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New antibiotics are urgently needed to counter the emergence of antimicrobial-resistant pathogenic bacteria. A major challenge in antibiotic drug discovery is to turn potent biochemical inhibitors of essential bacterial components into effective antimicrobials. This difficulty is underpinned by a lack of methods to investigate the physicochemical properties needed for candidate antibiotics to permeate the bacterial cell envelope and avoid clearance by the action of bacterial efflux pumps. To address these issues, here we used a target engagement assay to measure the equilibrium and kinetic binding parameters of antibiotics targeting dihydrofolate reductase (DHFR) in live bacteria. We also used this assay to identify novel DHFR ligands having antimicrobial activity. We validated this approach using the Gram-negative bacteria

Informal settlements, sometimes called slums, are sites of significant environmental risk in developing cities. Despite its environmental challenges, residents prefer to live in informal settlements rather than planned allocated plots. This paper assesses the determinants of households’ residential location decision in an informal settlement in Port Harcourt in order to gain understanding on what makes individuals consider a particular location in an informal settlement. The study employs a case study approach and uses both indepth face-to-face interviews and structured questionnaires on waterfront households using Cluster sampling to group the settlements into seven (7) zones based on their location in order to capture information on residential location choice decisions of respondents in the informal settlements. In each settlement, we interviewed two households, thereafter questionnaires were administered on 55 respondents’ household by trained graduate students who worked as enumerators. In all a total of 14 interviews were conducted and 385 questionnaires administered. Out of the 385 questionnaires administered, 315 were completed and returned. The results of the survey corroborated by an indebth interview revealed that the growing informality are not limited to income level, but household uses social networks (living close to family or friends), livelihood opportunities, proximity to work, and commuting cost to find accommodation, land for building and support for everyday life in an informal settlement.

Introduction Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. Methods The protein–protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. Results The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0–8.3, p value 0.0001). Odds ratios (3.4–8.8) were significant (p value, Plain Language Summary A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists’ confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.4–8.8 for targeted therapy-naïve patients and 3.3–26.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritis—a heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00330-y.

Objective Although evidence implicates striatal cholinergic impairment as a mechanism underlying tardive dyskinesia, trials of nonspecific cholinergic agents have been inconclusive. As a partial agonist at specific nicotinic receptor subtypes, varenicline reduces drug-induced dyskinesias in animal models suggesting promise as a treatment for tardive dyskinesia. Methods Three schizophrenia patients with tardive dyskinesia who were smokers underwent an open trial of varenicline. After a 2-week baseline, subjects received varenicline 1 mg twice daily. Changes from baseline on the Abnormal Involuntary Movement Scale were measured after a 4-week varenicline stabilization period, and 6 weeks after the smoking quit date in one patient. Results Varenicline had no effect on mean Abnormal Involuntary Movement Scale scores after 4 weeks. Although smoking decreased after 4 weeks on varenicline and diminished further in one patient after 10 weeks, this also appeared to have no effect on ratings of tardive dyskinesia. Conclusion In contrast to animal models, no significant change in tardive dyskinesia occurred in response to varenicline replacement in three schizophrenia patients. Further investigations of cholinergic mechanisms in tardive dyskinesia are worthwhile as agents for specific cholinergic targets become available for treatment. In addition, treatment trials of tardive dyskinesia should control for smoking status, while patients on antipsychotics receiving nicotine replacement therapies for smoking should be studied further for changes in movement.

