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Little evidence is available to provide context for understanding the experiences of parents and youth from historically marginalized groups as they age into adulthood, especially in regard to the transition experiences of Black autistic transition-age youth and their family members. This commentary builds upon recent publications that inform intersectional understandings of Black autistic experiences in America, and outlines research recommendations to better address the specific needs of Black autistic transition-age youth. Given the noted deficits in transition research and the transition process in regard to the experiences of Black autistic youth, we provide recommendations for improving autism transition research. We propose changes that are necessary to achieve equitable research processes, which could inform the design of targeted interventions to improve transition experiences for Black autistic youth.
Why is this topic important? There is little research on the experiences of Black autistic youth and young adults during the transition to adulthood. It is important to study this group of people, because they may have more unmet needs for services and supports during the transition years. They may have a harder time achieving employment or continuing their education because of the long-term effects of racism in communities. What is the purpose of this article? To add to what is known on this topic, we report on recent studies about Black autistic youth during the transition to adulthood. We provide research and practice recommendations. What personal or professional perspectives do the authors bring to this topic? The authors of this study are allistic researchers and research assistants who are members of a research team working on, or advising, autism transition research. A.M.R. is a White researcher, and a family member of autistic individuals, who studies the transition experiences of autistic youth. S.V. is a Black, nonbinary, public health social worker with experience in Black LGBTQIA+ mental health. E.-D.W. is a Black researcher who studies the mental health of Black autistic youth. H.S. is a White qualitative sociologist with experience studying the transition to young adulthood from the critical disability lens. K.A.A. is a mixed-race researcher who is White-presenting and who studies the intersectionality of autism, race, and poverty. T.M.H. is a Black researcher whose work focuses on intersecting identities, with a special focus on race and autism, and the way those intersections impact the lived experiences of individuals. L.L.S. is a White researcher with experience in studying health services disparities. The positionality of this team is that we identify as nonautistic researchers who seek to support increased focus on Black autistic youth and adults within autism research. What is already known about this topic? We know that there has been little attention given to studying how Black autistic youth and their families experience the transition to adulthood. We also know they are less likely to receive information about the transition in a timely manner. These disparities are unacceptable. What do the authors recommend? We need to find better ways to learn about the barriers that Black autistic youth face as they become adults. We also need to learn about the strengths they use to overcome these barriers. That information will help us to design ways to improve transitions. This work should be done with Black autistic youth and their families as partners. Researchers should use different approaches to invite Black youth into their studies. When researchers are designing studies they should think about the connections between people's identities such as being autistic, Black, or poor, because these identities combine to make discrimination worse. It would be helpful if the leaders of academic departments placed value on hiring Black and autistic scholars and encouraged more diversity within research. How will these recommendations help autistic adults now or in the future? It is possible to make changes in how Black autistic transition-age youth move through transition. However, the same solutions will not work for all communities. This is because different communities experience different barriers to receiving information and services during the transition years. We hope these recommendations will help researchers to think about how they can improve the participation of Black autistic youth and their family members.
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BACKGROUND: Prosthetic joint infection (PJI) caused by Candida spp is a severe complication of arthroplasty. We investigated the outcomes of Candida PJI. METHODS: This was a retrospective observational multinational study including patients diagnosed with Candida-related PJI between 2010 and 2021. Treatment outcome was assessed at 2-year follow-up. RESULTS: A total of 269 patients were analyzed. Median age was 73.0 (interquartile range [IQR], 64.0-79.0) years; 46.5% of patients were male and 10.8% were immunosuppressed. Main infection sites were hip (53.0%) and knee (43.1%), and 33.8% patients had fistulas. Surgical procedures included debridement, antibiotics, and implant retention (DAIR) (35.7%), 1-stage exchange (28.3%), and 2-stage exchange (29.0%). Candida spp identified were Candida albicans (55.8%), Candida parapsilosis (29.4%), Candida glabrata (7.8%), and Candida tropicalis (5.6%). Coinfection with bacteria was found in 51.3% of cases. The primary antifungal agents prescribed were azoles (75.8%) and echinocandins (30.9%), administered for a median of 92.0 (IQR, 54.5-181.3) days. Cure was observed in 156 of 269 (58.0%) cases. Treatment failure was associated with age >70 years (OR, 1.811 [95% confidence interval {CI}: 1.079-3.072]), and the use of DAIR (OR, 1.946 [95% CI: 1.157-3.285]). Candida parapsilosis infection was associated with better outcome (OR, 0.546 [95% CI: .305-.958]). Cure rates were significantly different between DAIR versus 1-stage exchange (46.9% vs 67.1%, P = .008) and DAIR versus 2-stage exchange (46.9% vs 69.2%, P = .003), but there was no difference comparing 1- to 2-stage exchanges (P = .777). CONCLUSIONS: Candida PJI prognosis seems poor, with high rate of failure, which does not appear to be linked to immunosuppression, use of azoles, or treatment duration.
