Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.

The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.

An orexigenic subnetwork within the human hippocampus.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a progressive, occlusive disease of the internal carotid arteries and their proximal branches, with the subsequent development of an abnormal vascular network that is rupture-prone. Steno-occlusive changes in the posterior cerebral arteries (PCAs) may contribute to worsened outcomes in patients with MMD; however, there is little information on the incidence and natural history of posterior circulation MMD (PCMMD). We describe clinical PCMMD characteristics in a large cohort of patients with MMD. METHODS: We retrospectively reviewed patients with MMD treated between 1991 and 2019 at a large academic medical center. Demographics, perioperative outcomes, and radiological phenotypes were recorded for 770 patients. PCA disease was graded as either 0 (no disease), 1 (mild), 2 (moderate), or 3 (severe or occluded) based on cerebral angiography. Patients with angiographically confirmed MMD diagnosis with at least 6 months follow-up and completion of revascularization surgery were included; patients with intracranial atherosclerosis, intracranial dissection, vasculitis, and undefined inflammatory processes were excluded. The presence of stenosis/occlusion was graded radiographically to assess for disease progression and the prevalence of risk factors related to reduced progression-free survival. RESULTS: In all, 686 patients met the inclusion criteria, with PCA disease identified in 282 (41.1%) patients. Of those 282 patients with PCMMD, disease severity ranged from 99 (35.1%) with mild, 72 (25.5%) with moderate, and 111 (39.4%) with severe. The total number of postoperative complications was significantly associated with PCMMD severity (P=0.0067). Additionally, PCMMD severity correlated with worse postoperative modified Rankin Scale scores (P<0.0001). At a mean follow-up of 6.0±3.9 (range, 0.1-25.0) years, a total of 60 (12.6%) patients showed new/worsening PCMMD. The overall postoperative, progression-free survival in patients with PCMMD was 95.4% at 1 year, 82.4% at 3 years, 68.8% at 5 years, and 28.3% at 10 years, with prognostic factors for progression including preoperative PCMMD status, history of tobacco use, and hypertension (P<0.0001, P<0.001, and P<0.0001, respectively). CONCLUSIONS: PCA disease involvement in MMD is associated with higher rates of ischemic perioperative complications and worsened functional outcomes, likely due to reduced collateral flow. Ten-year progression of PCA disease is highly likely and should be monitored throughout follow-up; future studies will assess the impact of PCA disease progression on long-term outcomes.

Aberrant impulse control circuitry in obesity.

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

Posteroinferior relevant scapular neck offset in reverse shoulder arthroplasty: key player for motion and friction-type impingement in a computer model.

BACKGROUND: Range of motion (ROM) and prevention of notching remain a challenge for reverse shoulder arthroplasty (RSA). Both may be affected by the morphology of the scapula. The purpose of this study was to define anteroinferior (a) and posteroinferior (p) relevant scapular neck offset (RSNO) and to examine the hypothesis that pRSNO is significantly smaller than aRSNO, and influences rigid body motion (RBM). Adapting glenosphere implantation strategies may therefore be of value. MATERIAL AND METHODS: In this computer model study, we used deidentified computed tomographic scans of 22 patients (11 male and 11 female; mean age: 72.9 years) with massive cuff tears without joint space narrowing. Eight RSA glenoid configurations were tested with a constant neck-shaft angle (145°). Two baseplate types (25 mm; 25 + 3 mm lateralized) and 4 glenospheres (GS) (36 mm; 36 +2 mm of eccentricity; 39 mm; 39 + 3 mm) were used. RSNO was defined as the standardized measurement of the horizontal distance from the inferior extent of the GS to the bony margin of the scapula after baseplate positioning (flush to inferior glenoid extent; neutral position: 0° inclination and 0° version-both software computed). RESULTS: There was a highly significant difference between pRSNO and aRSNO for both genders (P < .001). pRSNO was always smaller than aRSNO. pRSNO was strongly correlated with external rotation (ERO: 0.84) and extension (EXT: 0.74) and moderately correlated with global ROM (GROM: 0.68). There was a moderately strong correlation between aRSNO and internal rotation (IRO: 0.69). pRSNO was strongly correlated with aRSNO, EXT, ERO, IRO, adduction (ADD) and GROM (0.82, 0.72, 0,8, 0.71, 0.82, 0.76) in female patients and with EXT and ERO (0.82, 0.89) in male patients. The median pRSNO allowing for at least 45° ERO and 40° EXT was 14.2 mm for men and 13.8 mm for women. For all patients and models, pRSNO ≥14 mm increased EXT, ERO, and GROM significantly compared with pRSNO <14 mm (P < .001). The combination of lateralization and inferior overhang (eccentricity) led to the most significant increase of pRSNO for each GS size (P < .001). CONCLUSION: This is one of the first RSA modeling studies evaluating nonarthritic glenoids of both genders. The lateral scapular extent to glenoid relationship is asymmetric. pRSNO is always smaller than aRSNO for both genders and was a critical variable for EXT and ERO, demonstrating additional strong correlation with aRSNO, IRO, ADD, and GROM in female patients. pRSNO ≥14 mm was a safe value to prevent friction-type impingement. Combining increased glenosphere size, lateralization, and inferior overhang gives the best results in this computer-simulated setting.

