Time Point Of Administration Research Articles

Effects of intranasal oxytocin on fear extinction learning.

Once a threat no longer exists, extinction of conditioned fear becomes adaptive in order to reduce allotted resources towards cues that no longer predict the threat. In anxiety and stress disorders, fear extinction learning may be affected. Animal findings suggest that the administration of oxytocin (OT) modulates extinction learning in a timepoint-dependent manner, facilitating extinction when administered prior to fear conditioning, but impairing it when administered prior to extinction learning. The aim of the present study was to examine if these findings translate into human research. Using a randomized, double-blind, placebo-controlled, 2-day fear conditioning and extinction learning design, behavioral (self-reported anxiety), physiological (skin conductance response), neuronal (task-based and resting-state functional magnetic resonance imaging), and hormonal (cortisol) data were collected from 124 naturally cycling (taking no hormonal contraceptives) healthy females. When administered prior to conditioning (Day 1), OT, similar to rodent findings, did not affect fear conditioning, but modulated the intrinsic functional connectivity of the anterior insula immediately after fear conditioning. In contrast to animal findings, OT impaired, not facilitated, extinction learning on the next day and increased anterior insula activity. When administered prior to extinction learning (day 2), OT increased the activity in the bilateral middle temporal gyrus, and similar to animal findings, reduced extinction learning. The current findings suggest that intranasal OT impedes fear extinction learning in humans regardless of the timepoint of administration, providing new insights and directions for future translational research and clinical applications.

Delays to Antibiotics in the Emergency Department and Risk of Mortality in Children With Sepsis

Pediatric consensus guidelines recommend antibiotic administration within 1 hour for septic shock and within 3 hours for sepsis without shock. Limited studies exist identifying a specific time past which delays in antibiotic administration are associated with worse outcomes. To determine a time point for antibiotic administration that is associated with increased risk of mortality among pediatric patients with sepsis. This retrospective cohort study used data from 51 US children's hospitals in the Improving Pediatric Sepsis Outcomes collaborative. Participants included patients aged 29 days to less than 18 years with sepsis recognized within 1 hour of emergency department arrival, from January 1, 2017, through December 31, 2021. Piecewise regression was used to identify the inflection point for sepsis-attributable 3-day mortality, and logistic regression was used to evaluate odds of sepsis-attributable mortality after adjustment for potential confounders. Data analysis was performed from March 2022 to February 2024. The number of minutes from emergency department arrival to antibiotic administration. The primary outcome was sepsis-attributable 3-day mortality. Sepsis-attributable 30-day mortality was a secondary outcome. A total of 19 515 cases (median [IQR] age, 6 [2-12] years) were included. The median (IQR) time to antibiotic administration was 69 (47-116) minutes. The estimated time to antibiotic administration at which 3-day sepsis-attributable mortality increased was 330 minutes. Patients who received an antibiotic in less than 330 minutes (19 164 patients) had sepsis-attributable 3-day mortality of 0.5% (93 patients) and 30-day mortality of 0.9% (163 patients). Patients who received antibiotics at 330 minutes or later (351 patients) had 3-day sepsis-attributable mortality of 1.2% (4 patients), 30-day mortality of 2.0% (7 patients), and increased adjusted odds of mortality at both 3 days (odds ratio, 3.44; 95% CI, 1.20-9.93; P = .02) and 30 days (odds ratio, 3.63; 95% CI, 1.59-8.30; P = .002) compared with those who received antibiotics within 330 minutes. In this cohort of pediatric patients with sepsis, 3-day and 30-day sepsis-attributable mortality increased with delays in antibiotic administration 330 minutes or longer from emergency department arrival. These findings are consistent with the literature demonstrating increased pediatric sepsis mortality associated with antibiotic administration delay. To guide the balance of appropriate resource allocation with time for adequate diagnostic evaluation, further research is needed into whether there are subpopulations, such as those with shock or bacteremia, that may benefit from earlier antibiotics.

