Are Abnormal Muscle Biomechanics and Patient-reported Outcomes Associated in Patients With Hip Dysplasia?

BACKGROUND: Developmental dysplasia of the hip (DDH) is a major risk factor for the early development of hip osteoarthritis. Recent studies have demonstrated how DDH alters hip muscle moment arms and elevates muscle-induced biomechanical variables such as joint reaction forces and acetabular edge loads. Understanding the link between abnormal biomechanics and patient-reported outcome measures (PROMs) is important for evidence-based clinical interventions that improve patient symptoms and functional outcomes. To our knowledge, there are no reports of the relationships between muscle-induced biomechanics and PROMs. QUESTIONS/PURPOSES: (1) Are there associations between PROMs and muscle-induced hip biomechanics during gait for patients with DDH and controls? (2) Are there associations among PROMs and separately among biomechanical variables? METHODS: Participants in this prospective cross-sectional comparative study included 20 female patients with DDH who had no prior surgery or osteoarthritis and 15 female individuals with no evidence of hip pathology (controls) (age: median 23 years [range 16 to 39 years]; BMI: median 22 kg/m 2 [range 17 to 27 kg/m 2 ]). Muscle-induced biomechanical variables for this cohort were reported and had been calculated from patient-specific musculoskeletal models, motion data, and MRI. Biomechanical variables included joint reaction forces, acetabular edge loads, hip center lateralization, and gluteus medius muscle moment arm lengths. PROMs included the Hip Disability and Osteoarthritis Outcome Score (HOOS), the WOMAC, International Hip Outcome Tool-12, National Institutes of Health Patient-Reported Outcome Measure Information System (PROMIS) Pain Interference and Physical Function subscales, and University of California Los Angeles activity scale. Associations between PROMs and biomechanical variables were tested using Spearman rank-order correlations and corrected for multiple comparisons using the Benjamini-Yekutieli method. For this study, associations between variables were considered to exist when correlations were statistically significant (p < 0.05) and were either strong (ρ ≥ 0.60) or moderate (ρ = 0.40 to 0.59). RESULTS: Acetabular edge load impulses (the cumulative acetabular edge load across the gait cycle), medially directed joint reaction forces, and hip center lateralization most commonly demonstrated moderate or strong associations with PROMs. The strongest associations were a negative correlation between acetabular edge load impulse on the superior acetabulum and the HOOS function in daily living subscale (ρ = -0.63; p = 0.001), followed by a negative correlation between hip center lateralization and the HOOS pain subscale (ρ = -0.6; p = 0.003), and a positive correlation between hip center lateralization and the PROMIS pain subscale (ρ = 0.62; p = 0.002). The University of California Los Angeles activity scale was the only PROM that did not demonstrate associations with any biomechanical variable. All PROMs, aside from the University of California Los Angeles activity scale, were associated with one another. Although most of the biomechanical variables were associated with one another, these relationships were not as consistent as those among PROMs. CONCLUSION: The associations with PROMs detected in the current study suggest that muscle-induced biomechanics may have wide-reaching effects not only on loads within the hip, but also on patients' perceptions of their health and function. As the treatment of DDH evolves, patient-specific joint preservation strategies may benefit from targeting the underlying causes of biomechanical outcomes associated with PROMs. LEVEL OF EVIDENCE: Level III, prognostic study.

Neural correlates of risky decision making in Parkinson's disease patients with impulse control disorders.

Some patients with Parkinson's disease (PD) experience impulse control disorders (ICDs), characterized by deficient voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of impulsive, risky decision making in PD patients with ICDs by disentangling potential dysfunctions in decision and outcome mechanisms. We collected fMRI data from 20 patients with ICDs and 28 without ICDs performing an information gathering task. Patients viewed sequences of bead colors drawn from hidden urns and were instructed to infer the majority bead color in each urn. With each new bead, they could choose to either seek more evidence by drawing another bead (draw choice) or make an urn-inference (urn choice followed by feedback). We manipulated risk via the probability of bead color splits (80/20 vs. 60/40) and potential loss following an incorrect inference ($10 vs. $0). Patients also completed the Barratt Impulsiveness Scale (BIS) to assess impulsivity. Patients with ICDs showed greater urn choice-specific activation in the right middle frontal gyrus, overlapping the dorsal premotor cortex. Across all patients, fewer draw choices (i.e., more impulsivity) were associated with greater activation during both decision making and outcome processing in a variety of frontal and parietal areas, cerebellum, and bilateral striatum. Our findings demonstrate that ICDs in PD are associated with differences in neural processing of risk-related information and outcomes, implicating both reward and sensorimotor dopaminergic pathways.

