After the COVID-19 pandemic, several companies and organisations are actively developing, scaling up and optimising mRNA manufacturing processes to produce their vaccines and therapeutics. Herein, we evaluated tangential flow filtration (TFF) for high-recovery, and high-purity separation of mRNA from unreacted NTPs in the IVT reaction mixture. For the first time, the membrane fouling behaviour caused by mRNA and separation of nucleoside triphosphates (NTPs) was mathematically modelled. The mRNA membrane fouling model is necessary for optimising mRNA separation processes, designing a suitable strategy for membrane clean-up, estimating the end of production life and reducing the process cost. Recovery greater than 70% mRNA without degradation was obtained by implementing a capacity load of ~19 g/m2, <2.5 psi transmembrane pressure (TMP) and feed flux of 300 LMH. This approach enables the purification of multiple RNA drug substance sequences for the prevention and treatment of a wide range of diseases.

SARS-CoV-2, a positive-strand RNA virus, utilizes both genomic replication and subgenomic mRNA transcription. Whole genome sequencing (WGS) from clinical samples can estimate viral gene expression levels. We conducted WGS on 529 SARS-CoV-2 positive clinical samples from Assam and northeastern India to track viral emergence and assess gene expression patterns. Our results reveal differential expression across structural, non-structural, and accessory genes, with notable upregulation of the M gene, especially in the Omicron variant, followed by E and ORF6. The mean Transcript Per Million (TPM) expression levels of the M gene were significantly higher in Omicron variants (175611±46921), peaking in the KP.1/KP.2 sublineage (220493±34917), compared to the Delta variant (129717±33773). The relative fold change of M gene expression between Delta and Omicron 2024 subvariants showed a 1.6-fold change. Variant-wise gene expression analysis suggests a correlation between gene expression and viral mutation, impacting replication and transmission. As anticipated, the expression levels of genes surge with the increase in the virus mutation. The Chi-square trend for average substitution count vs. average TPM of the M gene was highly significant (72.78, p<0.0001). The M gene’s high expression and low mutation rate make it an ideal target for designing a real-time RT-PCR kit assay. These findings highlight the need for continuous surveillance and understanding of viral gene expression dynamics for effective COVID-19 management. Further studies are necessary to elucidate the significance of these observations in viral pathogenesis and transmission dynamics.

The occult insulinoma was localized using endoscopic ultrasound guidance：A case reportZhongqiu Guo1 Yanrong Chen1 Ronghuo Liu1 Yuhua Chen11Department of Endocrinology and Metabolism, Longgang District People’s Hospital of Shenzhen,The Second Affiliated Hospital of The Chinese University of Hong Kong, Longgang central city, Shenzhen, Guangdong, P.R. China.Corresponding Author:Yanrong Chen, Longgang District People’s Hospital of Shenzhen,The Second Affiliated Hospital of The Chinese University of Hong Kong, Longgang central city, Shenzhen, Guangdong, P.R. China.E-mail: Yanrong [email protected]

The image contrast and probing depth of optical methods applied to in vivo skin could be improved by reducing skin scattering using the optical clearing method. The aim of the present study was to quantify, from line-field confocal optical coherence tomography (LC-OCT) 3D images, the modifications of skin scattering properties in vivo during optical clearing. Nine mixtures of optical clearing agents were used in combination with physical and chemical permeation enhancers on human skin of three healthy volunteers. Scattering coefficient and anisotropy factor of the epidermis and the upper dermis were estimated from the 3D LC-OCT images of skin using an exponential decay model of the in-depth intensity profile. We were able to demonstrate a decrease in epidermal scattering (down to 33%)  related to optical clearing with the best results obtained by a mixture of Polyethylene Glycol, Oleic Acid and Propylene Glycol.

