has been comparatively higher among socially marginalized children (ST, SC, OBC) than in General. The investigation also outlines a significant (p < 0.001), and consistent effect of child age, maternal nutritional level, education status, household economic status, and geographic regions on the prevalence of undernutrition among all four social groups in India from 2005-2006 to 2019-2021. The policymakers must focus much on the ST, SC, and OBC sections for eliminating childhood undernutrition. Specifically, more attention is needed for the ST, SC, and OBC children living with non- or less-educated mothers, belonging to poor families, living in central, western, and eastern Indian states for eliminating the childhood CIAF. This might contribute to lowering intergroup inequality (SDG 10.2) in India in terms of the incidence of hunger (SDG 2.2), undernutrition, and child mortality (SDG 3.2)., (© 2023. W. Montague Cobb-NMA Health Institute.)

Background: Dengue is the most prevalent arboviral infection causing an estimated 50-60 million cases of febrile illness globally per year, exacting considerable disease burden. Few instruments exist to assess the patient illness experience, with most based on healthcare provider assessment, lacking standardization in timepoints and symptom assessment. This study aimed to evaluate the content validity of the novel 'Dengue Virus Daily Diary (DENV-DD)', designed to measure symptom intensity and disease burden within outpatient infant to adult populations., Methods: The Dengue Illness Index Report Card was used as a foundation to create the DENV-DD, consisting of patient- and observer-reported outcome (PRO/ObsRO) instruments. In two South American dengue-endemic communities, qualitative combined concept elicitation and cognitive debriefing interviews were conducted among individuals and caregivers of children with symptomatic laboratory-confirmed dengue. Interviews were conducted across two rounds allowing DENV-DD modifications. A small-scale quantitative assessment of the DENV-DD was also conducted with data from an independent Dengue Human Infection Model (DHIM) to generate early evidence of feasibility of DENV-DD completion, instrument performance and insight into the sign/symptom trajectory over the course of illness., Results: Forty-eight participants were interviewed (20 adults, 20 older children/adolescents with their caregivers, 8 caregivers of younger children). A wide spectrum of signs/symptoms lasting 3-15 days were reported with fever, headache, body ache/pain, loss of appetite, and body weakness each reported by > 70% participants. DENV-DD instructions, items and response scales were understood, and items were considered relevant across ages. DHIM data supported feasibility of DENV-DD completion., Conclusions: Findings demonstrate content validity of the DENV-DD (PRO/ObsRO instruments) in dengue-endemic populations. Psychometric and cultural validity studies are ongoing to support use of the DENV-DD in clinical studies., (© 2023. International Society for Quality of Life Research (ISOQOL).)

Background: Caste plays a significant role in individual healthcare access and health outcomes in India. Discrimination against low-caste communities contributes to their poverty and poor health outcomes. The Rashtriya Swasthya Bima Yojana (RSBY), a national health insurance program, was created to improve healthcare access for the poor. This study accounts for caste-based disparities in RSBY enrollment in India by decomposing the contributions of relevant factors., Methods: Using the data from the 2015-2016 round of the National Family Health Survey, we compare RSBY enrollment rates of low-caste and high-caste households. We use a non-linear extension of Oaxaca-Blinder decomposition and estimate two models by pooling coefficients across the comparison groups and all caste groups. Enrollment differentials are decomposed into individual- and household-level characteristics, media access, and state-level fixed effects, allowing 2000 replications and random ordering of variables., Results: The analysis of 480,766 households show that scheduled tribe households have the highest enrollment (18.85%), followed by 14.13% for scheduled caste, 10.67% for other backward caste, and 9.33% for high caste. Household factors, family head's characteristics, media access, and state-level fixed effects account for a 32% to 52% gap in enrollment. More specifically, the enrollment gaps are attributable to differences in wealth status, educational attainment, residence, family size, dependency ratio, media access, and occupational activities of the households., Conclusions: Weaker socio-economic status of low-caste households explains their high RSBY enrollments., (© 2022. W. Montague Cobb-NMA Health Institute.)