Environmental exposures and sleep outcomes: A review of evidence, potential mechanisms, and implications.

Environmental exposures and poor sleep outcomes are known to have consequential effects on human health. This integrative review first seeks to present and synthesize existing literature investigating the relationship between exposure to various environmental factors and sleep health. We then present potential mechanisms of action as well as implications for policy and future research for each environmental exposure. Broadly, although studies are still emerging, empirical evidence has begun to show a positive association between adverse effects of heavy metal, noise pollution, light pollution, second-hand smoke, and air pollution exposures and various sleep problems. Specifically, these negative sleep outcomes range from subjective sleep manifestations, such as general sleep quality, sleep duration, daytime dysfunction, and daytime sleepiness, as well as objective sleep measures, including difficulties with sleep onset and maintenance, sleep stage or circadian rhythm interference, sleep arousal, REM activity, and sleep disordered breathing. However, the association between light exposure and sleep is less clear. Potential toxicological mechanisms are thought to include the direct effect of various environmental toxicants on the nervous, respiratory, and cardiovascular systems, oxidative stress, and inflammation. Nevertheless, future research is required to tease out the exact pathways of action to explain the associations between each environmental factor and sleep, to inform possible therapies to negate the detrimental effects, and to increase efforts in decreasing exposure to these harmful environmental factors to improve health.

Utilization of Prophylactic Antibiotics After Nasal Packing for Epistaxis.

BACKGROUND: There have been few investigations examining the benefits, consequences, and patterns of use for prophylactic antibiotics for nasal packing in the emergency department setting. Given the frequency of epistaxis in the emergency department, it is an ideal setting to study the efficacy and utilization patterns of prophylactic antibiotics in nasal packing. OBJECTIVE: Our aim was to assess both rates of utilization and evidence of benefit for prophylactic antibiotics in patients with nasal packing for epistaxis. METHODS: A single-institution retrospective review of 275 cases of anterior nasal packing in an urban emergency department between September 2013 and April 2017 was performed. Chi-square statistical analysis was used to evaluate results. RESULTS: Among 275 cases studied, there were no instances of toxic shock syndrome. Roughly 73% of patients with nonabsorbable packing received prophylactic antibiotics. Only one (1.1%) case of sinusitis was noted among the nonabsorbable packing with prophylaxis group, with no such complication in the nonprophylaxis group. In contrast, 95% of patients with absorbable nasal packing were not given prophylactic antibiotics. Analysis of all cases given prophylactic antibiotics vs. no prophylaxis, regardless of packing type, revealed no statistically significant difference in the development of acute sinusitis (1% vs. 0.56%; p = 0.6793). CONCLUSIONS: There was no observed advantage or disadvantage to using prophylactic antibiotics in anterior nasal packing in the emergency department, regardless of whether patients received absorbable or nonabsorbable packing. However, patients who receive nonabsorbable nasal packing were more likely to receive antibiotic prophylaxis.

The Effectiveness of Collaborative Care on Depression Outcomes for Racial/Ethnic Minority Populations in Primary Care: A Systematic Review.

