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Death of mechanosensory hair cells in the inner ear is a common cause of auditory and vestibular impairment in mammals, which have a limited ability to regrow these cells after damage. In contrast, non-mammalian vertebrates, including zebrafish, can robustly regenerate hair cells after severe organ damage. The zebrafish inner ear provides an understudied model system for understanding hair cell regeneration in organs that are highly conserved with their mammalian counterparts. Here, we quantitatively examine hair cell addition during growth and regeneration of the larval zebrafish inner ear. We used a genetically encoded ablation method to induce hair cell death and we observed gradual regeneration with correct spatial patterning over a 2-week period following ablation. Supporting cells, which surround and are a source of new hair cells, divide in response to hair cell ablation, expanding the possible progenitor pool. In parallel, nascent hair cells arise from direct transdifferentiation of progenitor pool cells temporally uncoupled from supporting cell division. These findings reveal a previously unrecognized mechanism of hair cell regeneration with implications for how hair cells may be encouraged to regenerate in the mammalian ear.
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Transdiferenciación Celular , Oído Interno , Células Ciliadas Auditivas , Regeneración , Células Madre , Pez Cebra , Animales , Regeneración/fisiología , Oído Interno/citología , Células Madre/citología , Células Ciliadas Auditivas/citología , Células Ciliadas Auditivas/fisiología , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Animales Modificados Genéticamente , Larva/citologíaRESUMEN
BACKGROUND: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment. METHODS: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts. RESULTS: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant. CONCLUSION: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC.
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Policy Points Patients and families can identify clinically relevant errors, including "blindspots"-safety hazards that are difficult for clinicians or organizations to see. Health information transparency, including patient access to electronic visit notes, now federally mandated in the US and the subject of policy debate worldwide, creates a new opportunity to engage patients in diagnostic safety. However, not all patients access notes. Patient identification of blindspots in their notes underscores the need to systematically and equitably engage willing patients in safety, promote patient "good catches," and establish routine systems for patient feedback to help avoid preventable diagnostic errors and delays. CONTEXT: Policy shifts toward health information transparency provide a new opportunity for patients to contribute to diagnostic safety. We investigated whether sharing clinical notes with patients can support identification of "diagnostic safety blindspots"-potentially consequential breakdowns in the diagnostic process that may be difficult for clinical staff to observe. METHOD: We used mixed methods to analyze patient-reported ambulatory documentation errors among 22,889 patients at three US health care centers who read ≥ 1 visit note(s). We identified blindspots by tailoring a previously established taxonomy. We used multiple regression analysis to identify factors associated with blindspot identification. FINDINGS: 774 patients reported a total of 962 blindspots in 4 categories: (1) diagnostic misalignments (n = 421, 43.8%), including inaccurate symptoms or histories and failures or delay in diagnosis; (2) errors of omission (38.1%) including missed main concerns or next steps, and failure to listen to patients; (3) problems occurring outside visits (14.3%) such as tests, referrals, or appointment access; and (4) multiple low-level problems (3.7%) cascading into diagnostic breakdowns. Many patients acted on the blindspots they identified, resulting in "good catches" that may prevent potential negative consequences. Older, female, sicker, unemployed or disabled patients, or those who work in health care were more likely to identify a blindspot. Individuals reporting less formal education; those self-identifying as Black, Asian, other, or multiple races; and participants who deferred decision-making to providers were less likely to report a blindspot. CONCLUSION: Patients who read notes have unique insight about potential errors in their medical records that could impact diagnostic reasoning but may not be known to clinicians-underscoring a critical role for patients in diagnostic safety and organizational learning. From a policy standpoint, organizations should encourage patient review of visit notes, build systems to track patient-reported blindspots, and promote equity in note access and blindspot reporting.
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Registros Electrónicos de Salud , Pacientes , Humanos , Femenino , DocumentaciónRESUMEN
This article reviews three industry demands that will impact the future of Human Factors and Ergonomics in Healthcare settings. These demands include the growing population of older adults, the increasing use of telemedicine, and a focus on patient-centered care. Following, we discuss a path forward through improved medical teams, error management, and safety testing of medical devices and tools. Future challenges are discussed.
