Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections.

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC50, CC50) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (Cmax)/EC50, were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC50 was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound Cmax/EC50 ≥ 6.8 in Calu-3 or Caco-2 cells. EC50 of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials.

Precision or Pitfall? Evaluating the Accuracy of ICD-10 Coding for Cemented Total Hip Arthroplasty: A Multicenter Study.

BACKGROUND: The International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Procedure Coding System (ICD-10-PCS) was adopted in the U.S. in 2015. Proponents of the ICD-10-PCS have stated that its granularity allows for a more accurate representation of the types of procedures performed by including laterality, joint designation, and more detailed procedural data. However, other researchers have expressed concern that the increased number of codes adds further complexity that leads to inaccurate and inconsistent coding, rendering registry and research data based on ICD-10-PCS codes invalid and inaccurate. We aimed to determine the accuracy of the ICD-10-PCS for identifying cemented fixation in primary total hip arthroplasty (THA). METHODS: We retrospectively reviewed all cemented primary THAs performed at 4 geographically diverse, academic medical centers between October 2015 and October 2020. Cemented fixation was identified from the ICD-10-PCS coding for each procedure. The accuracy of an ICD-10-PCS code relative to the surgical record was determined by postoperative radiograph and chart review, and cross-referencing with institution-level coding published by the American Joint Replacement Registry (AJRR) was also performed. RESULTS: A total of 552 cemented THA cases were identified within the study period, of which 452 (81.9%) were correctly coded as cemented with the ICD-10-PCS. The proportion of cases that were correctly coded was 187 of 260 (72%) at Institution A, 158 of 185 (85%) at Institution B, 35 of 35 (100%) at Institution C, and 72 of 72 (100%) at Institution D. Of the 480 identified cemented THA cases at 3 of the 4 institutions, 403 (84%) were correctly reported as cemented to the AJRR (Institution A, 185 of 260 cases [71%]; Institution B, 185 of 185 [100%]; and Institution C, 33 of 35 [94%]). Lastly, of these 480 identified cemented THA cases, 317 (66%) were both correctly coded with the ICD-10-PCS and correctly reported as cemented to the AJRR. CONCLUSIONS: Our findings revealed existing discrepancies within multiple institutional data sets, which may lead to inaccurate reporting by the AJRR and other registries that rely on ICD-10-PCS coding. Caution should be exercised when utilizing ICD-10 procedural data to evaluate specific details from administrative claims databases as these inaccuracies present inherent challenges to data validity and interpretation.

Retrieval of a Lane Plate 82 Years After Implantation: Case Report, Metallurgical Analysis, and Historical Review.

Background: The Lane plate was one of the first widely used bone plates, utilized in the first decades of the twentieth century. Here we present the results of a retrieval analysis on a Lane plate, and a review of the history of these plates. Our patient underwent plating of her femur with a Lane plate in 1938. She developed a sciatic nerve palsy, managed surgically later that year by Dr. Arthur Steindler at the University of Iowa. Her femur healed, her nerve recovered, and she did well until 2020, at age 94, when she presented to the University of Iowa with a draining sinus that appeared to communicate with the plate. She underwent irrigation and debridement with hardware removal. The plate was sectioned, and its composition and structure characterized. Methods: We retrieved hard copies of the patient's archived medical records from 1938, which document in detail the treatments performed by Dr. Steindler. The plate was analyzed using scanning electron microscopy (SEM) to characterize the surface of the plate. A cross section was taken from the plate, and the composition of the alloy was determined using energy dispersive x-ray spectroscopy (EDS). A review of the literature surrounding early plating techniques was conducted. Results: Our patient recovered from her surgery and soon returned to her baseline state of health. Intraoperative cultures grew C. acnes. Analysis of the surface of the plate demonstrated significant corrosion, and the crystal structure seen on SEM suggested a strong alloy that is prone to corrosion. Analysis of the cross section with EDS demonstrated an alloy containing 94.9% iron, 1.7% aluminum, 1.2% chromium, and 1.1% manganese. Conclusion: The Lane plate was introduced around 1907 by Sir William Arbuthnot Lane, a British surgeon, and was one of the first widely used devices for the plating of fractures. Given that this patient was likely one of the last to be treated with a Lane plate, this may be the final opportunity for such a retrieval analysis. Level of Evidence: IV.

Orthopedic Manifestations of Hereditary Sensory and Autonomic Neuropathy IV in a 10-Year-Old Patient.

