Nociceptor spontaneous activity is responsible for fragmenting non-rapid eye movement sleep in mouse models of neuropathic pain.

Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund's complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non-rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient neuropathic pain model (sciatic nerve crush). Genetic silencing of peripheral sensory neurons or ablation of CGRP+ neurons in the parabrachial nucleus prevented sleep fragmentation, whereas pharmacological blockade of skin sensory fibers was ineffective, indicating that the neural activity driving the arousals originates ectopically in primary nociceptor neurons and is relayed through the lateral parabrachial nucleus. These findings identify NREMS fragmentation by brief arousals as an effective proxy to measure spontaneous neuropathic pain in mice.

Racial and Ethnic Disparities in Use of Colorectal Cancer Screening Among Adults With Chronic Medical Conditions: BRFSS 2012-2020.

Introduction: People with chronic conditions and people with colorectal cancer (CRC) may share common risk factors; thus, CRC screening is important for people with chronic conditions. We examined racial and ethnic differences in the use of CRC screening among people with various numbers of chronic conditions. Methods: We included data on adult respondents aged 50 to 75 years from the Behavioral Risk Factor Surveillance System in 2012 through 2020. We categorized counts of 9 conditions as 0, 1, 2, 3, and ≥4. We classified self-reported CRC screening status as up to date or not. We used Poisson models to estimate adjusted prevalence ratios (APRs) among the different counts of chronic conditions in 4 racial and ethnic groups: Hispanic adults with limited English proficiency (LEP), Hispanic adults without LEP, non-Hispanic Black adults, and non-Hispanic White adults. Results: Overall, 66.5% of respondents were up to date with CRC screening. The prevalence of being up to date increased with the number of chronic conditions. We found disparities among racial and ethnic groups. Hispanic respondents with LEP had lower rates than non-Hispanic White adults of being up to date with CRC screening across all counts of chronic conditions (APR for 0 conditions = 0.67; 95% CI, 0.64-0.71; APR for ≥4 conditions = 0.85; 95% CI, 0.79-0.91). Hispanic respondents without LEP with 0, 1, or 2 conditions were less likely than non-Hispanic White respondents to be up to date with CRC screening. We found no significant differences between non-Hispanic Black and non-Hispanic White respondents. Conclusion: We found disparities among Hispanic BRFSS respondents with LEP, who had lower rates than non-Hispanic White respondents of being up to date with CRC screening, regardless of the number of chronic conditions. Tailored interventions are needed to address these disparities and improve screening rates, particularly among Hispanic people.

Multiple myeloma incidence, mortality, and survival differences at the intersection of sex, age, and race/ethnicity: A comparison between Puerto Rico and the United States SEER population.

BACKGROUND: Multiple myeloma (MM) survival has increased during the last decades due to the introduction of new therapies. We investigated the intersectionality among age, sex, and race/ethnicity to better understand the pattern of MM incidence, mortality, and survival. METHODS: Puerto Rico (PR) Central Cancer Registry and the United States of America (US) Surveillance, Epidemiology, and End Results (SEER) Program databases were used. We analyzed MM incidence and mortality trends from 2001 to 2019 using Joinpoint regression models to calculate annual percent change (APC). Age-standardized rate ratios (SRR) for incidence and mortality were used to compare PR with US SEER racial/ethnic groups during 2015-2019. Five-year survival analyses were also performed stratified by age and sex. RESULTS: Regardless of age and race/ethnicity, males had higher MM incidence and mortality rates than females. PR had a higher increase in incidence rates of MM than other ethnic groups, regardless of sex and age (PR APC = 4.3 among males <65, 3.1 among males ≥65, 6.3 among females <65, and 2.6 among females ≥65 years old). No significant change in mortality APCs (p > 0.05) was observed in PR when stratified by age or sex while other groups showed a decrease. Among males < 65 years, PR had significantly higher incidence rates than non-Hispanic Whites (NHW), and US Hispanics (USH). However, among both males and females ≥ 65 years, PR had significantly lower MM mortality rates than NHW, non-Hispanic Blacks (NHB), USH, and US Overall. In terms of survival, PR showed the lowest 5-year overall survival among males < 65 years (54.6%, 95% CI: 47.2-61.5) and males ≥ 65 years (34.5%, 95% CI: 29.2-39.9) but not among females. CONCLUSION: The incidence of MM in PR increased significantly over the study period, particularly among younger women. Despite the introduction of new therapies, mortality rates in PR have remained stable while other ethnic groups show significant decreases among all intersections of sex and age.

