Prognostic accuracy of qSOFA score, SIRS criteria, and EWSs for in-hospital mortality among adult patients presenting with suspected infection to the emergency department (PASSEM) Multicenter prospective external validation cohort study protocol.

BACKGROUND: Early identification of a patient with infection who may develop sepsis is of utmost importance. Unfortunately, this remains elusive because no single clinical measure or test can reflect complex pathophysiological changes in patients with sepsis. However, multiple clinical and laboratory parameters indicate impending sepsis and organ dysfunction. Screening tools using these parameters can help identify the condition, such as SIRS, quick SOFA (qSOFA), National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS). We aim to externally validate qSOFA, SIRS, and NEWS/NEWS2/MEWS for in-hospital mortality among adult patients with suspected infection who presenting to the emergency department. METHODS AND ANALYSIS: PASSEM study is an international prospective external validation cohort study. For 9 months, each participating center will recruit consecutive adult patients who visited the emergency departments with suspected infection and are planned for hospitalization. We will collect patients' demographics, vital signs measured in the triage, initial white blood cell count, and variables required to calculate Charlson Comorbidities Index; and follow patients for 90 days since their inclusion in the study. The primary outcome will be 30-days in-hospital mortality. The secondary outcome will be intensive care unit (ICU) admission, prolonged stay in the ICU (i.e., ≥72 hours), and 30- as well as 90-days all-cause mortality. The study started in December 2021 and planned to enroll 2851 patients to reach 200 in-hospital death. The sample size is adaptive and will be adjusted based on prespecified consecutive interim analyses. DISCUSSION: PASSEM study will be the first international multicenter prospective cohort study that designated to externally validate qSOFA score, SIRS criteria, and EWSs for in-hospital mortality among adult patients with suspected infection presenting to the ED in the Middle East region. STUDY REGISTRATION: The study is registered at ClinicalTrials.gov (NCT05172479).

Leukoaraiosis Attenuates Diagnostic Accuracy of Large-Vessel Occlusion Scales.

BACKGROUND AND PURPOSE: Prehospital stroke scales may help identify patients likely to have large-vessel occlusion to facilitate rapid triage to thrombectomy-capable stroke centers. Scale misclassification may result in inaccurate decisions and possible harm. Pre-existing leukoaraiosis has been shown to attenuate the association between deficit type and stroke severity. We sought to determine whether leukoaraiosis affects the predictive ability of 5 commonly used large-vessel occlusion scales. MATERIALS AND METHODS: We retrospectively analyzed 274 consecutive patients with stroke with available brain MR imaging and vessel imaging. We used the following large-vessel occlusion scales: the 3-Item Stroke Scale; Field Assessment Stroke Triage for Emergency Destination; Rapid Arterial Occlusion Evaluation; Vision, Aphasia, Neglect score; and Cincinnati Prehospital Stroke Severity Scale. For diagnostic scale accuracy, we assessed sensitivity, specificity, positive predictive value, negative predictive value, and κ. Multivariable logistic regression was used to determine the predictive ability of the scales after adjustment for leukoaraiosis and potential confounders. RESULTS: In unadjusted analyses, all scales predicted the presence of large-vessel occlusion (n = 46, P < .01 each), though diagnostic accuracy was attenuated among patients with moderate-to-severe leukoaraiosis. After adjustment, the Field Assessment Stroke Triage for Emergency Destination (OR = 3.2; 95% CI, 1.1-9.5; P = .033) and Rapid Arterial Occlusion Evaluation (OR = 3.7; 95% CI, 1.3-10.8; P = .015), but not the 3-Item Stroke Scale (OR = 5.4; 95% CI, 0.86-33.9; P = .073), Vision, Aphasia, Neglect score (OR = 2.5; 95% CI, 0.8-7.2), and Cincinnati Prehospital Stroke Severity Scale (OR = 2.8; 95% CI, 1.0-8.0), predicted large-vessel occlusion. CONCLUSIONS: The diagnostic accuracy of the tested large-vessel occlusion scales was attenuated in the presence of moderate-to-severe leukoaraiosis. This information that may aid the design of future studies that require large-vessel occlusion scale screening of patients who are likely to have concomitant leukoaraiosis.

Transient hemiglossal denervation during acute internal capsule infarct in the setting of dysarthria-clumsy hand syndrome.

