A 3D bioprinted hydrogel gut-on-chip with integrated electrodes for transepithelial electrical resistance (TEER) measurements.

Conventional gut-on-chip (GOC) models typically represent the epithelial layer of the gut tissue, neglecting other important components such as the stromal compartment and the extracellular matrix (ECM) that play crucial roles in maintaining intestinal barrier integrity and function. These models often employ hard, flat porous membranes for cell culture, thus failing to recapitulate the soft environment and complex 3D architecture of the intestinal mucosa. Alternatively, hydrogels have been recently introduced in GOCs as ECM analogs to support the co-culture of intestinal cells inin vivo-like configurations, and thus opening new opportunities in the organ-on-chip field. In this work, we present an innovative GOC device that includes a 3D bioprinted hydrogel channel replicating the intestinal villi architecture containing both the epithelial and stromal compartments of the gut mucosa. The bioprinted hydrogels successfully support both the encapsulation of fibroblasts and their co-culture with intestinal epithelial cells under physiological flow conditions. Moreover, we successfully integrated electrodes into the microfluidic system to monitor the barrier formation in real time via transepithelial electrical resistance measurements.

Cervical impairments in subjects with migraine or tension type headache: an observational study.

Objective: The aim of this investigation was to compare the thickness of the deep local muscles in the neck region, as well as local and widespread sensitivity and functionality, between individuals with migraine, Tension-Type Headache (TTH), and healthy controls. To date, we know that the onset of migraine and TTH share similar pathophysiological pathways. Nevertheless, there may be some anatomical and functional differences which would explain why clinicians may obtain variable results when treating both pathological entities with similar or equal approaches. Methods: An observational study was conducted in accordance with STROBE guidelines. The flexor longus colli and multifidus, two neck-stabilizing muscles, were measured using B-mode ultrasound imaging. The upper trapezius, masseter, temporalis, tibialis anterior, and median nerve all underwent bilateral pressure-pain threshold (PPT) assessments. Results: Ninety participants were enrolled in the study. All subjects were equally divided into TTH, migraine and control groups. The PPT values exhibited lower thresholds in patients with TTH than both migraine and healthy participants. Specifically, in the temporal muscle on both sides, patients with TTH exhibited a significantly lower threshold (p < 0.001)than both migraine and healthy participants. Patients with TTH displayed significantly lower thresholds in both upper trapezius muscles (right: p < 0.001; left: p = 0.001). Similar results were obtained for the tibialis anterior PPTs from both sides (p = 0.001 in both). However, both clinical groups exhibited lower thresholds than the healthy subjects (p < 0.001). In multifidus muscle cross-sectional area (CSA), no statistically significant differences were found between migraine patients and healthy subjects, both in relaxation and contraction (right; p > 0.05 and p > 0.05; left: p > 0.05 and p > 0.05). However, patients with TTH exhibited a smaller CSA than both migraine patients and healthy controls in multifidus relaxed and contracted state (right: p < 0.001 in both relaxed and contracted multifidus; left: p = 0.001 and p < 0.001, respectively). Similar results were obtained for the left longus colli muscle in both relaxation and contraction for patients with TTH and migraine compared with healthy subjects (p = 0.001 and p < 0.001, respectively, for muscle relaxation and p < 0.001 for muscle contraction). However, no significant differences were observed between patients with TTH and migraine (p < 0.05 in both relaxation and contraction). In the right longus colli, TTH and migraine patients had a significantly smaller CSA during contraction than healthy subjects (p < 0.001 in both comparisons). In the craniocervical flexion test, both groups of patients with TTH and migraine showed significantly lower values than healthy subjects (p < 0.001 in both comparisons). However, no significant differences were found between patients with TTH and migraineurs (p > 0.05). Conclusion: The findings provide a significant message for clinicians since anatomical and functional impairments were shown in patients with TTH and migraine. This study corroborates a lack of strength and smaller CSA in both clinical groups compared to controls. Therefore, strengthening programs may be addressed successfully for people with these pathological entities. To be more accurate, according to PPTs and CSA lower values in patients with TTH compared to migraine and controls, manual therapy approaches to desensitize craniocervical soft tissues and exercise therapy to increase endurance of deep cervical muscles may become meaningful especially in subjects with TTH. Nevertheless, in order to distinguish precisely between patients with TTH and migraine, different diagnostic strategies may be used in the future to describe these populations in further detail, which will assist health professionals in a more accurate treatment selection.

TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction.

Epigenetic 'clocks' based on DNA methylation have emerged as the most robust and widely used aging biomarkers, but conventional methods for applying them are expensive and laborious. Here we develop tagmentation-based indexing for methylation sequencing (TIME-seq), a highly multiplexed and scalable method for low-cost epigenetic clocks. Using TIME-seq, we applied multi-tissue and tissue-specific epigenetic clocks in over 1,800 mouse DNA samples from eight tissue and cell types. We show that TIME-seq clocks are accurate and robust, enriched for polycomb repressive complex 2-regulated loci, and benchmark favorably against conventional methods despite being up to 100-fold less expensive. Using dietary treatments and gene therapy, we find that TIME-seq clocks reflect diverse interventions in multiple tissues. Finally, we develop an economical human blood clock (R > 0.96, median error = 3.39 years) in 1,056 demographically representative individuals. These methods will enable more efficient epigenetic clock measurement in larger-scale human and animal studies.

Real-World Outcomes of Adolescents and Young Adults with Diffuse Large B-Cell Lymphoma: A Multicenter Retrospective Cohort Study.

Purpose: Patients with diffuse large B-cell lymphoma (DLBCL) are typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, a standard of care for managing adolescents and young adults (AYAs) with DLBCL is lacking. We examine treatment approaches and outcomes of this population. Methods: We included 90 AYAs (15-39 years) diagnosed with DLBCL between 2008 and 2018 in three tertiary centers in Peru. Overall response rates (ORR) were available for all patients. Overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method. Results: The median age at diagnosis was 33 years, 57% were males, 57% had good performance status (Lansky/Karnofsky ≥90), and 61% were diagnosed with early-stage disease (Ann Arbor stages I-II). R-CHOP (n = 69, 77%) was the most frequently used first-line regimen, with an ORR of 91%. With a median follow-up of 83 months, the 5-year OS and PFS among all patients were 79% and 67%, respectively. Among the patients who received R-CHOP, the 5-year OS and PFS were 77% and 66%, respectively. Of the 29 (32%) patients with relapsed/refractory (R/R) disease, 83% received second-line treatment and only 14% underwent consolidation therapy with autologous transplantation. The 3-year OS for R/R DLBCL was 36%. Conclusion: Our data show that AYAs with DLBCL who received conventional therapy had comparable outcomes to those observed in studies conducted among the adult population. However, the prognosis for AYAs with R/R disease was dismal, indicating the unmet need for developing and increasing access to novel treatment modalities in AYAs.

Treatment outcomes of patients with classic and AIDS-related Kaposi Sarcoma: a single-center real-world experience.

The recommended first-line chemotherapy agents for managing Kaposi sarcoma (KS) in high-income countries are expensive and often unavailable in developing nations such as Peru. Limited data exist on whether management practices in these countries affect patient outcomes. We assessed the real-world treatment approaches and outcomes of patients with KS in Peru. We retrospectively reviewed the medical records of patients with acquired immunodeficiency syndrome-related KS (AIDS-related KS; n = 95) and classic KS (CKS; n = 81) diagnosed at a tertiary center between 2000 and 2014 in Lima, Peru. We used the Kaplan-Meier method to estimate overall survival (OS) rates. The median follow-up was 64 months for AIDS-related KS and 88 months for CKS. The median age of patients with AIDS-related KS was 35 years (range 20-63 years) and 70 years (range 33-91 years) for those with CKS. Most individuals had an Eastern Cooperative Oncology Group performance status of ≥ 2 (AIDS-related KS 75%; CKS 85%). Seventy-six percent and 40% of individuals with AIDS-related KS and CKS, respectively, received systemic chemotherapy. The most common first-line drug was paclitaxel, with relatively optimal overall response rates (ORRs) for AIDS-related KS (n = 64/72, 89%; ORR 61%) and CKS (n = 24/32, 75%; ORR 50%). The 5-year OS rates were 71% in the AIDS-related KS cohort and 81% in the CKS cohort. The findings from this real-world study may inform clinical practices and highlight the need for increased access to effective treatments and clinical trials for patients with KS in Peru and other developing countries.