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Atención a la Salud , Ergonomía , Anciano , Humanos , IndustriasRESUMEN
BACKGROUND: Errors and preventable harm to patients remain regrettably common and expensive in healthcare. Improvement requires transforming the culture of the healthcare industry to put a greater emphasis on safety. Safety culture involves holding collective attitudes, values, and behaviors that prioritize safety. The Safer Culture framework, previously established through a narrative review of literature in multiple industries, provides a consensus on what impacts safety culture, how it manifests in behavior, and how it influences safety-related outcomes. METHODS: Through a theoretical review, we validate, refine, and provide nuance to this framework for the development of safety culture in healthcare contexts. To accomplish this, we conceptually map existing dimensions pulled through the literature onto our Safer Culture framework. RESULTS: A total of 360 articles were reviewed. We present specific elements for each dimension in our framework and apply the dimension to healthcare contexts. CONCLUSION: We provide an evidence-based and comprehensive framework that can be used by patient safety leaders and researchers to guide the evaluation of safety culture and develop interventions to foster patient safety culture and improve patient safety outcomes.
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Seguridad del Paciente , Administración de la Seguridad , Atención a la Salud , Humanos , IndustriasRESUMEN
OBJECTIVE: This study reviews theoretical models of organizational safety culture to uncover key factors in safety culture development. BACKGROUND: Research supports the important role of safety culture in organizations, but theoretical progress has been stunted by a disjointed literature base. It is currently unclear how different elements of an organizational system function to influence safety culture, limiting the practical utility of important research findings. METHOD: We reviewed existing models of safety culture and categorized model dimensions by the proposed function they serve in safety culture development. We advance a framework grounded in theory on organizational culture, social identity, and social learning to facilitate convergence toward a unified approach to studying and supporting safety culture. RESULTS: Safety culture is a relatively stable social construct, gradually shaped over time by multilevel influences. We identify seven enabling factors that create conditions allowing employees to adopt safety culture values, assumptions, and norms; and four behaviors used to enact them. The consequences of these enacting behaviors provide feedback that may reinforce or revise held values, assumptions, and norms. CONCLUSION: This framework synthesizes information across fragmented conceptualizations to clearly depict the dynamic nature of safety culture and specific drivers of its development. We suggest that safety culture development may depend on employee learning from behavioral outcomes, conducive enabling factors, and consistency over time. APPLICATION: This framework guides efforts to understand and develop safety culture in practice and lends researchers a foundation for advancing theory on the complex, dynamic processes involved in safety culture development.
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Cultura Organizacional , Administración de la Seguridad , HumanosRESUMEN
The release of captive-bred animals into the wild is commonly practised to restore or supplement wild populations but comes with a suite of ecological and genetic consequences. Vast numbers of hatchery-reared fish are released annually, ostensibly to restore/enhance wild populations or provide greater angling returns. While previous studies have shown that captive-bred fish perform poorly in the wild relative to wild-bred conspecifics, few have measured individual lifetime reproductive success (LRS) and how this affects population productivity. Here, we analyse data on Atlantic salmon from an intensely studied catchment into which varying numbers of captive-bred fish have escaped/been released and potentially bred over several decades. Using a molecular pedigree, we demonstrate that, on average, the LRS of captive-bred individuals was only 36% that of wild-bred individuals. A significant LRS difference remained after excluding individuals that left no surviving offspring, some of which might have simply failed to spawn, consistent with transgenerational effects on offspring survival. The annual productivity of the mixed population (wild-bred plus captive-bred) was lower in years where captive-bred fish comprised a greater fraction of potential spawners. These results bolster previous empirical and theoretical findings that intentional stocking, or non-intentional escapees, threaten, rather than enhance, recipient natural populations.
