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1.
Doc Ophthalmol ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38825634

RESUMO

PURPOSE: Vitamin A is a lipid-soluble compound that is critical in maintaining phototransduction. Ocular manifestations of hypovitaminosis A may present with anterior segment signs of xeropthalmia, with advanced cases also causing classic retinal and electrophysiologic changes of vitamin A deficiency retinopathy. We present a case of vitamin A deficiency retinopathy, with corresponding retinal imaging and electrophysiology, in an adult patient with celiac disease and liver fibrosis. METHODS: A single case report was conducted in Toronto, Canada. RESULTS: A 77-year-old male with known celiac disease and liver fibrosis presented progressively worsening vision noticed primarily when driving. Vision was 20/50 OD and 20/200 OS. Bitot spots were noted on anterior segment examination. Fundus photography demonstrated bilateral peripheral macular hypopigmentation and far-peripheral granular retinal hypopigmentation with focal yellow dots and hyper-pigmented deposits. Optical coherence tomography (OCT) imaging demonstrated indistinct outer retinal banding with mild outer nuclear layer thinning, focal hyper-reflective deposits, and a thin choroid bilaterally. Full-field electroretinography (ERG) testing demonstrated reduced rod-isolated and combined rod-cone response amplitudes, and multifocal ERG testing demonstrated blunted individual responses throughout the field. The patient was treated with pulse vitamin A therapy. After 6 months of therapy, ERG responses were back within reference range, and the outer retinal changes reversed; visual acuity improved to 20/30 OD and 20/40 OS. CONCLUSION: This case represents the classic findings of vitamin A deficiency retinopathy on fundus examination and electrophysiologic testing secondary to gastrointestinal pathology. Prompt treatment of high dose vitamin A supplementation led to improvement of full-field and multifocal ERG results, as well as reconstitution of outer retinal architecture.

2.
FEBS Lett ; 598(13): 1591-1604, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38724485

RESUMO

Inhibition of the cyclic-AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta-amyloid (Aß) plaques in a mouse model of AD but that Aß directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aß as it possesses a unique binding site. Intriguingly, exogenous addition of Aß to cells overexpressing the PDE4D5 longform caused PDE4 activation and a decrease in cAMP. We suggest a novel mechanism where PDE4 longforms can be activated by Aß, resulting in the attenuation of cAMP signalling to promote loss of cognitive function in AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , AMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Neurônios , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Peptídeos beta-Amiloides/metabolismo , AMP Cíclico/metabolismo , Camundongos , Neurônios/metabolismo , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Ligação Proteica , Ativação Enzimática , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia
3.
Lancet Glob Health ; 12(7): e1209-e1213, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38801831

RESUMO

Sexual corruption or sextortion has gained recent attention in the anti-corruption space. It occurs when a sexual favour is used as the currency for a bribe. Sexual corruption is a manifestation of gender-based violence, is inherently a human rights violation, and is a grave public health concern because of its effects on the physical, emotional, and mental wellbeing of the person who has experienced sexual corruption. It impacts health systems' abilities to achieve universal health coverage and deliver services in the most effective, high-quality manner. Despite the health consequences, limited evidence exists on sexual corruption occurring in the health sector. This Viewpoint briefly reviews the literature on sexual corruption occurring within health systems focusing mainly on low-income to middle-income countries, with a concentration on its prevalence, the driving forces associated with it, and recommendations to address it.


Assuntos
Atenção à Saúde , Humanos , Atenção à Saúde/economia , Violência de Gênero , Países em Desenvolvimento
4.
Retina ; 44(7): 1115-1123, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38478760

