Search

To date, research on traumatic stress and treatment-seeking behavior has primarily focused on Western populations. Despite experiencing similar levels of symptomatology, mental health service utilization appears lower among East Asian populations. Stigma toward mental health services may be one barrier to treatment-seeking, especially among individuals who have experienced potentially traumatic events; however, previous research has been primarily conducted in the United States. Less is known about predictors of treatment-seeking attitudes among populations residing in East Asia, particularly college students. The present study examined the relationship between trauma, mental health services stigma, and treatment-seeking attitudes among undergraduate students in Southwestern China. Self-report measures of trauma exposure, posttraumatic stress disorder symptomatology, mental health services stigma, and treatment-seeking attitudes were administered. We hypothesized that students with greater severity of traumatic symptoms would endorse more positive attitudes toward treatment-seeking if they reported lower levels of mental health services stigma. Mental health services stigma was a strong predictor of negative attitudes toward treatment-seeking, whereas neither trauma exposure nor traumatic symptomatology were associated with treatment-seeking attitudes. The significant association between mental health services stigma and treatment-seeking attitudes underscores the importance of destigmatizing mental health to encourage treatment-seeking among the Chinese college student population.

Purpose: To assess the quality and presence of spin bias in the abstracts of systematic reviews and meta-analyses that evaluated the outcomes of using hip arthroscopy for the treatment of hip pathology in the setting of borderline hip dysplasia. Methods: PubMed and Embase were searched using the terms “borderline hip dysplasia” and “systematic review” or “meta-analysis.” Forty-one initial studies were identified, and 12 met the inclusion criteria. Study characteristics were then collected, and each study was evaluated for the 15 most common types of bias and study quality using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) rating system. Inclusion criteria included a systematic review with or without meta-analysis, published in a peer-reviewed journal, accessible in English, with outcomes after hip arthroscopy for borderline hip dysplasia. Results: The 12 reviewed studies were published between 2016 and 2023, and 10 of the studies represented Level IV evidence (2 studies were Level III evidence). At least 1 form of spin was identified in 83% (10/12) of the included studies. Regarding the specific categories of spin type, misleading interpretation was identified in 58% (7/12) of the studies, misleading reporting in 67% (8/12) of the studies, and inappropriate extrapolation in 50% (6/12) of the studies. On the basis of the AMSTAR 2 assessment, 92% (11/12) were categorized as either low quality or critically low quality, with 1 study being categorized as moderate. Conclusions: Spin bias is frequently encountered in the abstracts for systematic reviews and meta-analyses that evaluate outcomes after hip arthroscopy for the treatment of hip pathology in the setting of borderline hip dysplasia. Level of Evidence: Level IV, systematic review of Level III and IV studies.

Introduction:. There is a historic sex imbalance in the field of orthopaedic surgery in the United States, with female physicians being vastly underrepresented. In addition, this sex imbalance is particularly pronounced in certain subspecialties. As such, we sought to analyze the distribution of graduating female residents and their fellowship match trends from 2017 to 2022. Methods:. The American Medical Association Fellowship and Residency Electronic Interactive Database was used to identify all orthopaedic surgery residency programs in the United States during the 2016 to 2017 and the 2021 to 2022 academic years. The data were supplemented with the Accreditation Council for Graduate Medical Education (ACGME) Data Book to include data on all ACGME-accredited programs in 2017 and 2022. The percentage of female orthopaedic surgery residents matching into each subspecialty was calculated. Continuous data were analyzed with independent t test, and significance was set at p < 0.05. Results:. From 2017 to 2022, there has been a significant increase in the percentage of female residents matching in orthopaedic surgery fellowships (14.6% vs. 19.5%, p < 0.001). In the orthopaedic hand subspecialty, 24 (15.8%) female residents matched into a hand fellowship in 2017 vs. 56 (35.2%) in 2022 (p < 0.001). Spine, trauma, adult reconstruction, oncology, pediatrics, foot and ankle, shoulder and elbow, and sports medicine fellowships have not seen a significant change in the distribution of female residents matching over the past 5 years. Conclusion:. Between 2017 and 2022, the total number of female orthopaedic surgery fellows increased, and there was significant growth in the percentage of matched female fellows in the subspecialty of hand. Other orthopaedic subspecialties including spine, trauma, adult reconstruction, oncology, pediatrics, foot and ankle, shoulder and elbow, and sports medicine have seen no significant change in the distribution of women fellows over the past 5 years. Further investigation is warranted to determine factors leading to growth in certain fellowships among female residents to encourage sex diversity among all subspecialties in orthopaedic surgery.

