Search

Body lice transport B. recurrentis from man to man and humans are the only host. The presence of lice in Italy and an increasing number of cases in migrants can contribute to the onset of autochthonous cases. In this paper, we report a new case of Louse-borne Relapsing Fever (LBRF) diagnosed among migrants in Sicily exactly one year after the first case was recorded. We reviewed all cases reported in Europe from February 2016 until now. Our study identified two new cases of LBRF in migrants arrived in Europe: one who came from Somalia and one from Mali. Here we report data on a new case in Sicily. The number of migrants and refugees to transit in Sicily has increased, and this has led to the introduction of infectious diseases. Therefore, in our opinion it is essential to upgrade control of the sanitation conditions of migrants.

Escherichia coli ST131 is an emerging resistant agent recently called “superbug” in England. This strain is responsible of community-acquired urinary tract infections and nowadays showing increasing resistance to antibiotics like fluoroquinolones and cephalosporins. Survey of virulent bacterial clone is relevant to control its spreading in community. We aim to assess the circulation of resistant clones Escherichia coli ST131 outside of the hospital to prompt control of outbreak in our geographical area. We selected 105 E. coli resistant isolates from community-acquired urinary infections and performed a multiplex PCR to evaluate if they belonged to the ST131 type. We investigated their set of virulence factors; in particular, kpsMII, papA, sfaS, focG, iutA, papC, hlyD and afa genes, and finally, we evaluated beta lactamases genes and quinolone resistance determinants. E. coli ST 131 clone was present in 66.6% of our isolates and showed positivity to a wide range of resistance genes, in particular blaCTX-M-15 among beta lactamases and plasmid-related quinolone resistance genes (qnrA, qnrS and aac (6’)-Ib-cr). Moreover, 81% of the strains showed positivity to at least one of the virulence factor genes. Our results suggested a high presence of E. coli ST131 in community. We suggest antibiotic stewardship for outpatient clinicians and facilities to contain the spread of “superbug” agents.

We developed a high efficiency endocrine operative protocol based on a mathematical programming approach, process reengineering, and value-stream mapping to increase the number of operations completed per day without increasing operating room time at a tertiary-care, academic center.Using this protocol, a case-control study of 72 patients undergoing endocrine operation during high efficiency days were age, sex, and procedure-matched to 72 patients undergoing operation during standard days. The demographic profile, operative times, and perioperative complications were noted.The average number of cases per 8-hour workday in the high efficiency and standard operating rooms were 7 and 5, respectively. Mean procedure times in both groups were similar. The turnaround time (mean ± standard deviation) in the high efficiency group was 8.5 (±2.7) minutes as compared with 15.4 (±4.9) minutes in the standard group (P .001). Transient postoperative hypocalcemia was 6.9% (5/72) and 8.3% (6/72) for the high efficiency and standard groups, respectively (P = .99).In this study, patients undergoing high efficiency endocrine operation had similar procedure times and perioperative complications compared with the standard group. The proposed high efficiency protocol seems to better utilize operative time and decrease the backlog of patients waiting for endocrine operation in a country with a universal national health care program.

In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxy-phenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [35S]GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties.

This paper proposes a dual three-level, T-type, neutral-point clamped (T-NPC) inverter fed dual permanent magnet synchronous motor topology for low-voltage, high-power traction applications. The switching pulses of the T-NPC inverters are interleaved and controlled, such that they produce equal and opposite three-phase currents at their output. This maintains balanced dc-link voltages in steady-state and transient conditions, even with slight mismatches between two sets of three-phase loads. Thus, the proposed configuration decouples the modulation strategy from the capacitor balancing control. Simulation and experimental results demonstrate that in comparison to the conventional single T-NPC inverter, the proposed topology reduces dc-link capacitors’ voltage deviation and current stress by more than 90% while avoiding additional switching instances to balance capacitor voltages.

