Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines.

INTRODUCTION: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. METHODS: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. RESULTS: Of the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro. CONCLUSION: Taken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.

Sleep rebound leads to marked recovery of prolonged sleep deprivation-induced adversities in the stress response and hippocampal neuroplasticity of male rats.

BACKGROUND: Sleep disturbances are not only frequent symptoms, but also risk factors for major depressive disorder. We previously reported that depressed patients who experienced "Hypersomnia" showed a higher and more rapid response rate under paroxetine treatment, but the underlying mechanism remains unclear. The present study was conducted to clarify the beneficial effects of sleep rebound through an experimental "Hypersomnia" rat model on glucocorticoid and hippocampal neuroplasticity associated with antidepressive potency. METHODS: Thirty-four male Sprague-Dawley rats were subjected to sham treatment, 72-h sleep deprivation, or sleep deprivation and subsequent follow-up for one week. Approximately half of the animals were sacrificed to evaluate adrenal weight, plasma corticosterone level, hippocampal content of mRNA isoforms, and protein of the brain-derived neurotrophic factor (Bdnf) gene. In the other half of the rats, Ki-67- and doublecortin (DCX)-positive cells in the hippocampus were counted via immunostaining to quantify adult neurogenesis. RESULTS: Prolonged sleep deprivation led to adrenal hypertrophy and an increase in the plasma corticosterone level, which had returned to normal after one week follow-up. Of note, sleep deprivation-induced decreases in hippocampal Bdnf transcripts containing exons II, IV, VI, and IX and BDNF protein levels, Ki-67-(+)-proliferating cells, and DCX-(+)-newly-born neurons were not merely reversed, but overshot their normal levels with sleep rebound. LIMITATIONS: The present study did not record electroencephalogram or assess behavioral changes of the sleep-deprived rats. CONCLUSIONS: The present study demonstrated that prolonged sleep deprivation-induced adversities are reversed or recovered by sleep rebound, which supports "Hypersomnia" in depressed patients as having a beneficial pharmacological effect.

A new mouse-fixation device for IOP measurement in awake mice.

Glaucoma is an irreversible blinding eye disease. The mechanisms underlying glaucoma are complex. Up to now, no successful remedy has been found to completely cure the condition. High intraocular pressure (IOP) is an established risk factor for glaucoma and the only known modifiable factor for glaucoma treatment. Mice have been widely used to study glaucoma pathogenesis. IOP measurement is an important tool for monitoring the potential development of glaucomatous phenotypes in glaucoma mouse models. Currently, there are two methods of IOP measurement in mice: invasive and non-invasive. As the invasive method can cause corneal damage and inflammation, and most of the noninvasive method involves the use of anesthetics. In the course of our research, we designed a mouse fixation device to facilitate non-invasive measurements of mouse IOPs. Using this device, mouse IOPs can be accurately measured in awake mice. This device will help researchers to accurately assess mouse IOP without the use of anesthetics.

HIV viral suppression and risk of viral rebound in patients on antiretroviral therapy: a two- year retrospective cohort study in Northern Tanzania.

