Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations.

Lamin A/C (LMNA) is an important component of nuclear lamina. Mutations cause arrhythmia, heart failure, and sudden cardiac death. While LMNA-associated cardiomyopathy typically has an aggressive course that responds poorly to conventional heart failure therapies, there is variability in severity and age of penetrance between and even within specific mutations, which is poorly understood at the cellular level. Further, this heterogeneity has not previously been captured to mimic the heterozygous state, nor have the hundreds of clinical LMNA mutations been represented. Herein, we have overexpressed cardiopathic LMNA variants in HEK cells and utilized state-of-the-art quantitative proteomics to compare the global proteomic profiles of (1) aggregating Q353 K alone, (2) Q353 K coexpressed with WT, (3) aggregating N195 K coexpressed with WT, and (4) nonaggregating E317 K coexpressed with WT to help capture some of the heterogeneity between mutations. We analyzed each data set to obtain the differentially expressed proteins (DEPs) and applied gene ontology (GO) and KEGG pathway analyses. We found a range of 162 to 324 DEPs from over 6000 total protein IDs with differences in GO terms, KEGG pathways, and DEPs important in cardiac function, further highlighting the complexity of cardiac laminopathies. Pathways disrupted by LMNA mutations were validated with redox, autophagy, and apoptosis functional assays in both HEK 293 cells and in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) for LMNA N195 K. These proteomic profiles expand our repertoire for mutation-specific downstream cellular effects that may become useful as druggable targets for personalized medicine approach for cardiac laminopathies.

Improved reference genome of Aedes aegypti informs arbovirus vector control.

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.

Multimorbidity and associated informal care receiving characteristics for US older adults: a latent class analysis.

BACKGROUND: Older adults with varying patterns of multimorbidity may require distinct types of care and rely on informal caregiving to meet their care needs. This study aims to identify groups of older adults with distinct, empirically-determined multimorbidity patterns and compare characteristics of informal care received among estimated classes. METHODS: Data are from the 2011 National Health and Aging Trends Study (NHATS). Ten chronic conditions were included to estimate multimorbidity patterns among 7532 individuals using latent class analysis. Multinomial logistic regression model was estimated to examine the association between sociodemographic characteristics, health status and lifestyle variables, care-receiving characteristics and latent class membership. RESULTS: A four-class solution identified the following multimorbidity groups: some somatic conditions with moderate cognitive impairment (30%), cardiometabolic (25%), musculoskeletal (24%), and multisystem (21%). Compared with those who reported receiving no help, care recipients who received help with household activities only (OR = 1.44, 95% CI 1.05-1.98), mobility but not self-care (OR = 1.63, 95% CI 1.05-2.53), or self-care but not mobility (OR = 2.07, 95% CI 1.29-3.31) had greater likelihood of being in the multisystem group versus the some-somatic group. Having more caregivers was associated with higher odds of being in the multisystem group compared with the some-somatic group (OR = 1.09, 95% CI 1.00-1.18), whereas receiving help from paid helpers was associated with lower odds of being in the multisystem group (OR = 0.36, 95% CI 0.19-0.77). CONCLUSIONS: Results highlighted different care needs among persons with distinct combinations of multimorbidity, in particular the wide range of informal needs among older adults with multisystem multimorbidity. Policies and interventions should recognize the differential care needs associated with multimorbidity patterns to better provide person-centered care.

Sunscreen Use for Photoprotection in Skin of Color: A Literature Review.

BACKGROUND: To understand the prevalence and types of publications addressing darker skin types within the existing evidence base for sunscreen use.  Evidence Review: PubMed was searched from 1988, the time point at which the first skin of color (SOC) article was identified, through December 2022 using PubMed's Medical Subject Headings terms and keyword searches in title and abstract, with and without terms for SOC and ethnicity. Identified articles were reviewed for relevance, de-duplicated, and categorized; results are summarized. FINDINGS: Of the 5927 articles on sunscreen overall, only 314 (5.3%) articles addressed SOC, with the majority published since 2007 and representing only 4% to 7% of total publications annually except in 2022 when the proportion of SOC articles was 23.5%. Of the articles on SOC, many reported sunscreen knowledge and patient behaviors (29%), but very few reported clinical trials (5%). The 3 conditions most often discussed were melasma, post-inflammatory hyperpigmentation, and dyschromia. South Asian ethnicities (India, Pakistan, Bangladesh) had the highest representation within the literature, followed by Hispanics. CONCLUSIONS AND RELEVANCE: Although it was assumed there would be fewer papers discussing the use of sunscreen in darker skin types, the scale of the disparity revealed by this study is stark. The increase in a number of articles in 2022 suggests an increasing focus on SOC, but further discussion of the issues presented here will help the SOC community address gaps in the evidence base and better inform discussions on sunscreen and photoprotection between clinicians and patients.J Drugs Dermatol. 2024;23(7):575-577.  doi:10.36849/JDD.8250.

