Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride.

A novel reactivity of 1,1,1-trifluoroalkanones is reported, where the reaction with AlCl3 results in the formation of 1,1-dichloro-1-alkenones. The reaction scope was found to be broad, with various chain lengths and aryl substituents tolerated. For substrates containing an electron-rich aromatic ring, further reactions take place, resulting in bicyclic and/or rearrangement products.

Speech and language development in children with 49,XXXXY syndrome.

49,XXXXY is the rarest X and Y chromosomal variation and is frequently characterized by expressive and receptive language dysfunction, low muscle tonus, and intellectual deficits. Due to the low incidence of this disorder, comprehensive studies analyzing the specific aspects of the speech and language phenotype in these boys have been uncommon. This is the first in-depth investigation of the speech and language profiles in a large cohort of boys with 49,XXXXY. Based on the clinical judgment of speech and language pathologists, there was an increased incidence (91.8%) of Childhood Apraxia of Speech (CAS), which has not been previously described in this disorder. In preschool boys, some significant differences were demonstrated between boys who received early hormonal treatment (n = 16) and untreated boys (n = 4) on the language scales (p = .047) on the Bayley Scales of Infants and Toddlers, as well as significant differences between treated (n = 13) and untreated boys (n = 8) on the Expressive One Word Picture Vocabulary Test (p = .008). No significant differences between treatment groups were found in school age children, however, treated groups demonstrated less discrepancies between expressive and receptive language. More research and larger samples are needed to determine the extent of the impact of testosterone treatment on boys with 49,XXXXY. This study identifies CAS as a potential explanation for the significant expressive language dysfunction and subsequent behavioral dysfunction. These findings may assist in facilitating more targeted treatment and improved outcomes for boys with 49,XXXXY.

Dupilumab as a novel therapy for bullous pemphigoid: A multicenter case series.

BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disorder occurring mostly in the elderly that lacks adequate treatments. OBJECTIVE: To describe our experience using dupilumab in a series of patients with BP. METHODS: This is a case series of patients from 5 academic centers receiving dupilumab for BP. Patients were eligible if they had a clinical diagnosis of BP confirmed by lesional skin biopsy evaluated by one of more of the following: hematoxylin and eosin staining, direct immunofluorescence, or enzyme-linked immunosorbent assay for BP180 or BP230, or both. RESULTS: We identified 13 patients. Patients were an average age of 76.8 years, and the average duration of BP before dupilumab initiation was 28.8 months (range, 1-60 months). Disease clearance or satisfactory response was achieved in 92.3% (12 of 13) of the patients. Satisfactory response was defined as clinician documentation of disease improvement and patient desire to stay on the medication without documentation of disease clearance. Total clearance of the BP was achieved in 53.8% (7of 13) of patients No adverse events were reported. LIMITATIONS: Include small sample size, lack of a control group, lack of a standardized assessment tool, and lack of standardized safety monitoring. CONCLUSION: Dupilumab may be an additional treatment for BP, leading to disease clearance or satisfactory response in 92.3% of patients, including in those in whom previous conventional therapy had failed.

Treatment of pemphigus vulgaris: part 1 - current therapies.

Introduction: While biologic agents that can be used for treating pemphigus vulgaris (PV) are increasing, themajority of the world's PV patients can afford only corticosteroids (CS) and some immunosuppressive agents (ISA). Areas covered: The spectrum of side effects encountered when PV patients receive high-dose, long-term CS and ISA are presented based on total dose and duration of therapy. The steroid-sparing effect of individual ISA as documented in published studies and their clinical outcomes, in terms of duration of remissions, frequency of relapses and time to relapse, are presented, so that comparisons are possible. Thus, rational choices can be made for the individual patient. Expert opinion: In 2019, the majority of PV patients globally will continue to be treated with CS and ISA. This review will help clinicians and patients become aware of when to anticipate which side effects and if possible, to prevent or avoid them. It provides guidelines to maximize the clinical benefits of ISA in inducing and maintaining remission and minimizing side effects by monitoring them.

Treatment of pemphigus vulgaris: part 2 - emerging therapies.