Oral Inflammation and Human Papilloma Virus Association among Hispanics.

Background: Identifying factors related to persistent human papillomavirus (HPV) infection is essential to reduce the incidence of HPV-related cancers. Objective: To evaluate whether gingival/periodontal inflammation is associated with oral HPV infection. Methods: This cross-sectional study (n = 740) uses data from the follow-up visit of the San Juan Overweight Adults Longitudinal Study, which recruited overweight/obese adults aged 40-65 from Puerto Rico. Participants completed a dental examination and two interviews (face-to-face/ACASI) and provided oral rinse samples for HPV detection. Oral inflammation was assessed using two definitions: (1) the number of sites with bleeding on probing (BOP), and (2) the number of teeth with probing pocket depths (PPD) ≥ 4 mm and BOP. Multivariate logistic regression was used to assess the association between oral inflammation and oral HPV. Results: Nearly three-quarters (72%) of participants were female, and 68% had 50 years or older. Participants with HPV had a higher mean number of sites with BOP (15.5 vs. 10.1) and teeth with PPD ≥ 4 mm and BOP (8.5 vs. 3.2) than participants without HPV (p < 0.05). After adjusting for sex, age, income, and the number of oral sex partners, the odds of having an oral HPV infection increased by 3% (95% confidence interval (CI): 1.00-1.06) for any additional sites with BOP and 5% (95% CI: 1.02-1.09) for any other teeth with PPD ≥ 4 mm and BOP. Conclusions: We found that oral inflammation was associated with oral HPV infection among adults in Puerto Rico. Future studies need to further investigate the underlying mechanisms.

Synthesis of 2,3-Dihydropyrroles by Rhodium(II)-Catalyzed Transannulation of N-Sulfonyl-1,2,3-triazoles: Diversity Generation by One-Pot Methodologies.

A versatile one-pot strategy for the generation of compounds of synthetic interest has been presented, promoting the development of practical processes. First, the transannulation of N-sulfonyltriazoles through alkenes and rhodium catalysis was described, giving 2,3-dihydropyrroles in 13-76% yield. As contributions of the strategy, the evaluation of alkenes with different properties, and the use of only drops of solvent (0.40 M) was highlighted. In addition, we described a methodology for the modulation of the N-sulfonyltriazoles, to obtain selectively cyclopropyl tosylimines or 2,3-dihydropyrroles. For the latter products, neat conditions were also included. Finally, the potential of the methodology was demonstrated by the synthesis of six structurally different analogues starting from the same substrates and late-stage transformation of bioactive molecules. These compounds were generated in 38-63% yield, after two or more conversion steps carried out in the same reaction vessel.

Unraveling the Intertwined Effect of pH on Helicobacter pylori Motility and the Microrheology of the Mucin-Based Medium It Swims in.