The role of dopamine in reward-related behavior: shining new light on an old debate.

The role dopamine plays in reward-related behaviors has been debated for decades. Heymann et al. (Heymann G, Jo YS, Reichard KL, McFarland N, Chavkin C, Palmiter RD, Soden ME, Zweifel LS. Neuron 105: 909-920, 2020) identify subpopulations of dopamine-producing neurons that separately mediate reward association and motivation. Their results help demonstrate that dopamine signaling may partake in both reinforcement learning and incentive salience functions, instantiated by neuropeptide-defined subpopulations of the ventral tegmental area with different projection targets.

Computer navigation of the glenoid component in reverse total shoulder arthroplasty: a clinical trial to evaluate the learning curve.

BACKGROUND: Intraoperative computer navigation has been introduced recently to assist with placement of the glenoid component. The aim of this study was to evaluate the learning curve of a single surgeon performing computer navigation of glenoid implant placement in primary reverse total shoulder arthroplasty (RTSA). METHODS: Following training with the intraoperative computer navigation system, we conducted a prospective case-series study of the first 24 consecutive patients undergoing a primary RTSA with navigation performed by a single surgeon. Surgical times, complications, and accuracy of glenoid positioning compared with the preoperative plan were evaluated. Surgical times were compared with the preceding non-navigated series of 24 consecutive primary RTSA cases. Postoperative 3-dimensional computed tomography scans were performed to evaluate glenoid component version and inclination compared with the preoperative plan. RESULTS: The total surgical time was 77.3 minutes (standard deviation [SD], 11.8 minutes) in the navigated RTSA cohort and 78.5 minutes (SD, 18.1 minutes) in the non-navigated series. A significant downward trend in the total surgical time was observed in the navigated cohort (P = .038), which flattened after 8 cases. No learning curve was observed in deviation of glenoid version or inclination from the preoperative plan. The mean deviation of achieved version from planned version was 3° (SD, 2°), and the mean deviation of achieved inclination from planned inclination was 5° (SD, 3°). CONCLUSION: Findings from this study suggest that intraoperative computer navigation will not require substantially increased operating times compared with standard surgical techniques. With prior surgeon training, approximately 8 operative cases are required to achieve proficiency in intraoperative computer navigation of the glenoid component.

Accelerometry evaluation of shoulder movement and its association with patient-reported and clinical outcomes following reverse total shoulder arthroplasty.