In this study, we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues (5, 6a,b, and 7a,b), which are analogues of our lead structure epibatidine. All of the analogues had subnanomolar binding affinity for α4β2*-nAChRs, and all were potent antagonists of α4β2-nAChRs in an in vitro functional assay. Analogues 6a,b were also highly selective for α4β2- relative to α3β4- and α7-nAChRs. Surprisingly, all of the analogues were exceptionally potent antagonists of nicotine-induced antinociception in the mouse tail-flick test, relative to standard nAChR antagonists such as DHβE. 2'-Fluoro-(4-carbamoyl-3-pyridinyl)deschloroepitabidine (6a) displayed an attractive combination of properties, including subnanomolar binding affinity (Ki = 0.07 nM), submicromolar inhibition of α4β2-nAChRs in the functional assay (IC50 = 0.46 μM) with a high degree of selectivity for α4β2- relative to the α3β4/α7-nAChRs (54-/348-fold, respectively), potent inhibition of [(3)H]dopamine release mediated by α4β2*- and α6β2*-nAChRs in a synaptosomal preparation (IC50 = 21 and 32 nM, respectively), and an AD50 of 0.007 μg/kg as an antagonist of nicotine induced antinociception in the mouse tail-flick test which is 64 250 times more potent than DHβE. These data suggest that compound 6a will be highly useful as a pharmacological tool for studying nAChRs and merits further development.

The emerging trend for electric utilities to install wind-based generation on a large scale into distribution networks, employing a doubly fed induction generator or full-converter turbine technologies is raising issues for distribution planning engineers with regard to flicker among other power-quality (PQ) issues. This paper investigates dynamic volt/var control, a viable flicker mitigation technique which exploits the reactive power capabilities of modern power-electronic interfaced wind turbine generators. Dynamic volt/var control essentially mitigates flicker by solely dispatching reactive power based on voltage fluctuations within the flicker frequency band. This technique can be incorporated as part of a wind farm multiobjective reactive power-control scheme, which facilitates regulating: 1) the voltage level at the point of common coupling (PCC), employing slow-acting voltage control or power factor control and 2) the flicker level at the PCC with fast-acting dynamic volt/var control. This two-level approach can reduce the wind farm flicker level up to 80% and maintains the voltage level at the PCC well within acceptable bands. The results presented in this paper focus on a typical 25-kV medium-voltage distribution feeder integrating wind-based generation on a large scale. The performance of the two-level controller was tested for varying levels of penetration and wind speed conditions. The applicable standards and utility grid-code requirements are considered throughout.

IMPORTANCE: Frailty represents a multidimensional syndrome that is increasingly being used to stratify risk in surgical patients. Current frailty risk models are limited among those undergoing thyroid or parathyroid surgery. OBJECTIVE: To develop and compare preoperative risk indices to determine factors associated with short-term major postoperative adverse events in patients undergoing thyroid or parathyroid surgery. DESIGN, SETTING, AND PARTICIPANTS: This cohort study evaluated 154 895 patients in the American College of Surgeons National Surgical Quality Improvement Program who underwent thyroid or parathyroid surgery from January 1, 2007, to December 31, 2016. EXPOSURES: Preoperative frailty-related and surgical factors from a derivation cohort were evaluated using simple and multiple logistic regression. Variables potentially associated with postoperative adverse events were subsequently combined into a personalized preoperative Cervical Endocrine Surgery Risk Index (CESRI) and compared with existing risk models using the validation cohort. MAIN OUTCOMES AND MEASURES: Composite variable of any major postoperative adverse event, including death, within 30 days of surgery. RESULTS: Of the 154 895 operations reviewed, 3318 patients (2.1%; 2296 women and 1022 men; mean [SD] age, 56.1 [15.6] years) experienced a major postoperative adverse event, with 163 deaths (0.1%). Older age (age, ≥80 years: odds ratio [OR], 2.35; 95% CI, 1.74-3.13), inpatient status (OR, 3.55; 95% CI, 3.08-4.11), male sex (OR, 1.49; 95% CI, 1.29-1.71), current tobacco smoking (OR, 1.25; 95% CI, 1.05-1.48), dyspnea (OR, 1.58; 95% CI, 1.29-1.91), recent weight loss (OR, 1.88; 95% CI, 1.23-2.78), functional dependence (OR, 2.77; 95% CI, 2.05-3.69), obesity (OR, 1.33; 95% CI, 1.10-1.60), anemia (OR, 2.14; 95% CI, 1.82-2.52), leukocytosis (OR, 1.73; 95% CI, 1.38-2.14), hypoalbuminemia (OR, 1.87; 95% CI, 1.56-2.23), use of anticoagulation (OR, 2.16; 95% CI, 1.64-2.81), and length of surgery (>4 hours: OR, 2.92; 95% CI, 2.37-3.59) were independently associated with major adverse events or death on multiple regression analysis (C statistic, 0.77; 95% CI, 0.76-0.78). The area under the curve of the CESRI to determine major adverse events, including death, using the validation cohort was 0.63 (95% CI, 0.61-0.64), with a sensitivity of 0.66 (95% CI, 0.64-0.68) and specificity of 0.66 (95% CI, 0.65-0.66). The CESRI outperformed other risk models for determining adverse events (CESRI vs 5-Factor Modified Frailty Index: delta C index, 0.11; 95% CI, 0.09-0.13; CESRI vs American Society of Anesthesiologists Physical Status Classification System: delta C index, 0.05; 95% CI, 0.03-0.07; CESRI vs American College of Surgeons Risk Calculator: delta C index, 0.02; 95% CI, 0.01-0.03; and CESRI vs Head and Neck Surgery Risk Index: delta C index, 0.04; 95% CI, 0.03-0.06). CONCLUSIONS AND RELEVANCE: This study suggests that the CESRI is able to determine major postoperative adverse events in patients undergoing thyroid or parathyroid surgery.