Introduction: Corticosteroids and immunosuppressive agents have been the mainstay for the treatment of pemphigus vulgaris (PV). While they have benefited patients, they have been associated with the risks of prolonged immune suppression and a high incidence of significant and catastrophic side effects. Relapses are common. Novel agents promising targeted therapies, that may provide better outcomes, are being studied. Areas covered: Recently rituximab with corticosteroids has been recommended as the first-line treatment for PV. A number of known and new therapeutic agents currently investigated are BAFF, P13K, BTK inhibitors along with the use of IVIg and CAR-T therapy. The possible role of these therapeutic targets in the pathophysiology appears to be the rationale for the treatment of this potentially fatal disease. Expert opinion: While there is significant enthusiasm for these therapies, certain concerns and consequences are being under-discussed. None of the current clinical trials in progress are specific for PV, except possibly CAR-T therapy. The major issue(s) that are unclear is whether these therapies would be successful in providing long-term clinical remissions. Will these therapies require additional agents to be effective? Will the benefits be limited in duration? The answers to many questions will determine their final place in the algorithm for the treatment of PV.

Upper Bound of Neutrino Masses from Combined Cosmological Observations and Particle Physics Experiments.

We investigate the impact of prior models on the upper bound of the sum of neutrino masses, ∑m_{ν}. Using data from the large scale structure of galaxies, cosmic microwave background, type Ia supernovae, and big bang nucleosynthesis, we argue that cosmological neutrino mass and hierarchy determination should be pursued using exact models, since approximations might lead to incorrect and nonphysical bounds. We compare constraints from physically motivated neutrino mass models (i.e., ones respecting oscillation experiments) to those from models using standard cosmological approximations. The former give a consistent upper bound of ∑m_{ν}≲0.26 eV (95% CI) and yield the first approximation-independent upper bound for the lightest neutrino mass species, m_{0}^{ν}<0.086 eV (95% CI). By contrast, one of the approximations, which is inconsistent with the known lower bounds from oscillation experiments, yields an upper bound of ∑m_{ν}≲0.15 eV (95% CI); this differs substantially from the physically motivated upper bound.

Typical carcinoids, goblet cell carcinoids, mixed adenoneuroendocrine carcinomas, neuroendocrine carcinomas and adenocarcinomas of the appendix: a comparative analysis of survival profile and predictors.

BACKGROUND: Goblet cell carcinoids (GCC) and other atypical neuroendocrine tumors (NET) of the appendix as well as appendiceal adenocarcinoma are usually managed with the same algorithm as colon cancers. This study investigates clinicopathological features that are predictive of survival outcomes for appendiceal NET and adenocarcinoma. Survival profiles for the histologic subtypes of appendiceal NET and adenocarcinoma were compared. METHODS: A retrospective review of appendiceal NET and adenocarcinoma for patients who are 18 years and above in the SEER database from 2010 to 2014. RESULTS: Females outnumbered males in a 1.3 to 1 ratio in the NET subgroup and 1.1 to 1 ratio in the adenocarcinoma group. The mean age at diagnosis for all NET was 50.3±17 years while that of adenocarcinomas was 60.8±14.1 years. Within the NET subgroups, the mean ages for typical carcinoids (TC), GCC, NEC and MANEC were 42.9±17.3, 56.7±13.7, 45.6±17.4 and 59.7±12.8 years, respectively. Overall survival for adenocarcinoma was 86.3%, 73.5%, 65.7%, and 57.6% for 1-, 2-, 3- and 4-year OS, respectively. For NET, TC showed better survival profile with 1- and 4-year overall survival of 97.4% and 95.7%, respectively while MANEC had the worst survival outcome with 1- and 4-year OS of 88.6% and 62.2%, respectively. GCC had a better 1-year OS compared to NEC (95.5% versus 92.9%) but showed slightly worse 4-year OS (82% versus 84.8%). Age at diagnosis (HR 1.03), African-American race (HR 1.47) and stage IV disease (HR 9.58) were independent predictors of survival for appendiceal adenocarcinoma. For NET, advanced age at diagnosis, advanced disease stage and the African-American race were identified as negative independent predictors of survival. CONCLUSIONS: While prior studies have suggested that atypical NET (GCC, NEC and MANEC) are more likely to present at more advanced stages, this study showed that most cases of GCC, MANEC and NEC were diagnosed at stages I and II. Appendiceal adenocarcinoma, on the other hand, presented mostly at stage IV. With respect to OS, atypical histologic subtypes of NET have worse outcome compared to TC. Although better OS was noted for GCC, NEC and MANEC when compared to adenocarcinoma, this benefit was lost in stage IV disease where adenocarcinoma recorded better 1- and 4-year OS. Prospective and randomized studies which provide granular details of treatment are needed to better define treatment algorithm for appendiceal NET.