BACKGROUND: The world is moving towards the third target of the Joint United Nations Programme on HIV/AIDS to ensure most people receiving antiretroviral therapy (ART) are virologically suppressed. Little is known about viral suppression at an undetectable level and the risk of viral rebound phenomenon in sub-Saharan Africa which covers 67% of the global HIV burden.This study aimed to investigate the proportion of viral suppression at an undetectable level and the risk of viral rebound among people living with HIV receiving ART in northern Tanzania. METHODOLOGY: A hospital based-retrospective study recruited people living with HIV who were on ART for at least two years at Kibong'oto Infectious Disease Hospital and Mawenzi Regional Referral Hospital in Kilimanjaro Region, Tanzania. Participants' two-year plasma HIV were captured at months 6, 12, and 24 of ART. Undetectable viral load was defined by plasma HIV of viral load (VL) less than 20copies/ml and viral rebound (VR) was considered to anyone having VL of more than 50 copies/ml after having history of undetectable level of the VL less than 20copies/ml. A multivariable log-binomial generalized linear model was used to determine factors for undetectable VL and viral VR. RESULTS: Among 416 PLHIV recruited, 226 (54.3%) were female. The mean (standard deviation) age was 43.7 (13.3) years. The overall proportion of undetectable VL was 68% (95% CI: 63.3-72.3) and 40.0% had viral rebound (95% CI: 34.7-45.6). Participants who had at least 3 clinic visits were 1.3 times more likely to have undetectable VL compared to those who had 1 to 2 clinic visits in a year (p = 0.029). Similarly, participants with many clinical visits ( > = 3 visits) per year were less likely to have VR compared to those with fewer visits ( = 2 visits) [adjusted relative risk (aRR) = 0.64; 95% CI: 0.44-0.93]. CONCLUSION: Participants who had fewer clinic visits per year(ART refills) were less likely to achieve viral suppression and more likely to experience viral rebound. Enhanced health education and close follow-up of PLHIV on antiretroviral therapy are crucial to reinforce adherence and maintain an undetectable viral load.

Susceptibility of optic nerve head in children with posture-related elevation of intraocular pressure.

BACKGROUND/AIMS: This work aimed to investigate changes in optic nerve head (ONH) morphometry based on Bruch membrane opening in children with extensive nocturnal intraocular pressure (IOP) elevations. METHODS: The course of Bruch membrane opening-based optic nerve head (ONH) morphometry was analysed in thirty-two patients younger than 18 years with evaluable SD-OCT examinations of the ONH and nocturnal posture-dependent IOP elevation above 25 mmHg. Longitudinal changes in neuroretinal rim tissue, as measured by Bruch Membrane opening minimum rim width (BMO-MRW) and peripapillary retinal nerve fiber layer (RNFL) thickness, were assessed. RESULTS: One year after the 24 h IOP measurement, global BMO-MRW (- 1.61 ± 16.8 µm, n.s.; p = 0.611) and RNFL (+ 0.64 ± 3.17 µm; n.s.; p = 0.292) measurements were not significantly different from the baseline. No significant BMO-MRW reduction (- 3.91 ± 24.3 µm; n.s. p = 0.458) or deviation in RNFL thickness (+ 1.10 ± 3.52 µm) was observed at the four-year follow-up. Absolute IOP values measured in the supine position did not correlate with changes in global BMO-MRW or RNFL thickness. CONCLUSION: Posture-dependent IOP elevations do not seem to influence retinal nerve fibre layer thickness or Bruch membrane opening-based morphometric data in childhood.

Comparison of first, second, and third versus the average of six probe-corneal touches for intraocular measurement of two rebound tonometers in healthy horses.

The aim of this study was to evaluate the intraocular pressure (IOP) measurements obtained from first, second, and third probe-cornea touch (PCT) and compare them with the average of six PCTs using two rebound tonometers in horses. This study enrolled a total of thirty-eight stallions, comprising of 24 Arabian horses and 14 cross-breeds (with an average age of 8 ± 3 years). The IOP measurements of first, second, and third, as well as the average of six PCTs were obtained using either Tonovet (TV) or Tonovet Plus (TV+) rebound tonometers. The mean differences (95% limits of agreement) between the average of six PCTs and the first, second, and third PCTs were 0.1 (-4.8 to 5), 0.2 (-4.8 to 4.5), and 0.2 (-3.6 to 4.0) mmHg with TV, respectively. With TV+, the differences were 0.3 (-6.6 to 7.2), 1.1 (-8.6 to 10.8), and -0.2 (-3.6 to 4.0) mmHg, respectively. Compared to the average of six PCTs, only 89.5%, 92.1%, and 97.4% of IOP measurements obtained from TV and 78.9%, 73.3%, and 65.8% of IOP measurements obtained from TV+ were within 4 mmHg of the average of six PCTs for first, second, and third PCTs, respectively. In conclusion, the measurement of IOP in the first PCT achieved best agreement with the IOP measurement of six average PCTs. Therefore, the first PCT could be considered as an alternative option for measuring IOP in horses when obtaining an average of six PCTs is not feasible.

