CLINICAL OUTCOMES OF A TORIC CONTINUOUS RANGE OF VISION PRESBYOPIA-CORRECTING INTRAOCULAR LENS.

PURPOSE: To evaluate the clinical outcomes of the toric version of a presbyopia-correcting intraocular lens (IOL) based on the combination of a diffractive-based extended depth of focus (EDOF) pattern and a diffractive multifocal platform. SETTING: Miranza COI Bilbao, Spain. DESIGN: Prospective case series. METHODS: Thirty-five patients (51-84 years) with corneal astigmatism ranging from 0.75 to 2.19 D undergoing bilateral cataract surgery with implantation of the Synergy™ Toric II IOL (Johnson & Johnson Vision, Jacksonville, Florida, USA) were evaluated during a 3-month follow-up. Visual acuity, refraction, defocus curve, and patient-reported outcomes with the Catquest-9SF questionnaire were analyzed. A vectorial analysis was used to analyze the accuracy of astigmatic correction. RESULTS: Mean 3-month monocular postoperative uncorrected distance, intermediate (80 cm) and near (40 cm) visual acuities were 0.06±0.11, 0.13±0.12, and 0.13±0.09 logMAR, respectively. Mean monocular distance-corrected intermediate (80 cm) and near visual acuity (40 cm) were 0.11±0.12 and 0.10±0.10 logMAR, respectively. Mean binocular defocus curve showed visual acuities of 0.10 logMAR or better for defocus levels from +0.50 to -2.50 D. Residual cylinder was within ±0.50 D in 97.0% of eyes. The surgically induced astigmatism prediction error ranged between -0.49 and 0.50 D, with a mean value of 0.04±0.16 D. Mean absolute IOL rotation was 3.79±2.94º. Significant improvements were found in all Rasch calibrated scores obtained with Catquest-9SF (p<0.001). CONCLUSIONS: The implantation of the toric presbyopia correcting IOL evaluated provides an efficacious astigmatic correction while providing a fully restoration of the visual function across different distances.

Open-source electrochemical cell for in situ X-ray absorption spectroscopy in transmission and fluorescence modes.

X-ray spectroscopy is a valuable technique for the study of many materials systems. Characterizing reactions in situ and operando can reveal complex reaction kinetics, which is crucial to understanding active site composition and reaction mechanisms. In this project, the design, fabrication and testing of an open-source and easy-to-fabricate electrochemical cell for in situ electrochemistry compatible with X-ray absorption spectroscopy in both transmission and fluorescence modes are accomplished via windows with large opening angles on both the upstream and downstream sides of the cell. Using a hobbyist computer numerical control machine and free 3D CAD software, anyone can make a reliable electrochemical cell using this design. Onion-like carbon nanoparticles, with a 1:3 iron-to-cobalt ratio, were drop-coated onto carbon paper for testing in situ X-ray absorption spectroscopy. Cyclic voltammetry of the carbon paper showed the expected behavior, with no increased ohmic drop, even in sandwiched cells. Chronoamperometry was used to apply 0.4 V versus reversible hydrogen electrode, with and without 15 min of oxygen purging to ensure that the electrochemical cell does not provide any artefacts due to gas purging. The XANES and EXAFS spectra showed no differences with and without oxygen, as expected at 0.4 V, without any artefacts due to gas purging. The development of this open-source electrochemical cell design allows for improved collection of in situ X-ray absorption spectroscopy data and enables researchers to perform both transmission and fluorescence simultaneously. It additionally addresses key practical considerations including gas purging, reduced ionic resistance and leak prevention.

Efficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells.

