Development of the McMaster Embalming Scale (MES) to assess embalming solutions for surgical skills training.

Human cadavers used for surgical training are embalmed using various methods to facilitate tissue storage and longevity while preserving the natural characteristics required to achieve high fidelity functional task alignment. However, there are no standardized means to evaluate the suitability of embalming solutions for this purpose. The McMaster Embalming Scale (MES) was developed to assess the extent to which embalming solutions allow tissues to achieve physical and functional correspondence to clinical contexts. The MES follows a five-point Likert scale format and evaluates the effect of embalming solutions on tissue utility in seven domains. This study aims to determine the reliability and validity of the MES by presenting it to users after performing surgical skills on tissues embalmed using various solutions. A pilot study of the MES was conducted using porcine material. Surgical residents of all levels and faculty were recruited via the Surgical Foundations program at McMaster University. Porcine tissue was unembalmed (fresh- frozen) or embalmed using one of seven solutions identified in the literature. Participants were blinded to the embalming method as they completed four surgical skills on the tissue. After each performance, participants evaluated their experience using the MES. Internal consistency was evaluated using Cronbach's alpha. Domain to total correlations and a g-study were also conducted. Formalin-fixed tissue achieved the lowest average scores, while fresh frozen tissue achieved the highest. Tissues preserved using Surgical Reality Fluid (Trinity Fluids, LLC, Harsens Island, MI) achieved the highest scores among embalmed tissues. The Cronbach's alpha scores varied between 0.85 and 0.92, indicating a random sample of new raters would offer similar ratings using the MES. All domains except odor were positively correlated. The g-study indicated that the MES is able to differentiate between embalming solutions, but an individual rater's preference for certain tissue qualities also contributes to the variance in scores captured. This study evaluated the psychometric characteristics of the MES. Future steps to this investigation include validating the MES on human cadavers.

Retrospective Analysis of Retroperitoneal-Abdominal-Pelvic Ganglioneuromas: An International Study by the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

OBJECTIVE: The Transatlantic Australasian Retroperitoneal Sarcoma Working Group conducted a retrospective study on the disease course and clinical management of ganglioneuromas. BACKGROUND: Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series. METHODS: Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000, and January 1, 2020, were included. We examined demographic, clinicopathologic, and radiologic characteristics, as well as clinical management. RESULTS: Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of patients being female. Symptomatic presentation comprised 40.9% of cases, and tumors were often located in the extra-adrenal retroperitoneum (67.1%). At baseline, the median maximum tumor diameter was 7.2 cm. One hundred sixteen (35.4%) patients underwent active surveillance, whereas 212 (64.6%) patients underwent resection with 74.5% of operative cases achieving an R0/R1 resection. Serial tumor evaluations showed that malignant transformation to neuroblastoma was rare (0.9%, N=3). Tumors undergoing surveillance had a median follow-up of 1.9 years, with 92.2% of ganglioneuromas stable in size. With a median follow-up of 3.0 years for resected tumors, 84.4% of patients were disease free after resections, whereas recurrences were observed in 4 (1.9%) patients. CONCLUSIONS: Most ganglioneuromas have indolent disease courses and rarely transform to neuroblastoma. Thus, active surveillance may be appropriate for benign and asymptomatic tumors particularly when the risks of surgery outweigh the benefits. For symptomatic or growing tumors, resection may be curative.

Factors associated with hypothermia within the first 6 hours of life in infants born at ≥340 weeks' gestation: a multivariable analysis.