The gastric pathogen, Helicobacter pylori bacteria have to swim across a pH gradient from 2 to 7 in the mucus layer to colonize the gastric epithelium. Previous studies from our group have shown that porcine gastric mucin (PGM) gels at an acidic pH < 4, and H. pylori bacteria are unable to swim in the gel, although their flagella rotate. Changing pH impacts both the rheological properties of gastric mucin and also influences the proton (H+)-pumped flagellar motors of H. pylori as well as their anti-pH sensing receptors. To unravel these intertwined effects of acidic pH on both the viscoelastic properties of the mucin-based mucus as well as the flagellar motors and chemo-receptors of the bacterium, we compared the motility of H. pylori in PGM with that in Brucella broth (BB10) at different pH values using phase contrast microscopy to track the motion of the bacteria. The results show that the distribution of swimming speeds and other characteristics of the bacteria trajectories exhibit pH-dependent differences in both media. The swimming speed exhibits a peak at pH 4 in BB10, and a less pronounced peak at a higher pH of 5 in PGM. At all pH values, the bacteria swam faster and had a longer net displacement in BB10 compared to PGM. While the bacteria were stuck in PGM gels at pH < 4, they swam at these acidic pH values in BB10, although with reduced speed. Decreasing pH leads to a decreased fraction of motile bacteria, with a decreased contribution of the faster swimmers to the distributions of speeds and net displacement of trajectories. The body rotation rate is weakly dependent on pH in BB10, whereas in PGM bacteria that are immobilized in the low pH gel are capable of mechano-sensing and rotate faster. Bacteria can be stuck in the gel in various ways, including the flagella getting entangled in the fibers of the gel or the cell body being stuck to the gel. Our results show that in BB10, swimming is optimized at pH4, reflecting the combined effects of pH sensing by anti-pH tactic receptors and impact on H+ pumping of flagellar motors, while the increase in viscosity of PGM with decreasing pH and gelation below pH 4 lead to further reduction in swimming speed, with optimal swimming at pH 5 and immobilization of bacteria below pH 4.

ADAMTS-1 has nuclear localization in cells with epithelial origin and leads to decreased cell migration.

In the study of tumorigenesis, the involvement of molecules within the extracellular matrix (ECM) is crucial. ADAMTSs (A Disintegrin and Metalloproteinase with Thrombospondin motifs), a group of secreted proteases known for their role in ECM remodeling, were primarily considered to be extracellular proteases. However, our research specifically detected ADAMTS-1, a member of this family, predominantly within the nucleus of mammary cells. Our main objective was to understand the mechanism of ADAMTS-1 translocation to the nucleus and its functional significance in this cellular compartment. Our investigation uncovered that nuclear ADAMTS-1 was present in cells exhibiting an epithelial phenotype, while cells of mesenchymal origin contained the protease in the cytoplasm. Moreover, disruption of ADAMTS-1 secretion, induced by Monensin treatment, resulted in its accumulation in the cytoplasm. Notably, our research indicated that alterations in the secretory pathways could influence the protease's compartmentalization. Additionally, experiments with conditioned medium from cells containing nuclear ADAMTS-1 demonstrated its internalization into the nucleus by HT-1080 cells and fibroblasts. Furthermore, heightened levels of ADAMTS-1 within the ECM reduced the migratory potential of mesenchymal cells. This highlights the potential significance of nuclear ADAMTS-1 as a critical component within the tumor microenvironment due to its functional activity in this specific cellular compartment.

Racial/ethnic disparities for leukemias in Puerto Rico and the United States of America, 2015-2019.

BACKGROUND: Leukemia is a cancer of the early-forming cells. Over the past decade, leukemia racial/ethnic disparities have been documented in the United States of America (USA). Although the Puerto Rican population in the USA represents the second-largest Hispanic population in the nation, most of the existing studies do not include Puerto Rico. We compared the incidence and mortality rates for leukemia and its subtypes in Puerto Rico and four racial/ethnic groups in the USA. METHODS: We used data from the Puerto Rico Central Cancer Registry and the Surveillance, Epidemiology, and End Results Program (2015-2019). The racial/ethnic groups studied were non-Hispanic whites (NHW), non-Hispanic blacks (NHB), Hispanics (USH), and Asian/Pacific Islanders (NHAPI) living in the USA and the Puerto Rico population. We calculated the incidence and mortality rates. The relative risk of developing or dying due to leukemia was also calculated. RESULTS: Compared with Puerto Rico, NHW [standardized incidence rate (SIR) = 1.47; 95%CI = 1.40-1.53; standardized mortality rates (SMR) = 1.55; 95%CI = 1.45-1.65)] and NHB (SIR = 1.09; 95%CI = 1.04-1.15; SMR = 1.27; 95%CI = 1.19-1.35) had higher incidence and mortality rates; but lower than the NHAPI (SIR = 0.78; 95%CI = 0.74-0.82; SMR = 0.83; 95%CI = 0.77-0.89); and similar to USH. However, we found differences among leukemia subtypes. For example, NHAPI and USH had lower risk of developing chronic leukemias than Puerto Rico. We found a lower risk to develop acute lymphocytic leukemia in NHB than in Puerto Rico. CONCLUSIONS: Our study provides a better understanding of leukemia's racial/ethnic disparities and fills a knowledge gap by examining the incidence and mortality rates in Puerto Rico. Future studies are needed to better understand the factors influencing the differences found in the incidence and mortality of leukemia among different racial/ethnic groups.