The Sex-based Differences in Chemoreflex during Recovery from Acute Lung Injury

Introduction- Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the peripheral (or carotid body) chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI in not known. To bridge this gap, our current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery of ALI. Methods- ALI was induced using a single intra-tracheal instillation of bleomycin (bleo) (day 1). Resting fR (respiratory frequency) was measured at pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo time points. The chemoreflex response to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before bleo administration (pre-bleo) time point and 1 month (1 mth) post-bleo using whole-body plethysmography. Apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point. Results- Resting fR: There were no significant differences in resting fR, either at pre-bleo time point or at day 7 (D7) post-bleo between male and female rats. At 1 mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly slower in male rats compared to female rats. AHI, post-sigh apneas, and sighs: At the pre-bleo and 1 mth post-bleo time points, there were no significant differences in AHI, post-sigh apneas, and sighs between male and female rats. However, at D7 post-bleo, the male rats exhibited a higher AHI than female rats; Chemoreflex sensitivity: Both male and female rats exhibited a sensitized chemoreflex activation to hypoxia and normoxic-hypercapnia with no significant differences between sexes. Discussion- Our study showed a sex difference in resting ventilatory parameters including resting fR and AHI post ALI. On the other hand, we did not find any sex difference in chemoreflex sensitization at 1 mth post-bleo. This research contributes to a better understanding of sex-based variations in lung disorders. This study was supported by NIH grant R01 HL-152160 and in part, by NIH grants R01 HL-121012 and R01 HL126796. H-JW was also supported by Margaret R. Larson Professorship in Anesthesiology. IZ was partially supported by the Theodore F. Hubbard Foundation. KK was supported by the AHA predoctoral fellowship -AHA award #903872 by the American Heart Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium.

Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all p ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (p = 0.64, p = 0.32) between the groups. Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration.

Comparing remote versus in-person assessment of learning skills in children with specific learning disabilities.

Interactive telemedicine applications have been progressively introduced in the assessment of cognitive and literacy skills. However, there is still a lack of research focusing on the validity of this methodology for the neuropsychological assessment of children with Specific Learning Disorder (SLD). Seventy-nine children including 40 typically developing children (18 males, age 11.5 ± 1.06) and 39 children with SLD (24 males, age 12.3 ± 1.28) were recruited. Each participant underwent the same neuropsychological battery assessing reading accuracy, speed, and comprehension, writing, numerical processing, computation, and semantic numerical sense, twice (once during an in-person session (I) and once during a remote (R) home-based videoconference session). Four groups were subsequently defined based on the administration order. Repeated-measure-ANOVAs with assessment type (R vs. I testing) as within-subject factor and diagnosis (SLD vs. TR) and administration order (R-I vs. I-R) as between-subject factors, and between-group t-tests comparing the two assessment types within each time of administration, were run. No differences emerged between I and R assessments of reading accuracy and speed, numerical processing, and computation; on the contrary, potential biases against R assessment emerged when evaluating skills in writing, reading comprehension, and semantic numerical sense. However, regardless of the assessment type, the scores obtained with I and R assessments within the same administration time point overlapped. These results partially support the validity and reliability of the assessment of children's learning skills via a remote home-based videoconferencing system. Implementing telemedicine as an assessment tool may increase timely access to primary health care and to support research activity.

Quality of life with minimally invasive repair of pectus excavatum: a systematic review and meta-analysis.

Minimally invasive repair of pectus excavatum (MIRPE) is a popular method for surgical correction of PE, and its impact on quality of life is a growing area of interest. We performed a systematic review and meta-analysis to evaluate the impact of MIRPE on the quality of life of patients. This study was registered with PROSPERO under reference number CRD42020222061. A literature search of PubMed, Cochrane Library, EMBASE and Scopus was conducted from the date of inception till November 23, 2020. We included studies which administered one or more questionnaires on patients up to 60 years old, parents or both, to assess the quality of life before and after MIRPE. Studies not written in English, abstracts, articles without primary data, reviews and studies which combined data on PE and other deformities were excluded. Risk of bias was assessed using the Risk of Bias in Non-randomised Studies of Interventions and the Cochrane risk of bias tool. A random-effects meta-analysis was performed to obtain mean differences for key themes of quality of life before and after MIRPE. Responses from the same questionnaires, as well as common themes across different questionnaires, were compared. Of the 20 studies identified for systematic review, 7 studies that reported the responses of 478 patients were included in the meta-analysis. Patients who underwent MIRPE experienced an increased self-esteem [standardized mean difference (SMD): 1.38, 95% confidence interval (CI): 0.95 to 1.81, P<0.00001] and a smaller degree of chest interference with their social activities (SMD: 0.84, 95% CI: 0.60 to 1.08, P<0.00001). These findings were consistent even after the implanted bar was removed. MIRPE may be associated with a better quality of life for patients with PE as self-esteem and extent of chest interference with social activities are improved after the procedure. The key limitations of this study are the lack of high-quality evidence due to paucity of randomized trials, and the significant heterogeneity in reported outcomes due to variations in the questionnaires and timepoints of administration.

