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OBJECTIVE: Sensory testing has been advocated for the diagnosis, prognosis, and outcome evaluation of pain patients, but responses to controlled stimuli have not been well correlated to clinical pain. As an initial step for improving the clinical relevance of sensory testing, this investigation compared appraisals of and responses to controlled pain stimuli. DESIGN: A prospective within subjects design was used. METHODS: Heat, ischaemic, and delayed-onset muscle pain were induced in the upper extremity of 44 participants (47.7% women) during four experimental sessions. RESULTS: The threat of heat and ischaemic pain was higher than delayed-onset muscle pain (F(2,86) = 5.30, p<.01, eta(2) = .11). Threat, challenge, predictability, and controllability were related to heat pain most consistently. The affective-sensory ratios of ischaemic and delayed-onset muscle pain resembled those of clinical pain and were higher than heat pain (F(2,84) = 11.64, p<.01, eta(2) = .22). Delayed-onset muscle pain meaningfully affected daily activities, which correlated to delayed-onset muscle pain ratings (rs = .60-.68, ps <.001). CONCLUSIONS: Heat stimuli may be well suited for instructional manipulations of appraisals to improve the clinical relevance of quantitative sensory testing and delayed-onset muscle pain's effects on daily activities are clinically relevant. [ABSTRACT FROM AUTHOR]

Assessment of sincerity of effort is frequently used in clinical practice. However, the reliability and validity of current assessment methods have not been unequivocally demonstrated. This study focused on the detection of submaximal efforts and determination of the stability of the coefficient of variation (CV) in 20 asymptomatic subjects. The coefficient of variation of peak torque (CVpeak) and coefficient of variation of average torque (CVave) were obtained from maximal and submaximal torque curves during fast isokinetic (180 deg/s) leg extension strength tests. Significant differences between effort levels (maximal and submaximal) were found for CVpeak and CVave on both days of testing (p < .001). On Day 1 of testing, using an optimized 10% CVpeak cutoff resulted in a submaximal effort detection rate of 75% with an overall (maximal and submaximal efforts) correct classification rate of 88%. Correlation coefficients indicated relatively moderate stability using the CVpeak calculated using five trials for both maximal (r = .47, p < .05) and submaximal (r = . 78, p < .001) effort conditions. Findings suggest that use of an increased number of repetitions to calculate the CV may result in more stable measures. [ABSTRACT FROM AUTHOR]

Introduction: Portable sleep monitors (PMs) may be more expeditious and convenient than in-laboratory sleep studies in diagnosing obstructive sleep apnea (OSA). We report for the first time the use of PMs in a military population to demonstrate feasibility in predeployment assessments.Methods: A nested, descriptive study was undertaken at 7 military medical facilities as part of a larger clinical trial. Subjects answered two questionnaires to identify OSA symptoms and used an ApneaLink Plus portable monitor to test for OSA. Descriptive statistics were used to characterize the subjects and to report results of PM use.Results: 101 subjects were enrolled, and 77 subjects completed the study. 4.0% of subjects did not tolerate PM use. We found 15 subjects with OSA, with mean age of 31.4 +/- 12.8 years, mean body mass index of 33.0 +/- 7.4 kg/m2, and mean apnea-hypopnea index of 19.6 +/- 13.9 per hour. Subjects with OSA were more likely to have high pretest probability of disease than those without OSA.Conclusion: We demonstrate that PMs are well-tolerated and can successfully identify OSA in those with high pretest probability. We propose a method to implement PM use during predeployment assessments. [ABSTRACT FROM AUTHOR]

