HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

The induction of preterm labor in rhesus macaques is determined by the strength of immune response to intrauterine infection.

Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli-infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli-infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.

Teprotumumab for Thyroid Eye Disease-related Strabismus.

PURPOSE: To assess and quantify teprotumumab's effect on thyroid eye disease-related strabismus by change in measured horizontal and vertical deviations and change in extraocular motility. METHODS: We reviewed a series of patients with thyroid eye disease-related strabismus treated with teprotumumab. Exclusion criteria included age under 18 years, strabismus of alternate etiology, or thyroid eye disease-related reconstructive surgery during the treatment course. Primary outcomes were absolute (prism diopters) and relative (%) differences in horizontal and vertical deviations in primary position at distance, as well as change in ductions of the more affected eye. Secondary outcomes included incidence and timing of strabismus surgery postteprotumumab. RESULTS: Thirty-one patients were included, with mean age 63 years and thyroid eye disease duration 10 months. After teprotumumab, there was 6 prism diopters (39%) mean reduction in vertical deviation ( p < 0.001), without significant change in mean horizontal deviation ( p = 0.75). Supraduction, abduction, adduction, and infraduction significantly improved in the more restricted eye ( p < 0.01, p < 0.01, p = 0.04, and p = 0.01, respectively). Thirty-five percent of patients underwent strabismus surgery posttreatment, at an average 10 months after last infusion. CONCLUSIONS: Teprotumumab produced a statistically significant reduction in vertical but not horizontal strabismus angles in primary position at distance. Extraocular motility in all 4 ductions also improved. A substantial minority of patients still required strabismus surgery following teprotumumab.

Early Postoperative Volume Overload is a Predictor of 1-Year Post-Transplant Mortality in Pediatric Heart Transplant Recipients.

Fluid restriction and diuretic management are mainstays in the postoperative management of cardiac patients, at risk of volume overload and its deleterious effects on primary cardiac function and multi-organ systems. The importance of fluid homeostasis is further emphasized among orthotopic heart transplant recipients (OHT). We sought to investigate the relationship between postoperative volume overload, mortality, and allograft dysfunction among pediatric OHT recipients within 1-year of transplantation. This is a retrospective cohort study from a single pediatric OHT center. Children under 21 years undergoing cardiac transplantation between 2010 and 2018 were included. Cumulative fluid overload (cFO) was assessed as percent fluid accumulation adjusted for preoperative body weight. Greater than 10% cFO defined those with postoperative cFO and a comparison of postoperative cFO vs. no postoperative cFO (< 5%) is reported. 102 pediatric OHT recipients were included. Early cFO at 72 h post-OHT occurred in 14% and overall cFO at 1-week post-OHT occurred in 23% of patients. Risk factors for cFO included younger age, lower weight, and postoperative ECMO. Early cFO was associated with postoperative mortality at 1-year, OR 8.6 (95% CI 1.4, 51.6), p = 0.04, independent of age and weight. There was no significant relationship between cFO and allograft dysfunction, measured by rates of clinical rejection and cardiopulmonary filling pressures within 1-year of transplant. Early postoperative volume overload is prevalent and associated with increased risk of death at 1-year among pediatric OHT recipients. It may be an important postoperative marker of transplant survival, and this relationship warrants further clinical investigation.

Volumetric Assessment of the Anterior Digastric Muscles: A Deeper Understanding of the Volumetric Changes With Aging.

BACKGROUND: Targeting the deeper, subplatysmal structures in the neck has recently grown in popularity. In particular, interventions targeting the "bulky" anterior digastric (AD) muscle have been described with excellent results. However, much remains to be understood about the deep anatomy of the neck and the age-associated changes of the AD. OBJECTIVES: The aim of this study was to examine the relationship between AD volume and age. METHODS: This retrospective study calculated the AD volume from MRI segmentation in subjects between the ages of 20 to 92 years, scans of whom had previously been recorded. Those with compromised imaging due to pathology or artifact were excluded. Subjects were divided into 4 age-defined cohorts for clinical applicability. RESULTS: This study included 129 patients (male n = 64) with a mean age of 52.3. The AD volume of the reference group was 3.2 cm3. A linear decrease in muscle volume was observed with age compared with the reference group: 2.95 cm3 in the 45- to 54-year-old cohort (P = 0.3), 2.7 cm3 in the 55- to 64-year-old cohort (P = 0.05), and 2.45 cm3 in the >65-year-old cohort (P < 0.001). Male sex (P = 0.0001) and laterality (P = 0.003) were associated with significantly larger volumes. Overweight and obese BMI classification was not associated with a significantly different volume than normal or underweight subjects (P = 0.067). CONCLUSIONS: The study findings suggest an age-associated reduction in AD volume. Gender and laterality significantly affected volume, whereas BMI did not. Although the results do not support the theory of muscular hypertrophy with aging, they reveal that the perceived bulkiness may be due to changes in the surrounding anatomy affecting the morphology of the AD and subsequent blunting of the cervicomental angle.

