Dual Stimulation Research Articles

Dual Peripheral Stimulation of Musculocutaneous and Radial Nerves for Refractory Upper Extremity Pain: Case Report

BACKGROUND: Peripheral nerve stimulation has been available for many years, yet there is relatively little information available regarding stimulation of many of the large sensory and mixed nerves. CASE REPORT: A 42-year-old woman presented to the clinic for a 10-year history of intractable left upper extremity and forearm pain following a motor vehicle accident requiring skin grafting. Based on the patient’s failure of more conservative therapy, a shared decision was made to pursue opioid sparing interventional modalities. Implantable radial and musculocutaneous nerve stimulators were chosen for this patient for ease of use and high likelihood of favorable outcomes. CONCLUSIONS: Sequential radial and musculocutaneous stimulation provided a 45% and 50% reduction in pain respectively, with the summative reduction of pain from original presentation being greater than 72% relief in total. KEY WORDS: Peripheral nerve stimulation, neuromodulation, musculocutaneous nerve, radial nerve, regional anesthesia, upper extremity pain, pain medicine, implantable stimulation

Light and temperature dual stimuli-responsive micelles from carbamate-containing spiropyran-based amphiphilic block copolymers: Fabrication, responsiveness and controlled release behaviors

With the increasing demand for treating cancer and cardiovascular diseases in recent years, drug delivery therapy using intelligent nanocarriers has been investigated intensely. Usually, hydrophobic dyes were used as drug models for the development of drug-release carriers. In this study, light and temperature dual-responsive micelles were designed and fabricated, and the controlled release property was investigated using the hydrophobic fluorescent dye coumarin 102 as the model. A carbamate-containing spiropyran methacrylate monomer (SPMA) was adopted as the photosensitive unit because it is more conducive to stabilize the micelle structure compared to traditional spiropyran. Firstly, a light and temperature dual-responsive copolymer P[DMA50-b-(SPMA20-co-NIPAAm17)] was synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. Then, the copolymer was self-assembled into micelles with coumarin 102 encapsulated in the hydrophobic core above the lower critical solution temperature (LCST) and under visible light (Vis) irradiation. When the visible light was switched to ultraviolet (UV) radiation, the micelles' permeability increased as a result of the change from closed, three-dimensional spiropyrans (SP) to open, planar merocyanines (MC), resulting in the release rate of 51% for coumarin 102 in 15 min with “low” release capability. Lowering the temperature to room temperature (RT), the hydrophobic nuclei were partially destructed as a result of the changing of PNIPAAm segment from hydrophobicity to hydrophilicity. Meanwhile, the release rate was observed to be 77% in 15 min showing “medium” release capability. The micelles were almost wholly disintegrated under the dual stimulation of both UV irradiation and RT, achieving the release rate of 96% within the same time exhibiting “high ” release capability. This study offered an approach for the construction of controllable drug release carriers.

PH-Activated Scallop-Type Nanoenzymes for Oxidative Stress Amplification and Photothermal Enhancement of Antibacterial and Antibiofilm Effect.

Ferric phosphate (FePOs) nanoenzymes can express peroxidase (POD) activity under the dual stimulation of an acidic environment and high H2O2 concentrations. In living organisms, this generates reactive oxygen species (ROS) in sites of lesion infection, and thus FePOs nanoenzymes can act as antimicrobial agents. Here, CeO2 and ZnO2 were immobilized in a scallop-type FePOs nanoenzyme material loaded with a photosensitizer, indocyanine green, to synthesize a multifunctional cascade nanoparticle system (FePOs-CeO2-ZnO2-ICG, FCZI NPs). H2O2 concentrations could be adjusted through the ZnO2 self-activation response to the slightly acidic environment in biofilms, further promoting the release of ROS from the POD-like reaction of FePOs, achieving amplification of oxidative stress, DNA and cell membrane damage, and exploiting the photodynamic/photothermal effects of indocyanine green to enhance the antibiofilm effects. CeO2 can remove redundant ROS by switching from Ce4+ to Ce3+ valence, enhancing its ability to fight chronic inflammation and oxidative stress and thus promoting the regeneration of tissues around infection. By maintaining the redox balance of normal cells, increasing ROS at the infection site, eliminating redundant ROS, and protecting normal tissues from damage, the synthesized system maximizes the elimination of biofilms and treatment at the infection site. Therefore, this work may pave the way for the application of biocompatible nanoenzymes.

