Rejected

The precipitous and medically contraindicated reduction or "tapering" of opioids for patients with chronic pain due to serious medical conditions has caused needless suffering and, increasingly, suicide. Physicians could be liable for wrongful death based on negligent tapering of opioids.

Chronic inflammatory pain seriously affects patients' quality of life because of a paucity of effective clinical treatments caused, at least in part, by lack of full understanding of the underlying mechanisms. miRNAs are known to be involved in inflammatory pain via silencing or degrading of target mRNA in the cytoplasm. The present study provides a novel mechanism by which miRNA-22 positively regulates metal-regulatory transcription factor 1 () in the nuclei of neurons in the dorsal horn of the spinal cord. We found that miRNA-22 was significantly increased in the dorsal horn of mice with either inflammatory pain induced by plantar injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by unilateral sciatic nerve chronic constrictive injury (CCI). Knocking down or blocking miRNA-22 alleviated CFA-induced mechanical allodynia and heat hyperalgesia, whereas overexpressing miRNA-22 produced pain-like behaviors. Mechanistically, the increased miRNA-22 binds directly to the promoter to recruit RNA polymerase II and elevate expression. The increased subsequently enhances spinal central sensitization, as evidenced by increased expression of p-ERK1/2, GFAP, and c-Fos in the dorsal horn. Our findings suggest that the miRNA-22- signaling axis in the dorsal horn plays a critical role in the induction and maintenance of inflammatory pain. This signaling pathway may be a promising therapeutic target in inflammatory pain.

Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.

Mesenteric ischemia (MI) is a condition characterized by compromised intestinal perfusion, leading to varied patterns of bowel hypoxia that requires prompt diagnosis and surgical intervention. Here, we report a case in which indocyanine green (ICG) was utilized to evaluate intestinal blood flow in a patient with acute-on-chronic MI. A 65-year-old underweight female presented with abdominal pain out of proportion to exam and was found to have diffuse aortic atherosclerotic disease with chronic occlusion of both superior and inferior mesenteric arteries with distal reconstitution. After multidisciplinary evaluation, elective treatment with vascular surgery was planned; however, on day three of her hospitalization, the patient's abdominal pain acutely worsened. She was taken to the OR for exploratory laparotomy. Under white light, the small bowel from the ligament of Treitz (LOT) to the terminal ileum and the large bowel from the cecum to the splenic flexure appeared ischemic with patchy areas of necrosis. Fluorescence angiography was then performed; injection of indocyanine green (ICG) dye and imaging with the SPY-PHI near-infrared camera system demonstrated appropriate blood flow into the bowel mesentery, with complete absence of flow into the bowel mucosal surface from the LOT to the splenic flexure, confirming irreversible bowel necrosis. Introduction of ICG intraoperatively decreased the uncertainty associated with white light assessment of bowel viability, leading to a definitive intraoperative diagnosis and clear plan of care. The use of fluorescence guidance to diagnose fulminant small and large bowel necrosis prevented the surgical team from having to perform multiple takebacks to the operating room in the setting of a nonsurvivable injury. Had the surgical team relied on the white light appearance of the bowel, they would not have been able to diagnose the true extent of bowel demise. The patient was placed on comfort care for this devastating nonsurvivable injury.

Most patients with polio recover from the initial infection, but develop muscle weakness, pain and fatigue after 15-40 years, a condition called post-polio syndrome. Although poliovirus has been almost eliminated, 12-20 million people worldwide still have polio sequelae. The pain is described mainly as nociceptive, but some patients experience neuropathic pain. The aim of this study was to further characterize post-polio pain.

Epidermoids are rare intracranial neoplasms that grow slowly and present in the third to fifth decade of life. Giant epidermoid cysts are infrequent, and their occurrence in the posterior fossa is rare. We describe a similar case, where a patient presented with a long-standing history of headache, imbalance, and progressive weakness in the arms. Imaging revealed a giant space-occupying lesion in the posterior fossa measuring 6.25 cm x 7.56 cm x 6.8 cm, which was confirmed on histopathology to be an epidermoid cyst. The patient underwent suboccipital craniotomy extending up to the rectosigmoid junction to remove the same and was on a follow-up to check for recurrences.