Cysteamine Isobionic-Amide Complex Versus Kligman's Formula for the Treatment of Melasma: Equal Efficacy and Rapid Onset of Action.

BACKGROUND: Modified Kligman's formula (mKF) is the gold standard treatment for melasma; however, its prolonged use is not recommended due to side effects. Cysteamine is a potent, safe, and effective depigmenting agent. Here, we conducted a double-blind, randomized, and placebo-controlled clinical trial to assess the efficacy of cysteamine isobionic-amide -- a complex with enhanced depigmenting efficacy -- and compared it to mKF for the treatment of melasma. METHODS: This study involved a total of 80 patients divided into 3 groups: cysteamine-isobionic amide, placebo, or mKF. The modified Melasma Area Severity Index (mMASI) score and spectrophotometric evaluation were conducted at baseline, week 4, week 8, and week 16. Dermatological assessment, patients’ feedback, and satisfaction including quality-of-life scores were also collected. RESULTS: At week 4, cysteamine isobionic-amide and mKF groups showed an equivalent onset of action in terms of mMASI and skin pigmentation contrast reduction. The 2 groups significantly reduced melasma severity and improved the overall skin condition with a comparable efficacy at week 16. Quality of life of melasma patients was significantly improved in the cysteamine isobionic-amide group at week 8 and further at week 16 (P<0.001) compared to the mKF group. Patients’ feedback and satisfaction were higher with the cysteamine isobionic-amide product compared to mKF. CONCLUSION: Cysteamine isobionic-amide provided a rapid onset of action and was as effective as the mKF for the treatment of melasma. The data suggest that cysteamine isobionic-amide could potentially be an acceptable alternative to mKF for the long-term treatment of melasma. J Drugs Dermatol. 2024;23(2):9-16.  doi:10.36849/JDD.7428.

Permethrin resistance in Aedes aegypti: Genomic variants that confer knockdown resistance, recovery, and death.

Pyrethroids are one of the few classes of insecticides available to control Aedes aegypti, the major vector of dengue, chikungunya, and Zika viruses. Unfortunately, evolving mechanisms of pyrethroid resistance in mosquito populations threaten our ability to control disease outbreaks. Two common pyrethroid resistance mechanisms occur in Ae. aegypti: 1) knockdown resistance, which involves amino acid substitutions at the pyrethroid target site-the voltage-gated sodium channel (VGSC)-and 2) enhanced metabolism by detoxification enzymes. When a heterogeneous population of mosquitoes is exposed to pyrethroids, different responses occur. During exposure, a proportion of mosquitoes exhibit immediate knockdown, whereas others are not knocked-down and are designated knockdown resistant (kdr). When these individuals are removed from the source of insecticide, the knocked-down mosquitoes can either remain in this status and lead to dead or recover within a few hours. The proportion of these phenotypic responses is dependent on the pyrethroid concentration and the genetic background of the population tested. In this study, we sequenced and performed pairwise genome comparisons between kdr, recovered, and dead phenotypes in a pyrethroid-resistant colony from Tapachula, Mexico. We identified single-nucleotide polymorphisms (SNPs) associated with each phenotype and identified genes that are likely associated with the mechanisms of pyrethroid resistance, including detoxification, the cuticle, and insecticide target sites. We identified high association between kdr and mutations at VGSC and moderate association with additional insecticide target site, detoxification, and cuticle protein coding genes. Recovery was associated with cuticle proteins, the voltage-dependent calcium channel, and a different group of detoxification genes. We provide a list of detoxification genes under directional selection in this field-resistant population. Their functional roles in pyrethroid metabolism and their potential uses as genomic markers of resistance require validation.

Exploration of Skin of Color Dermatology Content on YouTube.