RESUMO

PURPOSE: To investigate the correlation between diabetic retinopathy (DR) severity and microscopic retinal and vascular alterations using adaptive optics imaging. METHODS: In this single-center, prospective cohort study, adult participants with healthy eyes or DR underwent adaptive optics imaging. Participants were classified into control/mild nonproliferative DR, moderate/severe nonproliferative DR, and proliferative DR. Adaptive optics imaging using the RTX1 camera was obtained from 48 participants (87 eyes) for photoreceptor data and from 36 participants (62 eyes) for vascular data. RESULTS: Photoreceptor parameters significantly differed between DR groups at 2° and 4° of retinal eccentricity. Wall-to-lumen ratio varied significantly at 2° eccentricity, while other vascular parameters remained nonsignificant. Cone density and dispersion were the strongest predictors for DR severity ( P < 0.001) in multivariable generalized estimating equation modeling, while other vascular parameters remained nonsignificant between DR severity groups. All photoreceptor parameters showed significant correlations with visual acuity overall and across most DR severity groups. CONCLUSION: To date, this is one of the largest studies evaluating the use of adaptive optics imaging in DR. Adaptive optics imaging was demonstrated to differentiate between various levels of disease severity in DR. These results support the potential role in diagnostic and therapeutic microstructural evaluation in research and clinical practice.


Assuntos
Retinopatia Diabética , Acuidade Visual , Humanos , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/fisiopatologia , Estudos Prospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Acuidade Visual/fisiologia , Adulto , Idoso , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia
5.
J Wound Care ; 33(Sup1a): S10-S14, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38194310

RESUMO

BACKGROUND: There is no clear guidance or comprehensive comparative evidence to help clinicians select between adjustable wraps for compression therapy. However, adjustable wraps could be compared with three metrics used for compression bandages: variation in pressure, stiffness and elasticity. AIMS: To determine whether easywrap (Haddenham Healthcare) had lower standard deviation (SD) in lying pressure, greater static stiffness index (SSI) and/or a greater mean elongation ratio than six other adjustable wraps. METHODS: In this preliminary exploratory study, seven adjustable wraps were tested in vivo 20 times each (140 tests in total), on 20 people (with a variable number of readings per participant), to give the SD in lying pressure and mean SSI. The same wraps were tested in vitro five times each to give the mean elongation ratio. FINDINGS: Of all seven adjustable wraps, easywrap had the second lowest SD in lying pressure at 5.9 mmHg, compared with 8.9 mmHg overall; the highest mean SSI at 13.2 mmHg, compared with 9.5 mmHg overall; and the highest mean elongation ratio at 137.0%, compared with 107.1% overall. CONCLUSIONS: These metrics suggest that easywrap has clinical advantages over other adjustable wraps. A lower variation in lying pressure suggests more consistent application of pressures within intended therapeutic levels. Higher SSI indicates greater resistance to stretching, which is linked to improved venous function and oedema reduction. Higher elongation ratio demonstrates greater tensile strength, which should maintain therapeutic pressure for longer without readjustment.


Assuntos
Doenças Linfáticas , Humanos , Bandagens Compressivas , Elasticidade , Instalações de Saúde , Massagem
6.
Retina ; 44(4): 689-699, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38011843

RESUMO

PURPOSE: To our knowledge, we present the first case series investigating the relationship between adaptive optics (AO) imaging and intravenous fluorescein angiography (IVFA) parameters in patients with diabetic retinopathy. METHODS: Consecutive patients with diabetic retinopathy older than age 18 years presenting to a single center in Toronto, Canada, from 2020 to 2021 were recruited. Adaptive optics was performed with the RTX1 camera (Imagine Eyes, Orsay, France) at retinal eccentricities of 2° and 4°. Intravenous fluorescein angiography was assessed with the artificial intelligence-based RETICAD system to extract blood flow, perfusion, and blood-retinal-barrier (BRB) permeability at the same retinal locations. Correlations between AO and IVFA parameters were calculated using Pearson's correlation coefficient. RESULTS: Across nine cases, a significant positive correlation existed between photoreceptor spacing on AO and BRB permeability (r = 0.303, P = 0.027), as well as perfusion (r = 0.272, P = 0.049) on IVFA. When stratified by location, a significant positive correlation between photoreceptor dispersion and both BRB permeability and perfusion (r = 0.770, P = 0.043; r = 0.846, P = 0.034, respectively) was observed. Cone density was also negatively correlated with BRB permeability (r = -0.819, P = 0.046). CONCLUSION: Photoreceptor spacing on AO was significantly correlated with BRB permeability and perfusion on IVFA in patients with diabetic retinopathy. Future studies with larger sample sizes are needed to understand the relationship between AO and IVFA parameters in diverse patient populations.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Humanos , Adolescente , Angiofluoresceinografia , Inteligência Artificial , Retina , Células Fotorreceptoras Retinianas Cones , Tomografia de Coerência Óptica/métodos
8.
J Wound Care ; 33(Sup1): S10-S14, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38150280

