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Objectives: The purpose is to report preliminary data on clinical response to dehydrated cell and protein concentrate (dCPC) versus corticosteroid (CSI). Design: A single-site prospective, randomized controlled single-blinded trial of patients with knee osteoarthritis. Methods: Pain and function were assessed using a visual analog scale (VAS), the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Emory Quality of Life (EQOL) measure at 1, 2, 3, 6, 9 and 12 months. Results: 51 patients were enrolled at the time of analysis (27 dCPC, 24 CSI). Both groups demonstrated improvement on the VAS, KOOS and EQOL. Largest differences were observed at 2 (p = 0.05), 3 (p = 0.012) and 6 months (p < 0.001) with a decrease of 1.66 in VAS at 6 months for dCPC (95% CI: -2.67 to -0.65) and 1.34 (95% CI: -2.37 to -0.3) for CSI. Time-averaged measures showed no difference between groups (p = 0.20). Limited data at 9 and 12 months trended toward improvement in the dCPC group. Conclusion: dCPC products may be used as a treatment for knee osteoarthritis. Larger trials are warranted. Clinical Trial Registration: NCT03710005 (ClinicalTrials.gov)

Background After stroke, increases in contralesional primary motor cortex (M1CL) activity and excitability have been reported. In pre-clinical studies, M1CL reorganization is related to the extent of ipsilesional M1 (M1IL) injury, but this has yet to be tested clinically. Objectives We tested the hypothesis that the extent of damage to the ipsilesional M1 and/or its corticospinal tract (CST) determines the magnitude of M1CL reorganization and its relationship to affected hand function in humans recovering from stroke. Methods Thirty-five participants with a single subacute ischemic stroke affecting M1 or CST and hand paresis underwent MRI scans of the brain to measure lesion volume and CST lesion load. Transcranial magnetic stimulation (TMS) of M1IL was used to determine the presence of an electromyographic response (motor evoked potential (MEP+ and MEP−)). M1CL reorganization was determined by TMS applied to M1CL at increasing intensities. Hand function was quantified with the Jebsen Taylor Hand Function Test. Results The extent of M1CL reorganization was related to greater lesion volume in the MEP− group, but not in the MEP+ group. Greater M1CL reorganization was associated with more impaired hand function in MEP− but not MEP+ participants. Absence of an MEP (MEP−), larger lesion volumes and higher lesion loads in CST, particularly in CST fibers originating in M1 were associated with greater impairment of hand function. Conclusions In the subacute post-stroke period, stroke volume and M1IL output determine the extent of M1CL reorganization and its relationship to affected hand function, consistent with pre-clinical evidence. ClinicalTrials.gov Identifier: NCT02544503

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection in pregnancy is associated with robust maternal immune response and neutralizing potency; however, antibody transfer across the placenta is less than expected., OBJECTIVE: To characterize maternal immune response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and quantify the efficiency of transplacental antibody transfer. METHODS: We conducted a prospective cohort study of pregnant patients who tested positive for SARS CoV-2 infection at any point in pregnancy and collected paired maternal and cord blood samples at the time of delivery. An enzyme-linked immunosorbent assay (ELISA) and neutralization assays were performed to measure maternal plasma and cord blood concentrations and neutralizing potency of immunoglobulin (Ig)G, IgA, and IgM antibodies directed against the SARS-CoV-2 spike protein. Differences in concentrations according to symptomatic compared with asymptomatic infection and time from positive polymerase chain reaction (PCR) test result to delivery were analyzed using nonparametric tests of significance. The ratio of cord to maternal anti–receptor-binding domain IgG titers was analyzed to assess transplacental transfer efficiency. RESULTS: Thirty-two paired samples were analyzed. Detectable anti–receptor-binding domain IgG was detected in 100% (n=32) of maternal and 91% (n=29) of cord blood samples. Functional neutralizing antibody was present in 94% (n=30) of the maternal and 25% (n=8) of cord blood samples. Symptomatic infection was associated with a significant difference in median (interquartile range) maternal anti–receptor-binding domain IgG titers compared with asymptomatic infection (log 3.2 [3.5–2.4] vs log 2.7 [2.9–1.4], P=.03). Median (interquartile range) maternal anti–receptor-binding domain IgG titers were not significantly higher in patients who delivered more than 14 days after a positive PCR test result compared with those who delivered within 14 days (log 3.3 [3.5–2.4] vs log 2.67 [2.8–1.6], P=.05). Median (range) cord/maternal antibody ratio was 0.81 (0.67–0.88). CONCLUSIONS: These results demonstrate robust maternal neutralizing and anti–receptor-binding domain IgG response after SARS-CoV-2 infection, yet a lower-than-expected efficiency of transplacental antibody transfer and a significant reduction in neutralization between maternal blood and cord blood. Maternal infection does confer some degree of neonatal antibody protection, but the robustness and durability of protection require further study.

Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART., Author summary A major obstacle to curing HIV infection is our incomplete understanding of the mechanisms regulating the immunologic reconstitution of CD4 T-cells and the establishment and persistence of the latent HIV reservoir. In particular, we still do not know whether and to what extent the relative distribution of HIV infection within the various CD4 T-cell subsets influences: (i) the magnitude of the CD4 T-cell reconstitution, and (ii) the size of the persistent HIV reservoir after ART. In this study, we found that immunological suboptimal responders (ISR), people with HIV having a suboptimal CD4 T-cell recovery during ART, compared with immunological responders (IR) presented: i) higher levels of HIV-DNA in multiple CD4 T-cell subsets, and ii) higher expression of PD-1 and TIGIT exclusively on CM and TM CD4 T-cells pre-ART, indicating higher HIV reservoir maintenance. Paradoxically, we found increased plasma levels of IL-7 and IL-15 (T-cell homeostatic cytokines) be associated with suboptimal CD4 T-cell recovery during ART, which could be explained by the lack of response to these cytokines in CD4 T-cells from ISR. Altogether, these data identify a greater abundance of immune checkpoint molecules, an increased maintenance of HIV infection in long-lived CD4 T-cell subsets, and a different responsiveness to IL-7 and IL-15 as key features of and a mechanism for suboptimal CD4 T-cell recovery in ART-treated, people with HIV.

