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The number of peptide-like scaffolds found in late-stage drug development is increasing, but a critical unanswered question in the field is whether substituents (side chains) or the backbone drive passive permeability. The backbone is scrutinized in this study. Five series of macrocyclic peptidic compounds were prepared, and their passive permeability was determined (PAMPA, Caco-2), to delineate structure-permeability relationships. Each series was based on the cell-permeable antiarrhythmic compound ent-verticilide, a cyclic oligomeric depsipeptide (COD) containing repeating ester/N-Me amide didepsipeptide monomers. One key finding is that native lipophilic ester functionality can impart a favorable level of permeability, but ester content alone is not the final determinant - the analog with highest P app was discovered by a single ester-to-N-H amide replacement. Furthermore, the relative composition of esters and N-Me amides in a series had more nuanced permeability behavior. Overall, a systematic approach to structure-permeability correlations suggests that a combinatorial-like investigation of functionality in peptidic or peptide-like compounds could better identify leads with optimal passive permeability, perhaps prior to modification of side chains.
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BACKGROUND: Alcohol withdrawal syndrome (AWS) is a complication of alcohol use disorder that manifests as a range of symptoms. Symptom-triggered benzodiazepines (BZDs) are often used as first-line treatment of AWS. However, recent literature suggests phenobarbital (PHB) may be safer and more efficacious, but studies are limited by exclusion of patients with neurological injuries. OBJECTIVE: We aimed to evaluate the safety of PHB compared to BZDs for the management of AWS among patients with primary neurologic injuries. METHODS: Retrospective cohort study of patients with primary neurologic injuries admitted to an ICU who received PHB or symptom-triggered BZD for AWS between December 2013 and February 2020. The primary outcome was incidence of oversedation, defined as Richmond Agitation Sedation Scale (RASS) scores from -5 to -3 within 24 hours of initial PHB or BZD dose. Secondary outcomes included largest decrease in RASS, need for mechanical ventilation, and additional sedative use within 24 hours of initial PHB or BZD dose. A multivariable analysis was performed to evaluate the association of PHB administration with the primary outcome. RESULTS: Among 600 patients treated for AWS, 84 patients were included in our analysis (PHB, n = 56; BZD, n = 28). In the unadjusted analysis, there were no differences between the PHB and BZD groups for the primary outcome of oversedation (21.4 vs. 7.1%, P = 0.13), or secondary outcomes of decrease in RASS (P = 0.34), or new ventilator requirement (P = 0.55). Patients who received PHB had higher rates of additional sedative use (P < 0.01). Multivariable regression revealed an increase in oversedation among intubated patients (P = 0.014), while PHB administration was not independently associated with oversedation (P = 0.516). CONCLUSION AND RELEVANCE: Phenobarbital did not independently increase the risk of oversedation compared to BZD for AWS in patients with primary neurologic injuries. Future studies should determine optimal dosing of PHB in this population.
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Significant technical challenges exist when measuring synaptic connections between neurons in living brain tissue. The patch clamping technique, when used to probe for synaptic connections, is manually laborious and time-consuming. To improve its efficiency, we pursued another approach: instead of retracting all patch clamping electrodes after each recording attempt, we cleaned just one of them and reused it to obtain another recording while maintaining the others. With one new patch clamp recording attempt, many new connections can be probed. By placing one pipette in front of the others in this way, one can "walk" across the tissue, termed "patch-walking." We performed 136 patch clamp attempts for two pipettes, achieving 71 successful whole cell recordings (52.2%). Of these, we probed 29 pairs (i.e., 58 bidirectional probed connections) averaging 91 µm intersomatic distance, finding 3 connections. Patch-walking yields 80-92% more probed connections, for experiments with 10-100 cells than the traditional synaptic connection searching method.
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BACKGROUND: Neurologically critically ill patients present with unique disease trajectories, prognostic uncertainties, and challenges to end-of-life (EOL) care. Acute brain injuries place these patients at risk for underrecognized symptoms and unmet EOL management needs, which can negatively affect their quality of care and lead to complicated grief in surviving loved ones. To care for patients nearing the EOL in the neurointensive care unit, health care clinicians must consider neuroanatomic localization, barriers to symptom assessment and management, unique aspects of the dying process, and EOL management needs. AIM: We aim to define current best practices, barriers, and future directions for EOL care of the neurologically critically ill patient.
