Search

Electroencephalogram (EEG) discontinuity can occur at high concentrations of anesthetic drugs, reflecting suppression of electrocortical activity. This EEG pattern has been reported in children and reflects a deep state of anesthesia. Isoelectric events on the EEG, a more extreme degree of voltage suppression, have been shown to be associated with worse long-term neurologic outcomes in neonates undergoing cardiac surgery. However, the clinical significance of EEG discontinuities during pediatric anesthesia for noncardiac surgery is not yet known and merits further research. In this study, we assessed the incidence of EEG discontinuity during anesthesia induction in neurologically normal infants and the clinical factors associated with its development. We hypothesized that EEG discontinuity would be associated with sevoflurane-induced alpha (8-12 Hz) power during the period of anesthesia induction in infants.We prospectively recorded 26 channels of EEG during anesthesia induction in an observational cohort of 54 infants (median age, 7.6 months; interquartile range [IQR] [4.9-9.8 months]). We identified EEG discontinuity, defined as voltage amplitude25 microvolts for2 seconds, and assessed its association with sevoflurane-induced alpha power using spectral analysis and multivariable logistic regression adjusting for clinically important variables.EEG discontinuity was observed in 20 of 54 subjects (37%), with a total of 25 discrete events. Sevoflurane-induced alpha power in the posterior regions of the head (eg, parietal or occipital regions) was significantly lower in the EEG discontinuity group (midline parietal channel on the electroencephalogram, International 10-20 System [Pz]; 8.3 vs 11.2 decibels [dBs]; P = .004), and this association remained after multivariable adjustment (adjusted odds ratio [aOR] = 0.51 per dB increase in alpha power [95% CI, 0.30-0.89]; P = .02). There were no differences in the baseline (unanesthetized) EEG between groups in alpha power or power in any other frequency band.We demonstrate that EEG discontinuity is common during anesthesia induction and is related to the level of sevoflurane-induced posterior alpha power, a putative marker of cortical-thalamic circuit development in the first year of life. This association persisted even after adjusting for age and propofol coadministration. The fact that this difference was only observed during anesthesia and not in the baseline EEG suggests that otherwise hidden brain circuit properties are unmasked by general anesthesia. These neurophysiologic markers observed during anesthesia may be useful in identifying patients who may have a greater chance of developing discontinuity.

Testosterone levels decline as men age. There is little consensus on what testosterone levels are normal for aging men. In this paper, we estimate age-specific prevalence of testosterone deficiency in men using nor- mal mixture models when no generally agreed on cut-off value for defining testosterone deficiency is available. The Box-Cox power transformation is used to determine which transformation is most appropriate for correcting skewness in data and best suits normal mixture distributions. Parametric bootstrap tests are used to determine the number of components in a normal mixture.

Context.— Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) testing is used for serosurveillance and will be important to evaluate vaccination status. Given the urgency to release coronavirus disease 2019 (COVID-19) serology tests, most manufacturers have developed qualitative tests. Objective.— To evaluate clinical performance of 6 different SARS-CoV-2 IgG assays and their quantitative results to better elucidate the clinical role of serology testing in COVID-19. Design.— Six SARS-CoV-2 IgG assays were tested using remnant specimens from 190 patients. Sensitivity and specificity were evaluated for each assay with the current manufacturer's cutoff and a lower cutoff. A numeric result analysis and discrepancy analysis were performed. Results.— Specificity was higher than 93% for all assays, and sensitivity was higher than 80% for all assays (≥7 days post–polymerase chain reaction testing). Inpatients with more severe disease had higher numeric values compared with health care workers with mild or moderate disease. Several discrepant serology results were those just below the manufacturers' cutoff. Conclusions.— Severe acute respiratory syndrome coronavirus 2 IgG antibody testing can aid in the diagnosis of COVID-19, especially with negative polymerase chain reaction. Quantitative COVID-19 IgG results are important to better understand the immunologic response and disease course of this novel virus and to assess immunity as part of future vaccination programs.

In the intestine, IgA antibody-secreting B cells (IgA-ASCs) and helper T cells coordinate to maintain local homeostasis while their dysregulation could lead to development of intestinal inflammatory diseases. However, mechanisms underlying the coordinated localization and function of the B and T cells into the intestine, particularly the colon, are poorly understood. We herein report the first evidence that the gut-homing chemokine receptor CCR10+ IgA-ASCs form conjugates with helper T cells, preferentially regulatory T cells, at their differentiation sites of gut-associated lymphoid organs for their coordinated co-localization into the colon to promote local homeostasis. In CCR10-knockout mice, defective migration of IgA-ASCs also resulted in defective T cell migration and homeostasis, and development of inflammatory symptoms in the colon. Antigen-specific interaction of CCR10+ IgA-ASCs and T cells is crucial for their homeostatic establishment in the colon. On the other hand, in IgA-knockout mice, preferential expansion of CCR10+ IgG1-ASCs with regulatory functions compensated for CCR10+ IgA-ASCs to help maintain colonic homeostasis. The preferential expansion of specific subclasses of CCR10+ IgG-ASCs with regulatory functions was also found in asymptomatic IgA-deficient patients. These findings suggest coordinated cell migration as a novel mechanism underlying localization and function of B and T cells in colonic homeostatic regulation.

Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a protooncogene; p27(Kip1) (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2-mediated ubiquitination. Overexpression of SKP2 and underexpression of p27 are common characteristics of cancer cells. The SCF(SKP2) E3 ligase ubiquitinates Thr187-phosphorylated p27 for proteasome degradation, which can be abolished by a Thr187Ala knock-in (p27(T187A) KI) mutation. RB1 and TP53 are two major tumor suppressors commonly coinactivated in osteosarcoma. We generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within cells of the osteoblastic lineage, which developed osteosarcoma with full penetrance. When p27(T187A) KI mice were crossed on to the DKO background, p27(T187A) protein was found to accumulate in osteosarcoma tumor tissues. Furthermore, p27(T187A) promoted apoptosis in DKO tumors, slowed disease progression, and significantly prolonged overall survival. RNA sequencing analysis also linked the SCF(SKP2)–p27(T187A) axis to potentially reduced cancer stemness. Given that RB1 and TP53 loss or coinactivation is common in human osteosarcoma, our study suggests that inhibiting the SKP2–p27 axis may represent a desirable therapeutic strategy for this cancer.

There has been increasing interest in the use of stemless humeral implants for total shoulder arthroplasty when compared with both short-stem (SS) and standard-length implants. Although evidence for decreased surgical time and blood loss exists for stemless versus standard-length stems, far less literature exists comparing these clinical parameters for stemless versus SS implants.A retrospective review of consecutive anatomic total shoulder arthroplasty (aTSA) cases conducted by a single, fellowship-trained shoulder surgeon was undertaken from January 2016 through January 2022 with the exception of March 2020 through January 2021 secondary to the COVID-19 pandemic. Demographic patient and surgical data, including age, sex, body mass index, American Society of Anesthesiologists score, age-adjusted Charlson Comorbidity Index, prior ipsilateral shoulder arthroscopy, surgical time, use of a Hemovac drain and/or tranexamic acid, hospital length of stay (LOS), and both postoperative day #1 (POD 1) and discharge visual analog scores. The use of a stemless or SS implant was recorded. Intraoperative total blood volume loss (TBVL) was calculated, in addition to the need for either intraoperative or postoperative transfusions. Nonparametric analysis of covariance was used to examine effects of stemless versus SS aTSA on surgical time and intraoperative TBVL adjusted for demographic, clinical, and surgical variables.There were 47 SS and 83 stemless anatomic implants included, of which 74 patients (57%) overall were women. The median surgical time for the stemless cohort was 111 minutes (IQR 96-130) versus 137 minutes (IQR 113-169) for the SS cohort (P0.00001). The median intraoperative TBVL for the stemless cohort was 298.3 mL (IQR 212.6-402.8) versus 359.7 mL (IQR 253.9-415.0) for the SS cohort (P = 0.05). After multivariable regression analysis, use of stemless humeral implants was independently associated with both decreased surgical time and intraoperative blood loss (P0.001 and P = 0.005, respectively). There was a shorter median hospital LOS in the stemless group (2 days [IQR 1-2] versus 2 days [IQR 2-3], P = 0.03). The visual analog score pain score at discharge was lower among the stemless cohort (0 [IQR 0-3] versus 4 [IQR 2-6], P0.00001). Increased surgical time was associated with intraoperative TBVL (r = 0.340, P0.0001).Stemless aTSA is associated with a markedly decreased surgical time and intraoperative TBVL when compared with a SS aTSA. Furthermore, the use of a stemless implant results in a shorter hospital LOS and lower discharge pain scores.

Short-term cancellation of elective ambulatory orthopaedic surgery can result in disruption to the process flow of the operating room, with resultant negative financial implications for the health system. The risk factors for patient-related short-term cancellations within 24 hours of the surgical date have not been well defined.A retrospective review of a single orthopaedic surgery electronic internal database was done to identify all cancellations from January 1, 2016, through December 31, 2019, which were made within 24 hours of the surgical date. Inclusion criteria included elective arthroscopic procedures canceled solely for patient-related issues. Any cancellation for surgeon-related or ambulatory center-related reasons was excluded. Demographic patient and surgical data, including insurance type, employment status, previous history of cancellation for the same surgery, socioeconomic status based on the Area Deprivation Index, and surgery type, were tabulated. Each cancellation was matched 1:2 with noncanceled cases based on the anatomic site of the arthroscopy scheduled. Multivariable logistic regression was used to examine associations of patient demographic and medical characteristics with surgical cancellation.There were 4,715 total arthroscopic procedures done during the study period, of which 126 (2.7%) were canceled within 24 hours of the surgery date. The mean age of the canceled cases was 44.9 ± 16.1 years (range, 14 to 77 years), with 46 females (43%) included. The presence of MRI of the involved joint within 6 months of surgery (adjusted odds ratio [aOR], 0.39, 95% confidence interval [CI], 0.17 to 0.91) and current employment (aOR, 0.56, 95% CI, 0.33-0.94) were independently predictive of noncancellation. Current smokers were more likely to cancel within 24 hours of surgery (aOR, 2.63, 95% CI, 1.4-4.9). Finally, having previously canceled the same surgery was significantly associated with a current surgical cancellation (P = 0.004).Identification of the factors associated with short-term patient-related cancellation of elective arthroscopy may serve as the basis for preoperative interventions aimed specifically at those more likely to cancel. In turn, these interventions can minimize preventable cancellations.

