Hypertrophic scars and keloids are two different manifestations of excessive dermal fibrosis and are caused by an alteration in the normal wound-healing process. Treatment with radiofrequency (RF)-based therapies has proven to be useful in reducing hypertrophic scars. In this study, the effect of one of these radiofrequency therapies, Capacitive Resistive Electrical Transfer Therapy (CRET) on biomarkers of skin fibrosis was investigated. For this, in cultures of human myofibroblasts treated with CRET therapy or sham-treated, proliferation (XTT Assay), apoptosis (TUNEL Assay), and cell migration (Wound Closure Assay) were analyzed. Furthermore, in these cultures the expression and/or localization of extracellular matrix proteins such as α-SMA, Col I, Col III (immunofluorescence), metalloproteinases MMP1 and MMP9, MAP kinase ERK1/2, and the transcription factor NFκB were also investigated (immunoblot). The results have revealed that CRET decreases the expression of extracellular matrix proteins, modifies the expression of the metalloproteinase MMP9, and reduces the activation of NFκB with respect to controls, suggesting that this therapy could be useful for the treatment of fibrotic pathologies. The wound-healing process comprises a complex succession of events that is organized into three consecutive phases: inflammation phase, proliferation phase, and remodeling phase ,2,3.During the proliferation phase, fibroblasts are activated and acquire the capacity to express alpha smooth muscle actin (α-SMA), differentiating into myofibroblasts. These differentiated fibroblasts allow the wound to contract and close. Once the wound is closed, under normal physiological conditions, the myofibroblasts enter into apoptosis and are replaced by fibroblasts. In wound healing, various biochemical/cellular signals, such as Wnt and Notch signaling, AKT/mTOR, transforming growth factor beta (TGF-β), mitogen-activated protein kinase (MAPK), or binding protein to the nuclear factor kappa enhancer (NF-ĸB) intervene in a tightly coordinated cascade to repair the damage . When thBoth types of fibrosis are differentiated by their etiology, symptoms, causes, and location, among others . The maiAt the tissue level, hypertrophic scars and keloids present hyperplasia, swelling, and redness, with aberrant growth being a specific characteristic of keloids, which usually invades beyond the margins of the original wound, unlike hypertrophic scars, which remain circumscribed to the original margins of the lesion . In bothCurrently, hypertrophic scars and keloids represent a great challenge for dermatologists and surgeons due to the lack of effective specific treatments. Corticosteroid administration, surgical excision, silicone gels, local radiotherapy, hormonal therapy, or laser have been the conventional treatments, but often do not achieve complete cure, especially in the case of keloids due to high rates of recurrence . There iHowever, in relation to fibrotic processes, besides cases of favorable effects of CRET observed in the clinic, the published experimental evidence is null and the biological bases of these effects are unknown. Given the absence of effective strategies for the treatment of these fibroses, it is of great interest to promote new therapeutic alternatives to the existing ones for their treatment. On this basis, the objective of this study was to investigate, in human cell models under normothermic conditions, the potential capacity of CRET to regenerate already formed hypertrophic or keloid scars and/or to prevent their formation in the initial phases of healing prior to their consolidation, in patients with a clinical predisposition to generate them.p = 0.011; Student’s t-test) over the control in α-SMA expression, in cultures treated with CRET for 48 h  A. On theThe results of the wound closure assay, performed at 24 and 48 h of CRET treatment, did not show statistically significant changes in the migration rate of electrically treated myofibroblasts compared to controls A,B.At 24 h, the CRET treatment increased the expression of MMP9 by 63% compared to controls and the differences were statistically significant. On the contrary, 48 h treatments did not modify the expression of this protein compared to the control. Neither did the expression of MMP1 show changes with respect to the control, at any of the moments analyzed A,B.The results of the immunoblot showed statistically significant decreases in the expression of ERK, compared to the control at 12 h, while at 24 h there were no changes in its expression. The active form of the protein (p-ERK) did not change its expression at 12 or 24 h compared to the control. On the other hand, the NFκB factor did not change its expression compared to controls, although its activation did. Thus, at both 12 and 24 h, the expression of p-NFκB decreased significantly with respect to the controls A,B.Cutaneous fibrosis is a skin pathology that involves pain, itching, lack of functionality and psychological problems for patients who suffer from it. The main treatments for hypertrophic scars or keloids are not considered fully satisfactory since they are not very effective, can cause pain, or have adverse side effects. Laser is one of the first line treatments, however, it is expensive and requires repeated sessions. Other alternatives, such as intralesional treatments with corticosteroids, bleomycin, or 5-fluorouracil are painful and require multiple infiltrations. Local radiotherapy is a good treatment alternative but it needs to be applied in specialized centers and in several sessions that produce the patient’s radiation. In any case, the approach needs to be multidirectional, which is why the combination of treatments is generally chosen. For this reason, these fibroses represent a challenge for medicine, and it is of great interest to find alternative therapies for their treatment.Currently, progress is being made in understanding the molecular mechanism of these fibroses, which is generating new therapeutic strategies for the treatment of this pathology. Since the pathological characteristics of cutaneous fibrosis are characterized by an excess of extracellular matrix produced by fibroblasts at the tissue level, the action mechanisms of these new therapies aim to achieve one or more of the following objectives: reduction or inhibition of the proliferation of fibroblasts and myofibroblasts, reduction or inhibition of the production of extracellular matrix , increased apoptosis or necrosis of fibroblasts, decreased expression of TGF-β1 (a key regulator of collagen synthesis), decreased expression of the GFR β1/Smad2/3 signaling pathway, changes in the activity of metalloproteinases, decreased or modulated inflammation, and/or increased production of IFN-α  . In thisDue to the relevance of extracellular matrix (ECM) production in the generation of the fibrotic process, we first investigated whether CRET could reduce the synthesis of matrix components or degrade the existing one. In fact, numerous investigations aimed at finding new pharmacological strategies focus on the reduction of collagen and extracellular matrix deposits such as hypertensives including the angiotensin-converting enzyme ACE-inhibitor , calcine2+ ions that interact with multiple components of the extracellular matrix [Indeed, MMPs also seem to play a critical role in wound healing and scar formation, and their inhibition could be a strategy to treat fibrosis. MMPs are endopeptidases with a catalytic domain of Znr matrix . It has r matrix  and MMP9r matrix  activityr matrix , while sr matrix , which wr matrix . In thisAnother of the objectives pursued by numerous emerging therapies for the treatment of fibrosis is the reduction of the proliferation of fibroblasts, responsible for most of the collagen