Plants play a key role in the treatment and prevention of diseases since ancient times. Eucalyptus has been traditionally used in the treatment of conditions related to the respiratory system, such as flu, colds, sore throats, bronchitis, as well as neuralgia, and stiffness. Eucalyptus camaldulensis has several phytoconstituents such as ellagitannins endowed with bioactivity, including antioxidant and inhibitory potential on various microorganisms causing foodborne diseases. Tellimagrandin I, pedunculagin, castalagin/vescalagin are among the most representative and have activity against pathogens such as Staphylococcus aureus, Escherichia coli, Listeria monocytogenes, and Bacillus cereus. These antioxidant ellagitannins may have potential application in the food, pharmaceutical, and cosmetic industries. The main industrial uses of E. camaldulensis are related to the production of wood, paper, and charcoal, with its leaves and branches considered by-products from these industrial activities. However, these plant by-products could be used to obtain bioactive compounds for the development of new and improved consumer goods. Therefore, the aim of this work was to review the main ellagitannins of E. camaldulensis and their antioxidant and antibacterial activities in foodborne microorganisms, as well as the relevance that these compounds may have in the food industry and related sectors.

Purpose: To analyze the annual use of hip arthroscopy (HA) and Bernese periacetabular osteotomy (PAO) for the treatment of hip dysplasia (HD), as well as postoperative outcomes, including ipsilateral reoperations. Methods: International Classification of Diseases, Ninth and Tenth Revision, codes were used to query the PearlDiver Mariner database from January 2010 through January 2022 to identify patients aged 10 to 59 years who had a presenting diagnosis of HD and subsequently underwent (1) HA; (2) PAO; or (3) combined HA and PAO (HA-PAO, defined as PAO on the same day or within 28 days after HA). We analyzed annual rates for each treatment, as well as rates of postoperative emergency visits, readmissions, and 5-year ipsilateral secondary operations (determined via Kaplan-Meier analysis). Results: There were 32,068 patients who underwent surgical treatment of HD. For HA, PAO, and HA-PAO, there were 29,700, 2,083, and 285 patients, respectively. All operations had the greatest percent-increase from 2015 to 2016. HA and HA-PAO peaked in 2021, whereas PAO peaked in 2019. For HA, PAO, and HA-PAO, most cases were performed in female patients and patients aged 30 to 49 years, 10 to 19 years, and 10 to 29 years, respectively. The 5-year incidence of ipsilateral secondary operations, which include revision HA, PAO, or conversion to total hip arthroplasty, was 9.2% (95% confidence interval 8.6%-9.8%) in the HA group and 6.5% (95% confidence interval 4.1%-8.8%) in the PAO group. Combining HA with PAO resulted in so few secondary operations that Kaplan-Meier analysis was infeasible. The PAO cohort had the greatest 30-day emergency visit and 90-day readmission rates, with infection as the most common cause for readmission. Conclusions: HA is more frequently performed than PAO for hip dysplasia. HA-PAO is increasing at the greatest rate, demonstrating fewer complications and reoperations. Level of Evidence: Level III, retrospective comparative trial.

Rationale & Objective: While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein–related metabolites are associated with incident chronic kidney disease (CKD). Study Design: Prospective cohort study. Setting & Participants: A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline. Exposures: Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites. Outcomes: Incident CKD (estimated glomerular filtration rate

Purpose: To evaluate patient-reported outcomes and risk for rerupture after surgical treatment of proximal hamstring tendon ruptures using all-suture anchors and a unique postoperative bracing strategy. Methods: A retrospective review of a prospectively collected database was conducted of patients undergoing proximal hamstring repair or reconstruction from 2020 to 2022 at a tertiary, academic institution. Patients were included if they reached minimum 1-year follow-up and completed postoperative patient-reported outcomes. The surgical protocol for proximal hamstring repairs included all-suture anchors placed either in an open or endoscopic fashion in the ischial tuberosity. After surgery, all patients underwent an accelerated rehabilitation protocol, including 6 weeks touchdown weight-bearing in a hinged knee brace locked in extension for ambulation, allowing passive knee flexion to 90° while seated. Descriptive statistics were used to analyze the data. Results: Twenty-one patients were included (mean age 50.4 ± 9.5 years, body mass index 24.4 ± 3.5, 66.7% female). Lower Extremity Functional Scale score achieved postoperatively was 74.2 ± 7.5 (out of 80). Patients had minimal pain (mean visual analog scale pain score of 0.9 ± 1.2). 61.9% of patients were able to return to the same level of activity after based on Tegner score by 1 year. Postoperative Single Assessment Numeric Evaluation activity of daily living was 94.3 ± 8.3, and Single Assessment Numeric Evaluation Sports was 82.3 ± 19.0. Mean Short Form Survey (SF-12) postoperative scores were 51.6 ± 6.8 for SF-12 Physical Component Score and 53.9 ± 9.7 for Mental Component Score. 95.2% (20 of 21) patients were satisfied with their outcome. There were no reruptures, infections, or reoperations. One patient of 21 (4.8%) incurred a postoperative deep venous thrombosis, which was treated with therapeutic anticoagulation for 3 months. Conclusions: All-suture anchors for proximal hamstring repair with a unique accelerated postoperative rehabilitation and bracing protocol result in good outcomes and patient satisfaction with minimal risk of complications. Level of Evidence: Level IV, case series, therapeutic.

