'Value-based methodology for person-centred, integrated care supported by Information and Communication Technologies' (ValueCare) for older people in Europe: study protocol for a pre-post controlled trial.

BACKGROUND: Older people receive care from multiple providers which often results in a lack of coordination. The Information and Communication Technology (ICT) enabled value-based methodology for integrated care (ValueCare) project aims to develop and implement efficient outcome-based, integrated health and social care for older people with multimorbidity, and/or frailty, and/or mild to moderate cognitive impairment in seven sites (Athens, Greece; Coimbra, Portugal; Cork/Kerry, Ireland; Rijeka, Croatia; Rotterdam, the Netherlands; Treviso, Italy; and Valencia, Spain). We will evaluate the implementation and the outcomes of the ValueCare approach. This paper presents the study protocol of the ValueCare project; a protocol for a pre-post controlled study in seven large-scale sites in Europe over the period between 2021 and 2023. METHODS: A pre-post controlled study design including three time points (baseline, post-intervention after 12 months, and follow-up after 18 months) and two groups (intervention and control group) will be utilised. In each site, (net) 240 older people (120 in the intervention group and 120 in the control group), 50-70 informal caregivers (e.g. relatives, friends), and 30-40 health and social care practitioners will be invited to participate and provide informed consent. Self-reported outcomes will be measured in multiple domains; for older people: health, wellbeing, quality of life, lifestyle behaviour, and health and social care use; for informal caregivers and health and social care practitioners: wellbeing, perceived burden and (job) satisfaction. In addition, implementation outcomes will be measured in terms of acceptability, appropriateness, feasibility, fidelity, and costs. To evaluate differences in outcomes between the intervention and control group (multilevel) logistic and linear regression analyses will be used. Qualitative analysis will be performed on the focus group data. DISCUSSION: This study will provide new insights into the feasibility and effectiveness of a value-based methodology for integrated care supported by ICT for older people, their informal caregivers, and health and social care practitioners in seven different European settings. TRIAL REGISTRATION: ISRCTN registry number is 25089186 . Date of trial registration is 16/11/2021.

Diagnostic value for culture of cerebrospinal fluid from HIV-1-infected individuals for opportunistic viruses: a prospective study.

OBJECTIVE: To investigate the diagnostic value of cerebrospinal fluid (CSF) culture for opportunistic viruses from HIV-1-infected individuals. METHODS: A 4-year prospective study was conducted using a participant population consisting of 186 HIV-1-infected individuals without neurologic disease, 73 HIV-1-infected individuals with encephalopathy, myelopathy, and/or peripheral neuropathy, and 10 controls. CSF samples recovered at 1-year intervals were subjected to virus culture using technique commonly used in the clinical laboratory setting. RESULTS: CSF samples obtained from only 15 of the 269 (5.6%) participants yielded an opportunistic virus upon culture. Cytomegalovirus, herpes simplex virus types 1 and 2, adenovirus, and presumptive enteroviruses were identified. No consistent correlation was observed between the detection of an opportunistic virus within a CSF sample and the presence or future development of neurologic disease. However, a significant correlation was observed between culture of virus from CSF and the future development of abnormal CD4+ (chi 2, P = 0.0286) and CD8+ (chi 2, P = 0.0018) lymphocyte counts in HIV-1-infected participants without neurologic disease. CONCLUSION: These results show that culture of CSF to screen for opportunistic viruses is neither diagnostic nor predictive of neurologic disease in HIV-1-infected individuals. Nevertheless, the presence of virus within CSF may be an indicator of HIV-1-mediated immune dysfunction and a predictor for future development of abnormal CD4+ and/or CD8+ lymphocyte counts.

Herpes simplex virus type 1 infection of rat astrocytes in primary culture: effects of dibutyryl cyclic AMP.

