Recent advances in uveitis therapy: focus on selected phase 2 and 3 clinical trials.

INTRODUCTION: Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract. It is a leading cause of blindness in developed countries and exerts significant psychological, social, and economic impact on both patients and the larger society. While there are numerous pharmacotherapy options, posterior segment noninfectious uveitis remains a significant challenge to treat due to its severity, chronicity, and high recurrence rates. AREAS COVERED: The index review highlights the unmet needs of uveitis pharmacotherapy and its research and the shortcomings of existing ocular and systemic therapeutic options for noninfectious uveitis. The more promising novel ocular drug delivery methods and therapeutic targets/drugs are discussed, and evidence from the clinical trials is evaluated. EXPERT OPINION: There has been incredible growth in the number of treatment options available to uveitis patients today, especially with the new generation of biologic drugs. Available evidence suggests that these newer options may be superior to conventional immunosuppressive therapies in terms of efficacy and side effect profiles. Further high-quality research and additional clinical trials will be needed to clarify their roles in the stepladder treatment approach of noninfectious uveitis.

Professional quality of life and its associated factors among Vietnamese doctors and nurses.

BACKGROUND: Prevalence of health workers with occupational health issues ranked fourth among all careers resulting in a reduction in quality of life. However, tools to measure professional quality of life (ProQoL) are unavailable in Vietnamese. This study aims to develop a Vietnamese version of the ProQoL, and examine ProQoL and its associated factors among doctors and nurses. METHODS: The ProQoL is comprised of 30 items measures compassion satisfaction (CS), burnout (BO), and secondary traumatic stress (STS). The tool was translated into Vietnamese following the Guideline by Guillemin et. al (1993), reviewed by expert panels, and validated for internal consistency and test-retest reliability among 38 health workers working at hospitals in HCMC. The validated tool was then used in a cross-sectional study to measure the ProQoL of full-time doctors and nurses working in clinical departments at the University Medical Center, University of Medicine and Pharmacy at Ho Chi Minh City, Vietnam. In addition to the ProQoL, self-reported data about demographic and occupational characteristics were collected. RESULTS: The Vietnamese version of ProQoL achieved high internal consistency (alphas between 0.85 and 0.91) and Intra-class Correlation Coefficients (ICCs between 0.71 and 0.89) for all subscales. Among 316 health workers, mean scores of CS, BO, STS were 36.4 (SD = 5.4), 24.9 (SD = 5.1), 25.9 (SD = 5.3), respectively, indicating moderate levels of CS, BO and STS. Participants who were older (b = 0.17, 95%CI = 0.08, 0.26), had sufficient perceived income (b = 2.59, 95%CI = 0.93, 4.24), and > 10 years of working experience (b = 2.15, 95%CI = 0.68, 3.62), had higher CS scores. Those who were older (b=-0.15, 95%CI=-0.23, -0.07), had sufficient perceived income (b=-2.64, 95%CI=-4.18, -1.09), > 10 years of experience (b=-1.38, 95%CI=-2.76, -0.01), worked in surgical department (b=-1.46, 95%CI=-2.54, -0.38) and 8 hours/day (b=-1.52, 95%CI=-2.61, -0.44), had lower BO scores. Moreover, those in a relationship (b=-2.27, 95%CI=-3.53, -1.01) and had sufficient perceived income (b=-1.98, 95%CI=-3.64, -0.32) had lower STS scores. CONCLUSIONS: The Vietnamese version of ProQoL is valid and reliable for use among Vietnamese health workers. Age, marital status, perceived income status, years of working experience, daily working hours, and specialty was associated with at least one component of ProQoL but gender, religion, education level, and monthly income were not.

A Sub-Clone of RAW264.7-Cells Form Osteoclast-Like Cells Capable of Bone Resorption Faster than Parental RAW264.7 through Increased De Novo Expression and Nuclear Translocation of NFATc1.