From the beginning of the COVID-19 pandemic, universities have experienced unique challenges due to their dual nature as a place of education and residence. Current research has explored non-pharmaceutical approaches to combating COVID-19, including representing in models different categories such as age groups. One key area not currently well represented in models is the effect of pharmaceutical preventative measures, specifically vaccinations, on COVID-19 spread on college campuses. There remain key questions on the sensitivity of COVID-19 infection rates on college campuses to potentially time-varying vaccine immunity. Here we introduce a compartment model that decomposes a campus population into constituent subpopulations and implements vaccinations with time-varying efficacy. We use this model to represent a campus population with both vaccinated and unvaccinated individuals, and we analyze this model using two metrics of interest: maximum isolation population and symptomatic infection. We demonstrate a decrease in symptomatic infections occurs for vaccinated individuals when the frequency of testing for unvaccinated individuals is increased. We find that the number of symptomatic infections is insensitive to the frequency of testing of the unvaccinated subpopulation once about 80% or more of the population is vaccinated. Through a Sobol’ global sensitivity analysis, we characterize the sensitivity of modeled infection rates to these uncertain parameters. We find that in order to manage symptomatic infections and the maximum isolation population campuses must minimize contact between infected and uninfected individuals, promote high vaccine protection at the beginning of the semester, and minimize the number of individuals developing symptoms.

Abstract Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

This article systematically reviews the advancements in processing litchi peel (Litchi chinensis), emphasizing drying, extraction, purification methods, and the potential of bioactive compounds obtained from litchi peel. This work also highlights the impact of various drying techniques on phytochemical profiles, focusing on how methods such as hot air and freeze-drying affect the preservation of bioactive compounds. The study delves into extraction methods, detailing how different solvents and techniques influence the efficiency of extracting bioactive compounds from litchi peel. Furthermore, the purification and characterization of active compounds, showcasing the role of chromatographic techniques in isolating specific bioactive molecules, is discussed. Biological properties and mechanisms of action, such as antioxidant, antihyperglycemic, cardioprotective, hepatoprotective, anti-atherosclerotic, and anticancer activities, are reviewed, providing insight into the potential health benefits of litchi peel compounds. This review highlights the importance of optimizing and selecting accurate drying and extraction methods to maximize the therapeutic effects of litchi peel and its bioactive compounds. This review also reveals the broad pharmacological potential of the isolated compounds, underscoring the need for further research to discover their specific actions and health benefits.

The management of chronic extensor mechanism injuries represents a significant challenge for orthopaedic surgeons, with numerous options for graft choice and fixation construct, but no clear consensus on which technique achieves optimal outcomes. Although there is little published data regarding outcomes of different fixation methods, small case series have demonstrated modest success using Achilles tendon bone block allografts and transverse patellar screw fixation. In this technical note, we describe a surgical technique for the treatment of a chronic inferior pole patella fracture, with extensor mechanism reconstruction using an Achilles tendon allograft with suture tape augmentation. Our technique describes the use of vertical cannulated screws in the patella for passing tape augmentation sutures, increased construct security by suturing of the Achilles graft directly to the quadriceps tendon, and the use of a post screw in the proximal tibia for suture tape augmentation.

Abstract Background Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II. Methods We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the ‘early course’ of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach. Results From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course. Conclusions and recommendations While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

Intro: A national SARS-CoV-2 genome sequencing consortium was established in Aug 2021 to help monitor the emergence of the COVID-19 variants. Tropical Infectious Diseases Research and Education Centre (TIDREC) received samples from the states of Kedah, Kelantan, Perak, and Terengganu between Aug 2021 and March 2022 and samples from Kedah and Perlis from 1 Apr 2022. In the current study, we sequenced and analyzed the SARS-CoV-2 strains received from Kedah between July 2021 to June 2022. Methods: The RNA was extracted and screened for the presence of SARS-CoV-2 RNA using qRT-PCR. Samples with a Ct value less than 32 were selected for sequencing. The genome libraries were prepared using Ion AmpliSeq™ SARSCoV-2 Research Panel and sequenced using the Ion GeneStudio™ S5 Prime System. The genome sequences were assembled, and SARS-CoV-2 lineages were assigned using PANGOLIN COVID-19 Lineage Assigner. Findings: A total of 310 samples were sequenced and analyzed. Results showed that all 310 samples belonged to two groups of Variants of Concern (VOC), Delta and Omicron. Our results revealed that between Aug 2022 and mid-December, the Delta variant was the only circulating VOC in Kedah, with AY.59 as the dominant circulating lineage. The Omicron, BA.1.1, was first detected on 21 Dec 2022 in our collection. The Delta and Omicron variants were co-circulated in Kedah between Jan and Feb 2022. After that, the Omicron BA.2 lineage was reported in Feb 2022, and it replaced the BA.1 and its descendent lineages as the dominant lineage starting in March 2022. The Omicron BA.5 lineage was first detected in samples collected on 26 May 2022, suggesting the emergence of BA.5 in Kedah. Conclusion: We reported the continuous introduction, dispersal, and replacement of SARS-CoV-2 variants in Kedah, Malaysia. Continuous monitoring of the circulating SARS-CoV-2 is vital to detect the emergence of newer SARSCoV-2 variants.

