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1.
Int Psychogeriatr ; : 1-6, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34763741

RESUMO

OBJECTIVES: We examined whether preadmission history of depression is associated with less delirium/coma-free (DCF) days, worse 1-year depression severity and cognitive impairment. DESIGN AND MEASUREMENTS: A health proxy reported history of depression. Separate models examined the effect of preadmission history of depression on: (a) intensive care unit (ICU) course, measured as DCF days; (b) depression symptom severity at 3 and 12 months, measured by the Beck Depression Inventory-II (BDI-II); and (c) cognitive performance at 3 and 12 months, measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) global score. SETTING AND PARTICIPANTS: Patients admitted to the medical/surgical ICU services were eligible. RESULTS: Of 821 subjects eligible at enrollment, 261 (33%) had preadmission history of depression. After adjusting for covariates, preadmission history of depression was not associated with less DCF days (OR 0.78, 95% CI, 0.59-1.03 p = 0.077). A prior history of depression was associated with higher BDI-II scores at 3 and 12 months (3 months OR 2.15, 95% CI, 1.42-3.24 p = <0.001; 12 months OR 1.89, 95% CI, 1.24-2.87 p = 0.003). We did not observe an association between preadmission history of depression and cognitive performance at either 3 or 12 months (3 months beta coefficient -0.04, 95% CI, -2.70-2.62 p = 0.97; 12 months 1.5, 95% CI, -1.26-4.26 p = 0.28). CONCLUSION: Patients with a depression history prior to ICU stay exhibit a greater severity of depressive symptoms in the year after hospitalization.

2.
Am J Infect Control ; 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34742749

RESUMO

BACKGROUND: Healthcare-associated infections (HAIs) are a persistent clinical challenge caused primarily by bacteria on the skin. Proper utilization of optimized antiseptic skin preparation solutions helps reduce the prevalence and impact of HAIs by decreasing patient skin microorganisms preoperatively. The purpose of this study was to evaluate the efficacy of two antimicrobial solutions containing iodine and isopropyl alcohol (IPA): Povidone iodine (PVP-I) with IPA (i.e., PVP-I+IPA, PurPrep™) and Iodine Povacrylex+IPA (DuraPrep™). METHODS: The antimicrobial activity of the test solutions was evaluated in vitro by determinations of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against 1105 diverse microbial isolates and a time-kill assay to evaluate efficacy against 120 strains of Gram-positive and Gram-negative bacteria and yeasts. Peel tests were performed between skin samples treated with test solutions and representative drape/dressing materials to determine effects of test solutions on the biomechanical adhesion properties. Finally, an Institutional Review Board (IRB)-approved, randomized, controlled, single-center, partially blinded in vivo study was performed to assess the immediate and persistent antimicrobial activity of the test solutions on the abdomen and groin. RESULTS: Both PVP-I+IPA and Iodine Povacrylex+IPA solutions demonstrated broad-spectrum antimicrobial activity with MIC and MBC at less than 1% of the full-strength concentration of each product against a wide variety of microorganisms. In the time-kill tests, both solutions were able to successfully reduce all microbial populations by 99.99% (i.e., 4log10) at the contact times of 30 seconds, 2 minutes and 10 minutes. The two solutions showed relatively similar adhesion results when tested with three representative operating room materials. Both PVP-I+IPA and Iodine Povacrylex+IPA met the expected Food and Drug Administration (FDA) efficacy requirements at 10 minutes and 6 hours post-treatment for both anatomical sites (i.e., groin and abdomen) in the clinical study, with no safety issues or adverse events. CONCLUSIONS: Analysis of the in vitro antimicrobial activity, biomechanical adhesive strength, and in vivo efficacy of PVP-I+IPA demonstrated similar results compared to Iodine Povacrylex+IPA. Both products were efficacious at reducing or eliminating a wide range of clinically-relevant microorganisms in lab-based and clinical settings, supporting their use as antiseptic skin preparation solutions to reduce bacteria on the skin that can cause infection.