BACKGROUND: Racial/ethnic minorities experience a greater burden of mental health problems than white adults in the United States. The collaborative care model is increasingly being adopted to improve access to services and to promote diagnosis and treatment of psychiatric diseases. OBJECTIVE: This systematic review seeks to summarize what is known about collaborative care on depression outcomes for racial/ethnic minorities in the United States. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method. Collaborative care studies were included if they comprised adults from at least one racial/ethnic minority group, were located in primary care clinics in the United States, and had depression outcome measures. Core principles described by the University of Washington Advancing Integrated Mental Health Solutions Center were used to define the components of collaborative care. RESULTS: Of 398 titles screened, 169 full-length articles were assessed for eligibility, and 19 studies were included in our review (10 randomized controlled trials, 9 observational). Results show there is potential that collaborative care, with or without cultural/linguistic tailoring, is effective in improving depression for racial/ethnic minorities, including those from low socioeconomic backgrounds. CONCLUSIONS: Collaborative care should be explored as an intervention for treating depression for racial/ethnic minority patients in primary care. Questions remain as to what elements of cultural adaptation are most helpful, factors behind the difficulty in recruiting minority patients for these studies, and how the inclusion of virtual components changes access to and delivery of care. Future research should also recruit individuals from less studied populations.

Acute stroke care in a New York City comprehensive stroke center during the COVID-19 pandemic.

BACKGROUND AND PURPOSE: The coronavirus disease-2019 (COVID-19) pandemic caused unprecedented demand and burden on emergency health care services in New York City. We aim to describe our experience providing acute stroke care at a comprehensive stroke center (CSC) and the impact of the pandemic on the quality of care for patients presenting with acute ischemic stroke (AIS). METHODS: We retrospectively analyzed data from a quality improvement registry of consecutive AIS patients at New York University Langone Health's CSC between 06/01/2019-05/15/2020. During the early stages of the pandemic, the acute stroke process was modified to incorporate COVID-19 screening, testing, and other precautionary measures. We compared stroke quality metrics including treatment times and discharge outcomes of AIS patients during the pandemic (03/012020-05/152020) compared with a historical pre-pandemic group (6/1/2019-2/29/2020). RESULTS: A total of 754 patients (pandemic-120; pre-pandemic-634) were admitted with a principal diagnosis of AIS; 198 (26.3%) received alteplase and/or mechanical thrombectomy. Despite longer median door to head CT times (16 vs 12 minutes; p = 0.05) and a trend towards longer door to groin puncture times (79.5 vs. 71 min, p = 0.06), the time to alteplase administration (36 vs 35 min; p = 0.83), door to reperfusion times (103 vs 97 min, p = 0.18) and defect-free care (95.2% vs 94.7%; p = 0.84) were similar in the pandemic and pre-pandemic groups. Successful recanalization rates (TICI≥2b) were also similar (82.6% vs. 86.7%, p = 0.48). After adjusting for stroke severity, age and a prior history of transient ischemic attack/stroke, pandemic patients had increased discharge mortality (adjusted OR 2.90 95% CI 1.77 - 7.17, p = 0.021) CONCLUSION: Despite unprecedented demands on emergency healthcare services, early multidisciplinary efforts to adapt the acute stroke treatment process resulted in keeping the stroke quality time metrics close to pre-pandemic levels. Future studies will be needed with a larger cohort comparing discharge and long-term outcomes between pre-pandemic and pandemic AIS patients.

Association Between Academic Medical Center Pharmaceutical Detailing Policies and Physician Prescribing.