BACKGROUND: Accelerometers provide a new method to objectively measure recovery of movement and physical activity in patients following reverse total shoulder arthroplasty (RTSA) and may overcome common limitations associated with patient-reported outcome measures (PROMs). The aim of this study was to assess changes in upper limb movement using accelerometers following RTSA and investigate their association with other clinical outcome measures. METHODS: Thirty-six patients who underwent RTSA wore accelerometers on both wrists and arms for 3 days at 3, 6, and 12 months postsurgery. PROMs (Constant score, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form, visual analog scale for pain, Single Assessment Numerical Evaluation, Shoulder Activity Level) and isometric shoulder strength were also assessed. Accelerometer outcomes were calculated to quantify counts of forearm and arm activity and the contribution of both arms to activity (limb symmetry and magnitude ratio). Changes and differences in all clinical measures and objective movement measures were evaluated with within-subjects analysis of variance. Correlations between limb activity and other clinical measures were investigated using Spearman correlation coefficients. RESULTS: Objective movement of the operated arm increased from 3-6 months postsurgery (P = .004), but not from 6-12 months (P = .240). Limb asymmetries were observed at 3 and 6 months and improved by 12 months postsurgery. No associations were demonstrated between PROMs and objective upper limb movement at 12 months postsurgery. DISCUSSION: Despite early recovery of function and pain relief assessed by PROMs, objective movement using accelerometers showed delayed recovery of the operated arm postoperatively, before normalizing by 12 months postsurgery. Accelerometers provide a unique insight into functional recovery following RTSA.

3D uniaxial mechanical stimulation induces tenogenic differentiation of tendon-derived stem cells through a PI3K/AKT signaling pathway.

The tendon is a mechanosensitive tissue, but little is known about how mechanical stimulation selectively signals tenogenic differentiation and neo-tendon formation. In this study, we compared the impact of uniaxial and biaxial mechanical loading on tendon-derived stem cells (TDSCs). Our data show that there are variations in cell signaling and cell differentiation of mouse TDSCs in response to uniaxial and biaxial loading in monolayer culture. Whereas uniaxial loading induced TDSCs toward tenogenic and osteogenic differentiation, biaxial loading induced osteogenic, adipogenic, and chondrogenic differentiation of TDSCs. Furthermore, by applying uniaxial loading on 3-dimensional (3D) TDSC constructs, tenogenic-specific differentiation and neo-tendon formation were observed, results that were replicated in human TDSCs. We also showed that uniaxial loading induced PKB (AKT) phosphorylation (pAKT), whereas biaxial loading induced pERK. Most importantly, we found that inhibition of the PI3K/AKT signaling pathway could attenuate tenogenic differentiation and tendon formation in 3D TDSC constructs subjected to uniaxial loading. Taken together, our study highlights the importance of appropriate mechanobiological stimulation in 3D cell niches on tendon-like tissue formation and demonstrates that uniaxial mechanical loading plays an essential role in tenogenic differentiation and tendon formation by activating the PI3K/AKT signaling pathway.-Wang, T., Thien, C., Wang, C., Ni, M., Gao, J., Wang, A., Jiang, Q., Tuan, R. S., Zheng, Q., Zheng, M. H. 3D uniaxial mechanical stimulation induces tenogenic differentiation of tendon-derived stem cells through a PI3K/AKT signaling pathway.

Head and Neck Sarcomas: A Review of Clinical and Imaging Findings Based on the 2013 World Health Organization Classification.

OBJECTIVE: Head and neck sarcomas are a complex, heterogeneous group of tumors that present a diagnostic challenge to radiologists because they have many overlapping imaging features. The purpose of this article is to review the imaging and clinical features and highlight distinguishing features of head and neck sarcomas. CONCLUSION: An understanding of characteristic imaging and clinical features of head and neck sarcomas is important for the radiologist to narrow the differential diagnosis and help guide management.

High-resolution study of the 3D collagen fibrillary matrix of Achilles tendons without tissue labelling and dehydrating.

Knowledge of the collagen structure of an Achilles tendon is critical to comprehend the physiology, biomechanics, homeostasis and remodelling of the tissue. Despite intensive studies, there are still uncertainties regarding the microstructure. The majority of studies have examined the longitudinally arranged collagen fibrils as they are primarily attributed to the principal tensile strength of the tendon. Few studies have considered the structural integrity of the entire three-dimensional (3D) collagen meshwork, and how the longitudinal collagen fibrils are integrated as a strong unit in a 3D domain to provide the tendons with the essential tensile properties. Using second harmonic generation imaging, a 3D imaging technique was developed and used to study the 3D collagen matrix in the midportion of Achilles tendons without tissue labelling and dehydration. Therefore, the 3D collagen structure is presented in a condition closely representative of the in vivo status. Atomic force microscopy studies have confirmed that second harmonic generation reveals the internal collagen matrix of tendons in 3D at a fibril level. Achilles tendons primarily contain longitudinal collagen fibrils that braid spatially into a dense rope-like collagen meshwork and are encapsulated or wound tightly by the oblique collagen fibrils emanating from the epitenon region. The arrangement of the collagen fibrils provides the longitudinal fibrils with essential structural integrity and endows the tendon with the unique mechanical function for withstanding tensile stresses. A novel 3D microscopic method has been developed to examine the 3D collagen microstructure of tendons without tissue dehydrating and labelling. The study also provides new knowledge about the collagen microstructure in an Achilles tendon, which enables understanding of the function of the tissue. The knowledge may be important for applying surgical and tissue engineering techniques to tendon reconstruction.

