The Effects of Injury Type on Health-Related Quality of Life in Youth Athletes: A Cross-Sectional Analysis.

OBJECTIVE: The relationship between health-related quality of life (HRQoL) and injury type has not been analyzed for young athletes. We hypothesized that there would be no difference in HRQoL between injured athletes, injured nonathletes, and normative data for healthy youth (NDHY) or among athletes with acute, overuse, or concussion injuries. DESIGN: Cross-sectional clinical cohort. SETTING: Primary care sports medicine clinics at 3 academic institutions. PARTICIPANTS: Patients aged 8 to 18 years presenting with injury. INDEPENDENT VARIABLES: Injury type and athletic participation. MAIN OUTCOME MEASURES: Health-related quality of life measured 1 month after injury through the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric-25 v2.0 assessed pain interference, peer relationships, depression, fatigue, anxiety, and mobility. One-way analysis of variance was performed with P values of <0.05 considered significant. Concussion Learning Assessment and School Survey (CLASS) evaluated academic performance. RESULTS: Three hundred fifty-seven patients (36% male), with average age of 14.2 years, completed HRQoL and CLASS surveys following injury. There were 196 overuse injuries (55%), 119 acute injuries (33%), and 42 concussions (12%). Ninety-four percent were athletes. Six percent were nonathletes; 90.5% of concussed patients reported grades worsening. Concussed athletes reported more fatigue (P = 0.008) compared with other injury types but no worse than NDHY. Athletes with overuse injuries had lower mobility (P = 0.005) than other injury types and NDHY. Patients with lower HRQoL were female, older age, or required surgery. No other domains had significant differences by injury type nor did HRQoL differ between the athletes, nonathletes, and NDHY. CONCLUSIONS: With the exception of injuries requiring surgery, HRQoL of injured young athletes was similar to NDHY in most domains.

Human Immunodeficiency Virus (HIV) Care Continuum Outcomes After Transition to Adult Care Among a Prospective Cohort of Youth With HIV in Atlanta, Georgia.

BACKGROUND: Healthcare transition from pediatric to adult-oriented clinical settings is often viewed as a high-risk time for care disengagement. However, there is a paucity of prospective, longitudinal research documenting human immunodeficiency virus (HIV) care outcomes after healthcare transition. METHODS: We conducted a prospective, observational cohort study of healthcare transition among youth enrolled at an HIV care center in Atlanta, Georgia. Pediatric clinic patients (average age, 24 years) were enrolled up to 3 months before the expected transition and were followed up to determine linkage, retention, and viral suppression in adult care through electronic medical record abstractions at the baseline and at 6, 12, 18, and 24 months. RESULTS: The majority of our cohort (n = 70) was male (88.6%) and black (92.9%) and acquired HIV horizontally (80%). Most of our cohort was linked to adult care by 12 months (84%) after enrollment. Of those who linked to adult care by 12 months, retention rates were 86% (95% confidence interval, 78%-94%) at 6 months, 76% (66%-86%) at 12 months, and 66% (55%-78%) at 18 and 24 months. Once in adult care, the proportion with viral suppression was stable (73% at baseline and 74%, 77%, 67%, and 78% at 6, 12, 18, and 24 months, respectively). CONCLUSIONS: Although most youth successfully linked to adult care, retention rates decreased over the 24-month follow-up period. Rates of viral suppression were stable for those who remained in care. Strategies to support retention in adult care will be critical to optimizing this transition for youth with HIV.

