Blood and immune development in human fetal bone marrow and Down syndrome.

Haematopoiesis in the bone marrow (BM) maintains blood and immune cell production throughout postnatal life. Haematopoiesis first emerges in human BM at 11-12 weeks after conception1,2, yet almost nothing is known about how fetal BM (FBM) evolves to meet the highly specialized needs of the fetus and newborn. Here we detail the development of FBM, including stroma, using multi-omic assessment of mRNA and multiplexed protein epitope expression. We find that the full blood and immune cell repertoire is established in FBM in a short time window of 6-7 weeks early in the second trimester. FBM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell subsets emerging for the first time. The substantial expansion of B lymphocytes in FBM contrasts with fetal liver at the same gestational age. Haematopoietic progenitors from fetal liver, FBM and cord blood exhibit transcriptional and functional differences that contribute to tissue-specific identity and cellular diversification. Endothelial cell types form distinct vascular structures that we show are regionally compartmentalized within FBM. Finally, we reveal selective disruption of B lymphocyte, erythroid and myeloid development owing to a cell-intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in Down syndrome (trisomy 21).

Spatial and molecular profiling of the mononuclear phagocyte network in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) has a rich immune infiltrate, which is an intrinsic component of the neoplastic process. Malignant Hodgkin Reed-Sternberg cells (HRSCs) create an immunosuppressive microenvironment by the expression of regulatory molecules, preventing T-cell activation. It has also been demonstrated that mononuclear phagocytes (MNPs) in the vicinity of HRSCs express similar regulatory mechanisms in parallel, and their presence in tissue is associated with inferior patient outcomes. MNPs in cHL have hitherto been identified by a small number of canonical markers and are usually described as tumor-associated macrophages. The organization of MNP networks and interactions with HRSCs remains unexplored at high resolution. Here, we defined the global immune-cell composition of cHL and nonlymphoma lymph nodes, integrating data across single-cell RNA sequencing, spatial transcriptomics, and multiplexed immunofluorescence. We observed that MNPs comprise multiple subsets of monocytes, macrophages, and dendritic cells (DCs). Classical monocytes, macrophages and conventional DC2s were enriched in the vicinity of HRSCs, but plasmacytoid DCs and activated DCs were excluded. Unexpectedly, cDCs and monocytes expressed immunoregulatory checkpoints PD-L1, TIM-3, and the tryptophan-catabolizing protein IDO, at the same level as macrophages. Expression of these molecules increased with age. We also found that classical monocytes are important signaling hubs, potentially controlling the retention of cDC2 and ThExh via CCR1-, CCR4-, CCR5-, and CXCR3-dependent signaling. Enrichment of the cDC2-monocyte-macrophage network in diagnostic biopsies is associated with early treatment failure. These results reveal unanticipated complexity and spatial polarization within the MNP compartment, further demonstrating their potential roles in immune evasion by cHL.

Regulation and Role of αE Integrin and Gut Homing Integrins in Migration and Retention of Intestinal Lymphocytes during Inflammatory Bowel Disease.

Targeting interactions between α4ß7 integrin and endothelial adhesion molecule MAdCAM-1 to inhibit lymphocyte migration to the gastrointestinal tract is an effective therapy in inflammatory bowel disease (IBD). Following lymphocyte entry into the mucosa, a subset of these cells expresses αEß7 integrin, which is expressed on proinflammatory lymphocytes, to increase cell retention. The factors governing lymphocyte migration into the intestinal mucosa and αE integrin expression in healthy subjects and IBD patients remain incompletely understood. We evaluated changes in factors involved in lymphocyte migration and differentiation within tissues. Both ileal and colonic tissue from active IBD patients showed upregulation of ICAM-1, VCAM-1, and MAdCAM-1 at the gene and protein levels compared with healthy subjects and/or inactive IBD patients. ß1 and ß7 integrin expression on circulating lymphocytes was similar across groups. TGF-ß1 treatment induced expression of αE on both ß7+ and ß7- T cells, suggesting that cells entering the mucosa independently of MAdCAM-1/α4ß7 can become αEß7+ ITGAE gene polymorphisms did not alter protein induction following TGF-ß1 stimulation. Increased phospho-SMAD3, which is directly downstream of TGF-ß, and increased TGF-ß-responsive gene expression were observed in the colonic mucosa of IBD patients. Finally, in vitro stimulation experiments showed that baseline ß7 expression had little effect on cytokine, chemokine, transcription factor, and effector molecule gene expression in αE+ and αE- T cells. These findings suggest cell migration to the gut mucosa may be altered in IBD and α4ß7-, and α4ß7+ T cells may upregulate αEß7 in response to TGF-ß once within the gut mucosa.