Examination of the validity of the Injury-Psychological Readiness to Return to Sport (I-PRRS) scale in male professional football players: A worldwide study of 29 professional teams

ABSTRACT Perceived confidence is an important dimension of an athlete’s psychological readiness to return-to-play. However, there is no established and validated tool to evaluate confidence in professional football. This study aimed to provide preliminary evaluation of the internal structure of the Injury-Psychological Readiness to Return-to-Sport scale (I-PRRS) in a cohort of injured male professional footballers. Over an 18-month period, 29 teams from 17 leagues participated. Players sustaining injuries eliciting ≥ 3 weeks’ time-loss were recruited. Cross culturally adapted to 4 further languages, the I-PRRS was administered on two occasions: 1) day before returning-to-training and 2) day before returning-to-match-play. In total, 113 injuries were recorded with 96 completed I-PRRS data sets collected. Confirmatory factor analysis indicated the I-PRRS was a unidimensional scale, with all items measuring the same construct. The scale demonstrated good internal consistency (ω = .88). When examining longitudinal invariance of the I-PRRS across administration time-points, indices of model fit supported scalar invariance. There was preliminary evidence of good internal structure for the I-PRRS in professional male footballers. However, before further research involving the I-PRRS can be endorsed, efforts to confirm or refute empirical developments pertaining to psychological readiness are necessary.

Ruscogenin timing administration mitigates cerebral ischemia-reperfusion injury through regulating circadian genes and activating Nrf2 pathway

BackgroundRuscogenin (Rus), a steroidal sapogenin extracted from Ophiopogon japonicus (L. f.) Ker-Gawl., has the effect of alleviating cerebral ischemia-reperfusion injury (IRI), acute lung injury. At present, the chronopharmacological effects of Rus are still unknown. PurposeThis study explored the alleviating effect and mechanism of Rus timing administration on mice cerebral IRI. MethodsThe animals in different groups were administrated Rus (10 mg/kg) by gavage at four time points (23:00–01:00, 05:00–07:00, 11:00–13:00, 17:00–19:00) respectively for 3 days. On the 4th day, middle cerebral artery occlusion (MCAO) surgery was operated during 5:00–7:00. Behavioral tests were executed and the brain was collected for infarct volume, qPCR and immunoblot detection. The levels of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin-1beta (IL-1β) and inducible nitric oxide synthase (iNOS) were detected by qPCR. Glutathione (GSH), superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in serum and cerebral cortex were detected. The clock genes were tested by western blot. Based on these results, 17:00–19:00 was selected to administrate Rus for further mechanism study and Nrf2 blocker group was administrated all-trans-retinoic acid (ATRA) at 14:00 for 3 days. ResultsAdministration of Rus reduced cerebral infarcted volume, ameliorated the behavior score and upregulated the mRNA and protein expression of Per1, Bmal1, Clock, Rev-erbα, transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), quinone oxidoreductase 1 (NQO1). Administration of Rus during 17:00–19:00 had better preventive effect than other three time points. Combined administration of ATRA blunted the preventive effect of Rus. ConclusionThe preventive effect of Rus is affected by the time of administration, which was regulated by Nrf2 pathway. Taken together, we provide solid evidence to suggest that different administration time point affect the effectiveness of Rus in alleviating IRI.

Trends in Patient-Reported Outcomes Reporting in Breast Reconstruction: A Scoping Literature Review.