Neural mechanisms of the temporal response of cortical neurons to intracortical microstimulation.

BACKGROUND: Intracortical microstimulation (ICMS) is used to map neuronal circuitry in the brain and restore lost sensory function, including vision, hearing, and somatosensation. The temporal response of cortical neurons to single pulse ICMS is remarkably stereotyped and comprises short latency excitation followed by prolonged inhibition and, in some cases, rebound excitation. However, the neural origin of the different response components to ICMS are poorly understood, and the interactions between the three response components during trains of ICMS pulses remains unclear. OBJECTIVE: We used computational modeling to determine the mechanisms contributing to the temporal response to ICMS in model cortical neurons. METHODS: We implemented a biophysically based computational model of a cortical column comprising neurons with realistic morphology and synapses and quantified the temporal response of cortical neurons to different ICMS protocols. We characterized the temporal responses to single pulse ICMS across stimulation intensities and inhibitory (GABA-B/GABA-A) synaptic strengths. To probe interactions between response components, we quantified the response to paired pulse ICMS at different inter-pulse intervals and the response to short trains at different stimulation frequencies. Finally, we evaluated the performance of biomimetic ICMS trains in evoking sustained neural responses. RESULTS: Single pulse ICMS evoked short latency excitation followed by a period of inhibition, but model neurons did not exhibit post-inhibitory excitation. The strength of short latency excitation increased and the duration of inhibition increased with increased stimulation amplitude. Prolonged inhibition resulted from both after-hyperpolarization currents and GABA-B synaptic transmission. During the paired pulse protocol, the strength of short latency excitation evoked by a test pulse decreased marginally compared to those evoked by a single pulse for interpulse intervals (IPI) < 100 m s. Further, the duration of inhibition evoked by the test pulse was prolonged compared to single pulse for IPIs <50 m s and was not predicted by linear superposition of individual inhibitory responses. For IPIs>50 m s, the duration of inhibition evoked by the test pulse was comparable to those evoked by a single pulse. Short ICMS trains evoked repetitive excitatory responses against a background of inhibition. However, the strength of the repetitive excitatory response declined during ICMS at higher frequencies. Further, the duration of inhibition at the cessation of ICMS at higher frequencies was prolonged compared to the duration following a single pulse. Biomimetic pulse trains evoked comparable neural response between the onset and offset phases despite the presence of stimulation induced inhibition. CONCLUSIONS: The cortical column model replicated the short latency excitation and long-lasting inhibitory components of the stereotyped neural response documented in experimental studies of ICMS. Both cellular and synaptic mechanisms influenced the response components generated by ICMS. The non-linear interactions between response components resulted in dynamic ICMS-evoked neural activity and may play an important role in mediating the ICMS-induced precepts.

Nasal Glucagon Reverses Insulin-induced Hypoglycemia With Less Rebound Hyperglycemia: Pooled Analysis of Clinical Trials.

Background: Rebound hyperglycemia may occur following glucagon treatment for severe hypoglycemia. We assessed rebound hyperglycemia occurrence after nasal glucagon (NG) or injectable glucagon (IG) administration in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D). Methods: This was a pooled analysis of 3 multicenter, randomized, open-label studies (NCT03339453, NCT03421379, NCT01994746) in patients ≥18 years with T1D or T2D with induced hypoglycemia. Proportions of patients achieving treatment success [blood glucose (BG) increase to ≥70 mg/dL or increase of ≥20 mg/dL from nadir within 15 and 30 minutes]; BG ≥70 mg/dL within 15 minutes; in-range BG (70-180 mg/dL) 1 to 2 and 1 to 4 hours postdose; and BG >180 mg/dL 1 to 2 and 1 to 4 hours postdose were compared. Incremental area under curve (iAUC) of BG >180 mg/dL and area under curve (AUC) of observed BG values postdose were analyzed. Safety was assessed in all studies. Results: Higher proportions of patients had in-range BG with NG vs IG (1-2 hours: P = .0047; 1-4 hours: P = .0034). Lower proportions of patients had at least 1 BG value >180 mg/dL with NG vs IG (1-2 hours: P = .0034; 1-4 hours: P = .0068). iAUC and AUC were lower with NG vs IG (P = .025 and P < .0001). As expected, similar proportions of patients receiving NG or IG achieved treatment success at 15 and 30 minutes (97-100%). Most patients had BG ≥70 mg/dL within 15 minutes (93-96%). The safety profile was consistent with previous studies. Conclusion: This study demonstrated lower rebound hyperglycemia risk after NG treatment compared with IG. Clinical Trial Registration: NCT03421379, NCT03339453, NCT01994746.