Breast, cervical, and colorectal cancer screening test use in the US territories of Guam, Puerto Rico, and the US Virgin Islands.

BACKGROUND: The United States Preventive Services Task Force (USPSTF) recommends breast, cervical, and colorectal cancer screening among eligible adults, but information on screening use in the US territories is limited. METHODS: To estimate the proportion of adults up-to-date with breast, cervical, and colorectal cancer screening based on USPSTF recommendations, we analyzed Behavioral Risk Factor Surveillance System data from 2016, 2018, and 2020 for the 50 US states and DC (US) and US territories of Guam and Puerto Rico and from 2016 for the US Virgin Islands. Age-standardized weighted proportions for up-to-date cancer screening were examined overall and by select characteristics for each jurisdiction. RESULTS: Overall, 67.2% (95% CI: 60.6-73.3) of women aged 50-74 years in the US Virgin Islands, 74.8% (70.9-78.3) in Guam, 83.4% (81.7-84.9) in Puerto Rico, and 78.3% (77.9-78.6) in the US were up-to-date with breast cancer screening. For cervical cancer screening, 71.1% (67.6-74.3) of women aged 21-65 years in Guam, 81.3% (74.6-86.5) in the US Virgin Islands, 83.0% (81.7-84.3) in Puerto Rico, and 84.5% (84.3-84.8) in the US were up-to-date. For colorectal cancer screening, 45.2% (40.0-50.5) of adults aged 50-75 years in the US Virgin Islands, 47.3% (43.6-51.0) in Guam, 61.2% (59.5-62.8) in Puerto Rico, and 69.0% (68.7-69.3) in the US were up-to-date. Adults without health care coverage reported low test use for all three cancers in all jurisdictions. In most jurisdictions, test use was lower among adults with less than a high school degree and an annual household income of < $25,000. CONCLUSION: Cancer screening test use varied between the US territories, highlighting the importance of understanding and addressing territory-specific barriers. Test use was lower among groups without health care coverage and with lower income and education levels, suggesting the need for targeted evidence-based interventions.

Motility of Different Gastric Helicobacter spp.

Helicobacter spp., including the well-known human gastric pathogen H. pylori, can cause gastric diseases in humans and other mammals. They are Gram-negative bacteria that colonize the gastric epithelium and use their multiple flagella to move across the protective gastric mucus layer. The flagella of different Helicobacter spp. vary in their location and number. This review focuses on the swimming characteristics of different species with different flagellar architectures and cell shapes. All Helicobacter spp. use a run-reverse-reorient mechanism to swim in aqueous solutions, as well as in gastric mucin. Comparisons of different strains and mutants of H. pylori varying in cell shape and the number of flagella show that their swimming speed increases with an increasing number of flagella and is somewhat enhanced with a helical cell body shape. The swimming mechanism of H. suis, which has bipolar flagella, is more complex than that of unipolar H. pylori. H. suis exhibits multiple modes of flagellar orientation while swimming. The pH-dependent viscosity and gelation of gastric mucin significantly impact the motility of Helicobacter spp. In the absence of urea, these bacteria do not swim in mucin gel at pH < 4, even though their flagellar bundle rotates.

Patient and provider-level drivers of healthcare utilization related to a diagnosis of a precancerous condition: monoclonal gammopathy of undetermined significance (MGUS).