IMPORTANCE: In an effort to regulate physician conflicts of interest, some US academic medical centers (AMCs) enacted policies restricting pharmaceutical representative sales visits to physicians (known as detailing) between 2006 and 2012. Little is known about the effect of these policies on physician prescribing. OBJECTIVE: To analyze the association between detailing policies enacted at AMCs and physician prescribing of actively detailed and not detailed drugs. DESIGN, SETTING, AND PARTICIPANTS: The study used a difference-in-differences multivariable regression analysis to compare changes in prescribing by physicians before and after implementation of detailing policies at AMCs in 5 states (California, Illinois, Massachusetts, Pennsylvania, and New York) that made up the intervention group with changes in prescribing by a matched control group of similar physicians not subject to a detailing policy. EXPOSURES: Academic medical center implementation of policies regulating pharmaceutical salesperson visits to attending physicians. MAIN OUTCOMES AND MEASURES: The monthly within-drug class market share of prescriptions written by an individual physician for detailed and nondetailed drugs in 8 drug classes (lipid-lowering drugs, gastroesophageal reflux disease drugs, diabetes drugs, antihypertensive drugs, hypnotic drugs approved for the treatment of insomnia [sleep aids], attention-deficit/hyperactivity disorder drugs, antidepressant drugs, and antipsychotic drugs) comparing the 10- to 36-month period before implementation of the detailing policies with the 12- to 36-month period after implementation, depending on data availability. RESULTS: The analysis included 16 121 483 prescriptions written between January 2006 and June 2012 by 2126 attending physicians at the 19 intervention group AMCs and by 24 593 matched control group physicians. The sample mean market share at the physician-drug-month level for detailed and nondetailed drugs prior to enactment of policies was 19.3% and 14.2%, respectively. Exposure to an AMC detailing policy was associated with a decrease in the market share of detailed drugs of 1.67 percentage points (95% CI, -2.18 to -1.18 percentage points; P < .001) and an increase in the market share of nondetailed drugs of 0.84 percentage points (95% CI, 0.54 to 1.14 percentage points; P < .001). Associations were statistically significant for 6 of 8 study drug classes for detailed drugs (lipid-lowering drugs, gastroesophageal reflux disease drugs, antihypertensive drugs, sleep aids, attention-deficit/hyperactivity disorder drugs, and antidepressant drugs) and for 9 of the 19 AMCs that implemented policies. Eleven of the 19 AMCs regulated salesperson gifts to physicians, restricted salesperson access to facilities, and incorporated explicit enforcement mechanisms. For 8 of these 11 AMCs, there was a significant change in prescribing. In contrast, there was a significant change at only 1 of 8 AMCs that did not enact policies in all 3 areas. CONCLUSIONS AND RELEVANCE: Implementation of policies at AMCs that restricted pharmaceutical detailing between 2006 and 2012 was associated with modest but significant reductions in prescribing of detailed drugs across 6 of 8 major drug classes; however, changes were not seen in all of the AMCs that enacted policies.

Adaptive auditory assistance for stride length cadence modification in older adults and people with Parkinson's.

Gait rehabilitation using auditory cues can help older adults and people with Parkinson's improve walking performance. While auditory cues are convenient and can reliably modify gait cadence, it is not clear if auditory cues can reliably modify stride length (SL), another key gait performance metric. Existing algorithms also do not address habituation or fluctuation in motor capability, and have not been evaluated with target populations or under dual-task conditions. In this study, we develop an adaptive auditory cueing framework that aims to modulate SL and cadence. The framework monitors the gait parameters and learns a personalized cue-response model to relate the gait parameters to the input cues. The cue-response model is represented using a multi-output Gaussian Process (MOGP) and is used during optimization to select the cue to provide. The adaptive cueing approach is benchmarked against the fixed approach, where cues are provided at a fixed cadence. The two approaches are tested under single and dual-task conditions with 13 older adults (OA) and 8 people with Parkinson's (PwP). The results show that more than half of the OA and PwP in the study can change both SL and cadence using auditory cues. The fixed approach is best at changing people's gait without secondary task, however, the addition of the secondary task significantly degrades effectiveness at changing SL. The adaptive approach can maintain the same level of SL change regardless of the presence of the secondary task. A separate analysis is conducted to identify factors that influence the performance of the adaptive framework. Gait information from the previous time step, along with the previous input cue, can improve its prediction accuracy. More diversity in the initialization data can also improve the GP model. Finally, we did not find a strong correlation between stride length and cadence when the parameters are contingent upon input cues.

A genotyping array for the globally invasive vector mosquito, Aedes albopictus.