Subtype-specific and co-occurring genetic alterations in B-cell non-Hodgkin lymphoma.

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study.

BACKGROUND: Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients. METHODS: Adult mild TBI patients recruited from Level I Emergency Department Trauma Centers completed study sessions at 1-2 weeks, 1-month, and 4-months post mild TBI. Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, temporal summation of pain and pressure pain thresholds of the head to measure sensitization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies - Depression Scale, and a standardized headache survey. Participants were classified into persistent PTH (PPTH) and no-PPTH groups based on the 4-month data. RESULTS: The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persistent PTH. Furthermore, logistic regression indicated that headache pain intensity at 1-2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1-2 weeks predicted persistent PTH classification at 4 months post injury. CONCLUSIONS: Overall, the results suggested that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the maintenance of PTH.

Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma.

Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+ and PD-1+ cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+ TAMs, which physically colocalize with PD-L1+ HRS cells in a microenvironmental niche. PD-L1+ TAMs are enriched for contacts with T cells, and PD-L1+ HRS cells are enriched for contacts with CD4+ T cells, a subset of which are PD-1+ Our data define a unique topology of cHL in which PD-L1+ TAMs surround HRS cells and implicate CD4+ T cells as a target of PD-1 blockade.

An Exploratory Study of Endogenous Pain Modulatory Function in Patients Following Mild Traumatic Brain Injury.

BACKGROUND: Recent animal research suggests that mild traumatic brain injury (mTBI) facilitates abnormal endogenous modulation of pain, potentially underlying the increased risk for persistent headaches following injury. However, no human studies have directly assessed the functioning of endogenous facilitory and inhibitory systems in the early stages after an mTBI. OBJECTIVE: The purpose of this exploratory study was to examine trigeminal sensitization and endogenous pain inhibitory capacity in mTBI patients in the acute stage of injury compared with matched controls. We also examined whether post-traumatic headache pain intensity within the mTBI sample was related to sensitization and pain inhibitory capacity. METHODS: Twenty-four mTBI patients recruited from emergency departments and 21 age-, race-, and sex-matched controls completed one experimental session. During this session, participants completed quantitative sensory tests measuring trigeminal sensitization (pressure pain thresholds and temporal summation of pain in the head) and endogenous pain inhibition (conditioned pain modulation). Participants also completed validated questionnaires measuring headache pain, depression, anxiety, and pain catastrophizing. RESULTS: The results revealed that the mTBI group exhibited significantly decreased pressure pain thresholds of the head and decreased pain inhibition on the conditioned pain modulation test compared with the control group. Furthermore, correlational analysis showed that the measures of trigeminal sensitization and depression were significantly associated with headache pain intensity within the mTBI group. CONCLUSIONS: In conclusion, mTBI patients may be at risk for maladaptive changes to the functioning of endogenous pain modulatory systems following head injury that could increase risk for post-traumatic headaches.

Undergraduate education in anaesthesia, intensive care, pain, and perioperative medicine: The development of a national curriculum framework.

INTRODUCTION: The study describes the development of the first UK national framework to guide undergraduate education in anesthesia, perioperative medicine, critical care, and pain medicine. METHODS: We followed an inclusive process of curriculum design aiming to promote high-level learning amongst students. We conducted telephone interviews with senior anesthetic educators at 33 UK medical schools to establish current provision and practice. We then held a consultative national workshop for educators, using focus group interviews to set broad aims for the final framework and gather information. RESULT: Anesthesia undergraduate educators demonstrated a conceptual focus that moves beyond simple acquisition of knowledge to one geared to encouraging clinical behavioral change in learners to equip them for practice as new doctors. Respondents also highlighted the opportunities for promoting spiral, integrated, and longitudinal learning within the undergraduate curriculum. We also formulated eight key domains of practice in anesthesia and critical care and mapped 63 of the 106 General Medical Council's Outcomes for Graduates against these domains, and created a brief suggested syllabus. CONCLUSIONS: The framework aims to provide support and guidance for medical schools in the development of competent, well-rounded doctors who are able to provide safe, patient-centered care in all areas of medical practice.