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma. This qualitative study described patient (n = 14) experiences and healthcare providers' (n = 8) opinions and practices concerning care for patients with MGUS in the US. METHODS: Semi-structured, in-depth interviews were analyzed using thematic analysis. RESULTS: We identified six overarching themes related to the care pathway for patients with MGUS: (1) Process of MGUS diagnosis, (2) Providers' explanations, (3) Patients' understanding, (4) Impact of the diagnosis, (5) Follow-up/management, and (6) Factors influencing healthcare utilization. Patients demonstrated a basic understanding of MGUS. However, some patients felt anxiety around the diagnosis, which may affect other aspects of their lives. Non-hematologist providers report having less MGUS-specific knowledge. Older age, high-risk MGUS, and insurance coverage/healthcare costs influenced healthcare utilization. CONCLUSION: Patients with MGUS may have difficulty processing this premalignant diagnosis. Non-hematologist providers may have gaps in knowledge around specific care for patients with MGUS.

Multimorbidity in patients with monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma, is present in over 5% of adults aged 70 and older, a population with a high prevalence of multimorbidity. MGUS is often diagnosed incidentally when patients seek care for unrelated conditions. Our study sought to examine patterns of multimorbidity among MGUS patients, as overall health may impact patient care and the prioritization of MGUS surveillance. We examined patterns of comorbidities in 429 patients diagnosed with MGUS (2007-2015) and 1287 matched controls. Twenty-seven conditions were defined at diagnosis/index date using algorithms developed by the Centers for Medicare and Medicaid Chronic Conditions Warehouse. Patterns of common comorbidities were identified individually, in dyads and triads, and compared between MGUS cases and controls. We conducted a latent class analysis to identify comorbidity patterns among cases only. We also examined comorbidity patterns among a subset of 32 MGUS cases who progressed to cancer during the study period. The most common comorbidities among both MGUS cases and controls included hypertension and hyperlipidemia. Anemia (cases: 43%; controls: 16%) and chronic kidney disease (CKD; cases: 36%; controls: 18%), and dyads and triads containing those conditions, were more common among cases. Latent class analysis identified three classes of comorbidity among MGUS cases: hypertension-hyperlipidemia plus anemia and CKD (31%); low comorbidity burden (17%); and hypertension-hyperlipidemia alone (52%). The higher prevalence among cases of anemia and CKD, which may be involved in the pathogenesis of, or surveillance for, MGUS, warrants additional investigation.

Trends and Factors Associated with Fecal Occult Blood Test Utilization among Hispanic Adults in Puerto Rico and the United States: BRFSS 2012-2020.

Identifying factors associated with colorectal cancer screening utilization is important to guide colorectal cancer prevention and control programs. We evaluated trends and factors associated with previous-year fecal occult blood test (FOBT) use among Hispanic adults living in Puerto Rico and the U.S. mainland. Using data from the Behavioral Risk Factor Surveillance System (2012-2020), trends in FOBT use were analyzed using joinpoint regression to estimate annual percentage change (APC). Logistic regression stratified by location identified factors associated with FOBT use. FOBT was more common among Hispanic adults ages 50 to 75 years living in Puerto Rico than in the U.S. mainland [Puerto Rico: 20.5%[2012] to 45.6%[2020], APC = 11.4%; U.S. mainland: 9.9%[2012] to 16.7%[2020], APC = 5.9%]. Factors inversely associated with FOBT use were similar in Puerto Rico and the U.S. mainland, including lack of health insurance, not having a personal doctor, having a checkup >12 months ago, and not being able to see a doctor due to cost, as were factors associated with higher FOBT use, including older age, retirement, or having two or more chronic diseases. Among Hispanics living in the U.S. mainland, lack of exercise and less education were inversely associated with FOBT. Factors related to poor access to healthcare were associated with lower use of FOBT among Hispanics. Efforts to improve colorectal cancer screening in Hispanics are necessary to address health disparities across the colorectal cancer care continuum. PREVENTION RELEVANCE: Colorectal cancer screening reduces cancer incidence and mortality. All screening modalities, including less invasive FOBT tests, are underutilized, especially in non-White and low-income populations. Evaluation of trends and factors associated with the increase in the use of colorectal cancer screening can inform programs to address the lack of screening among racial minorities.

