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1.
Soc Work Health Care ; : 1-18, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38899560

RESUMEN

Older adults often experience different forms of discrimination, whether it be on the basis of their age, gender, race, or ethnicity (Rochon et al. 2021). Many older adults have stated they have experienced the health care system differently because of their race or ethnicity . Understanding older adults' experiences and their perceptions of ageism and racism can guide future work. This observational cross-sectional study captured community-dwelling older adults' perceptions about their experiences with ageism and racism. A few opened-ended questions were included in the cross-sectional survey. While results did not yield differences with respect to perceptions of ageism by race; there were statistically significant results in regard to perceived racism, with higher scores on the racism scales for individuals who self-identified as Black. Discussion and implications for practice, policy and research are explored.

2.
Nat Commun ; 15(1): 5226, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38890291

RESUMEN

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.


Asunto(s)
Asma , Proteínas del Helminto , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Nematospiroides dubius , Animales , Interleucina-33/metabolismo , Interleucina-33/química , Nematospiroides dubius/inmunología , Proteínas del Helminto/metabolismo , Proteínas del Helminto/química , Proteínas del Helminto/inmunología , Ratones , Femenino , Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Asma/inmunología , Asma/metabolismo , Humanos , Transducción de Señal , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Infecciones por Strongylida/metabolismo , Unión Proteica , Modelos Animales de Enfermedad , Sitios de Unión , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
3.
Am J Hum Genet ; 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38843839

RESUMEN

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

4.
JAMA Netw Open ; 7(6): e2415331, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38842804

RESUMEN

Importance: Because unprofessional behaviors are associated with patient complications, malpractice claims, and well-being concerns, monitoring concerns requiring investigation and individuals identified in multiple reports may provide important opportunities for health care leaders to support all team members. Objective: To examine the distribution of physicians by specialty who demonstrate unprofessional behaviors measured through safety reports submitted by coworkers. Design, Setting, and Participants: This retrospective cohort study was conducted among physicians who practiced at the 193 hospitals in the Coworker Concern Observation Reporting System (CORS), administered by the Vanderbilt Center for Patient and Professional Advocacy. Data were collected from January 2018 to December 2022. Exposure: Submitted reports concerning communication, professional responsibility, medical care, and professional integrity. Main Outcomes and Measures: Physicians' total number and categories of CORS reports. The proportion of physicians in each specialty (nonsurgeon nonproceduralists, emergency medicine physicians, nonsurgeon proceduralists, and surgeons) who received at least 1 report and who qualified for intervention were calculated; logistic regression was used to calculate the odds of any CORS report. Results: The cohort included 35 120 physicians: 18 288 (52.1%) nonsurgeon nonproceduralists, 1876 (5.3%) emergency medicine physicians, 6743 (19.2%) nonsurgeon proceduralists, and 8213 (23.4%) surgeons. There were 3179 physicians (9.1%) with at least 1 CORS report. Nonsurgeon nonproceduralists had the lowest percentage of physicians with at least 1 report (1032 [5.6%]), followed by emergency medicine (204 [10.9%]), nonsurgeon proceduralists (809 [12.0%]), and surgeons (1134 [13.8%]). Nonsurgeon nonproceduralists were less likely to be named in a CORS report than other specialties (5.6% vs 12.8% for other specialties combined; difference in percentages, -7.1 percentage points; 95% CI, -7.7 to -6.5 percentage points; P < .001). Pediatric-focused nonsurgeon nonproceduralists (2897 physicians) were significantly less likely to be associated with a CORS report than nonpediatric nonsurgeon nonproceduralists (15 391 physicians) (105 [3.6%] vs 927 [6.0%]; difference in percentages, -2.4 percentage points, 95% CI, -3.2 to -1.6 percentage points; P < .001). Pediatric-focused emergency medicine physicians, nonsurgeon proceduralists, and surgeons had no significant differences in reporting compared with nonpediatric-focused physicians. Conclusions and Relevance: In this cohort study, less than 10% of physicians ever received a coworker report with a concern about unprofessional behavior. Monitoring reports of unprofessional behaviors provides important opportunities for health care organizations to identify and intervene as needed to support team members.