Perforin is a key effector of lymphocyte-mediated cell death pathways and contributes to transplant rejection of immunologically mismatched grafts. We have developed a novel series of benzenesulfonamide (BZS) inhibitors of perforin that can mitigate graft rejection during allogeneic bone marrow/stem cell transplantation. Eight such perforin inhibitors were tested for their murine pharmacokinetics, plasma protein binding, and their ability to block perforin-mediated lysis in vitro and to block the rejection of major histocompatibility complex (MHC)-mismatched mouse bone marrow cells. All compounds showed >99% binding to plasma proteins and demonstrated perforin inhibitory activity in vitro and in vivo . A lead compound, compound 1 , that showed significant increases in allogeneic bone marrow preservation was evaluated for its plasma pharmacokinetics and in vivo efficacy at multiple dosing regimens to establish a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The strongest PK/PD correlation was observed between perforin inhibition in vivo and time that total plasma concentrations remained above 900 μM, which correlates to unbound concentrations similar to 3× the unbound in vitro IC 90 of compound 1 . This PK/PD relationship will inform future dosing strategies of BZS perforin inhibitors to maintain concentrations above 3× the unbound IC 90 for as long as possible to maximize efficacy and enhance progression toward clinical evaluation., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Antitubercular 7-substituted 2-nitroimidazo[2,1- b ][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated in vitro and in vivo but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that O -carbamate 66 offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong in vivo efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg)., Competing Interests: The authors declare no competing financial interest., (© 2021 American Chemical Society.)

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Phenotypic screening of a 900 compound library of antitubercular nitroimidazole derivatives related to pretomanid against the protozoan parasite Trypanosoma cruzi (the causative agent for Chagas disease) identified several structurally diverse hits with an unknown mode of action. Following initial profiling, a first proof-of-concept in vivo study was undertaken, in which once daily oral dosing of a 7-substituted 2-nitroimidazooxazine analogue suppressed blood parasitemia to low or undetectable levels, although sterile cure was not achieved. Limited hit expansion studies alongside counter-screening of new compounds targeted at visceral leishmaniasis laid the foundation for a more in-depth assessment of the best leads, focusing on both drug-like attributes (solubility, metabolic stability and safety) and maximal killing of the parasite in a shorter timeframe. Comparative appraisal of one preferred lead (58) in a chronic infection mouse model, monitored by highly sensitive bioluminescence imaging, provided the first definitive evidence of (partial) curative efficacy with this promising nitroimidazooxazine class., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Perforin is a key effector protein in the vertebrate immune system and is secreted by cytotoxic T lymphocytes and natural killer cells to help eliminate virus-infected and transformed target cells. The ability to modulate perforin activity in vivo could be extremely useful, especially in the context of bone marrow stem cell transplantation where early rejection of immunologically mismatched grafts is driven by the recipient's natural killer cells, which overwhelmingly use perforin to kill their targets. Bone marrow stem cell transplantation is a potentially curative treatment for both malignant and nonmalignant disorders, but when the body recognizes the graft as foreign, it is rejected by this process, often with fatal consequences. Here we report optimization of a previously identified series of benzenesulfonamide-based perforin inhibitors for their physicochemical and pharmacokinetic properties, resulting in the identification of 16 , the first reported small molecule able to prevent rejection of transplanted bone marrow stem cells in vivo by blocking perforin function.

Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Study Objectives: Hospital readmissions are an important metric of quality and safety. This study seeks to characterize the relationship between readmissions and obstructive sleep apnea (OSA). A better understanding of this relationship could be utilized to develop preventative measures and reduce readmission rates., Methods: A retrospective review of patients discharged over a 24-month period to a Department of Defense hospital was conducted. Medical records review provided demographic data, presence of OSA and comorbid diseases, and whether readmission occurred within 30 days of discharge. Statistical analysis assessed risk factors for readmission, and multivariate analysis was performed. Next, 125 readmitted patients with OSA were randomly selected for detailed chart review and compared to a matched cohort that was not readmitted., Results: Of 22,261 unique patients discharged, 1,899 (8.5%) were readmitted. Patients with OSA had a readmission rate of 11.4% versus 7.6% for patients without OSA ( P < .00001). Multivariable analysis revealed an odds ratio of 1.46 for readmission in patients with OSA ( P < .0001). For the detailed chart review of 250 patients, length of hospital stay differed for the readmitted and non-readmitted groups (5.1 versus 3.6 days; P = .007). Apnea-hypopnea index (24.1 versus 27.2 events/h; P = .48) was similar between the groups. Also, inpatient (27.2% versus 26.4%) and outpatient (38.4% versus 37.6%) positive airway pressure (PAP) treatment rates were not different., Conclusions: This study found OSA to be an independent risk factor for readmission within 30 days of discharge. PAP therapy appears to be underutilized in patients with known OSA. Additional studies are needed to define the relationship between OSA, PAP adherence, and hospital readmission., (© 2018 American Academy of Sleep Medicine.)