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BACKGROUND: Nearly one-quarter of all Americans die in the ICU. Many of their deaths are anticipated and occur following the withdrawal of mechanical ventilation (WMV). However, there are few data on which to base best practices for interdisciplinary ICU teams to conduct WMV. RESEARCH QUESTION: What are the perceptions of current WMV practices among ICU clinicians, and what are their opinions of processes that might improve the practice of WMV at end of life in the ICU? STUDY DESIGN AND METHODS: This prospective two-center observational study conducted in Boston, Massachusetts, the Observational Study of the Withdrawal of Mechanical Ventilation (OBSERVE-WMV) was designed to better understand the perspectives of clinicians and experience of patients undergoing WMV. This report focuses on analyses of qualitative data obtained from in-person surveys administered to the ICU clinicians (nurses, respiratory therapists, and physicians) caring for these patients. Surveys assessed a broad range of clinician perspectives on planning, as well as the key processes required for WMV. This analysis used independent open, inductive coding of responses to open-ended questions. Initial codes were reconciled iteratively and then organized and interpreted using a thematic analysis approach. Opinions were assessed on how WMV could be improved for individual patients and the ICU as a whole. RESULTS: Among 456 eligible clinicians, 312 in-person surveys were completed by clinicians caring for 152 patients who underwent WMV. Qualitative analyses identified two main themes characterizing high-quality WMV processes: (1) good communication (eg, mutual understanding of family preferences) between the ICU team and family; and (2) medical management (eg, planning, availability of ICU team) that minimizes patient distress. Team member support was identified as an essential process component in both themes. INTERPRETATION: Clinician perceptions of the appropriateness or success of WMV prioritize the quality of team and family communication and patient symptom management. Both are modifiable targets of interventions aimed at optimizing overall WMV.
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Indoor air quality (IAQ) in vehicles can be important to people's health, especially for those whose occupations require them to spend extensive time in vehicles. To date, research on vehicle IAQ has primarily focused on direct emissions as opposed to chemistry happening in vehicle cabins. In this work, we conducted time-resolved measurements of the oxidants and oxidant precursors ozone (O3), nitric oxide (NO), nitrogen dioxide (NO2), and nitrous acid (HONO) inside the cabin of a 2012 Toyota Rav4 under varying ventilation conditions (i.e., car off, car on with passive ventilation, car on with mechanical ventilation via the recirculating fan, and car on with mechanical ventilation via the direct fan). Ozone levels inside the vehicle were significantly lower than outdoors under most conditions, and were approximately half the outdoor levels when the direct fan was in operation. Nitric oxide and NO2 concentrations were very low both inside the vehicle and outdoors. Nitrous acid levels in the vehicle were lower than reported values in other indoor environments, though much higher than expected outdoor levels. We also investigated the potential for photochemical production of radicals in the vehicle. Time- and wavelength-resolved solar irradiance spectra were collected, and steady state hydroxyl radical (OH) and nitrate radical (NO3) concentrations were calculated. Steady state OH concentrations were predicted to be similar to those in air masses in residences illuminated by sunlight, suggesting the importance of HONO photolysis in vehicles. Conversely, nitrate radicals (NO3) were not considered significant indoor oxidants in our study due to rapid titration by NO. Overall, our findings emphasize the importance of both air exchange and photochemistry in shaping the composition of air inside vehicles.
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In this report, we demonstrate olefin transposition/isomerization reactions catalyzed by a series of N,N,N-pincer (1,3-bis(2-pyridylimino)isoindoline) Ru-hydride complexes. The protocol proceeds at room temperature for most substrates, achieving excellent yields, regioselectivity, and diastereoselectivity in short reaction times. The air-stable Ru-chloride derivatives of these complexes exhibit comparable reactivity enabling benchtop setup and synthetic versatility. Furthermore, we demonstrate the potential for one-pot cascade sequences of the products derived from the transposition reactions.