Asunto(s)
Médicos , Humanos , Estudios Retrospectivos , Femenino , Masculino , Médicos/psicología , Médicos/estadística & datos numéricos , Mala Conducta Profesional/estadística & datos numéricos , Adulto , Persona de Mediana Edad , Medicina/estadística & datos numéricos
5.
Mol Ecol ; : e17435, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38877757

RESUMEN

Linking reproductive fitness with adaptive traits at the genomic level can shed light on the mechanisms that produce and maintain sex-specific selection. Here, we construct a multigenerational pedigree to investigate sex-specific selection on a maturation gene, vgll3, in a wild Atlantic salmon population. The vgll3 locus is responsible for ~40% of the variation in maturation (sea age at first reproduction). Genetic parentage analysis was conducted on 18,265 juveniles (parr) and 685 adults collected at the same spawning ground over eight consecutive years. A high proportion of females (26%) were iteroparous and reproduced two to four times in their lifetime. A smaller proportion of males (9%) spawned at least twice in their lifetime. Sex-specific patterns of reproductive fitness were related to vgll3 genotype. Females showed a pattern of overdominance where vgll3*EL genotypes had three-fold more total offspring than homozygous females. In contrast, males demonstrated that late-maturing vgll3*LL individuals had two-fold more offspring than either vgll3*EE or vgll3*EL males. Taken together, these data suggest that balancing selection in females contributes to the maintenance of variation at this locus via increased fitness of iteroparous vgll3*EL females. This study demonstrates the utility of multigenerational pedigrees for uncovering complex patterns of reproduction, sex-specific selection and the maintenance of genetic variation.

6.
Pediatr Blood Cancer ; : e30997, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38864147

RESUMEN

BACKGROUND: Sociodemographic and clinical factors associated with diagnostic delays in pediatric, adolescent, and young adult cancers are poorly understood. METHODS: Using the Optum Labs Data Warehouse's de-identified claims data for commercial health plan enrollees, we identified children (0-14 years) and adolescents/young adults (AYAs) (15-39 years) diagnosed with one of 10 common cancers from 2001 to 2017, who were continuously enrolled for 6 months preceding diagnosis. Time to diagnosis was calculated as days between first medical encounter with possible cancer symptoms and cancer diagnosis date. Median times from first symptom to diagnosis were compared using Wilcoxon rank sum test. Multivariable unconditional logistic regression identified sociodemographic factors associated with longer time (>3 months) to cancer diagnosis (from symptom onset). RESULTS: Of 47,296 patients, 87% presented prior to diagnosis with symptoms. Patients with central nervous system (CNS) tumors were most likely to present with symptoms (93%), whereas patients with cervical cancer were least likely (70%). Symptoms varied by malignancy. Of patients with symptoms, thyroid (105 days [range: 50-154]) and cervical (104 days [range: 41-151]) cancer had the longest median time to diagnosis. Females and patients at either end of the age spectrum were more likely to experience diagnosis delays of more than 3 months. CONCLUSION: In a commercially insured population, time to diagnosis varies by cancer type, age, and sex. Further work is needed to understand the patient, provider, and health system-level factors contributing to time from symptom onset to diagnosis, specifically in the very young children and the young adult patient population going forward.