Neuroscience, gene therapy, and vaccine have all benefited from the increased use of viral vectors. Sindbis virus (SINV) is a notable candidate among these vectors. However, viral vectors commonly suffer from a loss of expression of the transgene, especially RNA viral vectors. In this study, we used a directed evolution approach by continuous passage of selection to identify adaptive mutations that help SINV to stably express exogenous genes. As a result, we found two adaptive mutations that are located at aa 285 (G to S) of nsP1 and aa 422 (D to G) of nsP2, respectively. Further study showed that G285S was sufficient for SINV to stabilize the expression of the inserted gene, while D422G was not. Combined with AlphaFold2 and sequence alignment with the genus Alphavirus, we found that G285S is conserved. Based on this mutation, we constructed a new vector for the applications in neural circuits mapping. Our results indicated that the mutant SINV maintained its anterograde transsynaptic transmission property. In addition, when the transgene was replaced by another gene, granulocyte-macrophage colony-stimulating factor (GM-CSF), the vector still showed stable expression of the inserted gene. Hence, using SINV as an example, we have demonstrated an efficient approach to greatly augment the gene delivery capacity of viral vectors, which will be useful to neuroscience and oncolytic therapy.

Climate models are critical tools for developing strategies to manage the risks posed by sea-level rise to coastal communities. While these models are necessary for understanding climate risks, there is a level of uncertainty inherent in each parameter in the models. This model parametric uncertainty leads to uncertainty in future climate risks. Consequently, there is a need to understand how those parameter uncertainties impact our assessment of future climate risks and the efficacy of strategies to manage them. Here, we use random forests to examine the parametric drivers of future climate risk and how the relative importances of those drivers change over time. In this work, we use the Building blocks for Relevant Ice and Climate Knowledge (BRICK) semi-empirical model for sea-level rise. We selected this model because of its balance of computational efficiency and representation of the many different processes that contribute to sea-level rise. We find that the equilibrium climate sensitivity and a factor that scales the effect of aerosols on radiative forcing are consistently the most important climate model parametric uncertainties throughout the 2020 to 2150 interval for both low and high radiative forcing scenarios. The near-term hazards of high-end sea-level rise are driven primarily by thermal expansion, while the longer-term hazards are associated with mass loss from the Antarctic and Greenland ice sheets. Our results highlight the practical importance of considering time-evolving parametric uncertainties when developing strategies to manage future climate risks.

Introduction:. Female physicians have been historically underrepresented in orthopaedic surgery residencies. The purpose of this study was to determine whether sex diversity among orthopaedic residency programs and faculty is associated with an increased number of female residents matriculating into that program. In addition, we sought to analyze female resident matriculation trends in the past 5 years. Methods:. The American Medical Association Fellowship and Residency Electronic Interactive Database was used to identify all allopathic orthopaedic surgery residency programs during the 2021 to 2022 academic year. The number of female residents and interns; the number of female faculty, professors, and associate professors; and the number of women in leadership positions were compared with data from the academic year 2016 to 2017. Continuous data were analyzed with independent t-tests, and significance was set at p < 0.05. Results:. A total of 696 female residents (19.2%) were identified from 3,624 orthopaedic residents, an increase from 13.5% in 2016. Programs in the top quartile of female residents had 3 times the number of female residents per program when compared to other quartiles and almost double the number of female interns per program. Programs in the top quartile of female residents had a significantly greater number of female faculty per program than the lower quartiles; 5.76 vs. 4.18. Compared with 2016 to 2017, there were significant increases in female faculty per program from 2.77 to 4.54 along with female full professors from 0.274 to 0.694. These increases contribute to the overall growth in the number of women in leadership positions per program over the past 5 years to 1.01 from 0.35 (p < 0.001). Conclusion:. In the past 5 years, the percentage of female residents has increased from 13.5% to 19.2%. Furthermore, women make up 22.1% of interns. Orthopaedic surgery residency programs with higher percentages of female faculty had higher numbers of female residents. By encouraging programs to promote female representation within leadership and residents, we may continue to see the gap in orthopaedic sex diversity close. Level of Evidence:. III.