In the context of an aging population, concerns surrounding memory function become increasingly prevalent, particularly as individuals transition into middle age and beyond. This study investigated neurofeedback (NFB) as a potential early therapeutic intervention to address subjective cognitive decline in aging populations. NFB, a biofeedback technique utilizing a brain-computer interface, has demonstrated promise in the treatment of various neurological and psychological conditions. Here, we evaluated the efficacy of individualized NFB training, tailored to each participant’s EEG profile, compared to a standard NFB training protocol aimed at upregulating peak alpha frequency, in enhancing cognitive function among individuals experiencing subjective cognitive decline (SCD). Our NFB protocol incorporated innovative elements, including the implementation of a criterion for learning success to ensure consistent achievement levels by the conclusion of the training sessions. Additionally, we introduced a non-learners group to account for individuals who do not demonstrate the expected proficiency in NFB regulation. Analysis of electroencephalographic (EEG) signals during NFB sessions, as well as before and after training, provides insights into the modulatory effects of NFB on EEG frequencies. Contrary to expectations, our rigorous analysis revealed that the ability of individuals with SCD to modulate EEG signal power and duration at specific frequencies was not exclusive to the intended frequency target. Furthermore, examination of EEG signals recorded using a high-density EEG showed no discernible alteration in signal power between pre- and post-NFB training sessions. Similarly, no significant effects were observed on questionnaire scores when comparing pre- and post-NFB training assessments.

A document by Adrian Figueroa. Click on the document to view its contents.

In forest ecosystems, litter decomposition is essential to sustaining productivity and nutrient cycling. Large herbivores are crucial in determining the processes of nutrient cycling. The temperate woods of Asia are growing more and more damaged and broken up by the widespread increase in human activity, including excessive livestock grazing. However, less research has been done on the impact of wild ungulates and cattle on the decomposition of forest litter. In this study, the effects of adding cattle and sika deer (Cervus nippon) feces to litter decomposition were examined using a litterbag experiment. Northeastern China was the study’s location from July 2022 to October 2023. We found that the addition of deer feces significantly reduced litter decomposition, but the addition of cattle feces greatly increased litter decomposition. The presence of cattle and deer excrement significantly accelerated the release of C after one year of litter decomposition. Compared with the results of the control group (no addition of feces), the addition of cattle and sika deer feces increased C release by 37.45% and 22.69%, respectively. Fecal addition increased the release of N; however, for the three treatment groups, the maximum accumulation of N occurred in the middle of litter decomposition, which may have been due to the initial chemical quality of the leaves and snow melt as well as nutrient limitations at the sites. Compared with the results of the control group, P release in the feces of cattle increased by 4.35%, but P release in the feces of deer decreased by 27.55%. Our findings demonstrate that broad-scale patterns of nitrogen cycling should be closely monitored for the consequences of fecal deposition by an excess of large livestock and ungulates in forests.

Pandemics originating from zoonotic viruses have posed significant threats to human health and agriculture. Recent discoveries have revealed that wild-rice plants also harbor viral pathogens capable of severely impacting rice production, a cornerstone food crop. In this study, we conducted virome analysis on ~1000 wild-rice individual colonies and discovered a novel single-strand positive-sense RNA virus prevalent in these plants. Through comprehensive genomic characterization and comparative sequence analysis, this virus was classified as a new species in the genus Polerovirus, designated Rice less tiller virus (RLTV). Our investigations elucidated that RLTV could be transmitted from wild-rice to cultivated rice via a specific insect vector, the aphid Rhopalosiphum padi, causing less tiller disease symptoms in rice plants. We generated an infectious cDNA clone for RLTV and demonstrated systemic infection of rice cultivars and induction of severe disease symptoms following mechanical inoculation or stable genetic transformation. We further illustrated transmission of RLTV from stable transgenic lines to healthy rice plants by the aphid vector, leading to the development of disease symptoms. Notably, our database searches showed that RLTV and another polerovirus isolated from a wild plant species are widely circulating not only in wild rice but also cultivated rice around the world. Our findings provide strong evidence for a wild plant origin for rice viruses and underscore the imminent threat posed by aphid-transmitted rice Polerovirus to rice cultivar.

Genetically-targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK positive LMs, one with Gorham Stout Disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly-targeted therapies for LMs.

Pseudorandom values are often generated as 64-bit binary words. These random words need to be converted into ranged values without statistical bias. We present an efficient algorithm to generate multiple independent uniformly-random bounded integers from a single uniformly-random binary word, without any bias. In the common case, our method uses one multiplication and no division operations per value produced. In practice, our algorithm can triple the speed of unbiased random shuffling for small to moderately large arrays.