Patient-reported outcomes (PROs) provide essential information in reconstructive surgery, where interventions center on patients' functional and aesthetic goals. Although multiple patient-reported outcome measures (PROMs) have been validated for breast reconstruction since 2009, no studies have assessed recent frequency and consistency in use. This study aims to characterize recent trends in inclusion of PROs in recent breast reconstruction literature. Articles published between 2015 and 2021 pertaining to autologous and/or prosthetic breast reconstruction in Annals of Plastic Surgery and Journal of Plastic and Reconstructive Surgery were considered in a scoping review. Original breast reconstruction articles were reviewed for use of PROMs and characteristics of administration in accordance with PRISMA-Scr guidelines. Previously defined scoping review criteria were considered, including PROM used, timeline of collection, and topics addressed, with trends in frequency and consistency of usage assessed over the designated period. Of the 877 articles reviewed and 232 articles included, 24.6% reported using any PROM. The majority used BREAST-Q (n = 42, 73.7%), with the remainder being institutional surveys or previously validated questionnaires. Patient-reported outcomes were most often collected retrospectively (n = 20, 64.9%) and postoperatively (n = 33, 57.9%). The average time point of postoperative survey administration was 16.03 months (SD, 19.185 months). χ2 Analysis revealed no significant association between the numbers of articles, including PROMs and the year (P = 0.1047). This study demonstrates that only one-fourth of breast reconstruction articles report the use of PROMs with no interval increase over recent years. Patient-reported outcome measures were predominantly used retrospectively and postoperatively with notable variation in timing of administration. The findings highlight the need for improved frequency and consistency of PROM collection and reporting, as well as for further exploration into barriers and facilitators of PROM use.

Effect of Lactobacillus plantarum P9 on defecation, quality of life and gut microbiome in individuals with chronic diarrhoea: Protocol for a randomized, double-blind, placebo-controlled clinical trial

BackgroundProbiotics may be an ideal choice for these patients, given it can improve the defecation and quality of life of individuals with chronic diarrhoea. However, evidence-based medical research is still limited to support its use as a diarrhoea agent. MethodA randomized, double-blind, placebo-controlled clinical trial is designed to pinpoint the efficiency and possible action modes of probiotics for chronic diarrhoea. 200 eligible volunteers with chronic diarrhoea are randomly assigned to a probiotic group (orally taking Lactobacillus plantarum p9 probiotics powder) or a placebo group. Except an independent project administrator who will be responsible for unblinding, the other researchers are blinded. Primary outcome is diarrhoea severity score, and secondary outcomes include weekly mean frequency of defecation, weekly mean stool appearance score, weekly mean stool urgency score, emotional state score, gut microbiome, and faecal metabolome. Each outcome measure will be assessed at the timepoints of pre-administration (day 0), administration (day 14 and/or 28), and post-administration (day 42) to identity inter- and intra-groups differences. Adverse events will be recorded to evaluate the safety of L. plantarum p9. DiscussionThe study protocol will provide high-quality evidence for the use of probiotics as a diarrhoea agent when it is strictly conducted out, providing evidence regarding whether and to what extent L. plantarum p9 can improve the defecation and well-being of individuals with chronic diarrhoea. Trial registrationChinese Clinical Trial Registry (ChiCTR) (NO. ChiCTR2000038410). Registered on November 22, 2020, https://www.chictr.org.cn/showproj.aspx?proj=56542.

Comparative evaluation of two intranasal forms of Curcumin: Quantitation and impact on mouse model of asthma

Aim of the studyPresent study aimed to investigate impact of two different intranasal forms of curcumin on mouse model of asthma and detection of its absorption after different time points of administration. Since the systemic bioavailability of curcumin is very low, therefore, intranasal route of administration has been explored here where systemic absorption of two intranasal forms of curcumin was evaluated. Materials and methodsTo explore the possibilities of its absorption and role in amelioration of asthma, two intranasal forms of curcumin, nasal drop and aerosol were administered to control and asthmatic mice. Blood plasma and lungs were collected at different time points of curcumin administration. Separation was done by using isocratic reversed phase high performance liquid chromatography (HPLC). Airway inflammation and oxidative stress parameters like SOD, Catalase, ROS, lipid peroxidation, and total inflammatory cell recruitments were analyzed to study efficacy of two intranasal forms of curcumin. ResultsMaximum absorption was noted at 3 hrs of different intranasal forms of curcumin, administration, i.e., nasal drop (1.93 ± 0.050 plasma, 2.87 ± 0.26 in lungs) and aerosol form of curcumin where better absorption was noted in aerosol form as compared to nasal drop (Lungs 3.08 ± 0.12 aerosol, 2.05 ± 0.020 nasal drop) at 1 h. Both, curcumin aerosol and nasal drops were effective in ameliorating oxidative stress (p < 0.05) associated with asthma in mice model. The present study may pave the way towards the development of intranasal curcumin as complementary medication because of its better absorption in plasma and lungs.