The demonstrated role of PKC

Past studies have shown that it has been difficult to discover and develop potent and selective κ opioid receptor antagonists, particularly compounds having potential for clinical development. In this study, we present a structure—activity relationship (SAR) study of a recently discovered new class of tetrahydroisoquinoline κ opioid receptor antagonists which led to (3R)-7-hydroxy-N-{(1S)-2-methyl-1-[(−4-methylpiperidine-1-yl)methyl]propyl}−1,2,3,4-tetrahydroisoquinoline-3-carboxamide (12) (4-Me-PDTic). Compound 12 had a K(e) = 0.37 nM in a [(35)S]GTPγS binding assay and was 645- and >8100-fold selective for the κ relative to the μ and δ opioid receptors, respectively. Calculated log BB and CNS (central nervous system) multiparameter optimization (MPO) and low molecular weight values all predict that 12 will penetrate the brain, and pharmacokinetic studies in rats show that 12 does indeed penetrate the brain.

The one-carbon carrier of the formate oxidation level derived from the interaction of tetrahydrofolate and formiminoglutamate, which has been tentatively identified as 5-formiminoltetrahydrofolate, has been prepared by chemical synthesis. Treatment of a solution of (6S)-tetrahydrofolate in aqueous base with excess ethyl formimidate in the presence of anti-oxidant under anaerobic conditions afforded a gummy solid which, based on mass spectral analysis, conformed to a monoformimino derivative of tetrahydrofolate. Further physicochemical characterization by validated methods strongly suggested that the product of chemical synthesis was identical to the enzymatically produced material and that it was, in fact, (6S)-5-formiminotetrahydrofolate. Conditions and handling methods toward maintaining the integrity of this highly sensitive compound were identified and are described, as is analytical methodology, useful for research studies using it.

Objectives/Hypothesis Despite the transition to competency-based education in surgery, few standardized assessment tools exist in otolaryngology training. In particular, myringotomy and tympanostomy tube insertion (M+T) is a common surgical procedure with few validated assessment tools available. Our objectives were to develop an objective structured assessment of operative skills in M+T and to provide validity evidence for the developed assessment tool within otolaryngology training. Study Design Prospective study involving the evaluation of an assessment tool. Methods Through consultation with a panel of experts in otolaryngology and medical education we developed a Task-Specific Checklist and Global Rating Scale for M+T. Postgraduate year 2 junior residents, postgraduate year 3 senior residents, and attending otolaryngologists were video recorded performing M+T at a tertiary care pediatric hospital. The videos were subsequently reviewed and independently evaluated by three blinded raters from an unaffiliated academic institution. Results The average score of junior residents, senior residents, and attending otolaryngologists using the Task-Specific Checklist was 21.7/30 (±7.1), 26.3/30 (±3.5), and 27.3/30 (±6.2), respectively (P = .04). For the Global Rating Scale, the scores for junior residents, senior residents, and attending surgeons were 27.7/50 (±11.2), 34.5/50 (±9.5), and 45.1/50 (±4.6), respectively (P < .001). The inter-rater and intrarater reliability were both above 0.88. Conclusions The Task-Specific Checklist and Global Rating Scale for M+T appear reliable, with validity evidence supporting their use in otolaryngology training. Level of Evidence NA Laryngoscope, 2015

Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All of the analogs had high binding affinity for α4β2(∗)-nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound 6b had a Ki = 0.13 nM in the binding assay, 25- and 46-fold selectivity for the α4β2(∗)-nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD50 = 0.13 μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders.

Patients with cystic fibrosis (CF) frequently present with severe sinonasal disease often requiring radiologic imaging and surgical intervention. Few studies have focused on the relationship between radiologic scoring systems and the need for sinus surgery in this population. The objective of this study is to evaluate the Lund-Mackay (LM) and modified Lund-Mackay (m-LM) scoring systems in predicting the need for sinus surgery or revision surgery in patients with CF.We performed a retrospective chart review of CF patients undergoing computed tomography (CT) sinus imaging at a tertiary care pediatric hospital from 1995 to 2008. Patient scans were scored using both the LM and m-LM systems and compared to the rate of sinus surgery or revision surgery. Receiver-operator characteristics curves (ROC) were used to analyze the radiological scoring systems.A total of 41 children with CF were included in the study. The mean LM score for patients undergoing surgery was 17.3 (±3.1) compared to 11.5 (±6.2) for those treated medically (p0.01). For the m-LM, the mean score of patients undergoing surgery was 20.3 (±3.5) and 13.5 (±7.3) for those medically treated (p0.01). Using a ROC curve with a threshold score of 13 for the LM, the sensitivity was 89.3% (95% CI of 72-98) and specificity of 69.2% (95% CI of 39-91). At an optimal score of 19, the m-LM system produced a sensitivity of 67.7% (95% CI of 48-84) and specificity of 84.6% (95% CI of 55-98).The modified Lund-Mackay score provides a high specificity while the Lund-Mackay score a high sensitivity for CF patients who required sinus surgery. The combination of both radiologic scoring systems can potentially predict the need for surgery in this population.

Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein–coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family. Using real-time, live-cell assays, we identified the signaling profiles of several NOPR-selective ligands in upstream GPCR signaling (G protein and arrestin pathways) to determine their relative transduction coefficients and signaling bias. Complementing this analysis, we designed novel ligands on the basis of NOPR antagonist J-113,397 [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] to explore structure-activity relationships. Our study shows that NOPR is capable of biased signaling, and further, the NOPR selective ligands MCOPPB [1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-(3R)-3-piperidinyl-1H-benzimidazole trihydrochloride] and NNC 63-0532 [8-(1-naphthalenylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-3-acetic acid, methyl ester] are G protein–biased agonists. Additionally, minor structural modification of J-113,397 can dramatically shift signaling from antagonist to partial agonist activity. We explore these findings with in silico modeling of binding poses. This work is the first to demonstrate functional selectivity and identification of biased ligands at the nociceptin opioid receptor.

An array of genetic syndromes has been associated with intra-oral adhesions in neonates. The primary medical issues arise from airway obstruction, feeding difficulties and poor oral development, specifically with cleft palate lateral synechia syndrome (CPLSS). Despite this, a paucity of data exists for the clinical management of intra-oral adhesions in this population. We report the cases of a father and daughter diagnosed with CPLSS who presented with respiratory and feeding difficulties at birth undergoing surgical correction. Early surgical ligation of intra-oral bands allows for a stabilization of the airway, improved feeding and oral development with a good long-term outcome.