Functional Connectivity is Reduced in Early-stage Primary Progressive Aphasia When Atrophy is not Prominent.

Primary progressive aphasia (PPA) is a clinical syndrome of language decline caused by neurodegenerative pathology. Although language impairments in PPA are typically localized via the morphometric assessment of atrophy, functional changes may accompany or even precede detectable structural alterations, in which case resting state functional connectivity (RSFC) could provide an alternative approach. The goal of this study was to determine whether language network RSFC is reduced in early-stage PPA when atrophy is not prominent. We identified 10 individuals with early-stage agrammatic variant of PPA with no prominent cortical thinning compared with nonaphasic controls. RSFC between 2 nodes of the language network and 2 nodes of the default mode network were compared between agrammatic variant of PPA and healthy control participants. Language network connectivity was comparable with controls among patients with milder agrammatism, but was significantly reduced in patients with more pronounced agrammatism. No group differences were observed in default mode network connectivity, demonstrating specificity of findings. In early stages of PPA when cortical atrophy is not prominent, RSFC provides an alternative method for probing the neuroanatomic substrates of language impairment. RSFC may be of particular utility in studies on early interventions for neurodegenerative disease, either to identify anatomic targets for intervention or as an outcome measure of therapeutic efficacy.

Isokinetic shoulder strength correlates with level of sports participation and functional activity after reverse total shoulder arthroplasty.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is increasingly being performed. Many patients may wish to return to high levels of sporting activity. This study aimed to evaluate the correlation of isokinetic shoulder strength with level of participation in sport and recreation after RTSA. METHODS: We surveyed 51 patients at a mean of 29.5 months (range, 12-60 months) after surgery. Mean age was 74.1 years. Patient-reported sporting activity was classified as low, medium, or high demand. All patients completed the shortened Disabilities of the Arm, Shoulder, and Hand questionnaire and the Oxford Shoulder Score and underwent Biodex dynamometer testing of the RTSA evaluating isokinetic shoulder strength in flexion and extension, abduction and adduction, and internal and external rotation. RESULTS: Reported sporting activity was high demand in 35% and moderate demand in 43%. There was a large variation in shoulder isokinetic strength parameters especially for internal and external rotation. With the exception of abduction, a significant correlation was noted between strength and the level of sports participation that patients reported (P < .03). A significant correlation was also noted between strength and patient-reported outcome measures for internal rotation and arm flexion and abduction (P < .05). CONCLUSION: Most patients reported returning to moderate- or high-level sporting activity in the short term after RTSA. Isokinetic shoulder strength, especially in internal rotation and arm flexion, positively correlates with both patient-reported level of participation in sports and recreation and daily function.

Early postoperative repair status after rotator cuff repair cannot be accurately classified using questionnaires of patient function and isokinetic strength evaluation.