Discovery of the potent antileishmanial effects of antitubercular 6-nitro-2,3-dihydroimidazo[2,1- b][1,3]oxazoles and 7-substituted 2-nitro-5,6-dihydroimidazo[2,1- b][1,3]oxazines stimulated the examination of further scaffolds (e.g., 2-nitro-5,6,7,8-tetrahydroimidazo[2,1- b][1,3]oxazepines), but the results for these seemed less attractive. Following the screening of a 900-compound pretomanid analogue library, several hits with more suitable potency, solubility, and microsomal stability were identified, and the superior efficacy of newly synthesized 6 R enantiomers with phenylpyridine-based side chains was established through head-to-head assessments in a Leishmania donovani mouse model. Two such leads ( R-84 and R-89) displayed promising activity in the more stringent Leishmania infantum hamster model but were unexpectedly found to be potent inhibitors of hERG. An extensive structure-activity relationship investigation pinpointed two compounds ( R-6 and pyridine R-136) with better solubility and pharmacokinetic properties that also provided excellent oral efficacy in the same hamster model (>97% parasite clearance at 25 mg/kg, twice daily) and exhibited minimal hERG inhibition. Additional profiling earmarked R-6 as the favored backup development candidate.

The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection., (Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivatives were initially studied for tuberculosis within a backup program for the clinical trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.

Objective: The purpose of this study was to determine the effect of tonsillectomy as a single procedure in the treatment of adult obstructive sleep apnea (OSA)., Study Design: Prospective multi-institutional study evaluating adults with tonsillar hypertrophy scheduled to undergo tonsillectomy as an isolated surgery., Setting: Tertiary care medical centers within the US Department of Defense., Subjects and Methods: Adult subjects with tonsillar hypertrophy who were already scheduled for tonsillectomy were enrolled from October 2010 to July 2013. Subjects underwent physical examination, Epworth Sleepiness Scale, Berlin Questionnaire, and polysomnogram before surgery and after. Collected data included demographics, questionnaire scores, apnea-hypopnea index (AHI), and lowest saturation of oxygen., Results: A total of 202 consecutive subjects undergoing tonsillectomy were enrolled. The final analysis included 19 subjects testing positive for OSA. The mean age was 27.9 years; mean body mass index, 29.6; median tonsil size, 3; and most frequent Friedman stage, 1. The AHI before surgery ranged from 5.4 to 56.4 events per hour. The mean AHI decreased from 18.0 to 3.2 events per hour after surgery, a reduction of 82%. The responder rate--with subjects achieving at least a 50% reduction of AHI to a value <15--was 94.7%. Following tonsillectomy, there were statistically significant reductions in median lowest saturation of oxygen level and Epworth Sleepiness Scale and Berlin scores., Conclusions: Adult tonsillectomy alone has beneficial effect in OSA management, particularly in young overweight men with large tonsils, moderate OSA, and low Friedman stage., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)

Vagal nerve stimulators (VNS) are surgically implantable medical devices which are approved by the food and drug administration (FDA) for treatment of medically refractory epilepsy in children. Two children with seizures disorders presented to the pediatric otolaryngology clinic with complaints of stridor and sleep apnea following implantation of VNS devices. Both children were evaluated with flexible laryngoscopy, direct laryngoscopy and bronchoscopy. The children were noted to have contraction of their vocal folds and supraglottis and the settings of their VNS were adjusted until no further contractions were noted. Each child had resolution of their symptoms following adjustment., (Published by Elsevier Ireland Ltd.)

Background: Endoscopic extended maxillary mega-antrostomy (EMMA) is a mucosal sparing technique that allows maxillary drainage by gravity, with a reported symptomatic nasolacrimal duct injury incidence of 0-4%, based on history alone. Injury to the nasolacrimal duct is known to cause epiphora, a complication that is rare but more often seen in this revision surgery., Objective: The goal of this study was to determine the incidence of nasolacrimal system penetration during EMMA. We, in addition, sought to determine the minimal safe distance from the midpoint of the maxillary line (the "M" point) to the nasolacrimal system to avoid this injury., Methods: Six cadaveric heads underwent bilateral Jones II test followed by EMMA. Measurements from the M point to the antrostomy were recorded. The Jones II test was then repeated to assess for penetration and/or injury of the nasolacrimal system. If no penetration occurred at the surgical limit of EMMA, then dissection was continued incrementally until penetration occurred. This measurement was recorded., Results: Lacrimal duct violation was identified in 5 of 12 procedures (42%). Lacrimal duct penetration occurred at an average of 3.7 mm (range, 2-7 mm) posterior to the M point., Conclusion: Subclinical lacrimal system injury is likely to occur during EMMA. These findings would indicate that maintaining a distance of >7 mm from the maxillary line could avoid this injury.

