Hypoalgesia after exercises with painful vs. non-painful muscles in healthy subjects – a randomized cross-over study

Objectives Exercise-induced hypoalgesia (EIH) is a decrease in the pain sensitivity after exercise. Individuals with chronic pain show less EIH after one exercise session compared with pain-free individuals possibly due to pain in exercising muscles. The primary aim of this randomized controlled cross-over study was to compare the EIH response at the exercising thigh muscle following exercises performed with painful vs. non-painful muscles. Secondary aims were to explore if a reduced EIH response was confined to the painful muscle, and whether the muscle pain intensity and the EIH responses were negatively associated. Methods In two sessions, 34 pain-free participants received a painful (hypertonic saline, 5.8%) injection and a control (isotonic saline, 0.9%) injection in the right thigh muscle before performing a 3 min isometric wall squat exercise. Pressure pain thresholds (PPTs) were assessed at both thighs and the left neck/shoulder at baseline, after injections and after exercise. Pain intensities in the thighs were rated on numerical rating scales (NRS: 0–10). Results Hypertonic saline induced moderate thigh pain at rest (NRS: 4.6 ± 2.1) compared to the control injection (NRS: 0.3 ± 0.4; p<0.001). EIH at the thighs and neck/shoulder were not different between sessions (Injected thigh: 0 kPa; 95% CI: −51 to 52; Contralateral thigh: −6 kPa; 95% CI: −42 to 30; neck/shoulder: 19 kPa; 95% CI: −6 to 44). No significant associations between pain intensity ratings immediately after the Painful injection and EIH responses at any assessment sites were found (right thigh: β=0.08, 95% CI: −12.95 to 20.64, p=0.64, left thigh: β=−0.33, 95% CI: −27.86 to 0.44, p=0.06; neck/shoulder: β=−0.18, 95% CI: −15.11 to 4.96, p=0.31). Conclusions Pain in the area of an exercising muscle did not reduce local or systemic EIH responses. Trial registration number NCT04354948.

Evaluation of skin irritation and skin sensitization potential of Venusia max lotion (paraben-free, alcohol-free, mineral oil-free, animal origin free) using human repeat insult patch test

<p class="abstract"><strong>Background:</strong> Topical exposure to chemicals from cosmetics can lead to adverse skin effects or skin irritation. This study aimed to investigate the skin irritation and sensitizing potential of a moisturizer Venusia max lotion (paraben-free, alcohol-free, mineral oil-free, animal origin free (PAMA) free).</p><p class="abstract"><strong>Methods:</strong> In this single-center, non-randomized, observational study, skin irritation, and skin sensitization potential of a test product was assessed using the human repeat insult patch test (HRIPT) technique. Approximately 0.04 g of the test product and filter papers dipped in 0.9% isotonic saline solution (~0.04 ml of solution) were filled in different wells of patch chambers and applied occlusively, on the back of each participant. Scoring of the skin reactions in the induction phase and challenge phase was done using Draize and international contact dermatitis research group (ICDRG) scales respectively. Scores were compared to the baseline and the negative control (isotonic saline).<strong></strong></p><p class="abstract"><strong>Results:</strong> In total 234 participants (50 with sensitive skin), 224 and 221 participants completed the induction phase and challenge phase respectively. Scores for the induction phase for Venusia max lotion (PAMA free) and isotonic saline were 0.46 and 0.06 respectively. The mean cumulative score of erythema and oedema for Venusia max lotion (PAMA free) was below 2. For the challenge phase, none of the participants showed any positive reactions at any time point for test product and isotonic saline.</p><p class="abstract"><strong>Conclusions:</strong> Test product Venusia max lotion (PAMA free) found to be non-irritant and hypoallergenic. Thus, it can be used without fear of skin irritation or sensitization.</p>

Correction of ultrastructural paclitaxel-induced spinal cord motoneurons lesions

Background. Paclitaxel-induced peripheral neuropathy (PIPN) is a major side effect of paclitaxel in patients with cancer with no fully known mechanisms. The aim of the study was to investigate the fine sub-microscopic structure of the spinal cord anterior horn neurons in PIPN combined with 2-ethyl-6-methyl-3-hydroxypyridine succinate administration. Methods. The experiment was performed on 80 white rats, which were administered intraperitoneally with Paclitaxel (Actavis, Romania), pre-dissolved in an isotonic saline at a dose of 2 mg / kg body weight four times a day to achieve a dose of 8 mg / kg. Then 48 of these animals were injected intraperitoneally 2-ethyl-6-methyl-3-hydroxypyridine succinate at a dose of 10 mg / kg (32 rats received intraperitoneally water for injection). Observation periods were 1, 7, 14, 21, 28 days. Results. We found that 2-ethyl-6-methyl-3-hydroxypyridine corrects the morpho-functional state of the motor neurons of the spinal cord and revealed a positive metabolic effect on them. Conclusion. This was manifested by the improvement of the electron microscopic picture of the neuronal structures responsible for their protein-synthetic (granular endoplasmic reticulum, ribosomes and polysomes), respiratory (mitochondria), and protective (lysosomes) functions.