Multiple lines of evidence support the value of moderate fever to host survival, but the mechanisms involved remain unclear. This is difficult to establish in warm-blooded animal models, given the strict programmes controlling core body temperature and the physiological stress that results from their disruption. Thus, we took advantage of a cold-blooded teleost fish that offered natural kinetics for the induction and regulation of fever and a broad range of tolerated temperatures. A custom swim chamber, coupled to high-fidelity quantitative positional tracking, showed remarkable consistency in fish behaviours and defined the febrile window. Animals exerting fever engaged pyrogenic cytokine gene programmes in the central nervous system, increased efficiency of leukocyte recruitment into the immune challenge site, and markedly improved pathogen clearance in vivo, even when an infecting bacterium grew better at higher temperatures. Contrary to earlier speculations for global upregulation of immunity, we identified selectivity in the protective immune mechanisms activated through fever. Fever then inhibited inflammation and markedly improved wound repair. Artificial mechanical hyperthermia, often used as a model of fever, recapitulated some but not all benefits achieved through natural host-driven dynamic thermoregulation. Together, our results define fever as an integrative host response that regulates induction and resolution of acute inflammation, and demonstrate that this integrative strategy emerged prior to endothermy during evolution.

Graduation rates are a key measure of the long-term efficacy of academic interventions. However, challenges to using traditional estimates of graduation rates for underrepresented students include inherently small sample sizes and high data requirements. Here, we show that a Markov model increases confidence and reduces biases in estimated graduation rates for underrepresented minority and first-generation students. We use a Learning Assistant program to demonstrate the Markov model’s strength for assessing program efficacy. We find that Learning Assistants in gateway science courses are associated with a 9% increase in the six-year graduation rate. These gains are larger for underrepresented minority (21%) and first-generation students (18%). Our results indicate that Learning Assistants can improve overall graduation rates and address inequalities in graduation rates for underrepresented students.

Streptococcus pneumoniae is an important cause of fatal pneumonia in humans. These bacteria express virulence factors, such as the toxins pneumolysin and autolysin, that drive host inflammatory responses. In this study we confirm loss of pneumolysin and autolysin function in a group of clonal pneumococci that have a chromosomal deletion resulting in a pneumolysin-autolysin fusion gene Δ(lytA'-ply')593. The Δ(lytA'-ply')593 pneumococci strains naturally occur in horses and infection is associated with mild clinical signs. Here we use immortalized and primary macrophage in vitro models, which include pattern recognition receptor knock-out cells, and a murine acute pneumonia model to show that a Δ(lytA'-ply')593 strain induces cytokine production by cultured macrophages, however, unlike the serotype-matched ply+lytA+ strain, it induces less tumour necrosis factor α (TNFα) and no interleukin-1β production. The TNFα induced by the Δ(lytA'-ply')593 strain requires MyD88 but, in contrast to the ply+lytA+ strain, is not reduced in cells lacking TLR2, 4 or 9. In comparison to the ply+lytA+ strain in a mouse model of acute pneumonia, infection with the Δ(lytA'-ply')593 strain resulted in less severe lung pathology, comparable levels of interleukin-1α, but minimal release of other pro-inflammatory cytokines, including interferon-γ, interleukin-6 and TNFα. These results suggest a mechanism by which a naturally occurring Δ(lytA'-ply')593 mutant strain of S. pneumoniae that resides in a non-human host has reduced inflammatory and invasive capacity compared to a human S. pneumoniae strain. These data probably explain the relatively mild clinical disease in response to S. pneumoniae infection seen in horses in comparison to humans.

Craniofacial defects require a treatment approach that provides both robust tissues to withstand the forces of mastication and high geometric fidelity that allows restoration of facial architecture. When the surrounding soft tissue is compromised either through lack of quantity (insufficient soft tissue to enclose a graft) or quality (insufficient vascularity or inducible cells), a vascularized construct is needed for reconstruction. Tissue engineering using customized 3D printed bioreactors enables the generation of mechanically robust, vascularized bony tissues of the desired geometry. While this approach has been shown to be effective when utilized for reconstruction of non-load bearing ovine angular defects and partial segmental defects, the two-stage approach to mandibular reconstruction requires testing in a large, load-bearing defect. In this study, 5 sheep underwent bioreactor implantation and the creation of a load-bearing mandibular defect. Two bioreactor geometries were tested: a larger complex bioreactor with a central groove, and a smaller rectangular bioreactor that were filled with a mix of xenograft and autograft (initial bone volume/total volume BV/TV of 31.8 ± 1.6%). At transfer, the tissues generated within large and small bioreactors were composed of a mix of lamellar and woven bone and had BV/TV of 55.3 ± 2.6% and 59.2 ± 6.3%, respectively. After transfer of the large bioreactors to the mandibular defect, the bioreactor tissues continued to remodel, reaching a final BV/TV of 64.5 ± 6.2%. Despite recalcitrant infections, viable osteoblasts were seen within the transferred tissues to the mandibular site at the end of the study, suggesting that a vascularized customized bony flap is a potentially effective reconstructive strategy when combined with an optimal stabilization strategy and local antibiotic delivery prior to development of a deep-seated infection.