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Explotaciones Pesqueras , Salmo salar/fisiología , Animales , Animales Salvajes , Acuicultura , Cruzamiento , ReproducciónRESUMEN
Bryostatins with modified C17-C27 fragments have not been widely studied. The synthesis of 20,20-difluorinated analogues was therefore investigated. Such substitution would inhibit dehydration involving the C19-hydroxyl group and stabilise the ring-closed hemiacetal tautomers. Following preliminary studies, allyldifluorination was used to prepare difluorinated alkenols. Oxidation followed by stereoselective Wittig reactions of the resulting α,α-difluorinated ketones gave (E)-α,ß-unsaturated esters that were taken through to complete syntheses of 2-hydroxytetrahydropyrans corresponding to C17-C27 fragments of 20,20-difluorinated bryostatin. These compounds showed modest binding to protein kinase Cα isozyme. Attempts were also undertaken to synthesise macrocyclic 20,20-difluorinated analogues. During preliminary studies, allyldifluorination was carried out using a 2-alkyl-3-bromo-1,1-difluoropropene.
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Brioestatinas/química , Brioestatinas/síntesis química , Halogenación , Brioestatinas/metabolismo , Técnicas de Química Sintética , Modelos Moleculares , Conformación Molecular , Proteína Quinasa C/metabolismoRESUMEN
OBJECTIVE: To evaluate in a preliminary methodologic study, the Foot Function Index (FFI), a 3-subscale (pain, disability, and activity restriction) foot disability assessment questionnaire, in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). DESIGN: Monocentric exploratory cross-sectional study with 2 identical evaluations by the same physical medicine and rehabilitation physician at 14-day intervals (test-retest) according to international guidelines for validating health-related patient-reported outcomes, the Consensus-based Standards for the Selection of Health Measurement Instruments Criteria. SETTING: Physical medicine and rehabilitation and neurology departments in a French academic hospital. PARTICIPANTS: Patients with CMT1A confirmed by molecular biology (N=26). INTERVENTION: The FFI and a health-related quality-of-life questionnaire (Medical Outcomes Study Short Form 36 [SF-36] with mental and physical composite scores) combined with quantitative walk analysis by instrumental gait analysis and evaluation of isokinetic quadriceps and hamstrings peak torque by isokinetic dynamometer. MAIN OUTCOME MEASURES: FFI score and its dimensions. RESULTS: Acceptability was satisfactory, with less than 5% missing data and good distribution of results. Internal consistency was very satisfactory, with Cronbach α of 0.95. Reproducibility was very satisfactory, with Lin concordance coefficient 0.82. External consistency was satisfactory, with expected correlation coefficients: the FFI was significantly correlated with the SF-36 physical composite score and gait parameters (cadence) (r=-0.58 and r=-0.52; P<.005) but not with peak torque or SF-36 mental composite score. CONCLUSIONS: This study confirms the very good metrologic properties of the FFI in patients with CMT1A. The FFI could be a promising questionnaire to assess foot-related disability in a neurologic disease. Complementary studies are still needed to confirm these promising preliminary results.