Oncologic Outcomes of Multi-Institutional Minimally Invasive Inguinal Lymph Node Dissection for Melanoma Compared with Open Inguinal Dissection in the Second Multicenter Selective Lymphadenectomy Trial (MSLT-II).

BACKGROUND: Minimally invasive inguinal lymphadenectomy (MILND) is safe and feasible, but limited data exist regarding oncologic outcomes. METHODS: This study performed a multi-institutional retrospective cohort analysis of consecutive MILND performed for melanoma between January 2009 and June 2016. The open ILND (OILND) comparative cohort comprised patients enrolled in the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) between December 2004 and March 2014.The pre-defined primary end point was the same-basin regional nodal recurrence, calculated using properties of binomial distribution. Time to events was calculated using the Kaplan-Meier method. The secondary end points were overall survival, progression-free survival, melanoma-specific survival (MSS), and distant metastasis-free survival (DMFS). RESULTS: For all the patients undergoing MILND, the same-basin regional recurrence rate was 4.4 % (10/228; 95 % confidence interval [CI], 2.1-7.9 %): 8.2 % (4/49) for clinical nodal disease and 3.4 % (6/179) for patients with a positive sentinel lymph node (SLN) as the indication. For the 288 patients enrolled in MSLT-II who underwent OILND for a positive SLN, 17 (5.9 %) had regional node recurrence as their first event. After controlling for ulceration, positive LN count and positive non-SLNs at the time of lymphadenectomy, no difference in OS, PFS, MSS or DMFS was observed for patients with a positive SLN who underwent MILND versus OILND. CONCLUSION: This large multi-institutional experience supports the oncologic safety of MILND for melanoma. The outcomes in this large multi-institutional experience of MILND compared favorably with those for an OILND population during similar periods, supporting the oncologic safety of MILND for melanoma.

Factors Associated with Post-Acute Sequelae of SARS-CoV-2 (PASC) After Diagnosis of Symptomatic COVID-19 in the Inpatient and Outpatient Setting in a Diverse Cohort.

BACKGROUND: The incidence of persistent clinical symptoms and risk factors in Post-Acute Sequelae of SARS-CoV-2 (PASC) in diverse US cohorts is unclear. While there are a disproportionate share of COVID-19 deaths in older patients, ethnic minorities, and socially disadvantaged populations in the USA, little information is available on the association of these factors and PASC. OBJECTIVE: To evaluate the association of demographic and clinical characteristics with development of PASC. DESIGN: Prospective observational cohort of hospitalized and high-risk outpatients, April 2020 to February 2021. PARTICIPANTS: One thousand thirty-eight adults with laboratory-confirmed symptomatic COVID-19 infection. MAIN MEASURES: Development of PASC determined by patient report of persistent symptoms on questionnaires conducted 60 or 90 days after COVID-19 infection or hospital discharge. Demographic and clinical factors associated with PASC. KEY RESULTS: Of 1,038 patients with longitudinal follow-up, 309 patients (29.8%) developed PASC. The most common persistent symptom was fatigue (31.4%) followed by shortness of breath (15.4%) in hospitalized patients and anosmia (15.9%) in outpatients. Hospitalization for COVID-19 (odds ratio [OR] 1.49, 95% [CI] 1.04-2.14), having diabetes (OR, 1.39; 95% CI 1.02-1.88), and higher BMI (OR, 1.02; 95% CI 1-1.04) were independently associated with PASC. Medicaid compared to commercial insurance (OR, 0.49; 95% CI 0.31-0.77) and having had an organ transplant (OR 0.44, 95% CI, 0.26-0.76) were inversely associated with PASC. Age, race/ethnicity, Social Vulnerability Index, and baseline functional status were not associated with developing PASC. CONCLUSIONS: Three in ten survivors with COVID-19 developed a subset of symptoms associated with PASC in our cohort. While ethnic minorities, older age, and social disadvantage are associated with worse acute COVID-19 infection and greater risk of death, our study found no association between these factors and PASC.