The Effect of Isotonic Saline Nasal Lavages in Improving Symptoms in SARS-CoV-2 Infection: A Case-Control Study

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mainly colonizes nasopharynx. In upper airways acute infections, e.g., the common cold, saline nasal irrigations have a significant efficacy in reducing symptoms. The present study aimed to test the efficacy of nasal lavages in upper airways symptoms of Coronavirus Disease 2019 (COVID-19).Methods: A series of consecutive adult subjects who tested positive for SARS-CoV-2 from December 2020 to February 2021 performed daily nasal lavages with saline solution (Lavonase®—Purling, Lugo di Romagna, Italy) for 12 days, starting on the day after the SARS-CoV-2 positive swab. A control group included a historical series of patients who were infected in February-March 2020 and who did not perform lavages. An ad hoc questionnaire regarding symptoms was administered to each subjects at base-line and 10 days after diagnosis (i.e., on the same day of the control swab) in both cases and controls.Results: A total of 140 subjects were enrolled. 68 participants in the treatment group and 72 in the control group were included. 90% of respondents declared the lavages were simple to use and 70% declared they were satisfied. Symptoms of blocked nose, runny nose, or sneezing decreased by an average of 24.7% after the treatment. Blocked nose and sneezing increased in the same period of time in the control group. Ears and eyes symptoms, anosmia/ageusia symptoms, and infection duration (10.53 days in the treatment group and 10.48 days in the control group) didn't vary significantly among the two groups.Conclusion: Nasal lavages resulted to significantly decrease nasal symptoms in newly diagnosed SARS-CoV-2 patients. These devices proved to be well-tolerated and easy to be used. Further studies on a larger number of subjects are needed in order to possibly confirm these preliminary results.

Maternal and Fetal Response to Pre Anesthetic ‎Magnesium Sulphate in Cesarean Section

Background: Magnesium, the fourth most common cation in the body, has an ‎antagonistic effect at the N-methyl-D-aspartate (NMDA) receptor, as ‎well as calcium-channel blocker properties. Antagonism at the ‎NMDA receptor is thought to alter the mechanism of central ‎hypersensitivity and to subsequently decrease analgesic requirements ‎including opioid consumption.‎‎ This study aimed to assess the effects of preoperative administration of intravenous magnesium sulphate on the intubation stress response as a primary outcome and uterine, fetal middle cerebral and umbilical arterial blood flow, Apgar score and postoperative analgesia as secondary outcomes in participants undergoing elective caesarian section under general anesthesia. Methods: This prospective randomized controlled double blinded study ‎was carried out on 65 pregnant females between 21-35 years old undergoing elective caesarian section under general anesthesia. who were randomly classified randomly into two groups: Magnesium sulphate (Mg) group: received 25 mg/kg magnesium sulphate in 100 ml isotonic saline over 10 minutes before induction of anesthesia. Control group (C): received the same volume of isotonic saline over the same period. Results: Heart rate and mean arterial blood pressure were decreased significantly at post induction to the end of surgery in mg sulphate compared to control group and was insignificantly different between the studied groups at T0 and T1. VAS was significantly lower in mg sulphate group compared to control group at 1, 2, 4, 8, 12 and 24 hours and was insignificantly different among the two groups at PACU admission and 30 min. preoperative administration of magnesium sulphate (25 mg/kg) was associated with lower postoperative pain scores, less post-operative analgesic consumption, better hemodynamic stability without significant difference in umbilical, middle cerebral and uterine arteries blood flow or Apgar score compared to control group in patients undergoing cesarean section under general anesthesia. There was no statistically significant difference in the incidence of sedation and hypotension. No cases showed respiratory depression in the two groups. Conclusion: Preoperative administration of ‎magnesium sulphate (25mg/kg) was associated with better ‎hemodynamic stability, lower postoperative pain scores, less post-‎operative analgesic consumption without significant difference in ‎umbilical, middle cerebral and uterine arteries blood flow or Apgar ‎score with nil complications except for PONV compared to control ‎group in patients undergoing cesarean section under general ‎anesthesia.‎‎

