Redefining and Validating Digital Biomarkers as Fluid, Dynamic Multi-Dimensional Digital Signal Patterns

“Digital biomarker” is a term broadly and indiscriminately applied and often limited in its conceptualization to mimic well-established biomarkers as defined and approved by regulatory agencies such as the United States Food and Drug Administration (FDA). There is a practical urgency to revisit the definition of a digital biomarker and expand it beyond current methods of identification and validation. Restricting the promise of digital technologies within the realm of currently defined biomarkers creates a missed opportunity. A whole new field of prognostic and early diagnostic digital biomarkers driven by data science and artificial intelligence can break the current cycle of high healthcare costs and low health quality that is being driven by today's chronic disease detection and treatment approaches. This new class of digital biomarkers will be dynamic and require developing new FDA approval pathways and next-generation gold standards.

Identification and Determination of 1,3-Thiazinane-4-carboxylic Acid in Human Urine—Chromatographic Studies

It is well established that homocysteine (Hcy) and its thiolactone (HTL) are reactive towards aldehydes in an aqueous environment, forming substituted thiazinane carboxylic acids. This report provides evidence that Hcy/HTL and formaldehyde (FA) adduct, namely 1,3-thiazinane-4-carboxylic acid (TCA) is formed in vivo in humans. In order to provide definitive proof, a gas chromatography–mass spectrometry (GC–MS) based method was elaborated to identify and quantify TCA in human urine. The GC–MS assay involves chemical derivatization with isobutyl chloroformate (IBCF) in the presence of pyridine as a catalyst, followed by an ethyl acetate extraction of the obtained isobutyl derivative of TCA (TCA-IBCF). The validity of the method has been demonstrated based upon United States Food and Drug Administration recommendations. The assay linearity was observed within a 1–50 µmol L−1 range for TCA in urine, while the lowest concentration on the calibration curve was recognized as the limit of quantification (LOQ). Importantly, the method was successfully applied to urine samples delivered by apparently healthy volunteers (n = 15). The GC–MS assay may provide a new analytical tool for routine clinical analysis of the role of TCA in living systems in the near future.

Ponesimod oral therapy for the treatment of relapsing forms of multiple sclerosis in adults and its precautions in cardiovascular disease patients

The ponesimod oral therapy was approved in March 2021 by the United States Food and Drug Administration for relapsing forms multiple sclerosis (MS). Ponesimod is a sphingosine 1-phosphate (S1P) receptor 1 modulator that acts selectively as an anti- inflammatory agent and provides a suitable microenvironment for the function of the other neuroprotective agents. Ponesimod is contraindicated in patients who in the last 6 months, have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure. Also contraindicated in patients who have the presence of Mobitz type II second-degree, third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker. This article briefs the information about dosage, precautions and warnings required in cardiovascular disease patients before initiation of ponesimod oral therapy.

Treatment with clobetasol propionate 0.025% topical therapy in various dermatoses

Owing to their anti-inflammatory and vasoconstrictive properties. Topical corticosteroids (TCs) provide benefits in various dermatological conditions, including atopic eczema, psoriasis, chronic hand eczema, and localized vitiligo. Clobetasol propionate (CP) is the most common topical agent possessing anti-inflammatory, antimitotic, antipruritic, and immunosuppressive properties that are employed in the management of plaque psoriasis. CP 0.025% cream was approved by the United States food and drug administration for the treatment of moderate-to-severe psoriasis in adult patients. The formulation is free from known contact allergens, such as propylene glycol, short-chain alcohols, and sorbitol-based emulsifiers, and has demonstrated hypoallergenic effects. High penetration of active ingredients and a lower degree of systemic absorption make CP 0.025% an effective and safe agent. This case series discusses the clinical experience of using CP 0.025% cream in various dermatologic conditions, focusing on its efficacy and safety.

A comparison of mutagenic potential of Aji-no-Moto with a traditional chemical mutagen on microsporogenesis in barley (Hordeum vulagre L.)