Hereditary sensory and autonomic neuropathy type IV (HSAN) is a rare and debilitating disorder highlighted by congenital absence of pain and anhidrosis. Orthopedic sequelae include physeal fractures, Charcot joint development, excessive joint laxity, soft tissue infections and recurrent painless dislocations, all of which often present in a delayed fashion. While there is no accepted guideline on management of these patients, several case studies have highlighted the importance of early diagnosis and cautioned against surgical intervention in these patients due to their inability to perceive pain and comply with post-operative restriction. The purpose of this case report is to present the clinical course of a patient with HSAN IV and the unique orthopedic challenges it presented. While some of her orthopedic injuries healed appropriately following treatment, others have gone on to have devastating complications and progressive joint destruction. Level of Evidence: IV.

Retinal Displacement after Scleral Buckle versus Combined Buckle and Vitrectomy for Rhegmatogenous Retinal Detachment: ALIGN Scleral Buckle versus Pars Plana Vitrectomy with Scleral Buckle.

PURPOSE: To assess the risk of retinal displacement after scleral buckle (SB) versus pars plana vitrectomy with SB (PPV-SB). DESIGN: Multicenter prospective nonrandomized clinical trial. METHODS: The study took place at VitreoRetinal Surgery in Minneapolis, Minnesota, Sankara Nethralaya in Chennai, India, and St. Michael's Hospital in Toronto, Canada from July 2019 to February 2022. Patients who underwent successful SB or PPV-SB for fovea-involving rhegmatogenous retinal detachment with gradable postoperative fundus autofluorescence (FAF) imaging were included in the final analysis. Two masked graders assessed FAF images 3 months postoperatively. Metamorphopsia and aniseikonia were assessed with M-CHARTs and the New Aniseikonia Test, respectively. The primary outcome was the proportion of patients with retinal displacement detected with retinal vessel printings on FAF in SB versus PPV-SB. RESULTS: Ninety-one eyes were included in this study, of which 46.2% (42 of 91) had SB and 53.8% (49 of 91) underwent PPV-SB. Three months postoperatively, 16.7% (7 of 42) in the SB group and 38.8% (19 of 49) in the PPV-SB group had evidence of retinal displacement (difference = 22.1%; odds ratio = 3.2; 95% confidence interval [CI], 1.2-8.6; P = 0.02) on FAF. The statistical significance of this association increased after adjustment for extent of retinal detachment, baseline logarithm of the minimum angle of resolution, lens status, and sex in a multivariate regression analysis (P = 0.01). Retinal displacement was detected in 22.5% (6 of 27) of patients in the SB group with external subretinal fluid drainage and 6.7% (1 of 15) of patients without external drainage (difference = 15.8%; odds ratio = 4.0; 95% CI, 0.4-36.9; P = 0.19). Mean vertical metamorphopsia, horizontal metamorphopsia (MH), and aniseikonia were similar between patients in the SB and PPV-SB groups. There was a trend to worse MH in patients with retinal displacement versus those without retinal displacement (P = 0.067). CONCLUSIONS: Scleral buckle is associated with less retinal displacement compared with PPV-SB, indicating that traditional PPV techniques cause retinal displacement. There is a trend toward increased risk of retinal displacement in SB eyes that underwent external drainage compared with SB eyes without drainage, which is consistent with our understanding that the iatrogenic movement of subretinal fluid, such as that which occurs intraoperatively during external drainage with SB, may induce retinal stretch and displacement if the retina is then fixed in the stretched position. There was a trend to worse MH at 3 months in patients with retinal displacement. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Primary ocular toxoplasmosis secondary to venison consumption.

Purpose: To describe primary ocular toxoplasmosis infection related to ingestion of undercooked venison. Observations: This single site, retrospective case series reviewed 4 patients with primary ocular toxoplasmosis that was acquired by ingesting undercooked venison. De-identified data was collected regarding baseline patient characteristics including age, sex, past medical and ocular history, onset of symptoms, visual acuity (VA), response to treatment, and workup. All patients with acquired toxoplasmosis had similar chronology of systemic and ocular symptoms. Exposure occurred in October or November and systemic symptoms developed within 2 weeks, followed by ocular symptoms an average of 2.6 months later. Average age at onset was 56 ± 13 (age ± SD) years old and all were male. Average initial and final VA were 20/50 and 20/50, respectively. Positive anti-toxoplasma IgM and IgG serologies were found in all cases. All patients were treated with trimethoprim/sulfamethoxazole and achieved rapid improvement. Complications occurred in 50% of cases and included epiretinal membrane, cystoid macular edema, vitreoretinal traction, and neovascularization. Conclusions and importance: Consumption of undercooked venison is a source of primary ocular toxoplasmosis even in immunocompetent hosts and has a clear chronology. A presentation of retinochoroiditis during the winter months should prompt questioning for exposure to wild game.