Rationale & Objective Community racial composition has been shown to be associated with mortality in patients receiving maintenenance dialysis. It is unclear whether living in communities with predominantly Black residents is also associated with risk for hospitalization among patients receiving hemodialysis. Study Design Retrospective analysis of prospectively collected data from a cohort of patients receiving hemodialysis. Setting & Participants 4,567 patients treated in 154 dialysis facilities located in 127 unique zip codes and enrolled in US Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 5 (2010-2015). Exposure Tertile of percentage of Black residents within zip code of patients’ dialysis facility, defined through a link to the American Community Survey. Outcome Rate of hospitalizations during the study period. Analytic Approach Associations of patient-, facility-, and community-level variables with community’s percentage of Black residents were assessed using analysis of variance, Kruskal-Wallis, or χ2/Fisher exact tests. Negative binomial regression was used to estimate the incidence rate ratio for hospitalizations between these communities, with and without adjustment for potential confounding variables. Results Mean age of study patients was 62.7 years. 53% were White, 27% were Black, and 45% were women. Median and threshold percentages of Black residents in zip codes in which dialysis facilities were located were 34.2% and ≥14.4% for tertile 3 and 1.0% and ≤1.8% for tertile 1, respectively. Compared with those in tertile 1 facilities, patients in tertile 3 facilities were more likely to be younger, be Black, live in urban communities with lower socioeconomic status, have a catheter as vascular access, and have fewer comorbid conditions. Patients dialyzing in communities with the highest tertile of Black residents experienced a higher adjusted rate of hospitalization (adjusted incidence rate ratio, 1.32; 95% CI, 1.12-1.56) compared with those treated in communities within the lowest tertile. Limitations Potential residual confounding. Conclusions The risk for hospitalization for patients receiving maintenance dialysis is higher among those treated in communities with a higher percentage of Black residents after adjustment for dialysis care, patient demographics, and comorbid conditions. Understanding the cause of this association should be a priority of future investigation.

Rationale & Objective Group-based care provides an opportunity to increase patient access to providers without increasing physician time and is effective in the management of chronic diseases in the general population. This model of care has not been investigated in chronic kidney disease (CKD). Study Design Randomized controlled trial in adults (n = 50); observational study in adolescents (n = 10). Setting & Participants Adults and adolescents with CKD and hypertension in the Bronx, NY. Intervention Group-based care (monthly sessions over 6 months) versus usual care in adults. All adolescents received group-based care and were analyzed separately. Outcomes Participant attendance and satisfaction with group-based care were used to evaluate intervention feasibility. The primary clinical outcome was change in mean 24-hour ambulatory blood pressure. Secondary outcomes included physical activity, medication adherence, quality of life, and sodium intake as assessed by 24-hour urinary sodium excretion and food frequency questionnaires. Results Among adults randomly assigned to group-based care, attendance was high (77% of participants attended ≥3 sessions) and most reported higher satisfaction. Mean 24-hour ambulatory systolic blood pressure decreased by −4.2 (95% CI, −13.3 to 5.8) mm Hg in group-based care patients compared with usual care at 6 months but this was not statistically significant. Similarly, we did not detect significant differences in health-related behaviors (such as medication adherence, sodium intake, and physical activity) or quality-of-life measures between the 2 groups. Among the adolescents, attendance was very poor; self-reported satisfaction, although high, did not change from baseline compared with the 6-month follow-up. Limitations Small study size, missing data. Conclusions Group-based care is feasible and acceptable among adults with hypertension and CKD. However, a larger trial is needed to determine the effect on blood pressure and health-related behaviors. Patient participation may limit the effectiveness of group-based care models in adolescents. Funding National Institutes of Health R34 DK102174. Trial registration https://clinicaltrials.gov/show/NCT02467894., Graphical Abstract

In this retrospective study of 319 children with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we assessed whether age, asthma, obesity, diabetes, and socioeconomic status were associated with hospitalization for coronavirus disease 2019 (COVID-19). Demographic and clinical characteristics were assessed using univariate statistics, excluding incidental or unrelated positives. There was a bimodal distribution of age among hospitalized children. Obesity ( P < .001) and a past medical history of diabetes ( P = .001) were significantly more prevalent in hospitalized children, including cases of new-onset diabetes and diabetic ketoacidosis. Neither a past medical history of asthma nor lower socioeconomic status was associated with hospitalization. Although limited to a single center, the findings in this study may have important clinical implications. Targeted, proactive health outreach to children with obesity and diabetes, with prioritization of preventative efforts such as vaccination, may be important in preventing worse SARS-CoV-2 infection in this vulnerable group.

Background/objective Regular physical activity (PA) has been associated with improved cognitive function, but its effect on postoperative delirium (POD) has not been established. Our objectives were to determine the effect of baseline PA on the incidence of POD in older patients undergoing elective orthopedic surgery and to determine whether these effects were independent of cognitive reserve. We hypothesize that PA protects against POD by bolstering physiologic reserve needed to withstand the stressors of surgery. Design Secondary analysis of a prospective, single-center, cohort study. Setting Urban academic hospital. Participants A total of 132 nondemented, English-speaking adults older than 60 years undergoing elective orthopedic surgery. Measurements Subjects were screened for POD and delirium severity using the Confusion Assessment Method and the Memorial Delirium Assessment Scale. Baseline cognitive activities and PAs were assessed with a validated Leisure Activity Scale. Regular PA was categorized as 6 to 7 days per week. The association of regular PA with incidence of POD was assessed using multivariable logistic regression, adjusting for age, sex, Charlson Comorbidity Index, cognitive reserve, and cognitive function. Linear regression was used to assess the association of delirium severity with regular PA. Results Of 132 patients, 41 (31.1%) developed POD. Regular PA was associated with a 74% lower odds of developing POD (odds ratio [OR] = 0.26; 95% confidence interval [CI] = 0.08-0.82). There was no significant interaction between PA and cognitive reserve (P = .70). Of 85 women, 25 (29.4%), and of 47 men, 16 (34.0%) developed POD. In stratified analysis, women who engaged in regular PA had dramatically lower odds of POD (OR = 0.08; 95% CI = 0.01-0.63) compared with men (OR = 0.93; 95% CI = 0.18-4.97). Conclusions Regular PA is associated with decreased incidence of POD, especially among women. Future studies should address the basis of sex differences in PA benefits on delirium. J Am Geriatr Soc 67:2260-2266, 2019.