Assessment of Comfort during Less Invasive Surfactant Administration in Very Preterm Infants: A Multicenter Study

Introduction: This study was set up to investigate if and to what extent non-pharmacological analgesia is able to provide comfort to very preterm infants (VPI) during less invasive surfactant administration (LISA). Methods: This was a prospective non-randomized multicenter observational study performed in level IV NICUs. Inborn VPI with a gestational age between 22^0/7 and 31^6/7 weeks, signs of respiratory distress syndrome, and the need for surfactant replacement were included. Non-pharmacological analgesia was performed in all infants during LISA. In case of failure of the first LISA attempt, additional analgosedation could be administered. COMFORTneo scores during LISA were assessed. Results: 113 VPI with a mean gestational age of 27 weeks (+/− 2.3 weeks) and mean birth weight of 946 g (+/− 33 g) were included. LISA was successful at the first laryngoscopy attempt in 81%. COMFORTneo scores were highest during laryngoscopy. At this time point, non-pharmacological analgesia provided adequate comfort in 61% of the infants. 74.4% of lower gestational aged infants (i.e., 22⁰–26⁶ weeks) were within the comfort zone during laryngoscopy compared to 51.6% of higher gestational aged infants (i.e., 27⁰–32⁰ weeks) (p = 0.016). The time point of surfactant administration did not influence the COMFORTneo scores during the LISA procedure. Conclusion: Non-pharmacological analgesia provided comfort in as much as 61% of the included VPI during LISA. Further research is needed to both develop strategies to identify infants who, despite receiving non-pharmacological analgesia, are at high risk for experiencing discomfort during LISA and define patient-tailored dosage and choice of analgosedative drugs.

212 Use of Vitamin A on Developmental Studies in Ruminant Animals

Abstract Adipogenesis of intramuscular fat tissue in ruminant animals occurs from late pregnancy to first months of age. Therefore, the potential of intramuscular fat (IMF) deposition lasts from the fetal phase until weaning. This crucial period is known as the marbling window. Marbling is stablished by both hyperplasia and hypertrophy processes, and this attribute can be modulated by a strategic nutrient plan or bioactive compounds. Some studies showed that the angiogenesis process has a specific relationship, spatially and temporally, associated with adipogenesis. Adipose tissue is vastly vascularized with capillaries surrounding each adipocyte and this fact turns angiogenesis a target for manipulation, due to pericytes in the blood vessel’s cell wall differentiating into pre-adipocytes and adipocytes. Thus, the manipulation of the processes related to IMF deposition have been studied and the active form of vitamin A (retinoic acid) have been demonstrated to be a modulator of the key genes expression. However, there are still some remaining questions concerning adequate vitamin A dosage and its best administration time point. In Korean native cattle, they found that late pregnancy vitamin A supplementation increased, in the progeny, birth weight and upregulated the expression of genes related to preadipocyte and muscle development. When they supplemented vitamin A via oral to newborn calves, they observed an improvement in calf performance and upregulation in the expression of pre-adipogenic and myogenic genes. In research conducted in the United States using Angus cattle, it was found that neonatal vitamin A injections, at birth and at 30 d of age, promoted calf and muscle growth and IMF development in beef cattle. In the studies mentioned above were observed upregulation in myogenic, angiogenic and adipogenic genes, and also an increase in the pre-adipocytes formation. In our recent study in Brazil, using just one vitamin A injection at birth in crossbred beef cattle we found an increase in intramuscular fat deposition and upregulation in genes involved in angiogenesis and lipogenesis. In summary, through oral vitamin A supplementation during the gestational period or its oral supplementation or injection during the neonatal period, it is possible to upregulate expression of key genes of several biological processes (myogenesis, angiogenesis, adipogenesis and lipogenesis) and increase IMF deposition. Further research is needed to confirm if the vitamin A injection in pregnant cows results in similar or better outcomes in the progeny and the best dosages recommendations in injected or oral supplementation in newborn calves.

Optimizing study design in LPS challenge studies for quantifying drug induced inhibition of TNFα response: Did we miss the prime time?