Abstract Sea‐level rise and associated flood hazards pose severe risks to the millions of people globally living in coastal zones. Models representing coastal adaptation and impacts are important tools to inform the design of strategies to manage these risks. Representing the often deep uncertainties influencing these risks poses nontrivial challenges. A common uncertainty characterization approach is to use a few benchmark cases to represent the range and relative probabilities of the set of possible outcomes. This has been done in coastal adaptation studies, for example, by using low, moderate, and high percentiles of an input of interest, like sea‐level changes. A key consideration is how this simplified characterization of uncertainty influences the distributions of estimated coastal impacts. Here, we show that using only a few benchmark percentiles to represent uncertainty in future sea‐level change can lead to overconfident projections and underestimate high‐end risks as compared to using full ensembles for sea‐level change and socioeconomic parametric uncertainties. When uncertainty in future sea level is characterized by low, moderate, and high percentiles of global mean sea‐level rise, estimates of high‐end (95th percentile) damages are underestimated by between 18% (SSP1‐2.6) and 46% (SSP5‐8.5). Additionally, using the 5th and 95th percentiles of sea‐level scenarios underestimates the 5%–95% width of the distribution of adaptation costs by a factor ranging from about two to four, depending on SSP‐RCP pathway. The resulting underestimation of the uncertainty range in adaptation costs can bias adaptation and mitigation decision‐making.

Adverse childhood experiences (ACEs) are associated with dysregulation of inflammation and cortisol. The objectives of this study were to use principal component analysis to explore the inflammatory biomarker data to create inflammation composite variables; to examine the relationship between these composite measures of inflammation with ACEs and cortisol; and to assess whether these relationships were moderated by sex. The analysis included 232 young adults from the Niagara Longitudinal Heart Study (NLHS). After adjusting for covariates, higher exposure to ACEs significantly predicted higher low-grade inflammation. These results further support the use of multiple biomarkers to understand the complex relationships among ACEs, cortisol, and inflammation, which should be further examined in longitudinal studies to study biomarker trajectories.

Sickle cell disease (SCD) is an inherited blood disorder that affects about 100,000 people in the U.S., primarily Blacks/African-Americans. A multitude of complications negatively impacts quality of life. Hydroxyurea has been FDA approved since 1998 as a disease-modifying therapy for SCD, but is underutilized. Negative and uninformed perceptions of hydroxyurea and barriers to its use hinder adherence and promotion of the medication. As the largest real-world study to date that assessed hydroxyurea use for children and adults with SCD, we gathered and analyzed perspectives of providers, individuals with SCD, and families. Participants provided information about socio-demographics, hospital and emergency admissions for pain, number of severe pain episodes interfering with daily activities, medication adherence, and barriers to hydroxyurea. Providers reported on indications for hydroxyurea, reasons not prescribed, and current laboratory values. We found that hydroxyurea use was reported in over half of eligible patients from this large geographic region in the U.S., representing a range of sickle cell specialty clinical settings and practices. Provider and patient/caregiver reports about hydroxyurea use were consistent with one another; adults 26 years and older were least likely to be on hydroxyurea; and the likelihood of being on hydroxyurea decreased with one or more barriers. Using the intentional and unintentional medication nonadherence framework, we found that, even for patients on hydroxyurea, challenges to taking the medicine at the right time and forgetting were crucial unintentional barriers to adherence. Intentional barriers such as worry about side effects and “tried and it did not work” were important barriers for young adults and adults. For providers, diagnoses other than HgbSS or HgbS-β0 thalassemia were associated with lower odds of prescribing, consistent with evidence-based guidelines. Our results support strengthening provider understanding and confidence in implementing existing SCD guidelines, and the importance of shared decision making. Our findings can assist providers in understanding choices and decisions of families; guide individualized clinical discussions regarding hydroxyurea therapy; and help with developing tailored interventions to address barriers. Addressing barriers to hydroxyurea use can inform strategies to minimize similar barriers in the use of emerging and combination therapies for SCD.

Abstract Simulation models of multi‐sector systems are increasingly used to understand societal resilience to climate and economic shocks and change. However, multi‐sector systems are also subject to numerous uncertainties that prevent the direct application of simulation models for prediction and planning, particularly when extrapolating past behavior to a nonstationary future. Recent studies have developed a combination of methods to characterize, attribute, and quantify these uncertainties for both single‐ and multi‐sector systems. Here, we review challenges and complications to the idealized goal of fully quantifying all uncertainties in a multi‐sector model and their interactions with policy design as they emerge at different stages of analysis: (a) inference and model calibration; (b) projecting future outcomes; and (c) scenario discovery and identification of risk regimes. We also identify potential methods and research opportunities to help navigate the tradeoffs inherent in uncertainty analyses for complex systems. During this discussion, we provide a classification of uncertainty types and discuss model coupling frameworks to support interdisciplinary collaboration on multi‐sector dynamics (MSD) research. Finally, we conclude with recommendations for best practices to ensure that MSD research can be properly contextualized with respect to the underlying uncertainties.

