Rejected

New-Onset Headache in Adults: Evidence-Based Assessment in the Primary Care Setting Many people suffer from headaches. Primary (idiopathic) headaches such as migraine and tension type headaches are most common. They may significantly affect occupational and social aspects of daily life, but are usually not dangerous. On the contrary, secondary (symptomatic) headaches may be a symptom for an underlying life-threatening disorder. In these cases, the primary care physician may need to organize certain diagnostic measures such as brain imaging, blood work or lumbar puncture. Sometimes, emergency hospital admission may be required. In this article we summarize the recommended steps for the assessment of new-onset headaches in patients visiting the primary care practice.

The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40-100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).

Posterior knee pain after total knee arthroplasty (TKA) is common despite multimodal analgesia and regional anesthesia use. This review included randomized controlled trials (RCTs) comparing analgesic outcomes after inclusion of local anesthetic infiltration between the popliteal artery and capsule of the knee (iPACK) block versus pathways without iPACK. Electronic databases (MEDLINE, Cochrane Library, Web of Science, Scopus) were searched from inception to 10/11/2020. Eligible studies evaluated iPACK use on primary outcomes: opioid consumption and pain scores with movement. Secondary outcomes included rest pain, patient satisfaction, length of stay (LOS), gait distance, knee range of motion (ROM), and complications. Bias and quality were appraised using the Cochrane Risk of Bias tool and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guidelines. Eight RCTs (777 patients) were included. iPACK block use demonstrated similar opioid consumption in the PACU (4/7 RCTs) and 24 hours after TKA (5/7 RCTs) compared to without iPACK (moderate-quality GRADE evidence). Additionally, iPACK block use demonstrated lower movement pain scores in PACU (3/5 RCTs) but similar or higher pain scores after 24 hours (5/7 RCTs; low-quality GRADE evidence). Studies consistently reported no difference in gait distance (4/4 RCTs) or complications (7/7 RCTs) between treatment arms (high-quality GRADE evidence), although differing effect estimates were observed with resting pain, satisfaction, LOS, and knee ROM. This review provides a foundation of knowledge on iPACK efficacy. While evidence does not currently support widespread inclusion of iPACK within enhanced recovery pathways for TKA, limitations suggest further study is warranted.

Coiled-coil domain-containing 68 (CCDC68) plays different roles in cancer and is predicted as a tumor suppressor in human colorectal cancer (CRC). However, the specific role of CCDC68 in CRC and the underlying mechanisms remain unknown. Here, we showed that CCDC68 expression was lower in CRC than that in corresponding normal tissues, and CCDC68 level was positively correlated with disease-free survival. Ectopic expression of CCDC68 decreased CRC cell proliferation and suppressed the growth of CRC xenograft tumors . CCDC68 caused G0/G1 cell cycle arrest, downregulated CDK4, and upregulated ITCH, the E3 ubiquitin ligase responsible for CDK4 protein degradation. This increased CDK4 degradation, which decreased CDK4 protein levels and inhibited CRC tumor growth. Collectively, the present results identify a novel CDK4 regulatory axis consisting of CCDC68 and ITCH, which suggest that CCDC68 is a promising target for the treatment of CRC.

After the identification of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) and its cognate receptor, the unique functional profiles of the N/OFQ-NOP receptor system have been uncovered. NOP receptors are distributed in the key regions that regulate pain and reward processing in the central nervous system. In non-human primates (NHPs), activation of the NOP receptor causes antinociception and anti-hypersensitivity via spinal and supraspinal effects. Moreover, activation of the NOP receptor attenuates dopaminergic transmission and potentiates mu-opioid peptide (MOP) receptor-mediated analgesia. Here, we highlight the functional profiles of bifunctional NOP and MOP receptor agonists based on their promising effects for the treatment of pain and drug abuse. Bifunctional NOP/MOP receptor "partial" agonists, such as AT-121, BU08028, and BU10038, exert potent analgesic effects without MOP receptor-related side effects such as abuse liability, respiratory depression, physical dependence, and itching in NHPs. These novel NOP/MOP receptor agonists reduce rewarding and the reinforcing effects of abused drugs. Furthermore, a mixed NOP/opioid receptor "full" agonist, cebranopadol, is undergoing several clinical trials, and the therapeutic advantage of the coactivation of NOP and MOP receptors has also been confirmed in humans. Therefore, this class of drugs that coactivate NOP and MOP receptors proposes a wide therapeutic range with fewer side effects, indicating a greater potential for the development of novel safer opioid analgesics.

