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Promising antivirals for PLpro of SARS-CoV-2 using virtual screening, molecular docking, dynamics, and MMPBSA

J Biomol Struct Dyn. 2022 May 5:1-17. doi: 10.1080/07391102.2022.2071340. Online ahead of print.

ABSTRACT

The recent pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) is a viral respiratory disease that has been spread all over the globe. Therefore, it is an urgent requirement to identify and develop drugs for this contagious infection. The papain-like protease (PLpro) of SARS-CoV-2 performs critical functions in virus replication and immune evasion, making it an enticing therapeutic target. SARS-CoV-2 and SARS-CoV PLpro proteases have significant similarities, and an inhibitor discovered for SARS-CoV PLpro is an exciting first step toward therapeutic development. Here, a set of antiviral molecules were screened at the catalytic and S-binding allosteric sites of papain-like protease (PLpro). Molecular docking results suggested that five molecules (44560613, 136277567, S5652, SC75741, and S3833) had good binding affinities at both sites of PLpro. Molecular dynamics analysis like root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and hydrogen bond results showed that identified molecules with PLpro tend to form stable PLpro-inhibitor(s) complexes. Molecular Mechanics/Position-Boltzmann Surface Area (MMPBSA) analysis confirmed that antiviral molecules bound PLpro complex had lower energy (-184.72 ± 7.81 to -215.67 ± 6.73 kJ/mol) complexes. Noticeably, computational approaches revealed promising antivirals candidates for PLpro, which may be further tested by biochemical and cell-based assays to assess their potential for SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

PMID:35510600 | DOI:10.1080/07391102.2022.2071340

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Static postural stability and neuropsychological performance after awakening from REM and NREM sleep in patients with chronic insomnia: a randomized, crossover, overnight polysomnography study

J Clin Sleep Med. 2022 May 5. doi: 10.5664/jcsm.10052. Online ahead of print.

ABSTRACT

STUDY OBJECTIVES: Chronic insomnia disorder (CID) is a common sleep disorder, with a prevalence ranging from 6% to 10% worldwide. Individuals with CID experience more fragmented sleep than healthy controls do. They awaken frequently during the night and have a higher risk of injury from falling. Awakening from different sleep stages may have different effects on postural stability and waking performance. However, limited research has been conducted on this topic.

METHODS: This prospective randomized crossover study was conducted between January 2015 and January 2017. We included 20 adults aged 20-65 years who fulfilled diagnosis criteria for CID. Participants underwent two overnight polysomnography studies with an interval of at least 7 days. They were awakened during either rapid eye movement (REM) sleep or N1/N2 sleep alternatively. We compared measurements of static postural stability, vigilance scores, and neuropsychological tests between REM and N1/N2 sleep awakening.

RESULTS: Polysomnography parameters between the two nights were comparable. Participants who were awakened from REM sleep had worse static postural stability than those with N1/N2 awakening. Compared with N1/N2 awakening, larger mean sway areas of center of pressure (COP; p = 0.0413) and longer COP mean distances (p = 0.0139) were found in REM sleep awakening. There were no statistically significant differences in vigilance scores or neuropsychological tests between the two nights.

CONCLUSIONS: REM sleep awakening was associated with worse static postural stability than was N1/N2 awakening. No statistically significant differences were found in waking performance in alertness or in neuropsychological tests between N1/N2 and REM sleep awakening.

PMID:35510597 | DOI:10.5664/jcsm.10052

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Cardiogenic Shock From Heart Failure Versus Acute Myocardial Infarction: Clinical Characteristics, Hospital Course, and 1-Year Outcomes

Circ Heart Fail. 2022 May 5:101161CIRCHEARTFAILURE121009279. doi: 10.1161/CIRCHEARTFAILURE.121.009279. Online ahead of print.

ABSTRACT

BACKGROUND: Little is known about clinical characteristics, hospital course, and longitudinal outcomes of patients with cardiogenic shock (CS) related to heart failure (HF-CS) compared to acute myocardial infarction (AMI; CS related to AMI [AMI-CS]).

METHODS: We examined in-hospital and 1-year outcomes of 520 (219 AMI-CS, 301 HF-CS) consecutive patients with CS (January 3, 2017-December 31, 2019) in a single-center registry.