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Introduction: The transition to young adulthood can be a turbulent life stage, and this is often magnified for autistic youth. Young adults frequently profess different goals and values than their parents. While there is some indication in autism research about how parents, and to a lesser extent, autistic young adults, feel about this transition, little research leverages dyadic interviews with both populations or has used this method with Black and/or low-income families. Method: We conducted four sets of dyadic interviews with autistic young adults and their parents who live together. Results: We identified three key themes that both groups found important to the transition: independence, structured transition, and interpersonal relationships. However, we found that how the groups conceptualized these themes were divergent and revealed differences in goals and values. Parents were more oriented toward long-term normative views of fulfillment, whereas young adults spoke about what was meaningful to them currently. Conclusion: This work has implications for changes to how autism research will conceptualize the transition to young adulthood and how we can create better social opportunities for this population. Community brief: Why is this an important issue?: Autistic adults are at risk for difficulties getting work and education, which can lead to them feeling alienated or unfulfilled. Most research on autistic people becoming adults is based on White people with more cultural and financial resources and does not ask autistic people themselves or their families with them. Research is needed to improve transition outcomes for these underresearched and underserved groups.What was the purpose of this study?: This study explored how autistic youth and their parents thought about and experienced the transition to adulthood out of an urban, low-resourced school district.What did the researchers do?: Researchers interviewed four parents and four autistic youth. Three families were Black, and one family was White and from a low-income household. All autistic youth had received special education services, needed support to transition to adulthood, and had finished high school 1 to 6 years before the study. The young adults lived with their mothers and received support from them for daily tasks. We interviewed the parents and then the youth. In some cases, youths joined parents' interviews or parents joined youths' interviews to provide help with remembering information or giving answers.What were the results of the study?: Researchers identified three themes. First, parents and youth thought about independence differently. Parents focused more on work and financial independence. Youth focused more on social aspects of work and having independence in daily activities such as shopping. The second theme was that youth and parents approached ongoing structured supports differently. Youth reported positive experiences with a range of services but did not discuss the need for ongoing supports like their parents did. Third, youth emphasized the importance of social relationships and opportunities to connect with peers through shared interests.What do these findings add to what was already known?: We learned that standard questions about transition may not reflect how autistic youth and their parents think about becoming an adult. Interviewing families coming out of a predominantly Black and low-income urban school district helped us to understand how these groups experience and think about the transition to adulthood, even though they did not use these identities as a logic for how they thought about young adulthood. This suggests that parent and youth perspectives differ in groups that are not usually well represented in research studies related to transition for autistic youth.What are potential weaknesses in the study?: This study only included a small number of youth and parents. These results do not represent all Black autistic youth or low-income autistic youth coming from urban school districts. Families who are less connected to services may have been less likely to hear about or take part in the study.How will these findings help autistic adults now or in the future?: These findings could inform the development of better interviewing approaches and research to address the needs of diverse autistic youth entering adulthood. This work could improve transition support. Parents, youth, support providers, and researchers may think about adulthood differently. Improved support could help build mutual understanding and coordination around youths' and their families' goals.