The use of tramadol and other opioids for pain management has been accompanied by a multitude of challenges and concerns worldwide. The use of tramadol saw a decline in Denmark during 2017-2019 accompanied by a slight increase in the use of morphine and oxycodone. Using the Danish National Prescription Registry and utilizing data until and including 2023, we aimed to provide updated data on the utilization patterns of tramadol and other opioids in Denmark. We found a 35% decline in the use of tramadol from 2017-2023 most likely due to media attention, regulatory actions, health campaigns, and targeted education of physicians and patients by the Danish health authorities. This decline was accompanied by an increase in the number of new (+90%) and current users of morphine (+57%) which surpassed those of tramadol, oxycodone, and other opioids in 2023.

Centralization of Internet-based services in few key players has been a topic of study in recent years. One of such services, the Domain Name System (DNS), is one of the pillars of the Internet, which allows users to access websites on the Internet through easy-to-remember domain names rather than complex numeric IP addresses. In this DNS context, the reliance on a small number of large DNS providers can lead to (a) risks of data breaches and disruption of service in the event of failures and (b) concerns about the digital sovereignty of countries regarding DNS hosting. As several essential services are provided through Electronic-Government (E-Gov), it is highly important to be able to measure the digital sovereignty of a nation and the impacts that the lack of such feature can bring to its citizens. This work approaches the issue of DNS concentration on the Internet by presenting a solution to measure DNS hosting centralization and digital sovereignty in different countries, such as Brazil, India, China, Russia, and South Africa. With the data obtained through these measurements, relevant questions are answered, such as which are the top-10 DNS providers, if there is DNS centralization, and how dependent countries are on such providers to manage domains using their country code Top-Level Domains (ccTLD). Future opportunities could investigate the impacts on sovereignty under the lens of other layers of the Open Systems Interconnection (OSI) Network Sovereignty representation model presented in this work.

This study investigates the impact of various surface finishes on the low cycle fatigue (LCF) properties of laser powder bed fusion GRCop-42. The evaluated surfaces include as-built, machined, and chemically polished finishes (1 .0% and 2 .0%). LCF life of polished GRCop-42 was assessed at cryogenic (−195 ◦ C ), ambient, and elevated temperatures (200 ◦ C , 400 ◦ C , 600 ◦ C , and 800 ◦ C ) across three strain amplitudes. Results indicate that surface finish has minimal impact on LCF life. Stress across different strain levels showed minimal effect of surface finish on cyclic hardening/softening. Cryogenic temperatures led to cyclic hardening followed by stabilization, while ambient and 200 ◦ C temperatures showed initial hardening followed by softening. At 400 ◦ C and above, specimens displayed continuous cyclic softening. Fractography showed that surface finish impacts plastic deformation: as-printed and polished surfaces had brittle fractures, while machined specimens were ductile. Specimens at cryogenic and ambient temperatures exhibited brittle fractures, whereas those at elevated temperatures showed plastic deformation and microcracks.

A document by Xueqin Chen. Click on the document to view its contents.

It is common practice in PV system simulation to use the De Soto model, which describes how to use the 1-diode equivalent circuit model for modules. De Soto’s model scales the shunt with irradiance, making it disappear towards zero W/m 2. Also, the commercial software PVsyst uses a parameterization that reduces the shunt effect when the irradiance goes down. However, the Si solar cells that make up a module typically do not have an illumination dependent shunt. We therefore investigate the origin of the intensity dependent apparent shunt in modules. We show that this apparent shunt (derived from the slope of the quasi-linear region from I SC onwards) is a misinterpretation and has little to do with a shunt conductance. Instead, the module I- V curve slope of the quasi-linear region from I SC onwards stems from I SC mismatches between the cells. Such mismatch can occur from small illumination inhomogeneity or cell production variation. Abandoning the practice of using the I- V curve slope to determine the shunt value for equivalent circuit models of modules (and the corresponding shunt scaling in the De Soto model or PVsyst), contributes to physically more meaningful I- V curve parameterizations and possibly also more accurate PV system energy yield prediction.