Objective: To estimate the prevalence of dementia among American Indian and Alaska Native (AIAN) Medicare beneficiaries and compare the prevalence of dementia in AIANs and other racial and ethnic minority groups-non-Hispanic Blacks (NHBs) and Hispanics-with non-Hispanic Whites (NHWs) Medicare beneficiaries., Methods: We used survey data from Round 5 of the National Health and Aging Trends Study (NHATS, 2015) (N = 7,449), a nationally representative study of Medicare beneficiaries ages 65 years and older. We used logistic regression to estimate the age- and sex-adjusted prevalence of dementia with 95% confidence intervals by race/ethnicity as well as prevalence differences between groups., Results: The majority of participants were between 65 and 74 years old. Approximately half of them were female. NHWs had a prevalence of 5% for dementia, and AIAIs had a prevalence of 9%, four percentage points higher than NHWs (95%CI 1%, 11%). We estimated a similar difference in the prevalence of dementia in AIAN Medicare beneficiaries compared to NHBs., Conclusion: While previous research has reported that AIANs share a similar or lower prevalence of dementia than NHWs, our findings suggest a potentially higher prevalence of dementia among AIAN Medicare beneficiaries. A relatively small number of AIAN resulted in wide confidence intervals for many of our associations. Future research should focus on recruiting a larger sample and on dementia prevalence and unique risk factors within and among AIAN tribes., (© 2022. W. Montague Cobb-NMA Health Institute.)

Empirical evidence has shown that individuals from minority ethnic communities have been at an increased risk of COVID-19 infections and adverse clinical outcomes including hospitalization, intensive care unit admission, and mortality. The COVID-19 vaccine has been heralded as key in ending the global pandemic. However, evidence suggests that although minority ethnic communities have been disproportionately affected by COVID-19, vaccine delivery to these communities has been poor. A barrier to the vaccine uptake has been health information. Health information is an important variable in the health decision-making process. Lack of or wrong health information has serious implications. Health information leads to better understanding of personal health and appropriate utilization of health services and consequently improves an individual's health outcomes. This study sought to explore the health information seeking practices among participants from a Black ethnic minority community in the UK. This study interviewed six Black Africans from the UK. The study explored and highlighted the thoughts, perceptions, and experiences of the participants while health information seeking. This study found challenges in health information access, assumptions about health information and feelings of being dismissed, and an information void. Participants acknowledge that there is a lot that could be done to improve their health information experiences. Targeted health information and measures such as cultural sensitivity and competency could be important in improving health information seeking, not just for Black Africans but all ethnic minorities in the UK., (© 2023. W. Montague Cobb-NMA Health Institute.)

During the last few years, the pharmaceutical industry has adopted digital technologies/digital health technology (DHT) to improve the drug development process and the commercialization of new products. Technological advances are strongly supported by both the US-FDA and the EMA, but the regulatory landscape in the US seems to be more suitable to promote innovation in the digital health sector (e.g. Cures Act). In contrast, the new Medical Device Regulation sets high hurdles for Medical Device software to pass regulatory scrutiny.On both sides of the Atlantic, a digital tool must be fit-for-purpose for the intended use in the clinical drug trial. Irrespective of its status as a Medical Device, at least the basic safety and performance requirements according to local regulations should be met, quality system and surveillance requirements should be fulfilled, and the sponsor must ensure conformity with GxP and the local data privacy and cybersecurity legislations.There is an overlap in technical and clinical validation for drug development tool qualification in both regions to ensure that the digital tools deliver reliable data with tangible clinical benefits. Based on an analysis of the regulatory framework of the FDA and the EMA, this study proposes regulatory strategies for a global pharma company: It would be prudent for drug development companies to a) use approved solutions or b) consider qualification of drug development tools early and in parallel to clinical development. Early engagement with the FDA and the EMA/CA is recommended to define evidentiary standards and corresponding regulatory pathways for different contexts-of-use and to clarify regulator's expectations as to what extent data collected by digital tools are acceptable to support marketing authorization applications (MAA).Hence a harmonization of the partly disparate regulatory requirements in the US and the EU accompanied by further development of the regulatory landscape in the EU, could further foster the use of digital tools in drug clinical development. The outlook for the use of digital tools in clinical trials is hopeful., (© 2023. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Background: Evidence has documented racial wealth inequity as one of the key pathways linking structural racism and racial health inequity. Most prior studies on the wealth-health relationship use net worth as the measure of wealth. This approach provides little evidence on the most effective interventions as various types of assets and debt affect health differently. This paper examines how U.S. young adults' wealth components (e.g., financial assets, nonfinancial assets, secured debt, and unsecured debt) are associated with physical and mental health, and if the associations differ by race/ethnicity., Methods: Data were drawn from the National Longitudinal Survey of Youth 1997. Health outcomes were measured by mental health inventory and self-rated health. Logistic regressions and ordinary least square regressions were used to assess the association between wealth components and physical and mental health., Results: I found that financial assets and secured debt were positively associated with self-rated health and mental health. Unsecured debt was negatively associated with mental health only. The positive associations between financial assets and health outcomes were significantly weaker for non-Hispanic Black respondents. Unsecured debt was protective of self-rated health for non-Hispanic Whites only. For Black young adults, unsecured debt had more severe negative health consequences compared to other racial/ethnic groups., Conclusion: This study provides a nuanced understanding of the complex relationship among race/ethnicity, wealth components, and health. Findings could inform asset building and financial capability policies and programs to effectively reduce racialized poverty and health disparities., (© 2023. W. Montague Cobb-NMA Health Institute.)