Pharmacokinetics and Pharmacodynamics of Recombinant FIX Variants in the FIX Knockout Mouse Tail Clip Bleeding Model

Introduction: The recessive X-linked bleeding disorder Hemophilia B is caused by a mutation in the coagulation factor (F) IX gene leading to partial or total loss of its function. Preventive treatment with replacement long-acting FIX is an attractive option for patients to reduce administration frequency and prevent bleeding. New recombinant FIX therapeutics like the albumin-fused FIX (rFIX-FP) or the Fc-fused FIX (rFIX-Fc) enable longer half-life in circulation and thus less frequent administration, as compared to non-fused FIX (rFIX). Studies in FIX knockout (KO) mice were conducted to characterize the effect of the modifications on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the different recombinant FIX products. Methods: Pharmacokinetics: Recombinant FIXs were administered intravenously at doses of 25 nmol/kg (corresponding to ~175-400 IU/kg FIX clotting activity) to FIX KO mice. Blood samples were collected starting at 5 min, and up to 336 h. FIX plasma levels were measured with an ELISA-based assay with anti-human FIX paired antibodies. PK was evaluated by non-compartmental analysis. Biodistribution: 3H-labeled recombinant FIXs were administered intravenously at doses of 200 IU/kg to FIX KO mice. Plasma levels and organ distribution were quantified starting at 15 min, and up to 240 h. Pharmacodynamics: FIX KO mice were treated intravenously with 50 IU/kg FIX clotting activity (nominal or labeled potency) of different rFIX products at 24, 72, 120 168 and 336 h prior to determination of bleeding time and total blood loss in a tail clip bleeding model. Immediately upon lesion, the tail tip was submerged in isotonic saline (0.9 %), kept at the mice physiological body temperature. Time to hemostasis is quantified as the time until bleeding stops for a minimum of 2 min. The volume of total blood loss was calculated by measuring the hemoglobin present in the isotonic saline solution at the end of the experiment. Results: Distinct PK profiles were observed for the three FIX molecules, where rFIX and rFIX-Fc exhibit an initial rapid distribution phase from plasma, while rFIX-FP showed a monophasic elimination profile up to 120 h post administration (p.a.). In the terminal phase, rFIX levels were quantifiable for up to 48 h p.a., while both; rFIX-FP and rFIX-Fc were measurable in plasma up to 240 h p.a. In line with this, the overall exposure AUC 0-inf is ranked in the following order: rFIX-FP &gt; rFIX-Fc &gt; rFIX. In the biodistribution study, a similar plasma PK profile was determined. Given the sensitivity of the radioactive method, an exposure plateau was observed for rFIX-Fc, and at lower levels for rFIX, whereas rFIX-FP continued to exhibit monophasic plasma clearance behavior. rFIX-FP exposure in the extravascular space (EVS) was lower than for the other FIX products. This is in line with volumes of distribution (Vss and Vz) which were highest for rFIX-Fc (AUC ranking rFIX-Fc &gt; rFIX &gt; rFIX-FP). FIX hemostatic efficacy in tail clip model was comparable for all 3 FIXs at the early time points but diverged at later time points post dosing. The blood loss and bleeding time measurements returned to baseline within 168 h for rFIX and rFIX-Fc, while the rFIX-FP group maintained robust hemostatic activity for up to 336 h. In contrast to lowest tissue exposure of rFIX-FP, the plasma AUC for rFIX-FP was highest, compared to FIX-Fc or FIX. In line, efficacy over time was also highest for rFIX-FP, suggesting that tissue exposure might not be the main driver for hemostatic activity. Conclusion: Different FIX products exhibit divergent PK and PD behaviors. rFIX-FP plasma PK profile suggests somewhat lower tissue distribution in comparison to rFIX-Fc and rFIX, which was confirmed in the tissue biodistribution study. Despite its limited extravasation into tissue, rFIX-FP exhibits superior and prolonged hemostatic activity in the FIX KO mouse tail clip model. rFIX and rFIX-Fc show comparable tissue biodistribution behavior, with robust extravasation into the EVS. Despite having the longest half-life and overall (plasma and tissue) exposure in the mouse, rFIX-Fc lost hemostatic activity in the tail clip model significantly faster than rFIX-FP. As a result, hemostatic efficacy was highest for the FIX-FP, the product with the lowest distribution volumes. The results therefore suggest that EVS is not the main determining factor for FIX efficacy in vivo. Disclosures Pestel: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Peil: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Knoll Machado: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Claar: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Raquet: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Ponnuswamy: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Mischnik: CSL Behring Innovation GmbH: Current Employment, Current equity holder in publicly-traded company. Herzog: CSL Behring GmbH: Current Employment, Current equity holder in publicly-traded company.

