Mechanisms of cancer pain

Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain

In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP

Mechanistic insights into pain pathways are essential for a rational approach to treating this vast and increasing clinical problem. Sensory neurons that respond to tissue damage (nociceptors) may evoke pain sensations and are typically classified on the basis of action potential velocity. Electrophysiological studies have suggested that most of the C-fiber nociceptors are polymodal, responding to a variety of insults. In contrast, gene deletion studies in the sensory neurons of transgenic mice have frequently resulted in modality-specific deficits. We have used an in vivo imaging approach using the genetically encoded fluorescent calcium indicator GCaMP to study the activity of dorsal root ganglion sensory neurons in live animals challenged with painful stimuli. Using this approach, we can visualize spatially distinct neuronal responses and find that >85% of responsive dorsal root ganglion neurons are modality-specific, responding to either noxious mechanical, cold, or heat stimuli. These observations are mirrored in behavioral studies of transgenic mice. For example, deleting sodium channel Nav1.8 silences mechanical- but not heat-sensing sensory neurons, consistent with behavioral deficits. In contrast, primary cultures of axotomized sensory neurons show high levels of polymodality. After intraplantar treatment with prostaglandin E2, neurons in vivo respond more intensely to noxious thermal and mechanical stimuli, and additional neurons (silent nociceptors) are unmasked. Together, these studies define polymodality as an infrequent feature of nociceptive neurons in normal animals

Cohort-based kernel principal component analysis with Multi-path Service Routing in Federated Learning

Federated Learning (FL) is a machine learning (ML) strategy that is performed in a decentralized environment. The training is performed locally by the client on the global model shared by the server. Federated learning has recently been used as a service (FLaaS) to provide a collaborative training environment to independent third-party applications. However, the widespread adoption in distributed settings of FL has opened venues for a number of security attacks. A number of studies have been performed to prevent multiple FL attacks. However, sophisticated attacks, such as label-flipping attacks, have received little or no attention. From the said perspective, this research is focused on providing a defense mechanism for the aforesaid attack. The proposed approach is based on Type-based Cohorts (TC) with Kernel Principal Component Analysis (KPCA) to detect and defend against label-flipping attacks. Moreover, to improve the performance of the network, we will deploy Multi-path Service Routing (MSR) for edge nodes to work effectively. The KPCA will be used to secure the network from attacks. The proposed mechanism will provide an effective and secure FL system. The proposed approach is evaluated with respect to the following measures: execution time, memory consumption, information loss, accuracy, service request violations, and the request’s waiting time

Drug resistance profile and biofilm forming potential of Pseudomonas aeruginosa isolated from contact lenses in Karachi-Pakistan

BACKGROUND: The contaminated contact lens provides Pseudomonas aeruginosa an ideal site for attachment and biofilm production. Continuous contact of the eye to the biofilm-infested lens can lead to serious ocular diseases, such as keratitis (corneal ulcers). The biofilms also prevent effective penetration of the antibiotics, which increase the chances of antibiotic resistance. METHODS: For this study, 22 Pseudomonas aeruginosa isolates were obtained from 36 contact lenses and 14 contact lens protective fluid samples. These isolates were tested against eight commonly used antibiotics using Kirby-Bauer disk diffusion method. The biofilm forming potential of these isolates was also evaluated using various qualitative and quantitative techniques. Finally, a relationship between biofilm formation and antibiotic resistance was also examined. RESULTS: The isolates of Pseudomonas aeruginosa tested were found resistant to most of the antibiotics tested. Qualitative and quantitative biofilm analysis revealed that most of the isolates exhibited strong biofilm production. The biofilm production was significantly higher in isolates that were multi-drug resistant (p < 0.0001). CONCLUSION: Our study indicates that multi-drug resistant, biofilm forming Pseudomonas aeruginosa isolates are mainly involved in contact lens associated infections. This appears to be the first report from Pakistan, which analyzes both antibiotic resistance profile and biofilm forming potential of Pseudomonas aeruginosa isolates from contact lens of the patients with contact lens associated infections

Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia

Fibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2 to 4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, while adoptive transfer of immunoglobulin, serum, lymphocytes, or monocytes has no effect on pain behavior. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil-derived mediators and peripheral nerve sensitization is already established. Our observations suggest approaches for targeting fibromyalgia pain via mechanisms that cause altered neutrophil activity and interactions with sensory neurons

Delirium Incidence, Duration and Severity in Critically Ill Patients with COVID-19