A case of MR imaging-documented transient unilateral tongue denervation presenting during acute internal capsule infarction is described. Understanding the corticolingual pathway innervation of the hypoglossal nucleus is essential for explaining these findings. Awareness of the findings in this case will facilitate appropriate diagnosis, provide neuroanatomic explanation, and prevent misdiagnosis.

Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline.

CSF amyloid beta-peptide 42 (Abeta42) levels in presymptomatic subjects with pathogenic mutations in the PS1 gene are significantly lower than in an age-matched control group. Consequently, in these subjects, there is a window of opportunity estimated as at least 4 to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in Abeta42 metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur.

CCR5 and CXCR4 expression correlated with X4 and R5 HIV-1 infection yet not sustained replication in Th1 and Th2 cells.

OBJECTIVE: To investigate the infectivity of T-helper (Th)1 and Th2 cells (derived from ccr5 wild-type and homozygous ccr5 Delta 32) to R5 and X4 HIV-1. DESIGN: It remains unclear whether infection of Th1 and Th2 CD4 cells by R5 and X4 viruses mirrors their co-receptor expression profile as no direct quantitation of coreceptor levels and infection has been performed. In addition, it is unknown whether the lack of CCR5 expression affects the degree of Th1/Th2 polarization. METHODS: Surface expression of CCR5 and CXCR4 was determined by quantitative fluorescence activated cell sorter analysis on in vitro differentiated Th1 and Th2 cells. R5 (Ba-L) and X4 (IIIB) HIV-1 isolates were used for infection studies and the efficiency of viral entry was determined by quantitative real time polymerase chain reaction detection of reverse transcribed proviral DNA. RESULTS: Cell surface density of CCR5 molecules was eight-fold higher in Th1 versus Th2 subsets (P = 0.005) whereas CXCR4 surface density was four-fold higher in Th2 versus Th1 subsets (P = 0.006). Preferential infection and entry of Th1 cells by R5 HIV-1 was not associated with preferential replication, as eventually the R5-virus replicated to a higher level in Th2 cells in spite of lower initial viral infection/entry. By contrast, Th2 cells preferentially supported X4-virus infection and replication. High beta chemokine secretion by Th1 cells was associated with a lower R5 replication rate. CONCLUSIONS: Th1 and Th2 cells differ in their infection efficiency for R5 and X4 HIV-1. ccr5 Delta 32-homozygous individuals maintain the ability for Th1/Th2 polarization, i.e., the expression of CCR5 is not required for Th1/Th2 polarization.

Imaging of acute stroke.

The utility of diagnostic imaging during the critical first few hours after stroke onset has many important applications. First and foremost, imaging technologies that can reliably detect and quantify the location of acute stroke will greatly enhance the clinician's ability to accurately diagnose individual stroke patients. Secondly, if imaging technology could provide information about the likely severity of the ischemic injury, patient prognosis and management would be enhanced. The possibility of potentially distinguishing severely injured and likely irreversible ischemic brain tissue from ischemic tissue likely not yet irreversibly injured may soon be attainable. The ability of imaging technology to reliably distinguish the status of focally ischemic brain will presumably dramatically impact upon patient management. This information, along with the data about the severity and extent of blood flow and tissue perfusion abnormalities, will help acute stroke care evolve beyond rigid time windows to individualized, pathophysiologically based treatment decisions. Not only will decisions to treat or not be made based upon imaging-derived status, but also the most appropriate type of therapy to be employed, i.e. thrombolysis, neuroprotection, therapy to reduce secondary reperfusion-related injury or combinations of these modalities. In this brief and necessarily incomplete overview of acute stroke imaging, the focus will be on new developments in CT and MRI.

[Imaging of acute stroke]. / Vizualizatsiia v ostrom periode insul'ta.

The utility of diagnostic imaging during the critical first few hours after stroke onset has many important applications. First and foremost, imaging technologies that can reliably detect and quantify the location of acute stroke will greatly enhance the clinician's ability to accurately diagnose individual stroke patients. Secondly, if imaging technology could provide information about the likely severity of the ischemic injury, patient prognosis and management would be enhanced. The possibility of potentially distinguishing severely injured and likely irreversible ischemic brain tissue from ischemic tissue likely not yet irreversibly injured may soon be attainable. The ability of imaging technology to reliably distinguish the status of focally ischemic brain will presumably dramatically impact upon patient management. This information, along with the data about the severity and extent of blood flow and tissue perfusion abnormalities, will help acute stroke care evolve beyond rigid time windows to individualized, pathophysiological-based treatment decisions. Not only will decisions to treat or not be made based upon imaging-derived status, but also the most appropriate type of therapy to be employed, i.e., thrombolysis, neuroprotection, therapy to reduce secondary reperfusion-related injury or combinations of these modalities. In this brief and necessarily incomplete overview of acute stroke imaging, the focus will be on new developments in CT and MRI.