3.
J Psychosom Res ; 152: 110666, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34768029

RESUMO

OBJECTIVE: Apathy is prevalent in HIV disease and can significantly impact personal well-being; however, little is known about its neurobiological substrates in persons with HIV (PWH) disease. METHODS: This cross-sectional, correlational study examined the association between apathy and several plasma biomarkers (tumor necrosis factor alpha, kynurenine, tryptophan, quinolinic acid, brain-derived neurotrophic factor, glial fibrillary acidic protein, neurofilament light chain, and phosphorylated tau at position threonine 181) in 109 PWH and 30 seronegative participants ages 50 and older. Apathy was measured with a composite score derived from subscales of the Frontal Systems Behavior Scale and the Profile of Mood States. RESULTS: Multiple regressions showed that PWH had significantly greater severity of apathy symptoms, independent of both data-driven and conceptually-based covariates. Pairwise correlations in the PWH sample indicated that apathy was not significantly associated with any of the measured biomarkers and all of the effect sizes were small. CONCLUSION: Findings suggest that apathy is not strongly associated with peripheral biomarkers of inflammation, neurotrophic support, or neurodegeneration in older PWH. Limitations of this study include the cross-sectional design, the use of self-report measures of apathy, and low rates of viremia. Longitudinal studies in more representative samples of PWH that include a more comprehensive panel of fluid biomarkers, informant and behavioral indicators of apathy, and relevant psychosocial factors might help to further clarify the neurobiological substrates of this complex neuropsychiatric phenomenon.

4.
Neurol Clin ; 39(4): 1035-1049, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34602213

RESUMO

Electrodiagnostic testing is a useful tool in the evaluation of suspected myopathy and helps to confirm the presence of a myopathy and exclude disease mimickers. The electrodiagnostic pattern of findings during testing guides subsequent laboratory evaluation, genetic testing, and in identifying potential muscle biopsy targets. It also provides a baseline for subsequent assessment of disease progression or response to therapy. This article summarizes the approach to electrodiagnostic assessment in various myopathic disorders.


Assuntos
Doenças Musculares , Biópsia , Progressão da Doença , Eletromiografia , Testes Genéticos , Humanos , Doenças Musculares/diagnóstico
5.
Genes (Basel) ; 12(10)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34680937

RESUMO

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

6.
Antimicrob Agents Chemother ; : AAC0139721, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34633850

RESUMO

KBP-7072 is a novel third generation tetracycline (aminomethylcycline) antibacterial in clinical development (oral and intravenous formulations) for the treatment of acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, and complicated intra-abdominal infections. KBP-7072 is active against many of the World Health Organization-priority pathogens. In this study, KBP-7072 and tetracycline class comparators were susceptibility tested against 1,057 geographically diverse surveillance isolates from 2019 according to Clinical and Laboratory Standards Institute (CLSI) guidelines. KBP-7072 demonstrated potent in vitro activity against gram-positive and gram-negative bacterial pathogens. KBP-7072 was active against Staphylococcus aureus (MIC50/90, 0.06/0.12 mg/L), methicillin-resistant S. aureus (MIC50/90, 0.06/0.12 mg/L), S. lugdunensis (MIC50/90, 0.03/0.03 mg/L), and other coagulase-negative staphylococci (MIC50/90, 0.06/0.25 mg/L). KBP-7072 was active against Enterococcus faecalis (MIC50/90, 0.03/0.06 mg/L) and vancomycin-susceptible and -nonsusceptible E. faecium (MIC50/90, 0.03/0.03 mg/L); Streptococcus pneumoniae (MIC50/90, ≤0.015/0.03 mg/L), including penicillin- and tetracycline-resistant strains; S. agalactiae (MIC50/90, 0.03/0.06 mg/L), including macrolide-resistant strains; S. pyogenes (MIC50/90, 0.03/0.03 mg/L); and viridans group streptococci, including S. anginosus group (MIC50/90, ≤0.015/0.03 mg/L) isolates. KBP-7072 inhibited 90.2% (MIC50/90, 0.25/2 mg/L) of all Enterobacterales isolates, including ESBL-phenotype strains, at ≤2 mg/L. KBP-7072 demonstrated potent activity against Acinetobacter baumannii-calcoaceticus species complex and Stenotrophomonas maltophilia isolates (MIC50/90 values, 0.5/1 mg/L), Haemophilus influenzae (MIC50/90, 0.12/0.25 mg/L; 100.0% inhibited at ≤0.25 mg/L), and Moraxella catarrhalis (MIC50/90, 0.06/0.06 mg/L). Based on MIC90 values, KBP-7072 in vitro activity was generally superior to the other tetracycline class comparators tested. The potent activity of KBP-7072, including resistant organism groups, merits further clinical investigation in infections where these organisms are likely to occur.