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X-linked retinitis pigmentosa (XLRP) is characterized by progressive vision loss leading to legal blindness in males and a broad severity spectrum in carrier females. Pathogenic alterations of the retinitis pigmentosa GTPase regulator gene (RPGR) are responsible for over 70% of XLRP cases. In the retina, the RPGRORF15 transcript includes a terminal exon, called ORF15, that is altered in the large majority of RPGR-XLRP cases. Unfortunately, due to its highly repetitive sequence, ORF15 represents a considerable challenge in terms of sequencing for molecular diagnostic laboratories. However, in a recent preliminary work Yahya et al. reported a long-read sequencing approach seeming promising. Here, the aim of the study was to validate and integrate this new sequencing strategy in a routine screening workflow. For that purpose, we performed a masked test on 52 genomic DNA samples from male and female individuals carrying 32 different pathogenic ORF15 variations including 20 located in the highly repetitive region of the exon. For the latter, we have obtained a detection rate of 80-85% in males and 60-80% in females after bioinformatic analyses. These numbers raised to 100% for both status after adding a complementary visual inspection of ORF15 long-reads. In accordance with these results, and considering the frequency of ORF15 pathogenic variations in XLRP, we suggest that a long-read screening of ORF15 should be systematically considered before any other sequencing approach in subjects with a diagnosis compatible with XLRP.
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OBJECTIVES: Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune status. METHODS: We performed a multicenter retrospective study in France involving patients with documented NTM BJI over a 9-year period. We collected the clinical and microbiological characteristics, management, and clinical outcomes of the patients. RESULTS: Overall, 95 patients were included, of whom 50.5% (48/95) were immunosuppressed. Tenosynovitis was more frequent in the immunocompetent group, and native arthritis more common in the immunosuppressed group. Mycobacerium marinum and M. abscessus complex were significantly more frequent in the immunocompetent group, and M. avium and M. xenopi were significantly more frequent in the immunosuppressed group. The combination of antibiotherapy with surgery tended to be more frequent in the immunocompetent than the immunosuppressed group (63.8% (30/47) vs 47.8% (22/46), respectively); of the latter, 45.7% (21/46) received antimicrobial therapy alone, a higher frequency than in the immunocompetent group (23.4%, 11/47). The median duration of antimicrobial treatment was similar in the two groups (11 months). Mortality was significantly higher in the immunosuppressed group. CONCLUSIONS: Although the clinical presentations and the NTM species involved in BJI differed according to immune status, most recovered completely after treatment.
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Antibacterianos , Infecciones por Mycobacterium no Tuberculosas , Micobacterias no Tuberculosas , Humanos , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/mortalidad , Infecciones por Mycobacterium no Tuberculosas/microbiología , Estudios Retrospectivos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Micobacterias no Tuberculosas/inmunología , Resultado del Tratamiento , Antibacterianos/uso terapéutico , Francia/epidemiología , Huésped Inmunocomprometido , Anciano de 80 o más Años , Adulto , Artritis Infecciosa/microbiología , Artritis Infecciosa/tratamiento farmacológico , Artritis Infecciosa/inmunología , Artritis Infecciosa/mortalidadRESUMEN
Recent years have shown that secondary ice production (SIP) is ubiquitous, affecting all clouds from polar to tropical regions. SIP is not described well in models and may explain biases in warm mixed-phase cloud ice content and structure. Through modeling constrained by in-situ observations and its synergy with radar we show that SIP in orographic clouds exert a profound impact on the vertical distribution of hydrometeors and precipitation, especially in seeder-feeder cloud configurations. The mesoscale model simulations coupled with a radar simulator strongly support that enhanced aggregation and SIP through ice-ice collisions contribute to observed spectral bimodalities, skewing the Doppler spectra toward the slower-falling side at temperatures within the dendritic growth layer, ranging from -20 °C to -10 °C. This unique signature provides an opportunity to infer long-term SIP occurrences from the global cloud radar data archive, particularly for this underexplored temperature regime.
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INTRODUCTION: Similar to the management of periprosthetic joint infections of the lower limb, one-stage revision in total shoulder arthroplasty (TSA) infections is an option that has been highlighted in scientific publications since the early 2010s. However, there are only a few studies which validate this treatment and determine its scope of application in relation to two-stage treatment. HYPOTHESIS: Single-stage revision for infected TSA is a reliable treatment allowing good infection control and satisfactory functional results. METHODS: This single-center retrospective series of 34 consecutive patients operated on between 2014 and 2020 for a one-stage prosthetic revision was evaluated at a minimum of 2 years of follow-up. All of the patients included underwent revision shoulder arthroplasty during this period with the diagnosis of infection confirmed by microbiological analysis of surgical samples. Patients who did not benefit from a bipolar revision were excluded. All patients were followed at least 2 years after the intervention. Clinically suspected recurrence of infection was confirmed by a periprosthetic sample under radiographic guidance. Functional clinical outcomes as well as mechanical complications were also reported. RESULTS: The average follow-up was 40.4 months (24-102±21.6). A septic recurrence was observed in three patients (8.8%). A mechanical complication was present in four patients (14.7%), and three (11.8%) required at least one surgical revision. The mean Constant-Murley score at the last follow-up was 49 (42-57±21.83). DISCUSSION: Single-stage revision for shoulder periprosthetic joint infection results in a success rate of 91.2% with satisfactory functional results after more than 2 years of follow-up. LEVEL OF EVIDENCE: IV; retrospective study.