Enhancement of human immunodeficiency virus type 1-specific CD4 and CD8 T cell responses in chronically infected persons after temporary treatment interruption.

Immunologic and virologic outcomes of treatment interruption were compared for 5 chronically human immunodeficiency virus (HIV)-infected persons who have maintained antiretroviral therapy-mediated virus suppression, as compared with 5 untreated controls. After a median interruption of 55 days of therapy accompanied by rebound of virus, reinitiated therapy in 4 of 5 subjects resulted in suppression of 98.86% of plasma virus load by 21-33 days and no significant decrease in CD4 T cell percentage from baseline. Increased T helper responses against HIV-1 p24 antigen (P=. 014) and interferon-gamma-secreting CD8 T cell responses against HIV-1 Env (P=.004) were present during interruption of therapy and after reinitiation of treatment. The remaining subject whose treatment was interrupted did not resume treatment and continued to have a low virus load (<1080 HIV-1 RNA copies/mL) and persistent antiviral cell-mediated responses. In summary, cellular immunity against autologous HIV-1 has the potential to be acutely augmented in association with temporary treatment interruption in chronically infected persons.

The cognitive assessment screening test (CAST) for dementia.

The purpose of this study was to assess the usefulness, the sensitivity, and the specificity of the Cognitive Assessment. Screening Test (CAST), a paper-and-pencil self-administered cognitive test designed to screen elderly people for possible dementia, for use in general physicians' offices, requiring little expertise or staff time. CAST consists of three parts: part A (relatively easy), part B (more demanding), and part C (self-report of concerns). CAST was administered in two studies to: (1) 19 patients known to be mildly to moderately demented versus 24 age-matched normal controls (to establish cutoff standards); and (2) a "real world" sample of 26 elderly patients not known to be demented, attending a general medicine clinic. The sensitivity and specificity of CAST were compared with the Mini-Mental State Examination (MMSE) and the Blessed Dementia Scale cognitive portion (BDS-cog). In study 1, controls were given a detailed neuropsychological battery; in study 2, all patients were given the neuropsychological battery, which served as the "gold standard" to identify individuals with cognitive impairment. In study 1, the cutoff scores for dementia using CAST (Parts A and B) were established. CAST discriminated demented patients from controls with a sensitivity of 95% and a specificity of 88%; the MMSE had a sensitivity of 74% and a specificity of 100%; and the BDS-cog had a sensitivity of 100% and a specificity of 96%. In study 2, CAST discriminated cognitive impairment with a sensitivity of 88% and a specificity of 100%, the MMSE had a sensitivity of 38% and a specificity of 100%; and the BDS-cog had a sensitivity of 50% and a specificity of 94%. Part C was not used to discriminate demented from normal elderly individuals, but to screen for those concerned about their cognitive functioning. CAST is highly useful as a dementia screening test, with sensitivity and specificity equal to or better than the MMSE and BDS-cog, yet requiring minimal examiner time and little training or experience to administer.

Meningeal gliomatosis presenting as multiple cerebral infarcts: a case report.

A 70-year-old man presented to the hospital with a history of progressive cognitive decline, and shortly after admission he developed sudden neurologic deterioration leading to coma. CT revealed multiple contrast-enhancing lesions within the cerebral hemispheres and midbrain tectum. Autopsy revealed a left occipital glioblastoma associated with widespread meningeal dissemination of tumor, occlusive vasculopathy, and multifocal infarcts.

Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro.