Extracellular vesicles (EVs) are membrane-enclosed subcellular structures released by all cell types. EVs have important roles in both cellular homeostasis and intercellular communication. Recent progress in the field revealed substantial heterogeneity of EVs even within the size-based EV categories. Here we addressed the question whether the exportin-1 (XPO1)-mediated nuclear export of RNAs contributed to the EV heterogeneity. Size-based populations were separated from the conditioned media of three cell lines (U937, THP-1 and 5/4E8) in steady-state condition. The effects of activation and leptomycin B treatment (to inhibit the XPO1-mediated nuclear export of RNAs) were also tested in the case of the two monocytic cell lines. Agilent Pico and Small chips were used to characterize RNAs, fragment analysis was performed, and EV-associated miRNAs were tested by Taqman assays. As expected, we found the highest small RNA/total RNA ratio and the lowest rRNA/total RNA proportion in small EVs (~ 50-150 nm). Profiles of the small RNAs within different size-based EV categories significantly differed based on the activation status of the EV releasing cells. Leptomycin B had a differential inhibition on the tested small RNAs in EVs, even within the same EV size category. A similar heterogeneity of the EV miRNA content was observed upon cellular activation and nuclear export inhibition. Here we complement the already existing knowledge on EV heterogeneity by providing evidence that the RNA cargo varies depending on the EV size-based category, the releasing cell type, the functional status of the releasing cells and the exportin-1-mediated nuclear export of RNAs., (© 2023. The Author(s).)

Decision makers addressing the ecological crisis face the challenge of considering complex ecosystems in their socioeconomic decisions. Complementary to ecological sciences, other scientific frameworks, grouped under the umbrella term environmental sciences, offer decision makers the opportunity to pursue sustainable paths. Because the environmental sciences are drawn from different branches of science, environmental ethics must go beyond the legacy of ecology and the life sciences to describe the contribution of scientific knowledge to addressing the ecological crisis. In this regard, I analyze and compare three environmental sciences based on their seminal articles: Conservation Biology, Sustainability Science, and Sustainability Economics. My analysis shows that conservation biology and sustainability economics share strong similarities despite their different disciplinary backgrounds (life versus social sciences). Both seek to contrast a biocentric and an anthropocentric perspective. The goal of sustainability is therefore understood as a balance that must be found between these two perspectives. If the issue of balancing human and non-human interests is still relevant to sustainable science, it is more likely to take place in an ecocentric perspective based on alternative ontological and normative prescriptions. Based on this analysis, I distinguish between 'proscriptive value-based' scientific work that cannot be used for policy advice but is flexible to different value systems, and 'prescriptive value-based' scientific work that can be used for policy advice but is fixed within a given value system. Conflicting recommendations from environmental scientists therefore result from the coexistence of multiple 'prescriptive value-based' scientific approaches based on different conceptions of the relationship between humans and nature., (© 2023. Springer Nature Switzerland AG.)

