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Abstract This study investigates the desiccation process of soft-tissue in South Africa, analyzing its interaction with environmental parameters and its implications for estimating the post-mortem interval. Through the examination of four decomposing porcine bodies across two summer seasons and one winter season, the research quantifies desiccation patterns using custom-designed and constructed printed circuit boards to measure the moisture content of body tissue over time. Generalized additive models were used to determine the environmental forces driving desiccation. Tissue resistivity was tested against the environmental predictor variables to determine the amount of variation they account for, and predicted values of the region-specific tissue resistivity variables were measured for each decomposing body. Results reveal distinct desiccation trajectories between summer and winter, with summer conditions conducive to precocious natural mummification. Environmental factors, particularly temperature and solar radiation, emerge as significant drivers of desiccation. This study represents the first quantitative analysis of deep tissue desiccation internationally, but also the first quantitative assessment of desiccation and natural precocious mummification in the Western Cape, South Africa. The exploration of desiccation as a potential indicator for estimating PMI opens new avenues for research and the integration of innovative methodologies and technologies promises to revolutionize forensic taphonomy practices.

Abstract Youth screen media activity is a growing concern, though few studies include objective usage data. Through the longitudinal, U.S.-based Adolescent Brain Cognitive Development (ABCD) Study, youth (mage = 14; n = 1415) self-reported their typical smartphone use and passively recorded three weeks of smartphone use via the ABCD-specific Effortless Assessment Research System (EARS) application. Here we describe and validate passively-sensed smartphone keyboard and app use measures, provide code to harmonize measures across operating systems, and describe trends in adolescent smartphone use. Keyboard and app-use measures were reliable and positively correlated with one another (r = 0.33) and with self-reported use (rs = 0.21–0.35). Participants recorded a mean of 5 h of daily smartphone use, which is two more hours than they self-reported. Further, females logged more smartphone use than males. Smartphone use was recorded at all hours, peaking on average from 8 to 10 PM and lowest from 3 to 5 AM. Social media and texting apps comprised nearly half of all use. Data are openly available to approved investigators ( https://nda.nih.gov/abcd/ ). Information herein can inform use of the ABCD dataset to longitudinally study health and neurodevelopmental correlates of adolescent smartphone use.

This experiment (N = 1,019) examined how a state of processing fluency, induced through either an easy or difficult task (reading a simple vs. complex message or recalling few vs. many examples) impacted participants’ ability to subsequently detect misinformation. The results revealed that, as intended, easier tasks led to higher reports of processing fluency. In turn, increased processing fluency was positively associated with internal efficacy. Finally, internal efficacy was positively related to misinformation detection using a signal detection task. This work suggests that feelings of ease while processing information can promote confidence and a more discerning style of information processing. Given the proliferation of misinformation online, an understanding of how metacognitions – like processing fluency – can disrupt the tacit acceptance of information carries important democratic and normative implications.

Abstract Background Arrhythmia symptoms are frequent complaints in children and often require a pediatric cardiology evaluation. Data regarding the clinical utility of wearable technologies are limited in children. We hypothesize that an Apple Watch can capture arrhythmias in children. Methods We present an analysis of patients ≤18 years-of-age who had signs of an arrhythmia documented by an Apple Watch. We include patients evaluated at our center over a 4-year-period and highlight those receiving a formal arrhythmia diagnosis. We evaluate the role of the Apple Watch in arrhythmia diagnosis, the results of other ambulatory cardiac monitoring studies, and findings of any EP studies. Results We identify 145 electronic-medical-record identifications of Apple Watch, and find arrhythmias confirmed in 41 patients (28%) [mean age 13.8 ± 3.2 years]. The arrythmias include: 36 SVT (88%), 3 VT (7%), 1 heart block (2.5%) and wide 1 complex tachycardia (2.5%). We show that invasive EP study confirmed diagnosis in 34 of the 36 patients (94%) with SVT (2 non-inducible). We find that the Apple Watch helped prompt a workup resulting in a new arrhythmia diagnosis for 29 patients (71%). We note traditional ambulatory cardiac monitors were worn by 35 patients (85%), which did not detect arrhythmias in 10 patients (29%). In 73 patients who used an Apple Watch for recreational or self-directed heart rate monitoring, 18 (25%) sought care due to device findings without any arrhythmias identified. Conclusion We demonstrate that the Apple Watch can record arrhythmia events in children, including events not identified on traditionally used ambulatory monitors.

Abstract Predictions of total water levels, the elevation of combined tides, surge, and wave runup at the shoreline, are necessary to provide guidance on potential coastal erosion and flooding. Despite the importance of early warning systems for these hazards, existing real-time meteorological and oceanographic forecast systems at regional and national scales, until now, have lacked estimates of runup necessary to predict wave-driven overwash and erosion. To address this need, we present an approach that includes wave runup in an operational, national-scale modeling system. Using this system, we quantify the contribution of waves to potential dune erosion events along 4,700 km of U.S. Atlantic and Gulf of Mexico sandy coastlines for a one-year period. Dune erosion events were predicted to occur at over 80% of coastal locations, where waves dominated shoreline total water levels, representing 73% of the signal. This shows that models that neglect the wave component underestimate the hazard. This new, national-scale operational modeling system provides communities with timely, local-scale (0.5 km resolution) coastal hazard warnings for all wave conditions, allowing for rapid decision-making related to safety and emergency management. The modeling system also enables continued research into wave-driven processes at a broad range of coastal areas.