The complex neuromuscular network that controls body movements is the target of severe diseases that result in paralysis and death. Here, we report the development of a robust and efficient self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells that can be maintained long-term in simple adherent conditions. The timely application of specific patterning signals instructs the simultaneous development and differentiation of position-specific brachial spinal neurons, skeletal muscles, and terminal Schwann cells. High-content imaging reveals self-organized bundles of aligned muscle fibers surrounded by innervating motor neurons that form functional neuromuscular junctions. Optogenetic activation and pharmacological interventions show that the spinal neurons actively instruct the synchronous skeletal muscle contraction. The generation of a soNMJ model from spinal muscular atrophy patient-specific iPSCs reveals that the number of NMJs and muscle contraction is severely affected, resembling the patient's pathology. In the future, the soNMJ model could be used for high-throughput studies in disease modeling and drug development. Thus, this model will allow us to address unmet needs in the neuromuscular disease field.

Promotores' perspectives on the virtual adaptation of a hereditary breast cancer education program.

Breast cancer is the most common cancer in women in the United States (U.S.) and the leading cause of cancer related death among U.S. Hispanics/Latinas (H/Ls). H/Ls have lower rates of screening and longer time to follow up after an abnormal mammogram. We developed a comprehensive community health educator (promotores)-led education and risk identification program for Spanish-speaking H/Ls in California to increase mammography screening, genetic testing, and the understanding of the impact of family history on cancer risk. Due to COVID-19, we adapted the program to a virtual platform. The experience of transforming the program to a virtual platform provided unique opportunities for collaboration between researchers, community partners, and participants. Promotores are major partners in community based participatory research and in the provision of health care services, but their voices are often excluded from scientific reports. This commentary is an effort to provide a platform for promotores to share their experiences and for the readers to understand their approach in bridging the gap between health care services and communities.

Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma.

PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.

BACKGROUND: Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins. RESULTS: To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates. CONCLUSIONS: Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease.

An Integrated Characterization Strategy on Board for Recycling of poly(vinyl butyral) (PVB) from Laminated Glass Wastes.

Polyvinyl butyral (PVB) is widely used as an interlayer material in laminated glass applications, mainly in the automotive industry, but also for construction and photovoltaic applications. Post-consumed laminated glass is a waste that is mainly landfilled; nevertheless, it can be revalorized upon efficient separation and removal of adhered glass. PVB interlayers in laminated glass are always plasticized with a significant fraction in the 20-40% w/w range of plasticizer, and they are protected from the environment by two sheets of glass. In this work, the aim is to develop a thorough characterization strategy for PVB films. Neat reference PVB grades intended for interlayer use are compared with properly processed (delaminated) post-consumed PVB grades from the automotive and construction sectors. Methods are developed to open opportunities for recycling and reuse of the latter. The plasticizer content and chemical nature are determined by applying well-known analytical techniques, namely, FT-IR, TGA, NMR. The issue of potential aging during the life cycle of the original laminated material is also addressed through NMR. Based on the findings, a sensor capable of directly sorting PVB post-consumer materials will be developed and calibrated at a later stage.

Equine-assisted services for individuals with substance use disorders: a scoping review.

The implementation of equine-assisted services (EAS) during treatment for psychological disorders has been frequently documented; however, little is known about the effect of EAS on outcomes for populations with substance use disorder (SUD). The purpose of this scoping review was to synthesize existing literature reporting the effects of EAS when incorporated into SUD treatment. This review followed guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for scoping reviews. A search of four databases (MEDLINE/PubMed, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Academic OneFile) identified studies reporting quantitative and/or qualitative data for an EAS intervention that was implemented among a population receiving treatment for and/or diagnosed with SUD. Of 188 titles, 71 underwent full-text assessment and six met inclusion criteria. Three additional articles were identified through other sources. Quantitative data suggested a potential positive effect of EAS on SUD treatment retention and completion as well as participants' mental health; however, studies were limited by small sample sizes. Qualitative data indicated that in addition to participants developing bonds with the horses and perceiving EAS as welcomed breaks from traditional treatment, they experienced increased self-efficacy, positive emotional affect, and SUD treatment motivation. Due to methodological limitations and an overall dearth of available studies, the effectiveness of EAS as adjuncts to SUD treatment is inconclusive. Additional research is necessary before supporting broad implementation of EAS as adjuncts to SUD treatment.

Cancer screening and breast cancer family history in Spanish-speaking Hispanic/Latina women in California.

