Does open or closed reduction with internal fixation reduces the incidence of complications in neck of femur fractures in pediatrics: a meta-analysis and systematic review.

The neck of femur fracture (FNF) in children is a rare injury with a high incidence of complications such as avascular necrosis (AVN), coxa-vara and nonunion. The aim of this review is to compare the incidence of complications between open reduction with internal fixation (ORIF) and closed reduction with internal fixation (CRIF) of FNF in children. Two independent reviewers searched EMBASE, MEDLINE, COCHRANE and PUBMED databases from inception until April 2022 according to the preferred reporting items for systematic reviews and meta-analyses guidelines. Studies included comparison of complications between open and closed approaches with fixation of FNF in patients less than 18 years old. Publication bias was assessed using Egger's test while the Newcastle-Ottawa tool was used to assess the methodological quality of the studies. A total of 724 hip fractures from 15 included studies received either ORIF or CRIF. Overall, the rate of AVN was approximately 21.7% without statistical significance between both reduction methods [relative risk (RR) = 0.909, using fixed effect model at 95% confidence interval (CI, 0.678-1.217)]. No significant heterogeneity among AVN studies ( I2  = 3.79%, P  = 0.409). Similarly, neither coxa-vara nor nonunion rates were statistically significant in both treatment groups (RR = 0.693 and RR = 0.506, respectively). Coxa-vara studies showed mild heterogeneity ( I2  = 27.8%, P  = 0.218), while significant publication bias was encountered in nonunion studies ( P  = 0.048). No significant difference in the incidence of AVN, coxa-vara and nonunion between ORIF or CRIF of FNF in children. High-quality studies as Randomised Controlled Trials can resolve the inconsistency and heterogeneity of other risk factors including age, initial displacement, fracture type, reduction quality and time to fixation.

Rare Delayed Ifosfamide Encephalopathy: A Case Report of Chemotherapeutic Neurotoxicity.

Introduction: Neurotoxicity is a well-documented side effect of ifosfamide chemotherapy. The presentation includes hallucinations, seizures, disorientation, coma, and death. Treatment with methylene blue can shorten the duration and severity of symptoms. Ifosfamide neurotoxicity almost always happens during or shortly after drug infusion and so is usually immediately recognized. Here, we describe a case of ifosfamide neurotoxicity with onset 14 days after treatment started. Case Presentation: A 25-year-old woman with round cell sarcoma of the jaw presented to the emergency department with 2 days of encephalopathy and bizarre behavior. Antipsychotic medications and benzodiazepines produced no benefit. After consultation, oncology recommended methylene blue, hypothesizing that her symptoms could be a rare presentation of delayed ifosfamide-induced neurotoxicity, 14 days after first administration. After 4 days of methylene blue infusion, her functioning returned to baseline. Conclusion: Delayed ifosfamide-related neurotoxicity is a rare side effect of this chemotherapeutic agent and should be considered in the workup of altered mental status, even if symptoms occur after the previously accepted 5-day standard. In such patients, delayed symptomology may require extended use of methylene blue as treatment.

Exploring an Unknown Corner of a Well-Known Topic: HIIE Influence on Renal Health and Filtration in Healthy Individuals Free of Cardiometabolic Diseases.

Aerobic exercise, specifically high-intensity interval exercise (HIIE), and its effects on renal health and filtration (RHF) are not well understood. Several studies support incorporating contemporary biomarkers serum cystatin C (CyC) and urine epidermal growth factor (uEGF) to combat the volatility of serum creatinine (sCr). Using these biomarkers, we examined the acute influences HIIE has on RHF to determine if there is a ceiling effect in healthy populations. The purpose was to determine the influence of an acute bout of HIIE on RHF. Thirty-six participants (n = 22 males; n = 14 females; age 37.6 ± 12.4 years.; BF% 19.2 ± 7.1%; VO2max 41.8 + 7.4 mL/kg/min) completed 30 min of HIIE on a treadmill (80% and 40% of VO2reserve in 3:2 min ratio). Blood and urine samples were obtained under standardized conditions before, 1 h, and 24 h post-exercise. CyC, sCR, uEGF, urine creatinine (uCr), uCr/uEGF ratio, and multiple estimates of glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations were used. The analysis employed paired sample t-tests and repeated measures ANOVAs. CyC, uEGF, uCr, and uCr/uEGF ratio concentrations were not altered between timepoints. sCr increased 1 h post-exercise (p > 0.002) but not at 24 h post-exercise. eGFR decreased in the MDRD and CKD-EPI equations at 1 h (p > 0.012) with no changes at 24 h post-exercise. CyC and sCr/CyC demonstrated no significant changes. CyC and uEGF are not altered by acute HIIE. The results demonstrate a potential ceiling effect in contemporary and traditional biomarkers of RHF, indicating improvements in RHF may be isolated to populations with reduced kidney function.