Aji-no-Moto or Mono Sodium Glutamate (MSG) is a flavour enhancer being used extensively in South East Asian cuisine. The Federation of American Societies for Experimental Biology for the United States Food and Drug Administration (FDA) has concluded that MSG is safe when "eaten at customary levels" but there is still great confusion regarding its toxicity at higher concentrations. Therefore, it was decided to assess the mutagenic efficacy of MSG on a plant system and present the findings as a model for probably similar effects in the animal model. For this, a traditionally popular genus for genetic studies, Hordeum vulgare L. or winter barley, was used as the model system. The studies of microsporogenesis were done in order to see the long term effect. The sets were compared with experimental sets of plants grown from seeds treated with a traditional chemical mutagen Ethyl Methane Sulphonate (EMS). The study revealed that MSG does not induce much genotoxic effects at lower doses and the chromosomal damages induced were very few. However, at higher doses, it almost equals the effects of EMS in terms of heritable genetic damage. The work is significant as MSG continues to be one of the most popular flavouring agents and does not face any challenge to its biosafe status. However, the clastogenic and chromotoxic effects of higher doses of MSG as observed in the study are in total contradiction to the popular belief.

Healthy Food Environments in Food Pantries: Lessons Learned from a Sodium Reduction Intervention

In the United States, food pantries increasingly serve as regular food sources for low income households experiencing high rates of chronic disease, including hypertension. Sodium consumption is a modifiable risk factor for hypertension, so pantry customers would benefit from access to low-sodium foods. Pantry customers often experience difficulty acquiring healthy foods, however; little is known about pantry foods’ sodium content specifically. This study assesses the sodium content of pantry foods and lessons learned from an adaptable intervention to support pantries in adopting policies and environmental changes to make healthy, lower-sodium foods appealing and accessible. We conducted sodium assessments of food at 13 food pantries, tracked implementation of intervention strategies, and interviewed 10 pantry directors. More than half of food items in 11 categories met sodium standards for foods to be chosen “often”. Pantry directors reported valuing the intervention approach and implemented six of nine behavioral economics strategies, especially those targeting the visibility and convenience of foods, along with layout changes and expanded customer choice. One pantry adopted an agency-specific nutrition policy and 12 adopted a coalition-level policy. Results can inform intervention efforts to make available healthy options appealing and easy to select while also improving the customer experience in food pantries.

An audit of US FDA warning letters issued to sponsors, institutional review boards and investigators over a six-year period

The present audit was carried out with the objective of evaluating warning letters (WLs) issued to trial sponsors, clinical investigators and institutional review boards (IRBs) by the United States Food and Drug Administration during a six-year period and compare it with two similar earlier audits. WLs were reviewed and classified as per stakeholders and further categorised as per predefined violation themes. The chi-square test was performed for trend analysis of WLs. A total of 62 WLs were issued to the three stakeholders. The maximum number of WLs were issued to the clinical investigators (36/62, 58.06%), followed by sponsors (19/62, 30.64%), and least to the IRBs (7/62, 11.29%). Among sponsors, lack of standard operating procedures for the monitoring, receipt, evaluation and reporting of post-marketing adverse drug events was the most common violation theme (8/19, 42.1%). Among clinical investigators, deviation from investigational plan was the most common violation theme (31/36, 86.11%.). For IRBs, inadequate documentation was the most common violation theme (6/7, 85.71%). We saw an overall reduction in the number of WLs issued to the stakeholders. Thus, we identified multiple areas on which each stakeholder should work for improvement.

A narrative review on current duodenoscope reprocessing techniques and novel developments

Duodenoscopy-associated infections occur worldwide despite strict adherence to reprocessing standards. The exact scope of the problem remains unknown because a standardized sampling protocol and uniform sampling techniques are lacking. The currently available multi-society protocol for microbial culturing by the Centers for Disease Control and Prevention, the United States Food and Drug Administration (FDA) and the American Society for Microbiology, published in 2018 is too laborious for broad clinical implementation. A more practical sampling protocol would result in increased accessibility and widespread implementation. This will aid to reduce the prevalence of duodenoscope contamination. To reduce the risk of duodenoscopy-associated pathogen transmission the FDA advised four supplemental reprocessing measures. These measures include double high-level disinfection, microbiological culturing and quarantine, ethylene oxide gas sterilization and liquid chemical sterilization. When the supplemental measures were advised in 2015 data evaluating their efficacy were sparse. Over the past five years data regarding the supplemental measures have become available that place the efficacy of the supplemental measures into context. As expected the advised supplemental measures have resulted in increased costs and reprocessing time. Unfortunately, it has also become clear that the efficacy of the supplemental measures falls short and that duodenoscope contamination remains a problem. There is a lot of research into new reprocessing methods and technical applications trying to solve the problem of duodenoscope contamination. Several promising developments such as single-use duodenoscopes, electrolyzed acidic water, and vaporized hydrogen peroxide plasma are already applied in a clinical setting.