High frequency of antibiotic detection in groundwater in informal settlements is attributed to increased usage and improper disposal, thus difficult to identify sources of antibiotic resistance in the environment, worsened by inadequate sanitation facilities and increased population density, particularly in developing-countries. Reliance on groundwater exposes them to pollutants and risk of antibiotic resistance, in addition to experiencing inequities in accessing vital services. Sulfamethoxazole and trimethoprim, used for prophylaxis by HIV/AIDS patients were tested in 49 groundwater sources in Kisumu, Kenya. Only Sulfamethoxazole (SMX) was found, with a detection frequency of 14.3% and concentrations ranging from below limit of quantification (LOQ) to 258.2 ng/L. Trimethoprim (TMP), marketed in combination with sulfamethoxazole, was not detected, owing to its high distribution coefficient (kPa7.12) and, generally, being a bigger molecule with modest water mobility and solubility. Furthermore, TMP ratio in cotrimoxazole is low (5:1), it is expected that mass loading will be lower, as well as influence of the study area’s hydrogeology, where soil is clayey with high porosity and permeability. Escherichia coli was recovered in 98% (n = 48) of water samples, with counts ranging from 16 to 8,850 MPN/100ml. Additionally, resistance to sulfamethoxazole was identified in 6% (n = 3) samples with Inhibition Zone Diameters of 0.8mm(resistant), 10.5mm (resistant), and 11.5mm (intermediate), but not among samples where SMX was detected. Antibiotic concentrations in water that can cause resistance are unknown because antibiotic-resistant E. coli was not found in water samples where sulfamethoxazole was identified, raising concerns about f environmental resistance spread. Concentration of SMX was lower in a previous research, which only collected water from one groundwater source, than the current study, which included additional samples (49). Presence of SMX and Escherichia coli resistance is of concern and necessitates greater attention and regular monitoring for potential contaminants and resistance trigger to avert potential risks to human health.

ObjectivesCurrently utilized clinician-rated symptom scales for tardive dyskinesia (TD) have not kept up with the expanding spectrum of TD phenomenology. The objective of this study was to develop and test the reliability of a new instrument, the CTI.MethodsA movement disorder neurologist devised the outline of the scale. A steering committee (four neurologists and two psychiatrists) provided revisions until consensus was reached. The resulting instrument assesses frequency of abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, limb/trunk, complex movements (e.g., handwringing, self-caressing), and vocalizations. The CTI rates symptoms from 0–3 with 0 = absent, 1 = infrequent/intermittent or only present with activating maneuvers, 2 = frequent intermittent, brief periods without movements, 3 = constant or nearly constant. Functional impairments including activities of daily living (ADL), social impairment, symptom bother, and harm are rated 0–3 with 0 = patient is unaware or unaffected, 1 = symptoms mildly impact patient, 2 = symptoms moderately impact patient, 3 = symptoms severely impact patient. Following institutional review board approval, the CTI underwent inter-rater and test-retest reliability testing. Videos of patient TD examinations were obtained and reviewed by two movement disorder specialists to confirm the diagnosis of TD by consensus and the adequacy to demonstrate a TD-consistent movement. Vignettes were created to include patients’ symptom descriptions and functional, social, or occupational impairments/limitations. Four clinicians rated each video/vignette. Selected videos/vignettes were also subject to an intra-rater retest. Interrater agreement was analyzed via 2-way random-effects interclass correlation (ICC) and test-retest agreement assessment utilizing Kendall’s tau-b.Results45 video/vignettes were assessed for interrater reliability, and 16 for test-retest reliability. ICCs for movement frequency were as follows: abnormal eye movement .89; abnormal tongue/mouth movement .91; abnormal jaw movement .89; abnormal limb movement .76; complex movement .87; abnormal vocalization .77; and functional impairments including harm .82; social embarrassment .88; ADLs .83; and symptom bother .92. Retests were conducted on mean (SD) 15 (3) days later with scores ranging from .66–.87.ConclusionsThe CTI is a new instrument with good reliability in assessing TD symptoms and functional impacts. Future validation study is warranted.FundingNeurocrine Biosciences

Hyperthermia, or extreme elevations in body temperature, can be life-threatening and may be caused by prescription drugs or illegal substances acting at a number of different levels of the neuraxis. Several psychotropic drug classes and combinations have been associated with a classic clinical syndrome of hyperthermia, skeletal muscle hyper-metabolism, rigidity or rhabdomyolysis, autonomic dysfunction and altered mental status ranging from catatonic stupor to coma. It is critical for clinicians to have a high index of suspicion for these relatively uncommon drug-induced adverse effects and to become familiar with their management to prevent serious morbidity and mortality. Although these syndromes look alike, they are triggered by quite different mechanisms, and apart from the need to withdraw or restore potential triggering drugs and provide intensive medical care, specific treatments may vary. Clinical similarities have led to theoretical speculations about common mechanisms and shared genetic predispositions underlying these syndromes, suggesting that there may be a common "thermic stress syndrome" triggered in humans and animal models by a variety of pharmacological or environmental challenges.