BACKGROUND: This study investigated if patients with an intact tendon repair or partial-thickness retear early after rotator cuff repair display differences in clinical evaluations and whether early tendon healing can be predicted using these assessments. METHODS: We prospectively evaluated 60 patients at 16 weeks after arthroscopic supraspinatus repair. Evaluation included the Oxford Shoulder Score, 11-item version of the Disabilities of the Arm, Shoulder and Hand, visual analog scale for pain, 12-item Short Form Health Survey, isokinetic strength, and magnetic resonance imaging (MRI). Independent t tests investigated clinical differences in patients based on the Sugaya MRI rotator cuff classification system (grades 1, 2, or 3). Discriminant analysis determined whether intact repairs (Sugaya grade 1) and partial-thickness retears (Sugaya grades 2 and 3) could be predicted. RESULTS: No differences (P < .05) existed in the clinical or strength measures. Although discriminant analysis revealed the 11-item version of the Disabilities of the Arm, Shoulder and Hand produced a 97% true-positive rate for predicting partial thickness retears, it also produced a 90% false-positive rate whereby it incorrectly predicted a retear in 90% of patients whose repair was intact. The ability to discriminate between groups was enhanced with up to 5 variables entered; however, only 87% of the partial-retear group and 36% of the intact-repair group were correctly classified. CONCLUSIONS: No differences in clinical scores existed between patients stratified by the Sugaya MRI classification system at 16 weeks. An intact repair or partial-thickness retear could not be accurately predicted. Our results suggest that correct classification of healing in the early postoperative stages should involve imaging.

Biceps muscle fatty infiltration and atrophy. A midterm review after arthroscopic tenotomy of the long head of the biceps.

PURPOSE: Pathology of the long head of the biceps (LHB) tendon is commonly treated by tenotomy. High levels of clinical function and patient satisfaction are reported in the short-term. The purpose of this study was to investigate the midterm effects of tenotomy on biceps fatty infiltration and atrophy in active working-age male patients. METHODS: Twenty-five men (mean age, 57 years) were evaluated at a mean follow-up of 6.7 years after tenotomy. Bilateral magnetic resonance imaging (MRI) was performed, and fatty infiltration of the biceps was assessed relative to the ipsilateral triceps. Seventeen participants had an intact contralateral LHB tendon. To assess atrophy, anterior muscle compartment volume was measured by serial cross-sectional area measurements on MRI. The tenotomized side was then compared to the healthy side in these 17 participants. Clinical scores were obtained using the QuickDASH and Oxford Elbow Score, and the occurrence of a Popeye sign and residual pain were recorded. RESULTS: Good clinical function was maintained at a mean follow-up time of 6.7 years (range, 4 to 10 years) (QuickDASH score of 7.1; standard error [SE], 1.8) and Oxford Elbow Score of 97.9 [SE 1.2]). Eleven of the 25 participants had a Popeye deformity. Four participants showed signs of fatty infiltration, and all were minor (grade 1). The mean decrease in total volume of the anterior musculature was 3.6%. In participants without a Popeye deformity, it was 3.3%, whereas it was 4.1% in participants with a Popeye sign (P = .8). CONCLUSIONS: In the midterm, LHB tenotomy in active men of working age does not result in fatty degeneration or substantial atrophy in the anterior musculature of the arm. Clinical function remains good. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Humeral head size predicts baseplate lateralization in reverse shoulder arthroplasty: a comparative computer model study.

Background: In reverse shoulder arthroplasty (RSA), the ideal combination of baseplate lateralization (BL), glenosphere size (GS), and glenosphere overhang (GOH) with a commonly used 145° neck shaft angle (NSA) is unclear. This is the first study evaluating correlations of body height (BH), humeral head size (HS), glenoid height (GH), and association of gender with best glenoid configurations for range of motion (ROM) maintaining anatomic lateralization (aLAT) for optimized muscle length in 145° and less distalized 135° RSA. Methods: In this computer model study, 22 computed tomographies without joint narrowing were analyzed (11 male/female). A standardized semi-inlay 145° platform stem was combined with 20 glenoid configurations (baseplate [B] 25, 25 + 3/+6 lateralized [l], 29, 29 + 3/6l combined with glenosphere 36, 36 + 2 eccentric [e], 36 + 3l, 39, 39 + 3e, 39 + 3l , 42, 42 + 4e). Abduction-adduction, flexion-extension, external rotation-internal rotation, total ROM (TROM), and total notching relevant (TNR) ROM were computed, best TROM models respecting aLAT (-1 mm to +1 mm) and HS/GH recorded. Second, the 145° models (Ascend Flex stem; Stryker, Kalamazoo, MI, USA) were converted and compared to a 135° inlay RSA (New Perform stem; Stryker, Kalamazoo, MI, USA) maintaining GOH (6.5-7 mm) and aLAT. Results: Best 145° models had eccentric glenospheres (mean BL: 3.5 mm, GOH 8.8 mm, GS 38.1 mm, distalization 23 mm). The 135° models had concentric glenospheres, mean BL 3.8 mm, GOH 6.9 mm, GS 39.7 mm, and distalization 14.1 mm. HS showed the strongest positive correlation with BL in 145° and 135° models (0.65/0.79). Despite reduced GOH in smaller females with a 135° NSA, adduction, external rotation, extension, TNR ROM, and TROM were significantly increased (P = .02, P = .005, P = .005, P = .004, P = .003), abduction however reduced (P = .02). The same trends were seen for males. Conclusion: HS is a practical measure in surgery or preoperatively, and the strong positive correlation with BL is a useful planning aid. Despite reduction of GOH, conversion to a less distalized 135° NSAinlay design is powerful to maintain and even significantly increase all components of TNR ROM (extension/external rotation/adduction) in small females with the drawback of reduced abduction which may however be compensated by scapula motion. Lateralization with a less distalized 135° RSA optimizes muscle length, may facilitate subscapularis repair, and maintains highest rigid body motion.