Discovery of a 2'-Fluoro,2'-Bromouridine Phosphoramidate Prodrug Exhibiting Anti-Yellow Fever Virus Activity in Culture and in Mice.

Yellow fever virus (YFV) is a potentially lethal, zoonotic, blood-borne flavivirus transmitted to humans and non-human primates by mosquitoes. Owing to multiple deadly epidemics, the WHO classifies YFV as a "high impact, high threat disease" with resurgent epidemic potential. At present, there are no approved antiviral therapies to combat YFV infection. Herein we report on 2'-halogen-modified nucleoside analogs as potential anti-YFV agents. Of 11 compounds evaluated, three showed great promise with low toxicity, high intracellular metabolism into the active nucleoside triphosphate form, and sub-micromolar anti-YFV activity. Notably, we investigated a 2'-fluoro,2'-bromouridine phosphate prodrug (C9), a known anti-HCV agent with good stability in human blood and favorable metabolism. Predictive modeling revealed that C9 could readily bind the active site of the YFV RdRp, conferring its anti-YFV activity. C9 displayed potent anti-YFV activity in primary human macrophages, 3D hepatocyte spheroids, and in mice. In an A129 murine model, shortly after infection, C9 significantly reduced YFV replication and protected against YFV-induced liver inflammation and pathology with no adverse effects. Collectively, this work identifies a potent new anti-YFV agent with strong therapeutic promise.

What Is the Impact of Body Mass Index Cutoffs on Total Hip Arthroplasty Complications?

BACKGROUND: Body mass index (BMI) cutoffs are commonly utilized to decide whether to offer obese patients elective total hip arthroplasty (THA). However, weight loss goals may be unachievable for many, and some patients are thereby denied complication-free surgery. The purpose of this study was to assess the impact of varying BMI cutoffs on the rates of complication-free surgery after THA. METHODS: Patients undergoing THA between 2015 and 2018 were identified in the American College of Surgeons National Surgical Quality Improvement Program database using Common Procedural Terminology code 27130. BMI and rates of 30-day complications were collected. BMI cutoffs of 30, 35, 40, 45, and 50 kg/m2 were applied to model the incidence of complications if THA would have been allowed to proceed based on BMI. RESULTS: A total of 192,394 patients underwent THA, and 13,970 (7%) of them had a BMI ≥40 kg/m2. With a BMI cutoff of 40 kg/m2, 178,424 (92.7%) patients would have proceeded with THA. From this set, 170,296 (95.4%) would experience complication-free surgery, and 11.8% of complications would be prevented. THA would proceed for 191,217 (99.3%) patients at a BMI cutoff of 50 kg/m2, of which 182,123 (95.2%) would not experience a complication, and 1.3% of complications would be prevented. Using 35 kg/m2 as the BMI cutoff would prevent 28.6% of complications and permit 75.9% of complication-free surgeries to proceed. CONCLUSION: Lower BMI cutoffs for THA can result in fewer complications although they will consequentially limit access to complication-free THA. Consideration of risks of obesity in THA may be best considered as part of a holistic assessment and shared decision-making when deciding on goals for weight reduction.

Recent Increases in Outpatient Total Hip Arthroplasty Have Not Increased Early Complications.