This study aimed to determine whether autologous orthobiologic tissue source affects pain and functional outcomes in patients with symptomatic knee osteoarthritis (OA) who received microfragmented adipose tissue (MFAT) or bone marrow aspirate concentrate (BMAC) injection. We retrospectively reviewed prospectively collected data from patients who received BMAC or MFAT injection for symptomatic knee OA. Patients completed baseline and follow-up surveys. Each survey included the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, Emory Quality of Life (EQOL) questionnaire, and Visual Analog Scale (VAS) for pain. The follow-up responses were compared with baseline for all patients and between BMAC and MFAT groups. A total of 110 patients met inclusion criteria, with 76 patients (BMAC 41, MFAT 35) and 106 knees (BMAC 58, MFAT 48) having appropriate follow-up data. The BMAC group included 17 females and 24 males, with a mean age of 59 ± 11 years. The MFAT group included 23 females and 12 males, with a mean age of 63 ± 11 years. Minimum follow-up time was 0.5 years. Mean follow-up time was 1.80 ± 0.88 years for BMAC and 1.09 ± 0.49 years for MFAT. Both groups had significant improvement in EQOL, VAS, and all KOOS parameters preprocedure versus postprocedure (p

BackgroundCortical Spreading Depolarization (SD) is a propagating depolarization wave of neurons and glial cells in the cerebral gray matter. SD occurs in all forms of severe acute brain injury as documented using invasive detection methods. Based on many experimental studies of mechanical brain deformation and concussion, the occurrence of SDs in human concussion has often been hypothesized. However, this hypothesis cannot be confirmed in humans as SDs can only be detected with invasive detection methods that would require either a craniotomy or a burr hole to be performed on athletes. Typical electroencephalography (EEG) electrodes, placed on the scalp, can detect the possible presence of SD but have not been able to accurately and reliably identify SDs.MethodsTo explore the possibility of a non-invasive method to resolve this hurdle, we developed a finite element numerical model that simulates scalp voltage changes that are induced by a brain-surface SD. We then compared our simulation results with retrospectively evaluated data in aneurysmal subarachnoid hemorrhage (aSAH) patients from Drenckhahn et al. (Brain 135:853, 2012).ResultsThe ratio of peak scalp to simulated peak cortical voltage, Vscalp/Vcortex, was 0.0735, whereas the ratio from the retrospectively evaluated data was 0.0316 (0.0221, 0.0527) [median (1st quartile, 3rd quartile), n = 161, p < 0.001, one sample Wilcoxon signed rank test]. These differing values provide validation because their differences can be attributed to differences in shape between concussive- and aSAH-SDs, as well as the inherent limitations in human study voltage measurements. This simulated scalp surface potential was used to design a virtual scalp detection array. Error analysis and visual reconstruction showed that 1 cm is the optimal electrode spacing to visually identify the propagating scalp voltage from a cortical SD. Electrode spacings of 2 cm and above produce distorted images and high errors in the reconstructed image.ConclusionOur analysis suggests that concussive (and other) SDs can be detected from the scalp, which could confirm SD occurrence in human concussion, provide concussion diagnosis based on an underlying physiological mechanism, and lead to non-invasive SD detection in the setting of severe acute brain injury.

Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure HIV infection. In separate studies, we have previously shown that CD8+ T cells may contribute to the maintenance of viral latency and identified a novel SMAC mimetic/IAP inhibitor (AZD5582) capable of reversing HIV/SIV latency in vivo by activating the non-canonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody-mediated depletion of CD8α+ cells to further evaluate the role of CD8+ T cells in viral latency maintenance. Six rhesus macaques (RM) were infected with SIVmac239 and treated with ART starting at week 8 post-infection. After 84-85 weeks of ART, all animals received a single dose of the anti-CD8α depleting antibody (Ab), MT807R1 (50mg/kg, s.c.), followed by 5 weekly doses of AZD5582 (0.1 mg/kg, i.v.). Following CD8α depletion + AZD5582 combined treatment, 100% of RMs experienced on-ART viremia above 60 copies per ml of plasma. In comparator groups of ART-suppressed SIV-infected RMs treated with AZD5582 only or CD8α depletion only, on-ART viremia was experienced by 56% and 57% of the animals respectively. Furthermore, the frequency of increased viremic episodes during the treatment period was greater in the CD8α depletion + AZD5582 group as compared to other groups. Mathematical modeling of virus reactivation suggested that, in addition to viral dynamics during acute infection, CD8α depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-κB signaling pathway with AZD5582 can be enhanced by CD8α+ cell depletion.

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.