RESUMO

BACKGROUND: There is no clear guidance or comprehensive comparative evidence to help clinicians select between adjustable wraps for compression therapy. However, adjustable wraps could be compared with three metrics used for compression bandages: variation in pressure, stiffness and elasticity. AIMS: To determine whether easywrap (Haddenham Healthcare) had lower standard deviation (SD) in lying pressure, greater static stiffness index (SSI) and/or a greater mean elongation ratio than six other adjustable wraps. METHODS: In this preliminary exploratory study, seven adjustable wraps were tested in vivo 20 times each (140 tests in total), on 20 people (with a variable number of readings per participant), to give the SD in lying pressure and mean SSI. The same wraps were tested in vitro five times each to give the mean elongation ratio. FINDINGS: Of all seven adjustable wraps, easywrap had the second lowest SD in lying pressure at 5.9 mmHg, compared with 8.9 mmHg overall; the highest mean SSI at 13.2 mmHg, compared with 9.5 mmHg overall; and the highest mean elongation ratio at 137.0%, compared with 107.1% overall. CONCLUSIONS: These metrics suggest that easywrap has clinical advantages over other adjustable wraps. A lower variation in lying pressure suggests more consistent application of pressures within intended therapeutic levels. Higher SSI indicates greater resistance to stretching, which is linked to improved venous function and oedema reduction. Higher elongation ratio demonstrates greater tensile strength, which should maintain therapeutic pressure for longer without readjustment.


Assuntos
Doenças Linfáticas , Humanos , Bandagens Compressivas , Elasticidade , Instalações de Saúde , Massagem
9.
J Pharm Policy Pract ; 16(1): 141, 2023 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-37957711

RESUMO

BACKGROUND: Public health emergencies raise significant concerns about corruption and accountability; however, these concerns can manifest in different ways across diverse locations. For instance, more developed countries with a stronger rule of law may experience more corruption in vaccine procurement, whereas developing countries may experience more corruption at the point of distribution and delivery to end users. This research focuses on corruption concerns in Nigeria, specifically examining the procurement and distribution of COVID-19 vaccines. METHODS: This paper utilizes a scoping review and a qualitative research approach. Key informants (n = 40) involved in the procurement and distribution of COVID-19 vaccines across two states in Nigeria were interviewed. Findings from the scoping review were summarized, and collected data were inductively coded and analysed in themes, revealing clear examples of implementation irregularities and corruption in the country's COVID-19 vaccination processes. RESULTS: Vaccination programme budgeting processes were unclear, and payment irregularities were frequently observed, resulting in vaccinators soliciting informal payments while in the field. Recruitment and engagement of vaccination personnel was opaque, while target vaccination rates incentivized data falsification during periods of vaccine hesitancy. Accountability mechanisms, such as health worker supervision, vaccination data review, and additional technical support provided by donors were implemented but not effective at preventing corruption among frontline workers. CONCLUSIONS: Future accountability measures should be evidence-driven based on findings from this research. Personnel recruitment, contracting, budgeting, and remuneration should focus on transparency and accountability.

10.
J Am Chem Soc ; 145(29): 16142-16149, 2023 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-37431761

RESUMO

A key challenge in origin-of-life research is the identification of plausible conditions that facilitate multiple steps along the pathway from chemistry to biology. The incompatibility of nucleotide activation chemistry and nonenzymatic template-directed RNA copying has hindered attempts to define such a pathway. Here, we show that adding heteroaromatic small molecules to the reaction network facilitates in situ nucleotide phosphate activation under conditions compatible with RNA copying, allowing both reactions to take place in the same mixture. This is achieved using Passerini-type phosphate activation in concert with nucleophilic organocatalysts that intercept high-energy reactive intermediates; this sequence ultimately affords 5',5'-imidazolium-bridged dinucleotides─the active species in template-directed RNA polymerization. Our results suggest that mixtures of prebiotically relevant heteroaromatic small molecules could have played a key role in the transition from chemistry to biology.