Age-Related Changes in the Submandibular Gland: An Imaging Study of Gland Ptosis Versus Volume.

BACKGROUND: Debate surrounding the morphological evolution of the submandibular gland (SMG) with aging, and the uncertain influence of patient demographics, has led to hesitancy about incorporating targeted interventions of the SMG into clinical practice. OBJECTIVES: The aim of this study was to determine whether SMG ptosis, hypertrophy, or both is the primary etiology behind the increase in submandibular volume with age. METHODS: MRI segmentation was used to calculate the total and inframandibular (IM) volume and height of the SMG. Adult subjects with previous MRIs of the head and neck were used for analysis. Those with pathology or artifact compromising the SMG were excluded. Subjects were divided into 4 age-defined cohorts, for clinical applicability. RESULTS: The study included 129 patients (65 females; 64 males) with a mean age of 52.3 years (range, 20-85 years). No significant change in total SMG volume was observed between the reference group and all cohorts. The IM-SMG volume of the reference cohort was 5.77 cm3. All 3 cohorts had a greater IM-SMG volume than the reference group. The 45- to 54-year cohort had a mean volume of 6.7 cm3 (P = 0.4), the 55- to 64-year cohort, 7.5 cm3 (P = 0.01), and the ≥65-year cohort, 7.2 cm3 (P = 0.01). Male sex and overweight or obese BMI were associated with significantly larger total and IM-SMG volumes. CONCLUSIONS: The novel finding of a significantly larger IM-SMG volume with no change in total volume provides evidence for SMG ptosis rather than hypertrophy as a significant contributor to age-related submandibular fullness. The lack of any significant difference in total volume or height with aging emphasizes the role of glandular descent.

Filgrastim associations with CAR T-cell therapy.

Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T-cell therapy for diffuse large B-cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T-cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post-CAR T-cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T-cell therapy may lead to an increase in severity of CRS without decreasing infection rates.

Thrombomodulin is associated with increased mortality and organ failure in mechanically ventilated children with acute respiratory failure: biomarker analysis from a multicenter randomized controlled trial.

BACKGROUND: Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction. METHODS: This was a prospective observational study of 432 patients aged 2 weeks-17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-h intervals within 5 days after intubation. sTM was assayed by ELISA. The Hazard ratio (HR) for 90-day mortality was determined by Cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses. RESULTS: sTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n = 432, adjusted HR = 1.003, p = 0.02) and worse OI in the first 5 days after intubation (n = 252, Estimate = 0.02, p < 0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate = 0.003, p < 0.0001; and slope, Estimate = 0.01, p = 0.0009, n = 386). CONCLUSIONS: Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.

Impact of perceived contraceptive policy changes on long acting reversible contraception dispensing trends.

OBJECTIVE: We observed the long-term trend of Long Acting Reversible Contraception (LARC) usage before and after the 2016 presidential election. METHODS: We observed the rate of LARC dispensed at a university student health centre in the 18 months preceding and 27 months following the 2016 U.S. presidential election which posed threat to contraception access. We applied a segmented regression model using two linear regression line segments to evaluate whether there is a time point where the trend of LARC dispensing changed. We fit the regression models with a breakpoint at month 0 (election month) and 3 months with a Locally Estimated Scatterplot Smoothing (LOESS) estimate with parameters obtained by estimating simple linear regression models separately below and above the breakpoint '0'. RESULTS: There were a total of 2067 LARC methods dispensed from May 2015 to February 2019. The average number of LARC methods dispensed before November 2016 was 38/month and increased to 51/month post-presidential election. The LARC dispense rate significantly increased each month (0.38, 1.74; 95% confidence level, p < 0.05) until a breakpoint at 6 months (standard error 4.11) post-election followed by slower decrease (-0.59/month, 95% confidence level: -1.37, 0.20; p=not significant). CONCLUSION: Our study is the first to report long-term trends (27 months post-election) in LARC uptake amidst the public discourse that suggested the end of a policy that provided LARC insurance coverage. Although this observational study cannot suggest causality, the findings could reflect actions taken to prevent unintended pregnancy in response to the event of uncertain national policy.