Background: Delirium incidence, duration and severity in patients admitted to the intensive care unit (ICU) due to COVID-19 is not known. Methods: We conducted an observational study at two large urban academic Level 1 trauma centers. Consecutive patients admitted to the ICU with a positive SARS-CoV-2 nasopharyngeal swab polymerase chain reaction test from March 1st, 2020 to April 27, 2020, were included. Individuals younger than 18 years of age, without any documented delirium assessments (CAM-ICU), or without a discharge disposition were excluded. The primary outcomes were delirium rates and delirium duration and the secondary outcome was delirium severity. Outcomes were assessed for up to the first 14 days of ICU stay. Results: Of 243 consecutive patients with confirmed COVID-19 admitted to the ICU, 144 met eligibility criteria and were included in the analysis. Delirium occurred in 73.6% (106/144) and delirium or coma occurred in 76.4% (110/144). Sixty-three percent of patients were positive for delirium on the first CAM-ICU assessment. The median duration of delirium and coma was 7 days (IQR: 3-10), and the median delirium duration was 5 days (IQR: 2-7). The median CAM-ICU-7 score was 6 (IQR: 4-7) representing severe delirium. Mechanical ventilation was associated with greater odds of developing delirium (OR: 42.1, 95%CI: 13.0-137.1). Mortality was 26.4% in patients with delirium compared to 15.8% in patients without delirium. Conclusions: 73.6% of patients admitted to the ICU with COVID-19 experience delirium that persists for approximately 1 week. Invasive mechanical ventilation is significantly associated with odds of delirium. Clinical attention to prevent and manage delirium and reduce delirium duration and severity is urgently needed for patients with COVID-19.Babar Khan, Sujuan Gao, and Anthony Perkins are supported through NIA R01 AG 055391, R01 AG 052493 and NHLBI R01 HL131730. Anthony Perkins is also supported by NIA grants 1K23AG062555-01 and R01AG056325. Roberto Machado is supported by 1R01HL111656, 1R01HL127342 and 1R01HL133951. Sophia Wang is supported by K23AG062555-01. Edward Marcantonio is supported by grants R01AG044518 and K24AG035075 from the NIA. Malaz Boustani received funding from NIA R01AG034205 and disclosed that he has ownership equity in two for profit companies, Preferred Population Health Management and RestUp. The products and services of the two companies are not related to the research activities of the paper

A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study.

BACKGROUND: Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications. METHODS AND FINDINGS: From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability. CONCLUSIONS: The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care

Mortality Rates in a Diverse Cohort of Mechanically Ventilated Patients With Novel Coronavirus in the Urban Midwest

Objectives: Differences in mortality rates previously reported in critically ill patients with coronavirus disease 2019 have increased the need for additional data on mortality and risk factors for death. We conducted this study to describe length of stay, mortality, and risk factors associated with in-hospital mortality in mechanically ventilated patients with coronavirus disease 2019. Design: Observational study. Setting: Two urban, academic referral hospitals in Indianapolis, Indiana. Patients or Subjects: Participants were critically ill patients 18 years old and older, admitted with coronavirus disease 2019 between March 1, 2020, and April 27, 2020. Interventions: None. Measurements and Main Results: Outcomes included in-hospital mortality, duration of mechanical ventilation, and length of stay. A total of 242 patients were included with mean age of 59.6 years (sd, 15.5 yr), 41.7% female and 45% African American. Mortality in the overall cohort was 19.8% and 20.5% in the mechanically ventilated subset. Patients who died were older compared with those that survived (deceased: mean age, 72.8 yr [sd, 10.6 yr] vs patients discharged alive: 54.3 yr [sd, 14.8 yr]; p < 0.001 vs still hospitalized: 59.5 yr [sd, 14.4 yr]; p < 0.001) and had more comorbidities compared with those that survived (deceased: 2 [0.5–3] vs survived: 1 [interquartile range, 0–1]; p = 0.001 vs still hospitalized: 1 [interquartile range, 0–2]; p = 0.015). Older age and end-stage renal disease were associated with increased hazard of in-hospital mortality: age 65–74 years (hazard ratio, 3.1 yr; 95% CI, 1.2–7.9 yr), age 75+ (hazard ratio, 4.1 yr; 95% CI, 1.6–10.5 yr), and end-stage renal disease (hazard ratio, 5.9 yr; 95% CI, 1.3–26.9 yr). The overall median duration of mechanical ventilation was 9.3 days (interquartile range, 5.7–13.7 d), and median ICU length of stay in those that died was 8.7 days (interquartile range, 4.0–14.9 d), compared with 9.2 days (interquartile range, 4.0–14.0 d) in those discharged alive, and 12.7 days (interquartile range, 7.2–20.3 d) in those still remaining hospitalized. Conclusions: We found mortality rates in mechanically ventilated patients with coronavirus disease 2019 to be lower than some previously reported with longer lengths of stay.Drs. Perkins, Gao, and Khan are supported through National Institutes of Health (NIH)-National Institute on Aging (NIA) R01 AG 055391, R01 AG 052493, and National Heart, Lung, and Blood Institute R01 HL131730. Dr. Twigg is supported through NIH-NIA U01 AG060900. The remaining authors have disclosed that they do not have any potential conflicts of interest