A Distinction Without a Difference? A Multi-Method Approach to Understanding PTSD and Depression Symptom Overlap Among Disaster-Exposed Adolescents.

Among adolescents exposed to trauma, posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) commonly co-occur. Despite the prevalence of comorbidity, the question of how PTSD and MDD are related and appropriate conceptual models for understanding their linkage in adolescence remains unclear. This study applies a multi-methodological approach to advance conceptual and theoretical understanding of the overlap between PTSD and MDD diagnoses/symptoms. We tested three methodological approaches with three distinct theoretical underpinnings on the structure of each disorder proposed in the literature: confirmatory factor analysis (CFA) with dimensional constructs, latent class analysis (LCA) with person-based categorical constructs, and network analysis with symptom-to-symptom associations. Across the three different analytical approaches, there was a significant overlap between PTSD and MDD. Overall, there was no compelling evidence for distinct boundaries between disorders among trauma-exposed adolescents. Instead, we found considerable evidence that the typical latent-construct-based conceptualizations, whether categorical or dimensional, may need revision.

Effectiveness of a Web-Based Provider Communications Platform in Reducing Hospital Readmissions Among Patients Receiving Dialysis: A Pilot Pre-Post Study.

Rationale & Objective: Suboptimal care coordination between dialysis facilities and hospitals is an important driver of 30-day hospital readmissions among patients receiving dialysis. We examined whether the introduction of web-based communications platform ("DialysisConnect") was associated with reduced hospital readmissions. Study Design: Pilot pre-post study. Setting & Participants: A total of 4,994 index admissions at a single hospital (representing 2,419 patients receiving dialysis) during the study period (January 1, 2019-May 31, 2021). Intervention: DialysisConnect was available to providers at the hospital and 4 affiliated dialysis facilities (=intervention facilities) during the pilot period (November 1, 2020-May 31, 2021). Outcomes: The primary outcome was 30-day readmission; secondary outcomes included 30-day emergency department visits and observation stays. Interrupted time series and linear models with generalized estimating equations were used to assess pilot versus prepilot differences in outcomes; difference-in-difference analyses were performed to compare these differences between intervention versus control facilities. Sensitivity analyses included a third, prepilot/COVID-19 period (March 1, 2020-October 31, 2020). Results: There was no statistically significant difference in the monthly trends in the 30-day readmissions pilot versus prepilot periods (-0.60 vs -0.13, P = 0.85) for intervention facility admissions; the difference-in-difference estimate was also not statistically significant (0.54 percentage points, P = 0.83). Similar analyses including the prepilot/COVID-19 period showed that, despite a substantial drop in admissions at the start of the pandemic, there were no statistically significant differences across the 3 periods. The age-, sex-, race-, and comorbid condition-adjusted, absolute pilot versus prepilot difference in readmissions rate was 1.8% (-3.7% to 7.3%); similar results were found for other outcomes. Limitations: Potential loss to follow-up and pandemic effects. Conclusions: In this pilot, the introduction of DialysisConnect was not associated with reduced hospital readmissions. Tailored care coordination solutions should be further explored in future, multisite studies to improve the communications gap between dialysis facilities and hospitals.

A Web-Based, Provider-Driven Mobile App to Enhance Patient Care Coordination Between Dialysis Facilities and Hospitals: Development and Pilot Implementation Study.