Monolayer cultures of primary rat astrocytes grown with or without dibutyryl cyclic AMP (dBcAMP) for two weeks or longer were infected with round plaque-forming (Rd) or syncytia-forming (Syn) variants of herpes simplex virus type 1 (HSV-1). Infection with HSV-1 did not stimulate synthesis of glial fibrillary acidic protein (GFAP) or alter the general organization of the intermediate (glial) filaments in astrocyte cultures. However, the dBcAMP-treated astrocytes produced 10- to 100-fold lower titers of cell-free progeny HSV-1 than the untreated astrocyte cultures. Radiolabeled amino acid or glucosamine incorporated into acid precipitable cellular or viral glycoproteins was decreased by 10-25% in dBcAMP-treated astrocytes. Distinctive cell-rounding or syncytial cytopathology was produced by HSV-1 strains infecting untreated astrocytes, but the infected dBcAMP-treated astrocytes displayed only cell-rounding cytopathology. The dBcAMP-related effects on HSV-1 infection were specific to primary astrocyte cultures; they were not observed in HSV-1-infected human fibroblast cultures treated with dBcAMP. Comparison of HSV-1 infection of untreated versus dBcAMP-treated astrocytes suggests that the dBcAMP-induced "reactive" or differentiated state of the astrocyte can affect expression of virus-induced cytopathology and virus-specific polypeptide synthesis. The dBcAMP-treated primary astrocyte culture may afford a non-neoplastic, differentiated in vitro system for studying HSV-neural cell interactions.

Infection of human neural cell aggregate cultures with a clinical isolate of cytomegalovirus.

Human neural cell aggregate cultures were prepared from dissociated fetal brain tissue and maintained in rotation culture. After 35 days in culture, aggregates had the histologic appearance of dense, immature, neural cells in a tightly packed neuropil. Electron microscopy revealed ultrastructural features suggestive of immature neurons and neuroglia. In addition, neuron-specific enolase and glial fibrillary acidic protein associated with radial glial cells were detected within the aggregates by immunoperoxidase staining. When infected with a laboratory-adapted strain of cytomegalovirus (CMV), [AD169], cells containing large, bizarre, nuclei and CMV-induced intranuclear inclusion bodies were dispersed throughout the aggregates at 16 days postinfection. In situ hybridization using a CMV-specific DNA probe and electron microscopy confirmed the presence of virus sequences as well as virus particles at histologic sites of cytopathology. In sharp contrast, aggregate cultures infected with a CMV strain recovered from the retina of an acquired immune deficiency syndrome (AIDS) patient with CMV retinitis and encephalitis displayed distinct foci of cytopathology at 23 days postinfection, a pattern not observed in CMV [AD169]-infected aggregates. Our findings suggest that human neural cell aggregates represent a a promising multicellular non-neoplastic culture system in which to study the replication of human neurotropic viruses within neural tissue.

Efficacy and safety of Minipress XL, a new once-a-day formulation of prazosin.

The efficacy and safety of prazosin GITS (gastro-intestinal therapeutic system), a new extended-release once-a-day formulation, were assessed both as monotherapy in mild essential hypertension and in combination with a diuretic in moderate essential hypertension in two multicenter, double-blind, placebo-controlled trials. Prazosin GITS (Minipress XL) given once daily in doses of either 10 or 20 mg significantly reduced sitting and standing systolic and diastolic blood pressure compared with placebo in both mild and moderate essential hypertension. There were minimal, clinically insignificant changes in heart rate following prazosin-GITS treatment (2.5, 10, and 20 mg) compared with placebo treatment. Prazosin GITS was well tolerated; the most common adverse experiences reported were headache, dizziness, and fatigue. All adverse experiences in the moderate hypertension group and the majority (91 percent) in the mild hypertension group were mild-to-moderate in severity. The results from these multicenter trials demonstrate the efficacy and safety of this new extended-release once-a-day formulation of prazosin in the treatment of patients with mild and moderate essential hypertension.

Systemic cytokine immunotherapy for experimental cytomegalovirus retinitis in mice with retrovirus-induced immunodeficiency.

