A study of hospitalized COVID-19 patients with AKI in a setting of multiracial developing country.

BACKGROUND: The commonest indication for hospitalization in COVID-19 patients is hypoxemia or severe respiratory symptoms. However, COVID-19 disease may result in extrapulmonary complications including kidney-related pathology. The reported incidence of renal involvement related to COVID infection varies based on geographical location. OBJECTIVE: This study aimed to assess the incidence rate of AKI in hospitalized COVID-19 patients and identify risk factors and prognostic predictors. METHOD: In this retrospective study, we recruited hospitalized COVID-19 patients from January 2021 until June 2021 at the University Malaya Medical Center. The inclusion criteria were hospitalized for ≥ 48 h with confirmed COVID-19 infection and at least 18 years old. Patient demographic and clinical data were collected from electronic medical records. The staging of AKI was based on criteria as per KDIGO guidelines. RESULTS: One thousand five hundred twenty-nine COVID patients fulfilled the inclusion criteria with a male-to-female ratio of 759 (49.6%) to 770 (50.3%). The median age was 55 (IQR: 36-66). 500 patients (32.7%) had diabetes, 621 (40.6%) had hypertension, and 5.6% (n = 85) had pre-existing chronic kidney disease (CKD). The incidence rate of AKI was 21.1% (n = 323). The percentage of COVID patients in different AKI stages of 1,2 and 3 were 16.3%, 2.1%, and 2.7%, respectively. Fifteen hospitalized patients (0.98%) required renal replacement therapy. 58.8% (n = 190) of AKI group had complete recovery of kidney function. Demographic factors included age (p < 0.001), diabetes (p < 0.001), hypertension (p < 0.012), CKD (p < 0.001), and vaccination status (p = 0.042) were associated with an increased risk of developing AKI. We found that the AKI cohort had statistically significant lower platelet counts and higher ferritin levels than the non-AKI cohort. AKI is a risk predictor of prolonged hospitalization (p < 0.001) and higher mortality rates (P < 0.001). CONCLUSION: AKI is a common clinical complication among hospitalized COVID-19 patients. The etiology of AKI is multifactorial and may have an adverse impact on patient morbidity and mortality.

Identification of novel candidate autoantibodies in Alzheimer's disease.

BACKGROUND AND PURPOSE: Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD. METHODS: A total of 40 subjects with mild dementia (Clinical Dementia Rating = 1) were stratified into AD (n = 16) and non-AD (n = 24) groups according to their cerebrospinal fluid levels of tau and Aß42 . Their sera were collected and analyzed using a microarray containing > 1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change(AD)  ≥ 2, frequency(AD)  ≥ 15% and frequency(non-AD)  = 0%. RESULTS: All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects). CONCLUSIONS: Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.

The combination of apolipoprotein E4, age and Alzheimer's Disease Assessment Scale - Cognitive Subscale improves the prediction of amyloid positron emission tomography status in clinically diagnosed mild cognitive impairment.

BACKGROUND AND PURPOSE: Randomized clinical trials involving anti-amyloid interventions focus on the early stages of Alzheimer's disease (AD) with proven amyloid pathology, using amyloid positron emission tomography (amyloid-PET) imaging or cerebrospinal fluid analysis. However, these investigations are either expensive or invasive and are not readily available in resource-limited centres. Hence, the identification of cost-effective clinical alternatives to amyloid-PET is highly desirable. This study aimed to investigate the accuracy of combined clinical markers in predicting amyloid-PET status in mild cognitive impairment (MCI) individuals. METHODS: In all, 406 MCI participants from the Alzheimer's Disease Neuroimaging Initiative database were dichotomized into amyloid-PET(+) and amyloid-PET(-) using a cut-off of >1.11. The accuracies of single clinical markers [apolipoprotein E4 (ApoE4) genotype, demographics, cognitive measures and cerebrospinal fluid analysis] in predicting amyloid-PET status were evaluated using receiver operating characteristic curve analysis. A logistic regression model was then used to determine the optimal model with combined clinical markers to predict amyloid-PET status. RESULTS: Cerebrospinal fluid amyloid-ß (Aß) showed the best predictive accuracy of amyloid-PET status [area under the curve (AUC) = 0.927]. Whilst ApoE4 genotype (AUC = 0.737) and Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) 13 (AUC = 0.724) independently discriminated amyloid-PET(+) and amyloid-PET(-) MCI individuals, the combination of clinical markers (ApoE4 carrier, age >60 years and ADAS-Cog 13 > 13.5) improved the predictive accuracy of amyloid-PET status (AUC = 0.827, P < 0.001). CONCLUSIONS: Cerebrospinal fluid Aß, which is an invasive procedure, is most accurate in predicting amyloid-PET status in MCI individuals. The combination of ApoE4, age and ADAS-Cog 13 also accurately predicts amyloid-PET status. As this combination of clinical markers is cheap, non-invasive and readily available, it offers an attractive surrogate assessment for amyloid status amongst MCI individuals in resource-limited settings.