Adrenocortical oncocytic neoplasm: A systematic review.

BACKGROUND: Adrenocortical oncocytic neoplasms are rare tumors, generally regarded as benign and hormonally nonfunctional. We performed a systematic review to update the literature on adrenocortical oncocytic neoplasms by reviewing patient and tumor characteristics, as well as management trends, because the literature is composed of predominately single-case reports. METHODS: A systematic search was performed in PubMed, Embase, and Cochrane Library through June 2017. Malignant potential was determined by applying the Lin-Weiss-Bisceglia criteria to cases. RESULTS: Included for analysis were 84 citations describing 140 adrenocortical oncocytic neoplasms, including our own case. These were diagnosed predominantly in females (66%), on the left side (64%), and were nonfunctional (66%). Average age at diagnosis was 44 years (2.5-77), and median tumor size was 80 mm (16-285). A total of 35% of adrenocortical oncocytic neoplasms were benign, 41% borderline, and 24% malignant. Male patients were more likely to have a malignant tumor compared with females (36% versus 18%, P = .035). The 5-year overall survival for benign adrenocortical oncocytic neoplasms was 100%, borderline 88%, and malignant 47%. Hormonal function did not discriminate malignant from benign lesions. Adrenocortical oncocytic neoplasms that stained positive for synaptophysin (50%, P < .001) and negative for vimentin (62%, P = .009) are more often benign. CONCLUSION: We found that the majority of adrenocortical oncocytic neoplasms (65%) were either malignant or had malignant potential, contrary to the previous literature. The Lin-Weiss-Bisceglia criteria are useful in identifying those patients for whom closer surveillance is warranted, because their prognosis is dependent on the Lin-Weiss-Bisceglia diagnosis.

Comprehensive Multicenter Graduate Surgical Education Initiative Incorporating Entrustable Professional Activities, Continuous Quality Improvement Cycles, and a Web-Based Platform to Enhance Teaching and Learning.

BACKGROUND: It is increasingly important for faculty to teach deliberately and provide timely, detailed, and formative feedback on surgical trainee performance. We initiated a multicenter study to improve resident evaluative processes and enhance teaching and learning behaviors while engaging residents in their education. STUDY DESIGN: Faculty from 7 US postgraduate training programs rated resident operative performances using the perioperative briefing, intraoperative teaching, debriefing model, and rated patient visits/academic performances using the entrustable professional activities model via a web-based platform. Data were centrally analyzed and iterative changes made based on participant feedback, individual preferences, and database refinements, with trends addressed using the Plan, Do, Check, Act improvement methodology. RESULTS: Participants (92 surgeons, 150 residents) submitted 3,880 assessments during July 2014 through September 2017. Evidence of preoperative briefings improved from 33.9% ± 2.5% to 95.5% ± 1.5% between April and September 2014 compared with April and September 2017 (p < 0.001). Postoperative debriefings improved from 10.6% ± 2.7% to 90.2% ± 2.5% (p < 0.001) for the same period. Meaningful self-reflection by residents improved from 28.6% to 67.4% (p < 0.001). The number of assessments received per resident during a 6-month period increased from 6.4 ± 6.2 to 13.4 ± 10.1 (p < 0.003). Surgeon-entered assessments increased from 364 initially to 685 in the final period, and the number of resident assessments increased from 308 to 445. We showed a 4-fold increase in resident observed activities being rated. CONCLUSIONS: By adopting recognized educational models with repeated Plan, Do, Check, Act cycles, we increased the quality of preoperative learning objectives, showed more frequent, detailed, and timely assessments of resident performance, and demonstrated more effective self-reflection by residents. We monitored trends, identified opportunities for improvement and successfully sustained those improvements over time, applying a team-based approach.