Two- and three-drug combinations of lamivudine or stavudine with other antiretroviral drugs were evaluated for activity against human immunodeficiency virus type 1 (HIV-1) activity in peripheral blood mononuclear cells. Other agents included zidovudine, didanosine, nevirapine, and saquinavir. Paired zidovudine-sensitive and -resistant clinical HIV-1 isolates were used. Additive or synergistic interactions were observed against the zidovudine-sensitive isolate with the following combinations: lamivudine-zidovudine, lamivudine-stavudine, lamivudine-saquinavir, lamivudine-nevirapine, stavudine-zidovudine, stavudine-didanosine, stavudine-saquinavir, stavudine-nevirapine, lamivudine-zidovudine-saquinavir, lamivudine-zidovudine-stavudine, stavudine-zidovudine-nevirapine, lamivudine-zidovudine-nevirapine, and stavudine-zidovudine-saquinavir. Against the zidovudine-resistant isolate, additive or synergistic interactions were seen with most two- and three-drug combinations, but the combination of stavudine-zidovudine was antagonistic. The clinical implications of these in vitro observations should be explored.

Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities.

PIC 024-4 and PRO 2000 are naphthalene sulfonate polymers that bind to CD4 with nanomolar affinity and block binding of gp120. Both have activity against human immunodeficiency virus type 1 in H9 cells, peripheral blood mononuclear cells, and primary monocyte/macrophages, are synergistic with zidovudine, and do not inhibit tetanus toxoid-stimulated T-cell proliferation at anti-human immunodeficiency virus type 1 concentrations.

ERP indices and neuropsychological performance as predictors of functional outcome in dementia.

We compared the relative value of neuropsychological and event-related potentials (ERPs) obtained during both passive and active auditory oddball paradigm measures for determining functional outcome in dementia 4 years following initial assessment. Functional outcome was assessed by structured interview of family members of 29 patients with dementia, and patients' functional status was rated in seven areas: mortality, incontinence, institutionalization, ADL dependence, verbal responsiveness, recognition of family members, and capacity for social interaction. A total functional outcome score (ADLTOTAL) was obtained by summing across these individual outcome measures. Many of the neuropsychological measures correlated strongly with overall functional outcome, whereas P3 amplitude and latency on the active ERP condition were the only ERP indices to predict functional outcome. When ERP and neuropsychological measures were considered simultaneously using stepwise multiple regression analyses, the neuropsychological measures were better predictors of most functional outcomes, although P3 latency was the best predictor of mortality. However, neuropsychological performance and ERPs appear to be sensitive to different functional outcomes. Therefore, evaluation of both ERPs and neuropsychological performance may ultimately have prognostic utility in the assessment of patients with dementia.

Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro.

We compared the in vitro efficacies of two-, three-, and four-drug combinations given continuously or in alternating regimens against a clinical isolate of human immunodeficiency virus type 1. In H9 cells and peripheral blood mononuclear cells, at the drug concentrations used in this study, there was greater suppression of human immunodeficiency virus type 1 infection as the number of drugs in the regimen was increased from one to four simultaneously administered agents. Although alternating drug regimens were effective, they were not better than continuous administration of either single drugs or combinations of agents and were less effective than giving all drugs of an alternating regimen simultaneously.

Effect of elimination of phagocytic cells by liposomal dichloromethylene diphosphonate on aspergillosis virulence and toxicity of liposomal amphotericin B in mice.

The role of macrophages in the toxicity and efficacy of liposomal amphotericin B (L-Amp B) was studied in a murine aspergillosis model infection. Macrophages and polymorphonuclear phagocytes (PMN cells) were depleted in the liver and spleen of mice by the administration of liposome encapsulated dichloromethylene diphosphonate. Macrophage depletion had no effect on the lethality of Fungizone, a commercial deoxycholate preparation of Amp B, but significantly increased the lethality of L-Amp B (P < 0.01). Macrophage depletion led to an increase in the fungal loads in the lung, liver and kidney (P < 0.05) and to an increase in the virulence of aspergillosis (P < 0.05). Tissue distribution analysis of L-Amp B revealed that in macrophage/PMN-depleted mice there was a decrease in the concentration of Amp B in the liver, with concomitant increases in the circulation, spleen and lung, both in the uninfected and in the infected conditions. The results clearly demonstrate that depletion of macrophage/PMN cells increases the virulence of aspergillosis, as well as the toxicity of L-Amp B. Moreover, L-Amp B treatment does not improve the survival rate of macrophage/PMN-depleted mice subjected to aspergillosis challenge.

Liposomal hamycin in the control of experimental aspergillosis in mice: effect of phosphatidic acid with and without cholesterol.