7.
Neurology ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376509

RESUMO

OBJECTIVES: To longitudinally investigate patients with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, quantifying timing and location of sensory involvements in motor-onset patients, along with clinico-histopathological and electrophysiological findings to ascertain differences in patients with and without monoclonal gammopathy of uncertain significance (MGUS). METHODS: Patients with MADSAM neuropathy seen at Mayo Clinic and tested for monoclonal gammopathy and ganglioside antibodies, were retrospectively reviewed (January 1st, 2007-December 31st, 2018). RESULTS: Of 76 patients with MADSAM, 53% had pure motor, 16% pure sensory, 30% sensorimotor and 1% cranial nerve onsets. Motor-onset patients were initially diagnosed as multifocal motor neuropathy (MMN). MGUS occurred in 25% (89% IgM subtype), associating with ganglioside autoantibodies (p<0.001) and higher IgM titers (p<0.04). Median time to sensory involvements (confirmed by electrophysiology) in motor-onset patients was 18 months (range: 6-180). Compared to initial motor nerve involvements, subsequent sensory findings were within the same territory 35% (14/40), outside 20% (8/40), or both 45% (18/40). Brachial and lumbosacral plexus MRI was abnormal in 87% (34/39) and 84% (21/25), respectively, identifying hypertrophy and increased T2 signal predominantly in brachial plexus trunks (64%), divisions (69%), and cords (69%), and intrapelvic sciatic (64%) and femoral (44%) nerves. Proximal fascicular nerve biopsies (n=9) more frequently demonstrated onion-bulb pathology (p=0.001) and endoneurial inflammation (p=0.01) than distal biopsies (n=17). MRI and biopsy findings were similar amongst patient subgroups. Initial Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores were higher in patients with MGUS relative to without (p=0.02). Long-term treatment responsiveness by INCAT score reduction ≥1 or motor Neuropathy Impairment Score (mNIS) >8 point reduction occurred in 75% (49/65) irrespective of MGUS or motor-onsets. Most required ongoing immunotherapy (86%). Patients with MGUS more commonly required dual-agent immunotherapy for stability (p=0.02). DISCUSSION: Pure motor-onsets are the most common MADSAM presentation. Long-term follow-up, repeat electrophysiology and nerve pathology help distinguish motor-onset MADSAM from MMN. Better long-term immunotherapy responsiveness occurs in motor-onset MADSAM compared to MMN reports. Patients having MGUS commonly require dual immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that most clinical, electrophysiological, and histopathological findings were similar between patients with MADSAM with and without monoclonal gammopathy of unknown significance.