Title: Oh Groin: What to do with thou?Author: Gautam [email protected] of Missouri School of Medicine, Division of Cardiovascular MedicineThe field (art?) of electrophysiology (EP) has progressed exponentially over the last 3 decades. The delivery of ablative energy through transvenous catheters has revolutionized our ability to treat cardiac arrhythmia. At the time that this text is being put on paper, there are 3 remaining challenges in our field, namely, durable ablation for atrial fibrillation, ablation of non-focal non-ischemic ventricular tachycardia, and last but not the least, management of the pesky inguinal access region. The oral history of electrophysiology trainees is riddled with the litany of post-operative complaints from both patients and nurses, prolonged repeated compressions and late-night vascular imaging. Those of our ilk who have been unfortunate enough to deal with pseudoaneurysms and arteriovenous fistulae can never forget the resultant prolonged patient agony and depression. Thankfully, these have decreased significantly with the advent of ultrasound-guided vascular access.The ideal modality of post-ablation venous hemostasis should have each of the following characteristics: simple, fast, 100% effective, allow rapid patient mobility, and above all, cheap. This combination, however, has been surprisingly elusive. As opposed to the multitude of arterial closure options for our interventional colleagues, the electrophysiology field for long relied upon the old and non-tested method of plain manual compression (MC). As most of us have experienced, MC is unreliable and messy especially in procedures on uninterrupted anticoagulation. The degree and efficiency of MC is almost completely operator dependent. Luckily, the femoral veins are easily compressible and usually quite forgiving in the majority of cases. However, as we started to recognize the advantage of both uninterrupted anticoagulation and deep sedation (preferably general anesthesia) in left atrial ablation procedures, particularly atrial fibrillation (AF), MC became even more unreliable in ensuring venous haemostasis.The Figure-of-Eight (Fo8) suture was a handy replacement for MC. The goal of Fo8 is simple: create a compression zone of subcutaneous fat to allow healing of the venous puncture track. Fo8 seems to work well for all venous access procedures, allowing haemostasis even for large venous sheaths such as cryoablation, left atrial appendage closure systems and leadless pacemaker delivery sheaths. The Fo8 was a particular godsend for electrophysiologists without the luxury of MC by willing trainees or reliable lab staff. We and others also showed that it resulted in shorter lab recovery time after AF ablation and was reliable in presence of systemic anticoagulation. However, there remained a few drawbacks. The ideal duration of suture compression remains unknown and is variable by practice, from 2 to 4 hours, sometimes longer for larger or multiple sheaths. The degree of venous compression is lesser compared with MC, as evidenced by persistent oozing in some patients after Fo8 removal necessitating prolonged compression or administration of subcutaneous Lidocaine with Epinephrine. The requirement for ‘suture cutting’ also meant that nursing staff were uncomfortable removing it. The last and greatest drawback was that Fo8 is irreversible, that is, the suture could not be reapplied when cut, for patients with persistent oozing.The above drawbacks led to the development of the stopcock (SC) technique. This was being used by some vascular surgeons, called the ‘Woggle technique’ for suture closure of hemodialysis access catheterization sites (1). Sam Aznaurov first described this technique on ‘X’ (then Twitter) for femoral venous haemostasis (2). I and others tried it on a few patients and were impressed by the ease and sophistication of the technique. We published the first detailed description of this technique in 2018 showing it to be equivalent to Fo8 in achieving access site haemostasis in AF ablation patients (3). The SC technique, which is essentially using a simple 3-way stopcock to lock a tightened 0-Ethibond or 0-silk suture, has 2 major advantages over Fo8. It is easier to teach and apply, can be removed by nursing personnel and can be reapplied (the stopcock can simply be locked again) if haemostasis is incomplete. The technique is also inexpensive, as the stopcocks can simply be cut from the side arm of the venous sheaths. We also further showed that Heparin reversal with Protamine was not required for haemostasis with SC.As expected, Fo8 and SC have been widely taken up in EP labs around the world. In other centers, MC remains king. Many centers in the US have graduated to specialized venous closure devices which afford faster ambulation but are considerably more expensive. The time is ripe for the SC system to be commercialized and a few of these are being tested now in the EP community.In the present use of JCE, Katapadi and colleagues present a single-center retrospective observational analysis of 102 patient who underwent venous hemostasis with the LockeT vascular compression device (4). They report complete hemostasis in 97.8% of vascular access without major complications, mean time to ambulation 3.93 ± 1.10 hrs. The LockeT device is a commercial apparatus which uses a screw with 90 degrees rotation to lock or unlock the suture, with a flat round endplate (base) to provide uniform compression. Theoretically, the flat base would avoid one prior complaint with SC, namely skin pressure/ ulceration. Truly speaking, operators have long developed methods to avoid skin ulceration, including shorter SC retention times, use of an intervening gauze roll, and gentler compression in non-obese individuals. In this relatively small study, the authors have shown 98% complete hemostasis (likely prolonged compression in 2 patients), a stable mean ambulation time of 4 hours and mean time to discharge 8 hours (which could potentially be shortened with increased operator experience). The study has the usual drawbacks of retrospective observational studies, as acknowledged by the authors, as well as the lack of any comparative analysis to SC technique. We also do not have information about the financial implications of adding to the technical costs of EP studies or appendage closure. In the current reimbursement climate, especially with steadily rising healthcare costs, this would be important information.The LockeT device and other similar commercial devices that duplicate SC would be potentially useful if a) they add negligible incremental cost to the EP procedure and b) if they lead to further shortening of bedrest and time to discharge which would offset the device expenditure. One might argue against their use for simple EP procedures without systemic anticoagulation where MC has historically been simple and effective. These methods would be expected to hold an advantage over invasive venous closure devices of not requiring multiple devices (one for each access site), thus being less expensive, especially if the patient could be discharged within 2 hours as practiced by some operators with the venous closure devices. We need more larger volume studies on these issues to convince the greater the EP community.We could thus be finally reaching closer to a solution of the waxing problem: what to do with the groin?References:Simons ME, Rajan DK, Clark TW. The Woggle technique for suture closure of hemodialysis access catheterization sites. Journal of vascular and interventional radiology: JVIR 2003;14:485-8.https://x.com/epTicTocDoc/status/917473407524134914Payne J, Aznaurov S, Gautam S. Three-way stopcock suture technique for hemostasis after ablation for atrial fibrillation. J Cardiovasc Electrophysiol. 2018;29(12):1724-1727.(Attach reference for the LockeT manuscript )