Pyrido[3,4]homotropane (PHT) is a conformationally rigid, high affinity analogue of nicotine. (+)-PHT was previously shown to be 266 times more potent than (-)-PHT for inhibition of [(3)H]epibatidine binding to nAChRs but had no antinociceptive activity in mouse tail-flick or hot-plate tests and was not a nicotinic antagonist even when administered intrathecally. While (-)-PHT had no agonist activity, it was a potent, nicotinic antagonist in the test. Here, electrophysiological studies with rat nAChRs show (+)-PHT to be a low efficacy partial agonist selective for α4β2-nAChRs, relative to α3β4-nAChRs (15-fold) and α7-nAChRs (45-fold). (-)-PHT was an antagonist with selectivity for α3β4, relative to α4β2- (3-fold) and α7- (11-fold) nAChRs. In [(3)H]DA release studies in mice, (+)-PHT was 10-fold more potent than (-)-PHT at α4β2*-nAChRs and 30-fold more potent at α6β2*-nAChRs. Studies using α5KO mice suggested that much of the activity at α4β2*-nAChRs is mediated by the α4β2α5-nAChR subtype. In conditioned place preference studies, (-)-PHT was more potent than (+)-PHT in blocking nicotine reward. Off-target screens showed (+)- and (-)-PHT to be highly selective for nAChRs. The high potency, full agonism of (+)- and (-)-PHT at α6*-nAChR contrasts with the partial agonism observed for α4*-nAChR, making these ligands intriguing probes for learning more about the pharmacophores for various nAChRs.

Summary Background In-office laryngeal surgery is taking on a more commonplace role in the treatment of laryngeal disorders. The potassium-titanyl-phosphate (KTP) laser has been a resourceful adjunct to the management of patients with mucosal lesions of the vocal cords. However, a paucity of data exists for its use in postintubation granulomas treated in-office. Clinical Case A 43-year-old female presented with voice hoarseness and found to have a large obstructing postintubation granuloma which was treated by in-office KTP laser and en masse excision. Conclusions We report the successful case of a patient receiving in-office treatment for a large vocal process granuloma using the KTP laser with en masse excision. The combined use of the KTP laser and forceps in-office can be valuable to the surgical management of vocal process granulomas, given their numerous recurrences. New avenues in office-based surgical management of laryngeal disorders can offer accessibility and decreased morbidity to patients.

The photolabile analogue of the broad-spectrum opioid antagonist naloxone, 3-O-(4,5-dimethoxy-2-nitrophenyl)carboxymethyl naloxone (also referred to as “caged naloxone”, 3-O-(α-carboxy-6-nitroveratryl)naloxone, CNV-NLX), has been found to be a valuable biochemical probe. While the synthesis of CNV-NLX is simple, its characterization is complicated by the fact that it is produced as a mixture of αR,5R,9R,13S,14S and αS,5R,9R,13S,14S diastereomers. Using long-range and heteronuclear NMR correlations, the 1H NMR and 13C NMR resonances of both diastereomers have been fully assigned, confirming the structures. Monitoring of solutions of CNV-NLX in saline buffer, in methanol, and in DMSO has shown CNV-NLX to be stable for over a week under fluorescent laboratory lights at room temperature. Exposure of such solutions to λ 365 nm from a hand-held UV lamp led to the formation of naloxone and CNV-related breakdown products.

Metabolomics analysis depends on the identification and validation of specific metabolites. This task is significantly hampered by the absence of well-characterized reference standards. The one-carbon carrier 10-formyltetrahydrofolate acts as a donor of formyl groups in anabolism where it is a substrate in formyltransferase reactions in purine biosynthesis. It has been reported as an unstable substance and is currently unavailable as a reference standard for metabolomics analysis.The current study was undertaken to provide the metabolomics community thoroughly characterized 10-formyltetrahydrofolate along with analytical methodology and guidelines for its storage and handling.Anaerobic base treatment of 5,10-methenyltetrahydrofolate chloride in the presence of anti-oxidant was utilized to prepare 10-formyltetrahydrofolate.Pure 10-formyltetrahydrofolate has been prepared and physicochemically characterized. Conditions toward maintaining the stability of a solution of the dipotassium salt of 10-formyltetrahydrofolate in solution have been determined.This study describes the facile preparation of pure (90%) 10-formyltetrahydrofolate, its qualitative physicochemical characterization, as well as conditions to enable its use as a reference standard in physiologic samples.