Evaluation of Elecsys Syphilis Assay for Routine and Blood Screening and Detection of Early Infection.

Treponema pallidum infections can have severe complications if not diagnosed and treated at an early stage. Screening and diagnosis of syphilis require assays with high specificity and sensitivity. The Elecsys Syphilis assay is an automated treponemal immunoassay for the detection of antibodies against T. pallidum The performance of this assay was investigated previously in a multicenter study. The current study expands on that evaluation in a variety of diagnostic settings and patient populations, at seven independent laboratories. The samples included routine diagnostic samples, blood donation samples, samples from patients with confirmed HIV infections, samples from living organ or bone marrow donors, and banked samples, including samples previously confirmed as syphilis positive. This study also investigated the seroconversion sensitivity of the assay. With a total of 1,965 syphilis-negative routine diagnostic samples and 5,792 syphilis-negative samples collected from blood donations, the Elecsys Syphilis assay had specificity values of 99.85% and 99.86%, respectively. With 333 samples previously identified as syphilis positive, the sensitivity was 100% regardless of disease stage. The assay also showed 100% sensitivity and specificity with samples from 69 patients coinfected with HIV. The Elecsys Syphilis assay detected infection in the same bleed or earlier, compared with comparator assays, in a set of sequential samples from a patient with primary syphilis. In archived serial blood samples collected from 14 patients with direct diagnoses of primary syphilis, the Elecsys Syphilis assay detected T. pallidum antibodies for 3 patients for whom antibodies were not detected with the Architect Syphilis TP assay, indicating a trend for earlier detection of infection, which may have the potential to shorten the time between infection and reactive screening test results.

Identification of immunogenic proteins of Candida parapsilosis by serological proteome analysis.

AIMS: Systemic candidiasis is the leading fungal bloodstream infection, and its incidence has been on the rise. Recently, Candida parapsilosis has emerged as an increasingly prevalent fungal pathogen, but little is known about its antigenic profile. Hence, the current work was performed to discover immunogenic proteins of C. parapsilosis using serological proteome analysis. METHODS AND RESULTS: Cell wall proteins extracted from C. parapsilosis were resolved by two-dimensional electrophoresis followed by immunoblotting using antisera from experimentally infected mice. Mass spectrometry analysis of the 32 immunoreactive protein spots resulted in the identification of 12 distinct proteins. Among them, 11 proteins were known antigens of Candida albicans, whereas Idh2p was identified for the first time as an immunogenic protein of Candida species. Recombinant Idh2p was expressed in Escherichia coli, and its antigenicity was verified by immunoblot analysis. CONCLUSIONS: An immunoproteomic approach was successfully applied to identify immunogenic proteins of C. parapsilosis, with Idh2p as a novel candidate antigen. The identified antigens may serve as potential biomarkers for development of diagnostic assay and/or vaccine for C. parapsilosis. SIGNIFICANCE AND IMPACT OF THE STUDY: This work represents the first immunoproteomic analysis of C. parapsilosis, which provides new insights into host-pathogen interactions and pathogenesis of C. parapsilosis. The immunogenic proteins could be studied as biomarker candidates for C. parapsilosis.

Immunoproteomic analysis of antibody response to cell wall-associated proteins of Candida tropicalis.

AIMS: This study was conducted to identify antigenic proteins of Candida tropicalis that are targeted by the host immune system. METHODS AND RESULTS: An immunoproteomic approach was used to discover antigens from cell wall of C. tropicalis that were recognized by sera from experimentally infected mice. This resulted in the identification of twelve distinct proteins, of which ten have been previously reported as antigens of Candida albicans. For the remaining two proteins, Idh2p has been described as an antigen of Candida parapsilosis, whereas Kgd2p is revealed for the first time as an antigenic protein for Candida species. These two antigens were expressed as recombinant proteins in Escherichia coli and were shown to be specifically recognized by sera from infected host on Western blot. CONCLUSIONS: The present work investigated immunoproteome of C. tropicalis and identified several biomarker candidate antigens, with Kgd2p as a novel immunogenic protein that could be associated with pathogenesis of C. tropicalis. SIGNIFICANCE AND IMPACT OF THE STUDY: Findings from this study help to improve current understanding on host response to C. tropicalis infection and provide new insights into immune-pathogenesis of C. tropicalis. Besides, the immunogenic proteins could be considered as targets for the development of immunodiagnostic assay and/or vaccine.

