Uncommon yet critical: Pulmonary embolism in a 14-year-old Nigerian child: A case report.

Rationale: Pulmonary embolism is a rare life-threatening condition in pediatric populations. Diagnosis is often challenging in resource-constrained settings suffering chronic shortages of specialist and diagnostic services. We report the prompt recognition and challenging management of pulmonary embolism in an adolescent presenting to a private specialist hospital in a resource-constrained country.

Correlation between Transabdominal Sonographic Prostate Volume and Anthropometric Parameters.

Background: Prostate diseases commonly present with lower urinary tract symptoms (LUTS) resulting from prostatic enlargement. Prostate volume (PV) can be evaluated using transabdominal ultrasonography. Focus is currently on relative factors of prostatic enlargement which includes obesity and central adiposity.

Triplex Sonographic Evaluation of Portal Vein Indices Among Adults in Port Harcourt, Nigeria.

Background: Chronic liver disease is characterized by progressive hepatic fibrosis and changes in hepatic vascular hemodynamics. Sonography is a readily available tool in the assessment of the hepatic hemodynamic alterations that occur in chronic liver diseases.

Aim: This study was aimed at sonographically determining the portal vein indices in apparently healthy adults by estimating the portal vein diameter, cross-sectional area, and portal vein velocity.

Reducing Repeat Blood Cultures in Febrile Neutropenia: A Single-Center Experience.

Background: Limited data exist to guide blood culture ordering in persistent febrile neutropenia (FN), resulting in substantial variation in practice. Unnecessary repeat blood cultures have been associated with patient harm including increased antimicrobial exposure, hospital length of stay, catheter removal, and overall cost.

Methods: We conducted a single-center study of adult hematology-oncology patients with ≥3 days of FN.

The moderating effect of COVID-19 stress on school racial climate and parent and child mental well-being.

The deleterious and racially disparate health outcomes of COVID-19 have been on full display since the pandemic began in the United States; however, less exploration has been dedicated to understanding short- and long-term mental health outcomes for U.S. parents and their children as a result of COVID's impact on schooling.

Reasonable efforts to preserve families? An examination of service utilization and child removal.

Background: Recent federal policy has solidified the importance of preserving families, yet over 400,000 children enter foster care each year. Although a few studies have found that certain types of services, like intensive family preservation services, may reduce child removals, more research is needed.

Objective: This study examined the relationship between family preservation, family support, and basic need service utilization and child removal among families with substantiated cases of maltreatment.

The effects of avoiding extended antimicrobial drain prophylaxis on Clostridioides difficile and postprocedural infection rates: a 5-year retrospective.

Objective: Postprocedural infection is a consequential complication of neurosurgical intervention. Periprocedural antimicrobial prophylaxis is routinely administered to prevent infection, and in some cases, continued for extended periods while surgical drains remain in place. However, there is little evidence that extended antimicrobial administration is necessary to reduce postprocedural infection, and extended antimicrobials can be associated with harm, such as Clostridioides difficile infection.

Implementation of a Rapid Phenotypic Susceptibility Platform for Gram-Negative Bloodstream Infections With Paired Antimicrobial Stewardship Intervention: Is the Juice Worth the Squeeze?

Background: Implementation of the Accelerate PhenoTM Gram-negative platform (RDT) paired with antimicrobial stewardship program (ASP) intervention projects to improve time to institutional-preferred antimicrobial therapy (IPT) for Gram-negative bacilli (GNB) bloodstream infections (BSIs). However, few data describe the impact of discrepant RDT results from standard of care (SOC) methods on antimicrobial prescribing.

Methods: A single-center, pre-/post-intervention study of consecutive, nonduplicate blood cultures for adult inpatients with GNB BSI following combined RDT + ASP intervention was performed.

An Examination of Peer Victimization and Internalizing Problems through a Racial Equity Lens: Does School Connectedness Matter?

Although research has given ample consideration to the association between peer victimization and internalizing problems, little is known about the mediating and moderating influences on this relationship. This study investigated whether peer victimization at age 9 indirectly related to internalizing problems at age 15 via school connectedness and whether the direct and indirect associations between peer victimization and internalizing problems were moderated by race. Data were drawn from the Fragile Families and Child Wellbeing Study, which included 2467 adolescents.