BACKGROUND: Outpatient total hip arthroplasty (THA) has increased in recent years. Recent regulatory changes may allow and incentivize outpatient THA in more patients; however, there are concerns regarding safety. The purpose of this study is to assess early complications in outpatient THA compared to longer hospitalization. METHODS: We identified patients undergoing primary THA in the National Surgical Quality Improvement Program database between 2015 and 2018. Patients were stratified by length of stay (LOS): 0 days (LOS 0), 1-2 days, and ≥3 days. Thirty-day rates of any complication, wound complications, readmissions, and reoperation were assessed. Multivariate analysis was performed. RESULTS: In total, 4813 (4%) patients underwent outpatient THA, 84,627 (64%) had LOS of 1-2 days, and 42,293 (32%) had LOS ≥3 days. LOS 0 patients were younger, had lower body mass index, and less medical comorbidities compared to those with postsurgical hospitalization. Any complication was experienced in 3.2% of the LOS 0 group, 5.3% of the LOS 1-2 group, and 15.6% for the LOS ≥3 group (P < .0001). Readmission rates were 1.6%, 2.6%, and 4.7% for the 3 groups, respectively (P < .0001). After controlling for confounding variables, patients with LOS 1-2 days had higher odds for any complication (odds ratio 1.56 [1.32-1.83) and readmission (odds ratio 1.41 [1.12-1.78]) compared to LOS 0 days. Patients with LOS ≥3 days had higher odds for complications compared to LOS 0 or 1-2 days. CONCLUSION: Outpatient THA had lower odds for readmission or complications compared to LOS 1-2 days. Despite increased outpatient surgery, many patients had postsurgical hospitalization and, due to patient factors, this remains an integral patient of post-THA care.

Trends in the Clinical Presentation of Primary Rhegmatogenous Retinal Detachments During the First Year of the COVID-19 Pandemic.

PURPOSE: To evaluate the effect of 1 full year of the coronavirus disease 2019 (COVID-19) pandemic on clinical presentation of acute, primary rhegmatogenous retinal detachment (RRD). DESIGN: Single-center, retrospective observational cohort study. METHODS: Patients were divided into 2 cohorts: consecutive patients treated for primary RRD during the COVID-19 pandemic (March 9, 2020, to March 7, 2021; pandemic cohort) and patients treated during the corresponding time in previous year (March 11, 2019, to March 8, 2020; control cohort). MAIN OUTCOME MEASURES: Proportion of patients presenting with macula-involving (mac-off) or macula-sparring (mac-on) RRD. RESULTS: A total of 952 patients in the pandemic cohort and 872 patients in the control cohort were included. Demographic factors were similar. Compared with the control cohort, a significantly greater number of pandemic cohort patients presented with mac-off RRDs ([60.92%] pandemic, [48.17%] control, P = .0001) and primary proliferative vitreoretinopathy ([15.53%] pandemic, [6.9%] control, P = .0001). Pandemic cohort patients (10.81%) had significantly higher rates of lost to follow-up compared with the control cohort (4.43%; P = .0001). Patients new to our clinic demonstrated a significant increase in mac-off RRDs in the pandemic cohort (65.35%) compared with the control cohort (50.40%; P = .0001). Pandemic cohort patients showed worse median final best-corrected visual acuity (0.30 logarithm of the minimum angle of resolution) compared with the control cohort (0.18 logarithm of the minimum angle of resolution; P = .0001). CONCLUSIONS: Patients with primary RRD during the first year of the COVID-19 pandemic were more likely to have mac-off disease, present with primary proliferative vitreoretinopathy, be lost to follow-up, and have worse final best-corrected visual acuity outcomes.

Comparison of anti-SARS-CoV-2 activity and intracellular metabolism of remdesivir and its parent nucleoside.

Remdesivir, a monophosphate prodrug of nucleoside analog GS-441524, is widely used for the treatment of moderate to severe COVID-19. It has been suggested to use GS-441524 instead of remdesivir in the clinic and in new inhalation formulations. Thus, we compared the anti-SARS-CoV-2 activity of remdesivir and GS-441524 in Vero E6, Vero CCL-81, Calu-3, Caco-2 â€‹cells, and anti-HCoV-OC43 activity in Huh-7 â€‹cells. We also compared the cellular pharmacology of these two compounds in Vero E6, Vero CCL-81, Calu-3, Caco-2, Huh-7, 293T, BHK-21, 3T3 and human airway epithelial (HAE) cells. Overall, remdesivir exhibited greater potency and superior intracellular metabolism than GS-441524 except in Vero E6 and Vero CCL-81 â€‹cells.

In Situ Straightening of a Bent Tibiofemoral Intramedullary Nail: Case Report and Review of the Literature.

Background: Intramedullary nailing is considered the gold standard for the surgical management of diaphyseal long bone fractures of the lower extremity. A rare complication following intramedullary nailing of a femur or tibia fracture is periprosthetic fracture following secondary trauma with deformation of the nail itself. We present a case of a 51-year-old male with a long history of prior left knee arthrodesis with a tibiofemoral nail who sustained a work injury resulting in a proximal tibia fracture and bent tibiofemoral nail. Clinically, he presented with significant varus and procurvatum limb deformity and a six-centimeter limb length discrepancy. The patient was successfully managed with in situ straightening of the tibiofemoral nail under a general anesthetic with return to work three months following manipulation. Level of Evidence: IV.

