A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.     

Minilaparoscopic herniorrhaphy in pediatric inguinal hernia: a durable alternative treatment tostandard herniotomy

Background

The purpose of the article is to report our long-term results of minilaparoscopic inguinal hernia repair in children.

Methods

Between September 2003 and September 2008, 161 children with inguinal hernia were treated with minilaparoscopic herniorrhaphy. The asymptomatic contralateral internal ring was routinely explored and repaired if a patent processus vaginalis of not less than 2 cm was noted. Patients who were followed for less than 1 year and those who were lost to follow-up were excluded from the study. Intraoperative and postoperative complications and hernia recurrences were documented.

Results

In total, 146 patients were eligible for final analysis. A total of 196 minilaparoscopic herniorrhaphies were performed. The mean follow-up period was 3 years. There were 4 hernia recurrences (2%) in 3 boys. There were no procedure-related complications. None of the patients with a negative contralateral exploration or a contralateral patent processus vaginalis of less than 2 cm had a contralateral metachronous inguinal hernia.

Conclusions

Our long-term results reveal that minilaparoscopic herniorrhaphy combined with hernia sac transection is a safe and effective alternative treatment to standard open herniotomy.     

Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts.

Osteogenesis is synergistically enhanced by the combined effect of complimentary factors. This study showed that Nell-1 and BMP-2 synergistically enhanced osteogenic differentiation of myoblasts and phosphorylated the JNK MAPK pathway. The findings are important because of the osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of coordinated BMP-2 and Nell-1 delivery. INTRODUCTION: BMPs play an important role in the migration and proliferation of mesenchymal cells and have a unique ability to alter the differentiation of mesenchymal cells toward chondrogenic and osteogenic lineages. Signaling upstream of Cbfa1/Runx2, BMPs effects are not limited to cells of the osteoblast lineage. Thus, additional osteoblast-specific factors that could synergize with BMP-2 would be advantageous for bone regeneration procedures. NELL-1 (NEL-like molecule-1; NEL [a protein strongly expressed in neural tissue encoding epidermal growth factor like domain]) is a novel growth factor believed to preferentially target cells committed to the osteochondral lineage. MATERIALS AND METHODS: C2C12 myoblasts were transduced with AdLacZ, AdNell-1, AdBMP-2, or AdNell-1+AdBMP-2 overexpression viruses. Effects were studied by cell morphology, alkaline phosphatase activity, osteopontin production, and MAPK signaling. Additionally, in a nude mouse model, viruses were injected into leg muscles, and new bone formation was examined after 2 and 8 wk. RESULTS: C2C12 myoblasts co-transduced with AdNell-1+AdBMP-2 showed a synergistic effect on osteogenic differentiation as detected by alkaline phosphatase activity and osteopontin production. Nell-1 stimulation on AdNell-1 + AdBMP-2 preconditioned C2C12 cells revealed significant activation of the non-BMP-2 associated c-Jun N-terminal kinase (JNK) MAPK signaling pathway, but not the p38 or extracellular signal-regulated kinase (ERK1/2) MAPK pathways. Importantly Nell-1 alone did not induce osteogenic differentiation of myoblasts. In a nude mouse model, injection of AdNell-1 alone stimulated no bone formation within muscle; however, injection of AdNell-1+AdBMP-2 stimulated a synergistic increase in bone formation compared with AdBMP-2 alone. CONCLUSIONS: These findings are important because of the confirmed osteochondral specificity of Nell-1 signaling and the potential therapeutic effects of enhanced BMP-2 action with coordinated Nell-1 delivery.     

The association of pre‐operative STOP‐BANG scores with postoperative critical care admission

The STOP‐BANG questionnaire screens for obstructive sleep apnoea. We retrospectively analysed the independent association of pre‐operative variables with postoperative critical care admission using multivariable logistic regression for patients undergoing elective surgery from January to December 2011. Of 5432 patients, 338 (6.2%) were admitted postoperatively to the critical care unit. In multivariate analysis, the odds ratios (95% CI) for critical care admission were: 2.2 (1.1–4.6), p = 0.037; 3.2 (1.2–8.1), p = 0.017; and 5.1 (1.8–14.9), p = 0.002, for STOP‐BANG scores of 4, 5 and ≥ 6, respectively. The odds ratio was also independently increased for: each year of age, 1.015 (1.004–1.026), p = 0.019; asthma, 1.6 (1.1–2.4), p = 0.016; obstructive sleep apnoea, 3.2 (1.9–5.6), p < 0.001; and for ASA physical status 2, 3 and ≥ 4, 2.1 (1.4–3.3), 6.5 (3.9–11.0), 6.3 (2.9–13.8), respectively, p < 0.001 for all.     

Management of premature ejaculation -- a comparison of treatment outcome in patients with and without erectile dysfunction

This study evaluated the problem of premature ejaculation (PE) in patients treated for erectile dysfunction. The aim was to compare the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the management of primary PE and PE associated with sildenefil treatment. Eighty-seven patients with PE seen over a period of 17 months were recruited into this prospective study. They were categorized into two groups: primary PE (GPI) and PE in sildenefil-treated patients (GPII). All patients recruited into GPII had erectile dysfunction (ED) that was successfully treated with sildenefil citrate for at least a year. Both groups of patients were given sertraline 50 mg 4 h before expected time of sex. The minimum follow-up was 6 months. The ejaculation latency before and after treatment of the two groups were compared. The sexual satisfaction scores of the patients in the two groups were also sought and analysed. Twenty-eight percent of patients with ED who were successfully treated with sildenefil developed PE. Subjects in group GPI were younger and have less comorbid factors than those in group GPII. There was no significant difference in the mean ejaculation latency for both groups (46 vs. 34.6 sec for GPI and GPII, respectively). However, there was highly significant difference in the ejaculation latency between the two groups after treatment with sertraline for 6 months (247.2 vs. 111.6 sec for GPI and GPII, respectively). There was also significant difference in the sexual satisfaction score for group GPI post-treatment, but not for GPII. No significant side-effect of sertraline was reported from patients in both groups. Successful treatment of ED could not assure sexual satisfaction. At least a quarter of sildenefil treated ED patients might develop PE which would continue to frustrate these patients sexually. While selective serotonin re-uptake inhibitors (SSRIs) was effective in the management of primary PE, they were not as effective in patients with sildenefil corrected ED.     

Preoperative Opiate Use Independently Predicts Narcotic Consumption and Complications After Total Joint Arthroplasty

Background

Multimodal pain protocols have reduced opioid requirements and decreased complications after elective total hip arthroplasty (THA) and total knee arthroplasty (TKA). However, these protocols are not universally effective. The purposes of this study are to determine the risk factors associated with increased opioid requirements and the impact of preoperative narcotic use on the length of stay and inhospital complications after THA or TKA.