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Enfermedad de Charcot-Marie-Tooth/fisiopatología , Evaluación de la Discapacidad , Pie/fisiopatología , Modalidades de Fisioterapia , Calidad de Vida , Centros Médicos Académicos , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Charcot-Marie-Tooth/epidemiología , Estudios Transversales , Fatiga/epidemiología , Femenino , Humanos , Contracción Isométrica/fisiología , Masculino , Persona de Mediana Edad , Fuerza Muscular/fisiología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Safety climate is an important marker of patient safety attitudes within health care units, but the significance of intra-unit variation of safety climate perceptions (safety climate strength) is poorly understood. This study sought to examine the standard safety climate measure (percent positive response (PPR)) and safety climate strength in relation to length of stay (LOS) of very low birth weight (VLBW) infants within California neonatal intensive care units (NICUs). METHODS: Observational study of safety climate from 2073 health care providers in 44 NICUs. Consistent perceptions among a NICU's respondents, i.e., safety climate strength, was determined via intra-unit standard deviation of safety climate scores. The relation between safety climate PPR, safety climate strength, and LOS among VLBW (< 1500 g) infants was evaluated using log-linear regression. Secondary outcomes were infections, chronic lung disease, and mortality. RESULTS: NICUs had safety climate PPRs of 66 ± 12%, intra-unit standard deviations 11 (strongest) to 23 (weakest), and median LOS 60 days. NICUs with stronger climates had LOS 4 days shorter than those with weaker climates. In interaction modeling, NICUs with weak climates and low PPR had the longest LOS, NICUs with strong climates and low PPR had the shortest LOS, and NICUs with high PPR (both strong and weak) had intermediate LOS. Stronger climates were associated with lower odds of infections, but not with other secondary outcomes. CONCLUSIONS: Safety climate strength is independently associated with LOS and moderates the association between PPR and LOS among VLBW infants. Strength and PPR together provided better prediction than PPR alone, capturing variance in outcomes missed by PPR. Evaluations of NICU safety climate consider both positivity (PPR) and consistency of responses (strength) across individuals.
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Unidades de Cuidado Intensivo Neonatal , Tiempo de Internación/estadística & datos numéricos , Seguridad del Paciente/normas , Femenino , Humanos , Recién Nacido , Recién Nacido de muy Bajo Peso , Unidades de Cuidado Intensivo Neonatal/normas , Masculino , Cultura OrganizacionalRESUMEN
PURPOSE: Patients and families may experience 'non-physical' harm from interactions with the healthcare system, including emotional, psychological, socio-behavioral or financial harm, some of which may be related to experiences of disrespect. We sought to use the current literature to develop a practical, improvement-oriented framework to recognize, describe and help prevent such events. DATA SOURCES: Searches were performed in PubMed, Embase, PsychINFO, CINAHL, Health Business Elite and ProQuest Dissertations & Theses: Global: Health & Medicine, from their inception through July 2017. STUDY SELECTION: Two authors reviewed titles, abstracts, full texts, references and cited-by lists to identify articles describing approaches to understanding patient/family experiences of disrespect. DATA EXTRACTION: Findings were evaluated using integrative review methodology. RESULTS OF DATA SYNTHESIS: Three-thousand eight hundred and eighty two abstracts were reviewed. Twenty three articles were identified. Components of experiences of disrespect included: (1) numerous care processes; (2) a wide range of healthcare professional and organizational behaviors; (3) contributing factors, including patient- and professional-related factors, the environment of work and care, leadership, policies, processes and culture; (4) important consequences of disrespect, including behavioral changes and health impacts on patients and families, negative effects on professionals' subsequent interactions, and patient attrition from organizations and (5) factors both intrinsic and extrinsic to patients that can modify the consequences of disrespect. CONCLUSION: A generalizable framework for understanding disrespect experienced by patients/families in healthcare may help organizations better prevent non-physical harms. Future work should prospectively test and refine the framework we described so as to facilitate its integration into organizations' existing operational systems.
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Seguridad del Paciente , Relaciones Profesional-Paciente , Calidad de la Atención de Salud , Familia/psicología , Humanos , Satisfacción del Paciente , Atención Dirigida al Paciente , ProfesionalismoRESUMEN
BACKGROUND: Parents of neonates are integral components of patient safety in the neonatal intensive care unit (NICU), yet their views are often not considered. By understanding how parents perceive patient safety in the NICU, clinicians can identify appropriate parent-centered strategies to involve them in promoting safe care for their infants. PURPOSE: To determine how parents of neonates conceptualize patient safety in the NICU. METHODS: We conducted qualitative interviews with 22 English-speaking parents of neonates from the NICU and observations of various parent interactions within the NICU over several months. Data were analyzed using thematic content analysis. Findings were critically reviewed through peer debriefing. FINDINGS: Parents perceived safe care through their observations of clinicians being present, intentional, and respectful when adhering to safety practices, interacting with their infant, and communicating with parents in the NICU. They described partnering with clinicians to promote safe care for their infants and factors impacting that partnership. We cultivated a conceptual model highlighting how parent-clinician partnerships can be a core element to promoting NICU patient safety. IMPLICATIONS FOR PRACTICE: Parents' observations of clinician behavior affect their perceptions of safe care for their infants. Assessing what parents observe can be essential to building a partnership of trust between clinicians and parents and promoting safer care in the NICU. IMPLICATIONS FOR RESEARCH: Uncertainty remains about how to measure parent perceptions of safe care, the level at which the clinician-parent partnership affects patient safety, and whether parents' presence and involvement with their infants in the NICU improve patient safety.
