Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. Our clinical experience is that oral cancer patients report new sensitivity to spicy foods. We ...hypothesized that in cancer patients, mechanical and chemical sensitivity would be greater when measured at the cancer site compared to a contralateral matched normal site.
We determined mechanical pain thresholds (MPT) on the right and left sides of the tongue of 11 healthy subjects, and at the cancer and contralateral matched normal site in 11 oral cancer patients in response to von Frey filaments in the range of 0.008 to 300 g (normally not reported as painful). We evaluated chemical sensitivity in 13 healthy subjects and seven cancer patients, who rated spiciness/pain on a visual analog scale in response to exposure to six paper strips impregnated with capsaicin (0-10 mM).
Mechanical detection thresholds (MDT) were recorded for healthy subjects, but not MPTs. By contrast, MPTs were measured at the site of the cancer in oral cancer patients (7/11 patients). No MPTs were measured at the cancer patients' contralateral matched normal sites. Measured MPTs were correlated with patients' responses to the University of California Oral Cancer Pain Questionnaire. Capsaicin sensitivity at the site of the cancer was evident in cancer patients by a leftward shift of the cancer site capsaicin dose-response curve compared to that of the patient's contralateral matched normal site. We detected no difference in capsaicin sensitivity on the right and left sides of tongues of healthy subjects.
Mechanical and chemical sensitivity testing was well tolerated by the majority of oral cancer patients. Sensitivity is greater at the site of the cancer than at a contralateral matched normal site.
Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here, we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia ...compared with patients without PNI, suggesting that unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. Perineural invasion induced afterdischarge in A high-threshold mechanoreceptors (HTMRs), mechanical sensitization (ie, decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low-threshold mechanoreceptors. Perineural invasion resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically insensitive and electrically unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.
Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with ...sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.
Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the ...comparative efficacy of prevention regimens is largely unknown.
We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval CI: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio HR 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited.
In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted.
clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.
Oral cancer patients suffer pain at the site of the cancer, which degrades quality of life (QoL). The University of California San Francisco Oral Cancer Pain Questionnaire (UCSFOCPQ), the only ...validated instrument specifically designed for measuring oral cancer pain, measures the intensity and nature of pain and the level of functional restriction due to pain.
The aim of this study was to compare pain reported by untreated oral cancer patients on the UCSFOCPQ with pain they reported on the Brief Pain Inventory (BPI), an instrument widely used to evaluate cancer and non-cancer pain.
The correlation between pain measured by the two instruments and clinical characteristics were analyzed. Thirty newly diagnosed oral cancer patients completed the UCSFOCPQ and the BPI.
Pain severity measurements made by the UCSFOCPQ and BPI were concordant; however, the widely used BPI average pain over 24 hours score appeared less sensitive to detect association of oral cancer pain with clinical characteristics of patients prior to treatment (nodal status, depth of invasion, DOI). A BPI average score that includes responses to questions that measure both pain severity and interference with function performs similarly to the UCSFOCPQ in detection of associations with nodal status, pathologic T stage (pT stage), stage and depth of invasion (DOI).
Pain assessment instruments that measure sensory and interference dimensions of oral cancer pain correlate with biologic features and clinical behavior.
Background Although aerobic exercise improves quality of life as assessed by a disease-specific instrument in ambulatory HF patients with a reduced ejection fraction (EF), the impact of an exercise ...intervention on general health status has not been previously reported. Methods A secondary analysis was performed of the HF-ACTION trial ( ClinicalTrials.gov Number: NCT00047437 ), which enrolled 2331 medically stable outpatients with HF and an EF ≤35% and randomized them to aerobic exercise training, consisting of 36 supervised sessions followed by home-based training versus usual care for a median follow-up of 30 months. The EuroQOL 5-dimension questionnaire (EQ-5D) was administered to study participants at baseline, 3 months, and 12 months. EQ-5D includes functional dimensions (ie, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), which were mapped to corresponding utility scores (ie, 0 = death and 1 = perfect health), and a visual analogue scale (VAS) ranging from 0 (ie, “worst imaginable health state”) to 100 (ie, “best imaginable health state”). Results Study participants had a median (25th, 75th) age of 59 (51, 68) years and 71% were male. A history of ischemic heart disease was reported in 51% of participants and the EF was 25% (20%, 30%). Baseline VAS and mapped utility scores were 65± 19 and 0.81± 0.14. Exercise training led to an improvement in VAS score compared with usual care from baseline to 3 months (exercise training: 6 ± 17 vs usual care: 3 ± 20; P <.01) although there were no further significant changes at 12 months. Aerobic exercise training did not favorably change mapped utility scores over either timeframe. After multivariable adjustment, lower mapped utility (hazard ratio HR 1.19 per 0.1 decrease, 95% CI 1.09–1.29; P < .0001) and VAS scores (HR 1.05 per 10 point decrease, 95% CI 1.02–1.08; P < .01) at baseline were associated with increased risk of death or hospitalization. Conclusion Ambulatory HF patients with a reduced EF had impaired health status at baseline which was associated with increased morbidity and mortality, in part mitigated by a structured aerobic exercise regimen.