BACKGROUND: We piloted a web-based, provider-driven mobile app (DialysisConnect) to fill the communication and care coordination gap between hospitals and dialysis facilities. OBJECTIVE: This study aimed to describe the development and pilot implementation of DialysisConnect. METHODS: DialysisConnect was developed iteratively with focus group and user testing feedback and was made available to 120 potential users at 1 hospital (hospitalists, advanced practice providers [APPs], and care coordinators) and 4 affiliated dialysis facilities (nephrologists, APPs, nurses and nurse managers, social workers, and administrative personnel) before the start of the pilot (November 1, 2020, to May 31, 2021). Midpilot and end-of-pilot web-based surveys of potential users were also conducted. Descriptive statistics were used to describe system use patterns, ratings of multiple satisfaction items (1=not at all; 3=to a great extent), and provider-selected motivators of and barriers to using DialysisConnect. RESULTS: The pilot version of DialysisConnect included clinical information that was automatically uploaded from dialysis facilities, forms for entering critical admission and discharge information, and a direct communication channel. Although physicians comprised most of the potential users of DialysisConnect, APPs and dialysis nurses were the most active users. Activities were unevenly distributed; for example, 1 hospital-based APP recorded most of the admissions (280/309, 90.6%) among patients treated at the pilot dialysis facilities. End-of-pilot ratings of DialysisConnect were generally higher for users versus nonusers (eg, "I can see the potential value of DialysisConnect for my work with dialysis patients": mean 2.8, SD 0.4, vs mean 2.3, SD 0.6; P=.02). Providers most commonly selected reduced time and energy spent gathering information as a motivator (11/26, 42%) and a lack of time to use the system as a barrier (8/26, 31%) at the end of the pilot. CONCLUSIONS: This pilot study found that APPs and nurses were most likely to engage with the system. Survey participants generally viewed the system favorably while identifying substantial barriers to its use. These results inform how best to motivate providers to use this system and similar systems and inform future pragmatic research in care coordination among this and other populations.

Forecasting emergence of COVID-19 variants of concern.

We consider whether one can forecast the emergence of variants of concern in the SARS-CoV-2 outbreak and similar pandemics. We explore methods of population genetics and identify key relevant principles in both deterministic and stochastic models of spread of infectious disease. Finally, we demonstrate that fitness variation, defined as a trait for which an increase in its value is associated with an increase in net Darwinian fitness if the value of other traits are held constant, is a strong indicator of imminent transition in the viral population.

Examining the associations between PTSD symptoms and aspects of emotion dysregulation through network analysis.

Despite the clearly established link between posttraumatic stress disorder (PTSD) and emotion dysregulation, little is known about how individual symptoms of PTSD and aspects of emotion dysregulation interrelate. The network approach to mental health disorders provides a novel framework for conceptualizing the association between PTSD and emotion dysregulation as a system of interacting nodes. In this study, we estimated the structural relations among PTSD symptoms and aspects of emotion dysregulation within a large sample of women who participated in a multi-site study of sexual revictimization (N = 463). We estimated expected influence to reveal differential associations among PTSD symptoms and aspects of emotion dysregulation. Further, we estimated bridge expected influence to identify influential nodes connecting PTSD symptoms and aspects of emotion dysregulation. Results highlighted the key role of concentration difficulties in expected influence and bridge expected influence. Findings highlight several PTSD symptoms and aspects of emotion dysregulation that may be targets for future intervention.

The Influence of an Acute Bout of Aerobic Exercise on Vascular Endothelial Function in Moderate Stages of Chronic Kidney Disease.

Chronic kidney disease (CKD) is directly influenced by the deleterious effects of systemic inflammation and oxidative stress. The vascular endothelium may transiently respond to aerobic exercise and improve post-exercise vascular renal function in moderate stages of CKD. Brachial artery flow-mediated dilation (FMD) is a nitric-oxide-dependent measure of endothelial function that is transiently potentiated by exercise. The purpose of the study was to determine the acute influence of a single bout of high-intensity interval exercise (HIIE) or steady-state moderate-intensity exercise (SSE) on endothelial dysfunction in moderate stages of CKD. Twenty participants (n = 6 men; n = 14 women) completed 30 min of SSE (65%) and HIIE (90:20%) of VO2reserve in a randomized crossover design. FMD measurements and blood samples were obtained before, 1 h, and 24 h post-exercise. FMD responses were augmented 1 h post-exercise in both conditions (p < 0.005). Relative to pre-exercise measures, total antioxidant capacity increased by 4.3% 24 h post-exercise (p = 0.012), while paraoxonase-1 was maintained 1 h and elevated by 6.1% 24 h after SSE, but not HIIE (p = 0.035). In summary, FMD can be augmented by a single episode of either HIIE or SSE in moderate stages of CKD. Modest improvements were observed in antioxidant analytes, and markers of oxidative stress were blunted in response to either SSE or HIIE.

The Effects of Acute and Chronic Exercise on Paraoxonase-1 (PON1): A Systematic Review With Meta-Analysis.