Virologic and Immunologic Features of Simian Immunodeficiency Virus Control Post-ART Interruption in Rhesus 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 SIVmac239-infected rhesus macaques (RMs), defined as PTCs, who started ART 8 weeks postinfection, continued ART for >7 months, and controlled plasma viremia at <104 copies/ml for up to 8 months after ATI and <200 copies/ml at the latest time point. We characterized immunologic and virologic features associated with post-ART SIV control in blood, lymph node (LN), and colorectal (RB) biopsy samples compared to 15 noncontroller (NC) RMs. Before ART initiation, PTCs had higher CD4 T cell counts, lower plasma viremia, and SIV-DNA content in blood and LN compared to NCs, but had similar CD8 T cell function. While levels of intestinal CD4 T cells were similar, PTCs had higher frequencies of Th17 cells. On ART, PTCs had significantly lower levels of residual plasma viremia and SIV-DNA content in blood and tissues. After ATI, SIV-DNA content rapidly increased in NCs, while it remained stable or even decreased in PTCs. Finally, PTCs showed immunologic benefits of viral control after ATI, including higher CD4 T cell levels and reduced immune activation. Overall, lower plasma viremia, reduced cell-associated SIV-DNA, and preserved Th17 homeostasis, including at pre-ART, are the main features associated with sustained viral control after ATI in SIV-infected RMs.IMPORTANCE While effective, antiretroviral therapy is not a cure for HIV infection. Therefore, there is great interest in achieving viral remission in the absence of antiretroviral therapy. Posttreatment controllers represent a small subset of individuals who are able to control HIV after cessation of antiretroviral therapy, but characteristics associated with these individuals have been largely limited to peripheral blood analysis. Here, we identified 7 SIV-infected rhesus macaques that mirrored the human posttreatment controller phenotype and performed immunologic and virologic analysis of blood, lymph node, and colorectal biopsy samples to further understand the characteristics that distinguish them from noncontrollers. Lower viral burden and preservation of immune homeostasis, including intestinal Th17 cells, both before and after ART, were shown to be two major factors associated with the ability to achieve posttreatment control. Overall, these results move the field further toward understanding of important characteristics of viral control in the absence of antiretroviral therapy.

Enteral iron supplementation, red blood cell transfusion, and risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

BACKGROUND: Enteral iron supplementation and RBC transfusions are routinely administered to very-low-birth-weight (VLBW) infants, although the potential risks of these exposures have not been adequately quantified. This study evaluated the association between the cumulative dose of enteral iron supplementation, total volume of RBCs transfused, and risk of bronchopulmonary dysplasia (BPD) in VLBW infants. STUDY DESIGN AND METHODS: Retrospective, multicenter observational cohort study in Atlanta, Georgia. Cumulative supplemental enteral iron exposure and total volume of RBCs transfused were measured until the age at assessment of BPD. Multivariable generalized linear models were used to control for confounding, and the reliability of the factors was assessed in 1000 bootstrap models. RESULTS: A total of 598 VLBW infants were studied. In multivariable analyses, a greater cumulative dose of supplemental enteral iron exposure was associated with an increased risk of BPD (adjusted relative risk per 50-mg increase, 1.07; 95% confidence interval [CI], 1.02-1.11; p = 0.002). Similarly, a greater volume of RBCs transfused was associated with a higher risk of BPD (adjusted relative risk per 20-mL increase, 1.05; 95% CI, 1.02-1.07; p < 0.001). Both factors were reliably associated with BPD (>50%). Volume of RBCs transfused was similar to gestational age in reliability as a risk factor for BPD (present in 100% of models) and was more reliable than mechanical ventilation at 1 week of age. CONCLUSION: The cumulative dose of supplemental enteral iron exposure and total volume of RBC transfusion are both independently associated with an increased risk of BPD in VLBW infants.

Platelet transfusions and mortality in necrotizing enterocolitis.

BACKGROUND: Prior studies have suggested an association between platelet transfusions (PTXs) and worse outcomes among infants with necrotizing enterocolitis (NEC), potentially mediated by proinflammatory factors released by platelets. However, the effects of storage on platelet proinflammatory factor release and the confounding role of illness severity on NEC outcomes have not been determined. STUDY DESIGN AND METHODS: First, neuropeptide Y (a potent splanchnic vasoconstrictor released by platelets) was measured by enzyme-linked immunosorbent assay in fresh frozen plasma and in the supernatant of leukoreduced apheresis-derived platelets at different times during storage. Next, we evaluated the relationship between PTX rates and death in a multicenter cohort of very-low-birth-weight infants with NEC, adjusting for illness severity. RESULTS: Neuropeptide Y levels increased over time in the supernatant of leukoreduced apheresis-derived platelets and were 4.4-fold and 8.9-fold higher than in fresh frozen plasma on Days 2 and 3 of storage, respectively (p < 0.001). Among 598 very-low-birth-weight infants, 44 developed NEC. In unadjusted analysis, PTX rate was 30.3 (95% confidence interval [CI], 11.5-80.1) per 100 infant-days among infants who died, compared to 6.0 (95% CI, 3.2-11.2) among survivors (incidence rate ratio, 5.1; 95% CI, 1.6-16.2; p = 0.006). In multivariable analysis, there was no association between PTX rate and mortality (incidence rate ratio, 3.0; 95% CI, 0.6-15.0; p = 0.18), although estimation was imprecise. CONCLUSION: Proinflammatory mediators accumulate in platelet suspensions during storage. Although PTX rates were not associated with increased mortality among infants with NEC in our study, our estimates suggest the potential for such an association that needs evaluation in larger studies.