Improving Active Gaming's Energy Expenditure in Healthy Adults Using Structured Playing Instructions for the Nintendo Wii and Xbox Kinect.

Naugle, KE, Carey, C, Ohlman, T, Godza, M, Mikesky, A, and Naugle, KM. Improving active gaming's energy expenditure in healthy adults using structured playing instructions for the Nintendo Wii and Xbox Kinect. J Strength Cond Res 33(2): 549-558, 2019-Professionals work constantly to increase energy expenditure and improve cardiovascular outcomes. A newer form of physical activity used to improve cardiovascular outcomes and increase energy expenditure while also providing entertainment is active gaming. The purpose was to determine energy expenditure and enjoyment levels during participation in different games played with a directed set of instructions designed to enhance movement. Twenty-one adults completed 6 sessions (1 familiarization and 5 experimental) on separate days. During 4 of the experimental sessions, participants played 1 of 4 active games for two 15-minute periods. Two active games were from Xbox Kinect and 2 were from Nintendo Wii. During the first period, participants played at a self-selected level of activity. During the second period, participants were given specific instructions for play during both active and down times within games. Participants wore a portable gas analyzer to measure energy expenditure. Resting energy expenditure was measured during session 6. Outcome measures were analyzed with 4 Game × 2 Period repeated-measures analyses of variance. Energy expenditure, measured in metabolic equivalents (METS), was greatest while playing Kinect Fighter Within. METS, enjoyment levels, and percentage of time spent in whole-body activity were greater during the period with specific instructions compared to the self-selected levels of activity, regardless of active game. When played at a self-selected level of activity, energy expenditure during the active games was similar to that of light physical activity. However, energy expenditure improved during the second period of game play showing that specific instructions created energy expenditure of moderate intensity.

Preferences for Everyday Living: Understanding the Impact of Cognitive Status on Preference Importance Ratings in Nursing Homes.

Assessing everyday living preferences for nursing home residents is a cornerstone of delivering person-centered care (PCC), yet little is known about how cognitive ability can influence the importance of reported preferences. The current study examined the effect of cognitive ability on the level and stability of reported importance of preferences for everyday living in a sample of 255 nursing home residents across 3 months. Participants were grouped by cognitive impairment status (none-to-low, mild, and moderate) at baseline and completed the Preferences for Everyday Living Inventory, Nursing Home version interview at baseline and 3 months. Repeated measures analyses of covariance revealed no significant differences (p > 0.001) between cognitive groups on their reported level of importance of preferences at baseline and no significant change over 3 months. These data highlight the value of assessing everyday care preferences to help support delivery of PCC for individuals with and without cognitive impairment. [Journal of Gerontological Nursing, 44(5), 9-17.].

Lymphoma triage from H&E using AI for improved clinical management.

AIMS: In routine diagnosis of lymphoma, initial non-specialist triage is carried out when the sample is biopsied to determine if referral to specialised haematopathology services is needed. This places a heavy burden on pathology services, causes delays and often results in over-referral of benign cases. We aimed to develop an automated triage system using artificial intelligence (AI) to enable more accurate and rapid referral of cases, thereby addressing these issues. METHODS: A retrospective dataset of H&E-stained whole slide images (WSI) of lymph nodes was taken from Newcastle University Hospital (302 cases) and Manchester Royal Infirmary Hospital (339 cases) with approximately equal representation of the 3 most prevalent lymphoma subtypes: follicular lymphoma, diffuse large B-cell and classic Hodgkin's lymphoma, as well as reactive controls. A subset (80%) of the data was used for training, a further validation subset (10%) for model selection and a final non-overlapping test subset (10%) for clinical evaluation. RESULTS: AI triage achieved multiclass accuracy of 0.828±0.041 and overall accuracy of 0.932±0.024 when discriminating between reactive and malignant cases. Its ability to detect lymphoma was equivalent to that of two haematopathologists (0.925, 0.950) and higher than a non-specialist pathologist (0.75) repeating the same task. To aid explainability, the AI tool also provides uncertainty estimation and attention heatmaps. CONCLUSIONS: Automated triage using AI holds great promise in contributing to the accurate and timely diagnosis of lymphoma, ultimately benefiting patient care and outcomes.

Automated quantitative high-throughput multiplex immunofluorescence pipeline to evaluate OXPHOS defects in formalin-fixed human prostate tissue.

