Exploring Inflammation and Stress as Biological Correlates of Symptoms in Children With Advanced Cancer: A Longitudinal Feasibility Study.

Background: Few studies have examined biomarkers of stress and inflammation as underlying mechanisms of symptoms in adolescents and young adults with cancer. This study determined the feasibility of collecting blood and saliva samples across time, described the range and distribution of biomarkers, and explored the association of biomarkers with symptom adverse events (AEs). Method: This longitudinal, prospective repeated-measures single-site feasibility study recruited N = 10 children (M = 12.5 years) receiving treatment for advanced cancer. Symptom AE data and inflammation (cytokines and C-reactive protein) and physiologic response to stress (salivary cortisol and salivary alpha-amylase) biomarker levels were collected at three time points. Descriptive statistics were used to examine feasibility and acceptability and to summarize symptom AE, stress, and inflammatory biomarker data. A linear regression model was used to determine cortisol diurnal slopes. The relationship between symptom and inflammatory biomarker data was explored and Hedges's g statistic was used to determine its effect size. Results: Participants provided 83% of saliva samples (n = 199/240) and 185 samples were sufficient to be analyzed. Nurses collected 97% (n = 29/30) of blood samples. Participants reported the saliva collection instructions, kits, and reminders were clear and helpful. Insomnia, pain, fatigue, and anxiety demonstrated the most medium and large negative effects with inflammatory markers. Symptom AEs demonstrated the highest number of medium and large negative effects with interleukin-8 and tumor necrosis factor-alpha (-0.53 to -2.00). Discussion: The results indicate longitudinal concurrent collection of symptom and biomarker data is feasible and inflammatory and stress biomarkers merit consideration for inclusion in future studies.

IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.

Development of an α-Klotho Recognizing High-Affinity Peptide Probe from In-Solution Enrichment.

The kidney, parathyroid gland, and choroid plexus express the aging-related transmembrane protein α-Klotho, a coreceptor of the fibroblast growth factor 23 (FGF23) receptor complex. Reduced α-Klotho levels are correlated with chronic kidney disease and other age-related diseases, wherein they are released from membranes into circulation. Klotho's potential physiological action as a hormone is of current scientific interest. Part of the challenges associated with advancing these studies, however, has been the long-standing difficulty in detecting soluble α-Klotho in biofluids. Here, we describe the discovery of peptides that recognize α-Klotho with high affinity and selectivity by applying in-solution size-exclusion-based affinity selection-mass spectrometry (AS-MS). After two rounds of AS-MS and subsequent N-terminal modifications, the peptides improved their binding affinity to α-Klotho by approximately 2300-fold compared to the reported starting peptide Pep-10, previously designed based on the C-terminal region of FGF23. The lead peptide binders were shown to enrich α-Klotho from cell lysates and to label α-Klotho in kidney cells. Our results further support the utility of in-solution, label-free AS-MS protocols to discover peptide-based binders to target proteins of interest with high affinity and selectivity, resulting in functional probes for biological studies.

Risk Factors for Early Lower Limb Re-Amputation in Vascular Diseases.

BACKGROUND: Numerous risk factors for lower limb amputations are known; however, this study aimed to identify risk factors for re-amputation in patients within 6 months from an initial lower limb amputation procedure. METHODS: This single-center retrospective cohort study was performed at the Hospital Regional Hans Dieter Schmidt in Brazil. The study included patients who were aged at least 18 years and had undergone lower limb amputation between 2013 and 2022. Patients who died while hospitalized and patients who were lost to follow-up after hospital discharge were excluded from the study. Patient age, sex, number of amputations, revision time, comorbidities, and potential risk factors were extracted from the physical therapy service database and electronic medical records of the hospital. Chi-squared test and student's t-test were used to identify statistical significance. RESULTS: A total of 652 patients were included, of which 35.2% (230) patients underwent re-amputation within 6 months of the first operation. We found that dialysis (P = 0.004; odds ratio [OR] 8.36, 95% confidence interval [CI] 3.09-20.5), smoking (P = 0.004; OR 1.67, 95% CI 1.18-2.35), and hypertension (P = 0.02; OR 1.55, 95% CI 1.09-2.19) were predictive factors for re-amputation within 6 months of lower limb amputation. CONCLUSIONS: Therefore, it is important to intervene early and provide additional support to patients undergoing lower limb amputation with these risk factors to reduce the potential for re-amputation in the future.