To the Editor,

Spotlight Commentary: Examining Safety Profiles of Topical Ocular MedicationLorena Karla Šklebar1,2, Robert Likić2,3, Sonja Jandroković1,21 Department of ophthalmology, University Hospital Centre Zagreb, Zagreb, Croatia2 University of Zagreb, School of medicine, Zagreb, Croatia3 Division for clinical pharmacology and therapeutics, Department of internal medicine, University Hospital Centre Zagreb, Zagreb, CroatiaKeywords: eye drops; systemic side effect; ocular side effect; safety profile; topical ocular medicationWord count: 1085Table count: 1Figure count: 0Topical medications are frequently used in treating a wide range of ocular diseases due to their efficiency in delivery directly to the afflicted area. However, localized administration cannot prevent side effects, both local and systemic, which can sometimes be overlooked or underestimated. The aim of this spotlight commentary is to provide a review of safety profiles of topical ocular medications, analysing their effect on the ocular structures as well as their systemic and environmental impacts. 1Although topical ocular medications are designed for localized treatment and are administered directly on the surface of the eye, there is a significant systemic absorption of these drugs through several pathways. The first of two major pathways is from the lacrimal sac through the nasolacrimal duct into the nasopharynx where drugs can be systemically absorbed through the nasal mucosa. This pathway can easily be circumvented by manually providing pressure to the medial canthus or by closing the eyes for 5 minutes after the instillation of each drop, which will cause compression on the nasolacrimal duct. The other major pathway for systemic absorption is through the conjunctiva and conjunctival blood vessels. Minor pathways of systemic drug delivery are through the pharynx, gastrointestinal tract, skin of the cheeks and the eyelids, aqueous humour, and inner ocular tissues. Special care must be taken when treating the paediatric patients who have a much higher risk of developing systemic side effects, due to inadequate dosage and increased systemic permeability of the drugs. 2Localised adverse effects of topical ocular medications commonly arise due to preservatives, which are used in eye drops and ointments in order to prolong their shelf life and guard against microbiological contamination. Benzalkonium chloride (BAC) is the most used preservative in ophthalmic medications. Clinical studies have extensively examined the toxic effects of BAC, revealing that its prolonged use causes time- and dose-dependent cytotoxicity on the ocular surface, leading to tear film instability and the development of ocular surface disease, dry eye, and Meibomian gland dysfunction 3,4. Therefore, the European Medicine Agency recommends avoiding preservatives in patients who have pre-existing ocular surface disease or who develop dry eye or ocular irritation over time. 3Among eye drops, the most commonly discussed side effects, both local (as stated in Table 1) and systemic, in certain groups of topical ocular medications, pertain to antiglaucoma eyedrops, such as β receptor blockers, α receptor agonists and pilocarpine. Due to their chronic usage, physicians must take special care in choosing the right therapy for their patients as well as monitor for potential adverse events. β receptor blockers have a major limitation in their usage due to their frequent systemic side effects, although they are a potent antiglaucoma medications. Targeting β1-receptor causes reduced cardiac contractility and heart rate, bradycardia, and a blood pressure decrease and β2-receptor targeting leads to exacerbated asthma and chronic obstructive pulmonary disease symptoms. Additionally, central nervous system symptoms such as headaches, depression, and confusion may occur. Betaxolol is a selective β1-receptor antagonist which therefore causes fewer side effects to the respiratory system. 