8.
Pediatr Emerg Care ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34417790

RESUMO

OBJECTIVES: The Infectious Diseases Society of America (IDSA) guidelines regarding group A streptococcal (GAS) pharyngitis advise against routine testing for patients younger than 3 years, patients without pharyngitis, and patients with symptoms suggesting a viral infection. Group A streptococcal testing may be overused in some clinical settings; thus, we conducted this study to evaluate compliance with the IDSA guidelines in a pediatric emergency department (ED) setting. METHODS: This retrospective cohort study describes patients younger than 18 years presenting to 2 urban pediatric EDs in 2016 who underwent rapid antigen detection testing for GAS pharyngitis. Testing was classified as noncompliant with the IDSA guidelines if the chief complaint was not indicative of GAS infection and/or the patient age was younger than 3 years. Appropriate nonparametric tests compared groups by IDSA testing compliance status. RESULTS: A total of 13,585 patient encounters met inclusion criteria; 5255 (39%) were noncompliant with the IDSA testing guidelines, the majority due to a chief complaint inconsistent with GAS pharyngitis (67%) and secondarily due to the age of younger than 3 years (48%). Among the patients with noncompliant testing, 51% were prescribed an antibiotic, and return encounters were more likely to occur (13% vs 10%, P < 0.001). Return encounters more commonly resulted in respiratory diagnoses in those with noncompliant GAS testing (60% vs 45%, P < 0.001). CONCLUSIONS: Nearly 40% of all pediatric ED encounters with GAS testing were noncompliant with the IDSA guidelines and were associated with greater return encounter rates. Potential negative outcomes from noncompliant GAS testing include misdiagnosis, inappropriate use of antibiotics, allergic reactions, and loss of school days. Informed interventions to reduce unnecessary GAS testing are warranted.

9.
JAMA Netw Open ; 4(8): e2121429, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34410396

RESUMO

Importance: Prenatal experiences can influence fetal brain development. Objective: To examine associations of maternal prenatal body mass index (BMI) with cognition and behavior of offspring born full-term. Design, Setting, and Participants: This cohort study examined follow-up data from a breastfeeding promotion intervention at 31 hospitals and affiliated polyclinics in the Republic of Belarus. Participants included 11 276 children who were evaluated from birth (1996-1997) to adolescence (2017-2019), with maternal BMI information available in prenatal medical records. Exposures: Maternal BMI, calculated as weight in kilograms divided by height in meters squared, after 35 weeks gestation; secondary analyses examined maternal BMI at other time points and paternal BMI. Main Outcomes and Measures: Trained pediatricians assessed child cognition with the Wechsler Abbreviated Scales of Intelligence (WASI) at 6.5 years and the computerized self-administered NeuroTrax battery at 16 years, both with an approximate mean (SD) of 100 (15). Parents and teachers rated behaviors at 6.5 years using the Strengths and Difficulties Questionnaire (SDQ, range 0-40). Mixed-effects linear regression analyses corrected for clustering, adjusted for the randomized intervention group and baseline parental sociodemographic characteristics, and were considered mediation by child BMI. Results: Among 11 276 participants, 9355 women (83%) were aged 20 to 34 years, 10 128 (89.8%) were married, and 11 050 (98.0%) did not smoke during pregnancy. Each 5-unit increase in of maternal late-pregnancy BMI (mean [SD], 27.2 [3.8]) was associated with lower offspring WASI performance intelligence quotient (IQ) (-0.52 points; 95% CI, -0.87 to -0.17 points) at 6.5 years and lower scores on 5 of 7 NeuroTrax subscales and the global cognitive score at 16 years (-0.67 points; 95% CI, -1.06 to -0.29 points). Results were similar after adjustment for sociodemographic characteristics, pregnancy complications, and paternal BMI and were not mediated by child weight. Higher late pregnancy maternal BMI was also associated with more behavioral problems reported on the SDQ by teachers but not associated with parent-reported behaviors (externalizing behaviors: 0.13 points; 95% CI, 0.02 to 0.24 points; and total difficulties: 0.14 points, 95% CI, -0.02 to 0.30 points). Results were similar for maternal BMI measured in the first trimester or postpartum. In contrast, higher 6.5-year paternal BMI was associated with slightly better child cognition (WASI verbal IQ: 0.42 points; 95% CI, 0.02 to 0.82 points; NeuroTrax executive function score: 0.68 points; 95% CI, 0.24 to 1.12 points) and fewer teacher-reported behavioral problems (total difficulties: -0.29 points; 95% CI, -0.46 to -0.11 points). Conclusions and Relevance: This cohort study supports findings from animal experiments and human observational studies in settings with higher maternal BMI and obesity rates. Higher maternal prenatal BMI may be associated with poorer offspring brain development, although residual confounding cannot be excluded.