7.
Ann Surg Oncol ; 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38896228

RESUMEN

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

8.
Res Pract Thromb Haemost ; 8(4): 102433, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38882464

RESUMEN

Background: Hospital-acquired venous thromboembolism (HA-VTE) is a leading cause of morbidity and mortality among hospitalized adults. Guidelines recommend use of a risk-prediction model to estimate HA-VTE risk for individual patients. Extant models do not perform well for broad patient populations and are not conducive to automation in clinical practice. Objectives: To develop an automated, real-time prognostic model for venous thromboembolism during hospitalization among all adult inpatients using readily available data from the electronic health record. Methods: The derivation cohort included inpatient hospitalizations ("encounters") for patients ≥16 years old at Vanderbilt University Medical Center between 2018 and 2020 (n = 132,330). HA-VTE events were identified using International Classification of Diseases, 10th Revision, codes. The prognostic model was developed using least absolute shrinkage and selection operator regression. Temporal external validation was performed in a validation cohort of encounters between 2021 and 2022 (n = 62,546). Prediction performance was assessed by discrimination accuracy (C statistic) and calibration (integrated calibration index). Results: There were 1187 HA-VTEs in the derivation cohort (9.0 per 1000 encounters) and 864 in the validation cohort (13.8 per 1000 encounters). The prognostic model included 25 variables, with placement of a central line among the most important predictors. Prediction performance of the model was excellent (C statistic, 0.891; 95% CI, 0.882-0.900; integrated calibration index, 0.001). The model performed similarly well across subgroups of patients defined by age, sex, race, and type of admission. Conclusion: This fully automated prognostic model uses readily available data from the electronic health record, exhibits superior prediction performance compared with existing models, and generates granular risk stratification in the form of a predicted probability of HA-VTE for each patient.

9.
Artículo en Inglés | MEDLINE | ID: mdl-38875451

RESUMEN

PURPOSE: Surgical site infection (SSI) is the leading cause of nosocomial infections among surgical patients in the United States. Currently, there is compelling evidence suggesting that temperature dysregulation in surgical patients may be a risk factor for the development of SSI. We examined the relationship between perioperative hypothermia (PH) and SSI in a population of surgical patients with diabetes mellitus (DM). METHODS: This retrospective cohort review was conducted on patients with a history of DM undergoing orthopaedic surgery at our institution between May 1, 2018, and April 1, 2022. Inclusion criteria were age older than 15 years, a history of DM or recent hemoglobin A1c concentration of ≥6.5%, and operation of at least 60 minutes under general anesthesia. Perioperative hypothermia was defined as an intraoperative temperature ≤ 35.5°C. Continuous variables were compared using the t-test and Wilcoxon rank-sum test. Categorical variables were compared using the chi-squared test. We constructed a multivariable logistic regression model to estimate SSI risk while controlling for demographic variables. RESULTS: A total of 236 patients were included in the final analysis. The overall incidence of SSI was 5.93%. 99 patients (42%) experienced PH. No difference was observed in the risk of SSI between the normothermic and hypothermic cohorts. Among the 99 patients who experienced PH, increasing HbA1c was associated with increasing risk of SSI (OR = 2.39, 95% CI = 1.12 to 5.32, P-value = 0.0222). The multivariable logistic regression model had good discriminatory ability (c-statistic 0.74, 95% CI: 0.61 to 0.89) and good predictive accuracy (sensitivity 64%, specificity 73%). DISCUSSION: PH is not an independent risk factor of SSI. However, in the presence of elevated HbA1c, PH may more than double the risk of SSI. Perioperative hypothermia may be an additive risk factor in the setting of poor glycemic control and potentially in the setting of other known risk factors.


Asunto(s)
Hipotermia , Infección de la Herida Quirúrgica , Humanos , Estudios Retrospectivos , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/prevención & control , Masculino , Femenino , Persona de Mediana Edad , Hipotermia/prevención & control , Factores de Riesgo , Anciano , Procedimientos Ortopédicos , Temperatura Corporal , Adulto , Diabetes Mellitus/epidemiología , Hemoglobina Glucada , Incidencia
10.
Science ; 384(6697): eadj8321, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38753769

RESUMEN

Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos ampliamente neutralizantes , Regiones Determinantes de Complementariedad , Centro Germinal , Anticuerpos Anti-VIH , Animales , Humanos , Vacunas contra el SIDA/inmunología , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Regiones Determinantes de Complementariedad/inmunología , Microscopía por Crioelectrón , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Centro Germinal/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Macaca mulatta , Células B de Memoria/inmunología
11.
Hum Genet ; 143(6): 761-773, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38787418

RESUMEN

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.