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Comportamiento del Consumidor , Cuidado Intensivo Neonatal , Padres/psicología , Seguridad del Paciente , Administración de la Seguridad , Adulto , Femenino , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal/organización & administración , Cuidado Intensivo Neonatal/métodos , Cuidado Intensivo Neonatal/psicología , Cuidado Intensivo Neonatal/normas , Masculino , Relaciones Profesional-Familia , Investigación Cualitativa , Administración de la Seguridad/métodos , Administración de la Seguridad/normas , Percepción SocialRESUMEN
The vioprolides are novel depsipeptides that have not been synthesized. However, they have been identified as important targets for synthesis because of their novel biological activities and challenging chemical structures. Following early work on the synthesis of a modified tetrapeptide that contained both the (E)-dehydrobutyrine and thiazoline components of vioprolide D, problems were encountered in taking an (E)-dehydrobutyrine containing intermediate further into the synthesis. A second approach to vioprolides and analogues was therefore investigated in which (E)- and (Z)-dehydrobutyrines were to be introduced by selenoxide elimination very late in the synthesis. A convergent approach to advanced macrocyclic precursors of the vioprolides was then completed using a modified hexapeptide and a dipeptidyl glycerate. In this work, it was necessary to protect the 2-hydroxyl group of the glycerate as its acetate and not as its 2,2,2-trichloroethoxycarbonate. Preliminary studies were carried out on the introduction of the required dehydrobutyrine and thiazoline components into advanced intermediates.
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BACKGROUND: The nature and consequences of patient and family emotional harm stemming from preventable medical error, such as losing a loved one or surviving serious medical injury, is poorly understood. Patients and families, clinicians, social scientists, lawyers, and foundation/policy leaders were brought together to establish research priorities for this issue. METHODS: A one-day conference of diverse stakeholder groups to establish a consensus-driven research agenda focused on (1) priorities for research on the short-term and long-term emotional impact of harmful events on patients and families, (2) barriers and enablers to conducting such research, and (3) actionable steps toward better supporting harmed patients and families now. RESULTS: Stakeholders discussed patient and family experiences after serious harmful events, including profound isolation, psychological distress, damaging aspects of medical culture, health care aversion, and negative effects on communities. Stakeholder groups reached consensus, defining four research priorities: (1) Establish conceptual framework and patient-centered taxonomy of harm and healing; (2) Describe epidemiology of emotional harm; (3) Determine how to make emotional harm and long-term impacts visible to health care organizations and society at large; and (4) Develop and implement best practices for emotional support of patients and families. The group also created a strategy for overcoming research barriers and actionable "Do Now" approaches to improve the patient and family experience while research is ongoing. CONCLUSION: Emotional and other long-term impacts of harmful events can have profound consequences for patients and families. Stakeholders designed a path forward to inform approaches that better support harmed patients and families, with both immediately actionable and longer-term research strategies.