Assuntos
Nucleotídeos , RNA , RNA/química , Nucleotídeos/química , Polimerização
11.
J Dairy Sci ; 106(7): 4738-4758, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37225574

RESUMO

The health, longevity, and performance of dairy cattle can be adversely affected by heat stress. This study evaluated the in-barn condition [i.e., temperature, relative humidity, and resulting temperature-humidity index (THI)] at 9 dairy barns with various climates and farm design-management combinations. Hourly and daily indoor and outdoor conditions were compared at each farm, including both mechanically and naturally ventilated barns. On-site conditions were compared with on-farm outdoor conditions, meteorological stations up to 125 km away, and NASA Power data. Canadian dairy cattle face periods of extreme cold and periods of high THI, dependent on the regional climate and season. The northernmost location (53°N) experienced about 75% fewer hours of THI >68 compared with the southernmost location (42°N). Milking parlors had higher THI than the rest of the barn during milking times. The THI conditions inside dairy barns were well correlated with THI conditions measured outside the barns. Naturally ventilated barns with metal roofs and without sprinklers fit a linear relationship (hourly and daily means) with a slope <1, indicating that in-barn THI exceeded outdoor THI more at lower THI and reached equality at higher THI. Mechanically ventilated barns fit nonlinear relationships, which showed the in-barn THI exceeded outdoor THI more at lower THI (e.g., 55-65) and approached equality at higher THI. In-barn THI exceedance was greater in the evening and overnight due to factors such as decreased wind speed and latent heat retention. Eight regression equations were developed (4 hourly, 4 daily) to predict in-barn conditions based on outdoor conditions, considering different barn designs and management systems. Correlations between in-barn and outdoor THI were best when using the on-site weather data from the study, but publicly available weather data from stations within 50 km provided reasonable estimates. Climate stations 75 to 125 km away and NASA Power ensemble data gave poorer fit statistics. For studies involving many dairy barns, the use of NASA Power data with equations for estimating average in-barn conditions in a population is likely appropriate especially when public stations have incomplete data. Results from this study show the importance of adapting recommendation on heat stress to the barn design and guide the selection of appropriate weather data depending on the aim of the study.


Assuntos
Lactação , Tempo (Meteorologia) , Feminino , Bovinos , Animais , Canadá , Umidade , Temperatura , Temperatura Alta
12.
J Dairy Sci ; 106(6): 4030-4041, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37105881

RESUMO

The purpose of this study was to identify current practices and perceptions around trace element feeding for dairy cows through a Canadian dairy nutritionist survey. An online survey with 23 questions was used to collect data from Canadian dairy nutritionists with the help of professional associations and social media. The survey was active from November 2021 to April 2022. The first 7 questions collected descriptive information on respondents, and the subsequent 16 questions focused on trace element feeding. A total of 92 participants from all over Canada filled out the survey, and about 26% of Canadian herds and cows were represented by these respondents. The participants had diverse views on the importance of diet formulations for trace elements to optimize cow health and productivity, with perceptions varying from very important to not important. In comparison, macronutrients and selenium were consistently rated as very important by between 58% and 74% of respondents. Software reference values were used by 54%, 72%, and 73% of participants to estimate trace element concentrations of forages, cereals, and protein sources, respectively, highlighting the importance of regularly updating the feed library of the software. More than 60% of nutritionists participating in this study had intentionally formulated diets above trace element software recommendations, considered mineral interactions occurring in the rumen, and used a trace element source known for its better bioavailability (e.g., organic, chelate) when they formulated diets. Herds with more than 80 cows were more likely to be given trace element supplements known for their greater bioavailability. The most used supplement with enhanced bioavailability was selenium. In addition, different trace element feeding strategies pertaining to different stages of lactation and breeds were reported. This finding can be explained by the absence of clear recommendations on trace element feeding by breed. The participants who adjusted trace element feeding according to the stages of lactation considered the transition period as the most challenging period, and they identified the need for a source of trace element known for its greater bioavailability for this period. Further research should aim to identify environmental risk of trace element overfeeding using the One Health approach. Moreover, strategies to avoid trace element overfeeding should be evaluated.