Peritransplantation Red Blood Cell Transfusion Is Associated with Increased Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day -7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.

Social Capital, Depressive Symptoms, and HIV Viral Suppression Among Young Black, Gay, Bisexual and Other Men Who Have Sex with Men Living with HIV.

Social capital, the sum of an individual's resource-containing social network connections, has been proposed as a facilitator of successful HIV care engagement. We explored relationships between social capital, psychological covariates (depression, stigma and internalized homonegativity), and viral suppression in a sample of young Black gay, bisexual and other men who have sex with men (YB-GBMSM). We recruited 81 HIV-positive YB-GBMSM 18-24 years of age from a clinic setting. Participants completed a cross-sectional survey, and HIV-1 viral load (VL) measurements were extracted from the medical record. Sixty-five percent (65%) were virally suppressed (HIV-1 VL ≤ 40 copies/ml). Forty-seven percent (47%) had a positive depression screen. Depressive symptoms affected viral suppression differently in YB-GBMSM with lower vs. higher social capital (p = 0.046, test for statistical interaction between depression and social capital). The odds of viral suppression among YB-GBMSM with lower social capital was 93% lower among those with depressive symptoms (OR 0.07, p = 0.002); however, there was no association between depressive symptoms and viral suppression among those with higher social capital. Our results suggest that social capital may buffer the strong negative effects of depressive symptoms on clinical outcomes in YB-GBMSM living with HIV. In addition to treating depression, there is a role for interventions to augment social capital among YB-GBMSM living with HIV as a strategy for enhancing care engagement.

Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants.

IMPORTANCE: Data regarding the contribution of red blood cell (RBC) transfusion and anemia to necrotizing enterocolitis (NEC) are conflicting. These associations have not been prospectively evaluated, accounting for repeated, time-varying exposures. OBJECTIVE: To determine the relationship between RBC transfusion, severe anemia, and NEC. DESIGN, SETTING, AND PARTICIPANTS: In a secondary, prospective, multicenter observational cohort study from January 2010 to February 2014, very low-birth-weight (VLBW, ≤1500 g) infants, within 5 days of birth, were enrolled at 3 level III neonatal intensive care units in Atlanta, Georgia. Two hospitals were academically affiliated and 1 was a community hospital. Infants received follow-up until 90 days, hospital discharge, transfer to a non-study-affiliated hospital, or death (whichever came first). Multivariable competing-risks Cox regression was used, including adjustment for birth weight, center, breastfeeding, illness severity, and duration of initial antibiotic treatment, to evaluate the association between RBC transfusion, severe anemia, and NEC. EXPOSURES: The primary exposure was RBC transfusion. The secondary exposure was severe anemia, defined a priori as a hemoglobin level of 8 g/dL or less. Both exposures were evaluated as time-varying covariates at weekly intervals. MAIN OUTCOMES AND MEASURES: Necrotizing enterocolitis, defined as Bell stage 2 or greater by preplanned adjudication. Mortality was evaluated as a competing risk. RESULTS: Of 600 VLBW infants enrolled, 598 were evaluated. Forty-four (7.4%) infants developed NEC. Thirty-two (5.4%) infants died (all cause). Fifty-three percent of infants (319) received a total of 1430 RBC transfusion exposures. The unadjusted cumulative incidence of NEC at week 8 among RBC transfusion-exposed infants was 9.9% (95% CI, 6.9%-14.2%) vs 4.6% (95% CI, 2.6%-8.0%) among those who were unexposed. In multivariable analysis, RBC transfusion in a given week was not significantly related to the rate of NEC (adjusted cause-specific hazard ratio, 0.44 [95% CI, 0.17-1.12]; P = .09). Based on evaluation of 4565 longitudinal measurements of hemoglobin (median, 7 per infant), the rate of NEC was significantly increased among VLBW infants with severe anemia in a given week compared with those who did not have severe anemia (adjusted cause-specific hazard ratio, 5.99 [95% CI, 2.00-18.0]; P = .001). CONCLUSIONS AND RELEVANCE: Among VLBW infants, severe anemia, but not RBC transfusion, was associated with an increased risk of NEC. Further studies are needed to evaluate whether preventing severe anemia is more important than minimizing RBC transfusion.