RESULTS: Mean age was 61.5±13.5 years, 71% were male, 22% were Black patients, and 63% had chronic kidney disease. The HF-CS cohort was younger (58.5 versus 65.6 years, P<0.001), had fewer cardiac arrests (15.9% versus 35.2%, P<0.001), less vasopressor utilization (61.8% versus 82.2%, P<0.001), higher pulmonary artery pulsatility index (2.14 versus 1.51, P<0.01), lower cardiac power output (0.64 versus 0.77 W, P<0.01) and higher pulmonary capillary wedge pressure (25.4 versus 22.2 mm Hg, P<0.001) than patients with AMI-CS. Patients with HF-CS received less temporary mechanical circulatory support (34.9% versus 76.3% P<0.001) and experienced lower rates of major bleeding (17.3% versus 26.0%, P=0.02) and in-hospital mortality (23.9% versus 39.3%, P<0.001). Postdischarge, 133 AMI-CS and 229 patients with HF-CS experienced similar rates of 30-day readmission (19.5% versus 24.5%, P=0.30) and major adverse cardiac and cerebrovascular events (23.3% versus 28.8%, P=0.45). Patients with HF-CS had lower 1-year mortality (n=123, 42.6%) compared to the patients with AMI-CS (n=110, 52.9%, P=0.03). Cumulative 1-year mortality was also lower in patients with HF-CS (log-rank test, P=0.04).

CONCLUSIONS: Patients with HF-CS were younger, and despite lower cardiac power output and higher pulmonary capillary wedge pressure, less likely to receive vasopressors or temporary mechanical circulatory support. Although patients with HF-CS had lower in-hospital and 1-year mortality, both cohorts experienced similarly high rates of postdischarge major adverse cardiovascular and cerebrovascular events and 30-day readmission, highlighting that both cohorts warrant careful long-term follow-up.

REGISTRATION: URL: https://www.

CLINICALTRIALS: gov; Unique identifier: NCT03378739.

PMID:35510546 | DOI:10.1161/CIRCHEARTFAILURE.121.009279

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Ultrasound-guided versus landmark-guided subacromial corticosteroid injections for rotator cuff related shoulder pain: A systematic review of randomised controlled trials

Musculoskeletal Care. 2022 May 5. doi: 10.1002/msc.1643. Online ahead of print.

ABSTRACT

INTRODUCTION: Rotator cuff related shoulder pain (RCRSP) is the most common presentation of shoulder pain within physiotherapy. Corticosteroid injections (CSI) have become increasingly popular to reduce pain, increase range of motion (ROM) and improve shoulder function. Evidence around the use of ultrasound-guided (USG) versus landmark-guided (LMG) CSIs remains controversial.

OBJECTIVE: The objective of this appraisal was to compare the effectiveness of each approach in the management of RCRSP.

METHODS: Cochrane, PubMed and CINAHL electronic databases were searched (from January 2014 to February 2021). Randomised controlled trials (RCTs) were included comparing USG to LMG CSIs for RCRSP. An independent reviewer selected the studies, extracted and synthesised the data. Two reviewers carried out a quality appraisal. Outcome measures were pain, function and ROM.

RESULTS: Four RCTs (n = 179 participants, n = 184 shoulders) were reviewed. Both USG and LMG groups showed statistically significant within group improvements in clinical outcomes. There were no significant differences between groups. Three studies were identified as being a ‘low’ risk of bias (RoB) and did not favour the use of ultrasound. One study did favour the use of ultrasound for improving function, although it was found to have ‘high’ RoB. Adverse events were seldom reported.

CONCLUSION: There is limited evidence to suggest using USG CSIs has a superior effect on clinical outcomes compared to LMG, though small sample sizes and lack of long-term follow-up limit the generalisability of the findings.

PMID:35510534 | DOI:10.1002/msc.1643

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The study of clinicopathologic features of cervical squamous carcinoma with invasive micropapillary like pattern and phenotype

Histol Histopathol. 2022 May 5:18464. doi: 10.14670/HH-18-464. Online ahead of print.

ABSTRACT

Invasive micropapillary carcinoma has been reported in the adenocarcinoma of many organs including cervix, and many studies have proved it has more invasive biological behavior. This study, for the first time, reports cervical squamous carcinoma with invasive micropapillary like pattern and phenotype (IMLPP) and further investigates its clinicopathologic features. Cervical squamous carcinoma with IMLPP was selected by histological characteristics and immunohistochemical staining. All patients’ clinical information and pathological parameters were collected. Based on histological characteristics and immunohistochemical staining results, 24 cases, out of 104 cases of cervical squamous carcinoma, were identified as having invasive micropapillary like pattern. The staining of all 24 cases with EMA and MUC-1 showed the feature of “reverse polarity like”. Meanwhile, patient age at diagnosis (P=0.011), maximum invasion depth (P=0.001), maximum diameter (P=0.015), lymphvascular space invasion (P&#60;0.001), pelvic lymph node metastasis (P&#60;0.001), metastasis (P=0.020), death (P=0.025) and FIGO stages (P=0.001) were related to the existence of IMLPP, independently of the proportion of IMLPP to the whole tumor in size. Univariate and multivariate disease-free survival analyses (follow-up time &#62;12 months) showed significant statistical difference between cervical squamous carcinoma with or without IMLPP (P=0.016, P=0.043). Results from our study suggested that IMLPP may be associated with aggressive biological behavior in cervical squamous carcinoma. Therefore, pathologists should pay attention to the existence of it, no matter its proportion with relation to the whole tumor, and bring it to the attention of clinicians.