BACKGROUND: There is a lack of diversity in dermatology regarding skin of color-related content. This has negative implications for patients of color and continues to be a hurdle to providing proper care to these patient populations. As patients increasingly look to the internet as a resource to gain insight on dermatologic conditions and potential treatment options, the information presented must be accurate and informational. The goals of this study included identifying and analyzing skin of color-related dermatology content found on YouTube, characterizing the content creators, and comparing board-certified dermatologists’ content to that created by other YouTubers. METHODS: A total of 23 dermatology terms associated with skin of color were searched on YouTube. The top 9 relevant videos for each search term were analyzed for views, comments, likes, and content creator classification. Each video was also labeled as being promotional or educational. The content creator and the content subject were also analyzed. Content created by board-certified dermatologists as well as physicians was then compared to content created by non-physicians. Statistical comparison was done using Mann-Whitney U tests and Pearson’s Chi-squared test where appropriate. RESULTS: The most popular search term was dandruff while the least popular search terms were dermatosis papulose nigra, eczema, and central centrifugal cicatricial alopecia. Of the total 207 videos analyzed (Figure 1), the majority of video profiles consisted of medical interest groups (77, 37.2%), whereas the majority of video subjects consisted of board-certified dermatologists (50, 24.2%). In contrast, the least common video profiles belonged to patients (2, 1%), and the least common video subjects were news media (2, 1%). When comparing board-certified dermatologists to all other classifications of content creators, there was a significant difference in views, comments, and likes (views P=0.0477, comments P=0.0324, likes P=0.0203). When comparing all physicians to all other content creators, there was a similar trend (views P=0.0009, comments P<0.0001, likes P<0.0001). Physicians were significantly less likely to include promotional content in their videos when compared to other content creators (P=0.0170). CONCLUSION: Although skin of color-related dermatology content on YouTube is primarily educational, board-certified dermatologists are underrepresented as content creators on YouTube. It is pertinent that physicians continue to make content on YouTube and other social media platforms so that patients can have access to accurate yet salient information about their conditions. Patel J, Braswell AC, Jiminez VS, et al. Exploration of skin of color dermatology content on YouTube. J Drugs Dermatol. 2023;22(7):678-684. doi:10.36849/JDD.6995.

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Barriers and Translational Solutions to Improving Community Living Outcomes among People of Color with Disabilities with Opioid Use Disorder: A Focus Group Perspective.

This investigation examined vocational rehabilitation, substance abuse, and mental health service providers' perceptions about barriers and potentially translational solutions to poor community living outcomes for people of color with disabilities (i.e., African Americans, Latinx, Native Americans and Alaskan Natives, Asian Americans, and Pacific islanders) who have opioid use disorder. We conducted one focus group discussion (N = 12) that identified the proliferation of opioids in the community, treatment access, employment, and transportation as community living outcome barriers. The findings point to the need for further research that address poor outcomes among target group members.

Branched Multimeric Peptides as Affinity Reagents for the Detection of α-Klotho Protein.

α-Klotho, an aging-related protein found in the kidney, parathyroid gland, and choroid plexus, acts as an essential co-receptor with the fibroblast growth factor 23 receptor complex to regulate serum phosphate and vitamin D levels. Decreased levels of α-Klotho are a hallmark of age-associated diseases. Detecting or labeling α-Klotho in biological milieu has long been a challenge, however, hampering the understanding of its role. Here, we developed branched peptides by single-shot parallel automated fast-flow synthesis that recognize α-Klotho with improved affinity relative to their monomeric versions. These peptides were further shown to selectively label Klotho for live imaging in kidney cells. Our results demonstrate that automated flow technology enables rapid synthesis of complex peptide architectures, showing promise for future detection of α-Klotho in physiological settings.

Acylated and alkylated benzo(crown-ethers) form ion-dependent ion channels in biological membranes.

Synthetic ion channels based on benzo(crown-ether) compounds have been previously reported to function as ion-selective channels in planar lipid bilayers, with hydrogen bonding networks implicated in the formation of self-aggregated complexes. Herein, we report the synthesis and characterization of two new families of benzo(crown-ether) compounds, termed monoacylated and monoalkylated benzo(crown-ethers) (MABCE), both of which lack hydrogen bond donors. Depending on the length of alkyl chain substituent and the size of macrocycle, MABCE compounds inhibit bacterial growth and transport ions across biological membranes. Single-channel recordings show that the activity is higher in the presence of K+ as compared with Na+; however, under bionic conditions, open channels do not exhibit any preference between the two ions. These findings reveal that the ionic preference of benzo(crown-ether) compounds is either due to the regulation of assembly of ion-conducting supramolecular complexes or its membrane insertion by cations, as opposed to ion-selective transport through these scaffolds. Furthermore, our data show that the H-bonding network is not needed to form these assemblies in the membrane.