Characteristics and Outcomes of HIV-Infected Patients With Severe Sepsis: Continued Risk in the Post-Highly Active Antiretroviral Therapy Era.

OBJECTIVES: Although highly active antiretroviral therapy has led to improved survival in HIV-infected individuals, outcomes for HIV-infected patients with sepsis in the post-highly active antiretroviral therapy era are conflicting. Access to highly active antiretroviral therapy and healthcare disparities continue to affect outcomes. We hypothesized that HIV-infected patients with severe sepsis would have worse outcomes compared with their HIV-uninfected counterparts in a large safety-net hospital where access to healthcare is low and delivery of critical care is delayed. DESIGN: Secondary analysis of an ongoing prospective observational study between 2006 and 2010. SETTING: Three adult ICUs (medical ICU, surgical ICU, and neurologic ICU) at Grady Memorial Hospital, Atlanta, GA. PATIENTS: Adult patients with severe sepsis in the ICU. INTERVENTIONS: Baseline patient characteristics and clinical outcomes were collected. HIV-infected and HIV-uninfected patients with sepsis were compared using t tests, chi-square tests, and logistic regression; p values less than 0.05 indicated significance. MEASUREMENTS AND MAIN RESULTS: Of 1,095 patients with severe sepsis enrolled, 165 (15%) were positive for HIV, with a median CD4 count of 41 (8-167). Twenty-two percent of HIV-infected patients were on highly active antiretroviral therapy prior to admission, and 80% had a CD4 count less than 200. HIV-infected patients had a greater hospital mortality (50% vs 38%; p < 0.01). HIV infection (odds ratio = 1.78; p = 0.005) was an independent predictor of mortality by multivariate regression modeling after adjusting for age, history of pneumonia, history of hospital-acquired infection, and history of sepsis. CONCLUSIONS: HIV-infected patients with severe sepsis continue to suffer worse outcomes compared with HIV-uninfected patients in a large urban safety-net hospital caring for patients with limited access to medical care. Further studies need to be done to investigate the effect of socioeconomic status and mitigate healthcare disparities among critically ill HIV-infected patients.

Potential benefits for caregivers of stroke survivors receiving BTX-A and exercise for upper extremity spasticity.

PURPOSE: To explore possible extended benefits to caregivers of stroke survivors receiving a treatment of onabotulinumtoxinA (BTX-A) or saline with a structured exercise program. DESIGN: A comparative, prospective, companion study using a nonrandom sample of 16 caregivers of stroke survivors enrolled in a pilot clinical trial comparing BTX-A or saline and exercise for upper extremity spasticity. METHODS: The caregiver measures were depressive symptoms, care demands, family conflict surrounding stroke recovery, and mental and physical health status. FINDINGS: There were no statistically significant differences between caregiver groups. Caregivers of stroke survivors who received BTX-A had a greater change in depressive symptoms that may reflect a clinically important change. Estimates of effect sizes between the groups, controlling for baseline values, indicate a trend for moderate to large effects (last evaluation) for fewer depressive symptoms (d = 0.52) and less caregiver burden (d = 0.77 time, 0.85 difficulty) for caregivers of the BTX-A group. CONCLUSIONS AND CLINICAL RELEVANCE: Receiving BTX-A did not alter caregiving demands or depressive symptoms compared to those receiving saline. Further research with larger sample sizes is needed to better understand the interdependence of stroke survivors and caregivers on the health of each.

Three-year Outcomes After Conversion From Monthly to Every 2-month Belatacept Maintenance Therapy in Kidney Transplant Recipients: Results From a Randomized Controlled Trial.