Background Across many settings, lack of virologic control remains common in people with HIV (PWH) due to late presentation and lack of retention in care. This contributes to neuronal damage and neurocognitive impairment, which remain prevalent. More evidence is needed to understand these outcomes in both PWH and people without HIV (PWOH). Methods We recruited PWH initiating antiretroviral therapy (ART) as well as PWOH at two sites in the United States. 108 adults were enrolled (56 PWOH and 52 PWH), most of whom had a second assessment at least 24 weeks later (193 total assessments). Tumor necrosis factor alpha (TNFa), monocyte chemotactic protein-1 (MCP-1), neopterin, soluble CD14, and neurofilament light chain protein (NFL) were measured in plasma and cerebrospinal fluid (CSF). Using multivariate models including Bayesian Model Averaging (BMA), we analyzed factors associated with global neuropsychological (NP) performance (NPT-9) and CSF NFL at baseline and over time. Results At baseline, higher CSF MCP-1 and plasma sCD14 were associated with worse NPT-9 in PWH, while CSF HIV RNA decrease was the only marker associated with improved NPT-9 over time. Among PWH, higher CSF neopterin was most closely associated with higher NFL. Among PWOH, higher CSF MCP-1 was most closely associated with higher NFL. Following ART initiation, decrease in CSF MCP-1 was most closely associated with NFL decrease. Conclusion Monocyte-associated CSF biomarkers are highly associated with neuronal damage in both PWH and PWOH. More research is needed to evaluate if therapies targeting monocyte-associated inflammation may ameliorate HIV-associated neurobehavioral diseases.

Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/clowCD16+) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/clowCD16+ natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues., Infection of African green monkeys with SIV is associated with reduced pathogenicity. Here the authors explore the requirement of differentiated NK cell populations in a pathogenic Rhesus macaque model of SIV infection and show administration of IL-21 and IFNα rescues terminally differentiated NK cells, similarly to what found in African green monkeys, and limits the SIV reservoir in antiretroviral therapy treated macaques.

Antiretroviral therapy (ART) cannot eradicate human immunodeficiency virus (HIV) and a rapid rebound of virus replication follows analytical treatment interruption (ATI) in the vast majority of HIV-infected individuals. Sustained control of HIV replication without ART has been documented in a subset of individuals, defined as posttreatment controllers (PTCs). The key determinants of post-ART viral control remain largely unclear. Here, we identified 7 SIV(mac239)-infected rhesus macaques (RMs), defined as PTCs, who started ART 8 weeks postinfection, continued ART for >7 months, and controlled plasma viremia at

Study Design: Narrative review. Objectives: In this review, we address the question of whether the literature supports the notion that minimally invasive transforaminal interbody fusion (MIS-TLIF) improves outcome as compared with open TLIF (open-TLIF). Short and long-term outcomes, fusion rate, and cost-effectiveness were reviewed. Methods: This is a narrative review using various databases. Open-TLIF and MIS-TLIF studies were included and posterior lumbar interbody fusion studies were excluded. A description of paramedian incision in surgical technique was essential to the definition of MIS-TLIF. The present review included 14 prospective observational studies and 6 randomized controlled trials. Results: With short-term outcomes, some studies indicate a better outcome with MIS-TLIF regarding intraoperative bleeding, hospital stay, time to ambulation, postoperative narcotic use, and time to resume work. Both MIS-TLIF and open-TLIF surgeries improved Oswestry Disability Index, back pain, and leg pain. Some studies show that MIS-TLIF resulted in lower back pain than open-TLIF. Radiation exposure was higher with MIS-TLIF. In the longer term, clinical outcomes were improved in both MIS and open TLIF groups. Fusion rates were more than 90% in both MIS-TLIF and open-TLIF. Cost-effectiveness and length of surgery had mixed results. Conclusions: The potential benefits of MIS-TLIF might be present in the early recovery period after surgery. Long-term outcomes were similar with both MIS-TLIF and open-TLIF.

ObjectivesImmune non-responders (INR) have poor CD4 recovery and are associated with increased risk of serious events despite antiretroviral therapy (ART). A clinically relevant definition for INR is lacking.MethodsWe conducted a retrospective analysis of three large cohorts: Infectious Disease Clinic at the Atlanta Veterans Affairs Medical Center, the US Military HIV Natural History Study and Infectious Disease Program of the Grady Health System in Atlanta, Georgia. Two-stage modeling and joint model (JM) approaches were used to evaluate the association between CD4 (or CD4/CD8 ratio) slope within two years since ART initiation and a composite endpoint (AIDS, serious non-AIDS events and death) after two years of ART. We compared the predictive capacity of four CD4 count metrics (estimated CD4 slope, estimated CD4/CD8 ratio slope during two years following ART initiation and CD4 at 1 and 2 years following ART initiation) using Cox regression models.ResultsWe included 2,422 patients. Mean CD4 slope (±standard error) during two years of ART was 102 ± 2 cells/μl/year (95% confidence interval: 98-106 cells/μl/year), this increase was uniform among the three cohorts (p = 0.80). There were 267 composite events after two years on ART. Using the JM approach, a CD4 slope ≥100 cells/μL/year or CD4/CD8 ratio slope >0.1 higher rate per year were associated with lower composite endpoint rates (adjusted hazard ratio [HR] = 0.80, p = 0.04 and HR = 0.75 pConclusionsUsing a complex JM approach, CD4 slope and CD4/CD8 ratio slope the first two years after ART initiation were associated with lower rates of the composite outcome. Moreover, the uniformity observed in the mean CD4 slope regardless of the cohort suggests a common CD4 response pattern independent of age or CD4 nadir. Given the consistency observed with CD4 slope, availability and ease of interpretation, this study provides strong rationale for using CD4 gains

ObjectiveWhile fatigue and pain are pervasive symptoms in SLE, self-efficacy can mitigate their intensity and impact on patients’ daily activity. We examined the relationships of these domains and their interactions with demographics and depression in black women with SLE.MethodsThis is a cross-sectional analysis of data collected among 699 black women with SLE. We used validated, self-reported measures of fatigue, pain interference, symptom self-efficacy, treatment self-efficacy and depression. Linear regression analyses were conducted to examine the relationships between each outcome (fatigue and pain interference) and each predictor (symptom self-efficacy and treatment self-efficacy), and the interaction of demographics and depression.ResultsWe found inverse associations between fatigue and each of symptom self-efficacy (slope −0.556, pConclusionsSymptom self-efficacy and treatment self-efficacy were inversely related to fatigue and pain interference in black women with SLE. Depression disproportionately increased the intensity of these outcomes. While older women with low symptom self-efficacy reported disproportionately higher pain interference, those with higher education and mean or high levels of symptom self-efficacy reported lower pain interference. These findings may help predict who might benefit most from self-efficacy-enhancing interventions.