Duocarmycins are highly cytotoxic natural products that have potential for development into anticancer agents. Herein we describe proposed but previously unidentified NH analogues of the DNA-alkylating subunit and characterise these by solvolysis studies, NMR and computational modelling. These compounds are shown to be the exclusive intermediates in the solvolysis of their seco precursors and to possess very similar structural features to the widely studied O-based analogues, apart from an unusually high basicity. The measured pKa of 10.5 implies that the NH compounds are fully protonated under physiological conditions. Remarkably, their extremely high reactivity (calculated hydrolysis rate 10(8) times higher for protonated NH compared to the neutral O analogue) is still compatible with potent cytotoxicity, provided the active species is formed in the presence of cells. These surprising findings are of relevance to the design of duocarmycin-based tumour-selective therapies., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives/hypothesis: To determine the prevalence of otologic complaints in subjects with dysphonia and traumatic brain injury (TBI) in a sample population of the US Army., Study Design: Cross-sectional study., Methods: A total of 292 subjects were identified with a new diagnosis of voice disorder during a 3.5-year period at three large military medical centers. Of them, 70 subjects were also identified with TBI and had no history of dysphonia before this time period. In those with voice disorders and TBI, documentation of hearing complaints, hearing loss, tinnitus, or vertigo was recorded. Time to visit an otolaryngologist and audiologist were also recorded., Results: A total of 70 soldiers were identified with a diagnosis of a voice disorder and TBI. Of these soldiers, 83% had at least one otologic complaint and 50% had more than one. Approximately 60%, 39%, and 44% of the subjects reported tinnitus, hearing loss, or vertigo, respectively. A total of 62% of the subjects with otologic complaints, TBI, and dysphonia were seen by an otolaryngologist. Time until an otolaryngologist evaluated these soldiers varied widely, with an average of 17 months and standard deviation of 12.5 months., Conclusions: Otologic manifestations are common in soldiers with dysphonia and TBI. Careful consideration of communication impairment from otologic dysfunction in those with speech disorders after TBI is warranted., (Published by Mosby, Inc.)

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T1/2 values of 1.1-1.2 h (dose of 5 mg/kg i.v.) and MTDs of 60-80 mg/kg (i.p.).

Objectives/hypothesis: To evaluate voice disorder differences between deployed and nondeployed US army soldiers., Study Design: Cross-sectional study., Methods: More than 1.3 million health records of active duty US army soldiers with no history of dysphonia were queried for voice disorder diagnoses over a 3.5-year period. A sample of 292 soldiers was further evaluated for known factors linked to dysphonia., Results: US army soldiers were 1.13 times more likely to have a diagnosis of dysphonia if they were deployed. Risk factors and exposures common to patients with dysphonia were not statistically different between deployed and nondeployed soldiers. Additionally, the type of dysphonia diagnosis was not significantly different between deployed and nondeployed soldiers., Conclusions: US army soldiers deployed to war zones are more likely to be diagnosed with dysphonia. None of the reviewed parameters accounted for the difference in dysphonia rate between deployed and nondeployed soldiers, suggesting that occupational exposures of deployed soldiers account for the increase in the diagnoses of dysphonia., (Published by Mosby, Inc.)