In the middle of the twentieth century, physiologists interested in human biological rhythms undertook a series of field experiments in natural spaces that they believed could closely approximate conditions of biological timelessness. With the field of rhythms research was still largely on the fringes of the life sciences, natural spaces seemed to offer unique research opportunities beyond what was available to physiologists in laboratory spaces. In particular, subterranean caves and the High Arctic became archetypal 'natural laboratories' for the study of human circadian (daily) rhythms. This paper is explores the field experiments which occurred in these 'timeless spaces'. It considers how scientists understood these natural spaces as suitably 'timeless' for studying circadian rhythms and what their experimental practices can tell us about contemporary physiological notions of biological time, especially its relationship to 'environmentality' (Formosinho et al. in Stud History Philos Sci 91:148-158, 2022). In so doing, this paper adds to a growing literature on the interrelationship of field sites by demonstrating the ways that caves and the Arctic were connected by rhythms scientists. Finally, it will explore how the use of these particular spaces were not just scientific but also political - leveraging growing Cold War anxieties about nuclear fallout and the space race to bring greater prestige and funding to the study of circadian rhythms in its early years., (© 2023. The Author(s).)

Originating in the work of Ernst Haeckel and Wilhelm Preyer, and advanced by a Prussian embryologist, Wilhelm Roux, the idea of struggle for existence between body parts helped to establish a framework, in which population cell dynamics rather than a predefined harmony guides adaptive changes in an organism. Intended to provide a causal-mechanical view of functional adjustments in body parts, this framework was also embraced later by early pioneers of immunology to address the question of vaccine effectiveness and pathogen resistance. As an extension of these early efforts, Elie Metchnikoff established an evolutionary vision of immunity, development, pathology, and senescence, in which phagocyte-driven selection and struggle promote adaptive changes in an organism. Despite its promising start, the idea of somatic evolution lost its appeal at the turn of the twentieth century giving way to a vision, in which an organism operates as a genetically uniform, harmonious entity., (© 2023. Springer Nature Switzerland AG.)

Purpose: African animal trypanosomiasis (AAT) is a disease affecting livestock in sub-Saharan Africa. The use of trypanocidal agents is common practice to control AAT. This study aimed to identify drug-resistant Trypanosoma congolense in Lambwe, Kenya, and assess if molecular test backed with mice tests is reliable in detecting drug sensitivity., Methods: Blood samples were collected from cattle, in Lambwe, subjected to buffy coat extraction and Trypanosoma spp. detected under a microscope. Field and archived isolates were subjected to molecular characterization. Species-specific T. congolense and TcoAde2 genes were amplified using PCR to detect polymorphisms. Phylogenetic analysis were performed. Four T. congolense isolates were evaluated individually in 24 test mice per isolate. Test mice were then grouped (n=6) per treatement with diminazene, homidium, isometamidium, and controls. Mice were subsequently assessed for packed cell volume (PCV) and relapses using microscopy., Results: Of 454 samples, microscopy detected 11 T. congolense spp, eight had TcoAde2 gene, six showed polymorphisms in molecular assay. Phylogenetic analysis grouped isolates into five. Two archived isolates were homidium resistant, one was also diminazene resistant in mice. Two additional isolates were sensitive to all the drugs. Interestingly, one sensitive isolate lacked polymorphisms, while the second lacked TcoAde2, indicating the gene is not involved in drug sensitivity. Decline in PCV was pronounced in relapsed isolates., Conclusion: T. congolense associated with homidium and diminazene resistance exist in Lambwe. The impact can be their spread and AAT increase. Polymorphisms are present in Lambwe strains. TcoAde2 is unlikely involved in drug sensitivity. Molecular combined with mice tests is reliable drug sensitivity test and can be applied to other genes. Decline in PCV in infected-treated host could suggest drug resistance., (© 2022. The Author(s) under exclusive licence to Witold Stefański Institute of Parasitology, Polish Academy of Sciences.)

Background: Central monitoring, which typically includes the use of key risk indicators (KRIs), aims at improving the quality of clinical research by pro-actively identifying and remediating emerging issues in the conduct of a clinical trial that may have an adverse impact on patient safety and/or the reliability of trial results. However, there has to-date been a relative lack of direct quantitative evidence published supporting the claim that central monitoring actually leads to improved quality., Material and Methods: Nine commonly used KRIs were analyzed for evidence of quality improvement using data retrieved from a large central monitoring platform. A total of 212 studies comprising 1676 sites with KRI signals were used in the analysis, representing central monitoring activity from 23 different sponsor organizations. Two quality improvement metrics were assessed for each KRI, one based on a statistical score (p-value) and the other based on a KRI's observed value., Results: Both KRI quality metrics showed improvement in a vast majority of sites (82.9% for statistical score, 81.1% for observed KRI value). Additionally, the statistical score and the observed KRI values improved, respectively by 66.1% and 72.4% on average towards the study average for those sites showing improvement., Conclusion: The results of this analysis provide clear quantitative evidence supporting the hypothesis that use of KRIs in central monitoring is leading to improved quality in clinical trial conduct and associated data across participating sites., (© 2022. The Author(s).)