Purpose: To determine the acute and chronic effects of exercise on Paraoxonase-1 (PON1) concentration and activity. Methods: A literature search was performed using 16 electronic databases. Effect sizes (ES) were computed and two-tailed α values < .05 and non-overlapping 95% confidence intervals (95%CI) were considered statistically significant. Heterogeneity, inconsistency (I2), and small-study effects using the LFK index were examined. Results: Eighteen studies (n = 377 participants) met the criteria for inclusion. The acute effects of exercise on PON1 concentration were trivial and non-significant (ES = -.03, 95%CI = -.39 to .34, p > .05), heterogeneous (p = .05), moderately inconsistent (I2 = 48%), with minor asymmetry (LFK index = 1.34). The chronic effects of exercise on PON1 concentration were also trivial and non-significant (ES = -.04, 95%CI = -.53 to.45, p > .05), homogenous (p = .65), displayed low inconsistency (I2 = 0%), and minor asymmetry (LFK index = -1.14). The acute effects of exercise on PON1 activity were trivial and non-significant (ES = .11, 95%CI = -.02 to.24, p > .05), homogenous (p = .85), showed low inconsistency (I2 = 0%), and no asymmetry (LFK index = .82). The chronic effects of exercise on PON1 activity were trivial and non-significant (ES = .31, 95%CI = -.03 to.65, p > .05), homogenous (p = .17), moderately inconsistent (I2 = 36%), with no asymmetry (LFK index = .60). Conclusion: Acute and chronic exercise training, overall, exerted a trivial effect on PON1 concentration and activity.

Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis.

BACKGROUND: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. This study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. One hundred four anti-HIV phytochemicals were subjected to molecular docking with nsp3, 5, 10, 12, 13, 15, and 16. Top compounds in complex with the nsps were investigated further through molecular dynamics. The drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top compounds were also predicted using SwissADME. Their toxicity was likewise determined using OSIRIS Property Explorer. RESULTS: Among the top-scoring compounds, the polyphenolic functionalized natural products comprised of biflavones 1, 4, 11, 13, 14, 15; ellagitannin 9; and bisisoquinoline alkaloid 19 were multi-targeting and exhibited strongest binding affinities to at least two nsps (binding energy = - 7.7 to - 10.8 kcal/mol). The top ligands were stable in complex with their target nsps as determined by molecular dynamics. Several top-binding compounds were computationally druggable, showed good gastrointestinal absorptive property, and were also predicted to be non-toxic. CONCLUSIONS: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 non-structural proteins 3, 5, 10, 12, 13, 15, and 16. Our results highlight the importance of polyhydroxylated aromatic substructures for effective attachment in the binding/catalytic sites of nsps involved in post-translational mechanism pathways. As such with the nsps playing vital roles in viral pathogenesis, our findings provide inspiration for the design and discovery of novel anti-COVID-19 drug prototypes.

The Hydration Status of Female Collegiate Soccer Players Over Consecutive Training and Match Days / Estado de Hidratación de Jugadoras de Fútbol Universitarias Durante Días de Entrenamiento y Partidos Consecutivos

Abstract Purpose: Hydration has been shown to play a pivotal role in sport. Soccer is a team sport in which the integrity of all players is vital for team performance; thus, individual player hydration status is important. The primary aim of this study was to investigate the hydration status of female collegiate soccer players during regular season. Methods: Sixteen collegiate female soccer players (age: 20.4 ± 0.8 years; height: 163.6 ± 6.9 cm; weight: 65.3 ± 12 kg) provided urine over 9 days to monitor their hydration status. Hydration was determined by urine specific gravity (Usg). Usg was analyzed in the morning (AM) and in the afternoon before practice/game (PM). Results: All 16 players were at least minimally hypohydrated (Usg > 1.010) in the AM on 5 of the 9 days tested. Players had significantly higher Usg values in the AM as compared to PM (F(1,250) = 23.09; p < 0.0001); however, there was no significant time*day interaction (F(1,250) = 1.98; p = 0.16). Conclusion: Data show a high prevalence of hypohydration occurring in this specific population. This sub-optimal hydration status could be a cause for concern in terms of overall performance. Efforts should be made to integrate hydration interventions and daily monitoring to minimize hypohydration in players.