The murine macrophage cell line RAW264.7 is extensively used as a progenitor to study osteoclast (OC) differentiation. RAW264.7 is a heterogeneous cell line, containing sub-clones with different abilities to form OCs. The aim of this study was to identify characteristics within the heterogeneous RAW264.7 cells that define sub-clones with an augmented ability to form bone-resorbing OCs (H9), as well as sub-clones representing non-OCs (J8). RAW264.7 sub-clones were isolated by single cell cloning. Selection was based on TRAP/cathepsin K expression in sub-clone cultures without added RANKL. Sub-clones before and after differentiation with RANKL were assayed for multiple OC-characteristics. Sub-clone H9 cells presented a higher expression of OC-markers in cultures without added RANKL compared to the parental RAW264.7. After 6 days of RANKL stimulation, sub-clone H9 cells had equal expression levels of OC-markers with RAW264.7 and formed OCs able to demineralize hydroxyapatite. However, sub-clone H9 cells displayed rapid differentiation of OC already at Day 2 compared to Day 4 from parental RAW264.7, and when cultured on plastic and on bone they were more efficient in resorption. This rapid differentiation was likely due to high initial expression/nuclear translocation of OC master transcription factor, NFATc1. In contrast to H9, J8 cells expressed initially very low levels of OC-markers, and they did not respond to RANKL-stimulation by developing OC-characteristics/OC-marker expression. Hence, H9 is an additional clone suitable for experimental setup requiring rapid differentiation of large numbers of OCs.

Identifying core curricular components for behavioral health training in internal medicine residency: Qualitative interviews with residents, faculty, and behavioral health clinicians.

OBJECTIVE: Behavioral health services frequently delivered by primary care providers include care for mental health and substance abuse disorders and assistance with behavioral risk factor reduction. Internal medicine residencies in the United States lack formal expectations regarding training in behavioral health for residents. This qualitative study aimed to determine learners' and teachers' perceptions about appropriate behavioral health curricular components for internal medicine residents. METHOD: Focus groups and interviews were conducted with the following individuals from the Duke Outpatient Clinic: residents with continuity practice (n = 27), advanced practice providers (n = 2), internal medicine attending physicians (n = 4), internal medicine/psychiatry attending physicians (n = 2), and behavioral health clinicians (n = 4). A focus group leader asked regarding residents' successes and challenges in managing behavioral health issues and about specific learning components considered necessary to understand and manage these behavioral health conditions. Transcripts were coded using an editing analysis style to identify central themes and concordance/discordance between groups. RESULTS: Regarding mental health management (Theme 1), residents emphasized a need for better care coordination with specialty mental health, while attendings and behavioral health clinicians gave priority to residents' skills in primary management of mental health. Residents, attendings, and behavioral health clinicians all emphasized advanced interviewing skills (Theme 2) with subthemes: eliciting the patient's perspective, managing time in encounters, improving patients' understanding, and patient counseling. CONCLUSIONS: Internal medicine residents, attendings, and behavioral health clinicians may differ significantly in their perceptions of primary care's role in mental health care. Future internal medicine behavioral health curricula should specifically address these attitudinal differences. Curricula should also emphasize interview skills training as an essential component of behavioral health learning.

A Community-Engaged Research Approach to Improve Mental Health Among Latina Immigrants: ALMA Photovoice.

Recent Latina immigrants are at increased risk of poor mental health due to stressors associated with adapting to life in the United States. Existing social and health care policies often do not adequately address the mental health concerns of new Latino populations. Amigas Latinas Motivando el Alma, a community-partnered research project, seeks to improve immigrant Latinas' mental health outcomes. Using Photovoice methodology, promotoras (lay health advisors) reflected on community factors affecting mental health through photography and guided discussion. Discussions were audio-recorded, transcribed, and coded using content analysis to identify salient themes. Promotoras reviewed codes to develop themes that they presented in community forums to reach local policy makers and to increase community awareness. These forums included an exhibit of the promotoras' photographs and discussion of action steps to address community concerns. Themes included transitioning to life in the United States, parenting, education, and combating racism. Nearly 150 stakeholders attended the community forums and proposed responses to promotoras' photographic themes. Our findings suggest that Photovoice provides an opportunity for Latinas and the larger community to identify issues that they find most important and to explore avenues for action and change by creating sustainable partnerships between the community and forum attendees.

Risk of systemic toxicity with topical lidocaine/prilocaine: a review.