Nodular Vasculitis in a Patient With Crohn's Disease on Vedolizumab.

Erythema induratum (EI), or nodular vasculitis (NV), is a type of panniculitis that is often associated with vasculitis affecting various-sized veins, venules, and arteries in reaction to various causative factors. Historically, EI was highly linked to tuberculosis, but in 1946, Montgomery first proposed the term NV to describe cases of EI not associated with tuberculosis. Only 2 reports of NV associated with inflammatory bowel disease have been reported in the literature. The authors report a 60-year-old woman with Crohn's disease presenting with exacerbation of NV in the setting of vedolizumab therapy.

Quality-Based Procedures for Knee Replacement, Hip Replacement, and Hip Fracture: Physiotherapists' Perceptions of Adherence, Barriers, and Facilitators.

Purpose: This mixed-methods study examined the perceived barriers to and facilitators of implementing best-practice guidelines (BPGs) and adhering to provincial Quality-Based Procedures (QBPs) by Ontario physiotherapists working with patients after total knee replacement (TKR), total hip replacement (THR), and hip fracture (HF). Method: Using snowball sampling, 93 hospital and home care physiotherapists working with patients after TKR, THR, or HF completed a Web-based survey. A subset of these participated in follow-up semi-structured telephone interviews. Results: The perception of QBP adherence varied, with self-reported adherence rates across identified practice standards for TKR, THR, and HF reported as 62%, 69%, and 60%, respectively. Physiotherapists generally believed that BPGs improved outcomes; however, they identified clinical experience as their primary guide to practice. Only 66% perceived that their institutions met provincial standards. Barriers to BPG implementation and QBP adherence included insufficient time, lack of access to QBPs, and limited awareness of current BPGs. Qualitative themes included awareness and knowledge, flexibility and funding, communication, and availability of and equitable access to outpatient and community-based physiotherapy services. Conclusions: Physiotherapists reported that they primarily used clinical experience to inform care after TKR, THR, and HF, but they were also supportive of BPGs and QBPs. The results suggest that increased access to and education about QBPs, as well as supportive resources, could increase their integration into clinical practice.

Objectif : cette étude à méthodologie mixte se penche sur les facteurs qui entravent ou facilitent l'application des lignes directrices sur les pratiques exemplaires (LDPE) et des actes médicaux fondés sur la qualité (AMFQ), tels que perçus par les physiothérapeutes de l'Ontario qui traitent des patients ayant subi une arthroplastie totale du genou (ATG), une arthroplastie totale de la hanche (ATH) ou une fracture de la hanche (FH). Méthodologie : à l'aide d'une méthode d'échantillonnage cumulative, 93 physiothérapeutes qui travaillent à l'hôpital et en soins à domicile auprès de patients ayant subi une ATG, une ATH ou une FH ont répondu à un sondage en ligne. Un sous-ensemble de ces répondants a participé à des entrevues téléphoniques de suivi semi-structurées. Résultats : l'adhérence perçue aux AMFQ est variable, les taux de respect autodéclaré des normes de pratique ciblées pour l'ATG, l'ATH et la FH se situant à 62 %, 69 % et 60 %, respectivement. Les physiothérapeutes sont généralement d'avis que les LDPE améliorent les résultats ; cependant, ils considèrent que leur pratique est principalement guidée par l'expérience clinique. Seuls 66 % des répondants sont d'avis que leur établissement respecte les normes provinciales. Les obstacles à l'application des LDPE et des AMFQ comprennent le manque de temps, l'accès limité aux LDPE et la mauvaise connaissance des LDPE actuelles. Les thèmes qualitatifs dégagés comprennent la sensibilisation et les connaissances, la flexibilité et le financement, la communication, la disponibilité des services ambulatoires de physiothérapie ainsi que l'accès équitable à ces derniers. Conclusions : les physiothérapeutes ont indiqué qu'ils ont recours principalement à l'expérience clinique pour guider leurs soins aux patients ayant subi une ATG, une ATH ou une FH, mais qu'ils appuient également les LDPE et les AMFQ. Les résultats laissent penser qu'un meilleur accès aux AMFQ, une meilleure formation sur ceux-ci ainsi que des ressources de soutien pourraient augmenter leur intégration dans la pratique clinique.