Abstract Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK‐1654, a half‐life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo‐controlled, single‐site, double‐blind trial of MK‐1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK‐1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK‐1654 was generally well‐tolerated in Japanese adults. There were no serious drug‐related adverse events (AEs) reported in any MK‐1654 recipient and no discontinuations due to any AEs in the study. The half‐life of MK‐1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose‐dependent manner among participants who received MK‐1654. These data support the development of MK‐1654 for use in Japanese infants.

Here, Xiao et al. isolate a large panel of antibodies against human metapneumovirus fusion protein from human B cells, and characterize their epitopes, neutralization activities, and antigen binding specificity, providing a useful framework for understanding the immune response against hMPV.

Globally, Streptococcus pneumoniae is a leading cause of vaccine-preventable morbidity and mortality in infants and children. In recent decades, large-scale pediatric immunization programs have substantially reduced the incidence of invasive pneumococcal disease. Despite this, residual vaccine-type pneumococcal disease remains in the form of vaccine breakthrough and vaccine failure. This targeted literature review aims to discuss aspects of vaccine breakthrough and failure in infants and children, including disease epidemiology, clinical presentation, risk factors, vaccination schedules, vaccine serotypes, correlates of protection, comorbidities, disease surveillance, and potential implications for future vaccine development.

Severe vitamin D deficiency (VDD) typically presents with overt hypocalcemia, hypophosphatemia, high alkaline phosphatase (ALP) and high parathyroid hormone (PTH). The clinical presentation and the biochemical features in atypical cases of VDD can be similar to pseudohypoparathyroidism (PHP). We present 2 patients with atypical laboratory findings of severe VDD secondary to restrictive eating disorders. PHP was considered, given hyperphosphatemia rather than hypophosphatemia classically seen with severe VDD. Renal PTH resistance, mimicking PHP, was observed in both cases with high phosphorus and high PTH levels in the setting of severe VDD. Calcitriol was added to the treatment to normalize serum calcium levels and overcome PTH resistance. Hypocalcemia and hyperphosphatemia resolved and PTH normalized with calcium, cholecalciferol and calcitriol supplementations and dietary modification, eliminating the need for further workup for PHP.

Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. V181 is an investigational, live, attenuated, quadrivalent dengue vaccine. In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in baseline flavivirus-naïve (BFN) and flavivirus-experienced (BFE) healthy adults were evaluated in two formulations: TV003 and TV005. TV005 contains a 10-fold higher DENV2 level than TV003. Two-hundred adults were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against the 4 DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. There were no discontinuations due to adverse events (AE) or serious vaccine-related AEs in the study. Most common AEs after TV003 or TV005 were headache, rash, fatigue, and myalgia. Tri- or tetravalent vaccine-viremia was detected in 63.9% and 25.6% of BFN TV003 and TV005 participants, respectively, post-dose 1 (PD1). Tri- or tetravalent dengue VRNT60 seropositivity was demonstrated in 92.6% of BFN TV003, 74.2% of BFN TV005, and 100% of BFE TV003 and TV005 participants PD1. Increases in VRNT60 GMTs were observed after the first vaccination with TV003 and TV005 in both flavivirus subgroups for all dengue serotypes, and minimal increases were measured PD2. GMTs in the TV003 and TV005 BFE and BFN groups remained above the respective baselines and placebo through 1-year PD2. These data support further development of V181 as a single-dose vaccine for the prevention of dengue disease.

Lipids play a major role in bacterial cells. Foremost, lipids are the primary constituents of the cell membrane bilayer, providing structure and separating the cell from the surrounding environment. This makes the lipid bilayer a prime target for antimicrobial peptides and membrane-acting antibiotics such as daptomycin. In response, bacteria have evolved mechanisms by which the membrane can be adapted to resist attack by these antimicrobial compounds. In this review, we focus on the membrane phospholipid changes associated with daptomycin resistance in enterococci, Staphylococcus aureus, and the Viridans group streptococci.

Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.

Background: Diabetes and liver disease are life-threatening complications of cystic fibrosis (CF). CF-liver disease is a risk factor for CF related diabetes (CFRD) development, but the underlying mechanisms linking the two co-morbidities are not known. The objective of this pilot study was to characterize glucose metabolism in youth with CF with and without liver disease. Methods: In this two-center cross-sectional study, 20 youth with CF with and without liver disease underwent a 3-hour oral glucose tolerance test. Subjects were categorized by liver disease (LD) status [no LD, mild LD, severe LD] and diabetes status. Measures of glucose excursion, islet cell secretory responses, insulin sensitivity and clearance were obtained. Results: Participants with severe LD had the highest fasting, peak, and glucose area under the curve over 3 h (AUC3h) among individuals with CFRD (interaction p