BACKGROUND: Lack of appropriate temperature management has been associated with significant adverse outcomes in preterm and low birthweight neonates. There is a lack of similar investigations in the late preterm (340-366) and term (≥370) neonate population. Our aim was to identify key risk factors as well as clinical outcomes associated with hypothermia in this population. METHODS: A retrospective chart review was conducted at the Ottawa Hospital including all eligible infants ≥340 weeks' gestation over a one-month period in November 2020. Infant, maternal, and delivery room variables were collected, including prematurity, maternal temperature, delivery mode, birthweight, and premature rupture of membranes, as well as clinical outcomes such as NICU/SCN admission and length of stay. Regression models were generated, adjusted for covariates, and stepwise regression was performed. RESULTS: Four hundred forty infants were included in the analysis; 26.8% (118/440) were hypothermic within 6 hours of delivery. In the multivariable analysis, prematurity, low 5 minute Apgar score (< 7) or need for resuscitation, maternal hypertension, and absence of premature rupture of membranes > 18 hours or suspected maternal infection were significantly associated with hypothermia within 6 hours of delivery (p < 0.05). Multivariable analysis of clinical outcomes demonstrated a significant association between hypothermia within 6 hours of delivery and NICU/SCN admission (OR = 2.87; 95% CI 1.36, 6.04), need for respiratory support or diagnosis of respiratory distress syndrome (OR = 3.94; 95% CI 1.55, 10.50), and length of stay (exp(ß) = 1.20; 95% bootstrap CI 1.04, 1.37). CONCLUSIONS: Our results suggest there are similar factors associated with hypothermia in our study population of infants born at ≥340 weeks' gestation compared to prior studies in preterm and low-birthweight infants. Furthermore, hypothermia is associated with higher risk of adverse outcomes, which highlights the need to prevent hypothermia in all newborns.

A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice.

Epstein-Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several human cancers and, more recently, multiple sclerosis. Despite its prevalence and health impact, there are currently no vaccines or treatments. Four viral glycoproteins (gp), gp350 and gH/gL/gp42, mediate entry into the major sites of viral replication, B cells, and epithelial cells. Here, we designed a nanoparticle vaccine displaying these proteins and showed that it elicits potent neutralizing antibodies that protect against infection in vivo. We designed single-chain gH/gL and gH/gL/gp42 proteins that were each fused to bacterial ferritin to form a self-assembling nanoparticle. Structural analysis revealed that single-chain gH/gL and gH/gL/gp42 adopted a similar conformation to the wild-type proteins, and the protein spikes were observed by electron microscopy. Single-chain gH/gL or gH/gL/gp42 nanoparticle vaccines were constructed to ensure product homogeneity needed for clinical development. These vaccines elicited neutralizing antibodies in mice, ferrets, and nonhuman primates that inhibited EBV entry into both B cells and epithelial cells. When mixed with a previously reported gp350 nanoparticle vaccine, gp350D123, no immune competition was observed. To confirm its efficacy in vivo, humanized mice were challenged with EBV after passive transfer of IgG from mice vaccinated with control, gH/gL/gp42+gp350D123, or gH/gL+gp350D123 nanoparticles. Although all control animals were infected, only one mouse in each vaccine group that received immune IgG had detectable transient viremia. Furthermore, no EBV lymphomas were detected in immune animals. This bivalent EBV nanoparticle vaccine represents a promising candidate to prevent EBV infection and EBV-related malignancies in humans.

Global Health Security Preparedness and Response: An Analysis of the Relationship between Joint External Evaluation Scores and COVID-19 Response Performance.

OBJECTIVES: The COVID-19 pandemic has highlighted the importance and complexity of a country's ability to effectively respond. The Joint External Evaluation (JEE) assessment was launched in 2016 to assess a country's ability to prevent, detect and respond to public health emergencies. We examined whether JEE indicators could be used to predict a country's COVID-19 response performance to tailor a country's support more effectively. DESIGN: From April to August 2020, we conducted interviews with Centers for Disease Control and Prevention country offices that requested COVID-19 support and previously completed the JEE (version 1.0). We used an assessment tool, the 'Emergency Response Capacity Tool' (ERCT), to assess COVID-19 response performance. We analysed 28 ERCT indicators aligned with eight JEE indicators to assess concordance and discordance using strict agreement and weighted kappa statistics. Generalised estimating equation (GEE) models were used to generate predicted probabilities for ERCT scores using JEE scores as the independent model variable. RESULTS: Twenty-three countries met inclusion criteria. Of the 163 indicators analysed, 42.3% of JEE and ERCT scores were in agreement (p value=0.02). The JEE indicator with the highest agreement (62%) was 'Emergency Operations Center (EOC) operating procedures and plans', while the lowest (16%) was 'capacity to activate emergency operations'. Findings were consistent with weighted kappa statistics. In the GEE model, EOC operating procedures and plans had the highest predicted probability (0.86), while indicators concerning response strategy and coordination had the lowest (≤0.5). CONCLUSIONS: Overall, there was low agreement between JEE scores and COVID-19 response performance, with JEE scores often trending higher. JEE indicators concerning coordination and operations were least predictive of COVID-19 response performance, underscoring the importance of not inferring country response readiness from JEE scores alone. More in-depth country-specific investigations are likely needed to accurately estimate response capacity and tailor countries' global health security activities.