Assuntos
Nutricionistas , Selênio , Oligoelementos , Feminino , Bovinos , Animais , Humanos , Oligoelementos/metabolismo , Selênio/metabolismo , Leite/metabolismo , Canadá , Melhoramento Vegetal , Dieta/veterinária , Lactação , Inquéritos e Questionários , Ração Animal/análise
14.
Doc Ophthalmol ; 146(1): 3-6, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36478287

RESUMO

PURPOSE: To provide an overview of the effect that the COVID-19 pandemic has had on visual electrophysiology referral patterns and the subsequent effect this may have on patients. METHODS: All electrodiagnostic tests performed at Kensington Vision and Research Centre, Toronto Canada, in a 3-month period prior to the COVID-19 pandemic (1 September 2019 to 30 November 2019) were compared to a 3-month period after the start of the COVID-19 pandemic (1 September 2021 to 30 November 2021). RESULTS: A total of 502 patients had electrodiagnostic testing carried out in the designated time periods: 292 in the time period prior to the COVID-19 pandemic and 210 patients after. There was a significant change in the reason for referral in patients pre-COVID compared to post-COVID (p = 0.004). There was a 43% reduction in referrals for drug monitoring, 25% reduction for hereditary pathology and a 27% increase in acquired pathology after the start of the COVID-19 pandemic compared to before. CONCLUSIONS: There was a substantial decrease in the total number of patients referred after the start of the COVID-19 pandemic compared to pre-COVID with inherited retinal pathology and drug monitoring patients being 2 populations most affected by the disruption to healthcare services.


Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , Pandemias , Eletrorretinografia , Encaminhamento e Consulta , Retina
15.
Animals (Basel) ; 12(15)2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35892544

RESUMO

Light from the environment is important for vision and regulating various biological processes. Providing supplemental lighting in the stall area could allow for individually targeted or group-level control of light. This study aimed to determine whether dairy cattle had preferences for short-term exposure to white (full-spectrum) light-emitting diode (LED) light or no LED light, yellow-green or white LED light, and blue or white LED light in the stall area. In total, 14 lactating cows were housed in a free-stall pen with unrestricted access to 28 stalls. LED light was controlled separately for each side of the stall platform. Two combinations of light were tested per week, and each week consisted of three adaptation days and four treatment days. Lying behaviour and video data were recorded continuously using leg-mounted pedometers and cameras, respectively. Preference was assessed by the amount of time spent lying and the number of bouts under each light treatment. No differences occurred between treatments within each week for daily lying time and number of bouts. Similarly, no differences occurred between treatments within each time period. Further controlled studies of long-term exposure to different LED wavelengths and intensities are required to determine potential benefits on metabolic processes.

16.
Doc Ophthalmol ; 145(1): 53-63, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35732856

RESUMO

PURPOSE: Hydroxychloroquine (HCQ) is an anti-inflammatory drug in widespread use for the treatment of systemic auto-immune diseases. Vision loss caused by retinal toxicity is a significant risk associated with long term HCQ therapy. Identifying patients at risk of developing retinal toxicity can help prevent vision loss and improve the quality of life for patients. This paper presents updated reference thresholds and examines the diagnostic accuracy of a machine learning approach for identifying retinal toxicity using the multifocal Electroretinogram (mfERG). METHODS: A retrospective study of patients referred for mfERG testing to detect HCQ retinopathy. A consecutive series of all patients referred to Kensington Vision and Research Centre between August 2017 and July 2020 were considered eligible. Eyes suspect for other ocular pathology including widespread retinal disease and advanced macular pathology unrelated to HCQ or with poor quality mfERG recordings were excluded. All patients received mfERG testing and Ocular Coherence Tomography (OCT) imaging. Presence of HCQ retinopathy was based on ring ratio analysis using clinical reference thresholds established at KVRC coupled with structural features observed on OCT, the clinical reference standard. A Support Vector Machine (SVM) using selected features of the mfERG was trained. Accuracy, sensitivity and specificity are reported. RESULTS: 1463 eyes of 748 patients were included in the study. SVM model performance was assessed on 293 eyes from 265 patients. 55 eyes from 54 patients were identified as demonstrating HCQ retinopathy based on the clinical reference standard, 50 eyes from 49 patients were identified by the SVM. Our SVM achieves an accuracy of 85.3% with a sensitivity of 90.9% and specificity of 84.0%. CONCLUSIONS: Machine learning approaches can be applied to mfERG analysis to identify patients at risk of retinopathy caused by HCQ therapy.