Background: The COVID-19 pandemic disproportionately affected minorities in population rates of infection, hospitalization, and mortality. However, little is known about the broader racial disparities in fears and perceptions about the pandemic and getting treated., Objective: To examine disparities in perceived risks of COVID-19 and getting medical care., Methods: Using the nationally representative Stanford University School of Medicine Coronavirus Attitudes and Behaviors Survey fielded in May of 2020, we examine racial and ethnic disparities in eight measures on the perceived risks of COVID-19. We use regression analysis to risk adjust perceptions controlling for 10 socioeconomic, demographic, and health variables., Results: Black respondents were 15 percentage points more likely than White respondents to believe the pandemic would not end by Summer 2020 (92% vs 77%, p < .01), and were 19 percentage points more likely than any other race to feel a need to protect their family from COVID-19 (81% vs 62%, p < .01). Latinx respondents were 10 percentage points more fearful than White respondents of catching COVID-19 in public places (55% vs 45%, p < 0.01). Black respondents were 20 percentage points more likely than White respondents to think they would need medical care if infected (71% vs 51%, p < .01), and 18 percentage points more likely to think they would need to be hospitalized (59% vs 41%, p < .01). The proportion of Black respondents believing that the hospital would not have enough capacity to treat them if infected with COVID-19 was 12 percentage points higher than White respondents (41% vs 29%, p < 0.05)., Conclusion: Disparities in the COVID-19-related perceived risks and mistrust in healthcare across racial and ethnic groups existed at the beginning of the COVID-19 pandemic. As we enter into a post-COVID New Normal, new policies must ensure that the causes of this widespread fear and distrust in the healthcare system are understood and reversed., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Post-approval changes (PACs) to the registered information of authorised medicinal products are introduced routinely worldwide to enhance the robustness and efficiency of the manufacturing process, ensure timely supply in case of increased demand, improve quality control techniques, respond to changes in regulatory requirements and upgrade to state-of-the-art facilities. These are critical to prevent supply disruption and continuously improve existing medicines and vaccines. Due to the complexity of current PAC systems across markets, a change can take 3 to 5 years to approval globally (Hoath et al in BioProcess Int, 2016) thus hindering innovation and increasing the risk of shortages. The key messages are as follows: 1. Industry believes that global regulatory convergence of post-approval changes to Marketing Authorisations (MAs) using science- and risk-based approaches will enable a more efficient management of quality and supply improvements and will facilitate patients' access to innovative medicines and vaccines of the highest quality. 2. National Regulatory Authorities (NRAs) should establish national or regional guidelines in line with international standards (regarding a risk-based classification of changes and standardisation of requirements) (Guidelines on procedures and data requirements for changes to approved biotherapeutic products, in WHO Technical Report Series, 2018, Guidelines on procedures and data requirements for changes to approved vaccines, in WHO Technical Report Series, 2015), have clear procedural guidance including timelines and implement reliance pathways to accelerate the approval of changes. This paper briefly outlines the challenges for PACs and provides solutions for a more flexible and aligned global system., (© 2022. The Author(s).)

While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Digital health technology (DHT) is increasingly used to facilitate the conduct of clinical drug trials. The European regulatory environment would benefit from some adjustments to realize the full potential of DHTs. Considering current discussions such as the European Accelerating Clinical Trial Initiative (ACT EU), we propose four concrete adjustments to this regulatory landscape to introduce risk-based qualification approaches for DHTs. In our view, these changes would have the potential to facilitate the use of DHT in clinical research and thus provide access to innovative therapies in Europe., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Drug hypersensitivity reactions (DHRs) manifested as vasculitis are rare. Antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), sulphonamides, diuretics, immunosupressants and anticonvulsants are the most common culprits for drug-induced leukocytoclastic vasculitis (LCV) but there is scarce information about barbiturates. We present a case of 53-year-old female with severe vasculitis after phenobarbital- and NSAIDs-containing medications use. The preliminary diagnosis of drug-induced vasculitis was made based on anamnestic and clinical data. Further examinations confirmed the diagnosis of LCV and excluded other more common causes of vasculitis. The causative significance of used medications was assessed by long-term observation of the patient after the reaction, including the drug challenge series and Naranjo's Adverse Drug Reaction Probability Scale. It was concluded that phenobarbital is the most probable culprit drug. The patient's data were included in the Armenian Registry of Patients with Severe DHRs. Since then, the patient has avoided only barbiturate-containing drugs and no reactions were noted. Thus, the case indicates that even with limited diagnostic capabilities, the final diagnosis of rare drug-induced LCV and even rarer culprit drug can be established by comparing the available data. Awareness about phenobarbital and proper recording of the case are important in the management and prevention of DHRs manifested as vasculitis., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