Hepatitis B seroprevalence among University of Malaya Students in the Post-universal Infant Vaccination Era.

AIM: A nationwide HBV vaccination for neonates in the Expanded Programme on Immunization (EPI) was implemented in Malaysia in 1989. The objective of this study was to investigate the prevalence of HBsAg, anti-HBs and anti-HBc among the new student intakes in the Faculties of Medicine and Dentistry, University of Malaya from 2005 to 2011. MATERIALS AND METHODS: All new students enrolled for undergraduate and postgraduate courses were screened for HBV infection. Serum samples collected were tested for the presence of HBsAg, anti-HBs and anti-HBc with the use of fully automated analysers. Statistical analyses were done using Open Epi version 2.3.1 RESULTS: The overall HBsAg prevalence among the 2923 new intakes was 0.62%. The HBsAg prevalence rate was 1.08% (15/1390) for those born before 1989 and only 0.20% (3/1533) among those born in or after 1989. By year of testing, HBsAg prevalence declined steadily from 1.27% (5/394) in 2005 to 1.20% (5/418) in 2006, 0.95% (4/421) in 2007, 0.49% (2/410) in 2008, 0.49% (2/407) in 2009 and finally 0% in both 2010 (0/445) and 2011 (0/428). Although 66.14% of those vaccinated during infancy had no demonstrable immunity at the time of screening, only 6 (0.39%) students were found to have anti-HBc, including the 3 who were HBsAg positive. CONCLUSION: These findings suggested effective prevention of HBV transmission with the universal and voluntary vaccination programs in Malaysia.

Fusarium sp. infection in a patient with Acute Lymphoblastic Leukaemia.

In the past two decades, Fusarium species have been increasingly recognized as serious pathogens in immunocompromised patients. The outcome of fusariosis in the context of severe persistent neutropaenia has been almost universally fatal. The treatment of fusariosis in immunocompromised patients remains a challenge and the prognosis of systemic fusariosis in this population remains poor. This report presents a case of fatal fusariosis in a 37- year-old patient who was diagnosed with precursor-B cell Acute Lymphoblastic Leukaemia (ALL).

Viewpoint: Clinicians' Perspectives on How Disease Modifying Drugs for Alzheimer's Disease Impact Specialty Care.

Clinicians specialized in the diagnosis and management of persons living with early-stage Alzheimer's disease need to enable access, for those meeting criteria, to the new class of disease modifying drugs (DMDs). These drugs act on amyloid ß42 and delay progression of symptoms. Thus, there will be interest from patients and families. Over the short term, the use of antibodies administered intravenously with serial MRIs to detect amyloid-related imaging abnormalities (ARIA) may require participation in structured phase 4 studies or in registries with third party funding for support staff and MRI scans. In the mid term, the availability of oral anti-amyloid therapy, likely with lower risk of ARIA, may transform clinical practice to a model of screening suitable patients using plasma biomarkers, with a subsequent rapid referral to a specialized memory clinic. Eventually, the biological profile of patients for amyloid, tau, and inflammation will determine which type of DMD to use. We are optimistic that clinicians will gain confidence with the use DMDs and answer the increasing needs of our aging population.

White Matter Hyperintensity as a Vascular Contribution to the AT(N) Framework.

The AT(N) framework enables the classification of an individual within the biological Alzheimer's disease (AD) continuum by pairing the cognitive stage with the biomarker status of amyloid-beta (Aß, A), tau (T) and neurodegeneration (N). AD is a multifactorial disease that may involve different pathogenic mechanisms such as cerebrovascular disease (CVD). Therefore, biomarkers of these mechanisms can be added to the AT(N) framework to enhance the biomarker characterization of individuals within the AD continuum. In AD, white matter hyperintensities (WMH) which are postulated to develop as a result of chronic ischemia from small vessel CVD are shown to play a role in the aetiology. However, the interplay of WMH with Aß and tau pathophysiology in AD remains unclear. In this review, we summarized the studies that evaluated the associations between WMH and AD pathophysiology (Aß and tau). We found that the evidence supporting the association of WMH with Aß was mixed, and this may be explained by the relative contributions of WMH due to its differential load and anatomical distribution. More studies are also needed to determine the association of WMH with tau pathology. Future longitudinal studies with harmonized methodologies to quantify WMH and account for the anatomical differences of WMH are required to validate the relationship between WMH and AT(N) biomarkers. This will allow a clearer understanding of the utility of WMH as a vascular biomarker in the AT(N) framework. Novel CVD biomarkers will also have the potential to further elucidate the contributions of CVD to the AD pathophysiology.