Abstract Background Fused deposition modeling 3D printing is used in medicine for diverse purposes such as creating patient-specific anatomical models and surgical instruments. For use in the sterile surgical field, it is necessary to understand the mechanical behavior of these prints across 3D printing materials and after autoclaving. It has been previously understood that steam sterilization weakens polylactic acid, however, annealing heat treatment of polylactic acid increases its crystallinity and mechanical strength. We aim to identify an optimal and commercially available 3D printing process that minimizes distortion after annealing and autoclaving and to quantify mechanical strength after these interventions. Methods Thirty millimeters cubes with four different infill geometries were 3D printed and subjected to hot water-bath annealing then immediate autoclaving. Seven commercially available 3D printing materials were tested to understand their mechanical behavior after intervention. The dimensions in the X, Y, and Z axes were measured before and after annealing, and again after subsequent autoclaving. Standard and strength-optimized Army-Navy retractor designs were printed using the 3D printing material and infill geometry that deformed the least. These retractors were subjected to annealing and autoclaving interventions and tested for differences in mechanical strength. Results For both the annealing and subsequent autoclaving intervention, the material and infill geometry that deformed the least, respectively, was Essentium PLA Gray and “grid”. Standard retractors without intervention failed at 95 N +/− 2.4 N. Annealed retractors failed at 127.3 N +/− 10 N. Autoclave only retractors failed at 15.7 N +/− 1.4 N. Annealed then autoclaved retractors failed at 19.8 N +/− 3.1 N. Strength-optimized retractors, after the annealing then autoclaving intervention, failed at 164.8 N +/− 12.5 N. Conclusion For 30 mm cubes, the 3D printing material and infill geometry that deformed the least, respectively, was Essentium PLA and “grid”. Hot water-bath annealing results in increased 3D printed model strength, however autoclaving 3D prints markedly diminishes strength. Strength-optimized 3D printed PLA Army-Navy retractors overcome the strength limitation due to autoclaving.

Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.

Objective To assess the accuracy of principal investigators’ (PIs) predictions about three events for their own clinical trials: positivity on trial primary outcomes, successful recruitment and timely trial completion. Study design and setting A short, electronic survey was used to elicit subjective probabilities within seven months of trial registration. When trial results became available, prediction skill was calculated using Brier scores (BS) and compared against uninformative prediction (i.e. predicting 50% all of the time). Results 740 PIs returned surveys (16.7% response rate). Predictions on all three events tended to exceed observed event frequency. Averaged PI skill did not surpass uninformative predictions (e.g., BS = 0.25) for primary outcomes (BS = 0.25, 95% CI 0.20, 0.30) and were significantly worse for recruitment and timeline predictions (BS 0.38, 95% CI 0.33, 0.42; BS = 0.52, 95% CI 0.50, 0.55, respectively). PIs showed poor calibration for primary outcome, recruitment, and timelines (calibration index = 0.064, 0.150 and 0.406, respectively), modest discrimination in primary outcome predictions (AUC = 0.76, 95% CI 0.65, 0.85) but minimal discrimination in the other two outcomes (AUC = 0.64, 95% CI 0.57, 0.70; and 0.55, 95% CI 0.47, 0.62, respectively). Conclusion PIs showed overconfidence in favorable outcomes and exhibited limited skill in predicting scientific or operational outcomes for their own trials. They nevertheless showed modest ability to discriminate between positive and non-positive trial outcomes. Low survey response rates may limit generalizability.

The recently discovered insecticidal protein Mpp75Aa1.1 from Brevibacillus laterosporus is a member of the ETX_MTX family of beta-pore forming proteins (β-PFPs) expressed in genetically modified (GM) maize to control western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte). In this manuscript, bioinformatic analysis establishes that although Mpp75Aa1.1 shares varying degrees of similarity to members of the ETX_MTX2 protein family, it is unlikely to have any allergenic, toxic, or otherwise adverse biological effects. The safety of Mpp75Aa1.1 is further supported by a weight of evidence approach including evaluation of the history of safe use (HOSU) of ETX_MTX2 proteins and Breviballus laterosporus. Comparisons between purified Mpp75Aa1.1 protein and a poly-histidine-tagged (His-tagged) variant of the Mpp75Aa1.1 protein demonstrate that both forms of the protein are heat labile at temperatures at or above 55°C, degraded by gastrointestinal proteases within 0.5 min, and have no adverse effects in acute mouse oral toxicity studies at a dose level of 1920 or 2120 mg/kg body weight. These results support the use of His-tagged proteins as suitable surrogates for assessing the safety of their non-tagged parent proteins. Taken together, we report that Mpp75Aa1.1 is the first ETX-MTX2 insecticidal protein from B. laterosporus and displays a similar safety profile as typical Cry proteins from Bacillus thuringiensis.