How inhibitory and excitatory inputs gate output of the inferior olive.

The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.

P-211 “Survival rates after vitrification of oocytes obtained after luteal phase vs follicular phase ovarian stimulation”

Abstract Study question Do the oocytes retrieved after luteal phase ovarian stimulation (OS) have the same survival rate as those retrieved after follicular phase (OS)? Summary answer Oocyte survival rate after vitrification is similar in oocytes retrieved in a follicular phase OS compared to those in luteal phase. What is known already Oocytes retrieved in luteal phase have recently captured scientific interest as dual stimulation is gaining popularity. Oocytes obtained in luteal phase OS added to those obtained in follicular phase shorten time to pregnancy per intention to treat in poor responders. Embryos obtained with these oocytes show similar ploidy rates, as well as clinical outcomes. Study design, size, duration We analyzed data from a randomized, non-inferiority Duo Stim Preimplantation Genetic Testing for aneuploidies (PGT-A) trial performed from 2017 to 2021 in women >38 years old. Only cycles with at least one oocyte retrieved in both follicular and luteal were included. We compared survival rates from oocytes obtained in after follicular phase OS (n = 154 oocytes) versus luteal phase OS (n = 201 oocytes) within the same patient. Participants/materials, setting, methods A subtotal of 38 patients were included who underwent 2, 3, or 4 OS cycles to accumulate oocytes for subsequent ICSI with PGT-A. After retrieval and decumulation, oocyte vitrification was performed with Kitazato vitrification protocol (Kitazato, Japan) and Cryotop device, same as subsequent thawing. Main results and the role of chance Mean of age in the selected patients was 39,7 years. In total, 195 cumulus-oocyte complexes were retrieved after follicular phase OS vs 245 in luteal phase. From this group of oocytes, 145/195 were mature (78.97%) vs 201/245 (82.04%), respectively. No statistically significant differences were observed in survival rate whether oocytes came from a follicular phase OS 81.16 % (125/154) versus luteal phase 87.06% (175/201) (p = 0.3312). Our results confirm that survival rate of oocyte obtained in a luteal phase OS is comparable to conventional follicular phase OS, validating oocyte accumulation strategy in a Duo Stim protocol. Limitations, reasons for caution The limited sample size was due to the nature of the randomized, controlled trial. Our results need to be replicated in larger series for validation. Wider implications of the findings Luteal phase OS oocytes showed similar survival rates after thawing than conventional OS cycles, opening a new venue for oocyte vitrification in oncological patients or poor responders accumulating oocytes. This approach might be of interest as well in patients or countries where ethical/legal limitations may limit embryo accumulation. Trial registration number not applicable

O-069 Double vs. single stimulation in young poor prognosis patients followed by a fresh embryo transfer: a randomized controlled trial.