5 When α2 adrenergic agonists are applied, systemic side effects such as dry mouth, dizziness, fatigue, and drowsiness may occur, particularly in patients predisposed to bradycardia.6Excessive use of pilocarpine can also have numerous adverse effects due to its parasympathomimetic action which includes excessive sweating, drooling, bronchospasm, vomiting, diarrhea, stomach-ache, bradycardia, a drop in blood pressure, hallucinations and depression.Special caution also must be taken when prescribing topical ocular or systemic steroid medication. Because of their potential to change the microstructure of the trabecular meshwork, they can induce a rise in intraocular pressure by decreasing aqueous humour outflow and potentially causing the development of steroid induced glaucoma. Prolonged use of topical corticosteroids can also induce cataract formation and increase susceptibility to infection. If used in eyes with epithelial defects, they can inhibit growth factors and delay wound healing.Another group of eye drops which can have substantial systemic effects are mydriatics, such as phenylephrine and atropine. Phenylephrine, a selective α1-receptor, is applied in the form of eye drops for dilating the pupils during ophthalmological examinations. Due to its sympathomimetic effect it can cause major cardiovascular side effects, especially when administered in patients with pre-existing hypertension conditions.7 Atropine is a muscarinic receptor antagonist often used in ophthalmology in the form of eye drops for its mydriatic and cycloplegic effect. When systemically absorbed, it can potentially cause side effects like mouth and eye dryness, flushed skin and face, fever, tachycardia, delirium or restlessness, urinary retention, and constipation. If used in higher doses or over a longer period, in severe cases, central anticholinergic syndrome may occur, which is characterized by confusion, agitation, and hallucinations.8 Mydriatics also affect inner ocular structures. Phenylephrine is linked with a decrease in choroidal thickness, while atropine eye drops are associated with an increase in choroidal thickness. This necessitates careful monitoring of patients on long-term topical therapies for any alterations in choroidal structure because of their potential effect on visual function.9Other eyedrops, such as antiallergics, can also be sometimes used in treating eye conditions. Topical H1-receptor blockers and mast cell stabilizers in the form of antiallergic eye drops infrequently cause systemic side effects following ocular use. When they do occur, these side effects are usually mild, presenting as dry mouth, nausea, headache, or drowsiness.7The environmental effect is another part of pharmaceutical safety profiles which cannot be disregarded. Inappropriate disposal of drugs, including eye medications, poses a significant risk to public health and environmental sustainability by contaminating water supplies and disrupting ecosystems.10 Other than the drug itself, its packaging can also cause substantial waste, as is the case with monodose eye drops. These eyedrops are stored in small single-use containers, in order to prevent microbial growth which can occur in standard eye drop bottles after opening. However, their disposal creates a lot of waste. 11 Pharmaceutical companies should provide education and raise awareness among healthcare providers and patients about how to properly manage pharmaceutical waste.In conclusion, although topical ocular medication is the foundation of ophthalmic treatment, before prescribing physicians must be aware of their safety profiles. Although they are generally considered safe, their potential adverse effects on ocular and systemic health highlights challenges in the management of ocular diseases. Healthcare practitioners should choose preservative-free formulations where possible, monitor for both local and systemic side effects, and act responsibly while taking into consideration the environmental implications of pharmaceutical use. These safety concerns should be further investigated in future studies with the goal of improving therapeutic outcomes for patients while minimizing risks.