A case of early disease rebound after fingolimod discontinuation in a patient with multiple sclerosis and SARS-CoV-2 infection.

Fingolimod is approved in Italy as a second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Discontinuation of fingolimod may elevate the risk of relapses, typically manifesting after a relatively prolonged drug-free interval and often necessitating high doses of intravenous steroids for management. Similar to other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can act as a trigger for MS relapses. In this context, we present a case of rebound following fingolimod discontinuation during a SARS-CoV-2 infection. Notably, the rebound occurred shortly after stopping the medication and responded effectively to low doses of oral steroids. Our case is discussed in light of existing literature, with speculation on potential mechanisms governing this unconventional disease course rebound. We also consider the possibility that SARS-CoV-2 infection might have contributed to or even triggered the MS relapse.

Proximity Effects on the Reactivity of a Nonheme Iron (IV) Oxo Complex in C-H Oxidation.

Precise control of substrate positioning and orientation (its proximity to the reactive unit) is often invoked to rationalize the superior enzymatic reaction rates and selectivities when compared to synthetic models. Artificial nonheme iron (IV) oxo (Fe(IV)=O) complexes react with C(sp3)-H bonds via a biomimetic Hydrogen Atom Transfer/Hydroxyl Rebound mechanism, but rates, site-selectivity and even hydroxyl rebound efficiency (ligand rebound versus substrate radical diffusion) are smaller than in oxygenases. Herein, we quantitatively analyze how substrate binding modulates nonheme Fe(IV)=O reactivity by comparing rates and outcomes of C-H oxidation by a pair of Fe(IV)=O complexes that share the same first coordination sphere but only one contains a crown ether receptor that recognizes the substrate. Substrate binding makes the reaction intramolecular, exhibiting Michaelis-Menten kinetics and increased reaction rates. In addition, C-H oxidation occurs with high site selectivity for remote sites. Analysis of Effective Molarity reveals that the system operates at its maximal theoretical capability for the oxidation of these remote sites. Remarkably, substrate positioning also affects Hydroxyl Rebound, whose efficiency only increases on the sites placed in proximity by recognition. Overall, these observations provide evidence that supramolecular control of substrate positioning can effectively modulate the reactivity of oxygenases and its models.

Does business environment optimization improve carbon emission efficiency? Evidence from provincial panel data in China.

Previous research has yielded mixed conclusions regarding whether business environment (BE) optimization can enhance carbon emission efficiency (CEE). This study delves into the impact of the BE on CEE using panel data from 30 provinces in China, employing fixed effect, quantile, and mediated effect models. It innovates in three key areas: research perspective, mechanism of action, and heterogeneity analysis. The research found that the BE optimization enhances CEE. Meanwhile, the influence of the BE on CEE exhibits marginal decreasing characteristics. The mechanism analysis reveals that the BE enhances CEE through the industrial structure optimization effect and the progress of green technology, while it diminishes efficiency through the energy rebound effect. Heterogeneity analysis indicates that BE optimization has a stronger impact on improving CEE in provinces with robust government governance, younger governors, and highly educated officials. The policy implication suggests that local governments should continually optimize the BE, enhance government governance capacity, and prioritize the appointment of young and highly educated officials.

