In vitro–in vivo correlation of voriconazole resistance due to G448S mutation (cyp51A gene) in Aspergillus fumigatus

Invasive pulmonary aspergillosis continues to be associated with a high mortality despite timely and appropriate therapy. Although host immunity plays a major role in poor clinical response, antifungal drug resistance cannot be ignored. Our studies were aimed 1) to study the mechanism of drug resistance in voriconazole strains of Aspergillus fumigatus, 2) to establish a causal relationship between cyp51A mutation and voriconazole resistance (VRC-R), and 3) to determine whether VRC-R due to cyp51A mutation correlated with in vivo resistance. A point mutation (G448S) involving cyp51A gene in VRC-R isolate was associated with resistance to VRC but not to posaconazole (POS); POS had superior activity to VRC in reducing lung fungal burden and mortality in mice infected with a VRC-R mutant of A. fumigatus. Our study demonstrated that azole resistance is based on specific site of cyp51A mutation and that in vitro VRC-R correlates with in vivo resistance.     

Aggressive Presentation and Rapid Progression of Osteonecrosis of the Femoral Head After COVID-19

BackgroundWe aim to report the consecutive patients diagnosed with osteonecrosis of femoral head (ONFH) following recovery from COVID-19 disease and elucidate the unique features of ONFH associated with COVID-19.MethodsConsecutive 22 patients (39 hips) recovered from COVID-19 and presented with ONFH from November 2020 to October 2021 were included. All the patients received corticosteroids as a supportive treatment during COVID-19. Patients were classified into two types based on the type of presentation, namely classic ONFH and rapidly destructive coxarthrosis (RDC) depending on radiographs, MRI, inflammatory markers and hip aspiration findings. Harris hip score was used to evaluate the functional outcome before and after treatment.ResultsThe mean time to diagnose of ONFH from the onset of hip symptoms was 39.3 days (range 10–90 days). The average duration of onset of hip symptoms after COVID 19 infection was 7.5 months (range 3 – 11 months). The average cumulative dose of methylprednisolone equivalent was 811 mg (range 200–2100 mg) and the average duration of steroid intake was 2.8 weeks. There was significant elevation in the inflammatory markers in RDC group compared to classic ONFH (p < 0.05). The Harris hip score improved from 63.6 ± 23.2 at presentation to 82.6 ± 9.6 after treatment (p < 0.05). Three patients had features of RDC. Among the three patients with RDC, two patients had rapid progression of ONFH and underwent total hip arthroplasty (THA). The third patient is awaiting a THA.ConclusionONFH after COVID-19 can have a varied presentation. While the most common presentation is like classical ONFH, some patients can have an acute and aggressive presentation with rapid destruction. They have features like elevated serological markers and extensive periarticular bone and soft tissue edema. A low cumulative dose of steroids in our patients suggests that the COVID-19-associated vasculitis may play a role in the pathogenesis of ONFH.     

The Frequency,Characteristics, and Outcomes Among Cancer Patients With Delirium Admitted to an Acute Palliative Care Unit

Background.

Delirium is a common neuropsychiatric condition seen in patients with severe illness, such as advanced cancer. Few published studies are available of the frequency, course, and outcomes of standardized management of delirium in advanced cancer patients admitted to acute palliative care unit (APCU). In this study, we examined the frequency, characteristics, and outcomes of delirium in patients with advanced cancer admitted to an APCU.

Methods.

Medical records of 609 consecutive patients admitted to the APCU from January 2011 through December 2011 were reviewed. Data on patients’ demographics; Memorial Delirium Assessment Scale (MDAS) score; palliative care specialist (PCS) diagnosis of delirium; delirium etiology, subtype, and reversibility; late development of delirium; and discharge outcome were collected. Delirium was diagnosed with MDAS score ≥7 and by a PCS using Diagnostic and Statistical Manual, 4th edition, Text Revision criteria. All patients admitted to the APCU received standardized assessments and management of delirium per best practice guidelines in delirium management.

Results.

Of 556 patients in the APCU, 323 (58%) had a diagnosis of delirium. Of these, 229 (71%) had a delirium diagnosis on admission and 94 (29%) developed delirium after admission to the APCU. Delirium reversed in 85 of 323 episodes (26%). Half of patients with delirium (n = 162) died. Patients with the diagnosis of delirium had a lower median overall survival than those without delirium. Patients who developed delirium after admission to the APCU had poorer survival (p ≤ .0001) and a lower rate of delirium reversal (p = .03) compared with those admitted with delirium.

Conclusion.