Asunto(s)
Metilación de ADN , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Masculino , Femenino , Haploinsuficiencia/genética , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Niño
12.
Obstet Gynecol ; 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38723260

RESUMEN

OBJECTIVE: To develop and validate a predictive model for postpartum hemorrhage that can be deployed in clinical care using automated, real-time electronic health record (EHR) data and to compare performance of the model with a nationally published risk prediction tool. METHODS: A multivariable logistic regression model was developed from retrospective EHR data from 21,108 patients delivering at a quaternary medical center between January 1, 2018, and April 30, 2022. Deliveries were divided into derivation and validation sets based on an 80/20 split by date of delivery. Postpartum hemorrhage was defined as blood loss of 1,000 mL or more in addition to postpartum transfusion of 1 or more units of packed red blood cells. Model performance was evaluated by the area under the receiver operating characteristic curve (AUC) and was compared with a postpartum hemorrhage risk assessment tool published by the CMQCC (California Maternal Quality Care Collaborative). The model was then programmed into the EHR and again validated with prospectively collected data from 928 patients between November 7, 2023, and January 31, 2024. RESULTS: Postpartum hemorrhage occurred in 235 of 16,862 patients (1.4%) in the derivation cohort. The predictive model included 21 risk factors and demonstrated an AUC of 0.81 (95% CI, 0.79-0.84) and calibration slope of 1.0 (Brier score 0.013). During external temporal validation, the model maintained discrimination (AUC 0.80, 95% CI, 0.72-0.84) and calibration (calibration slope 0.95, Brier score 0.014). This was superior to the CMQCC tool (AUC 0.69 [95% CI, 0.67-0.70], P<.001). The model maintained performance in prospective, automated data collected with the predictive model in real time (AUC 0.82 [95% CI, 0.73-0.91]). CONCLUSION: We created and temporally validated a postpartum hemorrhage prediction model, demonstrated its superior performance over a commonly used risk prediction tool, successfully coded the model into the EHR, and prospectively validated the model using risk factor data collected in real time. Future work should evaluate external generalizability and effects on patient outcomes; to facilitate this work, we have included the model coefficients and examples of EHR integration in the article.

13.
Artículo en Inglés | MEDLINE | ID: mdl-38717600

RESUMEN

A number of factors may impinge on thermal homeostasis in the early embryo. The most obvious is the ambient temperature in which development occurs. Physiologically, the temperature in the lumen of the female tract is typically lower than the core body temperature, yet rises at ovulation in the human, while in an IVF setting, embryos are usually maintained at core body temperature. However, internal cellular developmental processes may modulate thermal control within the embryo itself, especially those occurring in the mitochondria which generate intracellular heat through proton leak and provide the embryo with its own 'central heating system'. Moreover, mitochondrial movements may serve to buffer high local intracellular temperatures. It is also notable that the preimplantation stages of development would generate proportionally little heat within their mitochondria until the blastocyst stage as mitochondrial metabolism is comparatively low during the cleavage stages. Despite these data, the specific notion of thermal control of preimplantation development has received remarkably scant consideration. This opinion paper illustrates the lack of reliable quantitative data on these markers and identifies a major research agenda which needs to be addressed with urgency in view of laboratory conditions in which embryos are maintained as well as climate change-derived heat stress which has a negative effect on numerous clinical markers of early human embryo development.

14.
bioRxiv ; 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38798415

RESUMEN

Capsaspora owczarzaki is a protozoan that may both reveal aspects of animal evolution and also curtail the spread of schistosomiasis, a neglected tropical disease. Capsaspora exhibits a chemically regulated aggregative behavior that resembles cellular aggregation in some animals. This behavior may have played a key role in the evolution of animal multicellularity. Additionally, this aggregative behavior may be important for Capsaspora 's ability to colonize the intermediate host of parasitic schistosomes and potentially prevent the spread of schistosomiasis. Both applications demand elucidation of the molecular mechanism of Capsaspora aggregation. Toward this goal, we first determined the necessary chemical properties of lipid cues that activate aggregation. We found that a wide range of abundant zwitterionic lipids induced aggregation, revealing that the aggregative behavior could be activated by diverse lipid-rich conditions. Furthermore, we demonstrated that aggregation in Capsaspora requires clathrin-mediated endocytosis, highlighting the potential significance of endocytosis-linked cellular signaling in recent animal ancestors. Finally, we found that aggregation was initiated by post-translational activation of cell-cell adhesion-not transcriptional regulation of cellular adhesion machinery. Our findings illuminate the chemical, molecular and cellular mechanisms that regulate Capsaspora aggregative behavior-with implications for the evolution of animal multicellularity and the transmission of parasites.