As females with cystic fibrosis (CF) increasingly reach their reproductive years, gynecologic issues have become an important area of clinical care and research. First, females with CF may have disease-specific gynecologic problems, including cyclic pulmonary symptoms, vaginal yeast infections, and urinary incontinence. Next, contraceptive methods are thought to be overall safe and effective, however further research is needed to confirm this and to understand the lower rates of uptake among females with CF compared to the general population. Further, females with CF have reduced fertility, although the etiology of this is unknown and under investigation. While assisted reproductive technologies may help achieve pregnancy, decision-making around parenthood remains complex. Finally, while patients and providers agree on the importance of sexual and reproductive health care, females with CF underutilize basic preventive services such as cervical cancer screening, and better approaches are needed to bridge the gap with gynecology. In this review, we discuss the current state of gynecologic care for females with CF, as well as clinical and research opportunities for improvement.

BackgroundConcerns abound regarding childhood smartphone use, but studies to date have largely relied on self-reported screen use. Self-reporting of screen use is known to be misreported by pediatric samples and their parents, limiting the accurate determination of the impact of screen use on social, emotional, and cognitive development. Thus, a more passive, objective measurement of smartphone screen use among children is needed. ObjectiveThis study aims to passively sense smartphone screen use by time and types of apps used in a pilot sample of children and to assess the feasibility of passive sensing in a larger longitudinal sample. MethodsThe Adolescent Brain Cognitive Development (ABCD) study used passive, objective phone app methods for assessing smartphone screen use over 4 weeks in 2019-2020 in a subsample of 67 participants (aged 11-12 years; 31/67, 46% female; 23/67, 34% White). Children and their parents both reported average smartphone screen use before and after the study period, and they completed a questionnaire regarding the acceptability of the study protocol. Descriptive statistics for smartphone screen use, app use, and protocol feasibility and acceptability were reviewed. Analyses of variance were run to assess differences in categorical app use by demographics. Self-report and parent report were correlated with passive sensing data. ResultsSelf-report of smartphone screen use was partly consistent with objective measurement (r=0.49), although objective data indicated that children used their phones more than they reported. Passive sensing revealed the most common types of apps used were for streaming (mean 1 hour 57 minutes per day, SD 1 hour 32 minutes), communication (mean 48 minutes per day, SD 1 hour 17 minutes), gaming (mean 41 minutes per day, SD 41 minutes), and social media (mean 36 minutes per day, SD 1 hour 7 minutes). Passive sensing of smartphone screen use was generally acceptable to children (43/62, 69%) and parents (53/62, 85%). ConclusionsThe results of passive, objective sensing suggest that children use their phones more than they self-report. Therefore, use of more robust methods for objective data collection is necessary and feasible in pediatric samples. These data may then more accurately reflect the impact of smartphone screen use on behavioral and emotional functioning. Accordingly, the ABCD study is implementing a passive sensing protocol in the full ABCD cohort. Taken together, passive assessment with a phone app provided objective, low-burden, novel, informative data about preteen smartphone screen use.

Background: Self-reported physical activity is often inaccurate. Wearable devices utilizing multiple sensors are now widespread. The aim of this study was to determine acceptability of Fitbit Charge HR for children and their families, and to determine best practices for processing its objective data. Methods: Data were collected via Fitbit Charge HR continuously over the course of 3 weeks. Questionnaires were given to each child and their parent/guardian to determine the perceived usability of the device. Patterns of data were evaluated and best practice inclusion criteria recommended. Results: Best practices were established to extract, filter, and process data to evaluate device wear, r and establish minimum wear time to evaluate behavioral patterns. This resulted in usable data available from 137 (89%) of the sample. Conclusions: Activity trackers are highly acceptable in the target population and can provide objective data over longer periods of wear. Best practice inclusion protocols that reflect physical activity in youth are provided.

Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.

Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization. Here, the authors isolate a human monoclonal antibody that binds to a highly conserved epitope on the RSV fusion protein, neutralizes RSV A and B subtypes equipotently and is protective in the cotton rat model.

Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.

In mid-March 2020, our institution removed most medical students from in-person clinical clerkships due to the COVID-19 pandemic. The Department of Pathology responded by transitioning a fourth-year clinical elective to an all-remote format composed of synchronous didactics, daily clinical sign-out utilizing digital microscopy, and asynchronous learning materials. Thirty-seven medical students completed 2- or 4-week anatomic pathology electives tailored to meet their career goals and allowing them to progress toward graduation. Institutional Review Board approval was granted to survey students’ perceptions of engagement in the remote learning environment. Quantitative and qualitative data were collected using a standardized school-wide end-of-rotation survey, an online survey developed by the authors, and students’ self-directed learning goals. End-of-rotation data showed the remote pathology course performed well (4.88 of possible 5) when compared to all advanced clinical clerkships (4.51, n = 156 courses), all elective rotations (4.41, n = 50 courses), and the traditional in-person pathology elective (4.73). Core strengths in the virtual environment included high educational value, flexibility of content and schedule, organization, tailoring to an individual’s learning goals, and a positive education environment. Deficits included the inability to gross surgical specimens, inadequate observation or feedback about students’ skills, and impaired social connections. Areas for improvement included requests for in-person experiences and development of themed tracks for career exploration. Many aspects of anatomic pathology appear well-suited to the remote learning environment. While the remote model may not be sufficient for students pursuing careers in pathology, it can be adapted to increase nonpathologists’ understanding of interdisciplinary clinical collaboration with pathologists.

AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9–10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study—a multi-site sample of 9–10 year-olds (n = 11,875)—and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child’s weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9–10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Traumatic brain injury (TBI) in children can result in long-lasting social, cognitive, and neurological impairments. In adults, TBI can lead to endocrinopathies (endocrine system disorders), but this is infrequently reported in children. Untreated endocrinopathies can elevate risks of subsequent health issues, such that early detection in pediatric TBI survivors can initiate clinical interventions. To understand the risk of endocrinopathies following pediatric TBI, we identified patients who had experienced a TBI and subsequently developed a new-onset hypothalamic regulated endocrinopathy (n = 498). We hypothesized that pediatric patients who were diagnosed with a TBI were at higher risk of being diagnosed with a central endocrinopathy than those without a prior diagnosis of TBI. In our epidemiological assessment, we identified pediatric patients enrolled in the Arizona Health Care Cost Containment System (AHCCCS) from 2008 to 2014 who were diagnosed with one of 330 TBI International Classification of Diseases (ICD)-9 codes and subsequently diagnosed with one of 14 central endocrinopathy ICD-9 codes. Additionally, the ICD-9 code data from over 600,000 Arizona pediatric patients afforded an estimate of the incidence, prevalence, relative risk, odds ratio, and number needed to harm, regarding the development of a central endocrinopathy after sustaining a TBI in Arizona Medicaid pediatric patients. Children with a TBI diagnosis had 3.22 times the risk of a subsequent central endocrine diagnosis compared with the general population (±0.28). Pediatric AHCCCS patients with a central endocrine diagnosis had 3.2-fold higher odds of a history of a TBI diagnosis than those without an endocrine diagnosis (±0.29). Furthermore, the number of patients with a TBI diagnosis for one patient to receive a diagnosis of a central endocrine diagnosis was 151.2 (±6.12). Female subjects were more likely to present with a central endocrine diagnosis after a TBI diagnosis compared to male subjects (64.1 vs. 35.9%). These results are the first state-wide epidemiological study conducted to determine the risk of developing a hypothalamic-pituitary disorder after a TBI in the pediatric population. Our results contribute to a body of knowledge demonstrating a TBI etiology for idiopathic endocrine disorders, and thus advise physicians with regard to TBI follow-up care that includes preventive screening for endocrine disorders.

Abstract Background Community-acquired pneumonia is a leading infectious cause of hospitalization. A few vaccines exist to prevent pneumococcal disease in adults, including a pneumococcal polysaccharide unconjugated vaccine and a protein conjugated polysaccharide vaccine. Previous studies on the human immune response to the unconjugated vaccine showed that the vaccine boosted the existing memory B cells. In the present study, we investigated the human B cell immune response following pneumococcal polysaccharide conjugate vaccination. Methods Plasmablast B cells from a pneumococcal polysaccharide conjugate vaccinee were isolated and cloned for analysis. In response to primary vaccination, identical sequences from the plasmablast-derived antibodies were identified from multiple B cells, demonstrating evidence of clonal expansion. We evaluated the binding specificity of these human monoclonal antibodies in immunoassays, and tested there in vitro function in a multiplexed opsonophagocytic assay (MOPA). To characterize the plasmablast B cell response to the pneumococcal conjugated vaccine, the germline usage and the variable region somatic hypermutations on these antibodies were analyzed. Furthermore, a serotype 4 polysaccharide-specific antibody was tested in an animal challenge study to explore the in vivo functional activity. Results The data suggests that the pneumococcal polysaccharide conjugate vaccine boosted memory B cell responses, likely derived from previous pneumococcal exposure. The majority of the plasmablast-derived antibodies contained higher numbers of variable region somatic hypermutations and evidence for selection, as demonstrated by replacement to silent ratio’s (R/S) greater than 2.9 in the complementarity-determining regions (CDRs). In addition, we found that VH3/JH4 was the predominant germline sequence used in these polysaccharide-specific B cells. All of the tested antibodies demonstrated narrow polysaccharide specificity in ELISA binding, and demonstrated functional opsonophagocytic killing (OPK) activity in the MOPA assay. The in-vivo animal challenge study showed that the tested serotype 4 polysaccharide-specific antibody demonstrated a potent protective effect when administered prior to bacterial challenge. Conclusions The findings on the pneumococcal polysaccharide conjugate vaccine responses from a vaccinated subject reported in this study are similar to previously published data on the pneumococcal polysaccharide unconjugated vaccine responses. In both vaccine regimens, the pre-existing human memory B cells were expanded after vaccination with preferential use of the germline VH3/JH4 genes.

