Altered outer hair cell mitochondrial and subsurface cisternae connectomics are candidate mechanisms for hearing loss in mice

Organelle crosstalk is vital for cellular functions. The propinquity of mitochondria, ER, and plasma membrane promote regulation of multiple functions, which include intracellular C

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Risk factors for discontinuation of intravenous patient-controlled analgesia after general surgery: a retrospective cohort study

Abstract Identifying patients at risk for developing side effects secondary to intravenous patient-controlled analgesia (IV PCA) and making the necessary adjustments in pain management are crucial. We investigated the risk factors of discontinuing IV PCA due to side effects following general surgery; adult patients who received IV PCA after general surgery (2020–2022) were included. Data on postoperative pain intensity, PCA pain relief, side effects, continuity of PCA use, and PCA pump settings were collected from the records of the acute pain management team. The primary outcome was identifying the risk factors associated with PCA discontinuation due to side effects. Of the 8745 patients included, 94.95% used opioid-containing PCA, and 5.05% used non-steroidal anti-inflammatory drug (NSAID)-only PCA; 600 patients discontinued PCA due to side effects. Female sex (adjusted odds ratio [aOR] 3.31, 95% confidence interval [CI] 2.74–4.01), hepato-pancreatic-biliary surgery (aOR 1.43, 95% CI 1.06–1.94) and background infusion of PCA (aOR 1.42, 95% CI 1.04, 1.94) were associated with an increased likelihood of PCA discontinuation. Preoperative opioid use (aOR 0.49, 95% CI 0.28–0.85) was linked with a decreased likelihood of PCA discontinuation. These findings highlight the importance of individualized pain management, considering patient characteristics and surgical procedures

Association of Immediate Postoperative Temperature in the Surgical Intensive Care Unit with 1-Year Mortality: Retrospective Analysis Using Digital Axillary Thermometers

Background Postoperative body temperature is closely associated with prognosis although there is limited research regarding this association at Postoperative intensive care unit (ICU) admission. Furthermore, no studies have used digital axillary thermometers to measure Postoperative body temperature. This study investigated the association between mortality and Postoperative temperature measured using a digital axillary thermometer within 10 minutes after ICU admission. Methods This retrospective observational study evaluated data from adult patients admitted to an ICU after elective or emergency surgery. The primary outcome was 1-year mortality after ICU admission. Multivariable logistic regression analysis with restricted cubic splines was used to evaluate the association between temperature and outcomes. Results We evaluated data from 5,868 patients admitted between January 1, 2013 and May 31, 2016, including 5,311 patients (90.5%) who underwent noncardiovascular surgery and 557 patients (9.5%) who underwent cardiovascular surgery. Deviation from the median temperature (36.6℃) was associated with increases in 1-year mortality (≤ 36.6℃: linear coefficient, –0.531; P<0.001 and ≥36.6℃: spline coefficient, 0.756; P<0.001). Similar statistically significant results were observed in the noncardiovascular surgery group, but not in the cardiovascular surgery group. Conclusions An increase or decrease in body temperature (vs. 36.6℃) measured using digital axillary thermometers within 10 minutes of Postoperative ICU admission was associated with increased 1-year mortality. However, no significant association was observed after cardiovascular surgery. These results suggest that Postoperative temperature is associated with longterm mortality in patients admitted to the surgical ICU in the Postoperative period

The Extract of Herbal Medicines Activates AMP-Activated Protein Kinase in Diet-Induced Obese Rats

Our study investigated whether the extract of six herbal medicines (OB-1) has an inhibitory effect on obesity. High-fat diet-(HFD-) induced rats and controls were treated with 40 mg/100 g body weight of OB-1 or saline once a day for 5 weeks. After significant changes in body weight were induced, OB-1 and saline were administered to each subgroup of HFD and control groups for additional 5 weeks. No statistically significant decrease of body weight in OB-1-treated rats was found compared to controls. However, OB-1-treated rats were found to be more active in an open-field test and have a reduction in the size of adipocytes compared to controls. We observed no changes in the mRNA expressions of leptin and adiponectin from adipocytes between OB-1- and saline-treated rats with HFD-induced obesity group. However, OB-1 treatments were shown to be inversely correlated with accumulation of lipid droplets in liver tissue, suggesting that OB-1 could inhibit a lipid accumulation by blocking the pathway related to lipid metabolism. Moreover, the phosphorylation of AMP-activated protein kinase (AMPK) was significantly increased in OB-1-treated rats with HFD compared to controls. These results suggest that OB-1 has no direct antiobesity effect and, however, could be a regulator of cellular metabolism

Lead Optimization of a Novel Series of Imidazo[1,2‑<i>a</i>]pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent

A critical unmet clinical need to combat the global tuberculosis epidemic is the development of potent agents capable of reducing the time of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis therapy. In this paper, we report on the optimization of imidazo­[1,2-<i>a</i>]­pyridine amide (IPA) lead compound <b>1</b>, which led to the design and synthesis of Q203 (<b>50</b>). We found that the amide linker with IPA core is very important for activity against Mycobacterium tuberculosis H37Rv. Linearity and lipophilicity of the amine part in the IPA series play a critical role in improving in vitro and in vivo efficacy and pharmacokinetic profile. The optimized IPAs <b>49</b> and <b>50</b> showed not only excellent oral bioavailability (80.2% and 90.7%, respectively) with high exposure of the area under curve (AUC) but also displayed significant colony-forming unit (CFU) reduction (1.52 and 3.13 log₁₀ reduction at 10 mg/kg dosing level, respectively) in mouse lung

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis.

New prophylactic and therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of extensively-drug resistant form of the disease. During the course of a high-content chemical screen, ImidazoPyridine Amides (IPA) were identified as a promising class of anti-tubercular agents. The optimized IPA compound Q203 inhibits the growth of multi- and extensively-drug resistant clinical isolates of M. tuberculosis in the low nanomolar range. Q203 was efficacious in vivo at a dose below 1mg/kg, making this compound one of the most potent discovered up to date. In addition, it shows pharmacokinetic and safety profiles compatible with once daily dosing. A reverse genetic approach identifies the ubiquinol cytochrome C reductase (QcrB, Rv2196) as the target of Q203. Mode of action studies revealed that Q203 inhibits the process of ATP synthesis in both replicating and hypoxic non-replicating M. tuberculosis. Altogether, our data indicates that Q203 is a promising clinical candidate for the treatment of tuberculosis