Efficacy of a strength-based exercise program in patients with chronic tension type headache: a randomized controlled trial.

Background: Strength-based exercise is widely used to treat tension-type headache, but the evidence of its benefit is unclear. This study aims to analyze the efficacy of a strength-based exercise program in patients with chronic tension-type headaches. Methods: A randomized controlled trial with a 12-week strength-based exercise program, with chronic tension-type headache. The headache characteristics (which were the primary outcomes: frequency, duration, and intensity), cervical muscle thickness at rest or contraction of multifidus and longus-colli muscle, cervical range of motion, pain pressure threshold of temporalis, upper trapezius, masseter, tibialis muscle and median nerve, and cervical craniocervical flexion test were assessed at baseline and 12-weeks of follow-up in the intervention group (n = 20) and the control group (n = 20) was performed on 40 patients (85% women, aged 37.0 ± 13.3 years). Results: Between baseline and week-12 of follow-up the intervention group showed statistically significant differences compared to control group in the following primary outcomes: duration and intensity of headaches. In addition, the intervention group improved the thickness of deep cervical muscles, reduced the peripheral sensitization, and improved the strength of deep cervical flexors. Conclusion: A 12-week strength training of neck and shoulder region induced changes in pain intensity and duration, and physical-related factors in patients with TTH. Future interventions are needed to investigate if normalization of pain characteristics and physical factors can lead to an increase of headache-related impact.

Understanding the Immunopathology of HTLV-1-Associated Adult T-Cell Leukemia/Lymphoma: A Comprehensive Review.

Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5-10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient's immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL.

Pain sensitization and atrophy of deep cervical muscles in patients with chronic tension-type headache.

OBJECTIVE: The aim of this study was to compare the pressure pain threshold and the thickness of the cervical muscles in patients with tension-type headache versus healthy participants. METHODS: An observational, retrospective, cross-sectional study was conducted at the Universidad Europea de Madrid between May and June 2022. Adults aged 18-65 years with tension-type headache diagnosed for more than 6 months were compared to healthy controls. B-mode ultrasound imaging was employed to measure the thickness of the neck stabilizing muscles, longus colli, and multifidus at the C5 and C6 levels, respectively. pressure pain threshold measurements were assessed bilaterally in the following regions: upper trapezius, masseter, temporalis, anterior tibialis, and median nerve. RESULTS: A total of 40 participants (90% females; 36.3±12.9 years, BMI 24.2±3.7 kg/m2) participated in the study. Compared with the control group (n=20), participants in the tension-type headache group (n=20) presented statistically significant lower values in all pressure pain threshold measures. Additionally, the tension-type headache group presented statistically significant lower values in the thickness of the following muscles: right multifidus at rest (1.0±0.2 cm versus 1.3±0.2 cm; p<0.001), left multifidus at rest (1.1±0.1 cm versus 1.3±0.1 cm; p<0.001) and during contraction (1.2±0.1 cm versus 1.5±0.2 cm; p<0.001), left longus colli at rest (1.0±0.2 cm versus 1.2±0.1 cm; p=0.01) and during contraction (1.2±0.2 cm versus 1.4±0.1 cm; p<0.001), and right longus colli during contraction (1.2±0.2 cm versus 1.4±0.2 cm; p=0.02). CONCLUSION: This study concluded that patients with tension-type headache showed lower thickness and lower pressure pain threshold of cervical muscles compared to healthy controls.