Evaluation of safety and efficacy of the S.M.A.R.T.® Flex Vascular Stent System (OPEN study).

OBJECTIVES: The OPEN study evaluated the safety and efficacy of the S.M.A.R.T.® Flex Vascular Stent System in patients with femoropopliteal arterial disease. BACKGROUND: Long-term data on endovascular treatments of femoropopliteal arterial disease are required to establish the repair durability. METHODS: The OPEN study was a multicenter, single-arm, prospective study comparing primary safety and efficacy outcomes to performance goals (PG) developed for bare nitinol stents. Patients with symptoms due to a single, ≤180 mm length, de novo femoropopliteal arterial lesion with >70% stenosis were enrolled and followed for 36 months. Subjects with lesions ≤150 mm served as the initial comparison cohort for the PG (other cohorts were analyzed if the PG was met). RESULTS: 257 subjects with lesions ≤180 mm were enrolled. The mean lesion length was 71 ± 46 mm, and 52.5% had severe claudication. The primary safety endpoint (freedom from all-cause death, index limb amputation, and target lesion revascularization [TLR] through 30 days) was met in 98.8% (96.5%, 99.6%) of subjects in the comparison cohort, meeting the PG (88.0%). The primary efficacy endpoint (comparison cohort vessel patency at 12 months) was 68.4% (61.1%, 74.8%), where the lower limit of the 95% confidence interval did not meet the 66.0% PG. Freedom from TLR in the per-protocol cohort at 12-, 24-, 36-month was 84.7%, 74.6%, and 72.8%, respectively. The 24-month stent fracture rate was 4.3%, with no new fractures identified at 36 months. CONCLUSION: The results show promising long-term safety and effectiveness for the S.M.A.R.T.® Flex Vascular Stent System in patients with femoropopliteal arterial disease.

Wolbachia wAlbB inhibits bluetongue and epizootic hemorrhagic fever viruses in Culicoides midge cells.

Culicoides midges are hematophagous insects that transmit arboviruses of veterinary importance. These viruses include bluetongue virus (BTV) and epizootic hemorrhagic fever virus (EHDV). The endosymbiont Wolbachia pipientis Hertig spreads rapidly through insect host populations and has been demonstrated to inhibit viral pathogen transmission in multiple mosquito vectors. Here, we have demonstrated a replication inhibitory effect on BTV and EHDV in a Wolbachia (wAlbB strain)-infected Culicoides sonorensis Wirth and Jones W8 cell line. Viral replication was significantly reduced by day 5 for BTV and by day 2 for EHDV as detected by real-time polymerase chain reaction (RT-qPCR) of the non-structural NS3 gene of both viruses. Evaluation of innate cellular immune responses as a cause of the inhibitory effect showed responses associated with BTV but not with EHDV infection. Wolbachia density also did not play a role in the observed pathogen inhibitory effects, and an alternative hypothesis is suggested. Applications of Wolbachia-mediated pathogen interference to impact disease transmission by Culicoides midges are discussed.

Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes.

The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano-Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the "benign" to a "pathogenic" binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.

Peer Multiple Mentor Model (P3M) for Training Disability/Health and Rehabilitation Equity Researchers: Case Study at a Historically Black College/University.

Post-doctoral mentorship and training is considered a critical research capacity building approach vital to successful research career development. Existing models, however, may be insufficient for improving research skills among fellows at minority-serving institutions. This study evaluated a Peer Multiple Mentor Model (P3M) at a historically Black college and/or University (HBCU) designed to provide advanced research training to post-doctoral fellows and alleviate long-standing employment, health and function, and community participation inequities among multiply marginalized people of color with disabilities. The results showed that fellows experienced improved research skills, scientific productivity, and collaboration/networking opportunities. The model represents a promising research training pipeline component.

Emerging Conceptual Frameworks for Co-Serving Veterans of Color Across the State-Federal Vocational Rehabilitation Program: SVRAs, AIVRPs, and VA-VR&E.