PMID:35510512 | DOI:10.14670/HH-18-464

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Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis

Int Wound J. 2022 May 5. doi: 10.1111/iwj.13830. Online ahead of print.

ABSTRACT

To evaluate the efficacy and safety of topical oxygen therapy (TOT) in diabetic foot ulcers (DFUs), researchers systematically retrieved relevant studies from PubMed, EMBASE, Web of Science, CENTRAL and ClinicalTrials.gov. Relevant studies were searched from database inception to January 2022. Two researchers independently screened the literature, extracted data and assessed the quality of the included studies. Statistical analysis was performed in Stata 16.0. A total of seven RCTs involving 614 participants were included. Compared with the control group, the TOT group had a higher healing rate (RR = 1.63, 95% CI [1.33, 2.00]). According to descriptive analysis, TOT reduced the ulcer area and improved healing durability and quality of life. Furthermore, it had no effect on the occurrence of adverse events. However, it was unclear whether it would be able to reduce the healing time. The existing evidence suggests that TOT is effective and safe for chronic DFUs. Further studies are warranted to validate our findings.

PMID:35510518 | DOI:10.1111/iwj.13830

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Residents’ Perspective on Need for Point-of-Care Ultrasound Education During Pediatric Residency

Hosp Pediatr. 2022 May 5:e2021006444. doi: 10.1542/hpeds.2021-006444. Online ahead of print.

ABSTRACT

OBJECTIVES: Many medical disciplines incorporate point-of-care ultrasound (POCUS) into their practice. Despite well-defined applications, POCUS has not been widely adopted in pediatrics and is not commonly taught during residency. Our objective was to profile the current state of POCUS education in pediatric residency training from the resident perspective.

METHODS: We surveyed pediatric trainees about their POCUS education, general opinions about POCUS, and perceived barriers to POCUS training in residency. We distributed the survey to a random sample of Ohio pediatric residents, stratified by program size and training level. Descriptive statistics were used to characterize responses.

RESULTS: We sampled 66.4% of the population (371 of 559) of Ohio pediatric residents and achieved a response rate of 59.3%. Only 15% of respondents received POCUS training during residency, with 85% having never performed a POCUS scan. Most (86%) desired POCUS education and 67% believed it should be required during residency. Residents felt that POCUS would be useful for procedural guidance (95%), clinical diagnosis (94%), and patient safety (74%). Most residents (61%) believed POCUS education would benefit their careers, particularly those planning on subspecialization. Barriers to POCUS education included lack of an established curriculum (75%), competing educational priorities (58%), and a shortage of qualified instructors (52%).

CONCLUSIONS: Although Ohio pediatric residents do not receive formal POCUS education in residency, they desire such training and believe it would benefit their future practice. Consensus on scope of practice, development of a standardized curriculum, and increased faculty training in POCUS may help address this educational gap.

PMID:35510494 | DOI:10.1542/hpeds.2021-006444

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Effects of mastoid and middle-ear volume on graft success and hearing outcomes in paediatric tympanoplasty

J Laryngol Otol. 2022 May;136(5):404-409. doi: 10.1017/S0022215121004400. Epub 2022 Jan 7.

ABSTRACT

OBJECTIVE: To examine the effects of mastoid and middle-ear volume on the anatomical and functional success of type 1 tympanoplasty in paediatric patients.

METHODS: This study included 45 paediatric patients who underwent type 1 cartilage tympanoplasty. Patients’ demographic data, pre- and post-operative audiological evaluation results, and post-operative graft status were evaluated. Middle-ear and mastoid cavity volumes were calculated (in cubic centimetres) using temporal bone high-resolution computed tomography. Middle-ear and mastoid cavity volume values were compared between patients with and without post-operative anatomical and functional success.

RESULTS: Anatomical success was achieved in 82.2 per cent of patients (n = 37), and functional success in 68.9 per cent (n = 31). When anatomical success and failure groups were compared, a statistically significant difference was found in mean mastoid volume (p = 0.037), while there was no significant difference in relation to mean middle-ear volume (p = 0.827). The comparison of functional success and failure groups revealed no significant difference in mean mastoid volume (p = 0.492) or middle-ear volume (p = 0.941).