Low-Pressure Pancake Bouncing on Superhydrophobic Surfaces.

A new form of pancake bouncing is discovered in this work when a droplet impacts onto micro-structured superhydrophobic surfaces in an environment pressure less than 2 kPa, and an unprecedented reduction of contact time by ≈85% is obtained. The mechanisms of forming this unique phenomenon are examined by combining experimental observation, numeical modelling and an improved theoretical model for the overpressure effect arising from the vaporisation inside micro-scaled structures. The competition among the vapor overpressure effect, the droplet impact force, and the surface adhesion determines if the pancake bouncing behavior could occur. After the lift-off the lamella, the pancake bouncing is initiated and its subsequent dynamics is controlled by the internal momentum transfer. Complementary to the prior studies, this work enriches the knowledge of droplet dynamics in low pressure, which allows new strategies of surface morphology engineering for droplet control, an area of high importance for many engineering applications.

Prophylactic dexamethasone for rebound pain after peripheral nerve block in adult surgical patients: systematic review, meta-analysis, and trial sequential analysis of randomised controlled trials.

BACKGROUND: Rebound pain occurs after the resolution of peripheral nerve block and hampers patient recovery in the postoperative period. We sought to synthesise available data from randomised controlled trials (RCTs) evaluating the efficacy of prophylactic dexamethasone for rebound pain in adult patients undergoing surgery with a peripheral nerve block. METHODS: In this systematic review and meta-analysis, RCTs reporting rebound pain and use of dexamethasone in the context of a peripheral nerve block were searched in various databases and updated in May 2023. The primary outcome was the incidence of rebound pain; secondary outcomes included the severity and time to onset of rebound pain, patient satisfaction with pain control, sleep disturbance because of pain, and adverse effects of dexamethasone. Subgroup analysis was conducted based on the effect of route of administration (intravenous or perineural) on the incidence of rebound pain. Trial sequential analysis was performed to rule out the possibility of a false positive result. RESULTS: Seven RCTs comprising 574 patients were included in this review. The dexamethasone group was associated with a reduction in the incidence of rebound pain with an odds ratio of 0.16 (95% confidence interval 0.10-0.27, P=0.00, I2=0%) compared with the control group. Trial sequential analysis confirmed the adequate information size for the beneficial effect of dexamethasone. Subgroup analysis showed that both intravenous and perineural administration were associated with a significant reduction in the incidence of rebound pain. CONCLUSIONS: Current evidence suggests that both intravenous and perineural dexamethasone reduce the incidence of rebound pain after a peripheral nerve block provided for postoperative analgesia. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42023424031.

Effect of intravenous magnesium on post-operative pain following Latarjet shoulder reconstruction.

Background: Single injection ropivacaine interscalene anesthesia (ISA) is frequently used in Latarjet reconstruction to enhance post-operative analgesia. A potential limitation is the occurrence of severe rebound pain on block resolution. We investigated the effect of intravenous magnesium on post-operative pain, particularly at the transition of block resolution to multimodal analgesia. Methods: Elective patients (n = 40) having Latarjet open shoulder reconstruction were randomised to receive either intravenous magnesium sulphate 50 mg/kg (M) or normal saline (S) before induction. Post-operatively, a standardised analgesic regimen was used, and post-operative pain was recorded using a verbal numerical rating assessment (VNRA) score. Requirement for injected opioid analgesia was recorded. Results: ISA provided longstanding analgesia in all patients with block duration slightly prolonged in the magnesium group (16.7(1.0) (S), 17.8(1.3) h (M), p = 0.049). Magnesium resulted in less rebound pain following ISA resolution (VNRA 4.0 (0.6) M, 6.2 (0.8) S, p = 0.03) and lower pain intensity at 24 h. Four patients had nausea and two required rescue opioid injection. Conclusion: Magnesium before Latarjet surgery results in less rebound pain following ropivacaine block and improves post-operative analgesia. Magnesium may be indicated in major upper limb surgery, where significant pain intensity is anticipated. Level of evidence: Treatment study; Randomised blinded; Level 2.