OBJECTIVESCoronavirus Disease 2019 (COVID-19) is a viral illness with public health importance. The Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study is a prospective, longitudinal cohort ...study designed to contribute valuable information on community prevalence of active COVID-19 infection and SARS-CoV-2 antibodies as the pandemic and responses to it have and continue to evolve. We present the rationale, study design, and baseline characteristics of the C3PI Study. METHODSWe recruited 1,426 participants between June 2020 and August 2020 from the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository, a previously established, community-based, longitudinal cohort. Participants completed a baseline survey and follow-up surveys every two weeks. A nested weighted, random sub-cohort (n=300) was recruited to measure the incidence and prevalence of active COVID-19 infection and SARS-CoV-2 IgG antibodies. RESULTSThe sub-cohort was younger (56 vs 61 years), had more men (39.0% vs 30.9%), and a higher proportion of Hispanic (11.0% vs 5.1%) and Black participants (17.0% vs 8.2%) compared with the overall cohort. They had similar anthropometrics and medical histories, but a greater proportion of the sub-cohort had a higher educational degree (36.1% vs 31.3%) and reported a pre-pandemic annual household income of >$90,000 (57.1% vs 47.9%). CONCLUSIONThis study is part of a multisite consortium that will provide critical data on the epidemiology of COVID-19 and community perspectives about the pandemic, behaviors and mitigation strategies, and individual and community burden in North Carolina.
The Coronavirus Disease 2019 (COVID-19) pandemic forced researchers to reconsider in-person assessments due to transmission risk. We conducted a pilot study to evaluate the feasibility of using the ...Tasso-SST (Tasso, Inc, Seattle, Washington) device for blood self-collection for use in SARS-CoV-2 antibody testing in an ongoing COVID-19 prevalence and immunity research study. 100 participants were recruited between January and March 2021 from a previously identified sub-cohort of the Cabarrus County COVID-19 Prevalence and Immunity (C3PI) Study who were under-going bimonthly COVID-19 antibody testing. Participants were given a Tasso-SST kit and asked to self-collect blood during a scheduled visit where trained laboratory personnel performed routine phlebotomy. All participants completed an after-visit survey about their experience. Overall, 70.0% of participants were able to collect an adequate sample for testing using the device. Among those with an adequate sample, there was a high concordance in results between the Tasso-SST and phlebotomy blood collection methods (Cohen’s kappa coefficient = 0.88, Interclass correlation coefficient 0.98 0.97, 0.99, p < 0.0001). The device received a high-level (90.0%) of acceptance among all participants. Overall, the Tasso-SST could prove to be a valuable tool for seroprevalence testing. However, future studies in larger, diverse populations over longer periods may provide a better understanding of device usability and acceptance among older participants and those with comorbidities in various use scenarios.
Cardiac toxicity remains a serious yet unsolved complication of doxorubicin. This study was designed to examine whether doxycycline, a tetracycline-derived synthetic antibiotic with potential ...cytoprotective properties, could ameliorate this complication of doxorubicin. Male mice at 4-week of age were administrated with vehicle, doxorubicin (3mg/kg intraperitoneally every other day at 3 doses), doxycycline (2.5mg/kg intraperitoneally every other day for 3 doses), or doxycycline plus doxorubicin (each dose given 1day post doxycycline). After 28days, left ventricular geometric and systolic parameters were measured by transthoracic echocardiography, and hearts were harvested for extensive analyses regarding oxidative stress and cellular apoptosis. At 28days, hearts of doxorubicin-treated mice were characterized by less weight compared with controls, also with remodeling and depressed systolic function of the left ventricle. Biochemical analyses disclosed that content of malondialdehyde was increased and activity of antioxidant enzymes, including superoxide dismutase and glutathione peroxidase, was decreased in these hearts. Both mitochondrion-dependent and endoplasmic reticulum stress-induced apoptotic pathways were also activated in the hearts of doxorubicin-treated mice as reflected by decreased Bcl-2/Bcl-XL and elevated Bax/Bad, p53/Apaf-1, endoplasmic reticulum glucose-related protein 78, C/EBP homologous protein, cytochrome c release from mitochondria, caspases-9/-3 cleavage, and cardiomyocyte apoptosis. In contrast, all the above left ventricular remodeling, systolic depressing, oxidative and pro-apoptotic actions of doxorubicin could be significantly alleviated by doxycycline pretreatment. Thus, doxycycline extensively counteracts multiple oxidative and apoptotic actions of doxorubicin in heart, hence may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application.
Water distribution and transmission lines are indispensable to urban infrastructure. The water pipelines are subject to both structural and functional deterioration due to various reasons including ...aging, negligence, and high demand for water supply. Hence, to ensure a safe and reliable water supply, the water utilities need to perform routine pipe condition assessment. The condition assessment is usually carried out by visual inspection with the machine vision system carried by a robotic platform. The inspection platforms will capture the internal condition of the water pipelines in a video stream. However, the robotic platform frequently experiences difficulties while traversing through the valves installed along the pipeline. This inhibits and disrupts the inspection process of the water pipelines. Therefore, this article proposes a deep learning-based automatic valve detection framework to facilitate the robot's navigation and ensure continuous inspection without any interruptions. The valve detection model is developed by combining MobileNet-160 and Feature Pyramid Network and is named as MFPN. The developed framework also employs a generative adversarial network to solve the sparse dataset issues and improve the generality of the framework. The comparative study and ablation analyses demonstrate that the proposed framework can achieve a higher mAP value of 89.11% in comparison with the state of the art. Hence, this light weight and efficient solution can be deployed to the robotic platform for real-time valve detection and enable autonomous navigation of the robotic platform for condition assessment of water pipelines.
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