Key Points Question Is the sex or age of a blood donor associated with morbidity or mortality in very low-birth-weight infants receiving blood transfusion? Findings In this cohort study of 181 very low-birth-weight infants at 3 centers, infants receiving red blood cell transfusion from female donors had a lower risk of death or serious morbidity compared with those who received transfusion from male donors. The protective association between female donor and adverse outcomes increased with increasing donor age, but diminished with increasing number of blood transfusions. Meaning These findings suggest that characteristics of blood donors, such as sex and age, may be associated with recipient outcomes in very-low-birth weight infants receiving blood transfusions., This cohort study evaluates the association between blood donor sex and age on mortality or serious morbidity in very low-birth-weight (VLBW) infants receiving blood transfusions., Importance There are conflicting data on the association between blood donor characteristics and outcomes among patients receiving transfusions. Objective To evaluate the association of blood donor sex and age with mortality or serious morbidity in very low-birth-weight (VLBW) infants receiving blood transfusions. Design, Setting, and Participants This is a cohort study using data collected from 3 hospitals in Atlanta, Georgia. VLBW infants (≤1500 g) who received red blood cell (RBC) transfusion from exclusively male or female donors were enrolled from January 2010 to February 2014. Infants received follow-up until 90 days, hospital discharge, transfer to a non–study-affiliated hospital, or death. Data analysis was performed from July 2019 to December 2020. Exposures Donor sex and mean donor age. Main Outcomes and Measures The primary outcome was a composite outcome of death, necrotizing enterocolitis (Bell stage II or higher), retinopathy of prematurity (stage III or higher), or moderate-to-severe bronchopulmonary dysplasia. Modified Poisson regression, with consideration of covariate interactions, was used to estimate the association between donor sex and age with the primary outcome, with adjustment for the total number of transfusions and birth weight. Results In total, 181 infants were evaluated, with a mean (SD) birth weight of 919 (253) g and mean (SD) gestational age of 27.0 (2.2) weeks; 56 infants (31%) received RBC transfusion from exclusively female donors. The mean (SD) donor age was 46.6 (13.7) years. The primary outcome incidence was 21% (12 of 56 infants) among infants receiving RBCs from exclusively female donors, compared with 45% (56 of 125 infants) among those receiving RBCs from exclusively male donors. Significant interactions were detected between female donor and donor age (P for interaction = .005) and between female donor and number of transfusions (P for interaction