In this work we evaluate the study design of LPS challenge experiments used for quantification of drug induced inhibition of TNFα response and provide general guidelines of how to improve the study design. Analysis of model simulated data, using a recently published TNFα turnover model, as well as the optimal design tool PopED have been used to find the optimal values of three key study design variables – time delay between drug and LPS administration, LPS dose, and sampling time points – that in turn could make the resulting TNFα response data more informative. Our findings suggest that the current rule of thumb for choosing the time delay should be reconsidered, and that the placement of the measurements after maximal TNFα response are crucial for the quality of the experiment. Furthermore, a literature study summarizing a wide range of published LPS challenge studies is provided, giving a broader perspective of how LPS challenge studies are usually conducted both in a preclinical and clinical setting.

Changes in Expression of DNA-Methyltransferase and Cannabinoid Receptor mRNAs in Blood Lymphocytes After Acute Cannabis Smoking.

BackgroundCannabis use is a component risk factor for the manifestation of schizophrenia. The biological effects of cannabis include effects on epigenetic systems, immunological parameters, in addition to changes in cannabinoid receptors 1 and 2, that may be associated with this risk. However, there has been limited study of the effects of smoked cannabis on these biological effects in human peripheral blood cells. We analyzed the effects of two concentrations of tetrahydrocannabinol (THC) vs. placebo in lymphocytes of a subset of participants who enrolled in a double-blind study of the effects of cannabis on driving performance (outcome not the focus of this study).MethodsTwenty four participants who regularly use cannabis participated in an experiment in which they smoked cannabis cigarettes (5.9 or 13.4% THC) or placebo (0.02%) ad libitum. Blood samples were drawn at baseline and several times after smoking. Lymphocytes were separated and stored at –80°C for further analysis. Samples were analyzed for mRNA content for cannabinoid receptors 1 (CB1) and 2 (CB2), methylation and demethylating enzymes (DNMT, TET), glucocorticoid receptor (NRC3) and immunological markers (IL1B, TNFα) by qPCR using TaqMan probes. The results were correlated with THC whole blood levels during the course of the day, as well as THCCOOH baseline levels. Statistical analyses used analysis of variance and covariance and t-tests, or non-parametric equivalents for those values which were not normally distributed.ResultsThere were no differences in background baseline characteristics of the participants except that the higher concentration THC group was older than the low concentration and placebo groups, and the low concentration THC group had higher baseline CB2 mRNA levels. Both the 5.9 and 13.4% THC groups showed increased THC blood levels that then decreased toward baseline within the first hour. However, there were no significant differences between THC blood levels between the 5.9 and 13.4% groups at any time point. At the 4-h time point after drug administration the 13.4% THC group had higher CB2 (P = 0.021) and DNMT3A (P = 0.027) mRNA levels than the placebo group. DNMT1 mRNA levels showed a trend in the same direction (P = 0.056). The higher 13.4% THC group had significantly increased CB2 mRNA levels than the 5.9% concentration group at several post drug administration time points and showed trends for difference in effects for between 5.9 and 13.4% THC groups for other mRNAs. TET3 mRNA levels were higher in the 13.4% THC group at 55 min post-cannabis ingestion. When the high and lower concentration THC groups were combined, none of the differences in mRNA levels from placebo remained statistically significant. Changes in THC blood levels were not related to changes in mRNA levels.ConclusionOver the time course of this study, CB2 mRNA increased in blood lymphocytes in the high concentration THC group but were not accompanied by changes in immunological markers. The changes in DNMT and TET mRNAs suggest potential epigenetic effects of THC in human lymphocytes. Increases in DNMT methylating enzymes have been linked to some of the pathophysiological processes in schizophrenia and, therefore, should be further explored in a larger sample population, as one of the potential mechanisms linking cannabis use as a trigger for schizophrenia in vulnerable individuals. Since the two THC groups did not differ in post-smoking blood THC concentrations, the relationship between lymphocytic changes and the THC content of the cigarettes remains to be determined.