Resumen Propósito: Se ha demostrado que la hidratación juega un papel fundamental en el deporte. El fútbol es un deporte de equipo en el que la integridad de todos los jugadores es vital para su rendimiento; por lo tanto, el estado de hidratación de cada jugador es importante. El objetivo principal de este estudio fue investigar el estado de hidratación de las jugadoras universitarias de fútbol durante la temporada regular. Métodos: Dieciséis jugadoras universitarias de fútbol (edad: 20.4 ± 0.8 años; estatura: 163.6 ± 6.9 cm; peso: 65.3 ± 12 kg) proporcionaron muestras de orina durante 9 días para controlar su estado de hidratación, la cual se determinó por la gravedad específica de la orina (Usg). La Usg se analizó en la mañana (AM) y en la tarde antes del entrenamiento o el juego (PM). Resultados: Las 16 jugadoras estaban al menos mínimamente hipohidratadas (Usg > 1.010) en la AM en 5 de los 9 días medidos. Las jugadoras tuvieron valores Usg significativamente más altos en AM en comparación con PM (F (1,250) = 23.09; p < 0.0001); sin embargo, no hubo interacción significativa de tiempo * día (F(1,250) = 1.98; p = 0.16). Conclusión: los datos muestran una alta prevalencia de hipohidratación en esta población específica. Este estado de hidratación subóptimo podría ser motivo de preocupación en términos de rendimiento general. Se deberían hacer esfuerzos para integrar las intervenciones de hidratación y el monitoreo diario para reducir al mínimo la hipohidratación en las jugadoras.

Resumo Objetivo: Foi demonstrado que a hidratação desempenha um papel fundamental no esporte. O futebol é um esporte coletivo no qual a integridade de todos os jogadores é vital para o desempenho da equipe; portanto, o estado de hidratação de cada jogador é importante. O objetivo principal deste estudo foi investigar o estado de hidratação de universitárias jogadoras de futebol do sexo feminino durante a temporada regular. Métodos: Dezesseis universitárias jogadoras de futebol (idade: 20,4 ± 0,8 anos; altura: 163,6 ± 6,9 cm; peso: 65,3 ± 12 kg) forneceram amostras de urina por 9 dias para monitorar seu estado de hidratação. A hidratação foi determinada pela gravidade específica da urina Usg. Sua Usg foi analisado pela manhã (matutino) e à tarde (vespertino) antes do treino ou jogo. Resultados: As 16 jogadoras estavam minimamente hipohidratadas (Usg > 1.010) no período matutino em 5 dos 9 dias medidos. As jogadoras apresentaram valores de Usg significativamente maiores no período matutino em comparação ao vespertino (F (1.250) = 23,09; p <0,0001); no entanto, não houve interação tempo * dia significativa (F (1.250) = 1,98; p = 0,16). Conclusão: os dados mostram uma alta prevalência de hipohidratação nesta população específica. Este estado de hidratação abaixo do ideal pode ser uma preocupação em termos de desempenho geral. Devem ser feitos esforços para integrar intervenções de hidratação e monitoramento diário para minimizar a hipohidratação em jogadoras.

Fast track dialysis: Improving emergency department and hospital throughput for patients requiring hemodialysis.

OBJECTIVE: To describe the impact of a novel communication and triage pathway called fast track dialysis (FTD) on the length of stay (LOS), resource utilization, and charges for unscheduled hemodialysis for end stage renal disease (ESRD) patients presenting to the emergency department (ED). METHODS: Prospective and retrospective cohorts of ESRD patients meeting requirements of routine or urgent hemodialysis at a tertiary academic hospital from September 25th, 2016 to September 25th, 2018 in 1 year cohorts. Two sample t-tests were used to compare most outcomes of the cohorts with a Mann-Whitney U test used for skewed data. Nephrology group outcomes were analyzed by two-way ANOVA and Kruskal-Wallis and chi-square tests. RESULTS: There were 98 encounters in the historical cohort and 143 encounters in the fast track dialysis cohort. FTD had significantly lowered median ED LOS (4.05 h, vs 5.3 h, p < 0.001), median hospital LOS (12.8 h vs 27 h, p < 0.001), time to hemodialysis (4.78 h vs 7.29 h, p < 0.001), and median hospital charges ($26,040 vs $30,747, p < 0.016). The FTD cohort had increased 30 day ED return for each encounter compared to the historical cohort (1.85 visits vs 0.73 visits, p < 0.001), however no significant increase in 1 year ED visits (6.52 visits vs 5.80, p = 0.4589) or 1 year readmissions (5.89 readmissions vs 4.81 readmissions, p = 0.3584). Most nephrology groups had significantly lower time to hemodialysis order placement and time to start hemodialysis. CONCLUSION: A multidisciplinary approach with key stakeholders using a standard pathway can lead to improved efficiency in throughput, reduced charges, and hospital resource utilization for patients needing urgent or routine hemodialysis. A study with a dedicated geographic observation unit for protocolized short stay patients including conditions ranging from low risk chest pain to transient ischemic events that incorporates FTD patients under this protocol should be considered.