Background: Breast cancer is the most common cancer among women in the U.S. and the leading cause of cancer death among Hispanics/Latinas (H/L). H/L are less likely than Non-H/L White (NHW) women to be diagnosed in the early stages of this disease. Approximately 5-10% of breast cancer can be attributed to inherited genetic mutations in high penetrance genes such as BRCA1/2. Women with pathogenic variants in these genes have a 40-80% lifetime risk of breast cancer. Past studies have shown that genetic counseling can help women and their families make informed decisions about genetic testing and early cancer detection or risk-reduction strategies. However, H/L are 3.9-4.8 times less likely to undergo genetic testing than NHW women. We developed a program to outreach and educate the H/L community about hereditary breast cancer, targeting monolingual Spanish-speaking individuals in California. Through this program, we have assessed cancer screening behavior and identified women who might benefit from genetic counseling in a population that is usually excluded from cancer research and care. Materials and Methods: The "Tu Historia Cuenta" program is a promotores-based virtual outreach and education program including the cities of San Francisco, Sacramento, and Los Angeles. Participants responded to three surveys: a demographic survey, a breast cancer family history survey, and a feedback survey. Survey responses were described for participants and compared by area where the program took place using chi-square, Fisher exact tests, and t tests. Multinomial logistic regression models were used for multivariate analyses. Results and Conclusion: We enrolled 1042 women, 892 completed the cancer family history survey and 62 (7%) provided responses compatible with referral to genetic counseling. We identified 272 women (42.8% ages 40 to 74 years) who were due for mammograms, 250 women (24.7% ages 25 to 65 years) due for Papanicolaou test, and 189 women (71.6% ages 50+) due for colorectal cancer screening. These results highlight the need of additional support for programs that spread awareness about cancer risk and facilitate access to resources, specifically within the H/L community.

Cysteine Oxidation in Proteins: Structure, Biophysics, and Simulation.

Cysteine side chains can exist in distinct oxidation states depending on the pH and redox potential of the environment, and cysteine oxidation plays important yet complex regulatory roles. Compared with the effects of post-translational modifications such as phosphorylation, the effects of oxidation of cysteine to sulfenic, sulfinic, and sulfonic acid on protein structure and function remain relatively poorly characterized. We present an analysis of the role of cysteine reactivity as a regulatory factor in proteins, emphasizing the interplay between electrostatics and redox potential as key determinants of the resulting oxidation state. A review of current computational approaches suggests underdeveloped areas of research for studying cysteine reactivity through molecular simulations.

Assessing the Activation of Tyrosine Kinase KIT through Free Energy Calculations.

KIT is a type 3 receptor tyrosine kinase that plays a crucial role in cellular growth and proliferation. Mutations in KIT can dysregulate its active-inactive equilibrium. Activating mutations drive cancer growth, while deactivating mutations result in the loss of skin and hair pigmentation in a disease known as piebaldism. Here, we propose a method based on molecular dynamics and free energy calculations to predict the functional effect of KIT mutations. Our calculations may have important clinical implications by defining the functional significance of previously uncharacterized KIT mutations and guiding targeted therapy.

Thermodynamic stabilization of von Willebrand factor A1 domain induces protein loss of function.

The von Willebrand disease (vWD) is the most common hereditary bleeding disorder caused by defects of the von Willebrand Factor (vWF), a large extracellular protein in charge of adhering platelets to sites of vascular lesions. vWF performs this essential homeostatic task via specific protein-protein interactions between the vWF A1 domain and the platelet receptor, the glycoprotein Ib alpha (GPIBα). The two naturally occurring vWF A1 domain mutations G1324A and G1324S, near the GPIBα binding site, induce a dramatic decrease in platelet adhesion, resulting in a bleeding disorder classified as type 2M vWD. However, the reason for the drastic phenotypic response induced by these two supposedly minor modifications remains unclear. We addressed this question using a combination of equilibrium-molecular dynamics (MD) and nonequilibrium MD-based free energy simulations. Our data confirms that both mutations maintain the highly stable Rossmann fold of the vWF A1 domain. G1324A and G1324S mutations hardly changed the per-residue flexibility of the A1 domain but induced a global conformational change affecting the region near the binding site to GPIBα. Furthermore, we observed two significant changes in the vWF A1 domain upon mutation, the global redistribution of the internal mechanical stress and the increased thermodynamic stability of the A1 domain. These observations are consistent with previously reported mutations increasing the melting temperature. Overall, our results support the idea of thermodynamic conformational restriction of A1-before the binding to GPIBα-as a crucial factor determining the loss-of-function of the G1324A(S) vWD mutants.