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Artroplastía de Reemplazo de Hombro , Infecciones Relacionadas con Prótesis , Reoperación , Humanos , Artroplastía de Reemplazo de Hombro/métodos , Estudios Retrospectivos , Masculino , Femenino , Infecciones Relacionadas con Prótesis/cirugía , Anciano , Estudios de Seguimiento , Persona de Mediana Edad , Prótesis de Hombro , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: To assess the performance of the rapid syndromic BioFire® Joint Infection Panel (BF-JIP) to detect bacterial and fungal pathogens, as well as antibiotic resistance genes, directly in synovial fluid specimens collected from patients with acute arthritis. METHODS: The study was conducted in six French bacteriological laboratories. To assess the performances of BF-JIP, results were compared with those of synovial fluid 14-day culture and, in case of discrepancy, with those of complementary molecular methods and intraoperative samples. A total of 308 synovial fluid specimens were tested after collection from 308 adults and children presenting with clinical and biological suspicion of acute arthritis; patients presenting with acute periprosthetic joint infection were included according to the European Bone and Joint Infection Society 2021 criteria. RESULTS: Only one specimen failed (no result). On the basis of the consolidated data, the BF-JIP was concordant with the 14-day culture in 280 (91.2%) of the 307 specimens finally included in the study. The positive percentage agreement was 84.9% (95% CI, 78.8-89.8%) and the negative percentage agreement was 100% (95% CI, 97.2-100%). The positive predictive value was extremely high (100%; 95% CI, 97.6-100%), whereas the negative predictive value was lower (82.6%; 95% CI, 75.7-88.2%), partially explained by the missing target species in the panel. DISCUSSION: The BF-JIP showed high performances to detect pathogens involved in acute arthritis.
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Artritis Infecciosa , Bacterias , Líquido Sinovial , Humanos , Estudios Prospectivos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Artritis Infecciosa/microbiología , Artritis Infecciosa/diagnóstico , Adulto , Niño , Bacterias/aislamiento & purificación , Bacterias/clasificación , Bacterias/genética , Líquido Sinovial/microbiología , Anciano de 80 o más Años , Francia , Hongos/aislamiento & purificación , Hongos/clasificación , Hongos/genética , Adolescente , Adulto Joven , Preescolar , Enfermedad Aguda , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/diagnóstico , Sensibilidad y Especificidad , Artritis/microbiología , Artritis/diagnósticoRESUMEN
OBJECTIVES: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France. METHODS: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality. RESULTS: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). Solid-organ transplant patients were most likely to have disseminated infections and a positive serum cryptococcal antigen result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265; p 0.029). The crude 90-day case-fatality ratio was 27.2% (95% CI, 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26]; p < 0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7]; p 0.002), and malignancy (aOR: 2.4 [1.14-5.07]; p 0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71]; p 0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80]; p 0.006). DISCUSSION: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management.
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Antifúngicos , Criptococosis , Humanos , Francia/epidemiología , Femenino , Masculino , Criptococosis/epidemiología , Criptococosis/mortalidad , Persona de Mediana Edad , Adulto , Estudios Transversales , Antifúngicos/uso terapéutico , Anciano , Flucitosina/uso terapéutico , Seronegatividad para VIH , Polienos/uso terapéutico , Adulto Joven , Huésped InmunocomprometidoRESUMEN
Although probiotics have been used in food products and supplements for decades, there has been a considerable increase in their use more recently. Recent technological advances have thus led to major advances in knowledge of the gut microbiota, enabling a significant development of biotics. In this review, we discuss the uses of traditional probiotics but also the discovery of next-generation probiotics that could be used as live biotherapeutics. These novel preventive and therapeutic strategies hold promise for the treatment of numerous diseases such as inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Probiotic bacteria can be consumed alone, or in combination with prebiotics as synbiotics, or mixed with other probiotic strains to form a consortium for enhanced effects. We also discuss the benefits of using postbiotics.