Making sense of DialysisConnect: a qualitative analysis of stakeholder viewpoints on a web-based information exchange platform to improve care transitions between dialysis clinics and hospitals.

BACKGROUND: U.S. hospitals and dialysis centers are penalized for 30-day hospital readmissions of dialysis patients, despite little infrastructure to facilitate care transitions between these settings. We are developing a third-party web-based information exchange platform, DialysisConnect, to enable clinicians to view and exchange information about dialysis patients during admission, hospitalization, and discharge. This health information technology solution could serve as a flexible and relatively affordable solution for dialysis facilities and hospitals across the nation who are seeking to serve as true partners in the improved care of dialysis patients. The purpose of this study was to evaluate the perceived coherence of DialysisConnect to key clinical stakeholders, to prepare messaging for implementation. METHODS: As part of a hybrid effectiveness-implementation study guided by Normalization Process Theory, we collected data on stakeholder perceptions of continuity of care for patients receiving maintenance dialysis and a DialysisConnect prototype before completing development and piloting the system. We conducted four focus groups with stakeholders from one academic hospital and associated dialysis centers [hospitalists (n = 5), hospital staff (social workers, nurses, pharmacists; n = 9), nephrologists (n = 7), and dialysis clinic staff (social workers, nurses; n = 10)]. Transcriptions were analyzed thematically within each component of the construct of coherence (differentiation, communal specification, individual specification, and internalization). RESULTS: Participants differentiated DialysisConnect from usual care variously as an information dashboard, a quick-exchange communication channel, and improved discharge information delivery; some could not differentiate it in terms of workflow. The purpose of DialysisConnect (communal specification) was viewed as fully coherent only for communicating outside of the same healthcare system. Current system workarounds were acknowledged as deterrents for practice change. All groups delegated DialysisConnect tasks (individual specification) to personnel besides themselves. Partial internalization of DialysisConnect was achieved only by dialysis clinic staff, based on experience with similar technology. CONCLUSIONS: Implementing DialysisConnect for clinical users in both settings will require presenting a composite picture of current communication processes from all stakeholder groups to correct single-group misunderstandings, as well as providing data about care transitions communication beyond the local context to ease resistance to practice change.

Uptake, toxicity, and maternal transfer of cadmium in the oribatid soil mite, Oppia nitens: Implication in the risk assessment of cadmium to soil invertebrates.

Cadmium (Cd) is a heavy metal of concern in contaminated sites because of its high toxicity to soil biota and humans. Typically, Cd exposure is thought to be dominated by dissolved Cd in soil pore water and, thus, dermal uptake. In this study, we investigated the uptake, toxicity, and maternal transfer of Cd in a standard soil invertebrate, the oribatid mite (Oppia nitens), which is common to boreal and temperate ecozones. We found total soil Cd predicted Cd uptake in adult and juvenile O. nitens with no significant uptake from pore water by juvenile mites. Cadmium significantly inhibited juvenile production and recruitment as well as reduced adult fecundity. Adult O. nitens maternally transferred 39-52% of their Cd body burden to juveniles (tritonymphs) while the maternally-acquired Cd accounted for 41% of the juvenile internal Cd load. Our results suggest that dermal adsorption of metal ions is not important for O. nitens and that maternal transfer of Cd in soil invertebrates has ecological and toxicological implications for populations of soil invertebrates. Maternal transfer should be incorporated as a criterion in setting environmental soil quality guidelines (SQGE) for cadmium and other non-essential heavy metals.

Effect of Adding Motolimod to Standard Combination Chemotherapy and Cetuximab Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck: The Active8 Randomized Clinical Trial.