Cervical Impairments in Subjects with Chronic Migraine: An Observational Study.

OBJECTIVE: The aim of this investigation was to compare the thickness of the deep local muscles in the neck region, as well as local and widespread sensitivity and functionality, between individuals with migraine and healthy control subjects. METHODS: An observational study was carried out in accordance with the STROBE statements. The flexor longus colli and multifidus, two neck-stabilizing muscles, were measured using B-mode ultrasound imaging. The upper trapezius, masseter, temporalis, anterior tibialis, and median nerve all underwent bilateral pressure-pain threshold (PPT) assessments. The statistical program SPSS 29.0 was used to implement the Mann-Whitney U test and Chi-squared test. Spearman Rho was utilized to establish the correlations between the variables. RESULTS: Sixty participants were enrolled in the study. The subjects, who were matched in terms of age, gender, and body mass index (BMI), were equally divided into migraine and control groups. No significant differences between the groups were found in the multifidus CSA regarding both sides at rest (right: p = 0.625; left: p = 0.203). However, in contraction, the multifidus CSA showed a significant decrease on the left side in the patients with migraine compared to the controls (p = 0.032), but no significant differences were found in the right multifidus CSA in contraction between the two groups (p = 0.270). In comparison to the healthy volunteers, the migraine sufferers showed a substantial reduction in CSA in the longus colli muscle on both the left side (p = 0.001) and the right side at rest (p = 0.003), as well as in the CSA of the left longus colli in contraction (p < 0.001). Furthermore, the migraine patients showed significantly lower PPT compared to the healthy subjects in local and widespread areas bilaterally. All the parameters revealed higher sensitization in the migraine group in the following areas: the right and left temporal regions (p < 0.001), the right and left upper trapezius (p < 0.001 and p < 0.01, respectively), the right and left masseter muscles (p < 0.01), the right and left median nerves (p < 0.001 and p < 0.01, respectively), and the right and left anterior tibialis muscles (p < 0.001). In terms of the craniocervical flexion test (CCFT), the migraine patients demonstrated significantly lower values than the healthy subjects (p < 0.001). A moderate positive correlation was noted between the PPT in the right temporalis muscle and that in the left longus colli and the right multifidus in contraction. The PPT in the right temporalis muscle also exhibited a positive correlation with the CCFT, although this correlation was low. Between the PPT values, the upper trapezius on both sides showed a moderate positive correlation with the median nerve bilaterally. CONCLUSIONS: This research suggests that individuals with migraine may experience local and widespread pain sensitization. A decrease in functionality due to the low muscle endurance of the deep cervical muscles is also accompanied by low values of muscle thickness in contraction. These findings may help to select more accurate treatment approaches for patients with migraine.

Epidemiological Features and Outcomes of HTLV-1 Carriers Diagnosed With Cancer: A Retrospective Cohort Study in an Endemic Country.

PURPOSE: Human T-lymphotropic virus type 1 (HTLV-1) is an endemic virus in Latin America that is directly linked to adult T-cell leukemia/lymphoma (ATL). Previous studies have suggested an oncogenic role of HTLV-1 in non-ATL neoplasms and have found higher mortality in HTLV-1 carriers without ATL. METHODS: In this retrospective cohort study, HTLV-1 carriers were identified through screening at a tertiary cancer center between 2006 and 2019. We compared the overall survival (OS) outcomes of patients with ATL with those with other solid or hematologic malignancies by sex stratification. RESULTS: We identified 1,934 HTLV-1 carriers diagnosed with cancer. The median age at diagnosis was 62 (range 20-114) years, 76% were female, 60% had no or elementary school education, and 50% were born in the Andean highlands. The most common non-ATL neoplasm was cervical cancer (50%) among females and non-ATL non-Hodgkin lymphoma (26%) among males. With a median follow-up of 66 months, the 5-year OS of HTLV-1 carriers with non-ATL neoplasms (26%-47% for females and 22%-34% for males) was inferior to those reported in the general population. As expected, patients with ATL had a worse prognosis (5-year OS: 10% for females and 8% for males). CONCLUSION: HTLV-1 carriers with cancer were middle age and from underprivileged settings, suggesting an undetected transmission among vulnerable populations, especially females. Survival estimates of HTLV-1 carriers with non-ATL neoplasms were lower than the regional outcomes. Future research should ascertain how the biology of HTLV-1 and health care disparities affect the outcomes of HTLV-1 carriers, as well as determine the burden of HTLV-1 infection in the cancer population to recommend screening in the outpatient setting of endemic regions.