MbtI is the salicylate synthase that catalyzes the first committed step in the synthesis of the iron chelating compound mycobactin in Mycobacterium tuberculosis. We previously developed a series of aromatic inhibitors against MbtI based on the reaction intermediate for this enzyme, isochorismate. The most potent of these inhibitors had hydrophobic substituents, ranging in size from a methyl to a phenyl group, appended to the terminal alkene of the enolpyruvyl group. These compounds exhibited low micromolar inhibition constants against MbtI and were at least an order of magnitude more potent than the parental compound for the series, which carries a native enolpyruvyl group. In this study, we sought to understand how the substituted enolpyruvyl group confers greater potency, by determining cocrystal structures of MbtI with six inhibitors from the series. A switch in binding mode at the MbtI active site is observed for inhibitors carrying a substituted enolpyruvyl group, relative to the parental compound. Computational studies suggest that the change in binding mode, and higher potency, is due to the effect of the substituents on the conformational landscape of the core inhibitor structure. The crystal structures and fluorescence-based thermal shift assays indicate that substituents larger than a methyl group are accommodated in the MbtI active site through significant but localized flexibility in the peptide backbone. These findings have implications for the design of improved inhibitors of MbtI, as well as other chorismate-utilizing enzymes from this family.

We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC(50) 0.9nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Beta-methoxymethyl enecarbamates (e.g., 1) have been prepared in a single step from alpha-methoxy carbamates. In the presence of a mild Lewis acid, compound 1 underwent substitution with a variety of nucleophiles including indoles, electron-rich aromatics, silyl enol ethers, and 2-trimethylsilyloxyfuran.

Surgery for obstructive sleep apnea is multimodal. Procedures and aims of treatment vary. Surgery, medical devices, and medical therapy each may contribute to individualized patient care. There is no single procedure or intervention that "cures" upper airway obstruction. Treatment varies as the disease varies. In addition, surgical treatment varies because the level of obstruction and influence on air flow occurs at multiple levels and from many structures. This article is not intended as a critical assessment of surgical outcomes but rather focuses on airway structures and the nature of the procedures applied to influence them.

The synthesis of enantiopure bicyclic alpha,alpha-disubstituted spirolactams is described using a diastereoselective Birch reductive alkylation as the key step. Hydrogenation of the resultant alkylated cyclohexadienes followed by intramolecular cyclization provides access to enantiopure 8-azaspiro[5.6]dodecan-7-ones.

In the current study, real gas effects in the propagation of sound waves are simulated using the direct simulation Monte Carlo method for a wide range of frequencies. This particle method allows for treatment of acoustic phenomena at high Knudsen numbers, corresponding to low densities and a high ratio of the molecular mean free path to wavelength. Different methods to model the internal degrees of freedom of diatomic molecules and the exchange of translational, rotational and vibrational energies in collisions are employed in the current simulations of a diatomic gas. One of these methods is the fully classical rigid-rotor/harmonic-oscillator model for rotation and vibration. A second method takes into account the discrete quantum energy levels for vibration with the closely spaced rotational levels classically treated. This method gives a more realistic representation of the internal structure of diatomic and polyatomic molecules. Applications of these methods are investigated in diatomic nitrogen gas in order to study the propagation of sound and its attenuation and dispersion along with their dependence on temperature. With the direct simulation method, significant deviations from continuum predictions are also observed for high Knudsen number flows.

The crystal structure of the title compound, C(12)H(21)NO, has been investigated to establish the absolute stereochemistry at position 1. The absolute stereochemistry at the quaternary centre at position 6 is established to be R using an asymmetric Birch reductive alkyl-ation reaction for which the stereochemical outcome is known. The crystal structure indicates the presence of two conformers of the bicyclic (1R,6R)-spiro-lactam ring system that differ in the conformation adopted by the six-membered ring. In one conformer, the meth-yl group adopts an axial position whereas in the other conformer, the same methyl group adopts an equatorial position. In both conformers, the seven-membered ring adopts a chair conformation. The two conformers of the bicyclic spiro-lactam are connected to each other via inter-molecular N-H⋯O hydrogen bonds forming a heterodimer. The asymmetric unit contains two such dimers.

An overview of the structure and biological activity of macrocyclic polyketides derived from dinoflagellates that contain unusual cyclic imine units is provided. The total and partial syntheses of these molecules are discussed with an emphasis on the construction of the spiroimine functionality thought to be the key pharmacophore of these fact-acting shellfish toxins.

Second-generation synthetic routes to enantiopure sulfone 21 and aldehyde 24 are described. The union of these two intermediates by means of a Julia-Kocienski coupling gave rise to a series of E-configured building blocks that did not prove amenable to transannular cyclization. Alternatively, when the C15-C16 double bond was introduced with Z-geometry by Wittig olefination, spontaneous closure to generate a tetrahydrofuran culminated an ensuing direct dihydroxylation step. The structural assignment to 35, undergirded by detailed 1H and 13C NMR studies, is consistent with proper transannular bonding so as to deliver the entire C1-C26 fragment of PTX2.