Importance: Immunotherapy for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is promising. The toll-like receptor 8 (TLR8) agonist motolimod may stimulate innate and adaptive immunity. Objective: To determine whether motolimod improves outcomes for R/M SCCHN when combined with standard therapy. Design, Setting, and Participants: The Active8 study was a multicenter, randomized, double-blind, placebo-controlled clinical trial enrolling adult patients (age ≥18 years) with histologically confirmed R/M SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx between October 2013 and August 2015. Follow-up ended September 2016. Analysis for the present report was conducted between June 2016 and December 2017. Interventions: Combination treatment with platinum (carboplatin or cisplatin), fluorouracil, cetuximab (the EXTREME regimen), and either placebo or motolimod, each administered intravenously every 3 weeks. Patients received a maximum of 6 chemotherapy cycles, after which patients received weekly cetuximab with either placebo or motolimod every 4 weeks. Main Outcomes and Measures: Progression-free survival (PFS) as determined by independent central review using immune-related RECIST (Response Evaluation Criteria in Solid Tumors). Key secondary end points included overall survival (OS) and safety. Results: Of 195 patients enrolled, 85% were men (n = 166); 82% were white (n = 159); median age was 58 years (range 23-81 years). Median PFS was 6.1 vs 5.9 months (hazard ratio [HR], 0.99; 1-sided 90% CI, 0.00-1.22; P = .47), and median OS was 13.5 vs 11.3 months (HR, 0.95; 1-sided 90% CI, 0.00-1.22; P = .40) for motolimod vs placebo. Increased incidence of injection site reactions, pyrexia, chills, anemia, and acneiform rash were noted with motolimod. Of 83 cases oropharyngeal cancer, 52 (63%) were human papillomavirus (HPV) positive. In a prespecified subgroup analysis of HPV-positive participants, motolimod vs placebo resulted in significantly longer PFS (7.8 vs 5.9 months; HR, 0.58; 1-sided 90% CI, 0.00-0.90; P = .046) and OS (15.2 vs 12.6 months; HR, 0.41; 1-sided 90% CI, 0.00-0.77; P = .03). In an exploratory analysis, patients with injection site reactions had longer PFS and OS (median PFS, 7.1 vs 5.9 months; HR, 0.69; 1-sided 90% CI, 0.00-0.93; P = .06; and median OS, 18.7 vs 12.6; HR, 0.56; 1-sided 90% CI, 0.00-0.81; P = .02). Conclusions and Relevance: Adding motolimod to the EXTREME regimen was well tolerated but did not improve PFS or OS in the intent-to-treat population. Significant benefit was observed in HPV-positive patients and those with injection site reactions, suggesting that TLR8 stimulation may benefit subset- and biomarker-selected patients. Trial Registration: ClinicalTrials.gov identifier: NCT01836029.

In vitro prediction of polycyclic aromatic hydrocarbon bioavailability of 14 different incidentally ingested soils in juvenile swine.

Predicting mammalian bioavailability of PAH mixtures from in vitro bioaccessibility results has proven to be an elusive goal. In an attempt to improve in vitro predictions of PAH soil bioavailability we investigated how energetic input influences PAH bioaccessibility by using a high and low energetic shaking method. Co-inertia analysis (COIA), and Structural Equation Modeling (SEM) were also used to examine PAH-PAH interactions during ingestion. PAH bioaccessibility was determined from 14 historically contaminated soils using the fed organic estimation of the human simulation test (FOREhST) with inclusion of a silicone rod as a sorption sink and compared to bioavailability estimates from the juvenile swine model. Shaking method significantly affected PAH bioaccessibility in the FOREhST model, with PAH desorption from the high energy FOREhST almost an order of magnitude greater compared to the low energy FOREhST. PAH-PAH interactions significantly influenced PAH bioavailability and when these interactions were used in a linear model, the model predicted benzo(a)anthracene bioavailability with an slope of 1 and r2 of 0.66 and for benzo(a)pyrene bioavailability has a slope of 1 and r2 of 0.65. Lastly, to confirm the effects as determined by COIA and SEM, we spiked low levels of benzo(a)anthracene into historically contaminated soils, and observed a significant increase in benzo(a)pyrene bioaccessibility. By accounting for PAH interactions, and reducing the energetics of in vitro extractions, we were able to use bioaccessibility to predict bioavailability across 14 historically contaminated soils. Our work suggests that future work on PAH bioavailability and bioaccessibility should focus on the dynamics of how the matrix of PAHs present in the soil interact with mammalian systems. Such interactions should not only include the chemical interactions discussed here but also the interactions of PAH mixtures with mammalian uptake systems.

Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 Stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals.