Perioperative self-reflection among surgical residents.

BACKGROUND: We studied prevalence and predictors of meaningful self-reflection among surgical residents and with prompting/structured interventions, sought to improve/sustain resident skills. METHODS: Residents from six programs recorded 1032 narrative self-reflective comments (120 residents), using a web-based platform. If residents identified something learned or to be improved, self-reflection was deemed meaningful. Independent variables PGY level, resident/surgeon gender, study site/Phase1: July2014-August2015 vs. Phase2: September2015-September2016) were analyzed. RESULTS: Meaningful self-reflection was documented in 40.6% (419/1032) of entries. PGY5's meaningfully self-reflected less than PGY1-4's, 26.1% vs. 49.6% (p = 0.002). In multivariate analysis, resident narratives during Phase 2 were 4.7 times more likely to engage in meaningful self-reflection compared to Phase1 entries (p < 0.001). Iterative changes during Phase2 showed a 236% increase in meaningful self-reflection, compared to Phase1. CONCLUSIONS: Surgical residents uncommonly practice meaningful self-reflection, even when prompted, and PGY5/chief residents reflect less than more junior residents. Substantial/sustained improvements in resident self-reflection can occur with both training and interventions.

Do female surgeons learn or teach differently?

BACKGROUND: Gender and/or gender-stereotypes might influence surgical education. We hypothesized that female surgeons might focus their learning and teaching differently from male surgeons. METHODS: Residents and surgeons (multi-institutional) individually recorded preoperatively discussed learning objectives (LO) for matching cases. Narratives were classified as knowledge-based, skill-based, or attitude-based. Multinomial logistic regression analyses, LO = dependent variable; independent variables = resident/surgeon gender, PGY level, timing of entry-to-procedure date, and quarters-of-year. RESULTS: 727 LOs from 125 residents (41% female) and 49 surgeons (20% female) were classified. Female residents were 1.4 times more likely to select knowledge over skill. With female surgeons, residents were 1.6 and 2.1 times more likely to select knowledge over skill and attitude over skill than if the surgeon was male. PGY 4/5 residents chose attitude-based LOs over junior residents. CONCLUSION: Resident, surgeon gender and year-of-training influence learning objectives. Whether this reflects gender stereotyping by residents or differences in attending teaching styles awaits further exploration.

A taxonomy of perioperative surgical learning: Trending resident skill acquisition.

BACKGROUND: Resident and curriculum evaluation require tracking surgical resident operative performance, yet what and when to measure remains unclear. METHODS: From a multi-institutional database, we reviewed 611 resident/surgeon-paired assessments of ACGME Milestones and modified OPRS ratings for different cases and postgraduate years. RESULTS: Faculty Milestone ratings increased with each PGY (p=<0.001) and correlated with resident self-ratings (ICC = 0.83). Mean OPRS scores increased in small increments with substantial intra-year variability. Progression among individual OPRS subcategories was not apparent from more global analyses. Interestingly, male faculty offered lower ratings than female faculty. CONCLUSIONS: Milestones and modified mean OPRS ratings suggest residents are learning, yet lack sufficient discrimination for promotion or curricular analysis. Differential progression through OPRS subcategories suggests a taxonomy of surgical learning that can be tailored to focus on different skills at each point in the training continuum. The effect of faculty gender on resident ratings awaits further study.

Decahydrobenzoquinolin-5-one sigma receptor ligands: Divergent development of both sigma 1 and sigma 2 receptor selective examples.

Analogues of the decahydrobenzoquinolin-5-one class of sigma (σ) receptor ligands were used to probe the structure-activity relationship trends for this recently discovered series of σ ligands. In all, 29 representatives were tested for σ and opioid receptor affinity, leading to the identification of compounds possessing improved σ1 selectivity and, for the first time in this series, examples possessing preferential σ2 affinity. Several structural features associated with these selectivity trends have been identified. Two analogues of improved selectivity were evaluated in a binding panel of 43 CNS-relevant targets to confirm their sigma receptor preference.

Efficient access to sp3-rich tricyclic amine scaffolds through Diels-Alder reactions of azide-containing silyloxydienes.