A Cancer Health Needs Assessment Reveals Important Differences Between US-Born and Foreign-Born Latinos in California.

Background: Cancer is the leading cause of death among Latinos, the largest minority population in the United States (US). To address cancer challenges experienced by Latinos, we conducted a catchment area population assessment (CAPA) using validated questions from the National Cancer Institute (NCI) population health assessment supplement at our NCI-designated cancer center in California. Methods: A mixed-methods CAPA was administered by bilingual-bicultural staff, with a focus on understanding the differences between foreign-born and US-born Latinos. Results: 255 Latinos responded to the survey conducted between August 2019 and May 2020. Most respondents were foreign-born (63.9%), female (78.2%), and monolingual Spanish speakers (63.2%). Results showed that compared to US-born Latinos, foreign-born individuals were older, had lower educational attainment, were most likely to be monolingual Spanish speakers, were low-income, and were more likely to be uninsured. Foreign-born Latinos had lower levels of alcohol consumption and higher consumption of fruits and vegetables. The rate of preventive cancer screenings for breast, cervical and colorectal cancer did not differ by birthplace, although a low fraction (35.3%) of foreign-born Latinas who were up-to-date compared to US-born Latinas (83.3%) with colorectal cancer screening was observed. Time since the last routine check-up for all preventable cancers (cervical p=0.0002, breast p=0.0039, and colorectal p=0.0196) is significantly associated with being up to date with cancer screening. Individuals who had a check-up of two or more years ago are 84% less likely to be up to date with pap smears than those who had a check-up within the year (p=0.0060). Individuals without health insurance are 94% less likely to be up to date with mammograms and colonoscopy/FIT tests (p=0.0016 and p=0.0133, respectively) than those who are insured. There is no significant association between screening and nativity. Conclusions: Considerable differences in socio-economic and environmental determinants of health and colorectal cancer screening rates were observed between US-born and foreign-born Latinos. The present study represents the foundation for future targeted intervention among immigrant populations at our cancer center's catchment area.

[Dioptric power of intraocular lens and dilatation in patients with cataract]. / Poder dióptrico del lente intraocular y dilatación en pacientes con catarata.

Background: Cataract surgery with intraocular lens implant is, nowadays, the most frequent surgical procedure in all the world. Its success depends on a lot of factors, one of the most important is the calculation of the exact dioptric power of intraocular lens. Objective: To compare the calculation of dioptric power of intraocular lens with and without dilatation in patients with cataract. Material and methods: Longitudinal study, the calculation of the dioptric power of the intraocular lens was determined in patients without and with pupillary dilation. The variables were age, gender, eye to study, keratometry, axial length, anterior chamber depth and dioptric power of the intraocular lens. Descriptive statistics and Student t test were performed. Results: There were 37 patients, 23 females and 14 males. The average age was 68 + 7.87 years. Sixty-four eyes were studied, 30 were right and 34 left. Statistically, there was only significant difference in K2 of the ocular biometry between patients without and with pupillary dilation when obtaining a value of p < 0.05. Conclusion: There are no changes in the calculation of the dioptric power of the Intraocular lens without and with pupillary dilation.