Circulating noradrenaline leads to release of neuropeptide Y from cardiac sympathetic nerve terminals via activation of ß-adrenergic receptors.

Cardiac disease is marked by sympathoexcitation and elevated levels of noradrenaline (NA) and cotransmitter neuropeptide Y (NPY). Increased NPY levels are associated with a greater risk of ventricular arrhythmias and mortality. Nonetheless, the factors that cause NPY release remain poorly understood. We hypothesized that circulating catecholamines might lead to NPY release from myocardial sympathetic nerve terminals via a ß-receptor-mediated mechanism that enhances sympathoexcitation. Ventricular interstitial NA and NPY levels were measured in six Yorkshire pigs after i.v. administration of NA (1 mg) and before and after propranolol infusion (1 mg/kg). Real-time interstitial NPY levels were measured using ventricular capacitive immunoprobes (CIs) affixed with NPY antibodies and quantified as the change in CI input current (INPY ) upon binding of NPY. Interstitial NA was measured with adjacent fast-scan cyclic voltammetry probes (INA ). A left ventricular pressure catheter and continuous ECGs were used for haemodynamic recordings, and an epicardial 56-electrode sock was used for measurements of activation recovery interval, a surrogate of action potential duration. Upon administration of NA, heart rate and left ventricular pressure increased, and activation recovery interval shortened. Notably, NA significantly increased interstitial myocardial NPY levels. After propranolol, changes in heart rate and activation recovery interval were largely mitigated. The INA increased to a similar extent post-propranolol vs. pre-propranolol, but changes in INPY were significantly reduced post-propranolol. Coronary sinus plasma analyses confirmed fast-scan cyclic voltammetry and CI findings. Hence, this study demonstrates that circulating NA induces NPY release from ventricular sympathetic nerve terminals, the mechanism for which is mediated via ß-adrenergic receptors and can be blocked by the non-selective ß-blocker, propranolol. KEY POINTS: Cardiovascular disease is characterized by sympathovagal imbalance, with increased plasma noradrenaline (NA) and neuropeptide Y (NPY) concentrations. Increased NPY levels are associated with increased ventricular arrhythmias and mortality in heart failure. Limited data are available on the specific factors that cause NPY release. In this study, fast-scan cyclic voltammetry and capacitive immunoprobes were used to allow for real-time in vivo measurements of interstitial myocardial neurotransmitters and neuropeptides, respectively. Using an in vivo porcine model with cardiac fast-scan cyclic voltammetry and capacitive immunoprobes, it was shown that systemic NA can increase ventricular interstitial NPY levels, suggesting that NA induces NPY release from postganglionic sympathetic nerves. The release of NPY was blocked by administration of the non-selective ß-blocker propranolol, suggesting that release of NPY is dependent on activation of ß-adrenergic receptors by NA.

Electrophile Scanning Reveals Reactivity Hotspots for the Design of Covalent Peptide Binders.

Protein-protein interactions (PPIs) are intriguing targets in drug discovery and development. Peptides are well suited to target PPIs, which typically present with large surface areas lacking distinct features and deep binding pockets. To improve binding interactions with these topologies and advance the development of PPI-focused therapeutics, potential ligands can be equipped with electrophilic groups to enable binding through covalent mechanisms of action. We report a strategy termed electrophile scanning to identify reactivity hotspots in a known peptide ligand and demonstrate its application in a model PPI. Cysteine mutants of a known ligand are used to install protein-reactive modifiers via a palladium oxidative addition complex (Pd-OAC). Reactivity hotspots are revealed by cross-linking reactions with the target protein under physiological conditions. In a model PPI with the 9-mer peptide antigen VL9 and major histocompatibility complex (MHC) class I protein HLA-E, we identify two reactivity hotspots that afford up to 87% conversion to the protein-peptide conjugate within 4 h. The reactions are specific to the target protein in vitro and dependent on the peptide sequence. Moreover, the cross-linked peptide successfully inhibits molecular recognition of HLA-E by CD94-NKG2A possibly due to structural changes enacted at the PPI interface. The results illustrate the potential application of electrophile scanning as a tool for rapid discovery and development of covalent peptide binders.