and ECM deposition that occurs in wound healing, both normal and pathological. These actions are promoted by fibrogenic growth factors, such as TGF-β1, PDGF, fibroblast growth factor β (FGF-β), and insulin-like growth factor I (IGF-I). Fibroblasts isolated from keloid tissue have elevated expressions of TGF-β1, periostin, PAI-2, and inhibin beta A compared to normal healthy tissues . For thiOn the other hand, fibroblasts derived from hypertrophic scars overexpress transglutaminase that could inhibit their apoptosis, thus enhancing the fibrotic phenotype by increasing the number of cells capable of generating extracellular matrix . For thiThe skin is considered a neuroendocrine organ that has immunological, endocrine, and neurological functions to maintain the body’s homeostasis. For this reason, its resident cells, and the circulating cells of the immune system express neuropeptides and neurotransmitters, and produce endocrine factors and cytokines in response to stress . This orSkin cells activate the CRH signaling pathway under physiological, pathological conditions, or after stimulation with microbial antigens or UVB spectrum radiation. Through the CRH pathway, these cells regulate cell proliferation and differentiation, as well as activities of the immune or endocrine system . CRH canNFkB is also modulated by the proopiomelanocortin POMC signaling pathway. In skin cells such as keratinocytes, NFkB is indirectly inhibited by α-melanocyte-stimulating hormones (α-MSH) , while i2 atmosphere at a temperature of 37 °C inside CO2 incubators . The cells were subcultured once a week.Human dermal fibroblasts (HF) isolated from neonatal foreskin  were seeded in medium composed of high-glucose D-MEM  supplemented with 10% inactivated fetal bovine serum , 1% glutamine, and 1% penicillin-streptomycin (Gibco) and maintained in a 5% CO2 density on the bottom of 60 mm Petri dishes , except for immunofluorescence assays, in which the cells were seeded on glass coverslips placed on the bottom of the plates. One day after seeding, cells were incubated with complete DMEM supplemented with 2 ng/mL of TGF-β1  for an additional 12 or 13 days depending on the experiment, renewing this conditioned culture medium every 4 days , while the remaining plates were sham-exposed simultaneously inside an identical, separate CO2 incubator. The intermittent stimulation pattern consisted of 5-min pulses of 448 kHz, sine wave current delivered at subthermal densities of 100 µA/mm2, separated by 4-h interpulse lapses, and administered for a total of 12, 24, or 48 h. Such exposure parameters have been shown to stimulate the proliferation and early differentiation of human, adipose-derived stem cells [The procedure for RF exposure has been described in detail elsewhere ,49. Brieem cells ,21,50 an2 atmosphere, as recommended by the manufacturer. The cell culture confluence reached 60–70%. The metabolically active cells reduced XTT into colored formazan compounds that were quantified with a microplate reader  at a 492 nm wavelength. At least 3 experimental replicates per cell type were conducted.Cell proliferation was determined with XTT assay . After 48 h of CRET or sham treatment, the cells were incubated for 3 h with the tetrazolium salt XTT in a 37 °C and 6.5% COTM Fluorometric TUNEL System  was used. Cells treated for 48 h with CRET or sham exposure were fixed with 4% paraformaldehyde  and then proceeded according to the manufacturer’s instructions. The fluorescence of apoptotic cells was detected with fluorescence microscopy. Nuclei were counterstained with ProLongTM Gold antifade reagent whit DAPI . TUNEL+ cells were assessed using an inverted fluorescence microscope  coupled to a digital camera (Nikon DS-Ri2). Photomicrographs were taken and the images were computer-analyzed with NIS-Elements Br image software . TUNEL+ cell identification and quantification were based on fixed thresholds of fluorescence (MHC mode) determined and automated for all images at the beginning of the analysis. The values obtained were normalized with respect to the number of cells per field. Three experimental replicates were performed.Apoptosis in cultures was assessed with the TUNEL assay. For this, the DeadEndIn each experimental replicate of the wound closure assay, HF were seeded on 8 plates and incubated at 37 °C. After 10 days of incubation with TGF-β1, a wound was scratched on the confluent monolayer of each of the plates, using a glass pipette tip. Dishes were washed with PBS (Gibco) to eliminate debris, and the cultures were maintained in high-glucose D-MEM medium supplemented with 10% inactivated fetal bovine serum (Gibco), 1% glutamine, 1% penicillin-streptomycin (Gibco), and 2 ng/mL of TGF-β1. Next, 4 plates were exposed to CRET for 24 or 48 h, while the remaining plates were sham-exposed for the same intervals. At 0, 24 and 48 h after scratching, 6 micrographs were taken of 3 equidistant points in the wounds, using a digital camera (Nikon DS-Ri2) coupled to an inverted microscope (Nikon Eclipse Ts2R). The wound closure rate was determined with dual analyses of the obtained images, using standard Photoshop software . Five experimental replicates were performed.TM 568 goat anti-mouse IgG  or Alexa FluorTM 488 goat anti-rabbit IgG  for 1 h at room temperature, and the cell nuclei were counterstained with ProLongTM Gold antifade reagent whit DAPI (Invitrogen). Photomicrographs were taken using an inverted fluorescence microscope (Nikon Eclipse Ts2R) coupled to a digital camera (Nikon DS-Ri2) and the images were computer-analyzed with NIS-Elements Br image software (Nikon). Fluorescence intensity measurement per MHC channel was used to assess the fluorescence of samples labeled with Alexa Green or Alexa Red. Prior to analysis, MHC mode fluorescence thresholds were set and applied to all images. The values obtained were normalized with respect to the number of cells per field. At least three replicates of each protein were performed.At the end of 48 h RF- or sham-exposure, the samples were fixed with 4% paraformaldehyde  and incubated overnight at 4 °C with mouse monoclonal anti- α-smooth muscle actin antibody α-SMA , rabbit polyclonal anti-collagen type I antibody  and rabbit polyclonal anti-collagen type III alpha 1 antibody . Afterwards, the samples were fluorescence-stained with Alexa FluorCultures were RF- or sham-exposed for 12 or 24 h. At the end of electric treatment, the cells were lysed for protein extraction. The immunoblot procedure has been described in detail elsewhere ,48. Briet-test was applied using GraphPad Prism 6.01 software . Differences p < 0.05 were considered significant statistically.All procedures and analyses were conducted in blind conditions for treatment. At least three independent replicates were conducted per experiment or exposure interval. Results were expressed as means ± standard deviation (SD) or standard error of the mean (SEM). Unpaired Student’s This study reveals that CRET therapy could act on cutaneous fibrosis, reducing the fibrotic extracellular matrix, intervening in the control of the expression of the proteins involved in its degradation, and reducing the activation of pro-inflammatory transcription factors such as NFkB. Thus, this study provides some of the biological bases of the effects of CRET. However, although the results would suggest the utility of this therapy for the treatment of cutaneous fibrosis, a deeper understanding of the cellular and molecular mechanisms of response to CRET is necessary. On the other hand, this study was carried out in vitro, which is a limitation for direct extrapolation to patients. Thus, it is essential to carry out studies at the organism level and preferably in humans through clinical trials, to determine the real usefulness of CRET therapy in this pathology.