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Congenital heart disease (CHD) is one of today's leading birth anomalies. Children with CHD are at risk for adaptive functioning challenges. Sleep difficulties are also common in children with CHD. Indeed, sleep-disordered breathing, a common type of sleep dysfunction, is associated with increased mortality for infants with CHD. The present study examined the associations between adaptive functioning and sleep quality (i.e., duration and disruptions) in children with CHD (n = 23) compared to healthy children (n = 38). Results demonstrated associations between mean hours slept and overall adaptive functioning in the CHD group r(21) = .57, p = .005 but not in the healthy group. The CHD group demonstrated lower levels of adaptive functioning in the Conceptual, t(59) = 2.12, p = .039, Cohen's d = 0.53 and Practical, t(59) = 2.22, p = .030, Cohen's d = 0.55 domains, and overall adaptive functioning (i.e., General Adaptive Composite) nearing statistical significance in comparison to the healthy group, t(59) = 2.00, p = .051, Cohen's d = 0.51. The CHD group also demonstrated greater time awake at night, t(56) = 2.19, p = .033, Cohen's d = 0.58 and a greater instance of parent-caregiver reported snoring, χ2 (1, N = 60) = 5.25, p = .022, V = .296 than the healthy group. Further exploration of the association between adaptive functioning and sleep quality in those with CHD is required to inform clinical practice guidelines.
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Optoelectronic devices based on lanthanide-containing materials are an emergent area of research due to imminent interest in a new generation of diode materials, optical and magnetic sensors, and ratiometric thermometers. Tailoring material properties through the employment of photo- or thermochromic moieties is a powerful approach that requires a deep fundamental understanding of possible cooperativity between lanthanide-based metal centers and integrated switchable units. In this work, we probe this concept through the synthesis, structural analysis, and spectroscopic characterization of novel photochromic lanthanide-based metal-organic materials containing noncoordinatively integrated photoresponsive 4,4'-azopyridine between lanthanide-based metal centers. As a result, a photophysical material response tailored on demand through the incorporation of photochromic compounds within a rigid matrix was investigated. The comprehensive analysis of photoresponsive metal-organic materials includes single-crystal X-ray diffraction and diffuse reflectance spectroscopic studies that provide guiding principles necessary for understanding photochromic unit-lanthanide-based metal-organic framework (MOF) cooperativity. Furthermore, steady-state and time-resolved diffuse reflectance spectroscopic studies revealed a rapid rate of photoresponsive moiety attenuation upon its integration within the rigid matrix of lanthanide-based MOFs in comparison with that in solution, highlighting a unique role and synergy that occurred between stimuli-responsive moieties and the lanthanide-based MOF platform, allowing for tunability and control of material photoisomerization kinetics.
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The cervical aortic arch (CAA) is an uncommon congenital anomaly in aortic development, characterized by an elongated aortic arch extending at or above the medial ends of the clavicles. Our objective was to examine the clinical and surgical characteristics of this infrequent condition in the adult population. PubMed, ScienceDirect, SciELO, DOAJ, and Cochrane Library databases were searched until December 2023 for case reports describing the presence of a cervical aortic arch in patients aged ≥18 years. Case reports and series were included if the following criteria were met: (1) description of the cervical aortic arch, (2) age ≥18 years, and (3) English language. The literature search identified 2,325 potentially eligible articles, 61 of whom met our inclusion criteria and included a combined number of 71 patients. Mean age was 38.6 ± 15.4 years, with a female prevalence of 67.1% (47/70). Two-thirds of the CAA were left-sided (48/71, 67.6%), and 62.0% (44/71) of patients presented a concomitant arch aneurysm. Asymptomatic patients were 45.7% (32/70), while of those that were symptomatic, 60.5% (23/38) had symptoms related to vascular-induced compression of trachea and esophagus. Surgery was performed in 42 patients (62.7%) among 67 cases that reported the patient's treatment, and 5 patients (11.9%) among those surgically treated underwent the procedure through an endovascular approach. CAA is an uncommon congenital abnormality that presents challenges in diagnosis and treatment due to its high anatomical variability, diverse clinical manifestations, and presence of concomitant diseases. Surgery seems to be a safe and effective option for the resolution of symptoms.
