Acridine photocatalysis enables tricomponent direct decarboxylative amine construction.

Amines are centrally important motifs in medicinal chemistry and biochemistry, and indispensable intermediates and linchpins in organic synthesis. Despite their cross-disciplinary prominence, synthetic access to amine continues to rely on two-electron approaches based on reductions and additions of organometallic reagents, limiting their accessible chemical space and necessitating stepwise preassembly of synthetic precursors. We report herein a homogeneous photocatalytic tricomponent decarboxylative radical-mediated amine construction that enables modular access to α-branched secondary amines directly from the broad and structurally diverse chemical space of carboxylic acids in a tricomponent reaction with aldehydes and aromatic amines. Our studies reveal the key role of acridine photocatalysis acting in concert with copper and Brønsted acid catalytic processes in facilitating the previously inaccessible homogeneous photocatalytic reaction and provide a streamlined segue to a wide range of amines and nonproteinogenic α-amino acids.

Multimodal Acridine Photocatalysis Enables Direct Access to Thiols from Carboxylic Acids and Elemental Sulfur.

Development of photocatalytic systems that facilitate mechanistically divergent steps in complex catalytic manifolds by distinct activation modes can enable previously inaccessible synthetic transformations. However, multimodal photocatalytic systems remain understudied, impeding their implementation in catalytic methodology. We report herein a photocatalytic access to thiols that directly merges the structural diversity of carboxylic acids with the ready availability of elemental sulfur without substrate preactivation. The photocatalytic transformation provides a direct radical-mediated segue to one of the most biologically important and synthetically versatile organosulfur functionalities, whose synthetic accessibility remains largely dominated by two-electron-mediated processes based on toxic and uneconomical reagents and precursors. The two-phase radical process is facilitated by a multimodal catalytic reactivity of acridine photocatalysis that enables both the singlet excited state PCET-mediated decarboxylative carbon-sulfur bond formation and the previously unknown radical reductive disulfur bond cleavage by a photoinduced HAT process in the silane-triplet acridine system. The study points to a significant potential of multimodal photocatalytic systems in providing unexplored directions to previously inaccessible transformations.

The "cesium effect" magnified: exceptional chemoselectivity in cesium ion mediated nucleophilic reactions.

Chemodivergent construction of structurally distinct heterocycles from the same precursors by adjusting specific reaction parameters is an emergent area of organic synthesis; yet, understanding of the processes that underpin the reaction divergence is lacking, preventing the development of new synthetic methods by systematically harnessing key mechanistic effects. We describe herein cesium carbonate-promoted oxadiaza excision cross-coupling reactions of ß-ketoesters with 1,2,3-triazine 1-oxides that form pyridones in good to high yields, instead of the sole formation of pyridines when the same reaction is performed in the presence of other alkali metal carbonates or organic bases. The reaction can be further extended to the construction of synthetically challenging pyridylpyridones. A computational study comparing the effect of cesium and sodium ions in the oxadiaza excision cross-coupling reactions reveals that the cesium-coordinated species changes the reaction preference from attack at the ketone carbonyl to attack at the ester carbon due to metal ion-specific transition state conformational accommodation, revealing a previously unexplored role of cesium ions that may facilitate the development of chemodivergent approaches to other heterocyclic systems.

Kinetically-driven reactivity of sulfinylamines enables direct conversion of carboxylic acids to sulfinamides.

Sulfinamides are some of the most centrally important four-valent sulfur compounds that serve as critical entry points to an array of emergent medicinal functional groups, molecular tools for bioconjugation, and synthetic intermediates including sulfoximines, sulfonimidamides, and sulfonimidoyl halides, as well as a wide range of other S(iv) and S(vi) functionalities. Yet, the accessible chemical space of sulfinamides remains limited, and the approaches to sulfinamides are largely confined to two-electron nucleophilic substitution reactions. We report herein a direct radical-mediated decarboxylative sulfinamidation that for the first time enables access to sulfinamides from the broad and structurally diverse chemical space of carboxylic acids. Our studies show that the formation of sulfinamides prevails despite the inherent thermodynamic preference for the radical addition to the nitrogen atom, while a machine learning-derived model facilitates prediction of the reaction efficiency based on computationally generated descriptors of the underlying radical reactivity.

The Use of Integra Dermal Regeneration Templates and Cortical Bone Fenestrations over Exposed Tibia.