The eutectic mixture of lidocaine and prilocaine (EMLA, APP Pharmaceuticals, LLC.) is an anesthetic cream frequently used by dermatologists. Although side effects of EMLA are usually mild local skin reactions (ie, edema, pallor, erythema), more severe complications can be encountered including methemoglobinemia, central nervous system toxicity, and cardiotoxicity. This article reviewed the literature regarding risk of systemic toxicity associated with use of EMLA in the pediatric and adult population. All 12 clinical trials evaluating the safety of EMLA in either the pediatric or adult population generally followed dosing and administration guidelines set by the manufacturer and reported clinically insignificant plasma levels of methemoglobin, lidocaine, prilocaine, and their respective metabolites. To date, nine pediatric cases and three adult cases of systemic toxicity associated with EMLA have been published. Possible factors that contributed to the development of systemic toxicity include excessive amount of EMLA, large application area, prolonged application time, diseased and/or inflamed skin (eg, vascular malformations, molluscum contagiosum, eczema, previously abraded skin), age less than 3 months, prematurity, and concomitant use of a methemoglobin-inducing agent. Recommendations are provided on how to safely use EMLA to minimize the risk of systemic toxicity.

Results from a pilot promotora program to reduce depression and stress among immigrant Latinas.

The stressful experiences that Latino immigrants face throughout the migration process to the United States put them at increased risk for poor mental health. Latinas are at heightened risk due to stigma, limited access to mental health resources, domestic violence, and gender role expectations. In addition, for those who live in new immigrant settlement areas, such as the Southeast, these disparities are magnified by even fewer culturally appropriate services and limited social support. This study evaluates the impact of ALMA (Amigas Latinas Motivando el Alma/Latina Friends Motivating the Soul), a pilot promotora intervention offered in three North Carolina counties to improve mental health among Latinas by offering coping skills training. The intervention trained community-based promotoras to conduct outreach to Latina women in their social network (compañeras). Using a pre-post test design, we assessed the mental health outcomes of compañeras. Compañeras improved on the following outcomes: depressive symptoms, attitudes of depression treatment, perceived and acculturative stress, perceived social support, and positive coping responses. Our findings suggest that promotora interventions, such as ALMA, that focus on building self-care strategies can be valuable to reducing preclinical symptoms and addressing health care disparities that are exacerbated by unavailable or underused mental health services.

Challenges for further successful development of tumor necrosis factor targeting therapies for uveitis.

INTRODUCTION: Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract and is one of the leading causes of vision impairment. In developed countries, noninfectious uveitis (NIU) represents most cases and is challenging to treat due to its severity, chronicity, and high recurrence rates. The advent of anti-tumor necrosis factor-α (anti-TNF-α) agents have dramatically improved outcomes and changed treatment paradigms in NIU. AREAS COVERED: The index article summarizes the present experience of anti-TNF-α agents in NIU pharmacotherapy and highlights the barriers to further research and development of anti-TNF-α agents for uveitis. Common challenges faced in NIU clinical drugs trials, specific difficulties in anti-TNF-α drug development, and promising competitor drug candidates are discussed and evaluated. EXPERT OPINION: Anti-TNF-α agents have revolutionized NIU pharmacotherapy and greatly improved outcomes with good safety profiles. The great success of systemic infliximab and adalimumab in NIU treatment has resulted in little impetus for further development of this class of medication. Attempts have been made to deliver anti-TNF-α agents intravitreally but that has not been successful thus far. With expiring patents, competition from biosimilars and newer, novel molecules, it may not be viable to continue pursuing anti-TNF-α drug development.

Deciphering the human platelet sheddome.

Activated platelets shed surface proteins, potentially modifying platelet function as well as providing a source of bioactive fragments. Previous studies have identified several constituents of the platelet sheddome, but the full extent of shedding is unknown. Here we have taken a global approach, analyzing protein fragments in the supernate of activated platelets using mass spectroscopy and looking for proteins originating from platelet membranes. After removing plasma proteins and microparticles, 1048 proteins were identified, including 69 membrane proteins. Nearly all of the membrane proteins had been detected previously, but only 10 had been shown to be shed in platelets. The remaining 59 are candidates subject to confirmation. Based on spectral counts, protein representation in the sheddome varies considerably. As proof of principle, we validated one of the less frequently detected proteins, semaphorin 7A, which had not previously been identified in platelets. Surface expression, cleavage, and shedding of semaphorin 7A were demonstrated, as was its association with α-granules. Finally, cleavage of semaphorin 7A and 12 other proteins was substantially reduced by an inhibitor of ADAM17, a known sheddase. These results define a subset of membrane proteins as sheddome candidates, forming the basis for further studies examining the impact of ectodomain shedding on platelet function.

Identification of barriers at the primary care provider level to improve inflammatory breast cancer diagnosis and management.