Association Between Indication for Descemet Stripping Automated Endothelial Keratoplasty and Rural Residency.

PURPOSE: Residing in rural locations can be a barrier to health care access. This study investigated the impact of residing in rural and small town (RST) areas on Descemet stripping automated endothelial keratoplasty (DSAEK) indications and outcomes in Atlantic Canada. METHODS: A retrospective cohort analysis examined consecutive DSAEKs performed in Nova Scotia between 2017 and 2020. Patient rurality was determined by the Statistical Area Classification system developed by Statistics Canada. Univariate and multivariate logistic regression models were used to assess for factors associated with DSAEK indication, including repeat keratoplasty, RST residence status, and travel time. RESULTS: Of 271 DSAEKs during the study period, 87 (32.1%) were performed on the eyes of RST residents. The median postoperative follow-up time was 1.6 years. Undergoing DSAEK for a previous failed keratoplasty was not associated with a higher odds of RST residency (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.19-1.16; P = 0.13) but was associated with travel time (OR, 0.78 for each increasing hour of travel; 95% CI, 0.61-0.99; P = 0.044). RST residency was not associated with the occurrence of graft failure (OR, 0.48; 95% CI, 0.17-1.17; P = 0.13). CONCLUSIONS: Residing in a rural area in Atlantic Canada was not associated with DSAEK graft failure. Repeat endothelial keratoplasty was associated with shorter travel time for corneal surgery but not rural residency status. Further research in this field could inform regional health strategies aimed at improving equity and accessibility to ophthalmology subspecialist care.

Symptom Adverse Events and Quality of Life of Children With Advanced Cancer: Results From a Longitudinal Study Using the Pediatric Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events.

Background: The presence of poorly controlled symptoms negatively impacts the quality of life (QoL) throughout cancer treatment. The purpose of this multisite study was to explore the relationship between QoL and symptom adverse events (AEs) in children with advanced cancer over 6 months. Method: A prospective and longitudinal descriptive study design was used to collect QoL and symptom AE data from children aged 2 to 18 with advanced cancer. QoL was measured using the Pediatric Quality of Life Inventory (PedsQLTM) Cancer Module 3.0 and symptom AEs were measured using the Pediatric Patient-Reported Outcome-Common Terminology Criteria for AEs (PRO-CTCAEs®). Descriptive statistics were used to describe QoL and symptom AE data. Correlational analyses and generalized linear mixed models were used to examine the relationship between symptom AEs and QoL. Results: Forty-nine children participated in the study. The mean total PedsQLTM score was 73.86 for the sample across all time points. Children diagnosed with a central nervous system (CNS) tumor reported poorer QoL compared to children diagnosed with a hematologic malignancy or non-CNS solid tumor. Symptom frequency AEs of anxiety, pain, nausea, insomnia, hot flashes, and fatigue severity demonstrated the strongest and most significant negative correlation with total QoL scores. Analyses of the relationship between QoL and symptom AEs over time revealed time-specific significant differences with children who experienced frequency AEs of nausea, and anxiety reporting poorer QoL at time point 4 (week 8). Discussion: The Ped PRO-CTCAE® and PedsQLTM can be used to evaluate the relationship between symptom AEs and QoL in practice and in future research.

Breakthrough SARS-COV-2 infection induces broad anti-viral T cell immunity.

