YokoCo

Coronavirus disease 2019 (COVID-19) has spread rapidly, giving rise to a pandemic, causing significant morbidity and mortality. In this context, many vaccines have emerged to try to deal with this disease.

To compare demographic and pain characteristics of older (≥ 65) vs younger (< 65) chronic non-cancer pain patients referred to a community pain clinic in the Greater Toronto Area (GTA), Ontario, Canada.

The transmembrane protein TMEM206 was recently identified as the molecular basis of the extracellular proton-activated Cl channel (PAC), which plays an essential role in neuronal death in ischemia-reperfusion. The PAC channel is activated by extracellular acid, but the proton-sensitive mechanism remains unclear, although different acid-sensitive pockets have been suggested based on the cryo-EM structure of the human PAC (hPAC) channel. In the present study, we firstly identified two acidic amino acid residues that removed the pH-dependent activation of the hPAC channel by neutralization all the conservative negative charged residues located in the extracellular domain of the hPAC channel and some positively charged residues at the hotspot combined with two-electrode voltage-clamp (TEVC) recording in the oocytes system. Double-mutant cycle analysis and double cysteine mutant of these two residues proved that these two residues cooperatively form a proton-sensitive site. In addition, we found that chloral hydrate activates the hPAC channel depending on the normal pH sensitivity of the hPAC channel. Furthermore, the PAC channel knock-out (KO) male mice (C57BL/6J) resist chloral hydrate-induced sedation and hypnosis. Our study provides a molecular basis for understanding the proton-dependent activation mechanism of the hPAC channel and a novel drug target of chloral hydrate.Proton-activated Cl channel (PAC) channels are widely distributed in the nervous system and play a vital pathophysiological role in ischemia and endosomal acidification. The main discovery of this paper is that we identified the proton activation mechanism of the human proton-activated chloride channel (hPAC). Intriguingly, we also found that anesthetic chloral hydrate can activate the hPAC channel in a pH-dependent manner. We found that the chloral hydrate activates the hPAC channel and needs the integrity of the pH-sensitive site. In addition, the PAC channel knock-out (KO) mice are resistant to chloral hydrate-induced anesthesia. The study on PAC channels' pH activation mechanism enables us to better understand PAC's biophysical mechanism and provides a novel target of chloral hydrate.

Immune checkpoint inhibitor (ICI)-induced hypophysitis is an immune-mediated pituitary inflammation that tends to cause long-term pituitary deficiency. Management of ICI-induced hypophysitis includes corticosteroids for acute inflammation and long-term hormone replacement due to irreversible pituitary cell damage. We report a case of recurrent hypophysitis following ICI rechallenge for metastatic melanoma. A 33-year-old woman with recurrent metastatic melanoma with adrenal, pelvic, and inguinal metastases developed recurrent hypophysitis during treatment with ipilimumab and nivolumab which recurred with rechallenge >5 years later. In both cases, headache was the most notable symptom and brain MRI showed pituitary enlargement and edema without evidence of metastases. Central adrenal insufficiency and symptoms caused by mass effect were treated with acute high-dose corticosteroids and long-term replacement corticosteroids. Based on recurrence and failure of symptomatic treatment with continued steroid treatment, ICI was discontinued. This case illustrates that hypophysitis may recur with ICI rechallenge, challenging traditional assumptions that chronic, irreversible irAEs are unlikely to recur or flare. The regenerative potential of pituitary cells after ICI-induced damage or additional damage to previously unaffected cells may be more conceivable than previously realized. Additional research on the potential for recurrent ICI-induced endocrinopathies are needed.

Migraine is a complex, neurobiological disorder usually presenting as a unilateral, moderate to severe headache accompanied by sensory disturbances. Migraine prevalence has risen globally, affecting 14% of individuals and 16% of students and carries many negative impacts in both cohorts. With no recent meta-analysis of global migraine prevalence, or associated factors in students, this systematic review and meta-analysis was conducted.

After studying this article, the participant should be able to: 1. Discuss the natural history and pathophysiology of sarcoma. 2. Summarize the most up-to-date multidisciplinary management of soft-tissue sarcoma. 3. Provide a synopsis of reconstructive modalities based on anatomical location. 4. Highlight some novel strategies for treatment of lymphedema and phantom limb pain that are common sequelae following treatment and resection of soft-tissue sarcomas.

Reducing postoperative incisional infection is the main reason to administer postoperative antimicrobials (AMD) after emergency laparotomy in horses, while reducing inflammation and providing analgesia are the reasons to administer anti-inflammatory drugs (AID). The basis for postoperative AMD and AID administration is empirical and only recently has been questioned. Empirical approaches can be changed, and these changes, along with the description of their outcomes, can help produce appropriate stewardship. The aim of this study is to report the changes in AMD and AID regimens in horses undergoing emergency laparotomy at a referral teaching hospital between 2017 and 2021. Signalment, pathology, surgery, prophylactic AMD and AID administration were obtained from the medical records. Difference in AMD and AID regimens throughout the study period were also reported. In 234 postoperative records considered, ninety-two horses received prophylactic AMD, while 142 received pre-operative antimicrobials only. There was a progressive change in regimens throughout the years, increasing the number of AID molecules used. AMD and AID administration in horses has changed in our practice over the years to modulate therapies according to the postoperative complications that eventually arise. In this study, horses not receiving postoperative routine AMD treatment did not show an increased incidence of complications.

The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is imperfectly understood. Recent studies reported that small-fiber polyneuropathy (SFPN) is common in fibromyalgia, a condition commonly comorbid with IC/BPS.

A systematic review of original research articles was conducted to evaluate the safety and efficacy of lidocaine infusion in the treatment of adult patients with chronic neuropathic pain.

Two decades after reports of the anti-pruritic effects of botulinum neurotoxins (BoNTs), there is still no approved product for the anti-itch indication of BoNTs, and most clinical case reports still focus on the off-label use of BoNTs for various itchy conditions. Few randomized clinical trials have been conducted with controversial results, and the beneficial effects of BoNTs against itch are mainly based on case studies and case series. These studies are valuable in presenting the potential application of BoNTs in chronic pruritic conditions, but due to the nature of these studies, they are categorized as providing lower levels of evidence or lower grades of recommendation. To obtain approval for the anti-pruritic indication of BoNTs, higher levels of evidence are required, which can be achieved through conducting large-scale and well-designed studies with proper control groups and established careful and reliable primary and secondary outcomes. In addition to clinical evidence, presenting the mechanism-based antipruritic action of BoNTs can potentially strengthen, accelerate, and facilitate the current efforts towards further investments in accelerating the field towards the potential approval of BoNTs for itchy conditions. This review, therefore, aimed to provide the state-of-the-art mechanisms underlying the anti-itch effect of BoNTs from basic studies that resemble various clinical conditions with itch as a hallmark. Evidence of the neuronal, glial, and immune modulatory actions of BoNTs in reducing the transmission of itch are presented, and future potential directions are outlined.