Potent and selective κ opioid receptor antagonists have been derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid receptor antagonists. In order to determine if the 3-hydroxyphenyl and/or the piperidine amino groups are required for obtaining the pure opioid antagonists, (3R)-7-hydroxy-N-[(1S)-2-methyl-1-(piperidine-1-ylmethyl)propyl]-1,2,3,4-tetrahydroiosquinoline-3-carboxamide (1), which does not have a 4-(3-hydroxyphenyl) group, and (3R)-N-(1R)-1-(cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (2), which does not have a 4-hydroxylphenyl or a piperidine amino group, were synthesized and evaluated for their [35S]GTPγS binding properties at the μ, δ, and κ opioid receptors. Surprisingly compound 1 remained a pure opioid antagonist with a Ke = 6.80 nM at the κ opioid receptor and is 21- and 441-fold selective for the κ receptor relative to the μ and δ opioid receptors, respectively. Even more unexpected and novel is t...

JDTic analogues 4–15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [35S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had Ke = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the Ke = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.

JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had Ke = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the Ke = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.

Over the past five years the number of internet sites advertising "legal highs" has literally exploded, as have user reports of experiences (both pleasurable and frightening) with these substances and the number of emergency room visits by users. Although the majority of these "legal highs" have been described as bath salts and herbal extracts, most contain neither plant derived compounds nor components of personal hygiene products. So-called "bath salts" largely contain synthetic analogs of the natural compound Khat; spice-related materials, claimed to be "legal marijuana," are mostly synthetic analogs of cannabinoid receptor ligands that were developed as research tools. This review describes the emergence and properties of these two groups of "legal highs" from a medicinal chemist's perspective.

Importance Patients 65 years or older are the most frequent users of operative resources and are also the most vulnerable to postoperative adverse events (AEs). Frailty indices are increasingly being used for preoperative risk stratification within head and neck cancer surgery, but most models lack a multifactorial basis and cannot be directly applied to clinical practice. A practical risk index is needed for clinicians to gauge risk factors preoperatively. Objective To develop a preoperative risk index of short-term major postoperative AEs for patients undergoing head and neck cancer surgery. Design Cohort analysis of patients from multiple medical centers undergoing inpatient ablative or reconstructive head and neck cancer surgery and registered in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) from 2006 to 2016. Exposures Inpatient ablative or reconstructive head and neck cancer surgery. Main Outcomes and Measures Sociodemographic, frailty-related, and surgical factors in the derivation cohort were evaluated using simple and multiple logistic regression. Risk factors were subsequently integrated into a preoperative head and neck surgery risk index (HNSRI) and compared with existing models using the validation cohort. A composite variable of major postoperative AEs was used, including death within 30 days of surgery. Results A total of 43 968 operations were found using the ACS NSQIP database. Of these, 12 569 cases were excluded as non–head and neck cancer or emergency surgery. Of the included 31 399 operations reviewed, the mean (SD) patient age was 56.9 (15.4) years, and 16 994 of the patients were women (54.1%). A total of 4556 (14.5%) patients had a major postoperative AE, and 209 (0.7%) died. Older age, male sex, smoking, anticoagulation, recent weight loss, functional dependence, free-tissue transfer, tracheotomy, duration of surgery, wound classification, anemia, leukocytosis, and hypoalbuminemia were independently associated with major AEs or death on multiple regression analysis (C statistic, 0.83). The area under the curve of the HNSRI to predict major AEs including death using the validation cohort (n = 15 699) was 0.84 (95% CI, 0.83-0.85) with a sensitivity of 80.1% (95% CI, 79.4%-80.8%) and specificity, 72.3% (95% CI, 70.3%-74.2%). The HNSRI outperformed existing risk models for prediction of AEs: delta C index of the HNSRI to the modified frailty index 11, 0.23 (95% CI, 0.22-0.25); the American Society of Anesthesiologists classification, 0.14 (95% CI, 0.13-0.16); and the ACS risk calculator, 0.02 (95% CI, 0.01-0.03). Conclusions and Relevance The proposed HNSRI demonstrated a high sensitivity and specificity for major postoperative AEs and death in the studied population. This risk index can be used to counsel patients awaiting head and neck cancer surgery.