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Introduction: The aim of this study was to assess the feasibility of sparing routine antibiotic prophylaxis in patients without preoperative urinary tract infection undergoing ureterorenoscopy (URS) for stone removal., Methods: A retrospective, monocentric study was conducted to evaluate the outcome of a modified perioperative antibiotic management strategy according to the principles of antibiotic stewardship. Patients with preoperative unremarkable urine culture received no antibiotic prophylaxis for URS stone removal (NoPAP). The NoPAP group was compared to a historic URS cohort, when antibiotic prophylaxis (PAP) was standard of care. Analysis focused on postoperative complications., Results: Postoperative fever occurred in 1% of the NoPAP and 2% of the PAP patients (p = 0.589). Clavien 1-3 complications did not differ between groups with 9% in the NoPAP and 6.2% in the PAP (p = 0.159). No Clavien 4-5 complications were seen. We identified a residual stone (p = 0.033) and an ASA score 3-4 (p = 0.004) as significant risk factors for postoperative fever. By sparing routine antibiotic prophylaxis, the overall antibiotic usage was reduced from 100% (PAP) to 8.3% (NoPAP)., Conclusion: Sparing a routine antibiotic prophylaxis during URS for stone removal seems feasible in patients with unremarkable preoperative urine culture for most of the patients. A prospective validation is warranted., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Objective: Heterogenous test batteries and methods applied in neurocognitive research on Gulf War Veterans (GWVs) limit the translation of findings to clinical practice. A clinical data set is necessary., Methods: Neurocognitive screening data from treatment-seeking GWVs were collected from multiple sites and compiled, informed by consideration of performance validity., Results: Repeatable Battery for the Assessment of Neuropsychological Status scores revealed the cognitive profile for GWVs (n = 189) as poorer across multiple domains when compared with similarly educated, nonveteran peers. However, mean scores generally remained within normal clinical limits. Data tables are presented to establish a comparison group for use in clinical care., Conclusions: When assessing cognitive symptoms in GWVs, attention to education level and interpretation of subtle deficits is warranted. Current results highlight the importance of nuanced translation of neurocognitive research findings into clinical practice with GWVs., Competing Interests: Conflicts of Interest for All Authors: None Declared. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. There are no financial, consultant, institutional, or other conflicts of interest to disclose. The manuscript below has not been published elsewhere and it has not been submitted simultaneously for publication in another source., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Occupational and Environmental Medicine.)

Background: Degenerative cervical myelopathy (DCM) is a common, chronic neurological condition that severely affects individuals by causing a range of disabling symptoms, frequently at a time around the peak of their careers. Subsequently, individuals with DCM often become dependent on informal care arrangements. The significant economic contribution of informal care and its burden on care providers are becoming increasingly recognized., Objective: This study aimed to measure the quality of life of DCM informal caregivers and provide preliminary insight into possible contributing factors., Methods: Carers of individuals with DCM completed a Web-based survey hosted by Myelopathy.org, an international DCM charity. Carer quality of life was assessed in the form of caregiver happiness and 7 dimensions of carer burden using the Care-Related Quality of Life (CarerQol) instrument. The relationships between patient disease severity, patient pain, and carer quality of life were investigated. Differences in carer quality of life were assessed across patient and carer demographic groups, including between UK and US carers., Results: DCM caregivers experienced substantial burden as a result of their caregiving (mean CarerQol-7D=64.1; 95% CI 58.8-69.5) and low happiness (mean CarerQol-VAS [Visual Analog Scale]=6.3; 95% CI 5.7-6.9). Burden was high and happiness was low in DCM carers when compared with a large, mixed-disease study of adult informal carers where CarerQol-7D was 79.1 and CarerQol-VAS was 7.1. No significant relationship was found between DCM carer quality of life and patient disease severity and pain scores. DCM carer quality of life appeared uniform across all patient and carer demographic groups., Conclusions: Caring for individuals with DCM is associated with reduced quality of life in the form of significant burden and reduced happiness. Reductions appear greater in DCM than in other diseases investigated. However, no simple relationship was identified between individual patient or carer factors and carer quality of life., (©Oliver Daniel Marshall Mowforth, Benjamin Marshall Davies, Mark Reinhard Kotter. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 07.11.2019.)

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 ( 3 ) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