In this video, the authors present the resection of a large thoracolumbar intradural ependymoma in a 33-year-old female. The patient underwent T9–L3 laminectomies, intradural tumor resection, and posterior instrumented fixation and fusion. The surgical procedure aimed to relieve the mass effect, obtain a diagnosis, prevent further neurological decline, and achieve a potential curative resection. The pathology confirmed a myxopapillary ependymoma, a rare tumor with a preference for the conus medullaris, cauda equina, or filum terminale. The video provides insights into the case, surgical steps, clinical outcomes, and background information on myxopapillary ependymomas and treatment options. The patient is a 33-year-old female who presented with 2 months of lower-back pain, right leg weakness, difficulty with ambulation, and intermittent bilateral lower-extremity paresthesias after a recent motor vehicle accident.On exam, the patient was confirmed to have right lower-extremity weakness, 2/5 proximally and 3/5 distally, with intact motor strength in her remaining three limbs.She was also found to have abnormal sensation to light touch and proprioception throughout her right lower extremity in a nondermatomal distribution, as well as increased tone with decreased patellar tendon reflex in that same right lower extremity.An MRI of the thoracolumbar spine was obtained demonstrating a longitudinally extensive enhancing intradural lesion from the level of T9 to the inferior aspect of L4. The lesion causes significant compression of the lower thoracic spinal cord parenchyma with T2 and STIR hyperintensity extending from T4/5 through T9/T10, as well as peripheral displacement of the cauda equina nerve roots within the thecal sac.Given the patient’s symptoms and presence of a mass lesion on imaging, the patient was recommended T9–L3 laminectomies and intradural tumor resection with a T9–T11 transpedicular approach and T8–L4 posterior instrumented fixation and fusion. The main goal of the procedure was to relieve the mass effect of the tumor on the spinal cord, especially in light of the patient’s presentation with a neurological decline. The potential benefits of the procedure included obtaining a diagnosis, preventing worsening neurological decline due to further tumor growth, and the potential for a curative resection. Risks of the procedure, in addition to common surgical risks, included lower-extremity paralysis; sensory, bowel, or bladder disturbance; adjacent-segment disease; wound complication or cerebrospinal fluid leak; and tumor recurrence.Alternatives included observation, radiation, or chemotherapy treatment. However, none of these options would allow for obtaining a tissue diagnosis, nor would the mass effect of the tumor be relieved. Furthermore, treatments such as chemotherapy are not a mainstay treatment for pathologies such as ependymoma. T9–L3 laminectomies and tumor resection without fusion may also be considered. However, in this case, given the ventral extension and size of the tumor, a transpedicular approach as well as multilevel facetectomies were needed to achieve gross-total resection and adequate thecal sac decompression. Thus, a fusion was needed to avoid long-term instability.In terms of positioning, preflip SSEP and MEP baselines were obtained. The patient was then flipped prone on a Jackson table and a midline incision was planned. The entirety of the thoracolumbar spine was prepped and draped in the usual fashion.Surgical equipment included the operative microscope, microsurgical instruments, ultrasound, an ultrasonic surgical aspirator, neuromonitoring, a high-speed drill, spinal instrumentation hardware, and allograft.In terms of surgical steps, a midline incision was made, monopolar electrocautery was used to open the soft tissue and fascia with subperiosteal dissection out to the transverse process at each level with preservation of the most cranial (T7/8) and caudal (L4/5) facet joints. Laminectomies from T9 to L4 to have access to both the cranial and caudal extent of the tumor were performed. Facetectomies were performed at T9/10, T10/11, T11/12, T12/L1, L1/2, L2/3, and L3/4 for further decompression. Transpedicular decompression at T9, T10, and T11 due to ventral positioning of the tumor was then performed. The ultrasound was then used to evaluate whether the amount of dural exposure would be sufficient to reach the top and bottom poles of the tumor. Durotomy was performed in a piecemeal fashion from T9 to L4. Microsurgical dissection of the tumor from the nerve roots was followed by microsurgical resection of the tumor utilizing a combination of sharp dissection, and ultrasonic aspiration for tumor debulking followed by dissection off of neural elements. A dural closure was then completed, followed by posterior instrumentation and preparation for arthrodesis utilizing autograft and allograft from T8 to L4. Multilayer closure after dural graft placement over the durotomy site was performed.Here we see after dural opening blunt dissection of the tumor taking care to separate the cauda equina nerve rootlets from the tumor tissue. Microsurgical instruments such as a Rhoton 6 can be useful for this maneuver. Patties are carefully placed to delineate already dissected elements. Sharp dissection is also often necessary. Here we demonstrate this technique using an 11 blade. Similarly, microsurgical scissors can also be used. Careful constant instillation of saline via a soft angiocatheter tip can be used to perform hydrodissection as well.A portion of tumor tissue was then removed to send for a frozen pathology specimen. Further blunt dissection was then performed until ventral dura was clearly identified.An ultrasonic surgical aspirator was then utilized to debulk the tumor, with bipolar electrocautery used to control bleeding. The durotomy was then carried superiorly using a combination of a Woodson elevator and an 11 blade, followed by hydrodissection on the lateral surfaces to free the cord from dural adhesions. Tumor removal was then continued and carried to the level of the conus, and the gutters and dural elements were inspected for residual tumor. The entirety of the dural exposure can be seen here from the inferior thoracic cord, down to the lower lumbar rootlets.The dura was then closed in a watertight manner using 5-0 Prolene suture on a VB-1 needle. This was followed by an overlay dural graft with spinal sealant. No CSF egress was noted after a Valsalva maneuver.The patient tolerated the procedure with no apparent complications. Pathology demonstrated a WHO grade II myxopapillary ependymoma. At 3 months postoperatively, the patient denied any new neurological deficits with slow improvement of her right lower-extremity weakness and paresthesias. Postoperative imaging demonstrated gross-total resection of the lesion.1Ependymomas are a rare CNS tumor that arise from ependymal cells in the central canal, filum terminale, choroid plexus, or white matter near the ventricular surface. Ependymomas are classified by the World Health Organization as grade I, II, or III based on histological findings.3 There are two incidence peaks, one in early adulthood between 25–29 years of age, and another between 45–49 years of age.Myxopapillary ependymomas are a rare subset of ependymoma classified as WHO grade II. Myxopapillary ependymomas have an incidence in the United States of around 1.00 per million person-years and are typically found in the conus medullaris, cauda equina, or filum terminale.4 Although adjuvant radiation is controversial, there appears to be some increase in progression-free survival with adjuvant radiation therapy.5Gross-total resection, and if possible, with an intact tumor capsule, are the historical and modern treatment modalities of choice and associated with the lowest recurrence rate.The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication.Primary surgeon: Shabani. Assistant surgeon: Aaronson. Editing and drafting the video and abstract: Aaronson, Laing, Treffy. Critically revising the work: all authors. Reviewed submitted version of the work: all authors. Approved the final version of the work on behalf of all authors: Shabani. Supervision: Aaronson.The necessary patient informed consent was obtained in this study.