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Aorta Torácica , Humanos , Aorta Torácica/anomalías , Aorta Torácica/cirugía , Aorta Torácica/diagnóstico por imagen , Adulto , Manejo de la Enfermedad , FemeninoRESUMEN
Previous work examining the extent to which individuals seek alcohol to enhance positive experiences (reward drinking) or relieve aversive states (relief drinking) has shown that reward/relief drinking predicts response to naltrexone and acamprosate treatment for alcohol use disorder. Yet, various measures of reward/relief drinking have been used in prior research, and the comparative psychometric properties of these measures are unknown. Evaluating and comparing the psychometric properties of these reward/relief drinking measures could identify measures with the most promise for translating precision medicine findings to clinical practice. In a community sample of 65 individuals with heavy/hazardous alcohol use on the Alcohol Use Disorder Identification Test, we showed good internal consistency reliability, test-retest reliability, and concurrent validity for theoretically aligned measures (e.g., reward drinking and reward responsiveness, relief drinking and depression/anxiety symptoms) of the reward and relief subscales across the six measures. We then used ecological momentary assessment to determine whether reward and relief drinking subscales predicted within-person associations between contextual factors of interest (e.g., negative affect, positive affect, distress intolerance, physical pain, hangover symptoms, social drinking situations, alcohol cues) and same-moment alcohol craving. All six measures demonstrated limited predictive validity for alcohol craving contexts in daily life as assessed via ecological momentary assessment. Despite these findings, reward and relief drinking measures show good reliability and concurrent validity and previously demonstrated clinical utility for predicting response to alcohol use disorder treatments, including naltrexone. Future research should aim to elucidate the mechanisms underlying the association between responses to reward/relief drinking measures and pharmacotherapy outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in -0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.NEW & NOTEWORTHY Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF.
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Ejercicio Físico , Antebrazo , Fuerza de la Mano , Insuficiencia Cardíaca , Volumen Sistólico , Sistema Nervioso Simpático , Vasoconstricción , Humanos , Masculino , Sistema Nervioso Simpático/fisiopatología , Femenino , Insuficiencia Cardíaca/fisiopatología , Persona de Mediana Edad , Antebrazo/irrigación sanguínea , Anciano , Flujo Sanguíneo Regional , Estudios de Casos y Controles , Función Ventricular Izquierda , Frío , Presión Arterial , DescansoRESUMEN
BACKGROUND: There is a need to identify clinically meaningful non-abstinent endpoints for cocaine use disorder (CUD) clinical trials. In this study, we sought to replicate and extend prior work validating reductions in cocaine use frequency levels as an endpoint by examining associations between reductions in cocaine use frequency and long-term functioning outcomes. METHODS: We conducted a secondary analysis of two randomized clinical trials (N = 445; 77.5 % male; mean age = 42.18 years; 86.5 % Black, 10.8 % non-Hispanic white) that evaluated telephone-based continuing care for a 12- and 24-month period. Cocaine use frequency levels, measured with the Timeline Followback, were (1) abstinence (no past-month cocaine use), (2) low-frequency use (1-4 days of use/month), and (3) high-frequency use (5+ days of use/month). RESULTS: Among those who completed the 12-month follow-up (n = 392), most reduced from high-frequency use at baseline to abstinence at the 12-month follow-up (n = 243; 62.0 %). An additional 21.2 % (n = 83) reported either high-to-low-frequency use (n = 35; 8.9 %) or low use-to-abstinence (n = 48; 12.2 %); 16.8 % of participants (n = 66) did not change or increased their cocaine frequency level. Compared to those who had no change/increases in frequency levels, at least a one-level reduction from baseline to 12-month follow-up (i.e., high-to-low-frequency use, high-to-abstinence, low-to-abstinence) was concurrently associated with lower levels of negative consequences at the 12-month follow-up and prospectively with lower levels of cocaine use and consequences at 24-month follow-up, with effect sizes in the medium-to-large range. Those who reduced to abstinence generally had fewer drug use consequences at the 12-month follow-up than those who reduced to a low-frequency level; however, these groups did not significantly differ on any outcomes at the 24-month follow-up. CONCLUSIONS: Categorical reductions in cocaine use frequency levels, including those short of abstinence, are associated with less cocaine use and lower problem severity up to two years following treatment entry. Low-frequency cocaine use following the initial treatment phase does not appear to forebode worsening functioning, such as escalations in cocaine use.