Vaccines have curtailed the devastation wrought by COVID-19. Nevertheless, emerging variants result in a high incidence of breakthrough infections. Here we assess the impact of vaccination and breakthrough infection on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cell immunity. We demonstrate that COVID-19 vaccination induces robust spike-specific T cell responses that, within the CD4+ compartment, display comparable IFN-γ responses to SARS-CoV-2 infection without vaccination. Vaccine-induced CD8+ IFN-γ responses however, were significantly greater than those primed by SARS-CoV-2 infection alone. This increased responsiveness is associated with induction of novel HLA-restricted CD8+ T cell epitopes not primed by infection alone (without vaccination). Despite these augmented responses, breakthrough infection still induced de novo T cell responses against additional SARS-CoV-2 CD8+ epitopes that display HLA-associated immunodominance hierarchies consistent with those in unvaccinated COVID-19 convalescent individuals. This study demonstrates the unique modulation of anti-viral T cell responses against multiple viral antigens following consecutive yet distinct priming events in COVID-19 vaccination and breakthrough infection.

Elevated BMI reduces the humoral response to SARS-CoV-2 infection.

Objective: Class III obesity (body mass index [BMI] ≥ 40 kg m-2) significantly impairs the immune response to SARS-CoV-2 vaccination. However, the effect of an elevated BMI (≥ 25 kg m-2) on humoral immunity to SARS-CoV-2 infection and COVID-19 vaccination remains unclear. Methods: We collected blood samples from people who recovered from SARS-CoV-2 infection approximately 3 and 13 months of post-infection (noting that these individuals were not exposed to SARS-CoV-2 or vaccinated in the interim). We also collected blood samples from people approximately 5 months of post-second dose COVID-19 vaccination (the majority of whom did not have a prior SARS-CoV-2 infection). We measured their humoral responses to SARS-CoV-2, grouping individuals based on a BMI greater or less than 25 kg m-2. Results: Here, we show that an increased BMI (≥ 25 kg m-2), when accounting for age and sex differences, is associated with reduced antibody responses after SARS-CoV-2 infection. At 3 months of post-infection, an elevated BMI was associated with reduced antibody titres. At 13 months of post-infection, an elevated BMI was associated with reduced antibody avidity and a reduced percentage of spike-positive B cells. In contrast, no significant association was noted between a BMI ≥ 25 kg m-2 and humoral immunity to SARS-CoV-2 at 5 months of post-secondary vaccination. Conclusions: Taken together, these data showed that elevated BMI is associated with an impaired humoral immune response to SARS-CoV-2 infection. The impairment of infection-induced immunity in individuals with a BMI ≥ 25 kg m-2 suggests an added impetus for vaccination rather than relying on infection-induced immunity.

Voltammetry in the spleen assesses real-time immunomodulatory norepinephrine release elicited by autonomic neurostimulation.

BACKGROUND: The noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the development of anti-inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits. METHODS: In mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravenous injections of norepinephrine (NE), and during stimulation of the vagus, splanchnic, or splenic nerves. We defined the stimulus-elicited charge generated at the oxidation potential for NE (~ 0.88 V) as the "NE voltammetry signal" and quantified the dependence of the signal on NE dose and intensity of neurostimulation. We correlated the NE voltammetry signal with the anti-inflammatory effect of splenic nerve stimulation (SpNS) in a model of lipopolysaccharide- (LPS) induced endotoxemia, quantified as suppression of TNF release. RESULTS: The NE voltammetry signal is proportional to the estimated peak NE blood concentration, with 0.1 µg/mL detection threshold. In response to SpNS, the signal increases within seconds, returns to baseline minutes later, and is blocked by interventions that deplete NE or inhibit NE release. The signal is elicited by efferent, but not afferent, electrical or optogenetic vagus nerve stimulation, and by splanchnic nerve stimulation. The magnitude of the signal during SpNS is inversely correlated with subsequent TNF suppression in endotoxemia and explains 40% of the variance in TNF measurements. CONCLUSIONS: FSCV in the spleen provides a marker for real-time monitoring of anti-inflammatory activation of the splenic innervation during autonomic stimulation.

Variability of scan quality and perfusion density in longitudinal optical coherence tomography angiography imaging.