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Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Probióticos , Humanos , Probióticos/uso terapéutico , Prebióticos , Enfermedades Inflamatorias del Intestino/terapia , Enfermedades Inflamatorias del Intestino/microbiología , BacteriasRESUMEN
PURPOSE: We used data from the National Survey of Children's Health to (1) examine differences in economic hardship and safety net program use after the implementation of federal relief efforts, and (2) assess whether the COVID-19 pandemic exacerbated autism-based disparities in hardship and program use. METHODS: We examined five dimensions of economic hardship (poverty, food insecurity, medical hardship, medical costs, and foregone work) and four safety net programs (cash assistance, Supplemental Nutrition Assistance Program (SNAP), Special Supplemental Nutrition Program for Women, Infants and Children (WIC), and free or reduced-cost meals). First, we calculated adjusted prevalence and odds ratios to compare pre-COVID (2018-2019) and during COVID (2021) outcomes by autism status. Next, we calculated the adjusted odds of each outcome among autistic children compared to those of children with and without other special healthcare needs at both time points. RESULTS: COVID-19 exacerbated autism-based disparities in food insecurity, SNAP, and public health insurance, but alleviated inequities in medical hardship, foregone work, and cash assistance. Autistic children did not experience declines in food insecurity or increases in SNAP like other children; medical hardship and foregone work decreased more for autistic children; and the magnitude of autism-based differences in public coverage significantly increased during the pandemic. CONCLUSION: Federal relief efforts likely improved economic outcomes of children; however, these effects varied according to type of hardship and by disability group. Efforts to promote economic well-being among autistic populations should be tailored to the financial challenges most salient to low-income autistic children, like food insecurity.
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Among 1107 cryptococcosis cases from the French surveillance network (2005-2020), the proportion of HIV-seronegative individuals has recently surpassed that of HIV-seropositive individuals. We observed marked differences in patient characteristics, disease presentations, cryptococcal antigen results, infecting species, and mortality according to HIV serostatus.
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Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.
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Cardiopatías Congénitas , Pez Cebra , Animales , Humanos , Polaridad Celular/genética , Células Germinativas/metabolismo , Mutación de Línea Germinal/genética , Cardiopatías Congénitas/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
OBJECTIVE: This paper examines the distribution, parameters, and determinants of safety net program use among a nationally representative sample of low-income children with autism spectrum disorder (ASD). METHODS: We used data from the 2021 National Survey of Children's Health to produce population estimates of material hardship and safety net program use among 554 low-income households of children with ASD, ages 3 to 17 years, relative to 2831 children with other special health care needs (SHCN) and 8758 children with no SHCN of the same age. Design-adjusted multivariate logistic regression models identified predictors of cash assistance, Supplemental Nutrition Assistance Program, and disconnection from both. RESULTS: There were few significant differences in material hardship between children with ASD and those with other SHCN, although children with ASD experienced significantly higher levels of hardships compared to children with no SHCN. Having a child with ASD did not significantly increase the odds of safety net use. Health insurance and household income were stronger predictors of use than disability. Nine percent of disconnected children lived in households under 100% federal poverty level and experienced some type of material hardship. CONCLUSIONS: Future research about the economic security of children with ASD and their families could focus on the following 3 areas of inquiry: assess how race, ethnicity, or socioeconomic position interact with disability to influence safety net program use; examine the intersection between Medicaid and safety net programs at the state and national levels; and identify specific subgroups of children at risk for disconnection and understand why they are not accessing benefits.