OBJECTIVES/GOALS: Cervical cancer is the fourth most common cancer among women worldwide, with approximately 570,000 newly diagnosed cases and 311,000 related deaths among women in 2018.In the United States, approximately 13,000 new cases of cervical cancer are diagnosed annually with approximately 4,000 women dying each year from cervical cancer. Nearly all cervical cancer is caused by oncogenic strains of the human papillomavirus (HPV). Prevention strategies to reduce cervical cancer after HPV exposure entail treatment of cervical dysplasia at the premalignant state, specifically low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL), along with the eventual clearance of HPV.The most common treatment for persistent LSIL or HSIL is the loop electrical excisional procedure (LEEP). This procedure is unfortunately not widely available in resource-limited countries and is associated with potential significant morbidities, including decreased fertility, preterm birth, premature rupture of membranes and cervical incompetence. Despite undergoing standard of care treatment, in certain high-risk populations, specifically HIV-infected women, there is a higher rate of premalignant HPV-related cervical disease persistence, progression and recurrence.There is a paramount need for novel nonsurgical treatments to stabilize or treat precancerous lesions of the cervix and to decrease the persistence of HPV infection. Medical treatment with the natural herb curcumin may allow subjects to receive treatment of cervical lesions without undergoing a surgical procedure.Curcumin is a major active component extracted from turmeric with anti-inflammatory, anti-infectious, and anti-cancer properties.Topical intravaginal curcumin has the promise of delivering this drug directly to the site of disease, ensuring adequate concentrations at the site of disease while avoiding systemic side effects. This proposed study will determine if there are higher rates of HPV clearance after curcumin administration among women with and without HIV who have premalignant HPV-related cervical disease, specifically LSIL or recently treated (with a LEEP) HSIL. METHODS/STUDY POPULATION: We are proposing a prospective double-blind randomized control trial to investigate the utility of topical intra-vaginal curcumin in increasing rates of HPV clearance and mitigating the high rates of disease recurrence in women with and without HIV. A sample of approximately 200 women with and without HIV who have biopsy-proven LSIL or recently treated HSIL will be randomized to one of two arms: 2000 mg of curcumin powder in capsules or placebo inserted intravaginally at bedtime once weekly for 20 weeks (excluding the time of menses). Cervical cytology and HPV testing will be performed at baseline and 6 months post-randomization. If a participant has abnormal cytology or a positive high-risk HPV test 6 months post-randomization, they will be scheduled to undergo a colposcopy with biopsies of all suspicious cervical lesions. If biopsy results are HSIL or greater, subjects will be referred back to routine clinical treatment, which may include a LEEP. Clinicians performing the colposcopies and the study participants will be blinded since the placebo has the same appearance as the curcumin capsules. At the end of the study, study participants will be offered the opportunity to participate in 2-3 hour focus groups to discuss acceptability of the product as a treatment for premalignant HPV-related cervical disease until data saturation is achieved. Power and sample size calculations are based on the primary outcome of interest, which is clearance of HPV at 6 months. Basu et al (2013) documented HPV clearance in as many as 80% of subjects with topical curcumin. To account for an expected lower success rate in HIV-infected women, who will also be included in the study, we intend to power our study to determine a more conservative 20% improvement in clearance rate at 6 months with curcumin treatment, assuming an expected clearance rate of HPV in HIV-infected women of 25%. In order to detect a 20% difference of HPV clearance among those treated with intravaginal curcumin vs. placebo at 6 months, about 80 patients per arm would achieve 80% power at the 5% significance level. To account for up to 20% loss to follow-up or discontinuation, the total sample size in each arm would be 100 subjects with a total of approximately 200 subjects enrolled in both arms. RESULTS/ANTICIPATED RESULTS: We are currently in the process of collecting data for this study. We hypothesize that intravaginal curcumin will have a 20% higher rate of HPV clearance at 6 months as compared to placebo. Primary outcome measures will include clearance of HPV at 6 months in curcumin vs. placebo. Secondary outcomes measures will include recurrence of disease by either cytologic or histologic abnormality requiring further surveillance or treatment at 6 months. We also hypothesize that intravaginal curcumin administered once weekly at bedtime for 20 weeks will be safe, acceptable, and well tolerated. This is based off of previous findings from the Phase 1 trial of intravaginal curcumin that we performed. During this Phase 1 trial, we explored daily intravaginal administration of 2000 mg of curcumin to further understand curcumin’s tolerability. Our focus group participants displayed an overwhelming consensus that daily administration affected quality of life, specifically due to the yellow-colored vaginal discharge from the medication. Study participants expressed that once or twice weekly administration was more tolerable and feasible. Our proposed study would therefore test the tolerability and effects of weekly curcumin administration and its ability to clear HPV infection. The primary outcome measure will be the proportion of study participants who discontinue treatment for any reason (acceptability) and the proportion of study participants who discontinue treatment due to adverse effects (tolerability). DISCUSSION/SIGNIFICANCE OF IMPACT: Non-surgical treatments that decrease the morbidity and risk of progression of premalignant HPV-related cervical disease are greatly needed, especially in low-resource settings and among women experiencing barriers to care and/or at high risk for disease progression. Medical treatment with the natural herb curcumin is an emerging strategy that may allow subjects to receive treatment of cervical lesions without undergoing a surgical procedure.Several preclinical and clinical studies have shown curcumin’s ability to reduce tumors and precancerous lesions in animal and human cancer cells. Curcumin can suppress the activation of transcription factor NF-κB and the expression and activity of VEGF and p16INK4a, biomarkers known to be elevated in premalignant HPV-related cervical disease.Studies have also shown that curcumin alters HPV-associated molecular pathways in cancer cells, suppressing cervical cancer growth by inhibiting the transcription of oncoproteins HPV16 and HPV18 (designated as E6 and E7) and restoring p53 and retinoblastoma function. Our proposed study would therefore test the tolerability and effects of weekly curcumin administration and its ability to clear HPV infection. Our results will generate novel data as to what is an acceptable and well-tolerated dosing regimen of intravaginal curcumin, which would be crucial in designing further curcumin intervention studies. The results of our proposal will explore the effect of intravaginal curcumin as a standalone and adjuvant therapy to a LEEP among women with premalignant HPV-related cervical disease. The potential to not just excise diseased tissue, but to directly augment the clearance of the causative agent HPV, would have profound long-term ramifications in resource-limited settings and among women experiencing barriers to care and/or at high risk for disease progression.

BACKGROUND: The use of central venous catheter (CVC) access for home parenteral nutrition (HPN) is associated with catheter-related blood stream infections (CRBSI). There is limited data on the use of ethanol lock therapy (ELT) to prevent CRBSI in adult HPN patients. Our aim was to determine whether the routine institution of ELT decreased the incidence of CRBSI compared to historic controls at Emory University Hospital (EUH) in Atlanta, Georgia, U.S.A. METHODS: EUH medical records of adult HPN patients discharged with a tunneled, silicone CVC on ELT were retrospectively studied during a pre-hoc determined 14-month observation period (n = 87; 13,386 catheter days) and compared to clinically similar HPN patients from the same institution before institution of the ELT protocol for all appropriate patients. The ELT protocol involved instilling 2 mL of 70% ethanol into each catheter lumen daily after the HPN cycle, following initial flushing with normal saline. RESULTS: Only five of 87 patients (5.7%) who received ELT were diagnosed with a CRBSI (0.45/1000 catheter-days) during observation. We compared these data with our previously published clinically matched patient population from EUH (n= 22) receiving HPN via a silicone CVC without ELT. Of these historical controls (45.5%) were diagnosed with one or more CRBSIs (8.7/1000 catheter-days) during observation (P