Hamycin incorporated into liposomes containing phosphatidylcholine (SPC) and phosphatidic acid (PA) had reduced toxicity and an enhanced antifungal activity in experimental aspergillosis in balb/c mice. Incorporation of cholesterol into liposomes led to a dose dependent decrease in the toxicity of hamycin. The LD50 (mg/kg) of hamycin contained in SPC/cholesterol/PA (molar ratio 4:5:1) liposomes was 2.8 whereas that in SPC/PA liposomes (molar ratio 9:1) was 0.35. Although the free drug had little or no protective effect on the animals, those administered liposomal hamycin at an equivalent dose (0.1 mg/kg) in the absence of cholesterol (SPC/PA; molar ratio 9:1) showed 90% survival after seven days of therapy. On the other hand the presence of cholesterol in the carrier phosphatidic acid liposomes (SPC/cholesterol/PA; molar ratio 4:5:1) at a similar dose (0.1 mg/kg) led to a 60% survival over the same time period. Hamycin incorporation in phosphatidic acid liposomes both in the presence or absence of cholesterol was found to be effective in reducing the fungal load in lung, liver, spleen and kidney. Studies with distribution of hamycin in various tissues by HPLC showed a significant reduction in the concentration of the liposomal drug in circulation as compared to those seem after administration of free drug.

Mannosylated liposomes as carriers for hamycin in the treatment of experimental aspergillosis in Balb/C mice.

Hamycin incorporated into mannosylated liposomes produced less toxicity and enhanced antifungal activity in experimental aspergillosis in balb/c mice in vivo. Incorporation of cholesterol into mannosylated liposomes led to a decrease in hamycin toxicity. The LD50 (mg/kg) values of hamycin contained in SPC/Chol/DPPE-Man (molar ratio 4:5:1) lipsomes was 2.8 whereas that in SPC/DPPE-Man liposomes (molar ratio 9:1) was 1.4. Incorporation of cholesterol into mannosylated liposomes increased the survival rates of infected animals: 70% survival was recorded after 7 days therapy as well as reduced fungal load in lung, liver, spleen and kidney. HPLC studies of distribution of hamycin in various tissues showed a reduction in the concentration of the liposomal drug in circulation compared to that observed for free drug and neutral liposomes after 1 hour.

Liposomal hamycin in the control of experimental aspergillosis in mice: relative toxicity, therapeutic efficacy and tissue distribution of free and liposomal hamycin.

Therapeutic efficacy of liposomal Hamycin has been evaluated in an animal model system for aspergillosis in Balb/c mice. Hamycin was intercalated into soya phosphatidyl choline (SPC), SPC: choline (1:1, vol./vol.) and DMPC liposomes. A single dose of either 0.1 mg/kg, 0.25 mg/kg or 0.5 mg/kg of liposomal Hamycin and 0.1 mg/kg of free Hamycin was injected (i.v.) into animals infected with Aspergillus fumigatus. An increase in the survival rate of animals along with decrease in fungal count in various organs was observed with liposomal administration. Incorporation of cholesterol into liposomes decreased the in vivo toxicity of Hamycin in a dose dependent manner. However, antifungal activity both in the presence and absence of cholesterol showed marked variation as compared to that of non-aromatic polyenes, e.g. amphotericin B. Analysis of Hamycin distribution by HPLC in various tissues revealed higher blood concentration of this drug, when given in free form, compared to its liposomised form. These studies suggest that liposomal Hamycin is more effective than free Hamycin in controlling the experimental Aspergillosis.

Macrophages in host defence--an overview.

The importance of macrophages in host defence is well documented. They are distributed in various tissues where they perform functions in normal steady state as well as in diseased condition. Macrophages secrete a number of enzymes, plasma proteins, complement and coagulation factors which regulate the effector functions of the macrophages. Exposure of macrophages to pathogens results in further metabolic changes which activate the former to secrete oxygen metabolites leading to their augmented microbicidal activity. Macrophages respond to the external stimuli by expressing a large repertoire of surface receptors which play an important role in the activation, recognition and endocytosis of foreign microorganisms. A large number of intracellular pathogens are harboured in the macrophages which can reside and replicate in them. A variety of strategem has been employed to target drugs to vacuolar apparatus of the macrophages in order to combat intracellular pathogens. This review covers some of these aspects particularly in relation to hose defence and methods by which therapeutic agents could be specifically delivered to macrophages.