Exploring the Associations Between MAP Growth and SBA by Demographics

MAP Growth (MAP) and Smarter Balanced assessment (SBA) are two of the most common standardized assessments used in Pre-Kindergarten to Grade 12 education in the United States. We show how scores on MAP relate to scores on SBA for third grade students. Previous studies examining the relationship between MAP Growth and SBA have been conducted by the test publisher. The current study expands on this and examines how scores on MAP Growth relate to scores on SBA and examine if these relationships vary by when the MAP Growth assessment is taken or by student demographics (by English language proficiency, gender, and ethnicity). Scores on these assessments are compared for 3rd grade students from Clark County, Nevada, which is the fifth largest school district in the United States. The scale scores were associated and, when using MAP to predict SBA scores, followed a quadratic pattern. While students' scores on the assessments varied by English language proficiency, gender, and ethnicity (i.e., discrepancies that are often referred to as achievement gaps), the relationships between these assessments showed a similar pattern across these demographics. Growth scores were calculated for three MAP administration time points. As well as showing a slight “rich get richer” effect (i.e., slightly more growth for those scoring high), there were regression toward the mean effects. The MAP growth curves were similar by English language proficiency, gender, and ethnicity.

Effects of Lactobacillus plantarum P9 Probiotics on Defecation and Quality of Life of Individuals with Chronic Constipation: Protocol for a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Background Although probiotics have been shown to improve constipation-related symptoms, a clear consensus on the use of probiotics as a constipation-relieving agent has not been reached, which is attributed to the limited available evidence and inconsistent protocols used in existing studies. Method A randomized, double-blind, placebo-controlled clinical trial is designed to study the efficiency and possible mechanism of action of probiotics for chronic constipation, in which 200 eligible volunteers with chronic constipation will be randomly assigned to a probiotic group (oral Lactobacillus plantarum P9 probiotic powder, 100 billion colony-forming units (CFUs)/day) or a placebo group. Volunteers, treatment distributors, data collectors, and data analysts will be blinded. The primary outcome is the weekly mean frequency of complete spontaneous bowel movements (CSBMs), and secondary outcomes include weekly mean frequency of CSBMs ≥3, weekly mean frequency of spontaneous bowel movements (SBMs), weekly mean stool appearance score, weekly mean difficulty of passing stool score, weekly percentage of volunteers who use auxiliary measures to assist with defecation (WPUAMA), quality-of-life (QOL) score, emotional status score, gut microbiome, and faecal metabolome. Each outcome measure will be assessed at the time points of preadministration (day 0), administration (day 14 and/or 28), and postadministration (day 42) to identify inter- and intragroup differences. Adverse events will be recorded to evaluate the safety of L. plantarum P9. Discussion. The protocol will provide methodological guidance for other similar studies, avoiding methodological bias and ultimately facilitating the formulation of consensus on the use of probiotics as a constipation-relieving agent. In addition, the results are more comprehensive than those of existing studies and may objectively and scientifically reflect the effectiveness of L. plantarum P9 on constipation. If the expected study findings are obtained, L. plantarum P9, taken as a probiotic, may become a complementary choice for chronically constipated patients. This trial is registered with Chinese Clinical Trial Registry (ChiCTR) (no. ChiCTR2000038396) registered on November 22, 2020, https://www.chictr.org.cn/showproj.aspx?proj=54024.

Early Enteral Nutrition Can Reduce Incidence of Postoperative Hydrocephalus in Patients with Severe Hypertensive Intracerebral Hemorrhage.

BackgroundHydrocephalus secondary to hypertensive intracerebral hemorrhage (HICH) dramatically affects the prognosis. Early enteral nutrition (EN) is beneficial to severe HICH patients, but the impact of early EN administration on hydrocephalus remains unknown. This study aimed to explore the predictors for hydrocephalus occurrence after HICH, with special focus on the effect of early EN application.Material/MethodsWe retrospectively analyzed 146 patients with severe HICH who underwent microsurgery between January 2014 and October 2019 in our department. Patients were divided into early EN (≤48 h) and delayed EN (>48 h) group according to the time-point of EN administration. The diagnosis of hydrocephalus was confirmed by both radiological evaluation and an Evan index method. Diagnosis confirmed within 2 weeks after HICH was identified as acute hydrocephalus, otherwise, it was considered as chronic hydrocephalus.ResultsTwenty-seven patients experienced acute hydrocephalus, while 20 patients developed chronic hydrocephalus. Low preoperative Glasgow coma scale (GCS), subarachnoid hemorrhage (SAH), intraventricular hemorrhage (IVH), delayed EN administration, high levels of postoperative white blood cell, neutrophil, neutrophil-to-lymphocyte ratio, C-reactive protein (CRP), and lactate dehydrogenase were positively related to the occurrence of chronic hydrocephalus (p<0.05), while only IVH was correlated with acute hydrocephalus occurrence (p<0.05). In addition, a multivariate analysis demonstrated that preoperative GCS, SAH, IVH, and early EN administration (p<0.05) were independent predictors for chronic hydrocephalus occurrence.ConclusionsEarly EN administration, SAH, IVH, and preoperative GCS were associated with the occurrence of chronic hydrocephalus in severe HICH patients. Early EN administration may inhibit the inflammatory response of brain-gut axis, which in turn reduces chronic hydrocephalus occurrence.