Pharmacokinetics of Ruxolitinib in HIV Suppressed Individuals on Antiretroviral Agent Therapy from the ACTG A5336 Study.

Ruxolitinib is a US Food and Drug Administration-approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P < .0001) in those administered efavirenz. There was  an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor-based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.

Teaching Smartphone Funduscopy with 20 Diopter Lens in Undergraduate Medical Education.

PURPOSE: To assess attitudes of pre-clinical undergraduate medical students toward learning smartphone funduscopy (SF) and its appropriateness as a teaching tool. PATIENTS AND METHODS: Second year medical students received instruction on direct ophthalmoscopy (DO) and SF; they were then paired with a peer and randomly assigned to perform DO or SF first. The SF technique involved freehand alignment of the axes of the smartphone camera with a condenser lens. Both techniques were done through a maximally dilated pupil. A questionnaire was completed to acquire data on baseline experience, performance of both examination techniques, attitudes, and appropriateness. Statistical significance testing and Bland-Altman analysis were used to determine differences between DO and SF, and a multivariable mixed regression model was fitted to identify any predictors for positive attitudes toward DO or SF. RESULTS: One hundred thirty-seven (137) individuals completed the study. A similar proportion of students could identify the optic nerve, macula, and vessels using DO and SF. However, self-reported quality scores were higher for DO for the optic nerve (p = 0.006) and macula (p = 0.08). The mean (standard deviation) attempts to identify these major structures were 2.7 (SD 2.3) for DO and 4.5 (SD 2.9) for SF (p < 0.001). Attitudes of students were consistently more positive toward DO across the five questions assessed. A small subset of students had equally positive attitudes toward DO and SF. Improved quality scores were predictive of positive attitudes for both DO and SF. Ultimately, 24% of students preferred SF over DO. CONCLUSION: Among inexperienced examiners of the fundus through a dilated pupil, SF is a non-inferior technique to DO in identifying structures. Despite overall favorable attitudes towards the more familiar DO, those students who quickly learned the SF technique had similar satisfaction scores. Teaching SF should be considered in undergraduate medical education.

Dental Screening in Elective Total Joint Arthroplasty: Risk Factors for Failure.

BACKGROUND: Active dental infection at the time of total joint arthroplasty (TJA) or in the acute postoperative period following TJA is thought to increase the risk of periprosthetic joint infection (PJI). Many surgeons recommend preoperative dental screening. This study aimed to identify how many elective TJA patients failed preoperative dental screening and what patient risk factors were associated with failure. METHODS: A consecutive series of elective, primary TJA was reviewed from 8/1/2016 to 8/1/2017. We studied 511 operations in 511 patients. All patients were referred for preoperative dental screening per protocol. Dental screening failure was defined as required dental intervention by the dentist. Screening failure rate was calculated for and logistic regression was used to evaluate the relationship between odds of screening failure and patient demographic data. RESULTS: In 94 of the 511 total cases (18.5%), patients failed dental screening and required dental procedures prior to TJA. Reasons for failure included tooth extractions, root canals, abscess drainage, and carious lesions requiring filling. Patient characteristics associated with failed dental screening included male gender (odds ratio 1.56, 95% confidence interval 1.0006-2.468, P = .047) and current smoker (odds ratio 3.6, 95% confidence interval 1.650-7.927, P = .001). CONCLUSION: Universal dental screening prior to primary TJA resulted in 18.5% of patients needing an invasive dental intervention. Universal dental screening results in extra cost and time for patients and providers. Although male gender and active smoking were associated with increased odds of requiring an invasive dental procedure, more work is needed to develop targeted screening to improve perioperative workflow and limit unnecessary dental evaluations for patients.

Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator.

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3-3 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC90 corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.

Novel method to quantify phenotypic markers of HIV-associated neurocognitive disorder in a murine SCID model.