Sperm are highly polarized cells, with a resting membrane potential of about −40 mV, which must rapidly adapt to the ionic changes occurring through the sperm membrane. This review summarizes the current knowledge about the relationship between variations in the sperm potential membrane, including depolarization and hyperpolarization, and their correlation with changes in sperm motility and capacitation to further lead to the acrosome reaction, a calcium-dependent exocytosis process. We also review the functionality of different ion channels that are present in spermatozoa in order to understand their association with human infertility.During the last seventy years, studies on mammalian sperm cells have demonstrated the essential role of capacitation, hyperactivation and the acrosome reaction in the acquisition of fertilization ability. These studies revealed the important biochemical and physiological changes that sperm undergo in their travel throughout the female genital tract, including changes in membrane fluidity, the activation of soluble adenylate cyclase, increases in intracellular pH and Ca Infertility is defined as the inability to conceive after 12 months or more of regular unprotected intercourse . During 3− influx to the sperm cell  may change from ~39 to 5–8 mM; [Cl−] varies from ~27 to 130 mM, and external [Na+] goes from 38 to 140 mM between the cauda epididymis and the oviduct [+], leading to a Na+ influx that induces membrane depolarization  is needed, which can be induced by a calcium influx through calcium channels and be accompanied by Ca2+ release from intracellular reservoirs i and [Ca2+]i [+] in the female reproductive tract, which induces a membrane depolarization caused by Na+ influx  in semen and in the female genital tract e or blockade of ENaC by amiloride causes membrane hyperpolarization and increases sperm motility in asthenozoospermic patients i and membrane depolarization, but it is insensitive to intracellular alkalinization i, and is inhibited by high concentrations of progesterone [2+]i-dependent K+ outward fluxes that hyperpolarize the human sperm membrane remains undefined. It has been suggested that human KSper can be mediated by SLO1 [2+]i while γ subunits affect SLO gating even at low [Ca2+]i i . Yang etpression . In mice+ channels, with 40 members, and belong to the VGC superfamily. The Kv family is formed by 12 subfamilies (Kv1–Kv12) that are widely distributed in a great variety of tissues  and [Na+] together with a decrease in [K+] [2+-induced wave that changes the flagellar beat pattern. The increase in intracellular [Ca2+] can be induced by a calcium influx through calcium channels and/or by Ca2+ release from intracellular reservoirs i is required not only for initiating but also for maintaining hyperactivated motility  . Althoug in [K+] ,22,144.  in [K+] ,145,146  in [K+] ,147. In servoirs ,149. Man also AR ,148. Mit2+ level . An incrmotility , which cmotility ,152.  located in the acrosomal region [The acrosome is a calcium reservoir, and an IPocytosis ,149. As ocytosis , an initl region ,184,185.l region .2+ channels and is the main channel responsible for Ca2+ influx in mammalian sperm [2+-binding domain-containing protein 9 (EFCAB9) form a complex associated with the cytoplasmic mouth of the channel pore, regulating its opening and closing [2+ and pH sensor [2+ binding to EFCAB9 causing the dissociation of the CATSPERζ-EFCAB9 complex and permitting the activation of the CatSper channel [2+ signaling and sperm fertilization ability.The cation channel of sperm, CatSper, is a sperm-specific voltage- and pH-dependent calcium channel localized in the principal piece of sperm flagellum ,162. Catan sperm ,189,190.an sperm ,162,166.an sperm ,156,159.an sperm ,169,171  closing . The CATH sensor ,172. ThuH sensor . The inc channel ,172. Ver channel ,174. Thi channel ,174. All channel ,174. Thi channel . This spActivation of CatSper requires membrane depolarization and intracellular alkalinization ,187. Cat2+ oscillations in human sperm are generated in the flagellum principal piece by Em-sensitive activity of CatSper [CatSper is also sensitive to different activators which vary between species ,24,76 an CatSper .CatSper1, CatSper2, CatSper3 or CatSper4 genes inhibits CatSper currents and sperm hyperactivation and causes infertility, although spermatogenesis and initial motility are unaffected [−/−CatSperd male mice, lacking the gene that encodes CATSPER∂, are infertile and their sperm do not express Catsper channels [−/−CatSperz and −/−Efcab9 mice lines or the double CatSperz/Efcab9 KO mice show severe subfertility but a functional, although disorganized, channel [2+, providing further evidence for the involvement of this dual complex in the modulation of Ca2+ influx mechanisms of CatSper channels [−/−C2cd6 mice show a disorganized but functional CatSper channel, with a highly reduced conductance [−/−C2cd6 mice have an apparently normal spermatogenesis, and spermatozoa with normal morphology and progressive motility. However, sperm cells from these mice are unable to acquire hyperactivated motility and to fertilize eggs, and are therefore infertile [The crucial role of CatSper is corroborated by the important alterations produced in sperm function as a consequence of mutations in any of the subunits that forms this complex channel . In miceaffected ,162,168.affected . Similarchannels . On the  channel ,171,172.channels ,172. Thechannels ,171,172.ductance ,174. C2cnfertile ,174.Studies in human patients have also been able to detect several deletions and/or mutations in the genes encoding different CATSPER subunits and their association with infertility ,165,170 2+ influx is proposed to be mainly dependent on CatSper in spermatozoa, it may also be mediated by classic voltage-gated calcium channels, Cav, which are also present in these cells of different species [Although Ca species ,193,194. species ,66. Ther species ,66,194.  species .VGCCs are expressed in sperm from a wide number of species ,193,194.2+ influx, leading to AR [2+ current, measured in CATSPER1 and Cav3.3 co-transfected mammalian HEK cells [2+ influx, proving that Cav channels may play a role in modulating AR [Patch clamp studies have not revealed Cav1 or Cav2 currents in spermatogenic cells . In contng to AR , suggestng to AR . In factEK cells . In addiating AR ,194.Several ion channels are involved in the correct functioning of sperm cells and their maturation. Thus, ion channel dysfunctions, as well as membrane potential alterations, have important consequences for fertilization. Mutations in different ion channels could be responsible for Em alterations in infertile patients and several ion channel dysfunctions have been associated with subfertility/infertility and related pathologies. The study of defective ion channels would lead to both, determining the origin of some infertility cases and the comprehension of the role of ion channels. Many studies have reported that depolarized human sperm membrane potential values are associated with lower fertilization rates ,132 and +/H+ exchanger sNHE is downregulated in asthenozoospermic men [Alterations in sodium currents have also been associated with altered semen parameters. Zhang et al., demonstrated that the expression of the Narmic men . Moreovermic men , which crmic men , probing+ conductance, generating a depolarization of the sperm plasma membrane [+ channels seem to be involved in this process. For example, SLO3 mutant mice are infertile, and they suffer membrane depolarization during capacitation [Several studies in spermatozoa from infertile men have also highlighted the importance of potassium conductance in the achievement of human fertility. Brown et al. (2016) showed that 10% of the IVF and ICSI patients with subfertility had abnormalities in Kmembrane . Depolarcitation . Mice wicitation . In addicitation . More stCATSPER1 and CATSPER2 mutations in human sperm are associated with infertility [It has been described that ertility ,165. Semertility  which maertility . Studiesertility ,165,170.