Reality of Accomplishing Surgery within 24 Hours for Complete Cervical Spinal Cord Injury: Clinical Practices and Safety.

Substantial clinical data support an association between superior neurological outcomes and early (within 24 h) surgical decompression for those with traumatic cervical spinal cord injury (SCI). Despite this, much discussion persists around feasibility and safety of this time threshold, particularly for those with a complete cervical SCI. This study aims to assess clinical practices and the safety profile of early surgery across a large sample of North American trauma centers. Data were derived from the Trauma Quality Improvement Program database from 2010-2016. Adult patients with a complete cervical SCI (American Spinal Injury Association [ASIA] A) who underwent surgery were included. Patients were stratified into those receiving surgery at or before 24 h and those receiving delayed intervention. Risk-adjusted variability in surgical timing across trauma centers was investigated using mixed-effects regression. In-hospital adverse events including death, major complications, and immobility-related complications were compared between groups after propensity score matching. There were 2862 patients from 353 North American trauma centers included; 1760 (61.5%) underwent surgery within 24 h. Case-mix and hospital-level characteristics explained only 6% of the variability in surgical timing both between centers and within centers. No significant differences in adverse events were identified between groups. These findings suggest a relatively large proportion of patients are not receiving surgery within the recommended time frame, despite apparent safety. Moreover, patient and hospital-level characteristics explain little of the variability in time-to-surgery. Further knowledge translation is needed to increase the proportion of patients in whom surgery is performed before the 24-h threshold so patients might reach their greatest potential for neurological recovery.

Drug-drug interactions with warfarin: A systematic review and meta-analysis.

AIMS: The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes. METHODS: MEDLINE, EMBASE and the International Pharmaceutical Abstract (IPA) databases were searched from January 2004 to August 2019. We included studies describing drug-drug interactions between warfarin and other drugs. Screening and data extraction were conducted independently and in duplicate. We synthesized pooled odds ratios (OR) with 95% confidence intervals (CIs), comparing warfarin plus another medication to warfarin alone. We assessed the risk of bias at the study level and evaluated the overall certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of 42 013 citations identified, a total of 72 studies reporting on 3 735 775 patients were considered eligible, including 11 randomized clinical trials and 61 observational studies. Increased risk of clinically relevant bleeding when added to warfarin therapy was observed for antiplatelet (AP) regimens (OR = 1.74; 95% CI 1.56-1.94), many antimicrobials (OR = 1.63; 95% CI 1.45-1.83), NSAIDs including COX-2 NSAIDs (OR = 1.83; 95% CI 1.29-2.59), SSRIs (OR = 1.62; 95% CI 1.42-1.85), mirtazapine (OR = 1.75; 95% CI 1.30-2.36), loop diuretics (OR = 1.92; 95% CI 1.29-2.86) among others. We found a protective effect of proton pump inhibitors (PPIs) against warfarin-related gastrointestinal (GI) bleeding (OR = 0.69; 95% CI 0.64-0.73). No significant effect on thromboembolic events or mortality of any drug group used with warfarin was found, including single or dual AP regimens. CONCLUSIONS: This review found low to moderate certainty evidence supporting the interaction between warfarin and a small group of medications, which result in increased bleeding risk. PPIs are associated with reduced hospitalization for upper GI bleeding for patients taking warfarin. Further studies are required to better understand drug-drug interactions leading to thromboembolic outcomes or death.

Cost-related medication nonadherence in Canada: a systematic review of prevalence, predictors, and clinical impact.