PURPOSE: To evaluate and compare the in vivo administration of interleukin-2 (IL-2) or interleukin-12 (IL-12) in the immunotherapy of necrotizing retinitis caused by murine cytomegalovirus (MCMV) in mice with a retrovirus-induced immunodeficiency syndrome (MAIDS). METHODS: Adult C57BL/6 mice with MAIDS of 8 weeks' duration were treated with either a single intramuscular injection of polyethylene glycol-modified human recombinant IL-2 (PEG-IL-2) or multiple intramuscular injections of murine recombinant IL-12; untreated mice with MAIDS received phosphate-buffered saline. Two days later, the left eyes of all mice were inoculated with MCMV by subretinal injection and evaluated at day 6 for intraocular MCMV titers or at day 10 for frequency of necrotizing MCMV retinitis. RESULTS: Infectious MCMV was significantly reduced in whole eyes of PEG-IL-2-treated mice with MAIDS (2.8 log10), but not in whole eyes of IL-12-treated animals (4.4 log10) when compared with whole eyes of untreated animals with MAIDS (4.5 log10). Similarly, whereas eyes from approximately 80% of IL-12-treated and untreated mice with MAIDS showed histopathologic features consistent with classic necrotizing MCMV retinitis (full-thickness retinal necrosis associated with virus inclusions and cytomegalocytes), none (0%) of PEG-IL-2-treated animals with MAIDS showed classic MCMV retinitis. Instead, eyes from these animals showed either retinal folding or outer retinal atrophy, a pattern of histopathology similar to that observed in eyes from immunologically normal C57BL/6 mice inoculated subretinally with MCMV. CONCLUSIONS: These results provide proof-of-principle for the hypothesis that systemic cytokine immunotherapy will reduce the frequency of CMV retinitis in a setting of retrovirus-induced immunosuppression. Because of the striking differential effects of IL-2 and IL-12 on MCMV-retinitis in mice with MAIDS, the authors conclude that cytokine immunotherapy for cytomegalovirus-induced retinitis is cytokine-specific, even for such cytokines as IL-2 and IL-12 that have T cell regulation in common.

HSV-2 alters retinal physiology and morphology bilaterally in mice.

Anterior chamber inoculation of 10(4) PFU of the MS strain of HSV-2 resulted in physiologic and morphologic changes in the retina of the inoculated and the uninoculated eyes. In the inoculated eyes, electroretinogram (ERG) depression was first detected on day 3 and abolished ERGs on day 8 postinoculation (PI). The decrease in the ERGs was rapid and the time course was similar for all of the eyes. In spite of a 90% decrease in the amplitude of the b-wave, the retinal sensitivity did not change. Of 23 eyes tested on or after day 10 PI, none had normal, 4.3% had reduced, and 95.6% had abolished ERGs. In the uninoculated eyes, ERG depression was first detected on day 8 and abolished ERGs on day 12 PI. The course of the ERG depression was more variable, and some of the eyes showed a decrease in retinal sensitivity. Of the 22 eyes tested on or after day 17 PI, 18% had normal, 32% had reduced, and 50% had abolished ERGs. The majority (17/33) of the retinas of the inoculated eyes showed panretinal necrosis, although 7 of 33 retinas had pathology confined to the outer layers of the retina. In the uninoculated eyes, only 5 of 30 retinas were necrotic and 14 of 30 retinas had pathology limited to the outer layers of the retina. These observations suggested that the physiologic and morphologic changes progress through two stages: an early stage with reduced ERGs and pathology limited to the outer retinal layers, and a second stage in which the ERG is abolished and the pathologic changes extend into the inner retina. Not all retinas progress to the second stage.

Bilateral alterations of the ERG and retinal histology following unilateral HSV-1 inoculation.

The physiological condition of the retinas of BALB/c mice inoculated unilaterally in the anterior chamber with the KOS strain of herpes simplex virus type 1 (HSV-1) was monitored by ERG recordings. After the ERG recordings, the retinas were examined for histopathological changes. In the inoculated eye, depressed ERGs were recorded on day 2 PI and abolished ERGs on day 4 PI. The changes in the ERGs were complete by day 5-6 PI. Of the 53 inoculated eyes followed for longer than day 6 PI, four (7.5%) remained normal, 30 (56.6%) had reduced ERGs and 19 (35.8%) had abolished ERGs. In the contralateral eyes, the first changes were noted on day 8 PI, and abolished ERGs were recorded on day 9 PI. Of the 55 contralateral eyes followed for longer than 10 days, 15 (27.3%) remained normal, four (7.2%) had reduced ERGs and 36 (65.4%) had abolished ERGs. The percentage of eyes with depressed ERGs was significantly higher in the inoculated than in the uninoculated eyes, and the percentage of eyes with abolished ERGs was significantly higher in the uninoculated eyes than in the inoculated eyes. The histopathological alterations were different for the two eyes. In the inoculated eyes, the changes were mainly in the outer retina, with characteristic folds in the photoreceptor and outer nuclear layer interspersed with normal appearing retina. The pigment epithelium was also abnormal. In the uninoculated eyes, the changes began in the inner retina but rapidly spread to all layers of the retina. This panretinal necrosis accounted for the higher percentage of abolished ERGs in the uninoculated eyes. The differences in the alterations of the ERG and the histopathological changes may be related to the underlying mechanism of action of the HSV-1 during the evolution of the experimental retinopathy.