Background: A significant proportion of adults have normal weight obesity (NWO), defined as a normal body mass index (BMI) but disproportionately high body fat percentage. Individuals with NWO may have increased risk of cardiometabolic disorders and lower exercise tolerance, but it is unclear if this obesity phenotype is linked with dysregulated production of adipokines or myokines such as adiponectin and apelin, respectively. Methods: This cross-sectional, secondary analysis included 177 working adults (mean age 49.6 ± 9.9 yrs, 64% female). Plasma high-molecular weight adiponectin and apelin levels were measured by ELISA. Body composition and fat distribution were assessed using dual energy X-ray absorptiometry. Exercise tolerance (VO2 maximum) was determined by treadmill testing. NWO was defined as a BMI 30% for women or >23% for men. Participants were categorized as lean, NWO, or overweight-obese. Results: A total of 14.7% of subjects were categorized as lean, 23.7% as having NWO, and 61.6% as having overweight-obesity. Plasma adiponectin levels were elevated in the overweight-obesity group (P 0.05). Adiponectin concentrations were inversely associated with BMI, fat mass, fat mass percent, visceral fat, and trunk to leg fat ratio and positively associated with leg fat mass (all P

Background:The Patient Protection Affordable Care Act has expanded Medicaid eligibility in recent years. However, the provisions of the act have not translated to improved Medicaid payments for specialists such as orthopaedic surgeons. The number of health care practitioners who accept Medicaid is already decreasing, with low reimbursement rates being cited as the primary reason for the trend.Hypothesis:Private practice orthopaedic groups will see patients with Medicaid or Medicare at lower rates than academic orthopaedic practices, and business days until appointment availability will be higher for patients with Medicaid and Medicare than those with private insurance.Study Design:Cross-sectional study.Methods:Researchers made calls to 2 regular-sized orthopaedic practices, 1 small orthopaedic practice, and 1 academic orthopaedic practice in each of the 50 states in the United States. Callers described a scenario of a recent injury resulting in a bucket-handle meniscal tear and an anterior cruciate ligament tear seen on magnetic resonance imaging at an outside emergency department. For a total of 194 practices, 3 separate telephone calls were made, each with a different insurance type. Data regarding insurance acceptance and business days until appointment were tabulated. Student t tests or analysis of variance for continuous data and χ2or Fisher exact tests for categorical data were utilized.Results:After completing 582 telephone calls, it was determined that 31.4% (n = 59) did not accept Medicaid, compared with 2.2% (n = 4) not accepting Medicare and 1% (n = 1) not accepting private insurance ( P < .001). There was no significant association between type of practice and Medicaid refusal ( P = 0.12). Mean business days until appointment for Medicaid, Medicare, and private insurance were 5.3, 4.1, and 2.9, respectively ( P < .001).Conclusions:Access to care remains a significant burden for the Medicaid population, given a rate of Medicaid refusal of 32.2% across regular-sized orthopaedic practices. If Medicaid is accepted, time until appointment was significantly longer when compared with private insurance.

ObjectiveTo evaluate the relationship between cytomegalovirus (CMV) exposure from breast milk and risk of necrotising enterocolitis (NEC).DesignSecondary analysis of a multicentre, observational cohort study. Maternal breast milk and infant serum or urine were serially evaluated by nucleic acid testing at scheduled intervals for CMV. Infants with evidence of congenital infection were excluded. Competing-risks Cox models, with adjustment for confounders, were used to evaluate the relationship between breast milk CMV exposure or postnatal CMV infection and NEC.SettingThree neonatal intensive care units in Atlanta, Georgia.PatientsInfants with a birth weight≤1500 grams.ExposuresMaximal CMV viral load in breast milk in the first 14 days after birth or postnatal CMV infection. Two different approaches were used to assess the timing of onset of CMV infection (midpoint or early).Main outcome measuresNEC, defined as Bell stage II or greater.ResultsAmong 596 enrolled infants, 457 (77%) were born to CMV seropositive mothers and 33 developed postnatal CMV infection (cumulative incidence 7.3%, 95% CI 5.0% to 10.1%). The incidence of NEC was 18% (6/33) among infants with CMV infection, compared with 7% (37/563) among infants without infection (adjusted cause-specific HR (CSHR): 2.81; 95% CI 0.73 to 10.9 (midpoint); 6.02; 95% CI 1.28 to 28.4 (early)). Exposure to higher breast milk CMV viral load was associated with a higher risk of NEC (adjusted CSHR per twofold increase 1.28; 95% CI 1.06 to 1.54).ConclusionsCMV exposure from breast milk may be associated with the development of NEC in very low birth weight infants.

Ledipasvir/sofosbuvir (LDV/SOF), an antiviral treatment for hepatitis C virus (HCV), and tenofovir disoproxil fumarate (TDF), an antiretroviral for treating human immunodeficiency virus (HIV), may be coadministered in patients coinfected with these viruses. A drug interaction between LDV and TDF could increase TDF-associated nephrotoxicity rates; however, there is minimal clinical evidence describing acute kidney injury (AKI) rates in this population. This study was conducted at a Ryan White-funded facility in Atlanta, Georgia, that cares for over 5,000 patients with AIDS. This retrospective cohort used chart review to assess occurrence of and risk factors for AKI in HIV/HCV-coinfected patients receiving LDV/SOF and antiretroviral therapy (ART). AKI rates were compared between TDF-containing and non-TDF-containing ART groups according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Additional evaluated risk factors for AKI included chronic kidney disease and use of boosted protease inhibitor-based ART. In the 117 included patients, the overall incidence of AKI was 27.3%. AKI occurred more frequently in the non-TDF group (13/86, 15.1% vs. 19/31, 61.3%, p