BACKGROUND: Cost-related nonadherence to medications (CRNA) is common in many countries and thought to be associated with adverse outcomes. The characteristics of CRNA in Canada, with its patchwork coverage of increasingly expensive medications, are unclear. OBJECTIVES: Our objective in this systematic review was to summarize the literature evaluating CRNA in Canada in three domains: prevalence, predictors, and effect on clinical outcomes. METHODS: We searched MEDLINE, Embase, Google Scholar, and the Cochrane Library from 1992 to December 2019 using search terms covering medication adherence, costs, and Canada. Eligible studies, without restriction on design, had to have original data on at least one of the three domains specifically for Canadian participants. Articles were identified and reviewed in duplicate. Risk of bias was assessed using design-specific tools. RESULTS: Twenty-six studies of varying quality (n = 483,065 Canadians) were eligible for inclusion. Sixteen studies reported on the overall prevalence of CRNA, with population-based estimates ranging from 5.1 to 10.2%. Factors predicting CRNA included high out-of-pocket spending, low income or financial flexibility, lack of drug insurance, younger age, and poorer health. A single randomized trial of free essential medications with free delivery in Ontario improved adherence but did not find any change in clinical outcomes at 1 year. CONCLUSION: CRNA affects many Canadians. The estimated percentage depends on the sampling frame, the main predictors tend to be financial, and its association with clinical outcomes in Canada remains unproven.

Symptom and Quality of Life Improvements After Pelvic Floor Physical Therapy in a Clinical Population of Women With Pelvic Pain and Other Symptoms.

OBJECTIVES: This study aimed to evaluate changes in validated symptom scores at intake and discharge in women undergoing pelvic floor physical therapy (PFPT) for pain and other pelvic floor symptoms. METHODS: Consecutive women starting PFPT during 1 year were reviewed. History, demographics, and Pelvic Floor Distress Inventory Questionnaire - Short Form 20 (PFDI) total and domain scores (Pelvic Organ Prolapse Distress Inventory-6, Urogenital Distress Inventory-6, Colorectal-Anal Distress Inventory-8), Pelvic Floor Impact Questionnaire (PFIQ-7), and pain levels on a numeric rating scale (NRS) were collected at intake and discharge. Data were analyzed with descriptive statistics and sign tests. RESULTS: Of 474 women, mean age was 50.3 ± 16.7 years (range, 18-87 years) and the most common indication for PFPT was pelvic pain (208/474; 43.9%). In women with complete data, pretreatment to posttreatment median scores improved on the PFDI (77.3 vs 41.8; P < 0.0001), Urogenital Distress Inventory (37.5 vs 16.0; P < 0.0001), and PFIQ (58.0 vs 19.0; P < 0.0001), and the minimal clinically important difference was met for the PFDI, PFIQ, and Colorectal-Anal Distress Inventory. Women with primarily pelvic pain (n = 208) achieved significant improvements in PFDI, PFIQ, and NRS scores (P < 0.0001 for all) as well as the minimal clinically important difference for these measures. Pain patients with a history of pelvic surgery (n = 50) also had significant improvements in PFIQ and NRS but not PFDI scores. CONCLUSIONS: Most women referred to PFPT demonstrated symptom improvements as measured by validated instruments.

Placement of mid-urethral mesh slings at the time of vaginal prolapse repair does not affect post-operative sexual function or orgasm.

INTRODUCTION AND HYPOTHESIS: Because of the relationship between the clitoral neurovascular supply and the urethra, the dissection for placement of mid-urethral slings (MUS) may negatively impact orgasmic function. We aimed to analyze the role of MUS in orgasmic and overall sexual function in patients undergoing prolapse surgery. METHODS: A single institution retrospective review was performed on 157 patients undergoing prolapse surgery with and without MUS from 2008 to 2014. Pelvic Organ Prolapse Incontinence Sexual Questionnaires (PISQ-12) scores at baseline, 6, and 12 months post-operatively were compared. The difference in overall mean post-operative PISQ-12 scores at 6 and 12 months in those undergoing POP with or without MUS placement was assessed using Wilcoxon rank tests. RESULTS: Of 157 women who underwent prolapse surgery, 81 (52%) had concomitant MUS. Mean baseline PISQ-12 scores were 32 in both groups (p = 0.98). Post-operative PISQ-12 scores between the two groups did not differ at 6 (p = 0.96) or 12 months (p = 0.65). Within the MUS group, mean overall PISQ-12 scores improved at 6 (p = 0.05) and 12 months (p < 0.01). Mean overall PISQ-12 scores did not improve in patients who did not have slings placed at 6 (p = 0.10) or 12 months (p = 0.15). Orgasm frequency and intensity did not differ between the two groups at 6 (p = 0.39, p = 0.91, respectively) or 12 months (p = 0.11, p = 0.44, respectively). CONCLUSION: MUS at the time of prolapse repair did not affect orgasmic or overall sexual function. PISQ-12 scores improved after prolapse surgery with concomitant MUS placement. Our findings may help counsel patients regarding the risk of MUS placement affecting sexual function.