1047. Development of a Next Generation 30+ Valent Pneumococcal Conjugate Vaccine (VAX-XP) Using Site-Specific Carrier Protein Conjugation

Background Due to the diversity of serotypes, exacerbated by the phenomenon of serotype replacement, there remains an unmet medical need for a pneumococcal conjugate vaccine (PCV) containing additional serotypes. Using a cell-free protein synthesis (CFPS) platform to produce an enhanced carrier protein (eCRM®) based on the CRM197 sequence, Vaxcyte is developing a PCV encompassing over 30 serotypes. The eCRM carrier protein contains multiple insertions of the non-native amino acid para-azidomethyl-L-phenylalanine (pAMF) that facilitates site-specific conjugation of the pneumococcal polysaccharides (PS) to eCRM. Unlike conventional methodologies, site-selective conjugation enhances process consistency and increases capacity for inclusion of additional serotypes in a PCV without promoting carrier suppression. Using this platform, the aim of the current study was to employ CFPS technology to construct a 31-valent PCV and evaluate its immunogenicity in New Zealand White (NZW) rabbits. Methods The eCRM carrier protein was individually conjugated to each of 31 selected pneumococcal PSs using copper-free click chemistry to produce 31 Conjugate Drug Substances (DS), which were then mixed with aluminum phosphate to produce the VAX-XP Drug Product. 24 of the DS conjugates in VAX-XP were generated at manufacturing scale. Two doses of VAX-XP were administered to NZW rabbits at 0 and 21 days to assess its ability to elicit anti-capsular IgG antibodies. Additionally, rabbits were also administered either Prevnar13 or a mixture of Pneumovax 23 and 8 incremental PS in isotonic saline, as comparators. Results VAX-XP showed conjugate-like immune responses for all 31 serotypes, as demonstrated by superior responses to PS-based vaccines and comparable responses to Prevnar13. IgG responses for VAX-XP compared with Prevnar13 and Pneumovax 23 at 14 days post dose 2 Conclusion These results demonstrate that increasing the number of pneumococcal serotypes does not result in immunological attenuation in any of the serotypes contained in VAX-XP relative to the current standard of care. Furthermore, the data confirm the scalability and reproducibility of the CFPS platform in the production of VAX-XP conjugates, creating the foundation for a next generation broad-valency PCV. Disclosures Chris Behrens, PhD, Vaxcyte, Inc. (Employee) Jeff Fairman, PhD, Vaxcyte, Inc. (Employee) Paresh Agarwal, PhD, Vaxcyte, Inc. (Employee) Shylaja Arulkumar, MS, Vaxcyte, Inc. (Employee) Sandrine Barbanel, MS, Vaxcyte, Inc. (Employee) Leslie Bautista, n/a, Vaxcyte, Inc. (Employee) Aym Berges, PhD, Vaxcyte, Inc. (Employee) John Burky, BS, Vaxcyte, Inc. (Employee) Peter Davey, MS, Vaxcyte, Inc. (Employee) Chris Grainger, PhD, Vaxcyte, Inc. (Employee) Sherry Guo, PhD, Vaxcyte, Inc. (Employee) Sam Iki, MS, Vaxcyte, Inc. (Employee) Mark Iverson, BS, Vaxcyte, Inc. (Employee) Neeraj Kapoor, PhD, Vaxcyte, Inc. (Employee) Olivier Marcq, PhD, Vaxcyte, Inc. (Employee) Thi-Sau Migone, PhD, Vaxcyte, Inc. (Employee) Lucy Pill, MS, Vaxcyte, Inc. (Employee) Mohammed Sardar, n/a, Vaxcyte, Inc. (Employee) Paul Sauer, MBA, Vaxcyte, Inc. (Employee) James Wassil, MS MBA, Vaxcyte, Inc. (Employee)

Aspects of differential diagnosis and treatment of rhinitis in children under 2 years of age