Abstract Study question Does double stimulation, followed by a fresh ET (DUO-STIM fresh) improve outcomes as compared with a single stimulation in young poor prognosis patients? Summary answer Compared to single stimulation, DUO-STIM fresh leads to significantly higher number of good quality embryos, without hindering fresh embryo transfer outcomes. What is known already Dual Stimulation (ovarian stimulation both in the follicular and luteal phase of the same cycle) is an innovative strategy to retrieve higher number of oocytes in a shorter time frame, thus it is particularly appealing for poor ovarian responders. Three current limitations of Dual-Stimulation are: (1) it is unclear whether outcomes of the second (luteal) wave results from the second stimulation, or a carry-over effect from previous follicular stimulation; (2) the desynchronization between endometrium and ovaries and, (3) lack of robust evidence. No previous studies explored Dual Stimulation starting from the luteal phase, and with a fresh embryo transfer (DUOSTIM-fresh). Study design, size, duration This study is a prospective, randomized, controlled, single-center, superiority clinical trial comparing two different ovarian stimulation protocols: a double stimulation cycle vs. a single stimulation cycle followed by fresh ET. The primary outcome was the number of good quality embryos obtained, while secondary outcomes included results from fresh embryo transfer (clinical pregnancy, miscarriage). A total of 120 women were enrolled in this study between October 2020 and October 2022, with a 1:1allocation. Participants/materials, setting, methods Only young (<40 years old) poor-prognosis (AMH<1.2 ng/mL) patients were recruited in the Fertility Clinic within a tertiary University Hospital. In the investigational group, DUOSTIM-fresh, the 1st stimulation was initiated in the luteal phase followed by a 2nd stimulation 5 days post first OPU, initiated in the follicular phase and a fresh ET of the best embryo generated (1st or 2nd cycle). The control group performed a follicular phase single stimulation cycle with fresh ET. Main results and the role of chance Overall, 107 patients were randomized, 53 in the investigational (DUO-STIM fresh) and 54 in the control arm (single stim). DUO-STIM fresh resulted in a significantly higher number of good quality embryos as compared to single stim (difference of mean 0.81, 95% CI 0.12-1.49). The mean percentage of embryo transfer was comparable (62.3 and 51.9, respectively for double vs single stimulation). No significant differences were found for fresh embryo transfer outcomes (ongoing pregnancy rates: 24.5 and 22.2, respectively for DUO-STIM fresh vs conventional IVF). Of interest comparisons between different stimulation cycles (A: luteal phase DUOSTIM-fresh, B: follicular phase DUOSTIM-fresh and C: single stim didn’t demonstrate any significant difference in terms of ovarian response with the mean (SD) number of mature oocytes being (A: 3.3 (2.9) B: 3.4 (3.4) C: 3.5 (2.9), respectively). Limitations, reasons for caution Study sample size was calculated to detect differences on the mean number of good-quality embryos. Therefore, results for secondary outcomes (embryo transfer rates and clinical pregnancy rates) should be interpreted with caution as exploratory findings that warrant future investigations. Wider implications of the findings Although DUOSTIM-fresh results in higher number of blastocysts as compared with a single stimulation in young poor-prognosis patients, the decision of performing dual stim should be evaluated with caution considering that whether this may improve embryo transfers rate and pregnancy outcomes is still unclear. Results on Cumulative-Live-Birth-Rate are warranted. Trial registration number NCT04446845

O-278 Medical and ethical perspectives of performing ovarian stimulation and oocyte cryopreservation for fertility preservation (FP) in adolescents: 5 years’ experience from a tertiary centre