BACKGROUND: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in advancing biological control methods and understanding the population dynamics of this pest species, with significant implications for public health. METHODS: We designed a SNP chip for Ae. albopictus (Aealbo chip) based on approximately 2.7 million SNPs identified using WGS data from 819 worldwide samples. We validated the chip using laboratory single-pair crosses, comparing technical replicates, and comparing genotypes of samples genotyped by WGS and the SNP chip. We then used the chip for a population genomic analysis of 237 samples from 28 sites in the native range to evaluate its usefulness in describing patterns of genomic variation and tracing the origins of invasions. RESULTS: Probes on the Aealbo chip targeted 175,396 SNPs in coding and non-coding regions across all three chromosomes, with a density of 102 SNPs per 1 Mb window, and at least one SNP in each of the 17,461 protein-coding genes. Overall, 70% of the probes captured the genetic variation. Segregation analysis found that 98% of the SNPs followed expectations of single-copy Mendelian genes. Comparisons with WGS indicated that sites with genotype disagreements were mostly heterozygotes at loci with WGS read depth < 20, while there was near complete agreement with WGS read depths > 20, indicating that the chip more accurately detects heterozygotes than low-coverage WGS. Sample sizes did not affect the accuracy of the SNP chip genotype calls. Ancestry analyses identified four to five genetic clusters in the native range with various levels of admixture. CONCLUSIONS: The Aealbo chip is highly accurate, is concordant with genotypes from WGS with high sequence coverage, and may be more accurate than low-coverage WGS.

Auditory cueing strategy for stride length and cadence modification: a feasibility study with healthy adults.

People with Parkinson's Disease experience gait impairments that significantly impact their quality of life. Visual, auditory, and tactile cues can alleviate gait impairments, but they can become less effective due to the progressive nature of the disease and changes in people's motor capability. In this study, we develop a human-in-the-loop (HIL) framework that monitors two key gait parameters, stride length and cadence, and continuously learns a person-specific model of how the parameters change in response to the feedback. The model is then used in an optimization algorithm to improve the gait parameters. This feasibility study examines whether auditory cues can be used to influence stride length in people without gait impairments. The results demonstrate the benefits of the HIL framework in maintaining people's stride length in the presence of a secondary task.Clinical relevance- This paper proposes a gait rehabilitation framework that provides a personalized cueing strategy based on the person's real-time response to cues. The proposed approach has potential application to people with Parkinson's Disease.

Adaptive cueing strategy for gait modification: A case study using auditory cues.

People with Parkinson's (PwP) experience gait impairments that can be improved through cue training, where visual, auditory, or haptic cues are provided to guide the walker's cadence or step length. There are two types of cueing strategies: open and closed-loop. Closed-loop cueing may be more effective in addressing habituation and cue dependency, but has to date been rarely validated with PwP. In this study, we adapt a human-in-the-loop framework to conduct preliminary analysis with four PwP. The closed-loop framework learns an individualized model of the walker's responsiveness to cues and generates an optimized cue based on the model. In this feasibility study, we determine whether participants in early stages of Parkinson's can respond to the novel cueing framework, and compare the performance of the framework to two alternative cueing strategies (fixed/proportional approaches) in changing the participant's cadence to two target cadences (speed up/slow down). The preliminary results show that the selection of the target cadence has an impact on the participant's gait performance. With the appropriate target, the framework and the fixed approaches perform similarly in slowing the participants' cadence. However, the proposed framework demonstrates better efficiency, explainability, and robustness across participants. Participants also have the highest retention rate in the absence of cues with the proposed framework. Finally, there is no clear benefit of using the proportional approach.

Recessive congenital methemoglobinemia caused by a rare mechanism: maternal uniparental heterodisomy with segmental isodisomy of a chromosome 22.

Recessive congenital methemoglobinemia (RCM) is a very rare disorder caused by NADH-cytochrome b5 reductase (cb5r) deficiency. Two distinct clinical forms, types I and II, caused by cb5r deficiency have been recognized. In type I, the enzyme deficiency is restricted only to erythrocytes with cyanosis being the only major symptom. In contrast, in type II, the enzyme deficiency is generalized to all tissues and associated with neurological impairment, mental and growth retardation and reduced life expectancy, in addition to cyanosis. Recently, we conducted a study on an 11-year-old boy with cb5r deficiency type I. The mutational analysis of the CYB5R3 gene revealed that the boy is homozygous for L72P mutation. Surprisingly, his mother is heterozygous for this L72P mutant, but not his father. Thirteen microsatellite markers of chromosome 22 were selected to analyze the origins of the patient's chromosome 22. The result showed that both of the chromosome 22(s) of this patient came from the maternal side (uniparental heterodisomy of chromosome 22 with segmental isodisomy). This is the first case report of a patient with cb5r deficiency type I resulting from uniparental disomy and also discloses an alternate mechanism whereby this enzymatic disorder can be derived from a single parent.