− and HCO3− transport compromising human sperm fertilizing capacity [The second most common male factor infertility cause is a ductal obstruction or dysfunction, which is produced by CFTR mutations . Defecticapacity ,81. It hcapacity . The rolcapacity . Moreovecapacity ,204.To fully understand the effect of sperm ion channel dysfunctions and their association with infertility, the role of ion channels and transporters in human sperm has to be deeply studied. With a better comprehension of the ion channel operation system, the description of new infertility etiologies will be elucidated, and idiopathic infertility could be reduced.The control of sperm Em is a complex process that involves the activation of a great number of ion channels, transporters and protein receptors present in the sperm surface. Between them, ion channels play a central role in the maintenance of sperm physiology and the achievement of a successful fertilization. The introduction of electrophysiological techniques has permitted a great advance in our knowledge of the role of ion channels, particularly CatSper, KSper and Hv1, and their important participation in different sperm maturation processes. However, although a large, increasing number of ion channels have been detected in spermatozoa, only a few of them have been functionally characterized in electrophysiological studies, probably reflecting the complex nature of this highly polarized cell and the difficulty of performing patch clamp studies in regions other than the flagellum. Important advances have also been produced by using ion-channel-null mice models, or by the finding of mutations in specific human genes and their association with male infertility. However, in many cases, men infertility is not associated with mutations in a certain gene, but is acquired throughout life, due to age, environmental conditions or other unknown factors. It must be considered that, in the particular case of humans, studies are performed in mature spermatozoa, following ejaculation and, in many cases, after a selection of the more motile cells present in the semen sample, thus precluding an analysis of the precise role of different sperm proteins. At this point, a better understanding of the physiological role of sperm ion channel activities appears essential to discover the mechanisms underlying a successful fertilization.


In recent decades, significant research efforts have been devoted to studying various types of actuators. Of particular interest are soft actuators based on electroactive polymers, which offer low operating voltage, light weight, and fast response. In this study, we demonstrate the feasibility of a soft linear actuator fabricated from polypyrrole (PPy), an electroactive polymer that is easy to synthesize, cost-effective, and biocompatible. By optimizing the polymerization conditions, the operation condition and environment, we were able to achieve improved and stable actuator performance. Furthermore, we developed a new actuator-contained component with a flexible counter electrode to build an actuator that operates in air. This approach enabled us to build small and lightweight actuators that operate in air, with a diameter of 5 mm, resembling artificial muscles. Our resulting miniaturized and integrated linear PPy-based actuators can be driven at low voltages (±1.5 V), making them suitable for use in various parts of the body. As such, this actuator holds significant potential for a wide range of applications in the fields of soft electronics, drug delivery, artificial organs, and muscles, as well as a component material for portable medical sensors and devices. An increasing aging population is a significant demographic trend in most developed countries, and it is especially pronounced in the EU and Japan. For example, the proportion of individuals aged sixty-five or older in the EU is projected to increase from 16% to 29% of the total population between 2010 and 2060 [Recent technological advancements in the Internet of Things, artificial intelligence, and wearable devices have made it possible to take care of the aging population using enhanced robotics and exoskeletons ,4,5. How3SO3) [4) [In recent years, there has been a significant focus on developing polymers for use as actuator materials ,15,16,173SO3) ,19, lith3SO3) , tetra-nSO3) [4) ,22, and SO3) [4) . The polSO3) [4) ,21,22,23Based on these results we obtained, we aimed to further our research by investigating the possibility of miniaturizing our devices, with the goal of developing an integrated actuator system that could operate in air. To achieve this goal, we conducted further experiments to electrochemically synthesize PPy on conductive fabric, which was utilized as a thin and flexible counter electrode with a thickness of 50 μm. This approach yielded small and lightweight integral actuators that have the potential to be utilized not only for artificial muscles but also as a component material for medical devices, including pacemakers, intraocular lenses, insulin pumps, and implantable medical devices ,25.4) from Sigma Aldrich , and Tetraethylammonium bis(trifluoromethylsulfonyl) imide (TEATFSI) from Kishida Chemical. Additionally, 2-Phenoxyethanol (PE), Ethyl Acetate (EA), and Diethyl Phthalate (DEP) were purchased from Tokyo Chemical Industry  as polymerization solvents. All the chemicals were used without further purification. We used TBABF4 and TEATFSI as electrolytes to enable the electrochemical polymerization of pyrrole. We also used PE, EA, and DEP as solvents to dissolve the TBABF4 and TEATFSI electrolytes and the pyrrole monomers for efficient polymerization.For our experiments, we obtained pyrrole monomers , Tetrabutylammonium tetrafluoroborate  were utilized as the working and counter electrodes, respectively. The distance between the electrodes was fixed using plates and spacers made of PTFE (Polytetrafluoroethylene or Teflon) at a distance of 6 mm. A schematic diagram of the experimental setup is depicted in The PPy films, which were electropolymerized galvanostatically as described above, were cut into pieces with a size of 10 mm width and 20 mm length for the evaluation of the actuator performance. PPy actuators were then fixed onto frames made of PTFE and suspended in an electrolyte solution, as depicted in 4 as electrolytes, and it also contained 0.15 M Pyrrole. The electrochemical polymerization temperature was kept at −10 °C, as mentioned above. The current density was set at 0.1 mA/cm2, and the polymerization was conducted for 20 h. After the polymerization was completed, the cylindrical PPy was swollen with acetone and then removed from the Ni wire. To preserve its shape, the removed PPy tube was dried by transferring it into a plastic rod  exhibited high conductivity with a resistance of 0.005 Ω and a thickness of 50 μm. We also successfully electrochemically polymerized PPy on this electrode and used the PPy composite flexible electrode as a counter electrode. To prevent short circuits between the actuator and the counter electrode, we used a separator film developed of TORAY . The actuator was assembled by placing a PPy-film-based flexible electrode as the counter electrode, a separator film, and a PPy actuator inside a cylindrical container with a diameter of 5 mm.To ensure high actuator performance, it is important to design a conducting polymer film with optimal properties. For PPy films, the conductivity, bulkiness, porosity, and stiffness, which are closely related to actuator performance, can be determined by polymerization conditions. Previous studies have reported that the desired actuator morphology can be obtained by controlling the polymerization conditions such as electrolyte, solvent, and temperature ,33. AccoTo prevent overvoltage of the counter electrode, it is commonly practiced having a significantly larger area compared with the working electrodes. This leads to a reduction in the current density of the counter electrode. Therefore, the size of the counter electrode can have a substantial impact on the performance and stability of the actuator. We investigated the effect of electrode size on strain response by varying the ratio of the working electrode (actuator) to counter electrode areas as 1:1, 1:6, and 1:9. The displacement of the actuator under these conditions is shown in Based on 2 of cross-sectional area. The cross-sectional area of the actuator used in this experiment was 0.002 cm2 (2 mm × 100 μm). Therefore, based on the cross-sectional area of the actuator used in this experiment, a load of 20 g corresponds to a generated force of 1 MPa. Using a PPy film actuator polymerized under polymerization solution III-2, as shown in We evaluated the generated force of a PPy film actuator. The actuator used for force measurement was a film with a length of 15 mm, a width of 2 mm, and a thickness of 100 μm. The force generated was measured using the apparatus illustrated in This type of ion-driven actuator requires sufficient electrolytes and a large-sized