Abstract Study question What are the medical and ethical challenges of performing ovarian stimulation and oocyte cryopreservation in adolescents and what are the barriers to provision? Summary answer Oocyte cryopreservation for benign and malignant indications in adolescents is associated with unique medical and ethical challenges. What is known already An improvement in childhood cancer survival, increased transgender care and benign conditions such as haemoglobinopathies requiring stem cell transplant have led to higher representation of adolescent birth-registered females in FP clinics. FP in adolescents has increased complexities, both physical (pubertal stage, diagnosis) and psychological (accepting diagnosis, processing information, decision-making). Concerns relate to reliability of AMH in adolescents, anticipated response to ovarian stimulation and oocyte quality. Counselling and consenting young people and their families about fertility decisions, often alongside receiving a life-changing diagnosis, is an ethically complex area. Assessing capacity to consent is not straightforward. We report our clinical experience. Study design, size, duration This was a retrospective, observational cohort study of 26 adolescent birth-registered females aged 13 to 18 years who underwent ovarian stimulation and oocyte cryopreservation in a specialist unit for fertility preservation between 2018 and 2022. The primary outcome was oocyte yield, secondary outcomes included complications and drop-out rate. Participants/materials, setting, methods We included post-pubertal adolescent birth-registered females aged 13 to 18 years who were referred for fertility preservation for high risk of gonadotoxicity from treatment and who commenced ovarian stimulation for oocyte cryopreservation. Data was retrieved from a prospectively managed database. We noted demographic data, ovarian reserve, method of monitoring, response to ovarian stimulation and oocyte cryopreservation and route of egg collection. Documentation on counselling conversations and psychological maturity was retrieved from clinical records. Main results and the role of chance There were a total of 29 ovarian stimulation cycles performed in 26 adolescent birth-registered females aged between 13 and 18 years. Indications for fertility preservation included malignancy 62% (16/26), immunological disorders 19% (5/26), gender reassignment treatment 8% (2/26), recurrent ovarian cyst surgery 8% (2/26) and benign haematological disease 4% (1/26). The youngest was aged 13 years and 10 months at the time of egg collection. Minimum time from menarche to ovarian stimulation was 11 months. 23% (6/26) adolescents had previously received chemotherapy. AMH was 2.8-37 pmol/L and AFC 2-36. AFC correlated well with AMH in the majority. Random-start was performed in 54% (14/26) and dual stimulation in 12% (3/26). Number of cryopreserved oocytes was 3-45 and number of MII oocytes cryopreserved 3-35. Ultrasound monitoring was performed transabdominally in 88% (23/26) and transvaginally in 12% (3/26). Egg collection was performed transvaginally in all cases in this cohort, comprising adolescents from varying ethnicities. All cycles proceeded to completion. There were no complications in any cycle, including the 42% (11/26) performed for haematological malignancy. All adolescents were counselled in association with a family member to obtain informed consent. All were assessed as able to comprehend discussions. Limitations, reasons for caution There is limited data on performing oocyte cryopreservation in adolescents. Further studies expanding on our findings are needed to support clinicians to perform oocyte cryopreservation in this population. Concerns remain regarding increased aneuploidy rates in this age group compared to women in their 20s. Livebirth outcome data is needed. Wider implications of the findings This is the largest case series to date. Post-pubertal adolescents as young as age 13 can undergo ovarian stimulation and oocyte cryopreservation. Transvaginal egg collection is an accepted procedure when counselled appropriately. Clinician experience, correct setting and funding enable a permissive environment for oocyte cryopreservation in this population. Trial registration number N/A

Reply: Evidence from a randomized controlled trial in the landscape of non-randomized studies in dual stimulation strategy.

Reply: Evidence from a randomized controlled trial in the landscape of non-randomized studies in dual stimulation strategy.

Low-quality evidence from a randomized controlled trial due to an inappropriate IVF setting to challenge Dual Stimulation strategy.

Journal Article Low-quality evidence from a randomized controlled trial due to an inappropriate IVF setting to challenge Dual Stimulation strategy Get access Filippo Maria Ubaldi, Filippo Maria Ubaldi IVIRMA Global Research Alliance, GENERA, Clinica Valle Giulia, Rome, Italy Correspondence address. IVIRMA Global Research Alliance, GENERA, Clinica Valle Giulia, Via G. de Notaris 2b, 00197 Rome, Italy. E-mail: ubaldi.fm@gmail.com https://orcid.org/0000-0002-6894-2147 Search for other works by this author on: Oxford Academic PubMed Google Scholar Alberto Vaiarelli, Alberto Vaiarelli IVIRMA Global Research Alliance, GENERA, Clinica Valle Giulia, Rome, Italy Search for other works by this author on: Oxford Academic PubMed Google Scholar Danilo Cimadomo, Danilo Cimadomo IVIRMA Global Research Alliance, GENERA, Clinica Valle Giulia, Rome, Italy https://orcid.org/0000-0002-5390-9221 Search for other works by this author on: Oxford Academic PubMed Google Scholar Maria Cerrillo, Maria Cerrillo IVIRMA Global Research Alliance, IVIRMA, Madrid, Spain Search for other works by this author on: Oxford Academic PubMed Google Scholar Laura Rienzi, Laura Rienzi IVIRMA Global Research Alliance, GENERA, Clinica Valle Giulia, Rome, ItalyDepartment of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino, Italy https://orcid.org/0000-0001-8104-3958 Search for other works by this author on: Oxford Academic PubMed Google Scholar Juan A Garcia-Velasco Juan A Garcia-Velasco IVIRMA Global Research Alliance, IVIRMA, Madrid, Spain https://orcid.org/0000-0003-1005-8727 Search for other works by this author on: Oxford Academic PubMed Google Scholar Human Reproduction, dead108, https://doi.org/10.1093/humrep/dead108 Published: 05 June 2023

