Can digital rectal examination be used to detect cauda equina compression in people presenting with acute cauda equina syndrome? A systematic review and meta-analysis of diagnostic test accuracy studies.

BACKGROUND: Digital rectal examination (DRE) is a commonly used test to help identify people with cauda equina compression (CEC). OBJECTIVE: To determine the diagnostic accuracy of DRE in assessment of anal tone, squeeze, sensation and reflexes, as predictors of CEC. DESIGN: A systematic review to investigate the diagnostic accuracy of DRE to detect CEC compared with lumbar Magnetic Resonance Imaging (MRI). METHOD: Six electronic databases were searched from inception to 6 July 2020 for studies published in English. Two assessors independently performed screening, data extraction and risk of bias assessment (QUADAS-2). Meta-analysis was performed using STATA-16. RESULTS: Six studies were included (n = 741). The sensitivity of anal tone was low across all studies (range: 0.23 to 0.53) with moderate quality evidence against the use of DRE of anal tone. One study on anal sensation found no correlation with CEC using Kendall's tau test: p = 0.102 and another found sensation had low test accuracy. One study identified sensitivity: 0.29 and specificity: 0.96 for anal squeeze, while another identified sensitivity: 0.38 and specificity: 0.6 for anal reflexes. CONCLUSION: The diagnostic accuracy of DRE of anal tone to detect CEC is low and carries a high risk of false reassurance. It is therefore not recommended in any clinical setting. More research is needed to determine the diagnostic accuracy of DRE of anal squeeze, sensation and reflexes and if done the results should be interpreted with caution.

Town-scale microbial sewer community and H2S emissions response to common chemical and biological dosing treatments.

Controlling hydrogen sulfide (H2S) odors and emissions using a single, effective treatment across a town-scale sewer network is a challenge faced by many water utilities. Implementation of a sewer diversion provided the opportunity to compare the effectiveness of magnesium hydroxide (Mg(OH)2) and two biological dosing compounds (Bioproducts A and B), with different modes of action (MOA), in a field-test across a large sewer network. Mg(OH)2 increases sewer pH allowing suppression of H2S release into the sewer environment while Bioproduct A acts to disrupt microbial communication through quorum sensing (QS), reducing biofilm integrity. Bioproduct B reduces H2S odors by scouring the sewer of fats, oils and grease (FOGs), which provide adhesion points for the microbial biofilm. Results revealed that only Mg(OH)2 altered the microbial community structure and reduced H2S emissions in a live sewer system, whilst Bioproducts A and B did not reduce H2S emissions or have an observable effect on the composition of the microbial community at the dosed site. Study results recommend in situ testing of dosing treatments before implementation across an operational system.

Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy.

Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

Simple anatomical information improves the accuracy of locating specific spinous processes during manual examination of the low back.

The objective of the study was to test whether a teaching protocol including simple anatomical information on the surface anatomy of spinous processes, improves physiotherapy students' ability to accurately locate selected thoracic and lumbar spinal segments - T12 and L3. First year physiotherapy students were allocated to Group 1 (n=35) and Group 2 (n=34). Both groups were taught to identify spinous processes by counting up from the sacrum, but Group 2 received supplementary anatomical information on the shapes and vertical length of the tips of L5 to T12 spinous processes. The spinous processes of L3 and T12 were located by two experienced physiotherapists and marked on a model using an invisible skin marker. Volunteer students were asked to locate these spinous processes and accuracy was confirmed using an ultraviolet lamp. Students with supplementary anatomical information (Group 2) were significantly better at locating T12 (difference in proportions 36% (95% confidence interval 14 to 51%)) and both T12 and L3 (difference in proportions 33% (11 to 48%)). Group 2 students were also better than Group 1 students at locating L3 (difference in proportions 28% (4 to 48%)), but the difference was not significant. Including simple anatomical information when teaching manual examination skills improved the accuracy of locating specific low back spinal levels.

Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma.

Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.

5(Z)-benzylidene-1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes as non-steroidal glucocorticoid receptor modulators.

A series of 5-benzylidene-1,2-dihydro-2,2,4-trimethyl-5H-1-aza-6-oxa-chrysenes was synthesized and profiled for their ability to act as selective glucocorticoid receptor modulators (SGRMs). The synthesis and structure-activity relationships for this series of compounds are presented.

Effects of 5'-alkyl-benzothiadiazides on (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor biophysics and synaptic responses.

Alkyl-substituted benzothiadiazides (BTDs) were tested for their effects on (R,S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. In excised patches, the 5'-ethyl derivative "D1" blocked the desensitization of AMPA receptor currents during prolonged application of glutamate (EC(50), 36 microM), and it slowed deactivation of responses elicited by 1-ms glutamate pulses greater than 10-fold. [(3)H]Fluorowillardiine binding to rat synaptic membranes was increased by D1 by a factor of 3.6 (EC(50), 17 microM) with a Hill coefficient near 2. In hippocampal slices, the compound reversibly increased excitatory postsynaptic currents and field excitatory postsynaptic potentials (EPSPs) with thresholds around 10 microM. The size of the alkyl substituent influenced both the potency and nature of the drug effect on synaptic currents: 5'-methyl compounds had a 2-fold greater effect on response amplitude than on response duration, whereas 5'-ethyl compounds like D1 caused greater increases in duration than amplitude. In tests with recombinantly expressed AMPA receptor subunits, D1 preferred the glutamate receptor (GluR) subunit GluR4 flip (0.64 microM) over GluR4 flop (5.3 microM); similar affinities but with smaller flip-flop differences were obtained for GluR1 through 3. These results show that D1 and congeners are significantly more potent than the parent compound IDRA-21 and that they differ in two fundamental aspects from cyclothiazide, the most widely studied BTD: 1) D1 markedly increases the agonist affinity of AMPA receptors and 2) it has immediate and large effects on field EPSPs. The large gain in potency conferred by alkyl substitution suggests that the 5' substituent is in intimate contact with the receptor, with the size of the substituent determining the way in which receptor kinetics is changed.

Total synthesis of dysiherbaine.

A convergent total synthesis of the marine natural product dysiherbaine was accomplished. The key steps of the synthesis are an alkylation at the gamma-carbon of a protected glutamate with a highly substituted pyran derived from mannose, which was followed by a ring-contraction cascade reaction, which simultaneously gave the tetrasubstituted carbon and the hexahydrofuro[3,2-b]pyran ring system of the natural product.

5'-alkyl-benzothiadiazides: a new subgroup of AMPA receptor modulators with improved affinity.

AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 microM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 5'-position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 5'-ethyl derivative exhibited an EC(50) value in the order of 22 microM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC(50) value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 5'-ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure--activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor--drug interactions.