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Trastornos Relacionados con Cocaína , Humanos , Trastornos Relacionados con Cocaína/terapia , Trastornos Relacionados con Cocaína/epidemiología , Masculino , Femenino , Adulto , Resultado del Tratamiento , Persona de Mediana Edad , Estudios de Seguimiento , Factores de Tiempo , Teléfono , Continuidad de la Atención al PacienteRESUMEN
Vascular stenting is a common procedure used to treat diseased blood vessels by opening the narrowed vessel lumen and restoring blood flow to ischemic tissues in the heart and other organs. In this work, we report a novel piezoelectric stent featuring a zigzag shape fabricated by fused deposition modeling three-dimensional (3D) printing with a built-in electric field. The piezoelectric composite was made of potassium sodium niobite microparticles and poly(vinylidene fluoride-co-hexafluoropropylene), complementing each other with good piezoelectric performance and mechanical resilience. The in situ poling yielded an appreciable piezoelectricity (d33 â¼ 4.2 pC N-1) of the as-printed stents. In vitro testing revealed that materials are nontoxic to vascular cells and have low thrombotic potential. Under stimulated blood pressure fluctuation, the as-printed piezoelectric stent was able to generate peak-to-peak voltage from 0.07 to 0.15 V corresponding to pressure changes from 20 to 120 Psi, giving a sensitivity of 7.02 × 10-4 V Psi-1. Biocompatible piezoelectric stents bring potential opportunities for the real-time monitoring of blood vessels or enabling therapeutic functions.
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Impresión Tridimensional , Stents , Humanos , Electricidad , Presión , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Polivinilos/químicaRESUMEN
OBJECTIVE: The laryngeal adductor reflex (LAR) is vital for airway protection and can be electrophysiologically obtained under intravenous general anesthesia (IGA). This makes the electrophysiologic LAR (eLAR) an important tool for monitoring of the vagus nerves and relevant brainstem circuitry during high-risk surgeries. We investigated the intra-class variability of normal and expected abnormal eLAR. METHODS: Repeated measures of contralateral R1 (cR1) were performed under IGA in 58 patients. Data on presence/absence of cR2 and potential confounders were also collected. Review of neuroimaging, pathology and clinical exam, allowed classification into normal and expected abnormal eLAR groups. Using univariate and multivariate analysis we studied the variability of cR1 parameters and their differences between the two groups. RESULTS: In both groups, cR1 latencies had coefficients of variation of <2%. In the abnormal group, cR1 had longer latencies, required higher activation currents and was more frequently desynchronized and unsustained; cR2 was more frequently absent. CONCLUSIONS: cR1 latencies show high analytical precision for measurements. Delayed onset, difficult to elicit, desynchronized and unsustained cR1, and absence of cR2 signal an abnormal eLAR. SIGNIFICANCE: Understanding the variability and behavior of normal and abnormal eLAR under IGA can aid in the interpretation of its changes during monitoring.