Clinical Features and Outcomes of Triple-Negative Breast Cancer Among Latin American Adolescents and Young Adults Compared to Middle-Aged and Elder Females: A Cohort Analysis Over 15 Years.

Purpose: Outcomes of females with triple-negative breast cancer (TNBC) are rarely explored in adolescents and young adults (AYAs). We compared clinical and survival outcomes of Latin American AYAs (≤39 years) with middle-aged (40-59 years) and older (≥60 years) females with TNBC by cancer stage. Methods: We performed a single-center retrospective cohort study among treated females with cancer stages I-III diagnosed from 2000 to 2014 in Peru. We evaluated overall survival (OS) and event-free survival (EFS). Time-to-event methods were used for analyses. Results: Of 1582 females with TNBC, 350 (22%) were AYAs, 887 (56%) were middle-aged, and 345 (22%) were older women. Tumor size >5 cm, histological grade III, and brain metastasis were more common features in AYAs. AYAs were treated more frequently with neoadjuvant chemotherapy. With a median follow-up of 102 months, the 5-year OS/EFS for AYAs was 55%/53%, similar to middle-aged (54%/49%) and older females (56%/51%). AYAs were not at higher risk for decreased OS or EFS in the multivariable Cox analysis. Our findings remained consistent by cancer stage. Conclusion: Although Latin American AYAs with TNBC have more aggressive clinical features at diagnosis, survival outcomes were comparable with middle-aged and older women with TNBC, suggesting that age is not a risk factor for worse survival outcomes if treatment is given according to cancer stage. Our findings should be interpreted with caution given the lack of information on certain covariates such as comorbidities. Strategies for early detection in primary care and prompt referral for treatment initiation should be developed.

Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Pain sensitization and atrophy of deep cervical muscles in patients with chronic tension-type headache

SUMMARY OBJECTIVE: The aim of this study was to compare the pressure pain threshold and the thickness of the cervical muscles in patients with tension-type headache versus healthy participants. METHODS: An observational, retrospective, cross-sectional study was conducted at the Universidad Europea de Madrid between May and June 2022. Adults aged 18-65 years with tension-type headache diagnosed for more than 6 months were compared to healthy controls. B-mode ultrasound imaging was employed to measure the thickness of the neck stabilizing muscles, longus colli, and multifidus at the C5 and C6 levels, respectively. pressure pain threshold measurements were assessed bilaterally in the following regions: upper trapezius, masseter, temporalis, anterior tibialis, and median nerve. RESULTS: A total of 40 participants (90% females; 36.3±12.9 years, BMI 24.2±3.7 kg/m2) participated in the study. Compared with the control group (n=20), participants in the tension-type headache group (n=20) presented statistically significant lower values in all pressure pain threshold measures. Additionally, the tension-type headache group presented statistically significant lower values in the thickness of the following muscles: right multifidus at rest (1.0±0.2 cm versus 1.3±0.2 cm; p<0.001), left multifidus at rest (1.1±0.1 cm versus 1.3±0.1 cm; p<0.001) and during contraction (1.2±0.1 cm versus 1.5±0.2 cm; p<0.001), left longus colli at rest (1.0±0.2 cm versus 1.2±0.1 cm; p=0.01) and during contraction (1.2±0.2 cm versus 1.4±0.1 cm; p<0.001), and right longus colli during contraction (1.2±0.2 cm versus 1.4±0.2 cm; p=0.02). CONCLUSION: This study concluded that patients with tension-type headache showed lower thickness and lower pressure pain threshold of cervical muscles compared to healthy controls.