Rebound Intracranial Hypertension.

PURPOSE OF REVIEW: Rebound intracranial hypertension (RIH) is a post-procedural treatment complication in patients with spontaneous intracranial hypotension (SIH) characterized by transient high-pressure headache symptoms. This article reviews the epidemiology, clinical features, risk factors, and treatment options for RIH. RECENT FINDINGS: This article discusses how changes in underlying venous pressure and craniospinal elastance can explain symptoms of RIH, idiopathic intracranial hypertension (IIH), and SIH. The pathophysiology of RIH provides a clue for how high and low intracranial pressure disorders, such as IIH and SIH, are connected on a shared spectrum.

A Comparative Analysis of Intraocular Pressure Measurement Accuracy With Reused iCare Probes.

PURPOSE: To assess the accuracy of reused iCare probes after disinfection with 70% isopropyl alcohol and ethylene oxide gas compared to new iCare probes and Goldmann applanation tonometry (GAT). DESIGN: Prospective comparative analysis. PARTICIPANTS: A total of 118 eyes from 59 patients recruited from the Aravind Eye Hospital glaucoma clinic in Tirupati, South India. METHODS: Intraocular pressure (IOP) was measured on each eye using a new iCare tonometer probe, an iCare probe previously used and disinfected 1 time prior (once used probe) and 5 times prior (multiply used probe), as well as with GAT. Probes were disinfected after each use with 70% isopropyl alcohol swabs and ethylene oxide sterilization. MAIN OUTCOME MEASURES: Agreement demonstrated with intraclass correlation coefficients (ICCs), mean difference in IOP values with limits of agreement, and Bland-Altman plots among IOP measurement approaches. RESULTS: Compared to new iCare probes, both once used probes (ICC = 0.989, 95% confidence interval [CI] 0.985-0.993) and multiply used probes (ICC = 0.989, 95% CI 0.984-0.992) showed excellent agreement, and the mean difference in IOP was minimal for both once used probes (0.70 mmHg, 95% CI 0.29-1.11) and multiply used probes (0.75 mmHg, 95% CI 0.66-0.82) compared to new probes. Bland-Altman plots demonstrated minimal differences between new and reused probes across the spectrum of IOP. When comparing multiply used probes to once used probes, there was a high level of agreement (0.993) (95% CI 0.990-0.995) and negligible mean IOP difference 0.04 mmHg (95% CI 0.32-0.40). Additionally, ICC values for new probes (0.966, 95% CI 0.951-0.976), once used probes (0.958, 95% CI 0.940-0.971), and multiply used probes (0.957, 95% CI 0.938-0.970) compared to GAT were similar and all showed excellent agreement. Both new and reused iCare probes underestimated IOP by 2 to 3 mmHg compared to GAT. CONCLUSIONS: In this prospective comparative analysis, we found that reusing iCare probes up to 5 times does not compromise the accuracy of IOP measurements when disinfected with 70% isopropyl alcohol swabs and ethylene oxide. Reusing iCare probes has the potential to transform care by reducing cost, decreasing environmental waste, and allowing for glaucoma screening camps and increased glaucoma monitoring in low resource settings leading to earlier identification and treatment of glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Viral rebound occurrence immediately after drug discontinuation involving neither drug resistance nor latent reservoir.

Some viruses exhibit "rebound" when the administration of antiviral drugs is discontinued. Viral rebound caused by resistance mutations or latent reservoirs has been studied mathematically. In this study, we investigated the viral rebound due to other causes. Since immunity is weaker during antiviral treatment than without the treatment, drug discontinuation may lead to an increase in the viral load. We analyzed the dynamics of the number of virus-infected cells, cytotoxic T lymphocytes, and memory cells and identified the conditions under which the viral load increased upon drug discontinuation. If drug is administered for an extended period, a viral rebound occurs when the ratio of viral growth rate in the absence to that in the presence of the antiviral drug exceeds the "rebound threshold." We analyzed how the rebound threshold depended on the patient's conditions and the type of treatment. Mathematical and numerical analyses revealed that rebound after discontinuation was more likely to occur when the drug effectively reduced viral proliferation, drug discontinuation was delayed, and the processes activating immune responses directly were stronger than those occurring indirectly through immune memory formation. We discussed additional reasons for drugs to cause viral rebound more likely.