Homocystinuria in Taiwan: an inordinately high prevalence in an Austronesian aboriginal tribe, Tao.

The newborn screening of homocystinuria in Taiwan has never been formally reported before. Since 1984, out of 5 million newborns screened, only 3 newborns (Han Taiwanese) suffering from homocystinuria were detected in this newborn screening program. Four mutations (p.R121L [c.362G>T], p.E176K [c.526G>A], p.V320G [c.959T>G] and p.G259D [c.776G>A]) were identified in these 3 patients. Unexpectedly, we recently found 8 patients presenting with homocystinuria in an Austronesian Taiwanese Tao tribe. Out of them, three patients participated in the newborn screening program but were unidentified by the current newborn homocystinuria (using methionine as a marker) screening. All the Tao patients are homozygous for a new p.D47E (c.141T>A) mutation. Among the 428 adult islanders screened for the D47E mutation, approximately 1 in 7.78 is a carrier of the mutation, and an estimated 1 in 240 islanders suffered from homocystinuria. This is the highest known prevalence of homocystinuria worldwide. The result of expression studies of all the mutations identified in Taiwan revealed that, except for p.D47E mutation, all mutations were severely limited in their ability to form functional tetramers. The clinical manifestations of the Tao patients varied widely, despite sharing the same mutation and very similar genetic and environmental backgrounds. Comparisons of clinical and biochemical phenotypes of these patients were presented in this report.

Demystifying borderline personality disorder in primary care.

Borderline personality disorder (BPD) is a common mental health diagnosis observed in the primary care population and is associated with a variety of psychological and physical symptoms. BPD is a challenging disorder to recognize due to the limitations of accurate diagnosis and identification in primary care settings. It is also difficult to treat due to its complexity (e.g., interpersonal difficulties and patterns of unsafe behaviors, perceived stigma) and healthcare professionals often feel overwhelmed when treating this population. The aim of this article is to describe the impact of BPD in primary care, review current state of knowledge, and provide practical, evidence-based treatment approaches for these patients within this setting. Due to the lack of evidence-based pharmacological treatments, emphasis is placed on describing the framework for treatment, identifying psychotherapeutic opportunities, and managing responses to difficult clinical scenarios. Furthermore, we discuss BPD treatment as it relates to populations of special interest, including individuals facing societal discrimination and adolescents. Through this review, we aim to highlight gaps in current knowledge around managing BPD in primary care and provide direction for future study.

Clinical observations, molecular genetic analysis, and treatment of sitosterolemia in infants and children.

The clinical observation and treatment of young children with sitosterolemia has rarely been reported. We report clinical, biochemical, and molecular genetic observations and treatment outcomes for five Chinese children from four separate families presenting with sitosterolemia in whom we identified two new (Y329X, G269R) and three known (R446X, N437K, R389H) mutations in the ABCG5 gene. The R389H mutation was found in 50% of alleles. Three of these five patients received cholestyramine therapy with a very good response. However, all patients discontinued this therapy because of poor compliance. Finally, all patients were on ezetimibe therapy and had satisfactory total serum cholesterol levels, though their plant sterol levels were still higher than normal. Another noteworthy finding is that a female infant had a serum cholesterol level of 654 mg/dl at 7 months of age, despite being breast fed (with very tiny amounts of plant sterols) since birth and undergoing 4 months of ezetimibe administration. Although she failed to respond to ezetimibe during this period, she did show improvement when the therapy was started again at 2 years of age. It is possible that another 23-month-old female patient also responded more slowly to ezetimibe treatment than older patients.

Modulation of the proteolytic activity of the complement protease C1s by polyanions: implications for polyanion-mediated acceleration of interaction between C1s and SERPING1.