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Errores Médicos/psicología , Seguridad del Paciente , Trauma Psicológico/epidemiología , Trauma Psicológico/psicología , Investigación/organización & administración , Consenso , Emociones , Familia/psicología , Humanos , Pacientes Internos/psicología , Atención Dirigida al Paciente/organización & administración , Proyectos de Investigación , Grupos de Autoayuda/organización & administración , Participación de los Interesados , Estados Unidos , United States Agency for Healthcare Research and QualityRESUMEN
OBJECTIVES: Surgery is a cornerstone for patients with gynecologic malignancies. Surgical site infections (SSI) remain a source of post-operative morbidity. Consequences range from escalated costs, delay in adjuvant therapy, and increased morbidity. Our primary objective was to evaluate the effectiveness of a cyanoacrylate microbial sealant (CMS) to reduce post-operative SSI following laparotomy for suspected gynecologic malignancy. METHODS: Patients were randomized using a 1:1 allocation to receive either standard skin preparation or standard preparation with CMS and stratified by BMI. Patients were followed for 6weeks for SSI. Demographic data was collected through the EMR. Associations between SSI, use of CMS, and clinicopathologic factors were explored using descriptive statistics, chi-square and multivariate analysis. RESULTS: 300 patients underwent randomization. Median age of the cohort was 58. Arms were matched and there was no difference in rate of medical comorbidities. Mean BMI was 38.8kg/m2 in patients randomized to BMI≥30 and 26.3kg/m2 randomized to BMI<30. Surgical characteristics for the entire cohort: 66% malignancy, 91% clean-contaminated, 21% bowel surgery, 25% transfusion. Seventy-six (25%) patients developed a SSI: 43 patients (28%) treated with CMS, compared to 33 (21%) patients treated without CMS (p=0.18). Multivariate model demonstrated that BMI≥30 (p<0.005), surgery for malignancy (p=0.010), transfusion in the OR (p<0.001), and closure with staples (p=0.0005) were associated with post-operative SSI. CONCLUSIONS: Patients presenting to a gynecologic oncologist for surgery frequently present with multiple risk factors for SSI and laparotomy is complicated by surgical-site complications in up to 30% of cases. The addition of CMS alone does not appear to reduce risk of overall SSI. Additional risk-reducing strategies including use of antimicrobial agents and optimization of modifiable risk factors prior to surgery should be explored as pathways for reducing this significant post-operative morbidity.
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Cianoacrilatos/uso terapéutico , Neoplasias de los Genitales Femeninos/cirugía , Infección de la Herida Quirúrgica/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Antiinfecciosos Locales/uso terapéutico , Clorhexidina/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Cuidados Preoperatorios , Estudios Prospectivos , Factores de Riesgo , Infección de la Herida Quirúrgica/terapia , Adulto JovenRESUMEN
The modified Julia reaction and acyl carbanion chemistry, especially reactions of 2-lithiated dithianes, have been investigated for the synthesis of intermediates that are the synthetic equivalents of the C11-C27 fragments of bryostatins. The modified Julia reaction using 2-benzothiazolylsulfones was found to be more useful for the formation of the C16-C17 double-bond than the classical Julia reaction using phenylsulfones, and bulky sulfones gave very good (E)-stereoselectivity. The alkylation of a dithiane monoxide that corresponded to a C19-acyl carbanion using (E)-1-bromobut-2-ene was efficient but the use of a more complex allylic bromide corresponding to the C20-C27 fragment of the bryostatins was unsuccessful, possibly due to competing elimination reactions. This meant that the use of C19 dithianes for the synthesis of 20-deoxybryostatins would have to involve the stepwise assembly of the C20-C27 fragment from simpler precursors. However, lithiated C19 dithianes gave good yields of adducts with aldehydes and conditions were developed for the stereoselective conversion of the major adducts into methoxyacetals that corresponded to the C17-C27 fragment of 20-oxygenated bryostatins. A convergent synthesis of the C11-C27 fragment of a 20-deoxybryostatin was subsequently achieved using a 2-benzothiazolylsulfone corresponding to the intact C17-C27 fragment.