Patient-reported outcome measures (PROMs) are commonly utilized to assess patient-derived orthopaedic health status and function. The prevalence of limited musculoskeletal health literacy (MHL) has been demonstrated to be high within the orthopaedic literature. The purpose of this study was to evaluate the association between MHL and upper extremity-specific PROMs and to determine which patient- and symptom-related factors affect baseline PROMs in patients with atraumatic shoulder pain.Patients with limited MHL would demonstrate lower median scores on baseline PROMs compared with those with adequate MHL.New patients with atraumatic shoulder pain presenting to an academic practice were administered the Literacy in Musculoskeletal Problems (LiMP), in addition to the American Shoulder and Elbow Surgeons (ASES), Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), and Single Assessment Numeric Evaluation (SANE) questionnaires. A detailed physical exam and history was performed by a fellowship-trained shoulder surgeon. Demographic patient data, in addition to prior imaging and orthopaedic treatment, was tabulated. The association between demographics, pain-related variables, and MHL with the ASES, SANE, and QuickDASH scores were examined using Spearman correlation coefficients for continuous variables and Wilcoxon rank-sum tests for categorical variables. Non-parametric analysis of covariance (ANCOVA) was used to examine the independent association of predictor variables with PROMs.A total of 439 patients met the inclusion criteria and were enrolled. The mean age was 58.8±12.6years (range: 24-93) with 162 (37%) being men. Overall, 172 patients (39.2%) attained a college degree or higher and 183 (41.7%) were currently employed. MHL was significantly associated with ASES (p=0.03), but not with the QuickDASH (p=0.75) or SANE score (p=0.16). Similarly, age, having been in the medical profession or having previously visited an orthopaedist were not associated with PROMs, while employment status correlated to the SANE score (p=0.002). Visual Analogue Scale (VAS) pain level demonstrated varying strengths of association with each of the scores [ASES (r=-0.729, p0.001), QuickDASH (r=0.557, p0.001), and SANE (r=-0.430, p0.001)]. MHL demonstrated no association with initial patient-derived treatment selection.The SANE and QuickDASH may be administered to patients presenting for atraumatic shoulder pain in the outpatient setting regardless of MHL. Further research should be focused on the utility of the ASES instrument amongst patients with lower educational levels and/or limited MHL.II; diagnostic.

Background Coronavirus disease 2019 (COVID-19) guidelines endorse early rehabilitation to improve outcomes in hospitalized patients, but the evidence base to support this recommendation is lacking. We examined the association between early rehabilitation and in-hospital deaths in COVID-19 patients. Method A single-center retrospective study, involving 990 COVID-19 patients (42.4% women, mean age 67.8 years) admitted between March 1, 2020 and May 31, 2020 to a community hospital, was conducted. Association of rehabilitation during hospitalization with in-hospital mortality was examined using logistic regression analysis adjusted for demographics, length of stay, body mass index, comorbid illnesses, functional status as well as for COVID-19 presentations, treatments, and complications. Results Over the 3-month study period, 475 (48.0%) inpatients were referred for rehabilitation. Patients who received rehabilitation were older (73.7 ± 14.0 vs 62.3 ± 17.2). There were 61 hospital deaths (12.8%) in the rehabilitation group and 165 (32.0%) in the nonrehabilitation group. Receiving rehabilitation was associated with an 89% lower in-hospital mortality (odds ratio [OR]: 0.11, 95% confidence interval [CI]: 0.06–0.19) after adjusting for multiple confounders and COVID-19 disease markers. In sensitivity analyses, the results were significant in subpopulations defined by age group, sex, race, length of hospitalization, or pulmonary presentations. Each additional rehabilitation session was associated with a 29% lower risk of in-hospital mortality (OR per session: 0.71, 95% CI: 0.64–0.79) in the fully adjusted model. Conclusion Among hospitalized COVID-19 patients, receiving early rehabilitation was associated with lower in-hospital mortality. Our findings support implementation of rehabilitation services for COVID-19 patients in acute care settings, but further research from randomized clinical trials is needed.