More than half of the patients admitted to the APCU had delirium. Reversibility occurred in almost one-third of cases. Diagnosis of delirium was associated with poorer survival.

Implications for Practice:

Delirium is the most common neuropsychiatric condition in patients with severe medical illness and those at the end of life. It can be a source of distress for patients, their families, and the medical team. When missed, or if symptoms are misinterpreted, delirium may also lead to unnecessary interventions. This underlines the importance of diagnosis and detection of delirium in populations that are at increased risk. This study has important implications in practice, as it can assist clinicians in making decisions regarding other medical interventions, advance care planning, and communicating with families relating to end-of-life issues.     

A proposed role for efflux transporters in the pathogenesis of hydrocephalus

Hydrocephalus is a common brain disorder that is treated only with surgery. The basis for surgical treatment rests on the circulation theory. However, clinical and experimental data to substantiate circulation theory have remained inconclusive. In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water-permeable tissue. As the osmolarity of ventricular CSF increases within the cerebral ventricles, water movement into the ventricles increases and causes hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. Efflux transporters, (p-glycoprotein), are located along the blood brain barrier and play an important role in the clearance of macromolecules (endobiotics and xenobiotics) from the brain to the blood. There is clinical and experimental data to show that macromolecules are cleared out of the brain in normal and hydrocephalic brains. This article summarizes the existing evidence to support the role of efflux transporters in the pathogenesis of hydrocephalus. The location of p-gp along the pathways of macromolecular clearance and the broad substrate specificity of this abundant transporter to a variety of different macromolecules are reviewed. Involvement of p-gp in the transport of amyloid beta in Alzheimer disease and its relation to normal pressure hydrocephalus is reviewed. Finally, individual variability of p-gp expression might explain the variability in the development of hydrocephalus following intraventricular hemorrhage.Hydrocephalus is a common brain disorder that affects children and individuals of all ages. It is the most common congenital abnormality in children (one out of 500 births) (1). If left untreated, hydrocephalus can lead to permanent brain damage and result in cognitive and physical handicap.Contemporary surgical management of hydrocephalus is based on the popular conceptualization of circulation theory. The circulation theory of hydrocephalus states that cerebrospinal fluid (CSF) produced by the choroid plexus flows along specific pathways to be absorbed by the venous sinuses. An obstruction in any part of these pathways leads to hydrocephalus. Surgical management of hydrocephalus is therefore directed at detecting and removing the source of obstruction (such as removal of tumor or blockage of pathways) or diverting the fluid bypassing the obstruction. As such, the most common treatment for hydrocephalus is the surgical implantation of a shunt system to divert the flow of CSF from the ventricles. However, although most cases of hydrocephalus are managed with a shunt system, it is rare for the device to last a lifetime without complications. Treatment of hydrocephalus leads to approximately 38 000 admissions per year in the US. Costs for treatment range from US $1.4-2 billion per year and approximately US $1 billion is spent on the revision of malfunctioning shunts (2).This may be a result of poor shunt design or a flawed approach to treatment.Circulation theory rests on the assumption that the brain parenchyma is impermeable to water, and is therefore incapable of independently absorbing the CSF that accumulates in the ventricles. However, we have previously seen that the brain is, in fact, permeable to water due to the presence of aquaporin channels and other ion channels (3,4). This permeability of brain parenchyma to water and several other observations question the validity and applicability of circulation theory to design treatment strategies for hydrocephalus.In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water permeable tissue. Alteration in osmolarity resulting from increase in the concentration of macromolecules and ions has been shown to increase the fluid content and hence the size of the ventricles (5-7). Any osmotic gradient between the ventricular or interstitial CSF and the blood is equilibrated with transport of water between the two compartments. Therefore, water movement into the ventricle is secondary to the presence of osmotic gradients due to excess macromolecules. Thus, water movement into and out of the ventricles is not independent but is dependent upon the presence and resolution of osmotic gradients due to increase or decrease in the macromolecular content (8).Within this article, we review the role played by osmotic gradients and macromolecular ventricular clearance in hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. At least two primary pathways of macromolecular ventricular clearance have been studied: paravascular pathways (also known as glymphatic pathways) and olfactory lymphatic pathways.In particular, we focus on the role played by efflux transporters, specifically p-gp (ABC-B1) in the pathogenesis of hydrocephalus. Efflux transporters are responsible for the transport and clearance of both endogenous (endobiotics) and exogenous (xenobiotics) substances. An understanding of these transporters is critical to designing effective pharmacological treatment for this problematic disorder.