Near infrared spectroscopy (NIRS) is an imaging-based diagnostic tool that provides non-invasive and continuous evaluation of regional tissue oxygenation in real-time. In recent years, NIRS has show promise as a useful monitoring technology to help detect relative tissue ischemia that could lead to significant morbidity and mortality in preterm infants. However, some issues inherent in NIRS technology use on neonates, such as wide fluctuation in signals, signal dropout and low limit of detection of the device, pose challenges that may obscure reliable interpretation of the NIRS measurements using current methods of analysis. In this paper, we propose new statistical methods to analyse mesenteric rSO2 (regional oxygenation) produced by NIRS to evaluate oxygenation in intestinal tissues and investigate oxygenation response to red blood cell transfusion (RBC) in preterm infants. We present a mean area under the curve (MAUC) measure and a slope measure to capture the mean rSO2 level and temporal trajectory of rSO2, respectively. Estimation methods are developed for these measures and nonparametric testing procedures are proposed to detect RBC-related changes in mesenteric oxygenation in preterm infants. Through simulation studies, we show that the proposed methods demonstrate improved accuracy in characterizing the mean level and changing pattern of mesenteric rSO2 and also increased statistical power in detecting RBC-related changes, as compared with standard approaches. We apply our methods to a NIRS study in preterm infants receiving RBC transfusion from Emory Univerity to evaluate the pre- and post-transfusion mesenteric oxygenation in preterm infants., Comment: 25 pages, Statistical Methods in Medical Research. (2018)

Within diverse cohorts, African Americans (AA) demonstrate higher rates of Alzheimer’s dementia (AD) and Alzheimer’s dementia combined with multiple comorbid conditions. AA are also two times more likely to develop late-onset AD than whites and less likely to be diagnosed. Yet, our understanding of this disparity in cognition remains limited. Cognitive impairment (CI) and dementia are both underdiagnosed and underreported in primary care patients. The lack of early detection of cognitive and functional decline in high risk populations results in failure to provide care and interventions to members of vulnerable groups. This talk will focus on research that seeks to identify a more sensitive cognitive marker for early identification of cognitive impairment for AA and advances this objective by linking the cognitive marker to AD cerebral spinal fluid biomarkers (Aβ1-42, p-tau) and testing whether this association differs between AA and whites.

Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals, but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1+ follicular helper T cells (Tfh) as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4+PD-1− memory CD4+ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV-DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1+ Tfh, SIV-enriched CTLA-4+PD-1− CD4+ T cells were found outside the B-cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4+PD-1− memory CD4+ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure.

OBJECTIVES/SPECIFIC AIMS: Persons living with HIV (PLWH) are at increased risk for fragility bone disease. Current osteoporosis screening guidelines do not account for HIV status, and clinical risk assessment tools are not sensitive in PLWH. We examined the value of traditional osteoporosis risk factors, HIV-specific indices, and bone turnover biomarkers in predicting low bone mineral density (BMD) in PLWH. METHODS/STUDY POPULATION: Demographic and clinical characteristics, dual energy x-ray absorptiometry (DXA)-derived BMD, HIV indices (viral load, CD4 count, antiretroviral therapy [ART]), and biomarkers of bone turnover (C-terminal telopeptide of collagen [CTx], osteocalcin [OCN]) were evaluated in a cross-sectional analysis of PLWH (n=248) and HIV- controls (n=183). The primary outcome was low BMD, defined as osteopenia or osteoporosis by WHO criteria. Multivariable logistic and modified Poisson regression models were used to assess associations between low BMD and covariates of interest. RESULTS/ANTICIPATED RESULTS: Overall, median age was 44 years, 48% were male, 88% were black, median body mass index (BMI) was 28 kg/m2, 72% smoked cigarettes, and 53% used alcohol; characteristics did not differ by HIV status. PLWH had a mean CD4 of 408 cells/mm3, 55% were ART-naïve, and 45% had viral suppression on ART. Overall, 25% (109/431) had low BMD, including 31% of PLWH compared to 16% of HIV- controls. In multivariable models, HIV was significantly associated with low BMD (aOR 2.46, 95%CI 1.39-4.34; aRR 1.90, 95%CI 1.18-3.07). Adjusting for HIV, three traditional risks– age, race, and BMI– were independently associated with low BMD in the full cohort. However, bone turnover markers, CTx and OCN, were better able to discriminate low vs. normal BMD in PLWH compared to HIV- controls. In PLWH, mean serum CTx was 23% higher in low vs. normal BMD (mean CTx difference=0.06 ug/mL); in HIV- controls, no association with BMD was observed (mean CTx difference=0 ug/mL). In PLWH, mean serum OCN was 38% higher in those with low vs. normal BMD (mean OCN difference=2.48 ug/mL); in HIV- controls, mean serum OCN was only 16% higher in those with low vs. normal BMD (mean OCN difference=1.08 ug/mL). DISCUSSION/SIGNIFICANCE OF IMPACT: In PLWH as opposed to HIV- controls, serum biomarkers reflecting a high bone turnover state, may discriminate individuals with low versus normal BMD. Because changes in biomarkers precede changes in BMD, these markers should be explored further either alone or in combination with traditional risk assessment tools to improve early screening for osteoporosis in PLWH.

The optimal mitigation strategy to prevent transfusion transmission of cytomegalovirus (TT-CMV) in preterm very low birthweight infants remains debated. Hospitals caring for this patient population have varied practices.A prospective observational comparative effectiveness pilot study was conducted to determine the feasibility for a larger study. The pilot was carried out at hospitals using a leukoreduction (LR)-only transfusion strategy. Specimen and data collection for this study was performed in a similar approach to a study completed at Emory University that employed the CMV-seronegative plus LR approach. All testing was performed at one laboratory. The rates of TT-CMV using the two transfusion strategies were compared.Zero incidence of TT-CMV was detected in infants (n = 20) transfused with LR-only blood (0/8; 95% confidence interval [CI], 0-25.3%) and is consistent with the previously reported zero incidence of TT-CMV finding in a cohort of infants transfused with CMV-negative plus LR blood (0/310; 95% CI, 0%-0.9%). The seroprevalence rate among enrolled mothers (n = 17) was 60%. Forty percent of those infants (8/20) received 43 transfusions; five were transfused with one or more CMV-seropositive blood components. One infant had tested positive for CMV before receiving blood transfusions; the infant's mother was CMV immunoglobulin (Ig)G positive and IgM negative.Using the LR-only transfusion approach, zero cases of TT-CMV were detected in this pilot study. A larger study is needed to reliably determine the most effective strategy for prevention of TT-CMV in this population.