CONCLUSION: The study showed that mastoid pneumatisation volume affects surgical success in paediatric tympanoplasty.

PMID:35510488 | DOI:10.1017/S0022215121004400

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Prevalence, Severity and Burden of Post-Traumatic Stress Disorder in Black Men and Women Across the Adult Life span

J Aging Health. 2022 May 5:8982643221086071. doi: 10.1177/08982643221086071. Online ahead of print.

ABSTRACT

Objectives: To examine post-traumatic stress disorder (PTSD) among Black adults in younger, middle, and older ages. Methods: Using nationally representative data from the National Survey of American Life, we estimated lifetime and 12-month prevalence of PTSD in Black men and women ages 18-34, 35-49, and 50+. We determined PTSD persistence and severity by age group, then associations of PTSD with socio-economic status, chronic stress, and racial discrimination in middle age. Results: The lifetime prevalence of PTSD was higher in Black women/men ages 18-34 (prevalence=14.0%/6.3%) and 35-49 (12.8%/4.6%) versus 50 and older (8.7%/5.1%). Those ages 35-49 were more likely than younger/older Black adults to have severe interference in work, relationships, and activities domains. In middle age, PTSD was associated with unemployment, lower education, poverty, and stress in Black men, and unemployment, divorce, poverty, stress, and discrimination in Black women. Discussion: Black women experience a disproportionate burden of PTSD in middle age.

PMID:35510479 | DOI:10.1177/08982643221086071

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Effect of Direct Transportation to Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT Randomized Clinical Trial

JAMA. 2022 May 5. doi: 10.1001/jama.2022.4404. Online ahead of print.

ABSTRACT

IMPORTANCE: In nonurban areas with limited access to thrombectomy-capable centers, optimal prehospital transport strategies in patients with suspected large-vessel occlusion stroke are unknown.

OBJECTIVE: To determine whether, in nonurban areas, direct transport to a thrombectomy-capable center is beneficial compared with transport to the closest local stroke center.

DESIGN, SETTING, AND PARTICIPANTS: Multicenter, population-based, cluster-randomized trial including 1401 patients with suspected acute large-vessel occlusion stroke attended by emergency medical services in areas where the closest local stroke center was not capable of performing thrombectomy in Catalonia, Spain, between March 2017 and June 2020. The date of final follow-up was September 2020.

INTERVENTIONS: Transportation to a thrombectomy-capable center (n = 688) or the closest local stroke center (n = 713).

MAIN OUTCOMES AND MEASURES: The primary outcome was disability at 90 days based on the modified Rankin Scale (mRS; scores range from 0 [no symptoms] to 6 [death]) in the target population of patients with ischemic stroke. There were 11 secondary outcomes, including rate of intravenous tissue plasminogen activator administration and thrombectomy in the target population and 90-day mortality in the safety population of all randomized patients.

RESULTS: Enrollment was halted for futility following a second interim analysis. The 1401 enrolled patients were included in the safety analysis, of whom 1369 (98%) consented to participate and were included in the as-randomized analysis (56% men; median age, 75 [IQR, 65-83] years; median National Institutes of Health Stroke Scale score, 17 [IQR, 11-21]); 949 (69%) comprised the target ischemic stroke population included in the primary analysis. For the primary outcome in the target population, median mRS score was 3 (IQR, 2-5) vs 3 (IQR, 2-5) (adjusted common odds ratio [OR], 1.03; 95% CI, 0.82-1.29). Of 11 reported secondary outcomes, 8 showed no significant difference. Compared with patients first transported to local stroke centers, patients directly transported to thrombectomy-capable centers had significantly lower odds of receiving intravenous tissue plasminogen activator (in the target population, 229/482 [47.5%] vs 282/467 [60.4%]; OR, 0.59; 95% CI, 0.45-0.76) and significantly higher odds of receiving thrombectomy (in the target population, 235/482 [48.8%] vs 184/467 [39.4%]; OR, 1.46; 95% CI, 1.13-1.89). Mortality at 90 days in the safety population was not significantly different between groups (188/688 [27.3%] vs 194/713 [27.2%]; adjusted hazard ratio, 0.97; 95% CI, 0.79-1.18).

CONCLUSIONS AND RELEVANCE: In nonurban areas in Catalonia, Spain, there was no significant difference in 90-day neurological outcomes between transportation to a local stroke center vs a thrombectomy-capable referral center in patients with suspected large-vessel occlusion stroke. These findings require replication in other settings.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02795962.

PMID:35510397 | DOI:10.1001/jama.2022.4404