We present the case of an 86-year-old woman who suffered full-thickness soft tissue loss secondary to degloving injury to the lower left limb, resulting in an exposed tibia. This patient underwent drilling to create artificial fenestrations in the cortical bone followed by placement of Integra dermal regeneration template. The technique of drilling fenestrations to expose underlying vasculature of cortical bone has not previously been described in its relationship with Integra dermal regeneration templates in large degloving injuries of the lower limb. This technique enabled us to perform earlier skin grafting and ultimately resulted in complete and timely wound closure. We present this case as a comparable alternative treatment in cases of reconstructive surgery secondary to severe burns or trauma to reduce the time required for successful wound closure over exposed bone in full-thickness tissue loss injuries of the lower limb.

Meeting the Challenge of Analgesia in a Pregnant Woman With Burn Injury Using Subanesthetic Ketamine: A Case Report and Literature Review.

Pain management guidelines for burn injury in pregnant women are scarce. Maternal and fetal morbidity and mortality in pregnant burn patients have been shown to be higher than that of the general population, especially in severe burns. Early intervention and interdisciplinary treatment are critical to optimize maternal and fetal outcomes. Proper pain management is central to wound treatment, as poor control of pain can contribute to delayed healing, re-epithelialization, as well as persistent neuropathic pain. We present this case of a 34-year-old female patient who suffered an 18% total body surface area burn during the third trimester of pregnancy to demonstrate that ketamine can be considered as an adjunct for procedural and background analgesia during the third trimester, as part of a multimodal strategy in a short-term, monitored setting after a thorough and complete analysis of risks and benefits and careful patient selection.

Laryngotracheal stenosis in burn patients requiring mechanical ventilation.

OBJECTIVE: To identify the incidence of laryngotracheal stenosis (LTS) in burn patients requiring mechanical ventilation at a regional academic burn center. METHODS: A retrospective review of all burn patients requiring endotracheal intubation or tracheostomy for airway management between 2003 and 2009 was performed. A group of trauma patients requiring similar airway instrumentation during the same period of time was used as a control. RESULTS: None of the trauma patients and 2 of the burn patients developed LTS. Both presented with stridor and were diagnosed within 2-5 weeks after extubation. One patient underwent successful carbon dioxide laser radial incision and dilation and continues to do well. The other patient failed endoscopic treatment and required T-tube placement. The incidence of LTS in burn patients requiring mechanical ventilation was 2.98% overall and 4.76% among those with inhalational injury. CONCLUSIONS: Patients become symptomatic within weeks of the initial injury. Treatment is challenging and multiple surgical procedures are often required. A larger study is necessary to determine if the incidence is higher among burn patients.

Maximizing functional mobility in an electrical burn patient using a patellar tendon bearing orthosis.

OBJECTIVE: Injury to the foot and ankle without involvement of the knee, requiring a patient to become non-weight-bearing or even needing amputation, is a common problem resulting from diverse causes, including diabetic foot ulcers and trauma. The patellar tendon bearing orthosis may be a good option for patients who would functionally deteriorate, attempting to live their lives without the use of a leg. This brace was introduced 58 years ago; however, it is under-utilized clinically and under-represented in the literature. CASE REPORT: A 25-year-old man with severe electrical burn injuries resulting in an unstable ankle who, through the use of patellar tendon bearing orthosis and therapeutic rehabilitation, was able to walk at a supervision level without additional assistive devices. CONCLUSION: The patellar tendon bearing orthosis is recommended, not only for other burn patients who are unable to weight-bear through their ankle-foot complex, but for other patients, such as trauma patients, to allow for ambulation.

Gastric Electric Stimulation for Refractory Gastroparesis: A Prospective Analysis of 151 Patients at a Single Center.