10.
Am J Physiol Endocrinol Metab ; 321(5): E581-E591, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34459218

RESUMO

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females (P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Hetdb dams (P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.


Assuntos
Adipogenia , Tecido Adiposo/metabolismo , Fatores de Risco Cardiometabólico , Doenças Metabólicas/metabolismo , Adipócitos/ultraestrutura , Tecido Adiposo/embriologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Tamanho Celular , Dieta Hiperlipídica , Feminino , Frutose/farmacologia , Hiperlipidemias/genética , Insulina/sangue , Lipidômica , Masculino , Doenças Metabólicas/patologia , Camundongos , Gravidez , Receptores para Leptina/genética , Células-Tronco , Triglicerídeos/sangue
11.
Clin Transl Gastroenterol ; 12(8): e00397, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34397043

RESUMO

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

12.
Clin Neuropsychol ; : 1-17, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34311657

RESUMO

OBJECTIVE: Health disparities are evident for Black Americans with HIV disease, who are disproportionally affected by the epidemic in the United States. The current study investigated whether the higher rates of neurocognitive impairment in Black Americans with HIV disease may be at least partly attributable to health literacy, which is a potentially modifiable factor. Method: Participants were 61 White and 25 Black participants (ages 27-70) with HIV disease who were enrolled in studies at an urban academic center in Southern California. Neurocognitive function was assessed by an age-adjusted global score from the Cogstate battery. Health literacy was measured by a composite score derived from the Rapid Estimate of Adult Literacy in Medicine, Newest Vital Sign, and 3-Brief. Results: Bootstrap confidence interval mediation analyses showed that health literacy was a significant mediator of the relationship between race and neurocognition; that is, there were no direct ethnoracial differences in neurocognition after accounting for health literacy. A follow-up model to confirm the directionality of this association demonstrated that neurocognition was not a significant mediator of the relationship between race and health literacy. Conclusions: Low health literacy may contribute to the higher rates of neurocognitive impairment for Black Americans with HIV disease. Future studies might examine the possible mechanism of this mediating relationship (e.g., access to health information, health behaviors, socioeconomics) and determine whether culturally tailored interventions that improve health literacy also confer broader brain health benefits for Black Americans with HIV disease.

14.
J Clin Epidemiol ; 138: 49-59, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34197941

RESUMO

OBJECTIVES: To describe the prevalence of risks of bias in cluster-randomized trials of individual-level interventions, according to the Cochrane Risk of Bias tool. STUDY DESIGN AND SETTING: Review undertaken in duplicate of a random sample of 40 primary reports of cluster-randomized trials of individual-level interventions. RESULTS: The most common reported reasons for adopting cluster randomization were the need to avoid contamination (17, 42.5%) and practical considerations (14, 35%). Of the 40 trials all but one was assessed as being at risk of bias. A majority (27, 67.5%) were assessed as at risk due to the timing of identification and recruitment of participants; many (21, 52.5%) due to an apparent lack of adequate allocation concealment; and many due to selectively reported results (22, 55%), arising from a mixture of reasons including lack of documentation of primary outcome. Other risks mostly occurred infrequently. CONCLUSION: Many cluster-randomized trials evaluating individual-level interventions appear to be at risk of bias, mostly due to identification and recruitment biases. We recommend that investigators carefully consider the need for cluster randomization; follow recommended procedures to mitigate risks of identification and recruitment bias; and adhere to good reporting practices including clear documentation of primary outcome and allocation concealment methods.