Background and aimsThe precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation.MethodsThis study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined.ResultsParticipants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (β = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (β = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (β = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (β = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (β = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable.ConclusionWe found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

Abstract ES-62, a glycoprotein secreted by the parasitic filarial nematode Acanthocheilonema viteae, subverts host immune responses towards anti-inflammatory phenotypes by virtue of covalently attached phosphorylcholine (PC). The PC dictates that ES-62 exhibits protection in murine models of inflammatory disease and hence a library of drug-like PC-based small molecule analogues (SMAs) was synthesised. Four sulfone-containing SMAs termed 11a, 11e, 11i and 12b were found to reduce mouse bone marrow-derived dendritic cell (DC) pathogen-associated molecular pattern (PAMP)-induced pro-inflammatory cytokine production, inhibit NF-κB p65 activation, and suppress LPS-induced up-regulation of CD40 and CD86. Active SMAs also resulted in a DC phenotype that exhibited reduced capacity to prime antigen (Ag)-specific IFN-γ production during co-culture with naïve transgenic TCR DO.11.10 T cells in vitro and reduced their ability, following adoptive transfer, to prime the expansion of Ag-specific T lymphocytes, specifically TH17 cells, in vivo. Consistent with this, mice receiving DCs treated with SMAs exhibited significantly reduced severity of collagen-induced arthritis and this was accompanied by a significant reduction in IL-17+ cells in the draining lymph nodes. Collectively, these studies indicate that drug-like compounds that target DCs can be designed from parasitic worm products and demonstrate the potential for ES-62 SMA-based DC therapy in inflammatory disease.

BackgroundIn previous pilot work we demonstrated that a novel automated signal analysis tool could accurately identify successful ablation sites during Wolff-Parkinson-White (WPW) ablation at a single center.ObjectiveWe sought to validate and refine this signal analysis tool in a larger multi-center cohort of children with WPW.MethodsA retrospective review was performed of signal data from children with WPW who underwent ablation at two pediatric arrhythmia centers from 2008-2015. All patients with WPW ≤ 21 years who underwent invasive electrophysiology study and ablation with ablation signals available for review were included. Signals were excluded if temperature or power delivery was inadequate or lesion time was < 5 seconds. Ablation lesions were reviewed for each patient. Signals were classified as successful if there was loss of antegrade and retrograde accessory pathway (AP) conduction or unsuccessful if ablation did not eliminate AP conduction. Custom signal analysis software analyzed intracardiac electrograms for amplitudes, high and low frequency components, integrated area, and signal timing components to create a signal score. We validated the previously published signal score threshold 3.1 in this larger, more diverse cohort and explored additional scoring options. Logistic regression with lasso regularization using Youden's index criterion and a cost-benefit criterion to identify thresholds was considered as a refinement to this score.Results347 signals (141 successful, 206 unsuccessful) in 144 pts were analyzed [mean age 13.2 ± 3.9 years, 96 (67%) male, 66 (45%) left sided APs]. The software correctly identified the signals as successful or unsuccessful in 276/347 (80%) at a threshold of 3.1. The performance of other thresholds did not significantly improve the predictive ability. A signal score threshold of 3.1 provided the following diagnostic accuracy for distinguishing a successful from unsuccessful signal: sensitivity 83%, specificity 77%, PPV 71%, NPV 87%.ConclusionsAn automated signal analysis software tool reliably distinguished successful versus unsuccessful ablation electrograms in children with WPW when validated in a large, diverse cohort. Refining the tools using an alternative threshold and statistical method did not improve the original signal score at a threshold of 3.1. This software was effective across two centers and multiple operators and may be an effective tool for ablation of WPW.

This article considers the reauthorization of the Elementary and Secondary Education Act (ESEA) in light of current educational inequities and the impact of the pandemic. The reauthorization presents an opportunity to center equity and justice and revitalize the civil rights aspects of the law. The authors review recent studies about the myriad ways the COVID-19 pandemic affected students, teachers and school systems and situates the reauthorization within the broader political context, including federal aid to states and districts during the pandemic. The authors present overarching policy recommendations: (1) a restructuring of the law's titles to focus on students, teachers, and systems (i.e. schools and districts); (2) a focus on the principles of racial equity, an ecosystem approach to serve students' needs across policy silos (i.e., housing and health), and a focus on research evidence; (3) policy targets for students; (4) policy targets for educators, including professional renewal and retention; (5) policy targets for the education system as a whole, including a focus on fiscal equity and facilitating regional approaches to cross-sector collaborations. The article presents a coherent conceptual framework for a redesign of ESEA with an emphasis on equity, evidence use, and ecosystems that is argued would directly address the needs of students, teachers, and systems.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), continues to wreak havoc, threatening the public health services and imposing economic collapse worldwide. Tailoring public health responses to the SARS-CoV-2 pandemic depends on understanding the mechanism of viral replication, disease pathogenesis, accurately identifying acute infections, and mapping the spreading risk of hotspots across the globe. However, effective identification and isolation of persons with asymptomatic and mild SARS-CoV-2 infections remain the major obstacles to efforts in controlling the SARS-CoV-2 spread and hence the pandemic. Understanding the mechanism of persistent viral shedding, reinfection, and the post-acute sequalae of SARS-CoV-2 infection (PASC) is crucial in our efforts to combat the pandemic and provide better care and rehabilitation to survivors. Here, we present a living literature review (January 2020 through 15 March 2021) on SARS-CoV-2 viral persistence, reinfection, and PASC. We also highlight potential areas of research to uncover putative links between viral persistence, intra-host evolution, host immune status, and protective immunity to guide and direct future basic science and clinical research priorities.