This investigation was designed to determine the effect of eccentric strength testing on delayed-onset muscle pain in 20 untrained university students. Initially, eccentric strength testing (5-repetition maximum [5RM]) was performed bilaterally. Next, 1 arm completed 3 sets of 10 eccentric repetitions to induce delayed-onset muscle pain. Then, in a subsequent session, whichever arm previously performed only the 5RM test completed the 5RM test a second time and the 3 sets of 10 eccentric repetitions. Statistical analyses supported significantly increased pain intensity and unpleasantness across 48 hours post-5RM test alone. However, pain intensity and unpleasantness after the eccentric training bouts were significantly lower in the arm that performed 2 5RM tests than the arm that performed only 1. Thus, the eccentric strength testing produced delayed-onset muscle pain and protected against future delayed-onset muscle pain. These effects should be considered when such testing is used in baseline strength assessments.

The hexacyclic himandrine skeleton 5, which is present in the most complex alkaloids of the tropical rain forest tree Galbulimima belgraveana, has been prepared for the first time. The synthesis begins from the known [3.2.1]benzobicyclooctene intermediate 10. Key steps include a Diels-Alder cycloaddition, Curtius rearrangement, Birch reduction, an intramolecular nucleophilic amination, and a palladium-mediated alkene amination. [reaction: see text]

A number of studies have investigated the use of variability measures in the detection of submaximal or insincere efforts in strength testing. The underlying assumption of these approaches is that submaximal efforts will be more variable than maximal efforts. Previous studies have investigated the variability of torque production in isometric or isokinetic tasks with mixed results. The present study investigated the variability of torque production and velocity in isometric and isotonic leg extension tasks, respectively. Fifteen asymptomatic subjects participated in a within-subject counterbalanced design in which they were asked to perform maximally and submaximally in both isometric and isotonic leg extension tasks. Results indicated that both isometric and isotonic tasks showed greater variability (measured by coefficient of variation) in the submaximal effort condition. However, the sensitivity to detect submaximal efforts was much greater for the isotonic velocity variability condition. It was concluded that the isotonic approach showed promise for clinical application, but that the isometric task had unacceptably poor classification rates, consistent with previous research.

Background and Purpose: The purpose of this study was to investigate the repeatability of spinal range of motion (ROM) and movement velocity measurements of patients with chronic low back pain, using a two-dimensional motion analysis system. This apparatus uses reflective markers placed on anatomical landmarks and video digitization to derive ROM measurements from three segments of the spine and associated velocities through the respective ROMs., Subjects: Forty-two patients with chronic LBP underwent ROM and movement velocity testing., Methods: Each subject was tested twice without removal of the markers to minimize error contribution from differences in marker placement., Results: Results indicated that both the ROM measures and the velocity measures were highly repeatable. Intraclass correlations for the ROM measures ranged from .77 to .96. Velocity measures were also reliable, with intraclass correlation coefficients ranging from .75 to .97., Conclusion and Discussion: Overall, the results seem to indicate that the video motion analysis system used in this study yields repeatable ROM and velocity measures on a clinical population. In practice, however, the measures may reflect greater errors due to the need of examiners to relocate markers at different testing sessions. These systems also offer distinct advantages over other means of obtaining ROM and velocity measures. The results of this study indicate that these measures may be obtained without undue concern for measurement artifact due to the instrumentation reliability.

Background and Purpose: Spinal range of motion (ROM) is an important indicator of spinal function and is used in the determination of disability and compensation. One technology that has been used to assess spinal ROM is video motion analysis. No studies, however, have been done to investigate the effects of marker placement on ROM. The purpose of this study was to investigate the effect of deviations in reflective marker placement on ROM measurements obtained via video motion analysis., Methods: A model of the spine was constructed and used to obtain ROM measurements from three segments of the model to isolate error from marker placement without the confounding effects of subject error. A standard placement and six altered placements were used to determine the effect of moving reflective markers on ROM., Results: Results indicated statistically significant effects of marker placement for a number of flexion/extension and lateral side-bending ROM measurements. When the mean differences were compared with data obtained in human test-retest studies with the same equipment, the differences from a 2.5-cm marker deviation did not appear to be clinically meaningful., Conclusion and Discussion: We conclude that small marker deviations (2.5 cm) are not likely to adversely affect clinical information obtained when using this type of apparatus.