Impact of dupilumab prescribing on utilization of medical and surgical therapies for chronic rhinosinusitis with nasal polyps.

KEY POINTS: Increased dupilumab utilization coincided with decreased ESS in patients with CRSwNP between 2019 and 2021. One potential confounder was the concurrent COVID-19 pandemic, which may have negatively impacted surgery utilization rates.

Impact of age and donor sites on bioactivities of tendon cells in autologous tenocyte implantation (OrthoATI™) for treatment of chronic tendinopathy.

OBJECTIVES: Autologous tenocyte implantation (OrthoATI™) therapy has demonstrated efficacy in treating patients with tendinopathy at various anatomical sites. This study evaluates the effect of patient age, gender, and tendon biopsy site on morphology, growth, and gene expression of autologous tendon cells used to treat chronic tendinopathy. METHODS: Patients undergoing OrthoATI™ for tendinopathies between 2020 and 2022 were initially treated by biopsies taken from patella tendon (PT) or palmaris longus tendon (PL). The biopsies were sent to a Good Manufacturing Practice (GMP) cell laboratory where tendon cells were isolated, cultured, and expanded for four to six weeks. Cell morphology was assessed using phase contrast microscopy. Droplet digital PCR (ddPCR) was utilized for gene expression analysis. Dichotomous results were compared between groups using x2 or Fisher's exact tests with no adjustment for multiple comparisons. The nonparametric Mann-Whitney U and Kruskal-Wallis tests were utilized for the sex and age (<35y, 35-44y, 45-54y, >55y) analyses, respectively. All analyses were performed using IBM SPSS v27, and a two-tailed P-value of <0.05 was considered statistically significant. RESULTS: 149 patients were included in the analysis. The PT was biopsied in 63 patients, and PL in 86 patients. There were no observer effects for age and gender between the PT and PL groups. There was no statistical significance between the PT and PL tendons for cell morphology, average cell population doubling time (PDT) (PT 83.9 vs PL 82.7 â€‹h, p â€‹= â€‹0.482), cellular yield (PT 16.2 vs PL 15.2 â€‹× â€‹106, p â€‹= â€‹0.099), and cell viability (PT 98.7 vs PL 99.0%, p â€‹= â€‹0.277). Additionally, ddPCR analyses showed no statistical significance found in tenogenic gene expression, including collagen type I (COL1, p â€‹= â€‹0.86), tenomodulin (TNMD, p â€‹= â€‹0.837) and scleraxis (SCX, p â€‹= â€‹0.331) between PT- and PL-derived tendon cells. An age stratification analysis found no effect on growth and gene expression. COL1 was found to be higher in males when compared to females (P â€‹< â€‹0.001), but otherwise no difference was seen in growth and gene expression in the gender analysis. No postbiopsy clinical complications were reported for either group. CONCLUSION: This study has shown that the growth and bioactivities of tendon cells from tendon biopsies for OrthoATI™ are not affected by tendon donor site and age. LEVEL OF EVIDENCE: IV.