Youth screen media activity is a growing concern, though few studies include objective usage data. Through the longitudinal, U.S.-based Adolescent Brain Cognitive Development (ABCD) Study, youth (mage = 14; n = 1415) self-reported their typical smartphone use and passively recorded three weeks of smartphone use via the ABCD-specific Effortless Assessment Research System (EARS) application. Here we describe and validate passively-sensed smartphone keyboard and app use measures, provide code to harmonize measures across operating systems, and describe trends in adolescent smartphone use. Keyboard and app-use measures were reliable and positively correlated with one another (r = 0.33) and with self-reported use (rs = 0.21-0.35). Participants recorded a mean of 5 h of daily smartphone use, which is two more hours than they self-reported. Further, females logged more smartphone use than males. Smartphone use was recorded at all hours, peaking on average from 8 to 10 PM and lowest from 3 to 5 AM. Social media and texting apps comprised nearly half of all use. Data are openly available to approved investigators ( https://nda.nih.gov/abcd/ ). Information herein can inform use of the ABCD dataset to longitudinally study health and neurodevelopmental correlates of adolescent smartphone use.

The exposed selvedge layers in slabs cast by the continuous process should be free from surface defects, which in most cases appear in the form of cracks on the casting surface and run to its interior. In addition to the parameters of the casting process, the occurrence of such defects depends on the chemical composition of cast steel, on the segregation of surface active elements and formation of the precipitates of carbides, nitrides and other phases. Due to the frequent occurrence of defects in corners of the slabs, non-destructive testing was performed on the mechanically cleaned surfaces of slabs. The test material was low-carbon API(American Petroleum Institute API 5L standard) steel micro alloyed with Nb and Ti designed for the production of pipes to handle gas, oil and other liquid and gaseous fuels. Despite the use of different methods of inspection, i.e. ultrasonic, magnetic particle and penetrant, cracks were not traced in the examined material. Then, from the corners of the examined slabs, specimens were cut out for metallographic examinations. The main purpose of these examinations was to disclose the presence of possible cracks and micro cracks on the surfaces transversal and longitudinal to the direction of casting. At the same time, studies were conducted to establish the number and morphology of non-metallic inclusions in selvedge layers of the slab corners and axis. Additionally, hardness of the slabs was measured. The conducted studies revealed only some minor differences in the slab hardness along its axis (130 ÷ 135 HB) and in selvedge layers (120 ÷ 123 HB).

This review has two primary objectives: (1) to offer a balanced examination of recent findings on the relationship between screen media activity (SMA) in young individuals and outcomes such as sleep patterns, mood disturbances, anxiety-related concerns, and cognitive processes; and (2) to introduce a novel multi-level system model that integrates these findings, resolves contradictions in the literature, and guides future studies in examining key covariates affecting the SMA-mental health relationship. Key findings include: (1) Several meta-analyses reveal a significant association between SMA and mental health issues, particularly anxiety and depression, including specific negative effects linked to prolonged screen time; (2) substantial evidence indicates that SMA has both immediate and long-term impacts on sleep duration and quality; (3) the relationship between SMA and cognitive functioning is complex, with mixed findings showing both positive and negative associations; and (4) the multifaceted relationship between SMA and various aspects of adolescent life is influenced by a wide range of environmental and contextual factors. SMA in youth is best understood within a complex system encompassing individual, caregiver, school, peer, and environmental factors, as framed by Bronfenbrenner's ecological systems theory, which identifies five interrelated systems (microsystem, mesosystem, exosystem, macrosystem, and chronosystem) that influence development across both proximal and distal levels of the environment. This model provides a framework for future research to examine these interactions, considering moderating factors, and to develop targeted interventions that can mitigate potential adverse effects of SMA on mental well-being.

Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory tract disease in young children and older adults throughout the world. Prevention of severe RSV disease through active immunization is optimal but no RSV vaccine has been licensed so far. Immune mechanisms of protection against RSV infection in humans have not been fully established, thus a comprehensive characterization of virus-specific immune responses in a relevant animal model will be beneficial in defining correlates of protection. In this study, we infected juvenile naive AGMs with RSV A2 strain and longitudinally assessed virus-specific humoral and cellular immune responses in both peripheral blood and the respiratory tract. RSV viral loads at nasopharyngeal surfaces and in the lung peaked at around day 5 following infection, and then largely resolved by day 10. Low levels of neutralizing antibody titers were detected in serum, with similar kinetics as RSV fusion (F) protein-binding IgG antibodies. RSV infection induced CD8+, but very little CD4+, T lymphocyte responses in peripheral blood. Virus-specific CD8+ T cell frequencies were ~10 fold higher in bronchoaveolar lavage (BAL) compared to peripheral blood and exhibited effector memory (CD95+CD28-) / tissue resident memory (CD69+CD103+) T (TRM) cell phenotypes. The kinetics of virus-specific CD8+ T cells emerging in peripheral blood and BAL correlated with declining viral titers, suggesting that virus-specific cellular responses contribute to the clearance of RSV infection. RSV-experienced AGMs were protected from subsequent exposure to RSV infection. Additional studies are underway to understand protective correlates in these seropositive monkeys.