The use of master protocols allows for innovative approaches to clinical trial designs, potentially enabling new approaches to operations and analytics and creating value for patients and drug developers. Pediatric research has been conducted for many decades, but the use of novel designs such as master protocols in pediatric research is not well understood. This study aims to provide a systematic review on the utilization of master protocols in pediatric drug development. A search was performed in September 2022 using two data sources (PubMed and ClinicalTrials.gov) and included studies conducted in the past10 years. General study information was extracted such as study type, study status, therapeutic area, and clinical trial phase. Study characteristics that are specific to pediatric studies (such as age of the participants and pediatric drug dosing) and important study design elements (such as number of test drug arms and whether randomization and/or concurrent control was used) were also collected. Our results suggest that master protocol studies are being used in pediatrics, with platform and basket trials more common than umbrella trials. Most of this experience is in oncology and early phase studies. There is a rise in the use starting in 2020, largely in oncology and COVID-19 trials. However, adoption of master protocols in pediatric clinical research is still on a small scale and could be substantially expanded. Work is required to further understand the barriers in implementing pediatric master protocols, from setting up infrastructure to interpreting study findings., (© 2024. The Author(s).)

Von-Hippel-Lindau (VHL) is a genetic multisystem disorder characterized by visceral cysts and benign and malignant tumors in various organs. Herein, we present the case of a 23-year-old woman with VHL presenting with multiple gastric neuroendocrine neoplasms (gNENs) type 1 in the context of chronic autoimmune gastritis (CAG). Although gNENs are not acknowledged as a typical entity in VHL patients, in the present case, gNENs were composed of neoplastic cells with clear cytoplasm usually seen in tumors related to VHL disease. We additionally performed a literature review on the presence of neuroendocrine clear cell tumors and report on further cases of clear cell NENs. The present case illustrates that clear-cell transformation in gNENs may be due to the dual genetic background of the patient; the real oncogenic stimulus may be more closely related to CAG than to VHL disease accompanied by an interplay between neoplastic and autoimmune processes. Therefore, close monitoring of patients with clear cell NENs appears to be important before excluding VHL disease, even in the context of phenotypically unrelated diseases., (© 2024. The Author(s).)

Perinatal mood and anxiety disorders (PMADs), perinatal substance use disorders (PSUDs), and intimate partner violence (IPV) are leading causes of pregnancy-related deaths in the United States. Screening and referral for PMADs, PSUDs and IPV is recommended, however, racial disparities are prominent: Black pregnant and postpartum people (PPP) are less likely to be screened and attend treatment compared to White PPP. We conducted qualitative interviews to better understand the experience of Black PPP who used a text/phone-based screening and referral program for PMADs/PSUDs and IPV-Listening to Women and Pregnant and Postpartum People (LTWP). We previously demonstrated that LTWP led to a significant reduction in racial disparities compared to in-person screening and referral, and through the current study, sought to identify facilitators of PMAD/PSUD symptom endorsement and treatment attendance. Semi-structured interviews were conducted with 68 Black PPP who were or had been pregnant within the last 24 months, and who either had or did not have a PMAD or PSUD. Participants were enrolled in LTWP and provided feedback on their experience. Using a grounded theory approach, four themes emerged: usability, comfort, necessity, and recommendations. Ease of use, brevity, convenience, and comfort in discussing mental health and substance use via text were highlighted. Need for a program like LTWP in Black communities was discussed, given the reduction in perceived judgement and access to trusted information and resources for PMADs/PSUDs, which may lessen stigma. These qualitative findings illuminate how technology-based adaptations to behavioral health screening and referral can reduce perceived negative judgment and facilitate identification and referral to treatment, thereby more adequately meeting needs of Black PPP., (© 2024. The Author(s).)