15.
Stem Cell Res ; 54: 102439, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34214897

RESUMO

Mutations in ABCA4 gene are causative for autosomal recessive Stargardt disease (STGD1), the most common inherited retinal dystrophy. Here, we report the generation of an induced pluripotent stem cell (iPSC) line from a STGD1 patient carrying biallelic c.[5461-10T>C;5603A>T];[6077T>C] mutations in the ABCA4 gene. Episomes carrying OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed for the reprogramming of patient-derived fibroblasts. This iPSC line expressed comparable pluripotency markers as in a commercially available human iPSC line, displayed normal karyotype and potential for trilineage differentiation, and were negative for both reprogramming episomes and mycoplasma test.


Assuntos
Células-Tronco Pluripotentes Induzidas , Transportadores de Cassetes de Ligação de ATP/genética , Diferenciação Celular , Humanos , Mutação , Doença de Stargardt
16.
Stem Cell Res ; 54: 102448, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34198153

RESUMO

Stargardt disease (STGD1) is the most common inherited retinal dystrophy and ABCA4 c.546--10 T>C is the most commonly reported splice mutation. Here, we generated and characterized two induced pluripotent stem cell (iPSC) lines from a STGD1 patient with compound heterozygous mutations in ABCA4 (c.[5461-10 T > C;5603A > T];[4163 T > C;455G > A]). Episomal vectors containing OCT4, SOX2, KLF4, L-MYC, LIN28 and mp53DD were employed to conduct the reprogramming of patient-derived fibroblasts. Both lines had a normal karyotype, displayed iPSC morphology, expressed pluripotency markers and showed trilineage differentiation potential. These lines can provide a powerful platform for further investigating the pathophysiological consequences of mutations in ABCA4.


Assuntos
Células-Tronco Pluripotentes Induzidas , Transportadores de Cassetes de Ligação de ATP/genética , Diferenciação Celular , Linhagem Celular , Humanos , Mutação , Doença de Stargardt
17.
Genes (Basel) ; 12(6)2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198599

RESUMO

PRPF31-associated retinopathy (RP11) is a common form of autosomal dominant retinitis pigmentosa (adRP) that exhibits wide variation in phenotype ranging from non-penetrance to early-onset RP. Herein, we report inter-familial and intra-familial variation in the natural history of RP11 using multimodal imaging and microperimetry. Patients were recruited prospectively. The age of symptom onset, best-corrected visual acuity, microperimetry mean sensitivity (MS), residual ellipsoid zone span and hyperautofluorescent ring area were recorded. Genotyping was performed using targeted next-generation and Sanger sequencing and copy number variant analysis. PRPF31 mutations were found in 14 individuals from seven unrelated families. Four disease patterns were observed: (A) childhood onset with rapid progression (N = 4), (B) adult-onset with rapid progression (N = 4), (C) adult-onset with slow progression (N = 4) and (D) non-penetrance (N = 2). Four different patterns were observed in a family harbouring c.267del; patterns B, C and D were observed in a family with c.772_773delins16 and patterns A, B and C were observed in 3 unrelated individuals with large deletions. Our findings suggest that the RP11 phenotype may be related to the wild-type PRPF31 allele rather than the type of mutation. Further studies that correlate in vitro wild-type PRPF31 allele expression level with the disease patterns are required to investigate this association.