ImportanceCOVID-19 has caused a worldwide illness and New York became the epicenter of COVID-19 in the United States from Mid-March to May 2020.ObjectiveTo investigate the coagulopathic presentation of COVID and its natural course during the early stages of the COVID-19 surge in New York. To investigate whether hematologic and coagulation parameters can be used to assess illness severity and death.DesignRetrospective case study of positive COVID inpatients between March 20, 2020-March 31, 2020.SettingMontefiore Health System main hospital, Moses, a large tertiary care center in the Bronx.ParticipantsAdult inpatients with positive COVID tests hospitalized at MHS.Exposure (for observational studies)Datasets of participants were queried for demographic (age, sex, socioeconomic status, and self-reported race and/or ethnicity), clinical and laboratory data.Main Outcome and MeasuresRelationship and predictive value of measured parameters to mortality and illness severity.ResultsOf the 225 in this case review, 75 died during hospitalization while 150 were discharged home. Only the admission PT, absolute neutrophil count (ANC) and first D-Dimer could significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 2.1 μg/mL. 15% of discharged patients required readmission and more than a third of readmitted patients died (5% of all initially discharged).ConclusionWe describe here a comprehensive assessment of hematologic and coagulation parameters in COVID-19 and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments. Furthermore, D-Dimer may be useful to follow up discharged patients.

ImportanceCOVID-19 has caused a worldwide illness and New York has become the epicenter of COVID-19 in the United States. Currently Bronx has the highest prevalence per capita in New York.ObjectiveTo investigate the coagulopathic presentation of COVID and its natural course and to investigate whether hematologic and coagulation parameters can be used to assess illness severity and death.DesignRetrospective case study of positive COVID inpatients between 3/20/2020-3/31/2020.SettingMontefiore Health System main hospital, Moses, a large tertiary care center in the Bronx.ParticipantsAdult inpatients with positive COVID tests hospitalized at MHS.Exposure (for observational studies)Datasets of participants were queried for physiological, demographic (age, sex, socioeconomic status and self-reported race and/or ethnicity) and laboratory data.Main Outcome and MeasuresRelationship and predictive value of measured parameters to mortality and illness severity.ResultsOf the 217 in this case review, 70 died during hospitalization while 147 were discharged home. Only the admission PT and first D-Dimer could very significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 1.65 μg/mLConclusionsWe describe here a comprehensive assessment of hematologic and coagulation parameters in COVID and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments.

OBJECTIVES: Depot medroxyprogesterone acetate (Depo-Provera) is the most commonly used injectable hormone contraceptive in Sub-Sahara Africa where HIV incidence is high. We determined the impact of Depo-Provera on cervical immune cells and mediators in healthy women. METHODS: In this longitudinal study, vaginal, endocervical, and rectal swabs were collected at baseline (visit 1), one month (visit 2), and three months (visit 3) after Depo-Provera injection. Cervical cells were collected by cytobrush and immune markers on cervical CD4(+) T cells were analyzed by multicolor flow cytometry at 3 different visits. The levels of immune mediators in cytobrush supernatants as well as vaginal, cervical, and rectal secretions from swabs were analyzed by multiplex assays and ELISA. RESULTS: Compared to baseline levels we found a significant increase in the frequency of cervical CCR5(+)CD4(+) T cells and a significant decrease in the frequency of cervical central memory CD4(+) T cells. Depo-Provera treatment had little effect on expression of immune mediators in rectal mucosa but significantly suppressed numerous immune mediators at cervicovaginal mucosa. Levels of MCP-1, G-CSF, IL-6, IL-10, GM-CSF, and IP-10 were significantly decreased in both vaginal and cervical secretions after Depo-Provera injection. In cervical samples collected by cytobrush, we found reduced levels of 22 of 25 immune mediators after Depo-Provera injection. Changes in immune mediators differed between vaginal and cervical mucosa, demonstrating compartment-specific responses. CONCLUSION: Depo-Provera altered immune profiles of cervical CD4(+) T cells and suppressed host immune response at cervicovaginal mucosa, suggesting its likely effect on transmission of sexually transmitted infections including HIV.

Background Mortality in coronavirus disease of 2019 (COVID-19) is associated with increases in prothrombotic parameters, particularly D-dimer levels. Anticoagulation has been proposed as therapy to decrease mortality, often adjusted for illness severity. Objective We wanted to investigate whether anticoagulation improves survival in COVID-19 and if this improvement in survival is associated with disease severity. Methods This is a cohort study simulating an intention-to-treat clinical trial, by analyzing the effect on mortality of anticoagulation therapy chosen in the first 48 hours of hospitalization. We analyzed 3,625 COVID-19+ inpatients, controlling for age, gender, glomerular filtration rate, oxygen saturation, ventilation requirement, intensive care unit admission, and time period, all determined during the first 48 hours. Results Adjusted logistic regression analyses demonstrated a significant decrease in mortality with prophylactic use of apixaban (odds ratio [OR] 0.46, p = 0.001) and enoxaparin (OR = 0.49, p = 0.001). Therapeutic apixaban was also associated with decreased mortality (OR 0.57, p = 0.006) but was not more beneficial than prophylactic use when analyzed over the entire cohort or within D-dimer stratified categories. Higher D-dimer levels were associated with increased mortality (p 10 µg/mL derived the most benefit. There was no increase in transfusion requirement with any of the anticoagulants used. Conclusion We conclude that COVID-19+ patients with moderate or severe illness benefit from anticoagulation and that apixaban has similar efficacy to enoxaparin in decreasing mortality in this disease.