Relationship between Self-Efficacy and Headache Impact, Anxiety, and Physical Activity Levels in Patients with Chronic Tension-Type Headache: An Observational Study.

Background: Chronic tension-type headache is the primary headache with the highest prevalence. The present study is aimed at analyzing the associations between patient self-efficacy and headache impact with pain characteristics, kinesiophobia, anxiety sensitivity, and physical activity levels in subjects with chronic tension-type headache. Materials and Methods: An observational descriptive study was carried out. A total sample of 42 participants was recruited at university environment with diagnosis of tension-type headache. Headache characteristics (frequency, intensity, and duration), physical activity levels, pain related-self-efficacy, kinesiophobia, anxiety sensitivity, and headache impact were measured. Results: The HIT-6 (61.05 ± 6.38) score showed significant moderate positive correlations with the ASI-3 score (17.64 ± 16.22; r = 0.47) and moderate negative correlations with the self-efficacy in the domains of pain management (31.9 ± 10.28; r = -0.43) and coping with symptoms (53.81 ± 14.19; r = -0.47). ASI-3 score had a negative large correlation with self-efficacy in the domains of pain management (r = -0.59), physical function (53.36 ± 7.99; r = -0.55), and coping with symptoms (r = -0.68). Physical activity levels showed positive moderate correlations with the self-efficacy in the domain of physical function (r = 0.41). Linear regression models determined that the self-efficacy and anxiety sensitivity with showed a significant relationship with the HIT-6 score (R 2 = 0.262; p = 0.008) and with the ASI-3 score (R 2 = 0.565; p < 0.001). In addition, no correlations were found between pain intensity, duration or frecuency with psychosocial factors, or headache impact. Conclusions: The present study showed that patients with chronic tension-type headache had a great negative impact on daily tasks and physical activity levels, which were associated with higher anxiety levels and lower self-efficacy.

Novel feature selection methods for construction of accurate epigenetic clocks.

Epigenetic clocks allow us to accurately predict the age and future health of individuals based on the methylation status of specific CpG sites in the genome and are a powerful tool to measure the effectiveness of longevity interventions. There is a growing need for methods to efficiently construct epigenetic clocks. The most common approach is to create clocks using elastic net regression modelling of all measured CpG sites, without first identifying specific features or CpGs of interest. The addition of feature selection approaches provides the opportunity to optimise the identification of predictive CpG sites. Here, we apply novel feature selection methods and combinatorial approaches including newly adapted neural networks, genetic algorithms, and 'chained' combinations. Human whole blood methylation data of ~470,000 CpGs was used to develop clocks that predict age with R2 correlation scores of greater than 0.73, the most predictive of which uses 35 CpG sites for a R2 correlation score of 0.87. The five most frequent sites across all clocks were modelled to build a clock with a R2 correlation score of 0.83. These two clocks are validated on two external datasets where they maintain excellent predictive accuracy. When compared with three published epigenetic clocks (Hannum, Horvath, Weidner) also applied to these validation datasets, our clocks outperformed all three models. We identified gene regulatory regions associated with selected CpGs as possible targets for future aging studies. Thus, our feature selection algorithms build accurate, generalizable clocks with a low number of CpG sites, providing important tools for the field.

Deep Cervical Muscles and Functionality in Patients with Chronic Tension-Type Headache: An Observational Study.