Assuntos
Antirreumáticos , Doenças Retinianas , Antirreumáticos/efeitos adversos , Eletrorretinografia/métodos , Humanos , Hidroxicloroquina/efeitos adversos , Aprendizado de Máquina , Qualidade de Vida , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/diagnóstico , Doenças Retinianas/patologia , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Transtornos da Visão/induzido quimicamente
17.
Front Oncol ; 12: 869752, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463381

RESUMO

Background: Childhood cancer represents a leading cause of death and disease burden in high income countries (HICs) and low-and-middle income countries (LMICs). It is postulated that the current COVID-19 pandemic has hampered global development of pediatric oncology care programs. This systematic review aimed to comprehensively review the global impact of COVID-19 on childhood cancer clinical outcomes and care delivery. Methods: A systematic search was conducted on PubMed, Embase, Medline, and the African Medical Index from inception to November 3, 2021 following PRISMA guidelines. A manual search was performed to identify additional relevant studies. Articles were selected based on predetermined eligibility criteria. Findings: The majority of studies reported patients with cancer and COVID-19 presenting as asymptomatic (HICs: 33.7%, LMICs: 22.0%) or with primary manifestations of fever (HICs: 36.1%, LMICs: 51.4%) and respiratory symptoms (HICs: 29.6%, LMICs: 11.7%). LMICs also reported a high frequency of patients presenting with cough (23.6%) and gastrointestinal symptoms (10.6%). The majority of patients were generally noted to have a good prognosis; however the crude mortality rate was higher in LMICs when compared to HICs (8.0% vs 1.8%). Moreover, the pandemic has resulted in delays and interruptions to cancer therapies and delays in childhood cancer diagnoses in both HICs and LMICs. However, these findings were disproportionately reported in LMICs, with significant staff shortages, supply chain disruptions, and limited access to cancer therapies for patients. Conclusions: The COVID-19 pandemic has resulted in delays and interruptions to childhood cancer therapies and delays in childhood cancer diagnoses, and disproportionately so within LMICs. This review provides lessons learned for future system-wide disruptions to care, as well as provides key points for moving forward better with care through the remainder of this pandemic. Systematic Review Registration: CRD42021266758, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=266758.

18.
Proc Natl Acad Sci U S A ; 119(7)2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35140183

RESUMO

Aminoacylated transfer RNAs, which harbor a covalent linkage between amino acids and RNA, are a universally conserved feature of life. Because they are essential substrates for ribosomal translation, aminoacylated oligonucleotides must have been present in the RNA world prior to the evolution of the ribosome. One possibility we are exploring is that the aminoacyl ester linkage served another function before being recruited for ribosomal protein synthesis. The nonenzymatic assembly of ribozymes from short RNA oligomers under realistic conditions remains a key challenge in demonstrating a plausible pathway from prebiotic chemistry to the RNA world. Here, we show that aminoacylated RNAs can undergo template-directed assembly into chimeric amino acid-RNA polymers that are active ribozymes. We demonstrate that such chimeric polymers can retain the enzymatic function of their all-RNA counterparts by generating chimeric hammerhead, RNA ligase, and aminoacyl transferase ribozymes. Amino acids with diverse side chains form linkages that are well tolerated within the RNA backbone and, in the case of an aminoacyl transferase, even in its catalytic center, potentially bringing novel functionalities to ribozyme catalysis. Our work suggests that aminoacylation chemistry may have played a role in primordial ribozyme assembly. Increasing the efficiency of this process provides an evolutionary rationale for the emergence of sequence and amino acid-specific aminoacyl-RNA synthetase ribozymes, which could then have generated the substrates for ribosomal protein synthesis.