Staining characteristics and antiviral activity of sulforhodamine B and lissamine green B.

PURPOSE: Fluorescein and rose bengal are dyes used routinely in the examination of the ocular surface. As part of an ongoing search for a superior ophthalmic dye with optimal specificity and sensitivity and a lack of interference with subsequent viral cultures, and as part of studies that use chemical dyes to understand better the pathophysiology of ocular surface disorders, the staining characteristics and antiviral activity of sulforhodamine B and lissamine green B were investigated. METHODS: Staining of rabbit corneal epithelial cell cultures by sulforhodamine B and lissamine green B was compared to that of fluorescein and rose bengal. Diffusion of each dye through a collagen gel was measured. Uptake of lissamine green B by herpes simplex virus type 1 (HSV-1)-infected Vero cell cultures was compared at several times postinfection. The effect of sulforhodamine B and lissamine green B on HSV-1 plaque formation in Vero cells was determined. The cellular toxicity of sulforhodamine B and lissamine green B in vitro was examined by a quantitative 14C-amino acid uptake assay and by a qualitative cell viability assay. Finally, the effect of sulforhodamine B and lissamine green B on viral replication was compared in vivo with that of rose bengal in a rabbit model of herpetic epithelial keratitis. RESULTS: Rose bengal vividly stained cell monolayers of explant cultures of rabbit corneal epithelium. By light microscopy, sulforhodamine B and lissamine green B, like fluorescein, did not stain the epithelial cells, but did stain the corneal explant stroma. Pretreatment of epithelial cells with 0.25% trypsin for 5 minutes failed to induce dye uptake; however, pretreatment with 0.5% Triton X-100 for 5 minutes resulted in nuclear staining by lissamine green B, but not sulforhodamine B. When added to a collagen gel, the relative diffusion rate was fluorescein > lissamine green B > sulforhodamine B > rose bengal. By spectrophotometric analysis, HSV-1-infected and uninfected Vero cells bound equivalent amounts of lissamine green B until late in infection, when infected cells took up more dye (P < 0.001). A direct neutralization assay showed that 0.06% lissamine green B or 0.5% sulforhodamine B reduced HSV-1 plaque formation in Vero cells by greater than 50%, when present at the time of viral adsorption. By a quantitative 14C-amino acid uptake assay, lissamine green B was toxic to Vero cells in a dose-dependent manner, whereas sulforhodamine B was relatively nontoxic at the concentrations tested. By a cell viability assay, however, neither dye showed significant cellular toxicity. In a rabbit model of herpetic epithelial keratitis, rose bengal significantly reduced viral replication and recovery, whereas sulforhodamine B and lissamine green B had no effect. CONCLUSIONS: Neither sulforhodamine B nor lissamine green B stain healthy, normal cells. Lissamine green B stains membrane-damaged epithelial cells, but sulforhodamine B does not. Both sulforhodamine B and lissamine green B stain corneal stroma. Lissamine green B inhibits HSV-1 plaque formation at low concentrations of dye in vitro, which correlates with suppression of cellular metabolism as demonstrated by a 14C-amino acid uptake assay, but does not affect cell viability. Neither sulforhodamine B nor lissamine green B inhibit viral replication or recovery in vivo.

Ocular histopathologic findings in a case of human herpes B virus infection.

A 37-year-old male laboratory technician who sustained a cutaneous penetrating wound from a rhesus monkey developed a progressive ascending encephalomyelitis due to culture-proven herpes B virus (Herpesvirus simiae) infection. He died 6 weeks after his injury despite acyclovir and ganciclovir treatment that was initiated after central nervous system symptoms developed. Histopathological examination of the patient's left eye revealed a multifocal necrotizing retinitis associated with a vitritis, optic neuritis, and prominent panuveitis. Herpes-type virus was identified in the involved retina by electron microscopy. Postmortem vitreous cultures taken from both eyes and retinal cultures taken from the right eye were positive for herpes B virus. Herpes B virus produces infection and destruction of retinal tissues similar to other herpesviruses. To our knowledge, this case represents the first histopathologic demonstration of herpes B virus infection in a human eye.