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Trastorno del Espectro Autista , Trastorno Autístico , Niño , Estados Unidos , Humanos , Trastorno Autístico/epidemiología , Trastorno del Espectro Autista/epidemiología , Pobreza , Seguro de Salud , MedicaidRESUMEN
There is an emblematic clinical and genetic heterogeneity associated with inherited retinal diseases (IRDs). The most common form is retinitis pigmentosa (RP), a rod-cone dystrophy caused by pathogenic variants in over 80 different genes. Further complexifying diagnosis, different variants in individual RP genes can also alter the clinical phenotype. USH2A is the most prevalent gene for autosomal-recessive RP and one of the most challenging because of its large size and, hence, large number of variants. Moreover, USH2A variants give rise to non-syndromic and syndromic RP, known as Usher syndrome (USH) type 2, which is associated with vision and hearing loss. The lack of a clear genotype-phenotype correlation or prognostic models renders diagnosis highly challenging. We report here a long-awaited differential non-syndromic RP and USH phenotype in three human disease-specific models: fibroblasts, induced pluripotent stem cells (iPSCs), and mature iPSC-derived retinal organoids. Moreover, we identified distinct retinal phenotypes in organoids from multiple RP and USH individuals, which were validated by isogenic-corrected controls. Non-syndromic RP organoids showed compromised photoreceptor differentiation, whereas USH organoids showed a striking and unexpected cone phenotype. Furthermore, complementary clinical investigations identified macular atrophy in a high proportion of USH compared with RP individuals, further validating our observations that USH2A variants differentially affect cones. Overall, identification of distinct non-syndromic RP and USH phenotypes in multiple models provides valuable and robust readouts for testing the pathogenicity of USH2A variants as well as the efficacy of therapeutic approaches in complementary cell types.
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Retinitis Pigmentosa , Síndromes de Usher , Humanos , Síndromes de Usher/diagnóstico , Retinitis Pigmentosa/diagnóstico , Organoides , Fenotipo , Proteínas de la Matriz Extracelular/genéticaRESUMEN
Policy Points Employment is a key social determinant of health and well-being for the estimated 5.4 million autistic adults in the United States-just as it is for citizens without disabilities. Evaluation and monitoring of publicly funded employment services is paramount given the dramatic increases in adults with autism who need job supports. Vocational Rehabilitation agencies appeared to be absorbing short-term employment needs of autistic people, but Medicaid was severely lacking-and losing ground-in serving those who need longer-term employment services. Across both Vocational Rehabilitation and Medicaid, we estimated that only 1.1% of working-age autistic adults who potentially need employment services are actually receiving them-leaving an estimated 1.98 million autistic individuals without the employment services that are associated with achievement of well-being. CONTEXT: Employment is a key social determinant of health. As such, high rates of unemployment, underemployment, and poverty across the rapidly growing autistic population are concerning. A web of publicly funded services exists to support the employment, and associated health and well-being, of United States citizens with autism and other intellectual and developmental disabilities, namely through Vocational Rehabilitation (VR) and Medicaid home- and community-based services (HCBS) waivers. Given an absence of overarching surveillance of employment services, this study aimed to characterize the distribution of autistic service users across Medicaid versus VR, understand the types of employment services utilized within these programs and expenditures, and assess overall capacity to provide employment services as needs continue to increase. METHODS: This study examined the distribution of employment services among autistic people compared with those with intellectual disability using 2008-2016 data from the Centers for Medicare & Medicaid Services and the Rehabilitation Services Administration. Estimated need for employment services among autistic individuals was compared with capacity derived from VR service counts and a review of HCBS waivers. FINDINGS: The number of autistic people served through VR tripled during the study years, whereas those served through Medicaid only increased slightly. VR spending increased by 384% over the study years, whereas Medicaid costs decreased by 29%. Across VR and Medicaid, we estimated that only 1.1% of working-age autistic adults who needed employment services received them. CONCLUSIONS: Although VR appeared to be absorbing short-term employment needs of autistic individuals, Medicaid was severely lacking-and losing ground-in serving those who needed longer-term employment services. VR far outpaced Medicaid in both the number of autistic people served and total expenditures across the study years. However, an estimated 1.98 million autistic adults did not receive employment services that could be critical to improving their health and well-being.