Collaborative Antimicrobial Stewardship for Surgeons.

Antimicrobial stewardship efforts that include surgeons rely on healthy and open communications between surgeons, infectious diseases specialists, and pharmacists. These efforts most frequently are related to surgical prophylaxis, the management of surgical infections, and surgical critical care. Policy should be based on best evidence and timely interactions to develop consensus on how to develop appropriate guidelines and protocols.

LMTK2 binds to kinesin light chains to mediate anterograde axonal transport of cdk5/p35 and LMTK2 levels are reduced in Alzheimer's disease brains.

Cyclin dependent kinase-5 (cdk5)/p35 is a neuronal kinase that regulates key axonal and synaptic functions but the mechanisms by which it is transported to these locations are unknown. Lemur tyrosine kinase-2 (LMTK2) is a binding partner for p35 and here we show that LMTK2 also interacts with kinesin-1 light chains (KLC1/2). Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2.

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease.

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.

Fructose-1,6-bisphosphatase inhibitors. 1. Purine phosphonic acids as novel AMP mimics.

Inhibition of FBPase is considered a promising way to reduce hepatic gluconeogenesis and therefore could be a potential approach to treat type 2 diabetes. Herein we report the discovery of a series of purine phosphonic acids as AMP mimics targeting the AMP site of FBPase, which was achieved using a structure-guided drug design approach. These non-nucleotide purine analogues inhibit FBPase in a similar manner and with similar potency as AMP.

Quinolines as a novel structural class of potent and selective PDE4 inhibitors: optimisation for oral administration.

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.

First-in-class pan caspase inhibitor developed for the treatment of liver disease.

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury.

Structure-activity relationships within a series of caspase inhibitors. Part 2: Heterocyclic warheads.

Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed.

Oxamyl dipeptide caspase inhibitors developed for the treatment of stroke.

Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.

Pyrrolidine-5,5-trans-lactams. 5. Pharmacokinetic optimization of inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the second of two Letters, the optimization of the pyrrolidine-5,5-trans-lactam template (exemplified by 1a) as a mechanism-based inhibitor of hepatitis C NS3/4A protease is described. "Right Box" analysis of cassette dosing screening pharmacokinetic data was used to rapidly categorize the compounds. GW0014 (compound 4d) emerged as the compound displaying an optimal balance of biochemical and replicon potency, along with low i.

Structure-activity relationships within a series of caspase inhibitors: effect of leaving group modifications.

Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified.

The design of potent, non-peptidic inhibitors of hepatitis C protease.

The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.

Pyrrolidine-5,5-trans-lactams. 2. The use of X-ray crystal structure data in the optimization of P3 and P4 substituents.

[reaction: see text] In this, the second of two letters, we describe the elaboration of the pyrrolidine-5,5-trans-lactam template to delineate the requirements for optimal substitution of the pyrrolidine and lactam nitrogen atoms. Central to the strategy is the use of rapid iterative synthesis in conjunction with X-ray crystal structure determination of ligand-protein complexes.

Pyrrolidine-5,5-trans-lactams. 1. Synthesis and incorporation into inhibitors of hepatitis C virus NS3/4A protease.

[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g.

Design and synthesis of ethyl pyrrolidine-5,5-trans-lactams as inhibitors of hepatitis C virus NS3/4A protease.

Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.

Acyl dipeptides as reversible caspase inhibitors. Part 2: further optimization.

A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.

Is active skeletal muscle functionally vasoconstricted during dynamic exercise in conscious dogs?

We investigated whether the increase in hindlimb blood flow and vascular conductance in conscious dogs during graded dynamic exercise is functionally restrained by the sympathetic nervous system. Dogs were chronically instrumented to monitor terminal aortic blood flow (TAQ) as an index of hindlimb skeletal muscle blood flow and mean arterial pressure (MAP). The extent of functional sympathetic tone was assessed by measuring the increase in TAQ and terminal aortic vascular conductance (TAC, calculated as TAQ/MAP) in response to intra-arterial infusion of the alpha-adrenergic antagonist prazosin (PZ; 50 micrograms/kg) into the hind-limbs at rest and during steady-state dynamic (treadmill) exercise ranging from mild (3.