The clinical rate of antibiotic change following empiric treatment for suspected urinary tract infections.

PURPOSE: To determine the rate of antibiotic change in an outpatient setting following empiric treatment of culture proven UTI and to identify risk factors associated with change. METHODS: Patients with suspected UTI and urine culture were reviewed (January 2016-June 2016). Those with a positive culture were categorized by whether or not they were treated empirically. Empiric treatment was evaluated for associations with clinical-demographic data, symptoms and urinalysis (UA). Antibiotic change was evaluated with clinical-demographic data, urine culture, and resistance patterns. RESULTS: 916 urine cultures (636 patients) were included. 391 (43%) cultures were positive, and 164 (42%) were treated empirically. Clinical-demographic data did not differ between groups. Those treated empirically had more documented UTI symptoms (93 vs 58%, P < 0.001), and UA abnormalities including positive nitrites (51 vs 29%, P < 0.001), 3 + leukocyte esterase (27 vs 19%, P = 0.002) and 3 + blood (13 vs 4%, P = 0.005). Of those treated empirically, 42/164 (26%) required an antibiotic change, and this was associated with immunosuppression (12 vs 2%, P = 0.027) resistance to > 3 antibiotics (33 vs 20%, P = 0.039) and also resistance to fluoroquinolone (50 vs 30%, P = 0.016), monobactam (19 vs 7% P = 0.042) and TMP-SMX (52 vs 19%, P < 0.001). CONCLUSIONS: Almost one-quarter of patients treated empirically required antibiotic change. This was driven largely by bacterial resistance. New technologies allowing rapid bacterial identification and sensitivity may improve patient care.

Strategies to Mitigate Anxiety and Pain in Intrauterine Device Insertion: A Systematic Review.

One barrier to the use of intrauterine devices (IUDs) as a contraceptive method is the experience of anxiety and pain during the insertion procedure. Previous reviews have focused on pharmacological methods used to relieve pain during IUD insertion; however, few similar reviews have examined non-pharmacological methods to relieve pain or strategies to reduce anxiety. The objectives of this study were to identify and categorize strategies for reducing anxiety and pain with respect to IUD insertion and the ways in which anxiety and pain were assessed. In particular, the study aimed to identify non-pharmacological interventions and studies that included anxiety as a research outcome. A literature search was conducted of all English-language studies between inception and the week of July 29, 2018 from the following online databases: Medline, Embase, Cochrane Library, and PubMed. The search revealed 426 studies after removal of duplicates, 35 of which fulfilled the inclusion criteria. A total of 29 studies were identified as assessing pharmacological interventions for the management of pain, and six studies assessed non-pharmacological interventions. Only one study included a measurement of patient anxiety during the procedure as an outcome measure. Research on non-pharmacological interventions for the management of anxiety and pain during IUD insertion is lacking. This review found that evidence for the studied pharmacological interventions is conflicting, and there is very little evidence on understanding the effectiveness of strategies to manage anxiety during the IUD insertion procedure. Further high-quality research on non-pharmacological pain and anxiety management strategies is warranted.

Evaluation of online clinical pharmacology curriculum resources for medical students.