Purpose: The response rate of patients with head and neck squamous cell carcinoma (HNSCC) to cetuximab therapy is only 15% to 20%, despite frequent EGFR overexpression. Because immunosuppression is common in HNSCC, we hypothesized that adding a proinflammatory TLR8 agonist to cetuximab therapy might result in enhanced T-lymphocyte stimulation and anti-EGFR-specific priming.Experimental Design: Fourteen patients with previously untreated HNSCC were enrolled in this neoadjuvant trial and treated preoperatively with 3 to 4 weekly doses of motolimod (2.5 mg/m2) and cetuximab. Correlative tumor and peripheral blood specimens were obtained at baseline and at the time of surgical resection and analyzed for immune biomarker changes. Preclinical in vitro studies were also performed to assess the effect of cetuximab plus motolimod on myeloid cells.Results: TLR8 stimulation skewed monocytes toward an M1 phenotype and reversed myeloid-derived suppressor cell (MDSC) suppression of T-cell proliferation in vitro These data were validated in a prospective phase Ib neoadjuvant trial, in which fewer MDSC and increased M1 monocyte infiltration were found in tumor-infiltrating lymphocytes. Motolimod plus cetuximab also decreased induction of Treg and reduced markers of suppression, including CTLA-4, CD73, and membrane-bound TGFß. Significantly increased circulating EGFR-specific T cells were observed, concomitant with enhanced CD8+ T-cell infiltration into tumors. These T cells manifested increased T-cell receptor (TCR) clonality, upregulation of the costimulatory receptor CD27, and downregulation of inhibitory receptor TIGIT.Conclusions: Enhanced inflammatory stimulation in the tumor microenvironment using a TLR agonist overcomes suppressive myeloid and regulatory cells, enhancing the cellular antitumor immune response by therapeutic mAb in HNSCC. Clin Cancer Res; 24(1); 62-72. ©2017 AACR.

A systematic review of cost-effectiveness, comparing traction to intramedullary nailing of femoral shaft fractures, in the less economically developed context.

INTRODUCTION: Femoral shaft fractures carry considerable morbidity and are increasingly common in less economically developed countries (LEDCs). Treatment options include traction and intramedullary (IM) nailing but in a limited-resource environment; cost-effectiveness is fundamental to policy development. The objective herein was to evaluate the cost-effectiveness of moving from traction to IM nailing for femoral shaft fractures, in adults, in LEDCs. Incorporating a systematic review of complications and functional outcomes and a cost-minimization analysis. METHODS: PubMed, EMBASE, Africa Journals Online and the Cochrane Library were searched from inception using the terms: femur* AND fracture AND traction AND (sign OR nail* OR intramedullary) AND (cost-effectiveness OR cost* OR outcome OR function) NOT paed* NOT child* NOT elastic NOT neck NOT intertrochanteric NOT periprosthetic (where asterisks indicate an unlimited truncation strategy). Abstracts were reviewed for all titles returned and full texts obtained as indicated. References of all relevant papers were also examined for further studies. RESULTS: IM nailing has been successfully used in several institutions and reported infection, union and reoperation rates are encouraging, although no randomised control trials were identified. Three studies assessed the cost aspect and all found IM nailing to be the cheaper strategy. CONCLUSION: To date, the improved complication profile and reduced cost of treatment suggest that IM nailing is more cost-effective than traction. Evidence, however, is limited and the necessity for appropriate training and audit with the introduction of new techniques must be emphasised.

Assessing human metal accumulations in an urban superfund site.

Butte, Montana is part of the largest superfund site in the continental United States. Open-pit mining continues in close proximity to Butte's urban population. This study seeks to establish baseline metal concentrations in the hair and blood of individuals living in Butte, MT and possible routes of exposure. Volunteers from Butte (n=116) and Bozeman (n=86) were recruited to submit hair and blood samples and asked to complete a lifestyle survey. Elemental analysis of hair and blood samples was performed by ICP-MS. Three air monitors were stationed in Butte to collect particulate and filters were analyzed by ICP-MS. Soil samples from the yards of Butte volunteers were quantified by ICP-MS. Hair analysis revealed concentrations of Al, As, Cd, Cu, Mn, Mo, and U to be statistically elevated in Butte's population. Blood analysis revealed that the concentration of As was also statistically elevated in the Butte population. Multiple regression analysis was performed for the elements As, Cu, and Mn for hair and blood samples. Soil samples revealed detectable levels of As, Pb, Cu, Mn, and Cd, with As and Cu levels being higher than expected in some of the samples. Air sampling revealed consistently elevated As and Mn levels in the larger particulate sampled as compared to average U.S. ambient air data.