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Trastorno Autístico , Personas con Discapacidad , Adulto , Humanos , Anciano , Estados Unidos , Trastorno Autístico/rehabilitación , Medicare , Empleo , Gastos en Salud , MedicaidRESUMEN
Cutibacterium avidum is an emerging causative agent of orthopedic device-related infections (ODRIs). There are no guidelines for the antimicrobial treatment of C. avidum ODRI, but oral rifampin is frequently used in combination with a fluoroquinolone following intravenous antibiotics. We describe the in vivo emergence of combined resistance to rifampin and levofloxacin in a C. avidum strain isolated from a patient with early-onset ODRI treated with debridement, antibiotic treatment, and implant retention (DAIR) using rifampin combined with levofloxacin as the oral treatment. Whole-genome sequencing of C. avidum isolates before and after antibiotic exposure confirmed strain identity and identified new mutations in rpoB and gyrA, leading to amino acid substitutions previously reported to be associated with resistance to rifampin (S446P) and fluoroquinolones (S101L), respectively, in other microbial agents, in the posttherapy isolate. Aside from the molecular insights reported here, this study highlights potential limitations of the combination of oral rifampin and levofloxacin in patients undergoing a DAIR procedure for C. avidum ODRI and the potential need to evaluate specific optimal therapy for emerging ODRI pathogens. IMPORTANCE In this study, we report for the first time the in vivo emergence of dual resistance to levofloxacin and rifampin in C. avidum isolated from a patient who received both antibiotics orally in the setting of a salvage debridement and implant retention of an ODRI. Aside from the molecular insights reported here, this study highlights potential limitations of the combination of oral rifampin and levofloxacin in patients undergoing these surgical procedures and the potential need to evaluate specific optimal therapy for emerging ODRI pathogens.
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Levofloxacino , Propionibacteriaceae , Humanos , Levofloxacino/farmacología , Levofloxacino/uso terapéutico , Rifampin/farmacología , Rifampin/uso terapéutico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Fluoroquinolonas , Pruebas de Sensibilidad MicrobianaRESUMEN
DFNA68 is a rare subtype of autosomal dominant nonsyndromic hearing impairment caused by heterozygous alterations in the HOMER2 gene. To date, only 5 pathogenic or likely pathogenic coding variants, including two missense substitutions (c.188 C > T and c.587 G > C), a single base pair duplication (c.840dupC) and two short deletions (c.592_597delACCACA and c.832_836delCCTCA) have been described in 5 families. In this study, we report a novel HOMER2 variation, identified by massively parallel sequencing, in a Sicilian family suffering from progressive dominant hearing loss over 3 generations. This novel alteration is a nonstop substitution (c.1064 A > G) that converts the translational termination codon (TAG) of the gene into a tryptophan codon (TGG) and is predicted to extend the HOMER2 protein by 10 amino acids. RNA analyses from the proband suggested that HOMER2 transcripts carrying the nonstop variant escaped the non-stop decay pathway. Finally, in vivo studies using a zebrafish animal model and behavioral tests clearly established the deleterious impact of this novel HOMER2 alteration on hearing function. This study identifies the fourth causal variation responsible for DFNA68 and describes a simple in vivo approach to assess the pathogenicity of candidate HOMER2 variants.
Asunto(s)
Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Animales , Codón de Terminación , Sordera/genética , Pérdida Auditiva/genética , Pérdida Auditiva Sensorineural/genética , Mutación , Linaje , Pez Cebra/genéticaRESUMEN
The cause of childhood hearing impairment (excluding infectious pathology of the middle ear) can be extrinsic (embryofoetopathy, meningitis, trauma, drug ototoxicity, noise trauma, etc [...].
RESUMEN
The transition from targeted to exome or genome sequencing in clinical contexts requires quality standards, such as targeted sequencing, in order to be fully adopted. However, no clear recommendations or methodology have emerged for evaluating this technological evolution. We developed a structured method based on four run-specific sequencing metrics and seven sample-specific sequencing metrics for evaluating the performance of exome sequencing strategies to replace targeted strategies. The indicators include quality metrics and coverage performance on gene panels and OMIM morbid genes. We applied this general strategy to three different exome kits and compared them with a myopathy-targeted sequencing method. After having achieved 80 million reads, all-tested exome kits generated data suitable for clinical diagnosis. However, significant differences in the coverage and PCR duplicates were observed between the kits. These are two main criteria to consider for the initial implementation with high-quality assurance. This study aims to assist molecular diagnostic laboratories in adopting and evaluating exome sequencing kits in a diagnostic context compared to the strategy used previously. A similar strategy could be used to implement whole-genome sequencing for diagnostic purposes.