AIMS: To identify and evaluate clinical pharmacology (CP) online curricular (e-Learning) resources that are internationally available for medical students. METHODS: Literature searches of Medline, EMBASE and ERIC databases and an online survey of faculty members of international English language medical schools, were used to identify CP e-Learning resources. Resources that were accessible online in English and aimed to improve the quality of prescribing specific medications were then evaluated using a summary percentage score for comprehensiveness, usability and quality, and for content suitability. RESULTS: Our literature searches and survey of 252 faculty (40.7% response rate) in 219 medical schools identified 22 and 59 resources respectively. After screening and removing duplicates, 8 eligible resources remained for evaluation. Mean total score was 53% (standard deviation = 13). The Australian National Prescribing Curriculum, ranked highest with a score of 77%, based primarily on very good ratings for usability, quality and suitable content. CONCLUSION: Using a novel method and evaluation metric to identify, classify, and rate English language CP e-Learning resources, the National Prescribing Curriculum was the highest ranked open access resource. Future work is required to implement and evaluate its effectiveness on prescribing competence.

Pelvic Floor Distress Inventory Scores Improve After Prolapse Surgery Regardless of Surgical Approach but Not After Observation Alone.

OBJECTIVE: To evaluate the effect of different surgical procedures on Pelvic Floor Distress Inventory (PFDI) scores in women with pelvic organ prolapse. MATERIALS AND METHODS: Women with prolapse were enrolled from 2008 to 2014. Baseline data and outcomes at 1 year were collected including subscales of the PFDI. Patients who had surgery (SGY) within the first year were compared to those who did not (N-SGY). Subanalyses of SGY included vaginal vs abdominal, with or without concurrent hysterectomy (HYST, N-HYST), placement of mesh (MESH, N-MESH), and concurrent posterior repair/perineorrhaphy (POST, N-POST). RESULTS: A total of 233/239 patients underwent surgery in the first year. For SGY vs N-SGY, SGY had significant improvements in PFDI and all subscale scores at 1 year while N-SGY did not. When comparing vaginal to abdominal approach, MESH to N-MESH and HYST to N-HYST, there were no differences between any scores at baseline or 1 year between the groups. However, all within group symptom scores improved from baseline to 1 year (P <.0001 for all). In comparing POST to N-POST, there were no differences between groups at 1 year in PFDI and Urogenital Distress Inventory and Pelvic Organ Prolapse Distress Inventory subscale scores. Colorectal-Anal Distress Inventory scores were significantly higher at baseline for POST (P <.0001) but not at 1 year (P = 0.37). All within group scores statistically significant improved at 1 year. CONCLUSION: Women who underwent surgical repair for prolapse had significantly improved overall PFDI and subscale scores regardless of surgical approach and concurrent procedures.

Recovery of urinary function after robotic-assisted laparoscopic prostatectomy versus radical perineal prostatectomy for early-stage prostate cancer.

INTRODUCTION: Robotic-assisted laparoscopic prostatectomy (RALP) has largely replaced open radical prostatectomy in many centers. Radical perineal prostatectomy (RPP) is another less invasive approach that has not been widely adopted. RPP offers excellent exposure of the urinary sphincter and bladder neck that may provide good urinary function outcomes. We evaluate urinary function after RALP and RPP. METHODS: Retrospective review of a prospective radical prostatectomy database was performed. Urinary modules from the Expanded Prostate Cancer Index Composite-Urinary Function (EPIC-UF) questionnaire were used to determine urinary symptoms at baseline and at 6, 12, 18, and 24 months after surgery. RESULTS: 753 men underwent RALP (n = 623) or RPP (n = 130). Of these, 558 had complete data and were included in our study (RALP: n = 458, RPP: n = 100). A higher number of patients undergoing RALP than RPP had pelvic lymph node dissection (20.2% vs. 0%, p < 0.0001) and cavernosal neurovascular bundle sparing (79.2% vs. 68.4%, p < 0.0001). 558 patients had complete EPIC-UF data. Overall urinary recovery was greater for RALP than RPP at 6 months (p = 0.028). Urinary incontinence and function were also more improved after RALP compared to RPP at 6 months (p = 0.021, p = 0.006). However, no differences in overall, urinary incontinence, or urinary function scores were seen at 12, 18, or 24 months. There was no difference between groups in urinary bother or irritative/obstructive symptoms at any time point. CONCLUSIONS: RALP had more rapid recovery of urinary function at 6 months vs. RPP; at 12-24 months, however, RALP and RPP had similar urinary function recovery in all urinary subdomains.

Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors.

Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor-binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.