Despite that it is commonly accepted that migraine is a disorder of the nervous system with a prominent genetic basis, it is comorbid with a plethora of medical conditions. Several studies have found bidirectional comorbidity between migraine and different disorders including neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metaboloendocrine, and immunological conditions. Each of these has its own genetic load and shares some common characteristics with migraine. The bidirectional mechanisms that are likely to underlie this extensive comorbidity between migraine and other diseases are manifold. Comorbid pathologies can induce and promote thalamocortical network dysexcitability, multi-organ transient or persistent pro-inflammatory state, and disproportionate energetic needs in a variable combination, which in turn may be causative mechanisms of the activation of an ample defensive system with includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This strategy is designed to maintain brain homeostasis by regulating homeostatic needs, such as normal subcortico-cortical excitability, energy balance, osmoregulation, and emotional response. In this light, the treatment of migraine should always involves a multidisciplinary approach, aimed at identifying and, if necessary, eliminating possible risk and comorbidity factors.

The aim of this multicenter trial was to compare the effects of whole-body electromyostimulation (WB-EMS) and whole-body vibration (WBV) with conventional back-strengthening training (CT) on changes in mean back pain intensity (MPI) and trunk strength in patients suffering from chronic non-specific low back pain (CNLBP). Two-hundred and forty CNLBP patients (40-70 years; 62% female) were randomly assigned to three intervention arms (WB-EMS: = 80 vs. WBV: = 80 vs. CT: = 80). All training intervention programs were performed for 12 weeks in their usual commercial training setting. Before and during the last 4 weeks of the intervention, MPI was recorded using a 4-week pain diary. Additionally, maximal isometric trunk extension and -flexion strength was assessed on the BackCheck® machine. A moderate but significant decrease of MPI was observed in all groups (WB-EMS: 29.7 ± 39.1% (SMD 0.50) vs. WBV: 30.3 ± 39.3% (SMD 0.57) vs. CT: 30.5 ± 39.6% (SMD 0.59); < 0.001). Similar findings were observed for maximal isometric strength parameters with a significant increase in all groups (extension: WB-EMS: 17.1 ± 25.5% vs. WBV: 16.2 ± 23.6% vs. CT: 21.6 ± 27.5%; < 0.001; flexion: WB-EMS: 13.3 ± 25.6% vs. WBV: 13.9 ± 24.0% vs. CT: 13.9 ± 25.4%; < 0.001). No significant interaction effects for MPI ( = 0.920) and strength parameters (extension: = 0.436; flexion: = 0.937) were observed. WB-EMS, WBV, and CT are comparably effective in improving MPI and trunk strength. However, training volume of WB-EMS was 43 or 62% lower, compared with CT and WBV.

Rheumatoid arthritis (RA) is a systemic immunodeficiency disease characterized by persistent synovial inflammation, pannus formation, and bone and cartilage destruction, resulting in joint malformations and function decline.

To evaluate the pharmacokinetics and pharmacodynamics, dosing, efficacy, and safety of ketorolac in postoperative patients younger than 6 months of age.

Chronic pain (CP) has serious medical and social consequences and leads to economic burden that threatens the sustainability of healthcare services. Thus, optimized management of pain tools to support CP patients in adjusting to their condition and improving their quality of life is timely. Although acceptance and commitment therapy (ACT) is considered an evidence-based psychological approach for CP, evidence for the efficacy of online-delivered ACT for CP is still scarce. At the same time, studies suggest that self-compassion mediates the change in disability and psychopathological symptoms in ACT interventions for CP, although self-compassion is not a specific target in ACT. Thus, an explicit focus on self-compassion might increase the efficacy of ACT interventions for CP, although this hypothesis has not been tested. This study aims to develop an eHealth ACT and compassion-based self-management intervention for CP, the iACTwithPain, and to compare its efficacy in improving health outcomes to a similar ACT-only intervention and a medical TAU group.