BACKGROUND Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by mutations in the tumor-suppressor gene TP53. Osteosarcoma is a sentinel cancer in LFS. Prior studies using Sanger sequencing platforms have demonstrated that 3% of individuals with osteosarcoma harbor a mutation in TP53. New data from next-generation sequencing have demonstrated that 3.8% of patients with osteosarcoma have a known pathogenic variant, and an additional 5.7% carry exonic variants of unknown significance in TP53. METHODS Pediatric oncologists were e-mailed an anonymous 18-question survey assessing their willingness to offer TP53 germline testing to a child with osteosarcoma with or without a family history, and they were evaluated for changes in their choices with the prior data and the new data. RESULTS One hundred seventy-seven pediatric oncologists (22%) responded to the survey. Respondents were more likely to offer TP53 testing to a patient with a positive family history (77.4% vs 12.4%; P < .0001). Significantly more providers responded that they would offer TP53 testing once they were provided with the new data (25.4% vs 12.4%; P = .0038). The proportion of providers who responded that they were unsure increased significantly when they were presented with the new data (25.4% vs 10.2%; P = .0002). Potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage were important factors influencing a provider's decision to offer TP53 testing. CONCLUSIONS Recent data increase the proportion of providers willing to offer testing, and this suggests concern on the part of pediatric oncologists that variants of unknown significance may be disease-defining in rare cancers. Cancer 2018;124:1242-50. © 2018 American Cancer Society.

Purpose To evaluate sensitivity, specificity and accuracy of a radiographic slipped capital femoral epiphysis (SCFE)-diagnosis among medical specialists. Methods Three paediatricians, three paediatric radiologists and three paediatric orthopaedic surgeons completed two rounds of a survey of anteroposterior and frog-leg lateral radiographs of patients with a diagnosis of SCFE (25), femoroacetabular impingement (four), Legg-Calvé-Perthes (11) or no hip pathology (ten). Intra- and interobserver agreement among specialties regarding the diagnosis of a SCFE were assessed using Cohen's kappa coefficient (κ). Diagnostic accuracy of SCFE relative to the benchmark, a combination of the radiographic diagnosis based on Klein's line, clinical symptoms and surgical treatment, was assessed computing sensitivity, specificity and accuracy. Results Intraobserver agreement between the surveys was moderate among paediatricians (κ-range, 0.44 to 0.52), moderate to almost perfect among orthopaedic surgeons (κ-range, 0.79 to 0.88) and almost perfect among paediatric radiologists (κ-range, 0.83 to 1.00). Interobserver agreement for survey 1 and 2 was slight among paediatricians (mean κ, 0.19), substantial among orthopaedic surgeons (mean κ, 0.77) and almost perfect among paediatric radiologists (mean κ, 0.86). Sensitivity of SCFE-diagnosis was high among radiologists and orthopaedic surgeons (88% to 100% for both specialties), but lower for paediatricians (24% to 76%). Specificity was high among radiologists and orthopaedic surgeons (72% to 84%), however, variable among paediatricians (56% to 80%). Accuracy of a SCFE-diagnosis was highest in radiologists (84% to 92%), followed by orthopaedic surgeons (80% to 88%) and paediatricians (48% to 78%). Conclusion SCFE can be detected on radiographs by different medical specialties. Intra- and interobserver agreement, specificity, sensitivity and accuracy for radiographic SCFE-diagnosis amongst paediatric radiologists and orthopaedic surgeons are better than that of general paediatricians. Level of Evidence II

Objective: Osteosarcoma is a highly aggressive malignancy for which treatment has remained essentially unchanged for years. Our previous studies found that the F-box protein SKP2 is overexpressed in osteosarcoma, acting as a proto-oncogene. p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases and a downstream substrate of SKP2. The present study focused on the role of SCF-SKP2-mediated ubiquitination and degradation of p27 in osteosarcoma (OS) tumorigenesis. Methods: We generated a genetically engineered mouse model with double-knockout of Rb1 and Trp53 within cells of the osteoblastic lineage using the Osterix1-Cre (Osx1-Cre;Rb1lox/lox;Trp53lox/lox, DKO). To block the interaction between Skp2 and p27, we cross DKO mice into the p27T187A knock-in mutation (p27:187site Thr to Ala) background to create Osx1-Cre;Rb1lox/lox;Trp53lox/lox;p27T187A/T187A (DKOAA) animals. Mice of both genotypes were monitored for overall survival and tumor growth. Early passage osteosarcoma cells were harvested from mice tumors and used for in vitro analysis. Annexin V staining and TUNEL assay were used for apoptosis analysis. RNA-seq and RT-qPCR were used to compare transcriptional differences. Further, a small-molecule SKP2/CKS1 pocket inhibitor (C1) and a neddylation inhibitor, Pevenodistat, were tested both in vitro using adherent cells and organoid culture, and in vivo using xenograft. Results: All genotypes were born at the expected ratios, and mutant animals are viable, fertile, and developmentally normal. The p27T187A mutation significantly prolonged the overall survival of DKO osteosarcoma mice. Western and IHC staining showed an accumulation of p27 in DKOAA, accompanied by an increased TUNEL staining level and apoptotic subpopulation determined by Annexin V staining. Hence, DKOAA tumors proliferate slower than DKO both in vivo and in vitro organoid. RNA-seq based enrichment analysis further confirmed an increase of apoptosis and cell cycle arrest in DKOAA tumors than DKO. RNA-seq also revealed a significant downregulation of multiple cancer stemness markers in DKOAA tumors. Further GESA enrichment analysis, ALDH activity assay, and sphere-formation assay consistently demonstrated a decreased stemness status in DKOAA tumors. Finally, SKP2 inhibitors, both C1 and Pevenodistat, showed selective inhibition in DKO than DKOAA in adherent culture, osteosarcoma organoid, and xenograft model. Conclusion: Blocking p27 degradation by SKP2 significantly delayed osteosarcoma tumorigenesis and prolonged survival, promoted apoptosis, and reduced tumor-initiating properties in OS model. Given that RB1 and TP53 co-inactivation is common in osteosarcoma, our study suggests that inhibiting the SKP2-p27 axis may represent a desirable therapeutic strategy for this cancer. Citation Format: Jichuan Wang, Osama Aldahamsheh, Alexander Ferrena, Swapnil Singh, Amit Singla, Hasibagan Borjihan, Simon Yaguare, Valentina Viscarret, Janet Tingling, Xiaolin Zi, Yungtai Lo, Richard Gorlick, Deyou Zheng, Edward L. Schwartz, Hongling Zhao, Rui Yang, David S. Geller, Bang H. Hoang. Targeting SKP2 by p27 Inhibits stemness and prolong the survival in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2008.