The purpose of this study, based in the United States, was to evaluate knowledge gaps and barriers related to diagnosis and care of inflammatory breast cancer (IBC), a rare but lethal breast cancer subtype, amongst Primary Care Providers (PCP) as they are often the first point of contact when patients notice initial symptoms. PCP participants in the Duke University Health System, federally qualified health center, corporate employee health and community practices, nearby academic medical center, Duke physician assistant and advanced practice nurse leadership program alumni were first selected in a convenience sample and for semi-structured interviews (n = 11). Based on these data, an online survey tool was developed and disseminated (n = 78) to assess salient measures of IBC diagnosis, health disparity factors, referral and care coordination practices, COVID-19 impact, and continuing medical education (CME). PCP reported access to care and knowledge gaps in symptom recognition (mean = 3.3, range 1-7) as major barriers. Only 31 % reported ever suspecting IBC in a patient. PCP (n = 49) responded being challenged with referral delays in diagnostic imaging. Additionally, since the COVID-19 pandemic started, 63 % reported breast cancer referral delays, and 33 % reported diagnosing less breast cancer. PCP stated interest in CME in their practice for improved diagnosis and patient care, which included online (53 %), lunch time or other in-service training (33 %), patient and provider-facing websites (32 %). Challenges communicating rare cancer information, gaps in confidence in diagnosing IBC, and timely follow-up with patients and specialists underscores the need for developing PCP educational modules to improve guideline-concordant care.

Longitudinal Comparative Analysis of Semi-Automated Aqueous Flare Measurements with Clinical Grading and Visual Outcomes in Uveitic Eyes.

PURPOSE: To evaluate the correlation between longitudinal changes in aqueous flare measured by laser flare photometer (LFP), best-corrected visual acuity (BCVA), and clinical grade using both Standardization of Uveitis Nomenclature (SUN) and modified SUN (MSUN) scales uveitis patients. METHODS: Patients were classified according to both SUN and MSUN grading scales. LFP measurements were acquired (Kowa FM-700) at each visit. Mean change in LFP was assessed longitudinally, comparing with those in visual acuity, SUN, and MSUN grading scales. RESULTS: Mean change in LFP was correlated to those in BCVA (p = .018), SUN scale (p < .001), and MSUN scale (p = .008). Cases within same initial SUN (0 and 1+) and MSUN (0.5+ and 1+) grades and different longitudinal flare prognosis (decreased/unchanged/increased) had significantly different initial LFP values (all p < .05). CONCLUSIONS: LFP measurement is beneficial in monitoring inflammatory activity. Cases of identical clinical flare scores with different clinical prognosis may be predicted by LFP.

Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.

BACKGROUND: Meningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles. METHODS: A previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugs in vitro and in vivo, including efficacy in conjunction with radiotherapy. RESULTS: We identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50 values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone. CONCLUSIONS: Global patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases.

Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D.

We recently reported that Semaphorin 4D (Sema4D) and its receptors are expressed on the platelet surface and showed that Sema4D((-/-)) mice have a selective defect in collagen-induced platelet aggregation and an impaired vascular injury response. Here we investigated the mechanisms involved, tested the role of platelet-platelet contacts in Sema4D-mediated events, and examined the relationship between Sema4D-dependent signaling and integrin α(IIb)ß(3) outside-in signaling. The results show that spleen tyrosine kinase (Syk) activation, an early step in collagen signaling via the glycoprotein VI (GPVI)/FcRγ complex, is greatly reduced in Sema4D((-/-)) platelets and can be restored by adding soluble Sema4D. Earlier events, including FcRγ phosphorylation, occur normally; later events are impaired. In contrast, when engagement of α(IIb)ß(3) was blocked, Sema4D((-/-)) and control platelets were indistinguishable in assays of Syk activation, adhesion, spreading on collagen, and activation of α(IIb)ß(3). Finally, we found that, unlike the Sema4D knockout, α(IIb)ß(3) blockade inhibited FcRγ phosphorylation and that stimulating aggregation with Mn(2+) failed to normalize Syk activation in the absence of Sema4D. Collectively, these results show that α(IIb)ß(3) and Sema4D jointly promote collagen responses by amplifying Syk activation, partly by forming integrin-mediated contacts that enable the binding of Sema4D to its receptors and partly through integrin outside-in signaling. These 2 processes are interdependent, but distinguishable.

α2,6 Sialylation mediated by ST6GAL1 promotes glioblastoma growth.