ID: 219222 Peripheral Nerve Stimulation for Refractory Plantar Fibromatosis Pain: A Case Report and Literature Review

41-year-old man was referred by orthopedics to the outpatient pain clinic with history of chronic bilateral plantar heel pain and a diagnosis of plantar fibromatosis following diagnostic ultrasound evaluation. He had failed numerous non-operative treatments including shoe wear modification, orthoses, physical therapy, acupuncture, shock wave therapy, ultrasound guided corticosteroid injection, and percutaneous needle tenotomy. Upon initial consultation, the patient endorsed a 5-year history of bilateral medial plantar heel pain, provoked with weight bearing activities. He denied paresthesias and weakness. Given his refractory symptoms joint the decision was made to proceed with a diagnostic block of his more symptomatic side with goal to pursue bilateral percutaneous 60-day peripheral nerve stimulator placement if he experienced a favorable response. Diagnostic target was the left tibial nerve just proximal to the medial malleolus and prior to its division into plantar and calcaneal branches. Diagnostic injectate consisted of 2cc 1% lidocaine and 5mg of dexamethasone for a total volume of 2.5cc. Patient rated his pain 8/10 prior to injection and 0/10 following. He subsequently underwent placement of dual peripheral nerve stimulators targeting the bilateral tibial nerves with implantation 5cm proximal to the medial malleoli. At 60 day follow up, the device was explanted. The patient was no longer tender with palpation of either foot. He reported 50% reduction compared to pre-operative pain, significant improvement in his quality of life and physical functioning, and a reduction in oral analgesic regimen. The patient is currently awaiting permanent stimulator placement.

Advances in intranasal vaccine delivery: A promising non-invasive route of immunization.

The importance of vaccination has been proven particularly significant the last three years, as it is revealed to be the most efficient weapon for the prevention of several infections including SARS-COV-2. Parenteral vaccination is the most applicable method of immunization, for the prevention of systematic and respiratory infections, or central nervous system disorders, involving T and B cells to a whole-body immune response. However, the mucosal vaccines, such as nasal vaccines, can additionally activate the immune cells localized on the mucosal tissue of the upper and lower respiratory tract. This dual stimulation of the immune system, along with their needle-free administration favors the development of novel nasal vaccines to produce long-lasting immunity. In recent years, the nanoparticulate systems have been extensively involved in the formulation of nasal vaccines as polymeric, polysaccharide and lipid ones, as well as in the form of proteosomes, lipopeptides and virosomes. Advanced delivery nanosystems have been designed and evaluated as carriers or adjuvants for nasal vaccination. To this end, several nanoparticulate vaccines are undergone clinical trials as promising candidates for nasal immunization, while nasal vaccines against influenza type A and B and hepatitis B have been approved by health authorities. This comprehensive literature review aims to summarize the critical aspects of these formulations and highlight their potential for the future establishment of nasal vaccination. Both preclinical (in vitro and in vivo) and clinical studies are incorporated, summarized, and critically discussed, as well as the limitations of nasal immunization.