Pneumocystis jirovecii pneumonia 13 years post renal transplant following a recurrent cytomegalovirus infection.

Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) is a rare but serious infection that usually occurs within a year after solid organ transplantation. PCP may occur after 1 year post transplantation, but the rate is reported to be very low. Studies have shown an association between cytomegalovirus (CMV) infection in solid organ transplant patients and an increased risk of opportunistic infection. This increased risk is thought to be a result of the immunomodulatory effects of the CMV infection. We present a case of PCP infection occurring 13 years after a renal transplantation. This occurred following a recurrent CMV infection while the patient was on low-dose immunosuppressants.

Tsukamurella tyrosinosolvens intravascular catheter-related bacteremia in a haematology patient: a case report.

Tsukamurella spp. are a rare but important cause of intravascular catheter-related bacteremia in immunocompromised patients. The organism is an aerobic, Gram-positive, weakly acid-fast bacillus that is difficult to differentiate using standard laboratory methods from other aerobic actinomycetales such as Nocardia spp., Rhododoccus spp., Gordonia spp., and the rapid growing Mycobacterium spp. We report a case of Tsukamurella tyrosinosolvens catheter-related bacteremia in a 51-year-old haematology patient who responded to treatment with imipenem and subsequent line removal. 16srRNA sequencing allowed for the prompt identification of this organism.

ABO-Incompatible Living-Donor Kidney Transplantation in a Developing Country: A Multicenter Experience in Malaysia.

Malaysia has a low deceased-donor donation rate and has not embarked on a paired kidney exchange program; therefore, ABO-incompatible and HLA-incompatible transplantation remain the main contributor to the sustainability of the national kidney transplantation (KT) program. There were 26 cases of ABO-incompatible KTs performed from 2011 to 2018 in 3 major transplant centers, namely, Hospital Kuala Lumpur, University Malaya Medical Centre, and Prince Court Medical Centre. We collected perioperative and follow-up data through June 2019. The desensitization protocol varies and is center specific: the localized Japanese protocol and Swedish protocol with a target anti-A/B isoagglutinin titer of 16 or 32 on the day of transplant. The induction and tacrolimus-based maintenance protocol was nearly identical. The median follow-up time was 62.3 months (interquartile range, 37.0-79.7). Fifteen subjects had the highest predesensitization anti-A/B titer of ≥32 (57.7%). The acute cellular rejection and antibody-mediated rejection incidence were 12.5% (3 cases) and 8.3% (2 cases), respectively. Patient, graft, and death-censored graft survival rates were 96.2%, 92.3%, and 96.0%, respectively, 1 year post-living-donor KT (LDKT) and 96.2%, 87.2%, and 90.7%, respectively, 5 years post-LDKT. Our experience shows that ABO-incompatible LDKT using a suitable desensitization technique could be a safe and feasible choice for LDKT even with varied desensitization regimens for recipients with relatively high baseline isoagglutinin titers.

Pericatheter herniation complicated by bowel incarceration in a patient on continuous ambulatory peritoneal dialysis (CAPD).

We report a rare case of pericatheter herniation with small bowel incarceration in a patient on continuous ambulatory peritoneal dialysis (CAPD). However, the predominant clinical features were signs of a severe catheter tunnel infection rather than ileus. We propose that pericatheter herniation should be considered as part of the differential diagnosis of CAPD tunnel infection, even when there are no clinical signs of bowel obstruction.

Aß1-42 increases the expression of neural KATP subunits Kir6.2/SUR1 via the NF-κB, p38 MAPK and PKC signal pathways in rat primary cholinergic neurons.