Introduction. Clinical manifestations of rhinitis have a negative impact not only on the physical, social, and psychological health of children, but also on their parents, especially in families with a first child. Nasal congestion, nasal breathing difficulty cause problems with sleep and feeding.Aim of the study. To estimate the occurrence of rhinitis in children under two years old in the outpatient practice of otorhinolar-yngologists, to consider features of the course and differential diagnostics of various rhinitis types, to evaluate the effectiveness of nasal irrigation-elimination therapy in the treatment of acute rhinitis symptoms.Materials and Methods. Between September 2020 and July 2021, 220 patients between 0 to 18 years were managed: preschool-aged patients comprised 120 patients (54.5%), of whom 27 patients under two years old had symptoms of rhinitis, including those with symptoms lasting more than two weeks.Results. Among the patients referred to us, infectious rhinitis was diagnosed in the majority of cases - in 18 patients (66,7%), which can be explained not only by the timing of the study but also by the highest prevalence of this pathology among the diseases of the nasal cavity. Allergic and non-allergic rhinitis occurred in only 4 (14.8%) and 5 (18.5%) persons, respectively. Symptomatic irrigation therapy with saline solutions is just as necessary for young children as it is for older children and adults. Some difficulties in nasal cavity care during rhinitis are the anatomical narrowness of the nasal passages and lack of blowing skills in young children. In these situations, preference should be given to gentle, non-traumatic, gentle aspiration with prior irrigation of the nasal cavity with an isotonic saline solution. When a nasal aspirator was used, there was a decrease in the duration of nasal discharge during the illness and a reduction in the duration of the disease.Conclusion. Rhinitis in young children is a common but underestimated problem. Clinical manifestations are more often associated with typical symptoms: nasal congestion, discharge, nasal breathing difficulty, and sneezing. The use of irrigation-elimination intranasal therapy with the use of a nasal cavity aspirator can reduce the timing of clinical symptoms of rhinitis and reduce the overall duration of the disease.

Role of Point of Care Ultra Sound (POCUS) in Assessment of Fluid Resuscitation in Septic Patients

Background: Initial fluid resuscitation in sepsis must be guided by clinical judgment based on ongoing reevaluation of the hemodynamic status (heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urine output) and ultrasound measurements (stroke volume, cardiac output, lung ultrasound and inferior vena cava diameter) as positive fluid balance is harmful. Methods: Adults Patients (≥ 18 years old) with symptoms or signs of tissue hypoperfusion (Sequential organ failure assessment score SOFA≥ 2) are included. Patients with elevated intra-abdominal pressure (as, ascites, pregnancy), Recent abdominal operation, cannot lie flat, Patient on mechanical ventilation and patients with valvular heart disease were excluded. IVC CI, SV, COP and B mean score were measured on patient arrival and after every 10 ml/kg isotonic saline over the first hour of patient arrival. Thereafter, patients were divided into two groups high caval index and low caval index according to inferior vena cava collapsibility index. Results: Among our 50 patients,38% of patients were with high caval index and 62% have low caval index. Conclusion: POCUS has additive value in guiding of fluid resuscitation in sepsis in order to avoid fluid overload and to identify proper timing of vasopressor use.

The effect of intravenous infusion of magnesium sulphate during spinal anesthesia on post-operative analgesia in patients undergoing total hip replacement

Introduction Fundamental of regional anesthesia is pharmacologically interrupting transmission of sensation in the specific nerve fiber. The sensory signals generated by tissue damage triggers a state of increased excitability, leading to prolonged post-operative pain or sensitization to such pain. The optimal pain treatment pre-empts the establishment of pain hypersensitivity during and after surgery by minimizing the patient discomfort while leaving physiologic nociceptive mechanisms intact so as to function as an early warning symptom. Aim To measure the effect of intravenous magnesium infusion during spinal anesthesia on post operative analgesia in patients undergoing total hip replacement. Patients and Methods Patients were randomly assigned to two groups using closed envelopes chosen by patients before the study. Patients in the magnesium group (Group M, n = 15) received magnesium sulphate 50 mg per Kg over 15 min after spinal anesthesia and then 15 mg per Kg per hr by continuous i.v. infusion until the end of surgery. Patients in the saline group (Group S, n = 15) received the same volume of isotonic saline over the same period. Infusions were prepared in pharmacy and they were administered using the infusion machines. Study data were recorded by an observer unaware of group assignments. Results the study showed that intravenous magnesium infusion during spinal anesthesia decreased VAS results in magnesium group specifically in the first 24 hours and hence decreasing need for post operative rescue analgesic consumption .Also post operative nausea,vomiting and shivering were lower in magnesium group. Conclusion We concluded that intravenous magnesium infusion during spinal anesthesia improves post operative analgesia and reduces incidence of nausea, vomiting and shivering in patients undergoing total hip replacement.