RATIONALE & OBJECTIVE: Metabolic acidosis associated with chronic kidney disease (CKD) may contribute to muscle dysfunction and bone disease. We aimed to test whether treatment with sodium bicarbonate improves muscle and bone outcomes. STUDY DESIGN: Multi-center, randomized, placebo-controlled clinical trial. SETTING & PARTICIPANTS: 149 patients with CKD stages 3 and 4 between 7/2011 and 4/2016 at three centers in Cleveland, OH and the Bronx, NY. INTERVENTION: Sodium bicarbonate (NaBicarb) (0.4 mEq per kilogram of ideal body weight per day) (n=74) or identical placebo (n=75). OUTCOMES: The dual primary outcomes were muscle function assessed by sit-to-stand test and bone mineral density. Muscle biopsies were collected at baseline and 2 months. Participants were seen at baseline, 2, 6, 12 and 24 months. RESULTS: The mean baseline serum bicarbonate level was 24.0 +/− 2.2 (SD) and mean baseline eGFR was 36.3 +/− 11.2 ml/min/1.7m(2). Baseline characteristics did not differ between groups. Mean serum bicarbonate levels in the intervention arm over follow-up were 26.4 +/− 2.2, 25.5 +/− 2.3, 25.6 +/− 2.6, and 24.4 +/− 2.8 mEq/L (at 2, 6, 12, and 24 months). These were significantly higher than in the placebo group (p

From our initial screening of applications, we assess that the 10% to 15% of applicants whom we will interview are all academically qualified to complete our residency training program. This initial screening to select applicants to interview includes a personality assessment provided by the personal statement, Dean’s letter, and letters of recommendation that, taken together, begin our evaluation of the applicant’s cultural fit for our program. While the numerical scoring ranks applicants preinterview, the final ranking into best fit categories is determined solely on the interview day at a consensus conference by faculty and residents. We analyzed data of 819 applicants from 2005 to 2017. Most candidates were US medical graduates (62.5%) with 23.7% international medical graduates, 11.7% Doctors of Osteopathic Medicine (DO), and 2.1% Caribbean medical graduates. Given that personality assessment began with application review, there was excellent correlation between the preinterview composite score and the final categorical ranking in all 4 categories. For most comparisons, higher scores and categorical rankings were associated with applicants subsequently working in academia versus private practice. We found no problem in using our 3-step process employing virtual interviews during the COVID pandemic.

Problem High-risk human papillomavirus (HR-HPV) is prevalent in HIV-infected women and may be associated with mucosal changes that promote HIV replication. Method of study Innate immune molecules, antimicrobial activity, HIV RNA, and HPV DNA genotypes were measured in a cross-sectional study of 128 HIV-infected women categorized into HPV-16 (n = 8), other HR-HPV (n = 41), and non-HR-HPV controls (n = 79). Results Compared to controls, HR-HPV groups had higher plasma viral loads (P = 0.004), lower CD4 cells (P = 0.02), more genital tract HIV RNA (P = 0.03), greater number of different HPV types (P < 0.001), higher cervicovaginal lavage (CVL) IL-1α (P = 0.03) and human beta-defensin 2 (HBD2) (P = 0.049), and less anti-HIVBal activity (P = 0.03). HPV-16 remained significantly associated with higher HBD2 (P = 0.03), higher IL-1α (P = 0.009), and lower anti-HIVBaL activity (P = 0.03) compared to controls after adjusting for plasma viral load and CD4 T cell count. Conclusion HR-HPV is associated with mucosal changes in HIV-infected women that could adversely impact genital tract health.

The Oncotype DX Breast Cancer Assay for ductal carcinoma in situ is used to determine local recurrence risk in patients with ductal carcinoma in situ. The results help select patients with low-risk ductal carcinoma in situ who could forgo radiation therapy after conservative surgery. The genes assessed include five proliferation genes, progesterone receptor (PR), and GSTM-1. Our objective was to determine if PR, mitotic counting, or any other pathologic feature of ductal carcinoma in situ could predict the Oncotype DX DCIS Score. We identified 46 cases of ductal carcinoma in situ with a Oncotype DX DCIS Score. In addition to information obtained from routine pathology, we counted mitotic figures in the ductal carcinoma in situ and noted presence of dense chronic inflammatory infiltrate surrounding ductal carcinoma in situ. We found that PR ≥ 90% (P = 0.004), mitotic count ≤ 1 (P = 0.045), estrogen receptor ≥ 90% (P = 0.046), and low nuclear grade (P0.0001) were associated with a low score. Dense chronic inflammation surrounding ductal carcinoma in situ was associated with a high score (P = 0.034).All 13 cases with PR ≥ 90%, ≤ 1 mitotic figure and absence of dense chronic inflammation around ductal carcinoma in situ had a low score (100% specificity). A low score was not observed in any case with at least two of the following--negative PR,1 mitotic figure, and/or presence of dense chronic inflammation around ductal carcinoma in situ (100% specificity). Our study suggests using a combination of PR (≥ 90% vs negative) with mitotic count in ductal carcinoma in situ (≤ 1 vs1) and dense chronic inflammation around ductal carcinoma in situ one could predict the Oncotype DX DCIS score. Mitotic counting and evaluation of immune response might provide prognostic information in ductal carcinoma in situ.