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Reflejo , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Reflejo/fisiología , Adulto , Músculos Laríngeos/fisiopatología , Músculos Laríngeos/fisiología , Electromiografía/métodosRESUMEN
BACKGROUND: Abdominal wall deficiencies or weakness are a common complication of temporary ostomies, and incisional hernias frequently develop after colostomy or ileostomy takedown. The use of synthetic meshes to reinforce the abdominal wall has reduced hernia occurrence. Biologic meshes have also been used to enhance healing, particularly in contaminated conditions. Reinforced tissue matrices (RTMs), which include a biologic scaffold of native extracellular matrix and a synthetic component for added strength/durability, are designed to take advantage of aspects of both synthetic and biologic materials. To date, RTMs have not been reported to reinforce the abdominal wall following stoma reversal. AIM: To evaluate the effectiveness of using an RTM to reinforce the abdominal wall at stoma takedown sites. METHODS: Twenty-eight patients were selected with a parastomal and/or incisional hernia who had received a temporary ileostomy or colostomy for fecal diversion after rectal cancer treatment or trauma. Following hernia repair and proximal stoma closure, RTM (OviTex® 1S permanent or OviTex® LPR) was placed to reinforce the abdominal wall using a laparoscopic, robotic, or open surgical approach. Post-operative follow-up was performed at 1 month and 1 year. Hernia recurrence was determined by physical examination and, when necessary, via computed tomography scan. Secondary endpoints included length of hospital stay, time to return to work, and hospital readmissions. Evaluated complications of the wound/repair site included presence of surgical site infection, seroma, hematoma, wound dehiscence, or fistula formation. RESULTS: The observational study cohort included 16 male and 12 female patients with average age of 58.5 years ± 16.3 years and average body mass index of 26.2 kg/m2 ± 4.1 kg/m2. Patients presented with a parastomal hernia (75.0%), incisional hernia (14.3%), or combined parastomal/incisional hernia (10.7%). Using a laparoscopic (53.6%), robotic (35.7%), or open (10.7%) technique, RTMs (OviTex® LPR: 82.1%, OviTex® 1S: 17.9%) were placed using sublay (82.1%) or intraperitoneal onlay (IPOM; 17.9%) mesh positioning. At 1-month and 1-year follow-ups, there were no hernia recurrences (0%). Average hospital stays were 2.1 d ± 1.2 d and return to work occurred at 8.3 post-operative days ± 3.0 post-operative days. Three patients (10.7%) were readmitted before the 1-month follow up due to mesh infection and/or gastrointestinal issues. Fistula and mesh infection were observed in two patients each (7.1%), leading to partial mesh removal in one patient (3.6%). There were no complications between 1 month and 1 year (0%). CONCLUSION: RTMs were used successfully to treat parastomal and incisional hernias at ileostomy reversal, with no hernia recurrences and favorable outcomes after 1-month and 1-year.
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Phthalimide-N-oxyl (PINO) and related radicals are promising catalysts for C-H functionalization reactions. To date, only a small number of N-oxyl derivatives have demonstrated improved activities over PINO. We postulate that the lack of success in identifying superior catalysts is associated not only with challenges in the design and synthesis of new structures, but also the way catalysts are evaluated and utilized. Catalyst evaluation typically relies on the use of chemical oxidants to generate N-oxyl radicals from their parent N-hydroxy compounds. Herein we provide an example where a potential-controlled electrochemical analysis reveals that succinimide-N-oxyl (SINO) compares favorably to PINO as a hydrogen atom transfer (HAT) catalyst-in contrast to previous claims based on other approaches. Our efforts to understand the basis for the greater reactivity of SINO relative to PINO have underscored that the HAT kinetics are significantly influenced by factors beyond changes in thermodynamics. This is perhaps best illustrated by the similar reactivity of tetrachloro-PINO and SINO despite the latter engaging in substantially more exergonic reactions. The key role of HAT transition state (TS) polarization prompted the design and initial characterization of a chlorinated SINO derivative, which we found to be the most reactive N-oxyl HAT catalyst reported to date.
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The design of N-oxyl hydrogen atom transfer catalysts has proven challenging to date. Previous efforts have focused on the functionalization of the archetype, phthalimide-N-oxyl. Driven in part by the limited options for modification of this structure, this strategy has provided only modest improvements in reactivity and/or solubility. Our previous mechanistic efforts suggested that while the electron-withdrawing carbonyls of the phthalimide are necessary to maximize the O-H bond dissociation enthalpy of the HAT product hydroxylamine and overall reaction thermodynamics, they undergo nucleophilic substitution leading to catalyst decomposition. In an attempt to minimize this vulnerability, we report the characterization of N-oxyl catalysts wherein the aryl ring in PINO is replaced with the combination of a substituted heteroatom and quaternary carbon. By rendering one carbonyl carbon less electrophilic and the other less sterically accessible, the corresponding N1-aryl-hydantoin-N3-oxyl radical showed significantly higher stability than PINO as well as a modest improvement in reactivity. This proof-of-principle in new scaffold design may accelerate future HAT catalyst discovery and development.