Background: Natural products such as extracts of plants have been seen as a possible alternative to conventional therapies in the treatment and management of male infertility. This study aimed at investigating the testicular antioxidant and testosterone enhancing ability of the hydro-alcoholic extract of Rauvolfia vomitoria in male rats. Methods: Twenty-four male rats were divided into four groups of 6 rats each, treated daily with either vehicle (distilled water; 5 mL/kg) or hydro-ethanolic extract of R. vomitoria (20 mg/kg, 40 mg/kg, and 100mg/kg) for 60 days, and body weights recorded once every three days. At the end of the treatment, each animal was sacrificed, and reproductive organs were dissected out and weighed. Serum from capillary blood was used for testosterone quantification, while testicular homogenates were used for the estimation of antioxidant biomarkers. Results: Treatment with R. vomitoria extract did not alter the animal’s body weight. Instead, the extract at the dose of 40 mg/kg significantly increased (P< 0.05) the weights of all reproductive organs investigated. The plant extract also increased serum testosterone concentrations significantly (P< 0.05), with the highest effect observed in the animals treated with a dose of 40 mg/kg. Testicular antioxidant markers, thiobarbituric acid substances, glutathione, and catalase were equally improved (P< 0.05) by treatment with the plant extract at the dose of 40 mg/kg. Conclusion: Hydro-ethanolic extract of R. vomitoria portrayed beneficial pharmacological properties on reproductive organs, testicular antioxidants, and testosterone concentrations in male rats. These pharmacological activities support the traditional use of the plant in the management of male fertility disorders.

The DSIF complex comprising the Supt4h and Supt5h transcription elongation proteins clamps RNA polymerase II (RNAPII) onto DNA templates, facilitating polymerase processivity. Lowering DSIF components can differentially decrease expression of alleles containing nucleotide repeat expansions, suggesting that RNAPII transit through repeat expansions is dependent on DSIF functions. To globally identify sequence features that affect dependence of the polymerase on DSIF in human cells, we used ultra-deep ChIP-seq analysis and RNA-seq to investigate and quantify the genome-wide effects of Supt4h loss on template occupancy and transcript production. Our results indicate that RNAPII dependence on Supt4h varies according to G + C content. Effects of DSIF knockdown were prominent during transcription of sequences high in G + C but minimal for sequences low in G + C and were particularly evident for G + C-rich segments of long genes. Reanalysis of previously published ChIP-seq data obtained from mouse cells showed similar effects of template G + C composition on Supt5h actions. Our evidence that DSIF dependency varies globally in different template regions according to template sequence composition suggests that G + C content may have a role in the selectivity of Supt4h knockdown and Supt5h knockdown during transcription of gene alleles containing expansions of G + C-rich repeats.

Accurate diagnosis and appropriate treatment of tardive dyskinesia (TD) are imperative, as its symptoms can be highly disruptive to both patients and their caregivers. Misdiagnosis can lead to incorrect interventions with suboptimal or even deleterious results. To aid in the identification and differentiation of TD in the psychiatric practice setting, we review its clinical features and movement phenomenology, as well as those of other antipsychotic-induced movement disorders, with accompanying links to illustrative videos. Exposure to dopamine receptor blocking agents (DRBAs) such as antipsychotics or antiemetics is associated with a spectrum of movement disorders including TD. The differential diagnosis of TD is based on history of DRBA exposure, recent discontinuation or dose reduction of a DRBA, and movement phenomenology. Common diagnostic challenges are the abnormal behaviors and dyskinesias associated with advanced age or chronic mental illness, and other movement disorders associated with DRBA therapy, such as akathisia, parkinsonian tremor, and tremor related to use of mood stabilizing agents (eg, lithium, divalproex). Duration of exposure may help rule out acute drug-induced syndromes such as acute dystonia or acute/subacute akathisia. Another important consideration is the potential for TD to present together with other drug-induced movement disorders (eg, parkinsonism, parkinsonian tremor, and postural tremor from mood stabilizers) in the same patient, which can complicate both diagnosis and management. After documentation of the phenomenology, severity, and distribution of TD movements, treatment options should be reviewed with the patient and caregivers.