BACKGROUND: Gastric electric stimulation (GES) is used to treat patients with refractory gastroparesis symptoms. However, the effectiveness of GES in clinical practice and the effect of GES on specific symptoms of gastroparesis are not well delineated. AIMS: To determine the effectiveness of GES for treatment for refractory symptoms of gastroparesis, the improvement in specific symptoms of gastroparesis, and clinical factors impacting on outcome. METHODS: Enterra GES was used to treat refractory gastroparesis symptoms. Patients filled out a symptom severity questionnaire (PAGI-SYM) prior to insertion. At each follow-up visit, the patient filled out PAGI-SYM and assessed their therapeutic response using the Clinical Patient Grading Assessment Scale (CPGAS). RESULTS: One hundred and fifty-one patients (120 females) with refractory gastroparesis (72 diabetic, 73 idiopathic, 6 other) underwent GES. Of the 138 with follow-up (1.4 ± 1.0 years), the average CPGAS was 2.4 ± 0.3 (SEM): 104 patients (75 %) improved (CPGAS > 0) and 34 (25 %) did not (CPGAS ≤ 0). Sixty patients (43 %) were at least moderately improved (CPGAS score ≥4). Clinical improvement was seen in both diabetic and idiopathic patients with the CPGAS in diabetic patients (3.5 ± 0.3) higher in idiopathic patients (1.5 ± 0.5; p < 0.05). Symptoms significantly improving the most included nausea, loss of appetite, and early satiety. Vomiting improved in both diabetic and idiopathic patients although the diabetic subgroup experienced a significantly greater reduction in vomiting than the idiopathic subgroup. CONCLUSIONS: In this cohort of patients with refractory gastroparesis, GES improved symptoms in 75 % of patients with 43 % being at least moderately improved. Response in diabetics was better than in nondiabetic patients. Nausea, loss of appetite, and early satiety responded the best.

Reimbursement for out-of-state burn patients is not always lower than that for in-state patients at regional burn centers.

Because burn care in the United States is regionalized, burn patients are often transported across state lines to receive their burn treatment. The authors hypothesized that there are differences between in-state and out-of-state reimbursement for burn care. This project was conducted by the American Burn Association (ABA) Government Affairs Committee through the ABA Multicenter Trials Group. Participation was open to any member of the ABA. This retrospective observational study was approved by the institutional review boards of each participating institution. Subjects were identified using registry of each site, selecting patients hospitalized for burn injuries during FY2004-FY2006 of the hospitals. Once identified by the registry, the ID numbers were used to collect billing and reimbursement data from the financial offices. Data were sorted by age (adult and pediatric), location (in state and out of state), and payor source (Medicare, Medicaid, commercial, workers compensation, and self-pay). The rate of reimbursement was calculated based on charges and recoveries. Comparisons on data of each center were performed using Student's t-test with type I error <1%. Six facilities contributed data. A total of 4850 burn patients were reviewed, of whom 3941 were in-state burn patients and 909 were out-of-state burn patients. When the results from all six states were analyzed together, reimbursement for adults from Medicaid and Medicare was higher for in-state patients than for out-of-state patients. However, when analyzed by state, Medicare reimbursement between in-state and out-of-state patients did not differ significantly. In one state (Kansas), in-state Medicaid reimbursement was higher, but in two others (Arizona and Pennsylvania), in-state Medicaid reimbursement was lower than that for out-of-state reimbursement. Reimbursement for the care of children did not differ significantly based on state of residence. From these data, we conclude that there are indeed variations between in-state and out-of-state reimbursement, but those variations differ regionally. Indeed, in some cases, out-of-state reimbursement exceeds in-state reimbursement. Careful examination of these data is necessary before recommending policy change, although consideration should be given to a national policy that guarantees uniformity of reimbursement across all payors for burn patients regardless of their state of residence.

Secondary abdominal compartment syndrome in children with burns and trauma: a potentially lethal complication.

Acute, rapid, and unimpeded increases in intra-abdominal pressure can lead to multiple organ dysfunction defined as the abdominal compartment syndrome (ACS). If this develops in the absence of obvious intra-abdominal injury, it has been termed secondary ACS (2 degrees ACS). Massive fluid resuscitation in the presence of large burns or shock can lead to 2 degrees ACS. The importance of early recognition and the need for urgent abdominal decompression have been recognized in adults; however, this has not been appreciated in the pediatric population. Medical records of four children diagnosed with 2 degrees ACS were reviewed. Secondary ACS occurred in three children with burns and in one child with a traumatic brain injury. Three children underwent decompressive laparotomy, and one underwent successful percutaneous drainage. There were two survivors. Secondary ACS may be observed in burnt or traumatized children needing large volume resuscitation. Early recognition of 2 degrees ACS by routine bladder pressure monitoring in this high-risk group of children may result in earlier decompression and a possible decrease in morbidity and mortality.