The complement system plays crucial roles in the immune system, but incorrect regulation causes inflammation and targeting of self-tissue, leading to diseases such as systemic lupus erythematosus, rheumatoid arthritis and age-related macular degeneration. In vivo, the initiating complexes of the classical complement and lectin pathways are controlled by SERPING1 [(C1 inhibitor) serpin peptidase inhibitor, clade G, member 1], which inactivates the components C1s and MASP-2 (mannan-binding lectin serine peptidase 2). GAGs (glycosaminoglycan) and DXS (dextran sulfate) are able to significantly accelerate SERPING1-mediated inactivation of C1s, the key effector enzyme of the classical C1 complex, although the mechanism is poorly understood. In the present study we have shown that C1s can bind to DXS and heparin and that these polyanions enhanced C1s proteolytic activity at low concentrations and inhibited it at higher concentrations. The recent determination of the crystal structure of SERPING1 has given rise to the hypothesis that both the serpin (serine protease inhibitor)-polyanion and protease-polyanion interactions might be required to accelerate the association rate of SERPING1 and C1s. To determine what proportion of the acceleration was due to protease-polyanion interactions, a chimaeric mutant of alpha1-antitrypsin containing the P4-P1 residues from the SERPING1 RCL (reactive-centre loop) was produced. Like SERPING1, this molecule is able to effectively inhibit C1s, but is unable to bind polyanions. DXS exerted a biphasic effect on the association rate of C1s which correlated strongly with the effect of DXS on C1s proteolytic activity. Thus, whereas polyanions are able to bind C1s and modulate its activity, polyanion interactions with SERPING1 must also play a vital role in the mechanism by which these cofactors accelerate the C1s-SERPING1 reaction.

Five commonly used markers (p53, TTF1, CK7, CK20, and CK34betaE12) are of no use in distinguishing between primary endocervical and endometrial adenocarcinomas in a tissue microarray extension study.

BACKGROUND: The choice of appropriate therapeutic plans for primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) depends on the tumor's site of origin. Some panels of antibodies help to distinguish primary ECA from EMA. However, unexpected expressions of those markers often exist, which causes this diagnostic dilemma to be still unresolved. In this study, we investigate five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34betaE12) to evaluate their potential use in distinguishing between these two gynecologic malignancies. METHODS: A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin-biotin (ABC) technique, tissue array sections were immunostained with the five aforementioned commercially available antibodies. RESULTS: Immunohistochemical (IHC) expressions of p53, TTF1, CK7, CK20, and CK34betaE12 were all nonsignificant (P>0.05) in frequency differences between the immunostaining results (positive vs. negative) in tumors from both the two primary adenocarcinomas (ECA vs. EMA). CONCLUSION: It is still uncertain which markers or panels would be the most appropriate for making diagnoses; hence, exploration of other useful markers, which make a definitive distinction between ECA and EMA merits further studies. This study, however, uncovered that the five commonly used monoclonal antibodies (p53, TTF1, CK7, CK20, and CK34betaE12) are of no beneficial value in distinguishing between primary ECA and EMA.

Comparing the scoring mechanisms of p16INK4a immunohistochemistry based on independent nucleic stains and independent cytoplasmic stains in distinguishing between endocervical and endometrial adenocarcinomas in a tissue microarray study.

BACKGROUND: Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect the uterus; however, their biological behaviors are quite different. This distinction has clinical significance because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate two different scoring mechanisms of p16INK4a immunohistochemical (IHC) stain in distinguishing between primary ECAs and EMAs. METHODS: A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 21 EMAs. Tissue array sections were stained with a commercially available antibody, p16INK4a. The avidin-biotin complex method was used to visualize antigens. The staining intensity and extent of the IHC reactions were evaluated using a semi-quantitative scoring system. Two scoring methods were defined on the following bases: (1) independent cytoplasmic staining alone, irrespective of nucleic stain (Method C) and (2) independent nucleic staining alone, irrespective of cytoplasmic staining. (Method N). RESULTS: Of the two scoring mechanisms for p16INK4a expression, Method N showed a significant difference (P=0.015), but Method C showed no significant (P=0.432) frequency differences in distinguishing between ECAs and EMAs. However, Method N had a higher overall accuracy rate (71.4%) in accurately diagnosing ECAs from EMAs in the total number of p16INK4a IHC cases. CONCLUSION: According to the data of p16(INK4a) expression in this TMA study, Method N is favorable and efficient in distinguishing between ECAs and EMAs, while Method C is not.