Multifunctional Gold Nanoparticles for Improved Diagnostic and Therapeutic Applications: A Review

The medical properties of metals have been explored for centuries in traditional medicine for the treatment of infections and diseases and still practiced to date. Platinum-based drugs are the first class of metal-based drugs to be clinically used as anticancer agents following the approval of cisplatin by the United States Food and Drug Administration (FDA) over 40 years ago. Since then, more metals with health benefits have been approved for clinical trials. Interestingly, when these metals are reduced to metallic nanoparticles, they displayed unique and novel properties that were superior to their bulk counterparts. Gold nanoparticles (AuNPs) are among the FDA-approved metallic nanoparticles and have shown great promise in a variety of roles in medicine. They were used as drug delivery, photothermal (PT), contrast, therapeutic, radiosensitizing, and gene transfection agents. Their biomedical applications are reviewed herein, covering their potential use in disease diagnosis and therapy. Some of the AuNP-based systems that are approved for clinical trials are also discussed, as well as the potential health threats of AuNPs and some strategies that can be used to improve their biocompatibility. The reviewed studies offer proof of principle that AuNP-based systems could potentially be used alone or in combination with the conventional systems to improve their efficacy.

Effects of feeding lubabegron on gas emissions, growth performance, and carcass characteristics of beef cattle housed in small-pen environmentally monitored enclosures during the last 3 months of the finishing period

The development of technologies that promote environmental stewardship while maintaining or improving the efficiency of food animal production is essential to the sustainability of producing a food supply to meet the demands of a growing population. As such, Elanco (Greenfield, IN) pursued an environmental indication for a selective β-modulator (lubabegron; LUB). LUB was recently approved by the United States Food and Drug Administration (FDA) to be fed to feedlot cattle during the last 14 to 91 d of the feeding period for reductions in gas emissions/kg of unshrunk final BW and HCW. A 4 × 2 factorial arrangement of treatments was used with the factors of dose (0.0, 1.38, 5.5 or 22.0 mg·kg-1 DM basis) and sex (steers or heifers). Three 91-d cycles were conducted (112 cattle/cycle) with each dose × sex combination being represented by a single cattle pen enclosure (CPE; 14 cattle/CPE) resulting in a total of 168 steers and 168 heifers (n = 6 replicates/dose). There were no interactions observed between dose and sex for any variable measured in the study (P ≥ 0.063). Five gases were evaluated for all pens based on CPE concentrations relative to ambient air: NH3, CH4, N2O, H2S, and CO2. Cumulative NH3 gas emissions were reduced by feeding cattle 5.5 and 22.0 mg·kg-1 LUB (P ≤ 0.023) and tended (P = 0.076) to be lower for the cattle fed 1.38 mg·kg-1 LUB compared to the negative controls (CON). The cumulative NH3 gas emission reductions of 960 to 1032 g, coupled with HCW increases (P ≤ 0.019) of 15 kg to 16 kg for all LUB doses vs. CON, led to reductions in NH3 gas emissions/kg HCW for all 3 LUB treatments (P ≤ 0.004). Similar to HCW, reductions in NH3 gas emissions/kg of unshrunk final BW were observed for all LUB doses (P ≤ 0.009) and were attributable to both decreases in NH3 gas emissions and numerical increases in BW. Dose had no effect on cumulative emissions or emissions standardized by BW or HCW for the other 4 gases (P ≥ 0.268). Lubabegron is a novel tool to reduce emissions of NH3 gas per kg of unshrunk live BW and hot carcass weight.