Time Rules the Efficacy of Immune Checkpoint Inhibitors in Photodynamic Therapy.

Lack of adequate effector T cells infiltrated in tumor is one of the main problems in the failure of immune checkpoint blockade therapy (ICBT). Photodynamic therapy (PDT) induced acute inflammation can sensitize tumors and activate T cells, thus assisting immune checkpoint inhibitors (ICI) against tumor growth and metastasis. T cells maturation and activation lag 3 to 7 days behind PDT. However, such timing in the combination therapy of ICI and PDT is commonly ignored in designing numerous multi‐functional integrated nanomedicines. Herein, the authors illustrate that intervention timing of ICI after PDT affects the anti‐tumor efficacy. A tumor‐targeting nanomedicine is prepared by encapsulating indocyanine green into CD44 specifically binding material, a hyaluronic acid conjugated lipid poly(ethylene glycol). The PDT nanomedicine is designed to induce a robust immune response in tumor. The optimal group (Combo‐STAR), ICI gave 5 days after PDT, significantly suppresses local tumor growth and eliminates metastasis. What should be highlighted is the time point of administration because if ICI is given too early, T cells are immature, otherwise, T cells are exhausted if ICI is given too late. This work presents theoretical guidance for raising awareness of intervention timing when augmenting ICBT with immune response inducers in clinic.

A Review of the Effects of Cervical Cancer Standard Treatment on Immune Parameters in Peripheral Blood, Tumor Draining Lymph Nodes, and Local Tumor Microenvironment.

Cervical cancer remains a public health concern despite all the efforts to implement vaccination and screening programs. Conventional treatment for locally advanced cervical cancer consists of surgery, radiotherapy (with concurrent brachytherapy), combined with chemotherapy, or hyperthermia. The response rate to combination approaches involving immunomodulatory agents and conventional treatment modalities have been explored but remain dismal in patients with locally advanced disease. Studies exploring the immunological effects exerted by combination treatment modalities at the different levels of the immune system (peripheral blood (PB), tumor-draining lymph nodes (TDLN), and the local tumor microenvironment (TME)) are scarce. In this systemic review, we aim to define immunomodulatory and immunosuppressive effects induced by conventional treatment in cervical cancer patients to identify the optimal time point for immunotherapy administration. Radiotherapy (RT) and chemoradiation (CRT) induce an immunosuppressive state characterized by a long-lasting reduction in peripheral CD3, CD4, CD8 T cells and NK cells. At the TDLN level, CRT induced a reduction in Nrp1+Treg stability and number, naïve CD4 and CD8 T cell numbers, and an accompanying increase in IFNγ-producing CD4 helper T cells, CD8 T cells, and NK cells. Potentiation of the T-cell anti-tumor response was particularly observed in patients receiving low irradiation dosage. At the level of the TME, CRT induced a rebound effect characterized by a reduction of the T-cell anti-tumor response followed by stable radioresistant OX40 and FoxP3 Treg cell numbers. However, the effects induced by CRT were very heterogeneous across studies. Neoadjuvant chemotherapy (NACT) containing both paclitaxel and cisplatin induced a reduction in stromal FoxP3 Treg numbers and an increase in stromal and intratumoral CD8 T cells. Both CRT and NACT induced an increase in PD-L1 expression. Although there was no association between pre-treatment PD-L1 expression and treatment outcome, the data hint at an association with pro-inflammatory immune signatures, overall and disease-specific survival (OS, DSS). When considering NACT, we propose that posterior immunotherapy might further reduce immunosuppression and chemoresistance. This review points at differential effects induced by conventional treatment modalities at different immune compartments, thus, the compartmentalization of the immune responses as well as individual patient’s treatment plans should be carefully considered when designing immunotherapy treatment regimens.