One of the least-investigated areas of brain pathology research is glycosylation, which is a critical regulator of cell surface protein structure and function. ß-Galactoside α2,6-sialyltransferase (ST6GAL1) is the primary enzyme that α2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion, thereby modulating cell signaling and behavior. We demonstrate a potentially novel, protumorigenic role for α2,6 sialylation and ST6GAL1 in the deadly brain tumor glioblastoma (GBM). GBM cells with high α2,6 sialylation exhibited increased in vitro growth and self-renewal capacity and decreased mouse survival when orthotopically injected. α2,6 Sialylation was regulated by ST6GAL1 in GBM, and ST6GAL1 was elevated in brain tumor-initiating cells (BTICs). Knockdown of ST6GAL1 in BTICs decreased in vitro growth, self-renewal capacity, and tumorigenic potential. ST6GAL1 regulates levels of the known BTIC regulators PDGF Receptor ß (PDGFRB), Activated Leukocyte Cell Adhesion Molecule, and Neuropilin, which were confirmed to bind to a lectin-recognizing α2,6 sialic acid. Loss of ST6GAL1 was confirmed to decrease PDGFRB α2,6 sialylation, total protein levels, and the induction of phosphorylation by PDGF-BB. Thus, ST6GAL1-mediated α2,6 sialylation of a select subset of cell surface receptors, including PDGFRB, increases GBM growth.

Correlation of Clinical Aqueous Flare Grading to Semi-Automated Flare Measurements Using Laser Flare Photometry.

PURPOSE: To compare laser flare photometry (LFP) measurements of aqueous flare with Standardization of Uveitis Nomenclature (SUN) and modified SUN grading. METHODS: In this prospective study with multicenter design, uveitis patients were classified according to SUN and modified SUN grading scales. LFP was performed with Kowa FM-700 flaremeter. Mean LFP values were compared with SUN and MSUN scores. RESULTS: The study included 475 LFP measurements, of which 216, 48, 150, 31, 28 and 2 had 0, 0.5+, 1+, 1.5+, 2+ and 3+ flare, respectively. LFP values were significantly different between each two consecutive steps for both clinical gradings (all P < .05). Cut-off values for modified SUN grading steps were defined as 5.7, 9.7, 15.7 and 43.2 for 0/0.5+, 0.5+/ 1+, 1+/1.5+ and 1.5/2+ borders of clinical flare, respectively. CONCLUSIONS: LFP proves to be an objective measurement in analyzing aqueous flare comparable to both SUN and MSUN clinical grading systems.

Coping With COVID-19: The Impact of the Pandemic on Latina Immigrant Women's Mental Health and Well-being.

INTRODUCTION: We sought to describe how Latina immigrants living in King County coped with the pandemic, including their attitudes and behaviors related to COVID-19, and the impact of the pandemic on their mental health and wellbeing. METHOD: We conducted surveys by phone with adult Spanish-speaking Latina immigrants (n = 137) in the summer of 2020. RESULTS: Very few women had been infected with COVID-19, and 23% reported having been tested. Most frequent reasons for not being tested were not knowing where to go (14%), concerns over the cost (15%), and not wanting to know if they were infected (12%). Most participants had concerns about paying for housing (76%) and food (73%). Depression and anxiety symptoms were in the moderate range. Almost all participants were practicing recommended preventive behaviors. CONCLUSION: Although few participants had COVID-19 infection, the pandemic had significant impacts on their mental health and ability to meet basic needs.

Current concepts in the diagnosis and management of antiphospholipid syndrome and ocular manifestations.

Antiphospholipid syndrome (APS) is an autoimmune disorder associated with obstetrical complications, thrombotic complications involving both arteries and veins, and non-thrombotic manifestations affecting multiple other systems presenting in various clinical forms. Diagnosis requires the presence of antiphospholipid antibodies. The exact pathogenesis of APS is not fully known. However, it has recently been shown that activation of different types of cells by antiphospholipid antibodies plays an important role in thrombosis formation. Ocular involvement is one of the important clinical manifestations of APS and can vary in presentations. Therefore, as an ophthalmologist, it is crucial to be familiar with the ocular findings of APS to prevent further complications that can develop. Furthermore, the ongoing identification of new and specific factors contributing to the pathogenesis of APS may provide new therapeutic options in the management of the disease in the future.

Applying Machine Learning to Identify Anti-Vaccination Tweets during the COVID-19 Pandemic.