Myopia progression after cessation of atropine in children: a systematic review and meta-analysis.

Purpose: To comprehensively assess rebound effects by comparing myopia progression during atropine treatment and after discontinuation. Methods: A systematic search of PubMed, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was conducted up to 20 September 2023, using the keywords "myopia," "rebound," and "discontinue." Language restrictions were not applied, and reference lists were scrutinized for relevant studies. Our study selection criteria focused on randomized control trials and interventional studies involving children with myopia, specifically those treated with atropine or combination therapies for a minimum of 6 months, followed by a cessation period of at least 1 month. The analysis centered on reporting annual rates of myopia progression, considering changes in spherical equivalent (SE) or axial length (AL). Data extraction was performed by three independent reviewers, and heterogeneity was assessed using I2 statistics. A random-effects model was applied, and effect sizes were determined through weighted mean differences with 95% confidence intervals Our primary outcome was the evaluation of rebound effects on spherical equivalent or axial length. Subgroup analyses were conducted based on cessation and treatment durations, dosage levels, age, and baseline SE to provide a nuanced understanding of the data. Results: The analysis included 13 studies involving 2060 children. Rebound effects on SE were significantly higher at 6 months (WMD, 0.926 D/y; 95%CI, 0.288-1.563 D/y; p = .004) compared to 12 months (WMD, 0.268 D/y; 95%CI, 0.077-0.460 D/y; p = .006) after discontinuation of atropine. AL showed similar trends, with higher rebound effects at 6 months (WMD, 0.328 mm/y; 95%CI, 0.165-0.492 mm/y; p < .001) compared to 12 months (WMD, 0.121 mm/y; 95%CI, 0.02-0.217 mm/y; p = .014). Sensitivity analyses confirmed consistent results. Shorter treatment durations, younger age, and higher baseline SE levels were associated with more pronounced rebound effects. Transitioning or stepwise cessation still caused rebound effects but combining optical therapy with atropine seemed to prevent the rebound effects. Conclusion: Our meta-analysis highlights the temporal and dose-dependent rebound effects after discontinuing atropine. Individuals with shorter treatment durations, younger age, and higher baseline SE tend to experience more significant rebound effects. Further research on the rebound effect is warranted. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=463093], identifier [registration number].

Efficacy of Intravenous Administration of Esketamine in Preventing and Treating Rebound Pain After Thoracic Paravertebral Nerve Block: A Prospective Randomized, Double-Blind, Placebo-Controlled Trial.

Purpose: Investigating the efficacy of intraoperative fractionated intravenous esketamine in the prevention of rebound pain after cessation of thoracic paravertebral nerve blockade. Methods: One hundred and twenty patients who underwent elective thoracoscopic lobectomy were selected for the study and were randomly divided into two groups, the esketamine group was given 0.5 mg/kg and 0.3 mg/kg of esketamine at the induction of anaesthesia and 30 minutes before the end of the operation, respectively, and the control group was given an equal amount of saline. The incidence of rebound pain (RP) 7 days after surgery and postoperative recovery were compared between the two groups. Results: The NRS pain scores at 24 and 48 hours postoperatively in the esketamine group were significantly lower than those in the control group (P < 0.05). The incidence of postoperative rebound pain was significantly lower in the esketamine group than in the control group (P < 0.05). The consumption of sufentanil was less in the esketamine group in the postoperative 48 hours (P < 0.05). Postoperative recovery was compared between the two groups and the difference was not statistically significant. Conclusion: Intravenous esketamine reduces postoperative pain scores, decreases the incidence of rebound pain after cessation of thoracic paravertebral block, and reduces opioid consumption.