Ultrasonic/electrical dual stimulation response nanocomposite bioelectret for controlled precision drug release

Electret materials have attracted extensive attention because of their permanent polarization and electrostatic effect. However, it is one of problem that needs to be solved in biological application to manipulate the change of surface charge of electret by external stimulation. In this work, a drug-loaded electret with flexibility and no cytotoxicity was prepared under relatively mild conditions. The electret can release the charge through stress change and ultrasonic stimulation, and the drug release can be accurately controlled with the help of ultrasonic and electric double stimulation response. Here, the dipoles like particles of carnauba wax nanoparticles (nCW) are fixed in the matrix based on the interpenetrating polymer network structure, and "frozen" oriented dipolar particles that are treated by thermal polarization and cooled at high field strength. Subsequently, the charge density of the prepared composite electret can reach 101.1​nC/m2 at the initial stage of polarization and 21.1​nC/m2 after 3 weeks. In addition, the stimulated change of electret surface charge flow under cyclic tensile stress and cyclic compressive stress can generate a current of 0.187​nA and 0.105​nA at most. The ultrasonic stimulation results show that when the ultrasonic emission power was 90% (Pmax​=​1200​W), the current of 0.472​nA can be generated. Finally, the drug release characteristics and biocompatibility of the nCW composite electret containing curcumin were tested. The results showed that it not only had the ability to accurately control the release by ultrasound, but also triggered the electrical effect of the material. The prepared drug loaded composite bioelectret provides a new way for the construction, design and testing of the bioelectret. Its ultrasonic and electrical double stimulation response can be accurately controlled and released as required, and it has broad application prospects.

Simulation of Hemorrhage Pathogenesis in Mice through Dual Stimulation with Dengue Envelope Protein Domain III-Coated Nanoparticles and Antiplatelet Antibody.

Dengue hemorrhagic fever (DHF) is a severe form of dengue virus (DENV) infection that can lead to abnormal immune responses, endothelial vascular dysfunction, and hemorrhage pathogenesis. The virion-associated envelope protein domain III (EIII) is thought to play a role in the virulence of DENV by damaging endothelial cells. However, it is unclear whether EIII-coated nanoparticles simulating DENV virus particles could cause a more severe pathogenesis than soluble EIII alone. This study aimed to investigate whether EIII-coated silica nanoparticles (EIII-SNPs) could elicit greater cytotoxicity in endothelial cells and hemorrhage pathogenesis in mice compared to EIII or silica nanoparticles alone. The main methods included in vitro assays to assess cytotoxicity and in vivo experiments to examine hemorrhage pathogenesis in mice. EIII-SNPs induced greater endothelial cytotoxicity in vitro than EIII or silica nanoparticles alone. Two-hit combined treatment with EIII-SNPs and antiplatelet antibodies to simulate DHF hemorrhage pathogenesis during secondary DENV infections resulted in higher endothelial cytotoxicity than either treatment alone. In mouse experiments, two-hit combined treatment with EIII-SNPs and antiplatelet antibodies resulted in more severe hemorrhage pathogenesis compared to single treatments of EIII, EIII-SNPs, or antiplatelet antibodies alone. These findings suggest that EIII-coated nanoparticles are more cytotoxic than soluble EIII and could be used to develop a tentative dengue two-hit hemorrhage pathogenesis model in mice. Additionally, our results indicated that EIII-containing DENV particles could potentially exacerbate hemorrhage pathogenesis in DHF patients who have antiplatelet antibodies, highlighting the need for further research on the potential role of EIII in DHF pathogenesis.

N°191 – When minimizing body movement from motor evoked potential monitoring becomes fundamental. The advantage of adding Linked-quadripolar methodology to dual train stimulation in a patient with osteogenesis imperfecta (OI)

N°191 – When minimizing body movement from motor evoked potential monitoring becomes fundamental. The advantage of adding Linked-quadripolar methodology to dual train stimulation in a patient with osteogenesis imperfecta (OI)

Retrospective study of influencing factors on the outcomes of luteal phase stimulation in patients with dual stimulation.