The preparation of sp3-rich scaffolds to obtain more natural product-like libraries for incorporation into screening decks is challenging. Here, we describe the use of a Diels-Alder reaction between an enone and an azide-containing silyloxydiene to gain efficient access to complex tricyclic amine scaffolds. Derivatization of these scaffolds provided a library of 80 amines, amides, sulfonamides, quinolines and indolenines, all in >20 mg quantities and >90% purities. These library compounds displayed properties more similar to alkaloid natural products than to drugs and commercial drug-like libraries, as shown by a high proportion of sp3 carbon centers.

Short inter-set rest blunts resistance exercise-induced increases in myofibrillar protein synthesis and intracellular signalling in young males.

What is the central question of this study? Does shorter rest between sets of resistance exercise promote a superior circulating hormonal and acute muscle anabolic response compared with longer rest periods? What is the main finding and its importance? We demonstrate that short rest (1 min) between sets of moderate-intensity, high-volume resistance exercise blunts the acute muscle anabolic response compared with a longer rest period (5 min), despite a superior circulating hormonal milieu. These data have important implications for the development of training regimens to maximize muscle hypertrophy. Manipulating the rest-recovery interval between sets of resistance exercise may influence training-induced muscle remodelling. The aim of this study was to determine the acute muscle anabolic response to resistance exercise performed with short or long inter-set rest intervals. In a study with a parallel-group design, 16 males completed four sets of bilateral leg-press and knee-extension exercise at 75% of one-repetition maximum to momentary muscular failure, followed by ingestion of 25 g of whey protein. Resistance exercise sets were interspersed by 1 min (n = 8) or 5 min of passive rest (n = 8). Muscle biopsies were obtained at rest, 0, 4, 24 and 28 h postexercise during a primed continuous infusion of l-[ring-(13) C6 ]phenylalanine to determine myofibrillar protein synthesis and intracellular signalling. We found that the rate of myofibrillar protein synthesis increased above resting values from 0 to 4 h postexercise with 1 (76%; P = 0.047) and 5 min inter-set rest (152%; P < 0.001) and was significantly greater in the 5 min inter-set rest group (P = 0.001). Myofibrillar protein synthesis rates at 24-28 h postexercise remained elevated above resting values (P < 0.05) and were indistinguishable between groups. Postexercise p70S6K(Thr389) and rpS6(Ser240/244) phosphorylation were reduced with 1 compared with 5 min inter-set rest, whereas phosphorylation of eEF2(Thr56) , TSC2(Thr1462) , AMPK(Thr172) and REDD1 protein were greater for 1 compared with 5 min inter-set rest. Serum testosterone was greater at 20-40 min postexercise and plasma lactate greater immediately postexercise for 1 versus 5 min inter-set rest. Resistance exercise with short (1 min) inter-set rest duration attenuated myofibrillar protein synthesis during the early postexercise recovery period compared with longer (5 min) rest duration, potentially through compromised activation of intracellular signalling.

Live strong and prosper: the importance of skeletal muscle strength for healthy ageing.

Due to improved health care, diet and infrastructure in developed countries, since 1840 life expectancy has increased by approximately 2 years per decade. Accordingly, by 2050, a quarter of Europe's population will be over 65 years, representing a 10 % rise in half a century. With this rapid rise comes an increased prevalence of diseases of ageing and associated healthcare expenditure. To address the health consequences of global ageing, research in model systems (worms, flies and mice) has indicated that reducing the rate of organ growth, via reductions in protein synthetic rates, has multi-organ health benefits that collectively lead to improvements in lifespan. In contrast, human pre-clinical, clinical and large cohort prospective studies demonstrate that ageing leads to anabolic (i.e. growth) impairments in skeletal muscle, which in turn leads to reductions in muscle mass and strength, factors directly associated with mortality rates in the elderly. As such, increasing muscle protein synthesis via exercise or protein-based nutrition maintains a strong, healthy muscle mass, which in turn leads to improved health, independence and functionality. The aim of this review is to critique current literature relating to the maintenance of muscle mass across lifespan and discuss whether maintaining or reducing protein synthesis is the most logical approach to support musculoskeletal function and by extension healthy human ageing.