Despite combined antiretroviral therapy (cART), HIV infection in the CNS persists with reported increases in activation of macrophages (MΦ), microglia, and surrounding astrocytes/neurons, conferring HIV-induced inflammation. Chronic inflammation results in HIV-associated neurocognitive disorders (HAND) with reported occurrence of up to half of individuals with HIV infection. The existing HAND mouse model used by laboratories including ours, and the effect of novel agents on its pathology present with labor-intensive and time-consuming limitations since brain sections and immunohistochemistry assays have to be performed and analyzed. A novel flow cytometry-based system to objectively quantify phenotypic effects of HIV using a SCID mouse HAND model was developed which demonstrated that the HIV-infected mice had significant increases in astrogliosis, loss of neuronal dendritic marker, activation of murine microglia, and human macrophage explants compared to uninfected control mice. HIV p24 could also be quantified in the brains of the infected mice. Correlation of these impairments with HIV-induced brain inflammation and previous behavioral abnormalities studies in mice suggests that this model can be used as a fast and relevant throughput methodology to quantify preclinical testing of novel treatments for HAND.

Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses.

Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world's population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2'-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.

Might Doctors Really "Know Best"?: Utilizing Surgeon Intuition to Strengthen Preoperative Surgical Risk Assessment.

Background: Many clinical factors are known to increase an individual patient's risk of perioperative complications and hospital readmission. Several novel risk calculators have been created to predict the risk of postoperative complications for specific procedures that rely entirely on objective measurements. Our goal was to determine if surgeon intuition (an estimate of the percent likelihood of minor and major medical and surgical complications and 30-day readmission) could provide an additional source of data in the preoperative setting that may enhance the prediction of complications after surgery. Methods: We targeted the operative practices of three subspecialized orthopedic surgeons over a 6-month period (February 1 to July 31, 2015). We administered surveys to attending surgeons and assisting residents or nurse practitioners prior to each operation. Surgeons were asked to predict each patient's likelihood, on a scale from <1-100, for experiencing a complication. Following the procedure, we analyzed each patient's electronic medical record to determine any adverse events and readmissions. We then looked at levels of association between predictor variables and complications. Analysis of maximum likelihood estimates for complication outcome was performed comparing objective variables and surgeon prediction. Results: A total of 417 surveys in 270 patients were available for analysis. Defining the predicted likelihood of minor medical complications as <10% (low), 10-40% (intermediate), and >40% (high), provided discrimination of postoperative complications for a single observer in the first three month. These cutoff ranges showed inter-observer consistency and a trend towards intra-observer consistency. The only three variables predictive of minor medical complications were ASA class (OR=3.63, 95%CI=1.76-7.52, p=0.0005; comparing >2 vs ≤2), age (ß=0.034±0.012, p=0.0032) and surgeon prediction when comparing high to low risk (ß=0.034±0.008 (0.018-0.049), p<0.0001). Conclusions: Quantitative surgeon preoperative risk assessment was able to accurately discriminate between low- and high-risk groups of minor medical complications. We did not find a similar association between major complications and readmissions.Level of Evidence: IV.

Mobile Health Intervention to Reduce HIV Transmission: A Randomized Trial of Behaviorally Enhanced HIV Treatment as Prevention (B-TasP).

OBJECTIVES: We conducted a randomized clinical trial to test a mobile health behavioral intervention designed to enhance HIV treatment as prevention (B-TasP) by simultaneously increasing combination antiretroviral therapies (cART) adherence and improving the sexual health of people living with HIV. METHODS: A cohort of sexually active men (n = 383) and women (n = 117) living with HIV were enrolled. Participants were baseline assessed and randomized to either (1) B-TasP adherence and sexual health intervention or (2) general health control intervention. Outcome measures included HIV RNA viral load, cART adherence monitored by unannounced pill counts, indicators of genital tract inflammation, and sexual behaviors assessed over 12 months. RESULTS: Eighty-six percent of the cohort was retained for 12-month follow-up. The B-TasP intervention demonstrated significantly lower HIV RNA, OR = 0.56, P = 0.01, greater cART adherence, Wald χ = 33.9, P = 0.01, and fewer indicators of genital tract inflammation, Wald χ = 9.36, P = 0.05, over the follow-up period. Changes in sexual behavior varied, with the B-TasP intervention showing lower rates of substance use in sexual contexts, but higher rates of condomless sex with non-HIV positive partners occurred in the context of significantly greater beliefs that cART reduces HIV transmission. CONCLUSIONS: Theory-based mobile health behavioral interventions can simultaneously improve cART adherence and sexual health in people living with HIV. Programs aimed to eliminate HIV transmission by reducing HIV infectiousness should be bundled with behavioral interventions to maximize their impact and increase their chances of success.