BACKGROUND/AIMS: Optical coherence tomography angiography (OCT-A) images are subject to variability, but the extent to which learning impacts OCT-A measurements is unknown. We determined whether there is a learning effect in glaucoma patients and healthy controls imaged with OCT-A. METHODS: Ninety-one open-angle glaucoma patients and 54 healthy controls were imaged every 4 months over a period of approximately 1 year in this longitudinal cohort study. We analysed 15°×15° scans, centred on the fovea, in one eye of each participant. Two-dimensional projection images for the superficial, intermediate and deep vascular plexuses were exported and binarised after which perfusion density was calculated. Linear mixed-effects models were used to investigate the association between perfusion density and follow-up time. RESULTS: The mean (SD) age of glaucoma patients and healthy controls was 67.3 (8.1) years and 62.1 (9.0) years, respectively. There was a significant correlation between perfusion density and scan quality in both glaucoma patients (r=0.50 (95% CI 0.42 to 0.58); p<0.05) and healthy controls (r=0.41 (95% CI 0.29 to 0.52); p<0.05). An increase in perfusion density occurred over time and persisted, even after adjustment for scan quality (1.75% per year (95% CI 1.14 to 2.37), p<0.01). CONCLUSIONS: Perfusion density measurements are subject to increasing experience of either the operator or participant, or a combination of both. These findings have implications for the interpretation of longitudinal measurements with OCT-A.

Risk for Surgical Team Hearing Loss With Vitrectomy.

Purpose: To assess sound-level exposure during vitrectomy using 3 of the most common commercially available machines. Methods: This noninterventional cross-sectional study examined sound emission from the Constellation, Stellaris, and EVA vitrector systems. For each machine, a noise dosimeter was used to measure the sound-level exposure of the surgeon during 3 surgical cases in which vitrectomy was performed. Sound levels associated with progressively increasing cut rates and vacuum pressures were also measured. Finally, sound measurements were taken during the use of various additional functions of each machine, including diathermy, laser, and extrusion. Sound levels were compared with occupational health guidelines in Canada and the United States. Results: The maximum sound level recorded during vitrectomy surgery was 88.2 dBA. The mean sound level during vitrectomy surgical cases ranged from 58.5 to 66.8 dBA. A strong positive linear correlation was found between the cut rate and sound level (r = 0.88-0.98) and the vacuum pressure and sound level (r = 0.83-0.97). This relationship was consistent across the 3 vitrector systems (P < .001). Conclusions: Noise exposure during vitrectomy procedures was acceptable but may be sufficient for surgical team activity interference, as described by World Health Organization recommendations. A strong correlation was found between the cut rate and noise exposure. If cut rates continue to increase, attention should be given to ensure that the resulting noise exposure does not threaten the hearing of vitreoretinal surgeons and the operating room staff.

A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting.

In vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.

Branched Multimeric Peptides as Affinity Reagents for the Detection of α-Klotho Protein.

α-Klotho, an aging-related protein found in the kidney, parathyroid gland, and choroid plexus, acts as an essential co-receptor with the fibroblast growth factor 23 receptor complex to regulate serum phosphate and vitamin D levels. Decreased levels of α-Klotho are a hallmark of age-associated diseases. Detecting or labeling α-Klotho in biological milieu has long been a challenge, however, hampering the understanding of its role. Here, we developed branched peptides by single-shot parallel automated fast-flow synthesis that recognize α-Klotho with improved affinity relative to their monomeric versions. These peptides were further shown to selectively label Klotho for live imaging in kidney cells. Our results demonstrate that automated flow technology enables rapid synthesis of complex peptide architectures, showing promise for future detection of α-Klotho in physiological settings.

Latarjet Procedure to Restore Glenohumeral Stability in a Patient With a Postage Stamp Fracture.