Existing models of interagency collaborations serving the United States (U.S.) Armed Forces veterans of color, i.e., African Americans, Latinx, Native Americans/Alaskan Natives and Asian Americans and/or Pacific islanders are sparse, and few co-service partnership models are available. This article proposes two different emerging conceptual frameworks, i.e., state vocational rehabilitation agency (SVRA) and the U.S. Department of Veterans Affairs Veterans Readiness and Employment Program (VA-VR&E) co-service model, and American Indian Vocational Rehabilitation Program (AIVRP) and VA-VR&E co-service model designed to enhance successful employment outcomes for these veterans. Diffusions of innovations Theory was used to develop the Co-Service Models. A set of recommended approaches that these agencies and researchers can consider are presented.

Factors in Utilization of Telehealth Treatment by Rural African-Americans with Opioid Use Disorder and Disabilities.

This study explored factors that impact telehealth service utilization for treatment of African Americans with disabilities with opioid use disorder in rural communities. A focus group was conducted involving 12 different mental health, substance use, and rehabilitation counseling professionals. The analysis was completed using NVivo (Version 12). The results identified critical barriers that included historical distrust of technology and healthcare systems, digital divide/unavailability of Internet modems, fear of losing confidentiality, and agency non-approval. The benefits were improved communication, reduction of stigma, continuity of care, and convenience of collaboration. The findings indicate the need for additional research in this topic area.

National Benchmark Study of Employment Equity Among Multiply Marginalized Persons of Color with Disabilities During the COVID-19 Pandemic: A Bootstrap Approach.

BACKGROUND: Research examining state vocational rehabilitation agency (SVRA) sponsored service patterns during the COVID-19 pandemic is needed to improve employment outcomes among multiply marginalized persons of color with disabilities (i.e., African Americans, Asian Americans, Native Americans or Alaska Natives, Latinx, and Native Hawaiians/Pacific Islanders). Scarce attention has been paid to examining outcome inequities in the crisis. OBJECTIVE: This study applied a stratified bootstrap data expansion approach to assess the relationship between race/ethnicity, gender, level of educational attainment at closure and employment outcomes among target group members. METHODS: National fiscal year (FY) 2019 Rehabilitation Services Administration (RSA)-911 case records (N =114,229) closed between January 20, 2020 (date of first reported COVID-19 infection in the U.S.) to June 30 2020 were extracted and re-sampled across multiple trials using bootstrap procedures to increase logistic regression model accuracy. RESULTS: The findings indicated that African Americans, Asian Americans and Native American or Alaska Natives were statistically significantly less likely to achieve successful employment than non-Latinx Whites. Success probabilities in the COVID-19 pandemic were 'poorest' for Native American or Alaska Native VR consumers followed by African Americans, Asian Americans, Latinx, non-Latinx Whites, and then Native Hawaiians/Pacific Islanders. African Americans and Native Americans or Alaska Natives were more often closed unsuccessful because they could not be located when compared to non-Latinx Whites. CONCLUSIONS: These findings call for new targeted SVRA service initiatives.

A Scoping Review of Opioid Use Disorder Treatment Barriers and Telehealth for African Americans with Disabilities in Rural Communities.

This article provided a comprehensive overview of challenges that African Americans with disabilities residing in rural areas often face in the United States when accessing telehealth treatment to mitigate opioid misuse. A scoping literature review was conducted focusing on this target population, telehealth, disabilities, opioid treatment, and rural healthcare systems. Systematic searches on eight electronic databases were carried out in line with the study's aims. The results identified treatment benefits and advantages, expansion challenges, and multicultural considerations for telehealth delivery. There may be a need to increase rehabilitation research in this area to inform needed changes in policies and practice.

Assistive Technology Workplace Accommodation and Employment among Diverse Populations with Disabilities: Does Race/Ethnicity Matter?

The purpose of this study was to examine the relationship between assistive technology workplace accommodation (AT-WA) usage and employment status among racial/ethnic populations with disabilities. Chi-square tests and logistic regression were used to analyze secondary data from the 2015 Kessler Foundation National Employment and Disability Survey (KFNEDS). Results indicated that significantly more consumers who used AT-WA were currently working, and a significantly greater proportion of them were White. Moreover, a significantly lower proportion of those who did not use AT-WA had less expected odds of being currently employed. Specific implications are discussed to inform practices, policy, and/or future research.