Dual/double stimulation (DS) is an ovarian stimulation strategy that has emerged in recent years; it is characterized by two rounds of ovarian stimulation and oocyte retrieval in the same menstrual cycle. DS can greatly shorten the time required to obtain valid embryos in assisted reproduction. For fertility preservation, DS can speed up oocyte storage process. However, factors influencing luteal phase ovarian stimulation (LPS) outcomes in DS have not been elucidated. A total of 156 cycles from 78 cases were studied. Patients were grouped and analyzed according to their follicular phase ovarian stimulation (FPS) types. Female ages, ovarian stimulation protocols, number of oocytes retrieved, embryo quality were recorded. Comparisons of outcomes were conducted between different groups. Our study found that LPS obtained similar outcomes to follicular phase stimulation (FPS), and that the choice of FPS protocol affected the efficiency of LPS, the antagonist protocol and progestin-primed ovarian stimulation (PPOS) protocol resulted in better embryo outcomes in LPS. In LPS of DS, sufficient stimulation duration was the guarantee of embryo quality (number of available embryos: β = 0.145, 95% CI [0.078-0.211], P = 0.000; number of high-quality embryos: β = 0.114, 95% CI [0.057-0.171], P = 0.000). This study provided ideas for the precise use of DS. We suggest to further expand the sample size of DS in the future, conduct prospective controlled studies, unify the sample size of each subgroup, include the ovarian reserve of patients in the grouping basis, and exclude the influence of male factors. We hope that this study will help further refinement of DS so as to maximize patient benefits from it. When the DS strategy is considered in the follicular phase, the antagonist protocol and PPOS protocol are more recommended for better embryo outcomes in LPS. During LPS, adequate ovarian stimulation duration is the most important guarantee for LPS efficiency.

B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1* 07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA'-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL.

JNK signaling during IL-3-mediated differentiation contributes to the c-kit-potentiated allergic inflammatory capacity of mast cells.

Mast cells are leukocytes that mediate various aspects of immunity and drive allergic hypersensitivity pathologies. Mast cells differentiate from hematopoietic progenitor cells in a manner that is largely IL-3 dependent. However, molecular mechanisms, including the signaling pathways that control this process, have yet to be thoroughly investigated. Here, we examine the role of the ubiquitous and critical mitogen-activated protein kinase signaling pathway due to its position downstream of the IL-3 receptor. Hematopoietic progenitor cells were harvested from the bone marrow of C57BL/6 mice and differentiated to bone marrow-derived mast cells in the presence of IL-3 and mitogen-activated protein kinase inhibitors. Inhibition of the JNK node of the mitogen-activated protein kinase pathway induced the most comprehensive changes to the mature mast cell phenotype. Bone marrow-derived mast cells differentiated during impaired JNK signaling expressed impaired c-kit levels on the mast cell surface, first detected at week 3 of differentiation. Following 1 wk of inhibitor withdrawal and subsequent stimulation of IgE-sensitized FcεRI receptors with allergen (TNP-BSA) and c-kit receptors with stem cell factor, JNK-inhibited bone marrow-derived mast cells exhibited impediments in early-phase mediator release through degranulation (80% of control), as well as late-phase secretion of CCL1, CCL2, CCL3, TNF, and IL-6. Experiments with dual stimulation conditions (TNP-BSA + stem cell factor or TNP-BSA alone) showed that impediments in mediator secretion were found to be mechanistically linked to reduced c-kit surface levels. This study is the first to implicate JNK activity in IL-3-mediated mast cell differentiation and also identifies development as a critical and functionally determinative period.

Gold Nanorods and Polymer Micelles Mediated Dual TLR Stimulators Delivery System CPG@Au NRs/M‐R848 Regulate Macrophages Reprogramming and DC Maturation for Enhanced Photothermal Immunotherapy of Melanoma (Small Methods 5/2023)

Back Cover In article number 2201087, ZhiYong Qian and co-workers show that in the hybrid delivery systems [email protected] NRs/m-R848, immunogenic cell death (ICD) induced by Au NRs could synergistically produce an in-situ vaccination effect with CPG ODN and R848. By triggering dendritic cells maturation and macrophage reprogramming, this photothermal immunotherapy strategy holds great potential in generating systemic and lasting antitumor immunity by inhibiting tumor growth and metastases simultaneously.