Advances in multiplex immunofluorescence (mIF) and digital image analysis has enabled simultaneous assessment of protein defects in electron transport chain components. However, current manual methodology is time consuming and labour intensive. Therefore, we developed an automated high-throughput mIF workflow for quantitative single-cell level assessment of formalin fixed paraffin embedded tissue (FFPE), leveraging tyramide signal amplification on a Ventana Ultra platform coupled with automated multispectral imaging on a Vectra 3 platform. Utilising this protocol, we assessed the mitochondrial oxidative phosphorylation (OXPHOS) protein alterations in a cohort of benign and malignant prostate samples. Mitochondrial OXPHOS plays a critical role in cell metabolism, and OXPHOS perturbation is implicated in carcinogenesis. Marked inter-patient, intra-patient and spatial cellular heterogeneity in OXPHOS protein abundance was observed. We noted frequent Complex IV loss in benign prostate tissue and Complex I loss in age matched prostate cancer tissues. Malignant regions within prostate cancer samples more frequently contained cells with low Complex I & IV and high mitochondrial mass in comparison to benign-adjacent regions. This methodology can now be applied more widely to study the frequency and distribution of OXPHOS alterations in formalin-fixed tissues, and their impact on long-term clinical outcomes.

Interleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy.

The function of interleukin-22 (IL-22) in intestinal barrier homeostasis remains controversial. Here, we map the transcriptional landscape regulated by IL-22 in human colonic epithelial organoids and evaluate the biological, functional and clinical significance of the IL-22 mediated pathways in ulcerative colitis (UC). We show that IL-22 regulated pro-inflammatory pathways are involved in microbial recognition, cancer and immune cell chemotaxis; most prominently those involving CXCR2+ neutrophils. IL-22-mediated transcriptional regulation of CXC-family neutrophil-active chemokine expression is highly conserved across species, is dependent on STAT3 signaling, and is functionally and pathologically important in the recruitment of CXCR2+ neutrophils into colonic tissue. In UC patients, the magnitude of enrichment of the IL-22 regulated transcripts in colonic biopsies correlates with colonic neutrophil infiltration and is enriched in non-responders to ustekinumab therapy. Our data provide further insights into the biology of IL-22 in human disease and highlight its function in the regulation of pathogenic immune pathways, including neutrophil chemotaxis. The transcriptional networks regulated by IL-22 are functionally and clinically important in UC, impacting patient trajectories and responsiveness to biological intervention.

Pim Kinases as Therapeutic Targets in Early Rheumatoid Arthritis.

OBJECTIVE: As well as being an established oncoprotein and therapeutic target in cancer, proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is implicated in human autoimmunity. This study was undertaken to investigate Pim-1 and its family members as potential therapeutic targets in early rheumatoid arthritis (RA). METHODS: A flow cytometry assay for PIM1 transcript measurement in peripheral blood mononuclear cells from patients with early arthritis was validated and applied as a biomarker of Pim-1 activity at the cellular level. Synovial protein expression was similarly determined by multiplex immunofluorescence in tissue samples from untreated RA patients and non-RA disease controls. Functional consequences of Pim kinase family manipulation in freshly isolated CD4+ T cells from these individuals were ascertained, along with the impact of Pim inhibition on mice with collagen-induced arthritis (CIA). RESULTS: The percentage of circulating CD4+ T cells positive for PIM1 transcript by flow cytometry proved a faithful surrogate for gene expression and was significantly higher in patients with early RA than in those with other diseases. Pim-1 protein levels were similarly up-regulated in synovial CD4+ T cells from patients with early RA. Ex vivo, exposure of T cell receptor-stimulated early RA CD4+ T cells to Pim kinase inhibitors restrained their activation and proliferative capacity. Diminished production of proinflammatory cytokines (interferon-γ and interleukin-17) and an expanded CD25high FoxP3+ Treg cell fraction were also observed in exposed versus unexposed cells. Finally, administration of Pim inhibitors robustly limited arthritis progression and cartilage destruction in CIA. CONCLUSION: Our findings indicate that Pim kinases are plausible therapeutic targets in a readily identifiable subgroup of patients with early RA. Repurposing of Pim inhibitors for this disease should be considered.

Developmental cell programs are co-opted in inflammatory skin disease.