18.
Neuropsychology ; 35(5): 461-471, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34292009

RESUMO

Objective: While HIV disease is associated with impairment in declarative memory, the ability of people with HIV (PWH) to describe past and future autobiographical events is not known. Method: Participants included 63 PWH and 28 seronegative individuals ages 50-78 who completed standardized neurocognitive and everyday functioning assessments. Participants described four events from the recent past and four imagined events in the near future, details from which were classified as internal or external to the main event. Result: PWH produced fewer autobiographical details with small-to-medium effect sizes but did not differ from seronegative participants in meta-cognitive ratings of their performance. Performance of the study groups did not vary across past or future probes or internal versus external details; however, within the entire sample, past events were described in greater detail than future events, and more external than internal details were produced. Within the PWH group, the production of fewer internal details for future events was moderately associated with poorer prospective memory, executive dysfunction, and errors on a laboratory-based task of medication management. Conclusion: Older PWH may experience difficulty generating autobiographical details from the past and simulated events in the future, which may be related to executive dyscontrol of memory processes. Future studies might examine the role of future thinking in health behaviors such as medication adherence and retention in healthcare among PWH. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Disfunção Cognitiva , Infecções por HIV , Memória Episódica , Idoso , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Imaginação , Transtornos da Memória/etiologia , Rememoração Mental , Pessoa de Meia-Idade
19.
Nat Commun ; 12(1): 3620, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131147

RESUMO

Host membrane remodeling is indispensable for viruses, bacteria, and parasites, to subvert the membrane barrier and obtain entry into cells. The malaria parasite Plasmodium spp. induces biophysical and molecular changes to the erythrocyte membrane through the ordered secretion of its apical organelles. To understand this process and address the debate regarding how the parasitophorous vacuole membrane (PVM) is formed, we developed an approach using lattice light-sheet microscopy, which enables the parasite interaction with the host cell membrane to be tracked and characterized during invasion. Our results show that the PVM is predominantly formed from the erythrocyte membrane, which undergoes biophysical changes as it is remodeled across all stages of invasion, from pre-invasion through to PVM sealing. This approach enables a functional interrogation of parasite-derived lipids and proteins in PVM biogenesis and echinocytosis during Plasmodium falciparum invasion and promises to yield mechanistic insights regarding how this is more generally orchestrated by other intracellular pathogens.


Assuntos
Membrana Eritrocítica/parasitologia , Eritrócitos/parasitologia , Tomografia Computadorizada Quadridimensional/métodos , Interações Hospedeiro-Parasita/fisiologia , Malária/parasitologia , Vacúolos/metabolismo , Animais , Membrana Eritrocítica/metabolismo , Humanos , Merozoítos , Parasitos , Plasmodium/metabolismo , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo
20.
J Clin Exp Neuropsychol ; 43(5): 497-513, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34142928

RESUMO

Introduction: The rapid development of coronavirus disease 2019 (COVID-19) into a pandemic required people to quickly acquire, evaluate, and apply novel complex health-related information about the virus and transmission risks. This study examined the potentially unique and synergistic roles of individual differences in neurocognition and health literacy in the early uptake and use of COVID-19 public health information.Method: Data were collected between April 23 and 21 May 2020, a period during which 42 out of 50 states were under a stay-at-home order. Participants were 217 healthy adults who completed a telephone-based battery that included standard tests of neurocognition, health literacy, verbal IQ, personality, and anxiety. Participants also completed measures of COVID-19 information-seeking skills, knowledge, prevention intentions, and prevention behaviors.Results: A series of hierarchical multiple regressions with data-driven covariates showed that neurocognition (viz, episodic verbal memory and executive functions) was independently related to COVID-19 knowledge (e.g. symptoms, risks) at a medium effect size, but not to information-seeking skills, prevention intentions, or prevention behaviors. Health literacy was independently related to all measured aspects of COVID-19 health information and did not interact with neurocognition in any COVID-19 health domain.Conclusions: Individual differences in neurocognition and health literacy played independent and meaningful roles in the initial acquisition of knowledge related to COVID-19, which is a novel human health condition. Future studies might examine whether neurocognitive supports (e.g. spaced retrieval practice, elaboration) can improve COVID-19-related knowledge and health behaviors in vulnerable populations.


Assuntos
COVID-19 , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Letramento em Saúde , Individualidade , Adolescente , Adulto , Idoso , COVID-19/epidemiologia , Estudos Transversais , Feminino , Saúde , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Adulto Jovem
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