Higher Initial Platelet Procoagulant Potential is Associated with Lower Cognitive Scores at 14 Months after COVID-19 (P2-12.004)

<h3>Objective:</h3> To examine whether coated-platelet levels measured at the time of acute SARS-CoV-2 infection predict cognitive impairment after recovery from COVID-19. <h3>Background:</h3> Coated-platelets are a subset of highly procoagulant platelets observed upon dual agonist stimulation with collagen and thrombin. Coated-platelet levels are increased in ischemic stroke compared to controls, and higher levels are associated with stroke recurrence. Previously, we have shown that higher coated-platelet levels at baseline are predictive of death at 90 days in COVID-19. Cognitive symptoms are frequently reported after recovery from SARS-CoV-2 infection. <h3>Design/Methods:</h3> After consent, patients with acute SARS-CoV-2 infection were enrolled. Coated-platelet levels were assayed at the time of admission and then weekly during the hospitalization. Symptoms of post-COVID-19 syndrome were evaluated using the CDC questionnaire. Cognitive screening was completed by telephone using the MoCA test for the blind, version 8.1. Regression analysis was used to evaluate the effect of clinical variables, demographics and coated-platelet levels on MoCA score. <h3>Results:</h3> We recruited 38 patients admitted with COVID-19. The 32 surviving patients were interviewed by telephone for long COVID symptoms at 14.8±2.4 months after infection. Twenty subjects (67%) reported having ≥1 long-COVID symptoms, most often brain fog and fatigue (39.4%). Among the 29 subjects (average age 65.5 years, range 33–88) who agreed to complete MoCA testing, mean MoCA score was 16.6 (range 10–21), with 17 (58.6%) screening positive for cognitive impairment. Coated-platelet levels drawn at enrollment during hospitalization for COVID-19 were inversely associated with MoCA scores after adjusting for age and time from symptom onset (adjusted R²=0.2, p=0.037). A 10% absolute increase in baseline coated-platelet levels corresponded to a 1.3-point decrease in MoCA score (p=0.009). <h3>Conclusions:</h3> These findings suggest that platelet procoagulant potential is linked to long-term lower cognitive performance after SARS-CoV-2 infection. Future work is needed to investigate coated-platelets and post-COVID cognitive decline. <b>Disclosure:</b> Dr. Delpirou Nouh has nothing to disclose. The institution of Dr. Prodan has received research support from US Department of Veterans Affairs (Merit award CX000340). Chao Xu has nothing to disclose. Andrea Vincent has received personal compensation for serving as an employee of Vista LifeSciences, Inc.. Eleanor Mathews has nothing to disclose. Leslie Guthery has nothing to disclose. Mr. Sharps has nothing to disclose. Jim Scott has nothing to disclose. George Dale has nothing to disclose. Angelia Kirkpatrick has nothing to disclose.

Self-powered stimuli responsive material for dual stimulation of heat and guest molecules

Stimuli-responsive smart materials exhibit reverse chemical/physical changes in response to external stimuli and research on stimuli-responsive smart materials with self-powered properties is still uncultivated ground. Here, we report perovskite crystalline self-powered multiple stimuli-responsive materials triggered by chemical and thermal stimuli. [HMEP]PbI3·(H2O) (1; HMEP is a hydroxytris(1-methylethyl)phosphorus cation) crystallizes in a chiral space group P21 at 293 K and has the piezoelectric reaction (d33 = 10 pC/N and output voltage = 1 V) of self-powered modes, this value is larger than the value of 3 pC/N for the classical piezoelectric material ZnO. Piezoelectric materials can generate energy due to mechanical deformation, and using thermal heating to lose water, [HMEP]PbI3 (2) can be obtained. 2 crystallizes in the non-centrosymmetric space group, undergoes two reversible phase transitions at 243/255 K and 315/348 K, and shows second harmonic generation switching. Interestingly, 2 can return to the hydrated form 1 after absorbing water. This work will lay the foundation for self-powered stimuli-responsive compounds and contribute to the construction of novel organic-inorganic hybrid materials with second harmonic generation switching.