Assuntos
RNA Catalítico/metabolismo , Aminoacilação de RNA de Transferência/fisiologia , Sequência de Bases , DNA , Conformação de Ácido Nucleico , RNA de Transferência/genética , RNA de Transferência/metabolismo
19.
Genes (Basel) ; 12(3)2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668843

RESUMO

Hemizygous pathogenic variants in CACNA1F lead to defective signal transmission from retinal photoreceptors to bipolar cells and cause incomplete congenital stationary night blindness in humans. Although the primary defect is at the terminal end of first-order neurons (photoreceptors), there is limited knowledge of higher-order neuronal changes (inner retinal) in this disorder. This study aimed to investigate inner retinal changes in CACNA1F-retinopathy by analyzing macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness and optic disc pallor in 22 subjects with molecularly confirmed CACNA1F-retinopathy. Detailed ocular phenotypic data including distance and color vision, refraction and electroretinogram (ERG) were collected. Distance vision was universally reduced (mean: 0.42 LogMAR), six had abnormal color vision and myopia was common (n = 15; mean: -6.32 diopters). Mean GCL-IPL thickness was significantly lower in patients (55.00 µm) compared to age-matched controls (n = 87; 84.57 µm; p << 0.001). The GCL-IPL thickness correlated with scotopic standard (p = 0.04) and bright-flash (p = 0.014) ERG b/a ratios and photopic b-wave amplitudes (p = 0.05). Twenty-one patients had some degree of disc pallor (bilateral in 19). Fifteen putative disease-causing, including five novel variants were identified. This study establishes macular inner retinal thinning and optic atrophy as characteristic features of CACNA1F-retinopathy, which are independent of myopia and could impact potential future treatment strategies.


Assuntos
Oftalmopatias Hereditárias/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Miopia/diagnóstico por imagem , Cegueira Noturna/diagnóstico por imagem , Atrofia Óptica/patologia , Retina/patologia , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Idoso , Criança , Eletrorretinografia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miopia/genética , Miopia/patologia , Cegueira Noturna/genética , Cegueira Noturna/patologia , Atrofia Óptica/diagnóstico por imagem , Refração Ocular , Retina/diagnóstico por imagem , Estudos Retrospectivos , Adulto Jovem
20.
Biochemistry ; 60(6): 477-488, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33523633

RESUMO

Aminoacylated tRNAs are the substrates for ribosomal protein synthesis in all branches of life, implying an ancient origin for aminoacylation chemistry. In the 1970s, Orgel and colleagues reported potentially prebiotic routes to aminoacylated nucleotides and their RNA-templated condensation to form amino acid-bridged dinucleotides. However, it is unclear whether such reactions would have aided or impeded non-enzymatic RNA replication. Determining whether aminoacylated RNAs could have been advantageous in evolution prior to the emergence of protein synthesis remains a key challenge. We therefore tested the ability of aminoacylated RNA to participate in both templated primer extension and ligation reactions. We find that at low magnesium concentrations that favor fatty acid-based protocells, these reactions proceed orders of magnitude more rapidly than when initiated from the cis-diol of unmodified RNA. We further demonstrate that amino acid-bridged RNAs can act as templates in a subsequent round of copying. Our results suggest that aminoacylation facilitated non-enzymatic RNA replication, thus outlining a potentially primordial functional link between aminoacylation chemistry and RNA replication.


Assuntos
Aminoacilação de RNA de Transferência/fisiologia , Aminoacilação/fisiologia , Fosfatos de Dinucleosídeos/metabolismo , Conformação de Ácido Nucleico , Nucleotídeos/metabolismo , RNA/metabolismo , Moldes Genéticos , Aminoacilação de RNA de Transferência/genética
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