Background: Degenerative cervical myelopathy (DCM) is a prevalent and progressively disabling neurological condition. Treatment is currently limited to surgery, the timing of which is not without controversy. New international guidelines recommend that all patients should undergo lifelong surveillance and those with moderate-to-severe or progressive disease should be offered surgery. Long-term surveillance will place substantial burden on health services and short clinic assessments may risk misrepresenting disease severity. The use of smart technology to monitor disease progression could provide an invaluable opportunity to lessen this burden and improve patient care. However, given the older demographic of DCM, the feasibility of smart technology use is unclear., Objective: The aim of this study was to investigate current usage of smart technology in patients with self-reported DCM to inform design of smart technology apps targeted at monitoring DCM disease progression., Methods: Google Analytics from the patient section of Myelopathy.org, an international DCM charity with a large online patient community, was analyzed over a 1-year period. A total of 15,761 sessions were analyzed., Results: In total, 39.6% (295/744) of visitors accessed the website using a desktop computer, 35.1% (261/744) using mobile, and 25.3% (188/744) using a tablet. Of the mobile and tablet visitors, 98.2% (441/449) utilized a touchscreen device. A total of 51.3% (141/275) of mobile and tablet visitors used iPhone Operating System (iOS) and 45.8% (126/275) used an Android operating system. Apple and Samsung were the most popular smart devices, utilized by 53.6% (241/449) and 25.8% (116/449) of visitors, respectively. The overall visitor age was representative of DCM trials. Smart technology was widely used by older visitors: 58.8% (113/192) of mobile visitors and 84.2% (96/114) of tablet visitors were aged 45 years or older., Conclusions: Smart technology is commonly used by DCM patients. DCM apps need to be iOS and Android compatible to be accessible to all patients., (©Oliver Daniel Mowforth, Benjamin Marshall Davies, Mark Reinhard Kotter. Originally published in JMIR Formative Research (http://formative.jmir.org), 09.05.2019.)

Degenerative cervical myelopathy (DCM) is the most common cause of adult spinal cord dysfunction, most classically presenting with a broad-based gait and clumsy hands. Limb sensory loss and paraesthesia are considered common symptoms of DCM. However, we report an unusual case of a patient presenting with prominent and atypical sensory symptoms. The patient repeatedly presented to accident and emergency complaining of her body resembling a wet gel-like substance that she attributed to the use of olive oil moisturising cream. The patient was found to have myelopathic signs on examination and MRI consistent with severe cervical myelopathy. She subsequently underwent successful decompressive anterior cervical discectomy, as recommended by international guidelines. This case serves to remind health professionals of uncommon presentations of common disease and the importance of maintaining a wide initial differential diagnosis., Competing Interests: Competing interests: MRN reports grants from National Institute of Health Research, travel cost grant from AOSpine and is founder and trustee of Myelopathy.org, the first charity dedicated to degenerative cervical myelopathy., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY. Published by BMJ.)

Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a K b of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3-20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30-240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists., (Copyright © 2016 The Author(s).)

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Plant MRS2 membrane protein family members have been shown to play important roles in magnesium uptake and homeostasis. Single and double knockouts for two Arabidopsis thaliana genes, AtMRS2-1 and AtMRS2-5, have previously not shown significant phenotypes even under limiting Mg(2+) supply although both are strongly expressed already in early seedlings. Together with AtMRS2-10, these genes form clade B of the AtMRS2 gene family. We now succeeded in obtaining homozygous AtMRS2-1/10 double and AtMRS2-1/5/10 triple knockout lines after selection under increased magnesium supply. Although wilting early, both new mutant lines develop fully and are also fertile under standard magnesium supply, but show severe developmental retardation under limiting Mg(2+) concentrations. To investigate nutrient dependency of germination and seedling development under various conditions, including variable supplies of Mg(2+), Ca(2+), Zn(2+), Mn(2+), Co(2+), Cd(2+) and Cu(2+), in a reproducible and economical way, we employed a small-scale liquid culturing system in 24-well plate set-ups. This allowed the growth and monitoring of individual plantlets of different mutant lines under several nutritional conditions in parallel, and the scoring and statistical evaluation of developmental stages and biomass accumulation. Detrimental effects of higher concentrations of these elements were similar in mutants and the wild type. However, growth retardation phenotypes seen upon hydroponic cultivation under low Mg(2+) could be ameliorated when Ca(2+) concentrations were concomitantly lowered, supporting indications for an important interplay of these two most abundant divalent cations in the nutrient homeostasis of plants.

As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the α-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo.

A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.

For the interpretation of chemical shift changes induced by pressure in proteins, a comparison with random-coil data is important. For providing such a data basis, the pressure dependence of the 1H-NMR chemical shifts of the amino acids X in the random-coil model peptides Gly-Gly-X-Ala were studied for the 20 common amino acids at two pH values (pH 5.0 and 5.4) at 305 K, in the pressure range from 0.1 to 200 MPa. The largest shift changes deltadelta with pressure p can be observed for the backbone amide protons. The average linear pressure coefficient delta(deltap) is 0.38 ppm GPa(-1), with a root mean square deviation of 0.2 ppm GPa(-1). In contrast to the downfield shift typical for amide protons, the H(alpha)-resonances typically shift upfield, with a pressure coefficient of -0.025 ppm GPa(-1) and a root mean square deviation of 0.05 ppm GPa(-1). The side chain resonances are only weakly influenced by pressure, on average they are shifted by 0.014 ppm GPa(-1)) with a root mean square deviation of 0.14 ppm GPa(-1). The exceptions are the side chain amide protons of asparagine and glutamine. Here, values of 0.214 (Asn H(delta21)), 0.417 (Asn H(delta22)), 0.260 (Gln H(varepsilon21)) and 0.395 (Gln H(varepsilon22)) ppm GPa(-1) can be observed. In both cases, the pressure dependent shift is larger for the pro-E proton than for the pro-Z proton. Within the limits of error the equilibrium constant for the trans- and cis-conformers at the proline peptide bond is independent of pressure in the pressure range studied.