Earth-system sensitivity (ESS) describes the long-term temperature response for a given change in atmospheric CO2 and, as such, is a crucial parameter to assess future climate change. Here, the authors use a Bayesian model with data from the last 420 Myrs to reduce uncertainties and estimate ESS to be around 3.4 °C.

Abstract In the beginning of the COVID-19 pandemic, there were major concerns regarding the huge demand for asthma inhalers. Using the primary-care medical records for 614,700 asthma patients between January and June 2020, we found that there was a substantial increase in inhalers solely in March 2020. Patients significantly associated with receiving higher inhaled corticosteroid prescriptions were younger, of higher socioeconomic status, and had milder asthma.

As college campuses reopened in fall 2020, we saw a large-scale experiment unfold on the efficacy of various strategies to contain the SARS-CoV-2 virus. Traditional individual surveillance testing via nasal swabs and/or saliva is among the measures that colleges are pursuing to reduce the spread of the virus on campus. Additionally, some colleges are testing wastewater on their campuses for signs of infection, which can provide an early warning signal for campuses to locate COVID-positive individuals. However, a representation of wastewater surveillance has not yet been incorporated into epidemiological models for college campuses, nor has the efficacy of wastewater screening been evaluated relative to traditional individual surveillance testing, within the structure of these models. Here, we implement a new model component for wastewater surveillance within an established epidemiological model for college campuses. We use a hypothetical residential university to evaluate the efficacy of wastewater surveillance for maintaining low infection rates. We find that wastewater sampling with a 1-day lag to initiate individual screening tests, plus completing the subsequent tests within a 4-day period can keep overall infections within 5% of the infection rates seen with traditional individual surveillance testing. Our results also indicate that wastewater surveillance can effectively reduce the number of false positive cases by identifying subpopulations for surveillance testing where infectious individuals are more likely to be found. Through a Monte Carlo risk analysis, we find that surveillance testing that relies solely on wastewater sampling can be fragile against scenarios with high viral reproductive numbers and high rates of infection of campus community members by outside sources. These results point to the practical importance of additional surveillance measures to limit the spread of the virus on campus and the necessity of a proactive response to the initial signs of outbreak.

Many diversity interventions for women are ineffective. One reason for this may be that the field that diversity interventions are usually based on, the social sciences, often do not consider intra-group differences among women. Specifically, differences by racialization may be excluded from such diversity interventions. The present research examines whether racially marginalized women have different diversity interventions needs than White women, and whether organizations are less likely to represent those needs (i.e., intersectional invisibility). Across an open-ended coding (n = 293) and a ranking study (n = 489), Black women noted a need to incorporate intersectional differences, Asian women prioritized methods to address challenges to their authority, and White women indicated a need to address agency perceptions. Improving work-life balance and networks was a shared concern among participants, though we theorized different racially gendered reasons for why these intervention needs are relevant to each group. In Study 3 (n = 92 organizations), we analyzed organizations’ websites using word count and textual analysis. Organizations— including the Education, Science, and Research sector— most readily advocated for women through enhancing agency. They were also less likely to mention dealing with perceptions of excessive agency or addressing intersectional considerations. The organizations broadly mentioned other marginalized groups besides women, but rarely did they do so intersectionality. Taken together, our findings demonstrate different intervention priorities across differently racialized groups. We found evidence of intersectional invisibility where organizations were more likely to address agency-enhancing intervention needs while failing to include other intervention needs relevant for Black women and Asian women. We discuss the implications of these findings for organizations, in general, as well as potential implications for the field of academic social sciences.

Antibody-mediated immune responses rely on antigen recognition by the B cell antigen receptor (BCR) and SLP65 is a key scaffold protein mediating BCR signaling. Here authors show that effective B cell activation requires tripartite phase separation of SLP65, CIN85, and lipid vesicles.

Projections of extreme sea levels (ESLs) are critical for managing coastal risks, but are made complicated by deep uncertainties. One key uncertainty is the choice of model structure used to estimate coastal hazards. Differences in model structural choices contribute to uncertainty in estimated coastal hazard, so it is important to characterize how model structural choice affects estimates of ESL. Here, we present a collection of 36 ESL data sets, from tide gauge stations along the United States East and Gulf Coasts. The data are processed using both annual block maxima and peaks-over-thresholds approaches for modeling distributions of extremes. We use these data sets to fit a suite of potentially non-stationary generalized extreme value distributions and generalized Pareto distributions by covarying the ESL statistics with multiple climate variables. For all of the sites and statistical model structures for tide surge considered here, we find that accounting for changes in the frequency of coastal extreme sea levels provides a better fit to data than using a stationary extreme value model. Further, when maximizing the a posteriori probability of the model parameters, given the available tide gauge data, generalized extreme value distribution structures with non-stationary scale parameter are preferred over non-stationary location parameter. These results have implications for how deep uncertainties in coastal flood hazards are characterized, particularly in how studies incorporate potential non-stationarity in storm surge statistics.