Selcuk Kara,1 Nilgun Yildirim,2 Ahmet Ozer,2 Omer Colak,3 Afsun Sahin21Department of Ophthalmology, Canakkale Onsekiz Mart University School of Medicine, Canakkale, 2Department of Ophthalmology, Eskisehir Osmangazi University Hospitals, Meselik, Eskisehir, 3Department of Biochemistry, Eskisehir Osmangazi University Hospitals, Meselik, Eskisehir, TurkeyPurpose: The aim of the study reported in this article was to determine the presence and quantitative differences of matrix metalloproteinase-2 (MMP-2), its tissue inhibitor (TIMP-2) and transforming growth factor beta 1 (TGF-β1) in the aqueous humor and serum samples of patients with pseudoexfoliation (PEX) syndrome.Methods: Aqueous humor and serum samples were collected from 32 patients with PEX syndrome (with and without glaucoma) and a control group, who underwent routine cataract surgery. Levels of MMP-2, TIMP-2, and TGF-β1 were determined by specific immunoassays (enzyme-linked immunosorbent assay).Results: MMP-2, TIMP-2, and TGF-β1 were identified in aqueous humor and serum samples from all groups of patients. The aqueous and serum samples of MMP-2, TIMP-2, and TGF-β1 showed no significant differences between PEX syndrome and control groups. Serum levels of MMP-2, TIMP-2, and TGF-β1 were statistically greater than their aqueous levels (P

Una serie de académicos han estudiado el contexto del distrito en el que se encuentran inmersos los centros educativos. Estos estudios sugieren la importancia de las oficinas municipales como apoyo o limitación del trabajo de los centros educativos ofreciendo estrategias para construir las relaciones entre los distritos y los líderes locales. Esta es una tarea importante y, sin embargo, frecuentemente se pasa por alto que las mejoras de los esfuerzos organizativos se construyen socialmente. Por ello, el análisis de las redes sociales y la confianza entre los líderes del distrito y de los centros educativos puede proporcionar una visión desde dentro respecto a los apoyos y limitaciones relacionados con la mejora. En este estudio de caso se utiliza una red social y datos sobre la confianza para explorar las mejores prácticas relacionadas con los líderes, en un distrito escolar de tamaño medio con bajo rendimiento. Los resultados sugieren unos lazos sociales de la red débiles, bajos niveles de confianza y una previsible relación entre la confianza y los intercambios recíprocos con las mejores prácticas relacionadas con la mejora.

Parasitic helminths and their isolated secreted products show promise as novel treatments for allergic and autoimmune conditions in humans. Foremost amongst the secreted products is ES-62, a glycoprotein derived from Acanthocheilonema viteae, a filarial nematode parasite of gerbils, which is anti-inflammatory by virtue of covalently-attached phosphorylcholine (PC) moieties. ES-62 has been found to protect against disease in mouse models of rheumatoid arthritis, systemic lupus erythematosus, and airway hyper-responsiveness. Furthermore, novel PC-based synthetic small molecule analogues (SMAs) of ES-62 have recently been demonstrated to show similar anti-inflammatory properties to the parent molecule. In spite of these successes, we now show that ES-62 and its SMAs are unable to provide protection in mouse models of certain autoimmune conditions where other helminth species or their secreted products can prevent disease development, namely type I diabetes, multiple sclerosis and inflammatory bowel disease. We speculate on the reasons underlying ES-62’s failures in these conditions and how the negative data generated may help us to further understand ES-62’s mechanism of action.

Research provides ample evidence that positive social relations and access to knowledge are supportive for educational change. However, few studies have examined how personnel turnover and restructuring in school districts influence these processes, specifically as they relate to leaders' access to research evidence and perception of organizational learning and culture. In this longitudinal exploratory mixed-methods case study, we examine the changes in social networks and organizational learning among school and district leaders during a 3-year district restructuring process. Our study uses social network analysis, bivariate analyses, and qualitative coding. We surveyed district and school leaders about their districts' capacity for organizational learning, organizational culture, and social ties around research evidence. Our results suggest a decrease in the district's capacity to diffuse ideas from research between Years 1 and 3, which may inhibit efforts for improvement. Further, the data on school and district leaders who did not leave the district indicates a decrease in the perception of organizational learning and culture in school sites, but not in the district with differences between principals and central office staff. Qualitative findings support an association between the restructuring and changes in organizational learning and social structures and provide further reasons for the changes (e.g., lack of communication, time to maintain/build relationships, and opportunities for professional development). These findings speak to the importance of leaders focusing on the social side of change during times of churn, including strengthening trust, fostering collective values and beliefs, and countering division.

BackgroundExpandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported.MethodsWe conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis.ResultsThirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years.ConclusionsThere is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery.Level of evidenceLevel IV, therapeutic study.

Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small molecule inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small molecule HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymatic inhibition of HDAC3 with the selective small-molecule inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.