Coffee consumption has been suggested to increase the risk of migraine. However, causality remains inconclusive. In the present study, we performed a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between coffee consumption and migraine. We obtained nine single-nucleotide polymorphisms (SNPs) associated with coffee consumption at genome-wide significance ( < 5 × 10) from a large genome-wide association study (GWAS) based on the UK Biobank study (included 375,833 individuals). Summary-level data for any migraine (AM) and its subtypes (migraine with aura (MA) and migraine without aura (MO)) were obtained from the largest available GWAS of migraine conducted by the International Headache Genetics Consortium (IHGC) (included 59,674 cases and 316,078 controls). MR estimates were pooled using fixed-effect inverse-variance weighted (IVW) as the main method. Sensitivity analyses were further performed using weighted median, MR-Egger, and MR-PRESSO to assess the robustness of our findings. Genetically-predicted 50% increase of coffee consumption was not causally associated with the risk of AM (odds ratio (OR), 0.97; 95% confidence interval (CI), 0.83-1.14; = 0.71), MA (OR, 0.81; 95%CI, 0.58, 1.12; = 0.19), or MO (OR, 0.97; 95%CI, 0.72, 1.30; = 0.83) in the fixed-effect IVW methods. Sensitivity analyses returned similar results. No directional pleiotropy was found. This MR study does not support a causal relationship between genetically predicted coffee consumption and the risk of migraine. Coffee consumption is likely not a trigger nor a prevention strategy for migraine headaches.

is amongst the most common chronic bacterial infection in humans. Pediatric patients appear to differ from their adult counterparts in terms of the prevalence, the complication rate, and the rate of antibiotic resistance. In this report, we present an 18-year-old man without any past medical history who was evaluated after an episode of syncope. Evaluation revealed a case of chronic gastritis leading to gastrointestinal (GI) bleeding and weight loss, and his syncope was the byproduct of symptomatic anemia and physical exertion. Pediatricians should think of peptic ulcer disease (PUD) in evaluating poor weight gain/feeding in younger patients, and abdominal pain in older patients. Early diagnosis can prevent complications such as perforation, bleeding and obstruction. Endoscopy is the gold standard of diagnosis for infection. Noninvasive testing with urease breath test and stool antigen test is reserved for post-treatment testing only. Treatment consists of a 14-day course of a proton-pump inhibitor (PPI) and amoxicillin. A third agent, either clarithromycin or metronidazole, is added depending on regional resistance patterns. Testing for eradication at least 4 weeks later is recommended. This case serves as a reminder to primary care providers to be aware of infection, diagnosis, treatment and complications.

A rat hyperalgesia model was induced using an intraplantar injection of Freund's complete adjuvant (FCA) or an intrathecal injection of IL-6. Mechanical allodynia was evaluated using von Frey filament tests after intrathecal injections of T-5224 (c-Fos/AP-1 inhibitor), minocycline (Mino, a specific microglia inhibitor), L-2-aminoadipic acid (LAA, an astroglial toxin), PKC inhibitor peptide, APTSTAT3-9R (STAT3 inhibitor), or anti-IL-6 antibody. The c-Fos, GFAP, Iba-1, PKC, STAT3, pSTAT3 and pSTAT3, and IL-6 expression at the spinal cord level was assessed by Western blot analysis. The interactive effects of PKC and STAT3 were determined using immunofluorescence staining and immunoprecipitation and . Interleukin-6 promoter activity was examined using luciferase assays.

Multisystem inflammatory syndrome in children (MIS-C) is a rare and serious COVID-19 manifestation characterised by generalised inflammatory response including inflammation of the heart, blood vessels, lungs, kidneys, brain, skin, eyes and gastrointestinal system. Children usually present with fever lasting for 24 hours or more along with other symptoms such as abdominal pain, vomiting, diarrhoea, skin rash, red eyes, and swelling of the lips, tongue, hands and feet. Children with MIS-C usually have negative results for a current infection with COVID-19 but positive antibody results indicating that these children were infected with the COVID-19 virus in the past. We present the case of a 12-month-old girl with multisystem inflammatory syndrome presenting as systemic-onset juvenile idiopathic arthritis (SoJIA) and positive Covid-19 PCR. She was treated successfully with Dexamethasone and Naproxen.