ATP-sensitive potassium channels (KATP) may mediate a potential neuroprotective role in Alzheimer's disease (AD). Given that exposure to Aß1-42 in cultured primary cholinergic neurons for 72 h significantly upregulates the expression of KATP subunits Kir6.2/SUR1, we aim to study the underlying signal transduction mechanisms that are involved in Aß1-42-induced upregulation of KATP subunits Kir6.2/SUR1. In the present study, we first identified the primary cultured rat cortical and hippocampal neurons using immunocytochemistry. 0.5 µM NF-κB inhibitor SN-50, 2 µM p38MAPK inhibitor SB203580 or 2 µM PKC inhibitor Chelerythrine chloride (CTC) were then added in three separate groups, followed by 2 µM Aß1-42 30 min later in all 3 groups. Western Blot was performed 72 h later to detect the expression of KATP subunits Kir6.2/SUR1. We found that Aß1-42 significantly increased the level of KATP subunits Kir6.2/SUR1 expression at 72 h when compared with the control group ( p < 0.05). However, when compared with the Aß1-42 group, the level of KATP subunits Kir6.2/SUR1 expression at 72 h significantly decreased in the SN50 + Aß1-42 group, SB203580 + Aß1-42 group, and the CTC + Aß1-42 group ( p < 0.05). Our findings suggest that the NF-κB, p38 MAPK, and PKC signal pathways are partially involved in the upregulation of KATP subunits Kir6.2/SUR1 expression induced by Aß1-42 cytotoxicity in neurons, which supports a potential theoretical basis of targeting these signal pathways in the treatment of AD.

Antimicrobial susceptibilities and random amplified polymorphic DNA-PCR fingerprint characterization of Candida glabrata, Candida parapsilosis and Candida rugosa from two major hospitals in Kuala Lumpur, Malaysia.

The purpose of this study is to characterize 3 non-albicans Candida spp. that were collected from two major hospitals in a densely populated area of Kuala Lumpur for their susceptibilities to azole and genetic background. Fifteen non-albicans Candida clinical isolates in two major hospitals in Kuala Lumpur area of Malaysia were collected by convenience sampling during 2007 and 2010. The genetic diversity of 15 non-albicans Candida species comprising C. glabrata (n = 5), C. parapsilosis (n = 5) and C. rugosa (n = 5) were assessed by RAPD-PCR typing. Strains were initially identified using biochemical tests and CHROMagar Candida medium. Fluconazole and voriconazole susceptibilities were determined by E-test method. Commercial kits were used for DNA extraction and amplification with RAPD primers (OPA02, OPA03 and OPA08). PCR conditions were optimized and simultaneous identification was possible by agarose gel electrophoresis of PCR products and the bands obtained were analyzed using BioNumerics Applied Maths v.6.6 software. The RAPD primers used in this study generated 100% polymorphic profile. Cluster analysis using the RAPD-PCR profile showed 12.5-25% similarity among the strains. The genetic diversity was based on the strain susceptibility towards both the azoles, site of isolation and place according to their unique banding patterns. In contrast, strains susceptible to azoles were found to be genetically similar with clonal dissimilarity. The use of OPA02, OPA03 and OPA08 primers in differentiating non-albicans Candida spp. underscores the higher resolution of RAPD-PCR as a reliable tool for strain/species level differentiation.

In vitro adhesion and invasion by Cladosporium sphaerospermum in human bronchial epithelial cells (BEAS-2B) and human pulmonary alveolar epithelial cells (HPAEpiC).

Cladosporium spores are ubiquitous in indoor and outdoor environment and may potentially trigger allergic responses upon inhalation. To date, there is limited investigation on the fate of Cladosporium spores after being inhaled into the respiratory tract. This study was conducted to investigate the interaction of Cladosporium sphaerospermum with Human Bronchial Epithelial Cells (BEAS-2B) and Human Pulmonary Alveolar Epithelial Cells (HPAEpiC). C. sphaerospermum conidia were harvested and co-cultured with BEAS-2B or HPAEpiC cells for 72 hours. At each time point (30 minutes, 2, 4, 24, 48 and 72 hours), adherence and invasion of the cells by C. sphaerospermum conidia (and hyphae) were investigated by immunofluorescence staining. This study demonstrated the adherence and internalization of C. sphaerospermum conidia within these epithelial cells. In addition, the conidia were able to germinate and invade the epithelial cells. The ability of the fungal conidia to adhere, internalize, germinate and invade both the bronchial and alveolar epithelial cells of the respiratory tract in vitro might contribute to the understanding of the pathogenesis of Cladosporium in respiratory infection and allergy in vivo.

Antifungal susceptibilities, biofilms, phospholipase and proteinase activities in the Candida rugosa complex and Candida pararugosa isolated from tertiary teaching hospitals.