Patterns of use of biological and genetic markers for chronic lymphocytic leukemia and acute myeloid leukemia in Puerto Rico.

BACKGROUND: The use of markers has stimulated the development of more appropriate targeted therapies for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). We assessed the use and prevalence of biological and genetic markers of CLL and AML in the homogeneous Hispanic population of Puerto Rico. METHODS: We used the Puerto Rico CLL/AML Population-Based Registry, which combines information from linked databases. Logistic regression models were used to examine factors associated with biological and genetic testing. RESULTS: A total of 926 patients 18 years or older diagnosed with CLL (n = 518) and AML (n = 408) during 2011-2015 were included in this analysis. Cytogenetic testing (FISH) was reported for 441 (85.1%) of the CLL patients; of those, 24.0% had the presence of trisomy 12, 9.5% carried deletion 11q, 50.3% carried deletion 13q, and 6.3% carried deletion 17p. Regarding AML, patients with cytogenetics and molecular tests were considered to determine the risk category (254 patients), of which 39.8% showed poor or adverse risk. Older age and having more comorbidities among patients with CLL were associated with a lower likelihood of receiving a FISH test. CONCLUSIONS: Although prognostic genetic testing is required for treatment decisions, the amount of testing in this Hispanic cohort is far from ideal. Furthermore, some tests were not homogeneously distributed in the population, which requires further exploration and monitoring. This study contributes to the field by informing the medical community about the use and prevalence of biological and genetic markers of CLL and AML. Similarly, it has the potential to improve the management of CLL and AML through benchmarking.

Oral microbiota and periodontitis severity among Hispanic adults.

Background: Periodontitis, one of the most common bacterial infections characterized by chronic inflammation, is also known to be a risk factor for chronic conditions, including cardiovascular disease and cancer. This inflammation is driven by an altered microbiota with an increase in pathogenic bacteria. We evaluated the association between oral microbiota and periodontitis severity in high-risk Hispanics. Method: This cross-sectional study recruited 134 sexually active participants aged 21 to 49 years old from STI Clinics in Puerto Rico. A periodontal examination, saliva collection, and an interviewer-administered questionnaire were performed. Periodontal severity was categorized as: having no disease, mild, and moderate/severe and BOP and tooth loos was noted. Saliva samples were collected for genomic DNA extraction, downstream 16S rDNA amplification sequencing, and bioinformatics analyses. Results: The structure, composition, and diversity of bacterial communities differed significantly according to periodontal severity. The richness and overall diversity also differed between participants without periodontitis and participants with some level of periodontal disease. A higher abundance of Prevotella, Veillonella, or Treponema was attributed to periodontal disease and Aggregatibacter to severe bleeding on probing, while Neisseria was found in higher abundance in healthy participants, decreasing its levels with drinking, smoking, and oral sex practices. Conclusions: Our findings indicate that dysbiosis occurs as periodontal disease progresses, and both alcohol consumption and smoking habits pose risk factors for oral dysbiosis. These results are of public health and clinical impact, as several bacteria identified could serve in the future as biomarkers for periodontitis and oral cancer risk.

Differences in Hospital, Emergency Room and Outpatient Visits Among Adults With and Without Monoclonal Gammopathy of Undetermined Significance.

INTRODUCTION: This study evaluated the impact of receiving a monoclonal gammopathy of undetermined significance (MGUS) diagnosis on healthcare utilization from patients at a community-based multispecialty provider organization. METHODS: A cohort of patients with MGUS (n = 429) were matched on sex, age, and length of enrollment to a cohort of patients without MGUS (n = 1286). Healthcare utilization was assessed: 1-12 months before, 1 month before and after, and 1-12 months after diagnosis/index date. Multivariable conditional Poisson models compared change in utilization of each service in patients with and without MGUS. RESULTS: During the 2 months around diagnosis/index date, the rates of emergency room, hospital and outpatient visits were higher for patients with MGUS than patients without MGUS. In the year before MGUS diagnosis, the association was still elevated, although attenuated. CONCLUSION: Understanding the care of MGUS patients is important given that multiple myeloma patients with a pre-existing MGUS diagnosis may have a better prognosis.