15.
Hum Mol Genet ; 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38776957

RESUMEN

Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.

16.
Science ; 384(6698): 846-848, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38781382

RESUMEN

Eliminating defects at interfaces enables perovskites to approach efficiency limits.

17.
Neurology ; 102(12): e209482, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38781559

RESUMEN

The role of immunosenescence, particularly the natural process of thymic involution during aging, is increasingly acknowledged as a factor contributing to the development of autoimmune diseases and cancer. Recently, a concern has been raised about deleterious consequences of the surgical removal of thymic tissue, including for patients who undergo thymectomy for myasthenia gravis (MG) or resection of a thymoma. This review adopts a multidisciplinary approach to scrutinize the evidence concerning the long-term risks of cancer and autoimmunity postthymectomy. We conclude that for patients with acetylcholine receptor antibody-positive MG and those diagnosed with thymoma, the removal of the thymus offers prominent benefits that well outweigh the potential risks. However, incidental removal of thymic tissue during other thoracic surgeries should be minimized whenever feasible.


Asunto(s)
Miastenia Gravis , Timectomía , Timoma , Timo , Neoplasias del Timo , Humanos , Timectomía/efectos adversos , Timectomía/métodos , Miastenia Gravis/cirugía , Timo/cirugía , Neoplasias del Timo/cirugía , Neoplasias del Timo/complicaciones , Timoma/cirugía , Timoma/complicaciones , Complicaciones Posoperatorias/etiología , Enfermedades Autoinmunes/cirugía
18.
RSC Adv ; 14(22): 15554-15559, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38741965

RESUMEN

Friedel-Crafts benzylation/alkylation using benzylic, tertiary, and homobenzylic alcohols; aryl aldehydes, aryl ketones, and the highly challenging aryl carboxylic acids and esters as proelectrophiles has been achieved using borane-ammonia and TiCl4, greatly broadening the scope of useable substrates. Incorporation of deactivated aromatic proelectrophiles and specificity for substitution at the benzylic position are demonstrated in the synthesis of various di- and triarylalkane products. Dual protocols allow for the use of standard nucleophilic solvents (benzene, toluene, etc.) or for stoichiometric addition of more valuable nucleophiles including furans, thiophenes, and benzodioxoles.

19.
Science ; 384(6697): 767-775, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38753792

RESUMEN

The efficiency and longevity of metal-halide perovskite solar cells are typically dictated by nonradiative defect-mediated charge recombination. In this work, we demonstrate a vapor-based amino-silane passivation that reduces photovoltage deficits to around 100 millivolts (>90% of the thermodynamic limit) in perovskite solar cells of bandgaps between 1.6 and 1.8 electron volts, which is crucial for tandem applications. A primary-, secondary-, or tertiary-amino-silane alone negatively or barely affected perovskite crystallinity and charge transport, but amino-silanes that incorporate primary and secondary amines yield up to a 60-fold increase in photoluminescence quantum yield and preserve long-range conduction. Amino-silane-treated devices retained 95% power conversion efficiency for more than 1500 hours under full-spectrum sunlight at 85°C and open-circuit conditions in ambient air with a relative humidity of 50 to 60%.

20.
Cureus ; 16(4): e58342, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38756315

RESUMEN

A 72-year-old woman with a prior sigmoid resection for colon cancer underwent a right hemicolectomy after a colonoscopy revealed a mass in the hepatic flexure. A preoperative biopsy at colonoscopy showed tubulovillous dysplasia with high-grade neoplasm. The final specimen pathology revealed benign mucosal elements with mucin pools consistent with colitis cystica profunda (CCP). CCP is a benign lesion; no further treatment was necessary after resection. To our knowledge, this is the first reported case of CCP in the right colon, presenting atypically in the hepatic flexure. This case report brings to light the difficulty and importance of making an accurate diagnosis of CCP.

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