Anti-vaccination attitudes have been an issue since the development of the first vaccines. The increasing use of social media as a source of health information may contribute to vaccine hesitancy due to anti-vaccination content widely available on social media, including Twitter. Being able to identify anti-vaccination tweets could provide useful information for formulating strategies to reduce anti-vaccination sentiments among different groups. This study aims to evaluate the performance of different natural language processing models to identify anti-vaccination tweets that were published during the COVID-19 pandemic. We compared the performance of the bidirectional encoder representations from transformers (BERT) and the bidirectional long short-term memory networks with pre-trained GLoVe embeddings (Bi-LSTM) with classic machine learning methods including support vector machine (SVM) and naïve Bayes (NB). The results show that performance on the test set of the BERT model was: accuracy = 91.6%, precision = 93.4%, recall = 97.6%, F1 score = 95.5%, and AUC = 84.7%. Bi-LSTM model performance showed: accuracy = 89.8%, precision = 44.0%, recall = 47.2%, F1 score = 45.5%, and AUC = 85.8%. SVM with linear kernel performed at: accuracy = 92.3%, Precision = 19.5%, Recall = 78.6%, F1 score = 31.2%, and AUC = 85.6%. Complement NB demonstrated: accuracy = 88.8%, precision = 23.0%, recall = 32.8%, F1 score = 27.1%, and AUC = 62.7%. In conclusion, the BERT models outperformed the Bi-LSTM, SVM, and NB models in this task. Moreover, the BERT model achieved excellent performance and can be used to identify anti-vaccination tweets in future studies.

Novel RPL13 Variants and Variable Clinical Expressivity in a Human Ribosomopathy With Spondyloepimetaphyseal Dysplasia.

Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of disorders with variable growth failure and skeletal impairments affecting the spine and long bone epiphyses and metaphyses. Here we report on four unrelated families with SEMD in which we identified two monoallelic missense variants and one monoallelic splice site variant in RPL13, encoding the ribosomal protein eL13. In two out of four families, we observed autosomal dominant inheritance with incomplete penetrance and variable clinical expressivity; the phenotypes of the mutation-positive subjects ranged from normal height with or without hip dysplasia to severe SEMD with severe short stature and marked skeletal dysplasia. In vitro studies on patient-derived dermal fibroblasts harboring RPL13 missense mutations demonstrated normal eL13 expression, with proper subcellular localization but reduced colocalization with eL28 (p < 0.001). Cellular functional defects in fibroblasts from mutation-positive subjects indicated a significant increase in the ratio of 60S subunits to 80S ribosomes (p = 0.007) and attenuated global translation (p = 0.017). In line with the human phenotype, our rpl13 mutant zebrafish model, generated by CRISPR-Cas9 editing, showed cartilage deformities at embryonic and juvenile stages. These findings extend the genetic spectrum of RPL13 mutations causing this novel human ribosomopathy with variable skeletal features. Our study underscores for the first time incomplete penetrance and broad phenotypic variability in SEMD-RPL13 type and confirms impaired ribosomal function. Furthermore, the newly generated rpl13 mutant zebrafish model corroborates the role of eL13 in skeletogenesis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

"Se vale llorar y se vale reír": Latina Immigrants' Coping Strategies for Maintaining Mental Health in the Face of Immigration-Related Stressors.

Latina immigrant women in the U.S. are at increased risk for poor mental health status, due to socioeconomic- and immigration-related stressors. We sought to describe the mechanisms linking immigration-related stressors and mental health, including how the current social and political climate affects women's mental health status, and which coping strategies are used to maintain well-being. We conducted four focus groups with Latina immigrants (N = 58) recruited through local community-based organizations. We drew on the stages of migration framework to guide our study design and analysis. Focus group transcripts were analyzed to identify emergent themes across groups. On average, focus group participants were 35.5 years old and had lived in the U.S. for 12.5 years. Most were from Mexico. Participants reported immigration-related stressors including unsafe migration, worry about immigration enforcement, broken social ties, and limited access to health and social services. In the face of these stressors, they relied on transnational social networks and connections with other Latina immigrant women. Social ties with family in the U.S. also helped them alleviate social isolation and overcome barriers to social services. Those who were mothers expressed that their children were a source of encouragement and comfort with feelings of stress. Immigration policies that contribute to unsafe migration, worry about immigration enforcement, limited social ties, and limited access to social services were associated with increased stress among Latina immigrants who participated in the focus groups. These participants could benefit from increased access to mental health care and community-based programs that connect them to resources.