Early Clinical Infancy Outcomes for Microcephaly and/or Small for Gestational Age Zika-Exposed Infants.

BACKGROUND: Zika-exposed infants with microcephaly (proportional or disproportional) and those who are small for gestational age without microcephaly should be closely followed, particularly their growth trajectories. They are at high risk of adverse outcomes in the first year of life.Antenatal Zika virus (ZIKV) exposure may lead to adverse infant outcomes including microcephaly and being small for gestational age (SGA). ZIKV-exposed infants with a diagnosis of microcephaly (proportional [PM] or disproportional [DM]) or SGA at birth were evaluated with anthropometric measurements and health outcomes. METHODS: Infants had laboratory-confirmed ZIKV exposure in Brazil. PM, DM, or SGA classification was based on head circumference and weight. First-year growth parameters and clinical outcomes were recorded with analyses performed. RESULTS: Among the 156 ZIKV-exposed infants, 14 (9.0%) were SGA, 13 (8.3%) PM, 13 (8.3%) DM, and 116 (74.4%) were neither SGA nor had microcephaly (NSNM). High rates of any neurologic, ophthalmologic, and hearing abnormalities were observed for PM (100%), DM (100%), and SGA (42.9%) vs NSNM infants (18.3%; P <.001); odds ratio [OR], 3.4 (95% confidence interval [CI], 1.1-10.7) for SGA vs NSNM. Neuroimaging abnormalities were seen in 100% of PM and DM and in 42.9% of SGA vs NSNM infants 16%; (P <.001); OR 3.9 (95% CI, 1.2-12.8) for SGA vs NSNM. Growth rates by z score, particularly for microcephaly infants, were poor after birth but showed improvement beyond 4 months of life. CONCLUSIONS: ZIKV-exposed infants with microcephaly (PM and DM) had similarly high rates of adverse outcomes but showed improvement in growth measurements beyond 4 months of life. While SGA infants had fewer adverse outcomes compared with microcephaly infants, notable adverse outcomes were observed in some; their odds of having adverse outcomes were 3 to 4 times greater compared to NSNM infants.Zika-exposed infants with microcephaly, irrespective of being proportional or disproportional, and those who are small for gestational age without microcephaly should be closely followed, particularly their growth trajectories. They are at high risk of adverse outcomes in the first year of life.

An Open Trial of a Mind-Body Intervention for Young Women with Moderate to Severe Primary Dysmenorrhea.

OBJECTIVE: To evaluate the feasibility, acceptability, and preliminary efficacy of a mind-body intervention for moderate to severe primary dysmenorrhea (PD). DESIGN: Open trial (single arm). SETTING: Academic medical school. SUBJECTS: A total of 20 young adult women with moderate to severe primary dysmenorrhea were included across four separate intervention groups. METHODS: All participants received five 90-minute sessions of a mind-body intervention and completed self-report measures of menstrual pain, depression, anxiety, somatization, and pain catastrophizing at baseline, post-treatment, and at one-, two-, three-, and 12-month follow-up. Self-report of medication use and use of skills learned during the intervention were also collected at all follow-up points. RESULTS: Participants reported significantly lower menstrual pain over time compared with baseline. No changes in anxiety, depression, or somatization were observed, although pain catastrophizing improved over time. Changes in menstrual pain were not associated with changes in medication use or reported use of skills. CONCLUSIONS: A mind-body intervention is a promising nondrug intervention for primary dysmenorrhea, and future research should focus on testing the intervention further as part of a randomized clinical trial.

Prevalence of Seizures and Risk Factors for Mortality in a Continuous Cohort of Pediatric Extracorporeal Membrane Oxygenation Patients.