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

Retroperitoneal repair of abdominal aortic aneurysms offers postoperative benefits to male patients in the Veterans Affairs Health System.

BACKGROUND: Transperitoneal (TP) and retroperitoneal (RP) approaches have equal efficacy in elective open abdominal aortic aneurysm (AAA) repair. The effect of open operative approach on patient-specific outcomes after AAA repair was tested. METHODS: Consecutive patients undergoing open AAA repair at the Veterans Affairs Tennessee Valley Healthcare System between January 2000 and August 2008 were retrospectively reviewed. Analysis was performed to examine the effects of demographic and clinical covariates on postoperative outcomes. RESULTS: A total of 106 patients were identified: 54 with TP approach and 52 with RP approach. Demographics and preoperative comorbidities were equivalent (p > or = 0.10), with the exception of chronic obstructive pulmonary disease which was more prevalent in the TP group (61 vs. 40%). Operative times were longer in the TP group (4.6 vs. 3.5 hours; p < 0.01); however, significantly more TP patients had reconstruction with a bifurcated graft (72 vs. 2%; p < 0.01). Postoperative nasogastric tube decompression times were shorter in the RP group (1 vs. 3 days; p < 0.01), and RP approach led to a quicker return to preoperative diet (4 vs. 6 days; p = 0.05). Patients undergoing RP repair developed fewer incisional hernias (2 vs. 15%; p = 0.03). CONCLUSION: RP approach to AAA repair offers patients faster return of bowel function and is associated with fewer incisional hernias.

The relationship between resolution of asymptomatic bacterial vaginosis and spontaneous preterm birth in fetal fibronectin-positive women.

OBJECTIVE: The purpose of this study was to determine the impact of persistent bacterial vaginosis (BV) on the occurrence of spontaneous preterm birth (SPB) in women who test positive for fetal fibronectin. STUDY DESIGN: This is a secondary analysis of a subset of pregnant women who tested positive for BV and fetal fibronectin between 16(0/7) and 25(6/7) weeks of gestation and who participated in randomized placebo controlled trials of antibiotic therapy. Nugent's criteria were used for the diagnosis of BV. Patients were reassessed for the presence of BV after treatment. The rate of SPB at <34 weeks of gestation was analyzed on the basis of treatment mode and BV status at the follow-up visit. RESULTS: The primary studies included a total of 3285 women. A subset of 215 women met the criteria for this analysis. Seventy-seven of 100 patients (77%) in the antibiotics group vs 33 of the 115 patients (28.7%) in the placebo group became BV negative (P < .0001). The rate of SPB at <34 weeks of gestation was lower for BV resolution compared with persistent BV (0 vs 5.7%, respectively; P = .01). CONCLUSION: In women who tested positive for fetal fibronectin and BV, resolution of BV is associated with less SPB before 34 weeks of gestation.

Active Gaming as a Form of Exercise to Induce Hypoalgesia.

OBJECTIVE: An acute bout of moderate-to-vigorous exercise temporarily reduces pain sensitivity in healthy adults. Recently, active gaming has been rising in popularity as a means of light-to-moderate exercise and may be particularly suitable for deconditioned individuals. Whether the physical activity elicited in active games can produce a hypoalgesic effect remains unknown. The purpose of this study was to determine whether active videogames can reduce pressure and heat pain sensitivity in healthy adults. We also evaluated the relationship between the physical activity elicited by the games and the magnitude of the hypoalgesic response. MATERIALS AND METHODS: Twenty-one healthy adults played four different active games on separate days, including Microsoft® Kinect Xbox® One's Fighter Within and Sports Rival's Tennis, and Nintendo® Wii™ Sports' Boxing and Tennis. Heat pain thresholds on the forearm and pressure pain thresholds (PPTs) on the trapezius and forearm were assessed immediately before and after a 15-minute active gaming or control session. Minutes spent in sedentary time and moderate-to-vigorous physical activity (MVPA) during active gaming were measured with an accelerometer. RESULTS: The analyses revealed that PPTs at the forearm and trapezius significantly increased from pretest to posttest following Kinect Fighter Within. PPTs at the trapezius also significantly increased from pretest to posttest following Wii Boxing. The magnitude of the hypoalgesic response was significantly correlated with MVPA and sedentary time during gameplay. CONCLUSION: These results suggest that an active gaming session played at a moderate intensity is capable of temporarily reducing pain sensitivity.