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Whether cerebral sympathetic-mediated vasomotor control can be modulated by local brain activity remains unknown. This study tested the hypothesis that the application or removal of a cognitive task during a cold pressor test (CPT) would attenuate and restore decreases in cerebrovascular conductance (CVC), respectively. Middle cerebral artery blood velocity (transcranial Doppler) and mean arterial pressure (finger photoplethysmography) were examined in healthy adults (n = 16; 8 females and 8 males) who completed a control CPT, followed by a CPT coupled with a cognitive task administered either 1) 30 s after the onset of the CPT and for the duration of the CPT or 2) at the onset of the CPT and terminated 30 s before the end of the CPT (condition order was counterbalanced). The major finding was that the CPT decreased the index of CVC, and such decreases were abolished when a cognitive task was completed concurrently and restored when the cognitive task was removed. As a secondary experiment, vasomotor interactions between sympathetic transduction pathways (α1-adrenergic and Y1-peptidergic) and compounds implicated in cerebral blood flow control [adenosine, and adenosine triphosphate (ATP)] were explored in isolated porcine cerebral arteries (wire myography). The data reveal α1-receptor agonism potentiated vasorelaxation modestly in response to adenosine, and preexposure to ATP attenuated contractile responses to α1-agonism. Overall, the data suggest a cognitive task attenuates decreases in CVC during sympathoexcitation, possibly related to an interaction between purinergic and α1-adrenergic signaling pathways.NEW & NOTEWORTHY The present study demonstrates that the cerebrovascular conductance index decreases during sympathoexcitation and this response can be positively and negatively modulated by the application or withdrawal of a nonexercise cognitive task. Furthermore, isolated vessel experiments reveal that cerebral α1-adrenergic agonism potentiates adenosine-mediated vasorelaxation and ATP attenuates α1-adrenergic-mediated vasocontraction.
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Adenosina Trifosfato , Simpaticolíticos , Adulto , Masculino , Femenino , Humanos , Animales , Porcinos , Velocidad del Flujo Sanguíneo/fisiología , Adrenérgicos , Adenosina/farmacología , Circulación Cerebrovascular/fisiología , Presión Sanguínea/fisiología , FríoRESUMEN
BACKGROUND/OBJECTIVES: There is a great unmet need for accessible adjunctive interventions to promote long-term recovery from substance use disorder (SUD). This study aimed to iteratively develop and test the initial feasibility and acceptability of Mindful Journey, a novel digital mindfulness-based intervention for promoting recovery among individuals with SUD. PATIENTS/MATERIALS: Ten adults receiving outpatient treatment for SUD. METHODS: Phase 1 (n = 5) involved developing and testing a single introductory digital lesson. Phase 2 included a separate sample (n = 5) and involved testing all 15 digital lessons (each 30- to 45-minutes) over a 6-week period, while also receiving weekly brief phone coaching for motivational/technical support. RESULTS: Across both phases, quantitative ratings (rated on a 5-point scale) were all at or above a 4 (corresponding with 'agree') for key acceptability dimensions, such as usability, understandability, appeal of visual content, how engaging the content was, and helpfulness for recovery. Additionally, in both phases, qualitative feedback indicated that participants particularly appreciated the BOAT (Breath, Observe, Accept, Take a Moment) tool for breaking down mindfulness into steps. Qualitative feedback was used to iteratively refine the intervention. For example, based on feedback, we added a second core mindfulness tool, the SOAK (Stop, Observe, Appreciate, Keep Curious), and we added more example clients and group therapy videos. In Phase 2, 4 out of 5 participants completed all 15 lessons, providing initial evidence of feasibility. Participants reported that the phone coaching motivated them to use the app. The final version of Mindful Journey was a smartphone app with additional features, including brief on-the-go audio exercises and a library of mindfulness practices. Although, participants used these additional features infrequently. CONCLUSIONS: Based on promising initial findings, future acceptability and feasibility testing in a larger sample is warranted. Future versions might include push notifications to facilitate engagement in the additional app features.