OBJECTIVES: To evaluate the risk factors for mortality in pediatric extracorporeal membrane oxygenation patients. DESIGN: Retrospective, single-center study. SETTING: PICU and Pediatric cardiothoracic ICU in an urban, quaternary care center. PATIENTS: All neonatal and pediatric patients requiring extracorporeal membrane oxygenation at our institution between January 2014 and December 2018, who underwent a standardized continuous electroencephalogram neuromonitoring protocol during most of the duration of extracorporeal membrane oxygenation support. We excluded patients who had extracorporeal membrane oxygenation initiated at another institution. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Sixty-six children required extracorporeal membrane oxygenation support during this period. Four patients were excluded, three due to lack of electroencephalogram data, one with extracorporeal membrane oxygenation initiated at other institution. In the remaining 62, 11 patients (17%) had seizures, of which 5 (45%) had status epilepticus. Eight of 11 patients (72%) had exclusively electrographic seizures. A total of 33 patients (53.2%) died, of which 22 died during extracorporeal membrane oxygenation course, and one died 3 years after hospital discharge. Mean survival from extracorporeal membrane oxygenation initiation was 766.9 days (standard deviation, 691.7; median, 546.5; interquartile range 1-3, 97.7-1255.0). In multivariate analysis, increased risk of mortality was associated with the use of extracorporeal cardiopulmonary resuscitation (hazard ratio, 4.33; 95% CI, 1.75-10.72; p = 0.002), imaging findings of cerebral edema (hazard ratio, 14.31; 95% CI, 5.18-39.54; p < 0.001), high lactate level (> 100 mg/dL within 2 hr preextracorporeal membrane oxygenation) (hazard ratio, 1.22; 95% CI, 1.03-1.44; p = 0.022), and prolonged deep hypothermic circulatory arrest (hazard ratio, 3.43; 95% CI, 1.65-7.13; p < 0.001). Presence of seizures was associated with imaging findings of cerebral edema (hazard ratio, 4.16; 95% CI, 1.04-16.58; p = 0.04). CONCLUSIONS: Seizures are common in children requiring extracorporeal membrane oxygenation support, with a high rate of electrographic seizures and status epilepticus, as in prior studies. Presence of cerebral edema is both risk factor for mortality and seizures. Other risk factors for mortality include extracorporeal cardiopulmonary resuscitation, high lactate levels, and prolonged deep hypothermic circulatory arrest.

Progressive increases in fat mass occur in adults living with HIV on antiretroviral therapy, but patterns differ by sex and anatomic depot.

OBJECTIVES: Although weight gain on ART is common, the long-term trajectory of and factors affecting increases in fat mass in people living with HIV are not well described. METHODS: Men and women living with HIV in the Modena HIV Metabolic Clinic underwent DXA scans every 6-12 months for up to 10 years (median 4.6 years). Regression modelling in both combined and sex-stratified models determined changes in and clinical factors significantly associated with trunk and leg fat mass over the study period. RESULTS: A total of 839 women and 1759 men contributed two or more DXA scans. The baseline median age was 44 years and BMI 22.9 kg/m2; 76% were virologically suppressed on ART at baseline. For both sexes, trunk and leg fat consistently increased over the study period, with mean yearly trunk and leg fat gain of 3.6% and 7.5% in women and 6.3% and 10.8% in men, respectively. In multivariate analysis, factors associated with greater fat mass included female sex, per-year ART use (specifically tenofovir disoproxil fumarate and integrase strand transfer inhibitor therapy), per-unit BMI increase, no self-reported physical activity and CD4 nadir <200 cells/mm3. CONCLUSIONS: Among people living with HIV on ART, trunk and leg fat mass increased steadily over a median of 4.6 years of follow up, particularly among women. After controlling for traditional risk factors, HIV- and ART-specific risk factors emerged.

Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts.

OBJECTIVE: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling. RESULTS: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data. CONCLUSION: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

Obese- and allergic-related asthma phenotypes among children across the United States.

OBJECTIVES: Pediatric asthma is heterogeneous with phenotypes that reflect differing underlying inflammation and pathophysiology. Little is known about the national prevalence of certain obesity- and allergy-related asthma phenotypes or associated characteristics. We therefore assessed the national prevalence, risk factors, and caregiver-reported severity of four asthma phenotypes: not-allergic-not-obese, allergic-not-obese, obese-not-allergic, and allergic-and-obese. METHODS: We analyzed data from the 2007-2008 National Survey of Children's Health (NSCH) of 10-17 year-olds with caregiver-reported asthma. We described sociodemographic and health risk factors of each phenotype and then applied logistic and ordinal regression models to identify associated risk factors and level of severity of the phenotypes. RESULTS: Among 4427 children with asthma in this NSCH cohort, the association between race and phenotype was statistically significant (p < 0.0001); white children with asthma were most likely to have allergic-not-obese asthma while black and Hispanic children with asthma were most likely to have the obese-nonallergic phenotype (p < 0.001). Attention-deficit disorder/attention-deficit hyperactivity disorder was more likely to be present in allergic-not-obese children (odds ratio (OR) 1.50, confidence interval (CI) 1.14-1.98, p = 0.004). The phenotype with the highest risk for more severe compared to mild asthma was the obese-and-allergic asthma phenotype (OR 3.34, CI 2.23-5.01, p < 0.001). CONCLUSIONS: Allergic-not-obese asthma comprised half of our studied asthma phenotypes, while obesity-related asthma (with or without allergic components) comprised one-fifth of asthma phenotypes in this cohort representative of the US population. Children with both obese and allergic asthma are most likely to have severe asthma. Future management of childhood asthma might consider more tailoring of treatment and management plans based upon different childhood asthma phenotypes.