Background and objectives: Chronic tension-type headache (TTH) is the type of headache with the highest prevalence. The involvement of musculoskeletal structures in TTH is supported by evidence in the scientific literature. Among these, deep cervical muscle strength appears to be related to the function of the cervical spine and the clinical characteristics of TTH. This study aimed to correlate anatomical, functional, and psychological variables in patients with TTH. Materials and methods: An observational descriptive study was carried out with 22 participants diagnosed with TTH for at least six months. The characteristics of headaches, including ultrasound-based deep neck flexor and extensor muscle thickness, range of motion (ROM), and pressure pain threshold (PPT), were recorded. We also conducted the Pain Vigilance and Awareness Questionnaire (PVAQ) and the Craniocervical Flexion Test (CCFT). Results: Moderate-large negative correlations were found between the PVAQ and the muscle thickness of right deep flexors contracted (r = -0.52; p = 0.01), left multifidus contracted (r = -0.44; p = 0.04), right multifidus at rest (r = -0.48; p = 0.02), and right multifidus contracted (r = -0.45; p = 0.04). Moderate-large positive correlations were found between the CCFT score and the left cervical rotation ROM (r = 0.53; p = 0.01), right cervical rotation ROM (r = 0.48; p = 0.03), muscle thickness of left multifidus contracted (r = 0.50; p = 0.02), and muscle thickness of right multifidus at rest (r = 0.51; p = 0.02). The muscle thickness of the contracted right deep cervical flexors showed a moderate negative correlation with headache intensity (r = -0.464; p = 0.03). No correlations were found between PPT and the rest of the variables analyzed. Conclusions: In patients with TTH, a higher thickness of deep cervical muscles was associated with higher ROM and higher scores in the CCFT. In turn, the thickness of deep cervical muscles showed negative correlations with pain hypervigilance and headache intensity. These results contribute to a better understanding of the physical and psychosocial factors contributing to the development of TTH, which is useful for implementing appropriate prevention and treatment measures.

Association between Ancestry-Specific 6q25 Variants and Breast Cancer Subtypes in Peruvian Women.

BACKGROUND: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer-protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry. METHODS: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region. RESULTS: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51-0.92), HR-HER2+ (OR, 0.63; 95% CI, 0.44-0.90) and HR-HER2- (OR, 0.77; 95% CI, 0.56-1.05) compared with HR+HER2-. Inclusion of other risk-associated variants did not change these observations. CONCLUSIONS: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region. IMPACT: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.

Rural and urban disparities in anemia among Peruvian children aged 6-59 months: a multivariate decomposition and spatial analysis.

INTRODUCTION: Anemia is a global public health issue that affects mainly children aged less than 5 years. In Peru, despite the reduction in the prevalence of anemia between 2010 and 2018, anemia remains a major concern, especially in high-risk zones such as rural areas. Several sociodemographic factors have been associated with anemia in children; however, components contributing to the urban-rural gap have not been previously assessed. The purpose of this study was to evaluate the determinants of the difference in anemia prevalence between urban and rural areas, and its spatial distribution in Peruvian children aged 6-59 months. METHODS: A secondary data analysis was conducted using the 2019 Peruvian Demographic Health Survey. The study population included 18 846 children aged 6-59 months. A multivariate decomposition analysis for non-linear response model was performed to identify the factors contributing to the gap in the prevalence of anemia across urban and rural areas. Global Moran´s I autocorrelation, Ordinary Kriging interpolation and Bernoulli-based purely spatial scan statistics were employed to assess the spatial pattern of anemia. RESULTS: Nationwide, the prevalence of anemia in Peru was 29.47% (95%CI 28.63-30.33). In rural areas, it was 38.25%, and in urban areas 26.39%. The decomposition analysis revealed that 88.61% of the difference in the prevalence of anemia between urban and rural areas was attributed to the difference in the respondents' characteristics. Wealth index, mother´s education, mother´s employment status, number of living children and mother´s age were key determinants contributing to the rural-urban gap. Spatial heterogeneity of anemia prevalence in childhood was observed at both inter- and intradepartmental level. The SaTScan spatial analysis identified six significant cluster areas with high prevalence of anemia in childhood. CONCLUSION: A considerable gap of anemia prevalence between urban and rural areas was found. Targeted interventions are necessary to reduce geographic disparities.

Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. SIGNIFICANCE: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.