Maintenance immunosuppression with belatacept following kidney transplantation results in improved long-term graft function as compared with calcineurin inhibitors. However, broad application of belatacept has been limited, in part related to logistical barriers surrounding a monthly (q1m) infusion requirement. Methods: To determine whether every 2-mo (q2m) belatacept is noninferior to standard q1m maintenance, we conducted a prospective, single-center randomized trial in low-immunologic-risk, stable renal transplant recipients. Here, post hoc analysis of 3-y outcomes, including renal function and adverse events, are reported. Results: One hundred sixty-three patients received treatment in the q1m control group (n = 82) or q2m study group (n = 81). Renal allograft function as measured by baseline-adjusted estimated glomerular filtration rate was not significantly different between groups (time-averaged mean difference of 0.2 mL/min/1.73 m2; 95% confidence interval: -2.5, 2.9). There were no statistically significant differences in time to death or graft loss, freedom from rejection, or freedom from donor-specific antibodies (DSAs). During the extended 12- to 36-mo follow-up, 3 deaths, 1 graft loss occurred in the q1m group, compared with 2 deaths, and 2 graft losses in the q2m group. In the q1m group, 1 patient developed DSAs and acute rejection. In the q2m group, 3 patients developed DSAs and 2 associated with acute rejection. Conclusions: Based on the similar renal function and survival at 36 mo compared with q1m, q2m belatacept is a potentially viable maintenance immunosuppressive strategy in low immunologic risk kidney transplant recipients that may facilitate increased clinical utilization of costimulation blockade-based immunosuppression.

Stroke Lesion Volume and Injury to Motor Cortex Output Determines Extent of Contralesional Motor Cortex Reorganization.

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.

Further assessment to determine the additive effect of botulinum toxin type A on an upper extremity exercise program to enhance function among individuals with chronic stroke but extensor capability.

OBJECTIVE: To determine whether dose-specified botulinum toxin type A (BTX-A) and a standardized exercise protocol produce better upper extremity function than placebo and the same exercise program. DESIGN: Double-blind randomized trial. SETTING: A rehabilitation research center. PARTICIPANTS: A convenience sample of patients (N=25, age range, 23-76 y) who sustained a stroke 3 to 24 months previously but could initiate wrist extension. INTERVENTIONS: Participants were randomly selected to receive either BTX-A (maximum 300 U) or saline, followed by 12 to 16 exercise sessions. MAIN OUTCOME MEASURES: The primary outcome was the Wolf Motor Function Test (WMFT). Secondary outcome measures included the Modified Ashworth Scale (MAS), active range of motion, and the Stroke Impact Scale (SIS; quality of life). RESULTS: There were no group-by-time interactions for changes in the WMFT and no treatment difference (P=.86), although the BTX-A group could complete more tasks governing proximal joint motions. MAS scores improved for the BTX-A group and worsened for the control group after injection (P=.02), as did the SIS emotion domain (P=.035). CONCLUSIONS: Among chronic stroke survivors, BTX-A did not impact function, movement, or tone more than a standardized exercise program.

The Movement Imagery Questionnaire-Revised, Second Edition (MIQ-RS) Is a Reliable and Valid Tool for Evaluating Motor Imagery in Stroke Populations.

Mental imagery can improve motor performance in stroke populations when combined with physical therapy. Valid and reliable instruments to evaluate the imagery ability of stroke survivors are needed to maximize the benefits of mental imagery therapy. The purposes of this study were to: examine and compare the test-retest intra-rate reliability of the Movement Imagery Questionnaire-Revised, Second Edition (MIQ-RS) in stroke survivors and able-bodied controls, examine internal consistency of the visual and kinesthetic items of the MIQ-RS, determine if the MIQ-RS includes both the visual and kinesthetic dimensions of mental imagery, correlate impairment and motor imagery scores, and investigate the criterion validity of the MIQ-RS in stroke survivors by comparing the results to the KVIQ-10. Test-retest analysis indicated good levels of reliability (ICC range: .83-.99) and internal consistency (Cronbach α: .95-.98) of the visual and kinesthetic subscales in both groups. The two-factor structure of the MIQ-RS was supported by factor analysis, with the visual and kinesthetic components accounting for 88.6% and 83.4% of the total variance in the able-bodied and stroke groups, respectively. The MIQ-RS is a valid and reliable instrument in the stroke population examined and able-bodied populations and therefore useful as an outcome measure for motor imagery ability.

Prospective comparison of dysphagia following anterior cervical discectomy and fusion (ACDF) with and without rhBMP-2.