PURPOSE: Non-albicansCandida species have emerged as fungal pathogens that cause invasive infections, with many of these species displaying resistance to commonly used antifungal agents. This study was confined to studying the characteristics of clinical isolates of the C. rugosa complex and C. pararugosa species. METHODOLOGY: Seven isolates of the C. rugosa complex and one isolate of C. pararugosa were obtained from two tertiary referral hospitals in Malaysia. Their antifungal susceptibilities, biofilm, proteinase, phospholipase, esterase and haemolysin activities were characterized. Biofilms were quantified using crystal violet (CV) and tetrazolium (XTT) reduction assays at 1.5, 6, 18, 24, 48 and 72 h.Results/Key findings. The E-test antifungal tests showed that both species have elevated MICs compared to C. albicans and C. tropicalis. The highest biomass was observed in one of the C. rugosa isolates (0.237), followed by C. pararugosa (0.206) at 18 h of incubation. However, the highest bioactivity was observed in the C. rugosa ATCC 10571 strain at 24 h (0.075), followed by C. pararugosa at 48 h (0.048) and the same C. rugosa strain at 24 h (0.046), with P<0.05. All isolates exhibited high proteinase activity (+++) whereas six isolates showed very strong esterase activity (++++). All the isolates were alpha haemolytic producers. None of the isolates exhibited phospholipase activity. CONCLUSION: Elevated MICs were shown for the C. rugosa complex and C. pararugosa for commonly used antifungal drugs. Further studies to identify virulence genes involved in the pathogenesis and genes that confer reduced drug susceptibility in these species are proposed.

Rostral-Caudal Hippocampal Functional Convergence Is Reduced Across the Alzheimer's Disease Spectrum.

Beginning in the early stages of Alzheimer's disease (AD), the hippocampus reduces its functional connections to other cortical regions due to synaptic depletion. However, little is known regarding connectivity abnormalities within the hippocampus. Here, we describe rostral-caudal hippocampal convergence (rcHC), a metric of the overlap between the rostral and caudal hippocampal functional networks, across the clinical spectrum of AD. We predicted a decline in rostral-caudal hippocampal convergence in the early stages of the disease. Using fMRI, we generated resting-state hippocampal functional networks across 56 controls, 48 early MCI (EMCI), 35 late MCI (LMCI), and 31 AD patients from the Alzheimer's Disease Neuroimaging Initiative cohort. For each diagnostic group, we performed a conjunction analysis and compared the rostral and caudal hippocampal network changes using a mixed effects linear model to estimate the convergence and differences between these networks, respectively. The conjunction analysis showed a reduction of rostral-caudal hippocampal convergence strength from early MCI to AD, independent of hippocampal atrophy. Our results demonstrate a parallel between the functional convergence within the hippocampus and disease stage, which is independent of brain atrophy. These findings support the concept that network convergence might contribute as a biomarker for connectivity dysfunction in early stages of AD.

Geographic and temporal trends in isolation and antifungal susceptibility of Candida parapsilosis: a global assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005.

We examined data from the ARTEMIS DISK Antifungal Surveillance Program to describe geographic and temporal trends in the isolation of Candida parapsilosis from clinical specimens and the in vitro susceptibilities of 9,371 isolates to fluconazole and voriconazole. We also report the in vitro susceptibility of bloodstream infection (BSI) isolates of C. parapsilosis to the echinocandins, anidulafungin, caspofungin, and micafungin. C. parapsilosis represented 6.6% of the 141,383 isolates of Candida collected from 2001 to 2005 and was most common among isolates from North America (14.3%) and Latin America (9.9%). High levels of susceptibility to both fluconazole (90.8 to 95.8%) and voriconazole (95.3 to 98.1%) were observed in all geographic regions with the exception of the Africa and Middle East region (79.3 and 85.8% susceptible to fluconazole and voriconazole, respectively). C. parapsilosis was most often isolated from blood and skin and/or soft tissue specimens and from patients hospitalized in the medical, surgical, intensive care unit (ICU) and dermatology services. Notably, isolates from the surgical ICU were the least susceptible to fluconazole (86.3%). There was no evidence of increasing azole resistance over time among C. parapsilosis isolates tested from 2001 to 2005. Of BSI isolates tested against the three echinocandins, 92, 99, and 100% were inhibited by concentrations of < or = 2 microg/ml of anidulafungin (621 isolates tested), caspofungin (1,447 isolates tested), and micafungin (539 isolates tested), respectively. C. parapsilosis is a ubiquitous pathogen that remains susceptible to the azoles and echinocandins; however, both the frequency of isolation and the resistance of C. parapsilosis to fluconazole and voriconazole may vary by geographic region and clinical service.