Purpose: This article aims to introduce the novel technique of utilization of a custom 3D titanium printed reconstruction combined with in-situ tissue engineering for the reconstruction and dental rehabilitation of an infected severely atrophic mandible. Technique: A 3-staged approach was used to remove the failing implants and debride the mandible, eradicating the infection, followed by reconstruction of the severely atrophic mandible using tissue engineering supported by a customized 3D-printed titanium undercarriage and reconstruction plate for vertical and horizontal augmentation. Finally, a CAD/CAM 3D-printed surgical guide was used for optimal placement of 4 dental implants. Conclusion: A predictable and satisfactory reconstruct of a severely infected mandible with failing hardware to full dental rehabilitation and aesthetics was achieved by utilizing an amalgamation of state-of-the-art technology and tissue engineering.

BackgroundThe Internet Gaming Disorder Scale–Short-Form (IGDS9-SF) is among the best with regard to its psychometric properties. Therefore, clinical psychologists are likely guided to use the IGDS9-SF if they want to assess or screen the disordered gaming in their practice. However, the information, especially psychometric evidence, concerning the IGDS9-SF has not been fully examined and summarized. ObjectiveThis systematic review evaluated the psychometric properties of different language versions of the IGDS9-SF and assessed its methodological quality in order to improve the clinicians’ understanding of the IGDS9-SF and facilitate its use. MethodsSystematic literature searches were carried out using Embase, MEDLINE, PsycINFO, PubMed, ScienceDirect, Scopus, and Web of Science. The review included English-language studies of any research design that have reported at least one psychometric property of the IGDS9-SF, as defined by the COnsensus-based Standards for the selection of health status Measurement INstrument (COSMIN), and have aimed at testing the psychometric properties of the IGDS9-SF. ResultsIn total, 21 studies comprising 15 language versions of the IGDS9-SF were included. Overall, the IGDS9-SF showed adequate internal consistency (although some items did not have satisfactory item-total correlation [IT]), excellent criterion validity, and the ability to distinguish different subgroups with measurement invariance being supported across gender and age. In terms of factor structure, the IGDS9-SF was shown to have a unidimensional factor structure across all 21 studies. ConclusionsAlthough there is insufficient evidence regarding the responsiveness and properties of the IGDS9-SF using item response theory, the existing evidence supports its use in assessing disordered gaming among individuals.

Neuroblastoma is the commonest extracranial pediatric malignancy. With few recurrent single nucleotide variations (SNVs), mutation-based precision oncology approaches have limited utility, but its frequent and heterogenous copy number variations (CNVs) could represent genomic dependencies that may be exploited for personalized therapy. Patient-derived cell culture (PDC) models can facilitate rapid testing of multiple agents to determine such individualized drug-responses. Thus, to study the relationship between individual genomic aberrations and therapeutic susceptibilities, we integrated comprehensive genomic profiling of neuroblastoma tumors with drug screening of corresponding PDCs against 418 targeted inhibitors. We quantified the strength of association between copy number and cytotoxicity, and validated significantly correlated gene-drug pairs in public data and using machine learning models. Somatic mutations were infrequent (3.1 per case), but copy number losses in 1p (31%) and 11q (38%), and gains in 17q (69%) were prevalent. Critically, in-vitro cytotoxicity significantly correlated only with CNVs, but not SNVs. Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Predictive Markov random field models constructed from CNVs alone recapitulated the true z-score-weighted associations, with the strongest gene-drug functional interactions in subnetworks involving PI3K and JAK-STAT pathways. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers.

Engineered magnetic nanoparticles (MNPs) are emerging as advanced tools for medical applications. The coating of MNPs using polyelectrolytes (PEs) is a versatile means to tailor MNP properties and is used to optimize MNP functionality. Dendritic cells (DCs) are critical regulators of adaptive immune responses. Functionally distinct DC subsets exist, either under steady-state or inflammatory conditions, which are explored for the specific treatment of various diseases, such as cancer, autoimmunity, and transplant rejection. Here, the impact of the PE coating of ferumoxytol for uptake into both inflammatory and steady-state DCs and the cellular responses to MNP labeling is addressed. Labeling efficiency by uncoated and PE-coated ferumoxytol is highly variable in different DC subsets, and PE coating significantly improves the labeling of steady-state DCs. Uncoated ferumoxytol results in increased cytotoxicity of steady-state DCs after labeling, which is abolished by the PE coating, while no increased cell death is observed in inflammatory DCs. Furthermore, uncoated and PE-coated ferumoxytol appear immunologically inert in inflammatory DCs, but they induce activation of steady-state DCs. These results show that the PE coating of MNPs can be applied to endow particles with desired properties for enhanced uptake and cell type-specific responses in distinct target DC populations.