The "postage stamp fracture" is an anterior glenoid rim fracture following arthroscopic repair of a Bankart lesion. Often occurring at the time of an acute trauma, a fracture line propagates though the previous Bankart repair anchor sites, resulting in recurrent anterior instability of the glenohumeral joint. The resultant glenoid rim fracture edge gives a similar appearance as the edge of a stamp, with the osseous edge having the classic "perforation" pattern. When patients present with a postage stamp fracture, even in the setting of subcritical glenoid bone loss, we believe that additional soft-tissue stabilization procedures and/or fracture fixation pose a significant risk of failure. In our opinion, a Latarjet procedure is recommended in a majority of patients with a postage stamp fracture for restoration of glenohumeral stability. The procedure offers a reliable, reproducible surgical intervention that controls for many of the factors that can make arthroscopic revision unreliable, such as poor bone quality, adhesions, labral degeneration, and bone loss. Here, we outline our preferred surgical technique to restore glenohumeral stability using the Latarjet procedure for a patient with a postage stamp fracture.

Adoptive T-cell therapy targeting Epstein-Barr virus as a treatment for multiple sclerosis.

Emergence of a definitive link between Epstein-Barr virus (EBV) and multiple sclerosis has provided an impetus to develop immune-based therapies to target EBV-infected B cells. Initial studies with autologous EBV-specific T-cell therapy demonstrated that this therapy is safe with minimal side effects and more importantly multiple patients showed both symptomatic and objective neurological improvements including improved quality of life, reduction of fatigue and reduced intrathecal IgG production. These observations have been successfully extended to an 'off-the-shelf' allogeneic EBV-specific T-cell therapy manufactured using peripheral blood lymphocytes of healthy seropositive individuals. This adoptive immunotherapy has also been shown to be safe with encouraging clinical responses. Allogeneic EBV T-cell therapy overcomes some of the limitations of autologous therapy and can be rapidly delivered to patients with improved therapeutic potential.

Robot-Assisted Nasal Reconstruction: A Cadaveric Study.

OBJECTIVE: Manual contouring of cartilage for nasal reconstruction is tedious and time-consuming. The use of a robot could improve the speed and precision of the contouring process. This cadaveric study evaluates the efficiency and accuracy of a robot methodology for contouring the lower lateral cartilage of the nasal tip. METHODS: An augmented robot with a spherical burring tool attached was utilized to carve 11 cadaveric rib cartilage specimens. In phase 1, the right lower lateral cartilage was harvested from a cadaveric specimen and used to define a carving path for each rib specimen. In phase 2, the cartilage remained in situ during the scanning and 3-dimensional modeling. The final carved specimens were compared with the preoperative plans through topographical accuracy analysis. The contouring times of the specimens were compared with 14 retrospectively reviewed cases (2017-2020) by an experienced surgeon. RESULTS: Phase 1 root mean square error of 0.40±0.15 mm and mean absolute deviation of 0.33±0.13 mm. Phase 2 root mean square error of 0.43 mm and mean absolute deviation of 0.28 mm. The average carving time for the robot specimens was 14±3 minutes and 16 minutes for Phase 1 and Phase 2, respectively. The average manual carving by an experienced surgeon was 22±4 minutes. CONCLUSIONS: Robot-assisted nasal reconstruction is very precise and more efficient than manual contouring. This technique represents an exciting and innovative alternative for complex nasal reconstruction.

Leadless Micra pacemaker implantation in patient with previous Senning procedure for dextro-transposition of the great arteries.

Leadless pacemakers have been developed with key advantages over traditional transvenous pacemakers by substantially mitigating the risks of device infection and lead related complications, and providing an alternative pacing strategy in patients with barriers to superior venous access. The Medtronic Micra leadless pacing system is designed for implantation through a femoral venous approach across the tricuspid valve, via Nitinol tine fixation into the trabeculated subpulmonic right ventricle. Patients with surgically corrected dextro-transposition of the great arteries (d-TGA) have an increased risk of pacing requirement. There is limited published experience of implantation of leadless Micra pacemakers in this population, with key challenges relating to trans-baffle access, and deployment of the device into the less trabeculated subpulmonic left ventricle. Here we describe a case report of leadless Micra implantation in a 49 year old male with d-TGA and Senning procedure in childhood, who required pacing for symptomatic sinus node disease, with anatomic barriers to transvenous pacing. Micra implantation was successfully performed following careful consideration of patient anatomy, including the utilisation of 3D modelling to guide the implantation procedure.