BACKGROUND CONTEXT: Previous studies have called into question the safety of using rhBMP-2 in anterior cervical fusion due to the possibility of airway compromise and dysphagia. A retrospective chart review identified a significant increase in the severity of dysphagia after II-level ACDF with rhBMP-2 compared to patients who did not receive rhBMP-2. To date, this topic has not been studied prospectively. PURPOSE: Compare the incidence of dysphagia following anterior cervical discectomy and fusion (ACDF) when recombinant human bone morphogenetic protein-2 (rhBMP-2) is used with allograft compared to allograft alone. STUDY DESIGN: Prospective cohort study. PATIENT SAMPLE: A total of 114 patients completed a baseline SWAL-QOL survey and met the inclusion criteria. Thirty-nine patients underwent I- or II-level ACDF with allograft plus 0.5mg rhBMP-2/level. 44 patients underwent ACDF with allograft alone. Thirty-one patients undergoing a lumbar decompression were enrolled in a third cohort to control for dysphagia secondary to intubation. OUTCOME MEASURES: The primary outcome measure was the 14-point SWAL-QOL dysphagia questionnaire. Other patient factors obtained from anesthesia and operative records were examined to evaluate their potential relationship to postoperative dysphagia. METHODS: The 14-point SWAL-QOL questionnaire was administered at multiple time points (pre-op, post-op 7 days, 6 weeks, 6 months, and at least 1 year). Multivariable repeated-measures analysis was applied to data. RESULTS: Baseline adjusted SWAL-QOL means 7 days after surgery were significantly different between the three study groups. These differences resolved by 6 weeks postoperative, beyond which point there were no differences. At final follow-up, baseline adjusted SWAL-QOL means at 1 year were similar for the three study groups. CONCLUSIONS: This single-center study of anterior cervical surgery demonstrated that the addition of rhBMP-2 to an ACDF increased postoperative dysphagia at 7 days after surgery, but these patients recover to levels comparable to those who underwent ACDF without rhBMP-2 or lumbar surgery within 6 weeks.

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy.

Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including Tfh cells, and predicted the frequency of CD4+ Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4+ T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.

Association of Blood Donor Sex and Age With Outcomes in Very Low-Birth-Weight Infants Receiving Blood Transfusion.

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 < .001). For the typical infant, who received a median (interquartile range) of 2 (1-3) transfusions, RBC transfusion from exclusively female donors, compared with male donors, was associated with a lower risk of the primary outcome (relative risk, 0.29; 95% CI, 0.16-0.54). The protective association between RBC transfusions from female donors, compared with male donors, and the primary outcome increased as the donor age increased, but decreased as the number of transfusions increased. Conclusions and Relevance: These findings suggest that RBC transfusion from female donors, particularly older female donors, is associated with a lower risk of death or serious morbidity in VLBW infants receiving transfusion. Larger studies confirming these findings and examining potential mechanisms are warranted.

IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques.

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.

A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates.

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.

The effects of roux en y gastric bypass surgery on neurobehavioral symptom domains associated with severe obesity.

BACKGROUND: Neurobehavioral symptoms and cognitive dysfunction related to mood disorders are present in individuals with severe obesity. We sought to determine acute improvements in these symptoms and relationships with adiposity, inflammation, and insulin sensitivity after roux-en-y gastric bypass (RYGB) surgery. METHODS: The self-report Zung Depression Rating (ZDRS) and Neurotoxicity Rating (NRS) scales were administered before, and at 6-months after RYGB surgery in severely obese women (body mass index > 35 kg/m2; N = 19). Symptom domains corresponding to depressed mood/suicide ideation, anxiety, cognitive, somatic, and neurovegetative symptoms were assessed. Biologic measures were of adiposity [leptin, abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue], inflammation [IL-6, C-reactive protein (CRP)], and insulin sensitivity (Si). Spearman correlations and linear regression (adjusted for biologic measures) assessed relationships between changes in biologic measures and changes in neurobehavioral domains. RESULTS: By 6-months after RYGB, VAT, SAT, Si, CRP, and IL-6 had improved (p < .05). Anxiety, somatic, and neurovegetative symptoms domains improved (p < .05), but depressed mood/suicidal ideation and cognitive domains did not. Reductions in VAT were associated with decreases in neurovegetative symptoms (beta = 295 ±â€¯85, p < .01). We also found significant positive longitudinal associations between IL-6 concentrations and minor changes in cognitive symptoms. CONCLUSION: Anxiety, somatic and neurovegetative symptoms, improved within 6 months after RYGB, but depressed mood/suicidal ideation and cognitive symptoms did not improve. Associations between visceral adiposity, IL-6 concentrations and neurovegetative and cognitive symptoms support links between obesity, inflammation and distinct neurobehavioral symptoms.