The use of the coefficient of variation (CV) to determine level of effort in grip strength testing was examined empirically. Twenty-nine asymptomatic subjects participated in two conditions of testing: 100% effort and 50% effort. Order of conditions was counterbalanced and each subject was run in both conditions twice in the same order in order to assess the stability of the method. The number of trials (grasps) per condition was three for a total of 12 grasps for the study. The submaximal (50%) effort condition showed significantly more variability than the maximal effort condition in both sets of conditions (p<.01). Intra-class correlation coefficients were very low for both maximal effort and submaximal efforts (.036 and .025) indicating very low stability for the coefficient of variation. Classification rates were also found to have unacceptably large errors with 69% of the submaximal efforts being classified as maximal with the traditional 15% CV cutoff and 55% misclassification of submaximal efforts with an optimized 11% CV cutoff. It was concluded that the currently practiced method of using a low number of repetitions to calculate the CV may result in very unstable measures. Furthermore the "false negative" rate in using this method is unacceptably high for practical application. The implications of using the method and suggestions for improvement are discussed.

Variability in trunk torque production has been suggested as a means of detecting submaximal effort in the assessment of chronic low back pain. Several investigations question the validity of using torque variability to detect submaximal efforts in patients with back injuries. However, few investigations have studied the correlates of text-retest torque variability in clinical populations. The present study investigated psychological distress, disability/flexibility/pain, and symptom magnification correlates of test-retest torque variability in chronic low back pain patients. Contrary to previous studies, psychological distress, tendency to report symptoms, and pain were negatively correlated with measures of torque variability. The findings indicate the potential for psychological variables to influence torque production, but on the whole provide little strong support for the use of test-retest torque variability as a means of detecting submaximal performance.

Two studies investigated the use of lumbar integrated electromyography (iEMG) during flexion-extension exercises of the lumbar spine. The first study compared the iEMG fatigue slopes of 12 pain-free controls during a standardized isotonic workout with a heavy weight and a light weight. Results indicated that the slopes of the iEMG across flexion-extension repetition was negative in both conditions, with the heavy weight producing significantly steeper fatigue slopes. In the second study, iEMG was compared from 16 chronic low back pain (CLBP) patients and 12 asymptomatic controls during isotonic exercise. Integrated EMG was recorded during 18 lumbar extension-flexion cycles (3 min) at a standard pace. Each subject exercised at a weight equal to 60% of his maximum isometric torque produced at the most extended position. Results indicated significantly less iEMG was produced by the CLBP group during both concentric and eccentric exertion. For both groups, eccentric exertion produced significantly less iEMG than concentric exertion. The groups showed significantly different iEMG fatigue slopes, with the control group showing declining iEMG by repetition, while the CLBP group showed flatter, slightly increasing iEMG. This occurred for both eccentric and concentric comparisons. A muscle deficiency model of CLBP is supported and results suggest the importance of endurance factors in addition to strength in rehabilitation efforts. Results also suggest the possibility of using this methodology for detecting insincere efforts in lumbar spine assessment.

The efficacy of a controversial treatment, using colored filters to remediate reading disabilities, was measured empirically, with colored overlays placed over reading material on white paper. Irlen's (1983) method is to prescribe specific tinted filters as lenses that she claims filter specific light frequencies and remove a range of perceptual disorders that adversely affect reading and related learning performance. Irlen calls this condition "scotopic sensitivity" and claims it is a significant factor in a high percentage of people with learning disabilities. Ninety-two children with significant reading disabilities were classified as either scotopic or nonscotopic using the Irlen Differential Perceptual Schedule, and were randomly assigned to one of six treatment groups using colored or clear overlays. Reading performance (rate, accuracy, and comprehension) as measured by the Neale Analysis of Reading Ability (Neale, 1987) and the Formal Reading Inventory (Wiederholt, 1986) improved significantly when the scotopic children read with the preferred colored overlay filter compared to clear or different-colored overlay filters. Nonscotopic children showed no change.