electrode surface area for ideal operation, as the driving mechanism is based on the injection and extraction of ions. However, considering various applications such as artificial muscles or flexible devices, the size of electrode and the amount of electrolyte are very limited for a practical use ,46,47,48In this study, by optimizing the polymerization conditions of the actuator polymer, polypyrrole, we successfully obtained a highly stretchable soft actuator. The polymerization conditions have a significant impact on the morphology, conductivity, and molecular structure of the actuator polymer, but obtaining the optimal conditions was challenging due to the trade-off relationship among the actuator properties. Furthermore, by designing the counter electrode and the structure, we achieved the fabrication of an atmospheric-operable actuator. Although the stretchability is not yet sufficient, we believe that further improvements can be achieved by refining factors such as electrode arrangement to improve both stretchability and stability.Compared with conventional actuators powered by small motors, hydraulics, or pneumatics that are commonly used in industrial robots and machinery, soft actuators based on polymer materials provide significant advantages of being compact, lightweight, and operating silently. Electroactive polymer actuators, which respond to electrical stimuli, have demonstrated the ability to operate at low voltages and achieve reliable and controllable deformation. Although the deformation of the actuator demonstrated in this study is still relatively small compared with motor-driven actuators, the miniaturization, lightweight design, and atmospheric-operability achieved with only a 5 mm diameter demonstrate the potential for application in biomimetic muscles and other biologically inspired actuators. The ability to operate at low voltages without motor noise or heat generation further enhances its suitability for such applications. Furthermore, the high biocompatibility of actuators using polypyrrole opens up possibilities for their application in various fields, including artificial muscles, as well as catheters, guide wires, patch insulin pumps, and autofocus-enabled contact lenses.


Bisphenol A (BPA) is one of the most commonly used substances in the manufacture of various everyday products. Growing concerns about its hazardous properties, including endocrine disruption and genotoxicity, have led to its gradual replacement by presumably safer analogues in manufacturing plastics. The widespread use of BPA and, more recently, its analogues has increased their residues in the environment. However, our knowledge of their toxicological profiles is limited and their combined effects are unknown. In the present study, we investigated the toxic effects caused by single bisphenols and by the combined exposure of BPA and its two analogues, BPAP and BPC, after short (24-h) and prolonged (96-h) exposure in HepG2 spheroids. The results showed that BPA did not reduce cell viability in HepG2 spheroids after 24-h exposure. In contrast, BPAP and BPC affected cell viability in HepG2 spheroids. Both binary mixtures (BPA/BPAP and BPA/BPC) decreased cell viability in a dose-dependent manner, but the significant difference was only observed for the combination of BPA/BPC (both at 40 µM). After 96-h exposure, none of the BPs studied affected cell viability in HepG2 spheroids. Only the combination of BPA/BPAP decreased cell viability in a dose-dependent manner that was significant for the combination of 4 µM BPA and 4 µM BPAP. None of the BPs and their binary mixtures studied affected the surface area and growth of spheroids as measured by planimetry. In addition, all BPs and their binary mixtures studied triggered oxidative stress, as measured by the production of reactive oxygen species and malondialdehyde, at both exposure times. Overall, the results suggest that it is important to study the effects of BPs as single compounds. It is even more important to study the effects of combined exposures, as the combined effects may differ from those induced by single compounds. Bisphenols are a group of synthetic chemicals used to produce polycarbonate plastics, epoxy resins, and thermal paper ,2,3. AmoDespite the increased production and use of BP analogues, little is known about whether the presence, chemical structures, and exposure risks of BPs are related to their effects. However, BPA has attracted considerable attention over the past two decades because of its toxicity ,33,35. NA number of human biomonitoring studies have shown that the general population, including children, is often exposed to chemical mixtures present in the environment, food, and consumer products, rather than to a single compound . FurtherThe present study investigated the potential cytotoxicity and induction of oxidative stress caused by BPA, BPAP, and BPC as single compounds or binary BPA/BPAP and BPA/BPC mixtures. BPAP and BPC were selected based on their occurrence in foodstuffs ,47, humaBPA has become a significant concern worldwide due to its harmful effects on human health. These potential health effects have led to the increasing use of alternative bisphenols such as BPAP, BPC and many others. Due to the expected increase in the use of BPA analogues, exposure will also increase, and human co-exposure to these substances is inevitable. Unfortunately, not much is known about their toxicity, and there is a lack of information about their adverse effects, especially chronic exposure, and the combined effects of BPs. Therefore, this should be a priority for further investigation as there is insufficient information in the literature on co-exposure of BPs concerning their toxicity and mechanism of action. Human health risk assessment is still performed on data of individual compounds ,61 whereTherefore, this study investigated the effects of BPA, BPAP, and BPC as single compounds and their complex mixtures on metabolically competent HepG2 spheroids See . The stuThe effect of BPA, BPAP, BPC, and their combinations on the viability of cells in 3-day-old HepG2 spheroids was evaluated using the MTS assay after short-term (24 h) and long-term exposure (96 h)  significantly induce the formation of MDA by approximately 2.3 (8.02 ± 2.07 µM/mg of protein) and 3.97-fold change (13.12 ± 5.3) µM/mg of protein) after 24 and 96 h of exposure, respectively, compared to solvent control. In contrast to our results, Ozyurt et al. .Significant differences in cell viability between the treated groups and the solvent control group were analyzed using a One-Way Analysis of Variance (ANOVA) and Dunnett’s multiple comparison test using GraphPad Prism V8 . .In each experiment, a negative control (cell medium), solvent control , and positive control (15% DMSO) were included. Graphical and statistical analyses were performed using GraphPad 8 software by one-way analysis of variance (ANOVA) test with a Dunnett post hoc .Significant differences between the treated and solvent control groups were analysed by One-way analysis of variance (ANOVA) and Dunnett’s multiple comparison test using GraphPad Prism V8 . .Significant differences between the treated and solvent control groups were analysed by one-way analysis of variance (ANOVA) and Dunnett’s multiple comparison test using GraphPad Prism V8 . [The present study investigated the toxic effects of BPA, BPAP, BPC, and binary mixtures of BPA/BPAP and BPA/BPC in an in vitro 3D HepG2 cell model. The results showed that BPA did not affect cell viability under the applied conditions. In contrast, after short-term exposure, BPAP and BPC and the binary mixtures (BPA/BPAP and BPA/BPC) decreased cell viability in the HepG2 3D cell model. None of the bisphenols studied affected cell viability after prolonged exposure, except for the BPA/BPAP binary mixture. In addition, none of the bisphenols and their binary mixtures studied affected spheroids’ compactness, size, surface area, and growth. All three bisphenols and their binary mixtures induced increased MDA and ROS levels, with BPC being the least effective. Overall, the results of the present study indicate that BPA and its analogues, BPAP and BPC, induce oxidative stress, which is involved in their toxic activity. However, further research is needed to fully understand the mechanisms and potential health risks associated with exposure to the studied bisphenols. It is important to investigate the effects of complex mixtures, as the combined effects may differ from those induced by single compounds.