Misclassification is a long-standing statistical problem in epidemiology. In many real studies, either an exposure or a response variable or both may be misclassified. As such, potential threats to the validity of the analytic results (e.g., estimates of odds ratios) that stem from misclassification are widely discussed in the literature. Much of the discussion has been restricted to the nondifferential case, in which misclassification rates for a particular variable are assumed not to depend on other variables. However, complex differential misclassification patterns are common in practice, as we illustrate here using bacterial vaginosis and Trichomoniasis data from the HIV Epidemiology Research Study (HERS). Therefore, clear illustrations of valid and accessible methods that deal with complex misclassification are still in high demand. We formulate a maximum likelihood (ML) framework that allows flexible modeling of misclassification in both the response and a key binary exposure variable, while adjusting for other covariates via logistic regression. The approach emphasizes the use of internal validation data in order to evaluate the underlying misclassification mechanisms. Data-driven simulations show that the proposed ML analysis outperforms less flexible approaches that fail to appropriately account for complex misclassification patterns. The value and validity of the method are further demonstrated through a comprehensive analysis of the HERS example data. Copyright © 2015 John Wiley & Sons, Ltd.

Preclinical HIV prevention models use either a single high-dose viral challenge in depot medroxyprogesterone acetate-treated macaques or repeated viral challenges in cycling macaques. We tested the efficacy of an intravaginal tenofovir disoproxil fumarate (TDF) ring in a model combining repeated 30-mg injections of depot medroxyprogesterone acetate every 6 weeks with vaginal viral challenges weekly for 12 weeks. Twelve macaques were randomized to TDF or placebo rings. All placebo macaques became infected after a median of 2 exposures, whereas only 1 TDF macaque became infected at the eighth exposure (P = 0.0012). The TDF ring provides durable protection in a stringent challenge model.

Background Spectrins are the principal skeletal proteins involved in cellular adhesion migration and signal transduction and have been shown to be associated with integrate structure and function in complex tissue of all multi cellular organisms The present study investigates the role of spectrins in metastasis Methods Spectrin expression patterns were examined initially in cases normal benign and malignant samples Then primary tumor cases included in which were counts of metastasis and cases of body fluid metastasis without available primary tumor samples were studied Expression of spectrin isoforms aII bI bII and bIII were studied by immunohistochemistry in primary tumors cases with lymph node remote organ and body fluid metastasis the cases of malignant body fluids were paired with their corresponding primary tumors and analyzed Results In this paper we focus on the expression of aII and bIII isoforms We found an aberrant loss of aII mainly in breast invasive ductal carcinoma among other cancers Positive body fluids had markedly reduced aII and bIII expression P lt P lt respectively bII remained present in all the primary tumors and cytology samples No difference was identified in lymph node or remote organ metastasis Conclusion We posit based on the established role of spectrins in various forms of cancer and in cell structure and adhesion that spectrins play an important role in maintaining tissue structure with aberrant expression associated with body fluid metastasis

Background Hepatocellular carcinoma (HCC) appears to have worse prognosis among Hispanics and other ethnic minorities in the United States. We investigated the overall survival (OS) of Hispanics with HCC and compared it with non-Hispanic (NH) whites and NH blacks. Methods Patients diagnosed and treated for HCC at an urban medical center between 2000 and 2011 were identified from the institutional cancer registry. A Cox proportional-hazard model was used to assess survival differences between Hispanics, NH whites, and NH blacks after adjusting for clinically and statistically significant variables. Results A total of 681 patients were identified, 24 of whom were excluded due to inability to confirm the diagnosis of HCC based on radiologic criteria and 24 due to unavailable ethnicity data. The remaining 633 patients were used for analysis. Of this final cohort, 49% (n = 309) were Hispanic, 23% (n = 144) were NH white, and 28% (n = 180) were NH black. The median OS among Hispanics was 16.3 months and was similar to that of NH whites (14.0 months) and NH blacks (17.3 months) (P = 0.76). Multivariate analysis revealed a hazard ratio for death for Hispanics of 0.78 (95% confidence interval 0.58-1.07, P = .12) when compared with NH whites and a hazard ratio for death of 0.89 (95% confidence interval 0.68-1.19, P = 0.46) when compared with NH blacks. Conclusions In contrast to previous reports, Hispanics with HCC from this cohort experienced similar OS when compared with NH whites and NH blacks. Cancer 2014;120:3683–3690. © 2014 American Cancer Society.

A reservoir intravaginal ring (IVR) eluting tenofovir disoproxil fumarate (TDF) was evaluated for 6 months of continuous use in normally cycling female pigtailed macaques with monthly IVR exchanges to define pharmacokinetics and safety. Tenofovir levels in vaginal secretions and tissue remained consistent for six months with no adverse safety concerns.