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Brioestatinas/química , Brioestatinas/síntesis química , Aldehídos/química , Alquilación , Técnicas de Química Sintética , Oxígeno/química , EstereoisomerismoRESUMEN
Two approaches to the synthesis of compounds corresponding to the C17-C27 fragment of the 20-deoxybryostatins are described. The first approach is based on the palladium(0) catalysed coupling of tin enolates, generated in situ from enol acetates using tributyltin methoxide, with vinylic bromides. The vinylic bromides were prepared using the Sharpless asymmetric dihydroxylation to introduce the hydroxyl groups corresponding to those at C25 and C26 in the bryostatins. Following several steps to introduce alkynyl ester functionality, the stereoselective addition of a tributyltin cuprate followed by tributyltin-bromine exchange gave the required vinylic bromides. The palladium(0) catalysed couplings worked very well for enol esters containing thioether substituents and gave products with retention of the position and geometry of the trisubstituted double bond derived from the vinylic bromide. These were taken through to compounds corresponding to fully developed C17-C27 fragments ready for assembly of the 16,17-double-bond of bryostatins by Julia reactions. This chemistry was also applied to prepare intermediates suitable for incorporation into bryostatins by ring-closing metathesis but, in this case, the coupling reaction gave mixtures of products including both the required ßγ-unsaturated ketone and a conjugated diene formed by a competing Heck reaction. To avoid this problem, a second approach to compounds suitable for incorporation into a metathesis-based assembly of 20-deoxybryostatins was developed. In this organotin-free synthesis, the key step was the conjugate addition of an organic cuprate generated from allylmagnesium bromide to an alkynoate that gave the required (Z)-trisubstituted alkene with excellent stereoselectivity. This was converted into metathesis precursors in a few steps.
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Preliminary studies into the use of ring-closing metathesis (RCM) in a convergent approach for the total synthesis of bryostatins are described. An ester that would have provided an advanced intermediate for a synthesis of a 20-deoxybryostatin by a RCM was prepared from an unsaturated acid and alcohol corresponding to the C1-C16 and C17-C27 fragments. However, studies of the formation of the C16-C17 double-bond by RCM were not successful and complex mixtures of products were obtained. To provide an insight into factors that may be involved in hindering RCM in this system, a slightly simplified C1-C16 acid and modified C17-C25 alcohols were prepared and their use for the synthesis of analogues of bryostatins was investigated. Although only low yields were obtained, it appeared that macrolides analogous to the bryostatins can be prepared by RCM, using the Grubbs II catalyst, if the precursors lack the two methyl groups at C18. RCM was not observed, however, for substrates in which these methyl groups were present.
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Brioestatinas/síntesis química , Brioestatinas/química , Estructura MolecularRESUMEN
The first total synthesis of a derivative of a 20-deoxybryostatin, namely 7-des-O-pivaloyl-7-O-benzylbryostatin 10 is described. Preliminary studies demonstrated that the modified Julia reactions of 2-benzothiazolylsulfones corresponding to the C17-C27 fragment with aldehydes corresponding to the C1-C16 fragment, provided an efficient and stereoselective assembly of advanced intermediates with the (E)-16,17-double-bond. The synthesis of the C1-C16 fragment was then modified so that the C1 acid was present as its allyl ester before the Julia coupling. A more efficient synthesis of the C17-C27 sulfone was developed in which a key step was the bismuth mediated coupling of an allylic bromide with an aldehyde in the presence of an acrylate moiety in the allylic bromide. A scalable synthesis of an advanced macrolide was completed using the modified Julia reaction followed by selective deprotection and macrolactonisation. The final stages of the synthesis required selective hydroxyl deprotection and the introduction of the sensitive C19-C21 unsaturated keto-ester functionality. Unexpected selectivities were observed during studies of the hydroxyl group deprotections. In particular, cleavage of tri-isopropylsilyl ethers of the exocyclic primary allylic alcohols was observed in the presence of the triethylsilyl ether of the secondary alcohol at C19. Model studies helped in the design of the methods used to introduce the C19-C21 keto-ester functionality and led to the completion of a total synthesis of a close analogue of bryostatin 10 in which a benzyloxy group rather than the pivaloyloxy group was present at C7.