Multiple sclerosis (MS) is a chronic systemic autoimmune disorder characterized by plaques of demyelination, autoimmune inflammation, and astrocytic gliosis. The primary cells involved in the pathophysiology of MS are T cells. However, B cells have recently been implicated in the pathophysiology of the disease. Therefore, researchers have been exploring B cell therapy as an alternative treatment option for MS. B cell therapy is based on the targeted depletion of CD20-positive B cells. Rituximab, ocrelizumab, and ofatumumab are anti-CD20 antibodies already approved. Briumvi, the fourth type of anti-CD20 antibody was approved by FDA in December 2022, for the treatment of relapsing types of MS, including relapsing-remitting multiple sclerosis, active secondary progressive multiple sclerosis, and clinically isolated syndromes after the drug was tested in two randomized, double-blind, phase III, ULTIMATE I, and II trials which compared Briumvi (ublituximab) with Aubiago (teriflunomide). Ublituximab was found to have a much lower annual relapse rate in the ULTIMATE II trials than teriflunomide. Briumvi is a chimeric recombinant IgG1 monoclonal antibody directed against human CD20 with potential antineoplastic activity. Its mechanism of action involves several distinct processes that collectively lead to the depletion of B cells and suppression of the immune response. The primary mode of action of Briumvi is its high-affinity binding to CD20. Infusion-related reactions are the most common side effects encountered following intravenous administration of ublituximab. HighlightsThe lower annual relapse rate, higher potency, and shorter infusion time make Briumvi’s approval a significant step forward in the treatment of relapsing multiple sclerosis.The short infusion times of Briumvi could assist medical facilities with a high patient volume to treat more patients during a given period.More studies about the efficacy and safety of the drug are necessary to confirm the side effects of prolonged treatment.1. MS lesions can occur anywhere in the CNS, but certain regions of predilection include the supratentorial brain, particularly the frontal lobe and sub-lobar region2. The course of disease progression varies greatly amongst individuals, according to which MS is classified into three major types: relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS). In most cases, the disease initially follows a relapsing and remitting course. RRMS shows clear exacerbations of neurological symptoms known as relapses, followed by a stage of remission with no disease progression. SPMS often follows RRMS and is characterized by a deterioration of symptoms, with a reduction in relapses and no apparent signs of remission. In PPMS, symptoms progressively worsen without clearly defined relapses or remission periods1. Clinically, MS is diagnosed based on visually evoked potential tests, lesions demonstrated by MRI, and cerebrospinal fluid analysis1.Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by plaques of demyelination, autoimmune inflammation, and astrocytic gliosis1. Consequently, the most common treatment options include medications to manage these symptoms, such as corticosteroids to reduce inflammation during exacerbations, muscle relaxants to reduce muscle spasms and stiffness, antidepressants, and analgesics3. Specific treatment options for relapsing forms of MS include disease-modifying therapies, which reduce exacerbations and slow down the progression of the disease by modulating the immune system4. Injectable disease-modifying therapies used for RRMS include beta-interferons (IFN-β) and glatiramer acetate, both of which reduce the overexpression of proinflammatory genes to slow down the progression of the disease5.MS is a systemic disorder that can cause various symptoms, such as vertigo, double vision, tingling or numbness in the limbs, bowel disturbances, and cognitive impairment6. The primary cells involved in the pathophysiology of MS are T cells; autoreactive T cells develop resistance to regulatory mechanisms, and antigens are presented to naïve T cells by antigen-presenting cells (APCs), which cause the phenotypic differentiation of T cells into CD 8+ T cells, and CD4+ Th1 and Th17 cells6. However, B cells have recently been implicated in the pathophysiology of the disease; B cells act as both APCs for the activation of T cells into inflammatory cells7 and are precursors of antibody-secreting plasma cells, which are involved in the demyelination of axons and formation of lesions in the CNS7. Furthermore, along with releasing proinflammatory cytokines, a subset of B cells, B2 cells, are also involved in the activation of regulatory T cells, which are anti-inflammatory7 and might be manipulated to control the progression of MS. Therefore, researchers have been exploring B cell therapy as an alternative treatment option for MS.MS is a complex neurodegenerative disorder involving neuronal injury and inflammatory plaques, resulting from overactivation of the immune system, that causes immune cells to cross the blood-brain barrier8.B cell therapy is based on the targeted depletion of CD20-positive B cells, which aid in the propagation of MS by releasing proinflammatory cytokines and acting as APCs. Anti-CD20 monoclonal antibodies bind to specific epitopes on CD20, a transmembrane protein, which acts as a surface marker present during the differentiation of B cells. Rituximab, a chimeric monoclonal antibody, was the first anti-CD20 antibody developed and tested in phase I and a subsequent phase II trial on 439 patients with PPMS. While it was associated with a lower annualized relapse rate (ARR) and a reduction in the number of T2 and gadolinium-enhancing brain lesions, it was limited by its efficacy8. Ocrelizumab was approved by the US Food and Drug Administration (FDA) in 2017, but further trials were required to judge its efficacy and safety in young adults. Ofatumumab, the third anti-CD20 antibody, is fully humanized and binds to two different epitopes on CD20, the small and large extracellular loops. It was tested to have a 99% decrease in the development of new T1 and T2 gadolinium-enhancing lesions, along with a lower relapse rate8. However, several adverse effects were reported with ofatumumab, such as thrombocytopenia, anemia, and infusion reactions, casting doubts on its use as a broad-scale treatment for various forms of MS7.Further progress led to the development of ocrelizumab, a humanized anti-CD20 IgG1 antibody administered intravenously and binds to a different epitope on CD20. Orcelizumab was tested in various trials, including two randomized phase III trials conducted over a period of 96 weeks, which demonstrated a lower ARR with ocrelizumab and a 94% decrease in gadolinium-enhancing lesions9.On 28 December 2022, the US Food and Drug Administration (FDA) approved Briumvi, the third type of anti-CD20 B cell antibody, for the treatment of relapsing types of MS, including RRMS, active SPMS, and clinically isolated syndrome10, and promotes antibody-dependent cellular cytolysis (ADCC) of the B cell by natural killer (NK) cells10. Ublituximab’s affinity for CD16A, a membrane receptor involved in the activation of NK cells, is increased by the reduction in frucose concentration after glycoengineering11, which increases its