A reappraisal of three-marker (ER/Vim/CEA), four-marker (ER/Vim/CEA/PR), and five-marker (ER/Vim/CEA/PR/p16INK4a) panels in the diagnostic distinction between primary endocervical and endometrial adenocarcinomas in a tissue microarray study.

BACKGROUND: The choice of appropriate therapeutic plans for primary endocervical adenocarcinomas (ECA) and endometrial adenocarcinomas (EMA) depend on the tumor's site of origin. The purpose of this study was to compare the performances of the commonly used three-marker (ER/Vim/CEA), four-marker (ER/Vim/CEA/PR) and five-marker (ER/Vim/CEA/PR/p16INK4a) panels in distinguishing between primary ECA and EMA. METHODS: A tissue microarray was constructed using paraffin-embedded, formalin-fixed tissues from 35 hysterectomy specimens, including 14 ECA and 21 EMA. Utilizing the avidin-biotin (ABC) technique, tissue array sections were immunostained with five commercially available antibodies (ER, Vim, CEA, PR and p16INK4a) to evaluate the performances of their respective three-, four- and five-marker panels in distinguishing between primary ECA and EMA. RESULTS: ER, PR and Vim were more likely to be expressed in EMA, while CEA and p16INK4a were frequently expressed in ECA. The three-marker (ER/Vim/CEA) panel exhibits the most favorable performance in the distinction between these two gynecologic malignancies (ECA vs. EMA). CONCLUSION: According to our data, when histomorphological and clinical doubt exists as to the primary site of origin, we recommend that the conventional three-marker (ER/Vim/CEA) panel is sufficient, appropriate and useful in distinguishing between primary ECA and EMA, instead of the four-marker (ER/Vim/CEA/PR) and five-marker (ER/Vim/CEA/PR/p16INK4a) panels. Ancillary PR and p16INK4a add no supplementary value to the performance of the conventional three-marker (ER/Vim/CEA) panel.

Air pollution exposure and adverse sleep health across the life course: A systematic review.

An increasing number of epidemiological studies have examined air pollution as a possible contributor to adverse sleep health, but results are mixed. The aims of this systematic review are to investigate and summarize the associations between exposures to air pollutants and various sleep measures across the lifespan. PubMed, CINAHL, Cochrane, Scopus, Web of Science, and PsycInfo were searched through October 2019 to identify original data-based research examining direct epidemiological associations between ambient and indoor air pollution exposures and various sleep health measures, including sleep quality, sleep duration, sleep disturbances, and daytime sleepiness. Twenty-two articles from 2010 to 2019 were selected for inclusion in this review, including a wide range of study populations (from early childhood to elderly) and locations (10 Asian, 4 North American, 3 European, 5 other). Due to variation in both exposure and outcome assessments, conducting a meta-analysis was not plausible. Twenty-one studies reported a generally positive association between exposure and poor sleep quality. While most studies focused on ambient air pollutants, five assessed the specific effect of indoor exposure. In children and adolescents, increased exposure to both ambient and indoor pollutants is associated with increased respiratory sleep problems and a variety of additional adverse sleep outcomes. In adults, air pollution exposure was most notably related to sleep disordered breathing. Existing literature generally shows a negative relationship between exposures to air pollution and sleep health in populations across different age groups, countries, and measures. While many associations between air pollution and sleep outcomes have been investigated, the mixed study methods and use of subjective air pollution and sleep measures result in a wide range of specific associations. Plausible toxicological mechanisms remain inconclusive. Future studies utilizing objective sleep measures and controlling for all air pollution exposures and individual encounters may help ameliorate variability in the results reported by current published literature.