The Negative Impact of Body Mass Index on the Tumor Microenvironment in Colon Cancer: Results of a Prospective Trial.

BACKGROUND: The association between tumor mismatch repair status and obesity in colon cancer is not well understood. The authors of this study hypothesized that mismatch repair deficiency in colon cancer may be associated with a lower Body Mass Index (BMI) and improved patient outcome due to an enhanced tumor immune microenvironment. METHODS: For this study, 70 patients were randomly selected from a prospective trial evaluating nodal ultrastaging for colon cancer. The mismatch repair status of tumors and immunomarker expression were correlated with clinicopathologic characteristics and evaluated for disease-free survival. RESULTS: Patients with mismatch repair-deficient tumors (n = 11) had a lower mean BMI than those with mismatch repair-proficient tumors (n = 59) (22.16 vs. 26.30 kg/m2, respectively; p = 0.029).The findings showed that CD3+ T cells were inversely associated with mismatch repair proficiency (p = 0.048). Mismatch repair-proficient tumors in nonobese patients (BMI < 30 kg/m2) versus obese patients had a higher density of CD8+ (p = 0.008) and FOXP3+ (p = 0.005) T cells. Multivariable analysis linked CD4+ (hazard ratio [HR] 0.52; 95% confidence interval [CI] 0.35-0.76), CD8+ (HR 0.67; 95% CI 0.50-0.89), and number of tumor-positive lymph nodes (HR 1.19; 95% CI 1.03-1.36) to disease-free survival for patients with mismatch repair-proficient tumors. CONCLUSIONS: Tumor mismatch repair status and obesity are correlated in patients with colon cancer. Increased intratumoral T cells in nonobese patients suggests an unexplored link between tumor mismatch repair and immunoprofile.

Thin Melanoma with Nodal Involvement: Analysis of Demographic, Pathologic, and Treatment Factors with Regard to Prognosis.

BACKGROUND: Although only a small proportion of thin melanomas result in lymph node metastasis, the abundance of these lesions results in a relatively large absolute number of patients with a diagnosis of nodal metastases, determined by either sentinel lymph node (SLN) biopsy or clinical nodal recurrence (CNR). METHODS: Independent cohorts with thin melanoma and either SLN metastasis or CNR were identified at two melanoma referral centers. At both centers, SLN metastasis patients were included. At center 1, the CNR cohort included patients with initial negative clinical nodal evaluation followed by CNR. At center 2, the CNR cohort was restricted to those presenting in the era before the use of SLN biopsy. Uni- and multivariable analyses of melanoma-specific survival (MSS) were performed. RESULTS: At center 1, 427 CNR patients were compared with 91 SLN+ patients. The 5- and 10-year survival rates in the SLN group were respectively 88 and 84 % compared with 72 and 49 % in the CNR group (p < 0.0001). The multivariate analysis showed age older than 50 years (hazard ratio [HR] 1.5; 95 % confidence interval [CI] 1.2-1.9), present ulceration (HR 1.9; 95 % CI 1.2-2.9), unknown ulceration (HR 1.6; 95 % CI 1.3-2.1), truncal site (HR 1.6; 95 % CI 1.2-2.2), and CNR (HR 3.3; 95 % CI 1.8-6.0) to be associated significantly with decreased MSS (p < 0.01 for each). The center 2 cohort demonstrated remarkably similar findings, with a 5-year MSS of 88 % in the SLN (n = 29) group and 76 % in the CNR group (n = 39, p = 0.09). CONCLUSION: Patients with nodal metastases from thin melanomas have a substantial risk of melanoma death. This risk is lower among patients whose disease is discovered by SLN biopsy rather than CNR.