Objective To evaluate the patient-perceived effects of Wegener's granulomatosis (WG) on health, function, income, and interpersonal relationships. Methods A self-administered questionnaire, originally designed by the authors and subsequently revised with the aid of a patient focus group, was completed by 60 patients with well-defined features of WG. Patients had WG for a median period of 5 years. Results Patients with chronic WG experienced substantial medical and functional morbidity and incurred significant socioeconomic losses. A prolonged delay in diagnosis (mean 16.8 months) and the need for multiple consultations prior to initiation of therapy may have contributed to medical morbidity. Although 73% of patients perceived their disease to be in remission following therapy, 78% of these patients required continuing immunosuppressive treatment many years after diagnosis. Eighty percent of patients reported that their normal activities of daily living were compromised. Half of those who were employed prior to diagnosis were required to modify their job or accept total disability (31%). A 26% (median) reduction in income within 1 year after diagnosis was reported. The effects of the disease on interpersonal relationships with a patient's spouse, family, and friends varied considerably. Conclusion Advances in medical care have, for most patients, transformed WG from being a disease with a high potential for short-term mortality to being a chronic illness. This is the first study that has evaluated patients' assessments of the medical, socioeconomic, and quality of life effects of WG and its treatment. The effects of mortality, disability, and outpatient medical expenses indicate that the financial impact alone substantially exceeds prior estimates of $30 million per year in charges for hospitalizations in the US.

Background Comprehensive international travel preparation often requires several vaccines. Up to 90% of adults have some fear of injections, mostly due to injection-related pain. Pediatric studies with routine vaccines have shown topical anesthetic EMLA cream (lidocaine and prilocaine, Astra Pharmaceuticals, Inc.) and the topical vapocoolant Fluori-Methane (dichlorodifluoromethane and trichlorodifluoromethane, Gebauer Co.) to be equally effective in reducing pain from vaccinations. EMLA cream is expensive and requires a 60-min application, while Fluori-Methane (FM) is immediate in onset of action and inexpensive. Skin anesthesia begins at 10°C. Fluori-Methane can briefly cool the skin to 0°C. Methods We studied the effectiveness of topical vapocoolant on adult clients at our international travel clinic in a randomized, controlled trial of topical FM vs. cold (4°C) saline placebo. Using a preset randomization table, participants served as their own controls, receiving placebo/control or active agent (participant blinded) in one arm (left or right), and a similar number of vaccines in the untreated arm. Vaccines were administered according to a set protocol per arm to minimize the risk of bias. Pain was measured using a modified McGill present pain intensity (PPI) pain index. Subjects rated their pain immediately and at 5min on a six-level scale, noting treated and untreated arms separately. A questionnaire was completed on intervention preferences. Sample size was predetermined to achieve 90% statistical power estimating 25% efficacy (minimum n = 172). Results One hundred and eighty-five participants were enrolled; 93 FM and 92 cold saline placebo. FM-treated arms had a significant reduction in immediate pain compared to untreated arms (pain scale mean 2.2 vs. 3.1; p < .0001), and compared to placebo (mean 2.2 vs. 2.8; p < .01). Delayed pain at 5min was not affected by FM or control (mean 1.9 vs. 2.0) compared to no intervention (pain scale 1.9). The intervention preference questionnaire indicated that participants did not find FM therapy uncomfortable. They would choose FM therapy in the future, over a cream, especially if a wait was involved. Conclusion The topical vapocoolant Fluori-Methane is an effective, quick, preferred, inexpensive agent for reducing vaccine-associated injection pain for international travel clients.

We compared three methods of reporting maximal expiratory flow (V'maxFRC) measured in partial expiratory flow-volume curves (PEFVCs) at the point of functional residual capacity (FRC). PEFVCs were obtained with the rapid thoracoabdominal compression technique (RTC) on a total of 446 occasions in 281 HIV-negative, asymptomatic infants (4.8-28.1 months old). Three different expressions of V'maxFRC were recorded: 1) the highest measured flow (maxV'FRC), 2) the mean of the three highest flows (mean3V'FRC), and 3) the flow at FRC in a composite curve (compV'FRC) consisting of PEFVCs, obtained at different jacket pressures and superimposed at their distal limb. The numerical value of maxV'FRC was 7.4% (+/-5.6%) higher than the mean3V'FRC, and 11.9% (+/-17.7%) higher than the compV'FRC; the mean3V'FRC was 5% (+/-18.3%) higher than the compV'FRC. Bland-Altman analysis was used to evaluate the agreement between the three indices. The mean difference and 95% limits of agreement were: maxV'FRC -mean3V'FRC, 14 +/- 18 ml/sec; maxV'FRC - compV'(FRC), 23 +/- 58 ml/sec; and mean3V'(FRC) - compV'(FRC), 10 +/- 52 ml/sec. The differences between the slopes of the three indices (regressed against height) were statistically significant, although clinically unimportant. We conclude that despite their high correlation, the mean3V'FRC and maxV'FRC should not be used interchangeably, and that the composite analysis, although useful, does not improve the reproducibility of V'maxFRC, and thus it cannot be recommended for routine use in its current form.