antibody-dependent cellular cytolysis activity by 25–30 times10. In addition to conserving CD20-negative plasma cells, this targeted depletion of CD20-positive immature and mature B cells is associated with a decrease in the frequency of new and progressing brain lesions7.Briumvi (ublituximab) is a glycoengineered chimeric IgG1 antibody that targets a specific epitope on the B cell antigen CD20, distinct from the ones targeted by rituximab, ocrelizumab, and oftamumab10. Patients were randomly divided in an equal ratio to receive IV ublituximab and an oral placebo OR oral teriflunomide and an IV placebo. The outcome was to assess the ARR in the two groups. The study compared Briumvi (ublituximab) with Aubiago (teriflunomide) over 96 weeks and found ublituximab to have a much lower ARR in the ULTIMATE II trials than teriflunomide, at 0.09 as opposed to 0.1810. The trials also reported that the probability of development of T1 and T2 gadolinium-enhancing lesions was reduced in patients treated with ublituximab10. However, the comparison also revealed that at 12 weeks, 5.2% of the ublituximab group showed worsening of disability as compared to 5.9% of participants in the teriflunomide group, which was reduced to 3.3 and 4.8%, respectively, by week 2410. Affecting nearly half of the patients treated with ublituximab, the most insidious of the outcomes were infusion-related reactions (IRR) and severe infections, which were reported in 5% of the patients, as compared to 2.9% of those on teriflunomide10. The mean number of new and hyperintense lesions was also more significant in the teriflunomide group. The average count in CD19+ B cells at the end of the double-blind trial was reduced by 97% in the ublituximab group and 18% in those on teriflunomide. However, the percent change in brain volume was not reported to be considered significant between the two groups10.Briumvi was approved after the drug was tested in two randomized, double-blind, phase III, ULTIMATE I, and II trials conducted on 1094 patients with RRMS12. The results depicted a similar picture as the trial evaluating teriflunomide and ublituximab. In trial 1, ofatumumab had an ARR of 0.11 and teriflunomide 0.22, which in trial two was found to be 0.10 and 0.25, respectively. Disability worsening outcomes confirmed at 3 months were reportedly seen in 10.9% of patients in the ofatumumab group and 15% in the teriflunomide group, but at 6 months, the number was reduced to be seen in 8.1 and 12% of participants in the respective groups. Hence, disability worsening outcomes confirmed at 3 months and 6 months were lower in the ofatumumab group than in teriflunomide. However, as was reported for ublituximab, ofatumumab reported IRR in 20.2% of the group and serious infections in 2.5% of the population as compared to 15.0% IRR and 1.8% seriously infected patients treated with teriflunomide12.In another trial of a similar set-up, teriflunomide was compared with ofatumumab in efficacy13. As mentioned previously, disability worsening outcomes for ofatumumab were confirmed to be lower than that of teriflunomide13; however, the ULTIMATE trials revealed no significant reduction in the risk of disability worsening when comparing ublituximab and teriflunomide12. Thus, studies comparing ublituximab and ofatumumab are needed to unfold the relative efficacy of these two drugs.Among the MS patients, ofatumumab and ublituximab reported better ARR in their individualized trials with teriflunomide. The drugs differ in their pharmacokinetics and route of administration, which alter the patient’s response significantly. Ublituximab is given intravenously, whereas ofatumumab is administered subcutaneously, reflecting the rapid bioavailability of ublituximab; however, a slower absorption abrogates side effects, as is the case with ofatumumab13. Severe infections can ensue as a side effect of ublituximab. Most commonly encountered are upper and lower respiratory tract infections and herpes-virus-associated infections9. Prolonged B cell depletion following anti-CD20 antibodies is the precipitating factor in the pathogenesis of infections. The trial data reflects the need to control these infections, as reported in nearly 5% of patients treated with ublituximab13. Ublituximab is generally a well-tolerated drug with great bioavailability following its intravenously administration; no fatal side effects are reportedly associated except for mild pain in the extremities, insomnia, and fatigue9. However, its rapid action might present a similar surge of side effects. The formation of antidrug antibodies ADAs is another challenge that aligns with using these monoclonal antibodies. Fully human monoclonal antibodies like ofatumumab are the least immunogenic13. However, more statistical data are required following the use of ublituximab for reports on its immunogenicity. Briumvi is contraindicated in pregnancy and prior hepatitis B infection9.IRRs are the most commonly encountered complication of ublituximab administration. These present within 24 h of the first dose administration with symptoms ranging from mild to moderate severity, usually subsiding with subsequent doses9. Lastly, improved patient support programs and competitive pricing are essential to compete with other anti-CD20 B cell antibodies and gain a large patient share in the MS market.The lower ARR, higher potency, and shorter infusion time make Briumvi’s approval a significant step forward in the treatment of relapsing MS, a condition affecting millions worldwide. The short infusion times of Briumvi could assist medical facilities with a high patient volume to treat more patients during a given period. This could be crucial in treating MS in middle-income and lower-middle-income nations with a shortage of medical professionals, limited access to resources, and underdeveloped healthcare infrastructure. However, considering the potential severity of the side effects associated with Briumvi, healthcare workers must approach its administration responsibly. Specialized physicians with ample experience in diagnosing and treating neurological conditions and access to appropriate medical support to manage severe reactions such as IRR and immunosuppression should be entrusted with initiating this drug. More studies about the efficacy and safety of the drug are necessary to confirm the side effects of prolonged treatment, such as progressive multifocal leukoencephalopathy or the safety of immunization with live or live-attenuated vaccines during or following administration of BriumviNot applicable.Not applicable.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors declare that they have no conflicts of interest.A.A.: writing – original draft, writing – review and editing; M.A.T.: writing – original draft, writing – review and editing; A.I.: writing – original draft; S.A.: writing – review and editing; T.A.: writing – review and editing; Y.K.: writing – original draft; S.F.S.: writing – review and editing.Name of the registry: not applicable.Unique identifying number or registration ID: not applicable.Hyperlink to your specific registration (must be publicly accessible and will be checked): not applicable.Ayesha Azhar, Muskan Asim Taimuri, Yumna Khabir.Not commissioned, externally peer reviewed.Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.