Introducción: la cirugía de catarata con implante de un lente intraocular es, hoy en día, el procedimiento quirúrgico más frecuente en todo el mundo. Su éxito depende de muchos factores, uno de los más importantes es el cálculo exacto del poder dióptrico del lente intraocular. Objetivo: comparar el cálculo del poder dióptrico del lente intraocular en los pacientes sin y con dilatación pupilar. Material y métodos: estudio longitudinal, en el que se determinó el cálculo del poder dióptrico del lente intraocular en pacientes con y sin dilatación pupilar. Las variables de estudio fueron: edad, género, ojo a estudiar, queratometría, longitud axial, profundidad de cámara anterior y poder dióptrico del lente intraocular. Se realizó estadística descriptiva y t de Student. Resultados: se estudiaron 37 pacientes, 23 mujeres y 14 hombres. La edad promedio fue de 68 ± 7.87 años. Se estudiaron 64 ojos, 30 fueron derechos y 34 izquierdos. Estadísticamente solo hubo diferencia significativa en K2 de la biometría ocular entre pacientes sin y con dilatación pupilar al obtenerse un valor de p ≤ 0.05. Conclusión: no existen cambios en el cálculo del poder dióptrico del LIO sin y con dilatación pupilar.

Rationale, design, and methodology of a randomized pilot trial of an integrated intervention combining computerized behavioral therapy and recovery coaching for people with opioid use disorder: The OVERCOME study.

Background: Opioid use disorder (OUD) has led to a staggering death toll in terms of drug-related overdoses. Despite the demonstrated benefits and effectiveness of buprenorphine, retention is suboptimal, and patients typically present with high rates of ongoing polysubstance use during treatment. A pilot trial provided preliminary support for the efficacy of computer-based cognitive-behavioral therapy (CBT4CBT) as an add-on to buprenorphine in reducing substance use. Recovery coaching services provided by individuals with substance use experience and successful recovery have also shown to positively influence recovery outcomes for people with OUD by increasing buprenorphine initiation and reducing opioid use. Methods: The OVERCOME study is a randomized clinical trial (RCT) aimed to tests an integrated intervention combining CBT4CBT and Recovery Coaching relative to treatment-as-usual (TAU) among individuals with OUD on buprenorphine. The primary outcome measure is the percentage of samples with any drug tested as positive at each research visit conducted during treatment (visits 1 to 8). Secondary outcomes include the percentage of samples with any drug tested as positive at 1- and 3- month follow-up and retention to buprenorphine at 3- month follow-up. Results: We describe the rationale, design, and methodology of the OVERCOME Study. Conclusion: This trial will provide evidence of the efficacy of an integrated intervention combining CBT4CBT and Recovery Coaching for reducing substance use and increasing buprenorphine adherence which has the potential to reduce mortality among people with OUD.

[Vitamin D deficiency/insufficiency on healthy infants receiving standard supplementation]. / Deficiencia e insuficiencia de vitamina D en lactantes sanos recibiendo suplementación estándar.

Vitamin D (VD) is essential for calcium and phosphorus metabolism. Its deficiency can cause rickets. In Chile, newborns receive 400UI/day supplementation from the first day of age until the first year. OBJECTIVE: To describe the VD plasma levels in healthy infants who received supplementation and secondarily to correlate this with seasonality and nutritional status. SUBJECTS AND METHOD: Cross sectional study. Infants on exclusive or mixed breastfeeding, with monthly pediatric checkups recei ving 400 UI VD supplementation were evaluated, measuring VD plasma levels at 6 months of age, weight, and length, and their nutritional status was classified according to the WHO growth referen ces (weight/age and weight/length). The VD cut-off concentration values were < 20 ng/ml, 21- 29 ng/ ml, and ≥ 30 ng/ml considered as deficiency, insufficiency, and sufficiency, respectively. RESULTS: 40 infants were studied, 40% had insufficient levels and 40% presented deficiency. Season and nutritio nal status were variables significantly related to lower VD values (Winter-Spring p = 0.007; at risk of malnutrition p = 0.038). CONCLUSIONS: The population who received supplementation presented a high frequency of VD deficiency and insufficiency which increases during winter and spring and in subjects at risk of malnutrition.